Point-of-Care Genetic Testing Market 2020

This report studies the Point-of-Care Genetic Testing Market with many aspects of the industry like the market size, market status, market trends and forecast, the report also provides brief information of the competitors and the specific growth opportunities with key market drivers. Find the complete Point-of-Care Genetic Testing Market analysis segmented by companies, region, type and applications in the report.

The major players covered in Point-of-Care Genetic Testing Market Abbott (US), Roche (Switzerland), Thermo Fisher Scientific (US), Cepheid (US), IQuum (US), Biocartis (Switzerland), Idaho Technologies (US), Optigene (UK), and Lumora (UK)

The final report will add the analysis of the Impact of Covid-19 in this report Point-of-Care Genetic Testing industry.

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Point-of-Care Genetic Testing Market continues to evolve and expand in terms of the number of companies, products, and applications that illustrates the growth perspectives. The report also covers the list of Product range and Applications with SWOT analysis, CAGR value, further adding the essential business analytics. Point-of-Care Genetic Testing Market research analysis identifies the latest trends and primary factors responsible for market growth enabling the Organizations to flourish with much exposure to the markets.

Market Segment by Regions, regional analysis covers

North America (United States, Canada and Mexico)

Europe (Germany, France, UK, Russia and Italy)

Asia-Pacific (China, Japan, Korea, India and Southeast Asia)

South America (Brazil, Argentina, Colombia etc.)

Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria and South Africa)

Research objectives:

To study and analyze the global Point-of-Care Genetic Testing market size by key regions/countries, product type and application, history data from 2013 to 2017, and forecast to 2026.

To understand the structure of Point-of-Care Genetic Testing market by identifying its various sub segments.

Focuses on the key global Point-of-Care Genetic Testing players, to define, describe and analyze the value, market share, market competition landscape, SWOT analysis and development plans in next few years.

To analyze the Point-of-Care Genetic Testing with respect to individual growth trends, future prospects, and their contribution to the total market.

To share detailed information about the key factors influencing the growth of the market (growth potential, opportunities, drivers, industry-specific challenges and risks).

To project the size of Point-of-Care Genetic Testing submarkets, with respect to key regions (along with their respective key countries).

To analyze competitive developments such as expansions, agreements, new product launches and acquisitions in the market.

To strategically profile the key players and comprehensively analyze their growth strategies.

The Point-of-Care Genetic Testing Market research report completely covers the vital statistics of the capacity, production, value, cost/profit, supply/demand import/export, further divided by company and country, and by application/type for best possible updated data representation in the figures, tables, pie chart, and graphs. These data representations provide predictive data regarding the future estimations for convincing market growth. The detailed and comprehensive knowledge about our publishers makes us out of the box in case of market analysis.

Table of Contents: Point-of-Care Genetic Testing Market

Chapter 1: Overview of Point-of-Care Genetic Testing Market

Chapter 2: Global Market Status and Forecast by Regions

Chapter 3: Global Market Status and Forecast by Types

Chapter 4: Global Market Status and Forecast by Downstream Industry

Chapter 5: Market Driving Factor Analysis

Chapter 6: Market Competition Status by Major Manufacturers

Chapter 7: Major Manufacturers Introduction and Market Data

Chapter 8: Upstream and Downstream Market Analysis

Chapter 9: Cost and Gross Margin Analysis

Chapter 10: Marketing Status Analysis

Chapter 11: Market Report Conclusion

Chapter 12: Research Methodology and Reference

Key questions answered in this report

What will the market size be in 2026 and what will the growth rate be?

What are the key market trends?

What is driving this market?

What are the challenges to market growth?

Who are the key vendors in this market space?

What are the market opportunities and threats faced by the key vendors?

What are the strengths and weaknesses of the key vendors?

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Impact of COVID-19 Outbreak on Point-of-Care Genetic Testing Market to Witness Abbott (US), Roche (Switzerland), Thermo Fisher Scientific (US),...

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Pierce Brosnan, 67, returns to the screen Friday as Will Ferrells father in the upcoming Eurovision Song Contest: The Story of Fire Saga on Netflix. Brosnan shares the photo above with the man himself and actor Bjorn Stefansson.Before playing comedic roles in Mama Mia and now Eurovision Brosnan overcame tragedy when ovarian cancer ended the lives

RELATED: Has Ovarian Cancer Treatment Changed During COVID-19?

of his first wife, Cassandra, their daughter Charlotte, and Cassandras mother. His life now inspires others in the cancer community.

I play Erick, the father, possibly the most handsome man in Iceland.' Brosnan told RTE. The song contest, Brosnan told The List,is like Americas Got Talent they battle it out and its the birthplace of ABBA, he says, adding; The films got heart.

Doting family man, Pierce Brosnan, 67, has lived through the tragedy of ovarian cancer. His first wife, Cassandra died after undergoing four years of treatment for the disease. Cassandra Brosnans mother also died of ovarian cancer.

RELATED: Pierce Brosnan, a Role Model for Finding Joy After Cancer, Celebrates His Granddaughter on Instagram

In 2013, their daughter, Charlotte, lost her battle with ovarian cancer as well.The familys tragedy underscores why doctors urge women with a family history of ovarian cancer to pursue genetic testing.I was in a helpless state of confusion and anger, he told PEOPLE, of his grief.

He credits his wife of 26 years, Keely, who joined him in Iceland for the movies filming, with restoring his happiness.

Brosnan was quiet during the early days of quarantine, but hes become a thoughtful presence on social media, sharingcomforting words with his followers: In the face of such uncertainty, it has never been more important for us to think, create and imagine a better future, he wrote. We may be confined to our houses at the moment, but our imaginations are still free to dream, create, and collaborate.

The actor has been celebratinghappy milestones lately. In May, he marked his son, Dylans graduation fromUSC School of Cinematic Arts with the words:Go forth into this new world and make it your own. Be fearless, courageous and generous. Love, Dad.

Joanna Gutermuth, an ovarian cancer survivor, shares how genetic testing saved her life.

He capped his May 14th birthday with loving words for his wife: Thank you for the moon and sun and all the days of our lives together my darling heart Keely. I had a great 67th birthday. Thanks to one and all of you out there who wished me so. God bless, stay strong. The two recently celebrated their 26th wedding anniversary.

The link between the ovarian cancer deaths of Brosnans first wife, Cassandra, her mother, and their daughter is likely in the womens shared genes, and their story could be an important one to note for other women diagnosed with ovarian cancer.

RELATED: Ovarian Cancer And COVID-19: How Has Treatment Changed?

Dr. Beth Karlan, gynecologic oncologist at UCLA Medical Center did not treat Cassandra or Charlotte but advises genetictesting can have life-saving benefits, especially because ovarian cancer is curable in over 90 percent of cases when diagnosed early.

RELATED: Exciting Developments in Immunotherapy for Ovarian Cancer

Its important when youre deciding whether or not genetic testing would benefit you to find out what cancers run in your family, Dr. Karlan says. Because it can really help to save lives.

Dr. Ursula Matulonis of Dana-Farber Cancer Institute sayspatients diagnosed with ovarian cancer, she should undergo genetic testing for BRCA mutations.

A recent study found that too few women are being tested for mutations of the BRCA1 and BRCA2 gene. Both place those who carry the mutation at a heightened risk for breast cancer or ovarian cancer.

RELATED VIDEO:How PARP Inhibitors Work For Ovarian Cancer

Ovarian cancer usually develops in women who are post-menopause. But younger women may also get the disease. A woman who inherits the BRCA1 gene has a 44% lifetime risk (by age 80) for developing ovarian or fallopian tube cancer and 70-80% risk of developing breast cancer.

With the BRCA2 gene, the risk for ovarian and fallopian tube cancer is 17% higher, while the breast cancer risk is around 70%. Women should consult with their doctor, rather than relying on home genetic test kits to identify BRCA genes

Learn more about SurvivorNet's rigorous medical review process.

Constance Costas is a writer for SurvivorNet.

Pierce Brosnan, 67, returns to the screen Friday as Will Ferrells father in the upcoming Eurovision Song Contest: The Story of Fire Saga on Netflix. Brosnan shares the photo above with the man himself and actor Bjorn Stefansson.Before playing comedic roles in Mama Mia and now Eurovision Brosnan overcame tragedy when ovarian cancer ended the lives

RELATED: Has Ovarian Cancer Treatment Changed During COVID-19?

I play Erick, the father, possibly the most handsome man in Iceland.' Brosnan told RTE. The song contest, Brosnan told The List,is like Americas Got Talent they battle it out and its the birthplace of ABBA, he says, adding; The films got heart.

Doting family man, Pierce Brosnan, 67, has lived through the tragedy of ovarian cancer. His first wife, Cassandra died after undergoing four years of treatment for the disease. Cassandra Brosnans mother also died of ovarian cancer.

RELATED: Pierce Brosnan, a Role Model for Finding Joy After Cancer, Celebrates His Granddaughter on Instagram

In 2013, their daughter, Charlotte, lost her battle with ovarian cancer as well.The familys tragedy underscores why doctors urge women with a family history of ovarian cancer to pursue genetic testing.I was in a helpless state of confusion and anger, he told PEOPLE, of his grief.

He credits his wife of 26 years, Keely, who joined him in Iceland for the movies filming, with restoring his happiness.

Brosnan was quiet during the early days of quarantine, but hes become a thoughtful presence on social media, sharingcomforting words with his followers: In the face of such uncertainty, it has never been more important for us to think, create and imagine a better future, he wrote. We may be confined to our houses at the moment, but our imaginations are still free to dream, create, and collaborate.

The actor has been celebratinghappy milestones lately. In May, he marked his son, Dylans graduation fromUSC School of Cinematic Arts with the words:Go forth into this new world and make it your own. Be fearless, courageous and generous. Love, Dad.

Joanna Gutermuth, an ovarian cancer survivor, shares how genetic testing saved her life.

He capped his May 14th birthday with loving words for his wife: Thank you for the moon and sun and all the days of our lives together my darling heart Keely. I had a great 67th birthday. Thanks to one and all of you out there who wished me so. God bless, stay strong. The two recently celebrated their 26th wedding anniversary.

The link between the ovarian cancer deaths of Brosnans first wife, Cassandra, her mother, and their daughter is likely in the womens shared genes, and their story could be an important one to note for other women diagnosed with ovarian cancer.

RELATED: Ovarian Cancer And COVID-19: How Has Treatment Changed?

Dr. Beth Karlan, gynecologic oncologist at UCLA Medical Center did not treat Cassandra or Charlotte but advises genetictesting can have life-saving benefits, especially because ovarian cancer is curable in over 90 percent of cases when diagnosed early.

RELATED: Exciting Developments in Immunotherapy for Ovarian Cancer

Its important when youre deciding whether or not genetic testing would benefit you to find out what cancers run in your family, Dr. Karlan says. Because it can really help to save lives.

Dr. Ursula Matulonis of Dana-Farber Cancer Institute sayspatients diagnosed with ovarian cancer, she should undergo genetic testing for BRCA mutations.

A recent study found that too few women are being tested for mutations of the BRCA1 and BRCA2 gene. Both place those who carry the mutation at a heightened risk for breast cancer or ovarian cancer.

RELATED VIDEO:How PARP Inhibitors Work For Ovarian Cancer

Ovarian cancer usually develops in women who are post-menopause. But younger women may also get the disease. A woman who inherits the BRCA1 gene has a 44% lifetime risk (by age 80) for developing ovarian or fallopian tube cancer and 70-80% risk of developing breast cancer.

With the BRCA2 gene, the risk for ovarian and fallopian tube cancer is 17% higher, while the breast cancer risk is around 70%. Women should consult with their doctor, rather than relying on home genetic test kits to identify BRCA genes

Learn more about SurvivorNet's rigorous medical review process.

Constance Costas is a writer for SurvivorNet.

Here is the original post:
Pierce Brosnan As Will Ferrells Dad? Their Eurovision Song Contest Debuts Friday: The Films Got Heart - SurvivorNet

Recommendation and review posted by Bethany Smith

Autologous Stem Cell Based Therapies Market 2020-2026 research report is an in-depth analysis of the latest trends, market size, status, upcoming technologies, industry drivers, challenges opportunity with key company profiles and strategies of players.The Autologous Stem Cell Based Therapies Market report also provides the market impact and new opportunities created due to the COVID19 catastrophe.

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Autologous Stem Cell Based TherapiesMarket report 2020-2026, discusses various factors driving or restraining the market, which will help the future market to grow with promising CAGR. This Report encompasses the manufacturers data, including shipment, price, revenue, gross profit, interview record, business distribution, etc., these data tend the consumer to know about the competitors better.

The Autologous Stem Cell Based Therapies market report covers major market players like Regeneus, Mesoblast, Pluristem Therapeutics Inc, U.S. STEM CELL, INC., Brainstorm Cell Therapeutics, Tigenix, Med cell Europe

The worldwide Autologous Stem Cell Based Therapiesmarket for Industry is expected to grow at a CAGR of roughly xx% over the next five years, will reach xx million US$ in 2026, from xx million US$ in 2019, according to a new study.

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Research MethodologyTo get complete information onAutologous Stem Cell Based Therapies Market, researchers of this report have opted for a bottom-up and top-down approach. The bottom-up approach gives access to the numbers for each product, and the top-down approach helps in counter-validating those numbers with end-use market numbers. The figures mentioned in theAutologous Stem Cell Based TherapiesMarketreport are equally justified along with examples as per need. It also helps in creating clear knowledge about the market, and as to what rate it is expected to grow in the next six to seven years.

Autologous Stem Cell Based Therapies Market 2020-2025: Segmentation

Autologous Stem Cell Based Therapies Market is segmented as below:

Breakup Product Type:Embryonic Stem Cell, Resident Cardiac Stem Cells, Umbilical Cord Blood Stem Cells

Breakup by Application:Neurodegenerative Disorders, Autoimmune Diseases, Cardiovascular Diseases

Geographic segmentation

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INTRODUCTION

Cardiovascular disease associated with myocardial infarction (MI) is a major cause of morbidity and mortality worldwide (1, 2). The heart is composed of dynamic and multicellular tissues that exhibit highly specific structural and functional characteristics. Adult cardiac muscle is thought to lack the ability to self-repair and regenerate after MI. Traditional cardiac patches serve as temporary mechanical supporting systems to prevent the progression of postinfarction left ventricular (LV) remodeling (2). However, the damaged myocardium is still unable to self-restore, and the subsequent maladaptive remodeling is typically irreversible (2). Because of the shortage of organ donors and the limited retention of cellular therapies, the field of cardiac engineering has emerged to generate functional cardiac tissues to provide a promising alternative means to repair damaged heart tissue (3, 4). In addition to playing a role in providing mechanical support, cellularized cardiac patches and scaffolds have also been investigated to restore the functionality of the damaged myocardium (5, 6). Compared to synthetic materials, hydrogel-based materials derived from, or partially derived from, natural sources can mimic the specific aspects of the tissue microenvironment and can support both cell adhesion and growth (7). Hence, these hydrogel-based materials can provide a more favorable matrix for the growth and differentiation of cardiomyocytes (7, 8). However, limitations of structural design and manufacturing techniques, as well as the low mechanical strength and weak processability of hydrogel-based patches, still make their clinical application challenging (3, 7, 8).

Because of the limited expansion and regeneration capacity of primary cardiomyocytes, the use of human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) provides a continuous cell source by which to produce terminally differentiated cells and avoid controversial ethical issues in biomedical research (9, 10). Although several studies have been performed with hiPSC-CMs to generate functional cardiac tissue constructs (11, 12), more studies are required to explore the interaction between hiPSC-CMs and the matrix microenvironment (i.e., scaffolds and other cells) for therapeutic improvement. Hence, further studies should focus on exploring material bioactivity, architectural design and manufacturing, the biomechanical properties of tissue constructs, and the long-term in vivo development of these tissue constructs, which will ultimately affect three-dimensional (3D) cell assembly and neotissue remodeling for clinical research purposes (2, 10, 13).

In this study, a 4D hydrogel-based cardiac patch was developed with a specific smart design for physiological adaptability (or tunability) using a beam-scanning stereolithography (SL) printing technique. Beam-scanning SL printing offers an effective methodology for creating microfabricated tissue constructs with photocurable hydrogels, which are able to achieve many essential requirements in manufacturing tissue micropatterns and macroarchitectures (14). The printing speed and laser intensity are able to be varied as required, which provides the ability to tailor the cross-linking degree of the inks and, therefore, affects the physicochemical properties of hydrogels. Moreover, it was observed that a light-induced graded internal stress, followed by a solvent-induced relaxation of material, drove an autonomous 4D morphing of the objects after printing (15, 16). It was found that this self-morphing process was able to achieve conformations that were nearly identical to the surface curvature of the heart. Moreover, taking the physiological features of the cardiac tissue and the physical properties of the hydrogel into account, a highly stretchable microstructure was created to allow for an easy switch of fiber arrangement from a wavy pattern to a mesh pattern, in accordance with the diastole and systole in the cardiac cycle. The specific design was expected to increase the mechanical tolerance of the printed hydrogel and to decrease the unfavorable effect of hiPSC-CM residence on the printed patches when exposed to the dynamic mechanics. By triculturing cardiomyocytes, mesenchymal stromal cells, and endothelial cells, the printed microfibers with specific nonlinear microstructures could reproduce the anisotropy of elastic epicardial fibers and vascular networks, which plays a crucial role in supporting the effective exchange of nutrients and metabolites, as well as guiding contracting cells for engineered cardiac tissue.

The cardiac muscle fibers mainly consist of longitudinally bundled myofibrils (cardiomyocytes and collagen sheaths), which are surrounded by high-density capillaries (17, 18). This anisotropic (directionally dependent) muscular architecture results in the coordinated electromechanical activity of the ventricles, which involves the directionally dependent myocardial contraction and the propagation of the excitation wave (19, 20). As can be observed by diffusion tensor imaging (DTI) (21, 22), a helical network of myofibers in the LV is organized to form a sheet structure, and the orientation of the fiber angles varies from approximately +60 to 60 across the ventricular wall (Fig. 1A). The visualization of the fiber structure illustrates the left-handed to the right-handed rotation of the fibers going from the epicardium to the endocardium in the LV (21). Computer-aided design (CAD)driven 3D printing offers a promising technique by which to transform the anatomical detail of cardiac fiber maps into a highly complex arrangement of fibers within an engineered cardiac tissue (23). Figure 1B shows that the spiral arrangement of 3D myocardial fibers crosses the ventricular wall (a left-handed to right-handed spiral of the fibers going from the epicardium to the endocardium) and their 2D mesh pattern projections at different angles.

(A) Photograph of the anatomical heart and the fiber structure of the LV visualized by DTI data. (B) Schematic illustration of a short-sectioned LV that illustrates the variation of fiber angle from the epicardium to the endocardium. The orientation (2D mesh pattern projection) of the fiber angles varies continuously with the position across the wall and distribution changes from the apical region to the basal region. (C) Curvature change of cardiac tissue at two different phases (diastole and systole) of the cardiac cycle, which occurs as the heartbeat and pumping blood. (D) CAD design of 3D stretchable architecture on the heart. It provides dynamic stretchability without material deformation or failure when the heart repeatedly contracts and relaxes. (E) Representation of a simplified geometric model of the fibers in the printed object. In the selected region, the angle (), the length of fiber (L), spatial displacement (D) and the ventricular curvature () are defined with systole (1) and diastole (2) states. (F) Mechanism of the internal stress-induced morphing process. Uneven cross-linking density results in different volume shrinkage after stress relaxation. Photo credit: Haitao Cui, The George Washington University (GWU).

Moreover, another specific feature of the cardiac tissue is the diastole and systole in the cardiac cycle induced by the contraction of cardiac muscle, which generates the force for blood circulation (8, 24). When taking the volume change of the heart into account, the arrangement of fibers is dynamically stretched in a selected region (Fig. 1C). Hence, the mesh pattern was changed to hexagon or wavy pattern in the 2D plane to adapt the change of ventricular curvature (Fig. 1D). It was able to create a highly stretchable structure with very limited deformability, which is expected to decrease the negative effect on the attached, susceptible cardiomyocytes. To mathematically characterize this design, we simplified the solid geometric model with a plane curve prototype to elaborate on the relationship between the redundant length of the stretchable structure (L) and the ventricular curvature () in the systole state (Fig. 1E). By the calculation, it can be estimated asL=cos1(1D22/2)D(1)where L is the redundant length of the stretchable structure from straight to curve, is the ventricular curvature in the systole state, and D is the approximate length of fiber in the diastole state (here, D = 400 m from our study). In the previous study, a light-induced 4D morphing phenomenon was demonstrated when using our customized beam-scanning SL printer (15, 16). The laser-induced graded internal stress, introduced through the printing process, is a major driving force of this 4D dynamic morphing (15, 16, 25). The uneven cross-linking density of photocrosslinkable inks generates the difference of modulus between the upper and lower surfaces of thin objects due to laser energy attenuation, leading to different volume shrinkage after stress relaxation (15). However, when multilayers were printed, the beam-scanning SL printing resulted in the repeated cross-linking of previous layers. The bottom layers had a higher cross-linking density. In this case, the bottom layer, which was cured the earliest, adhered to the substrate and could not shrink freely, while the top layer during printing could gradually and spontaneously shrink because of the release of internal stress. Thus, the printed objects have a tendency to bend toward the newly cured layer. We also found the humidity-responsive, reversible 4D phenomenon, which is swelling-induced stretching and dehydration-induced bending (15). After printing, the printed patch can transform from a 3D flat pattern to the 4D curved architecture when appropriate printing parameters are selected (Fig. 1F), which will be elaborated upon in the next section. It was hypothesized that by integrating a unique 4D self-morphing ability within the construct, the structural expandability of the design would improve the physiological adaptability of the engineered cardiac patch to the heart for in vivo cardiac regeneration.

A gelatin-based printable ink consisting of gelatin methacrylate (GelMA) and polyethylene glycol diacrylate (PEGDA) was used to create the anisotropic cardiac patch with myocardial fiber orientation. As a chemical derivative of gelatin [gelatin is derived from the hydrolysis of collagen, which is a major component of the extracellular matrix (ECM)], GelMA is a photocurable biomaterial with many arginine-glycine-aspartic acids and other peptide sequences that can significantly promote cell attachment and proliferation (14). The PEGDA solution was mixed with GelMA to decrease the swelling volume and to increase the mechanical modulus and structural stability of the printed hydrogels. The structural characteristics and mechanical properties of the printed hydrogels were determined by fiber design, printing parameters, the ink concentration, and mixing ratio of GelMA and PEGDA. To optimize the fiber design, stacked wavy architectures were generated with fiber width of 100, 200, and 400 m, fill density of 20, 40, and 60%, and fiber angles () of 30, 45, and 60 between each layer with two, four, and eight layers, respectively, using 10% GelMA and 10% PEGDA. The laser intensity, working distance, ink volume, and temperature were set to the same conditions as our previous studies (15, 26, 27) to eliminate the effect of the printing parameters. In this situation, the printing speed of the laser-based SL printing affects the photocuring performance, the structural accuracy (fineness), and the curvature of the 4D self-morphing. To ensure the complete solidification of the inks, a printing speed of 10 mm/s was set on the basis of our previous trials. By varying the printing speed (cross-linking density), a series of 4D self-morphing patches (wave pattern) were obtained with different curvatures. The mesh-patterned patches also exhibited a similar 4D morphing behavior. In all 4D self-morphing structures, the degree of deformation largely depends on the swelling, water content, and ionic strength. After 4D morphing, the wave-patterned patches maintained their wavy structure with a slight deformation. In our study, the bending of macrostructure does not significantly affect the microstructure. Figure 2A shows the curvature change of 4D morphing with increasing printing speed. Similar to the 4D morphing mathematical model by stress relaxation in the previous study (15), the relationship between the 4D curvature and printing speed can be modeled with the materials and printing parameters using the following equation1/r=4.7802.53lnv[mm1](2)where r is the radius of the object curvature after 4D morphing, is the printing speed (millimeters per second), and 0 is the shrinkage, which is dependent on both the material and the immersion medium. Here, 0 = 0.012 s1 in aqueous solution. The results demonstrated that the patches printed with a print speed (6 mm/s) had an appropriate curvature with the 4D morphing to obtain a sufficient integration with the LV surface of the mouse hearts.

(A) Curvature change of 4D morphing versus printing speed (means SD, n 6, *P < 0.05). (B) Printing accuracy of the hydrogel patches versus fiber width for different fill density (fd; means SD, n 6, *P < 0.05, **P < 0.01, and ***P < 0.001). (C) Color map of tensile moduli of the patches with varying GelMA and PEGDA concentrations. (D) Optical and 3D surface plot images of the patches. Scale bars, 200 m. (E) Average elasticity values of the wave-patterned patches in horizontal (x) and vertical (y) directions. Number sign (#) shows the statistical comparison between the horizontal and vertical directions (means SD, n 6, **P < 0.01 and ##P < 0.01). (F) Uniaxial tensile stress-strain curves of 5% GelMA and 15% PEGDA. Immunostaining of cell morphology (F-actin; red), sarcomeric structure (-actinin; green), gap junction [connexin 43 (Cx43); red], and contractile protein [cardiac troponin I (cTnI); red] on the patches on (G) day 1 and (H) day 7. Scale bars, 20 m. (I) Beating rate of hiPSC-CMs on the patch and well plate on day 3 and day 7 (means SD, n 6, *P < 0.05; n.s. no significant difference). BPM, beats per minute. Photo credit: Haitao Cui, GWU.

As is shown in Fig. 2B, the printing accuracy of different fiber width, fiber angle, layer number, and fill density of the fiber arrangement was investigated. The fiber pattern with a 100-m width showed significantly lower accuracy (50%) when compared to both fibers with 200-m (>70%) and 400-m (>90%) widths. In addition, the fiber pattern with a 60% fill density showed lower accuracy than the fiber pattern with 40% fill density. This implies that the fiber pattern with higher fill density or lower width is associated with more directional changes of the laser head per unit area, which is a function of the limitation of the printing resolution. In addition, there was no significant difference in the accuracy observed when increasing the number of stacked fibers (or fiber angles) due to the high reproducibility of the SL printing (fig. S1A). It was observed that smaller fiber widths or higher fill densities had a higher surface area per unit area, which was beneficial for the attachment of more cells, as the increased surface area better mimics the native myofibers. According to a previous study, the quantitative measurement of fiber angles showed that the dominant distribution of fiber angle was +45 to 45 from the epicardium to the endocardium (21). Therefore, a fiber pattern was printed with a 200-m width, 40% fill density, and a maximum angle of 45 for adjacent layers to optimize the mechanical properties of the hydrogel patches.

To test and measure the mechanical (both compression and tensile) modulus of the hydrogels, we varied the mixed weight ratio of GelMA and PEGDA from 5 to 20% (Fig. 2C and fig. S1, B and C). The results demonstrated that the mechanical moduli of the hydrogels fall within the range of the native myocardium modulus (101 to 102 kPa) in the physiological strain regime (28, 29). In addition, swelling testing showed that when GelMA was mixed with PEGDA, the printed hydrogels maintained excellent structural stability without notable swelling (fig. S1D). With consideration for the optimized ink viscosity and hydrogel elasticity, the inks used to fabricate our myofiber patches were formulated with concentrations of 5% GelMA and PEGDA (5, 10, and 15%) and were effectively printed on the basis of our design. Figure 2D shows the optical and 3D surface plot images of the patches printed by 5% GelMA and 15% PEGDA with a 200-m width, 40% fill density, and a 45 angle for adjacent layers. The fluorescent images of the 3D printed patches are also displayed (fig. S2A). The anisotropic behaviors of the wavy-patterned patches in the horizontal (x) and the vertical (y) direction demonstrated that uniaxial tension on the fiber pattern resulted in different deformation and stress generation in a directionally dependent manner (Fig. 2E). In particular, the stress-strain curve of the patch with 5% GelMA and 15% PEGDA was consistent with the tensile features of the native myocardium within the physiological strain regime (Fig. 2F) (19, 30). The fatigue was obvious along the y direction at the initial stage, which is attributed to the lower connectivity of fibers in the y direction and higher extendibility of the wavy-patterned fibers in the x direction. It is expected that this physiologically adaptable design would increase the stretchability and stability of the hydrogel patches, allowing them to absorb and release energy against the force of cardiac contraction (31, 32). Compared to the mesh design, the current architecture would allow for structural compliance of the hydrogel fibers without notable deformation. Moreover, the successfully printed patterns also well represent the microstructure of the native myocardial tissue, which is formed from collagen fibers and other ECM proteins, together with cardiomyocytes. However, the width of the myofibers within the myocardial tissue was much smaller (30 to 40 m) than the printed pattern (200 m), which is largely a limitation of the resolution of the currently available technology.

After the optimization of both the printing parameters and the ink formulation, the cardiac patches were manufactured with 5% GelMA and 15% PEGDA using a beam-scanning SL printing system. The wavy-patterned patches with a diameter of 8 mm and a thickness of 600 m were used to perform the in vitro studies, while the mesh-patterned patches of the same fiber volume fraction served as the control. By keeping the same surface area across the different construct patterns, we could ensure that there would be the same available cell number for each of the patches. Upon analysis, the redundant length (L) of the stretchable structure was determined to be around 140 m. Because of their capacity for restoring cardiac function in previous studies, hiPSC-CMs were cultured using the same protocol developed at the National Heart, Lung, and Blood Institute (NHLBI) (33). Before cell seeding, a thin layer of Matrigel was precoated on the well plate or patches surface to improve the hiPSC-CM adhesion. By day 7, spontaneous contractions of monolayer hiPSC-CMs were observed (fig. S2B and movie S1), and immunostaining results demonstrated that hiPSC-CMs displayed specific myocardial protein expression, including sarcomeric alpha-actinin (-actinin), connexin 43 (Cx43), and cardiac troponin I (cTnI). (fig. S2, C and D). The cell-laden ink was printed by mixing 1 106 per ml of hiPSC-CMs with 5% GelMA and 15% PEGDA. However, a decrease in the metabolic activity of the hiPSC-CMs was observed, and the distinct cardiac beating behavior was not evident (fig. S2, E and F). These observations were likely the result of the limited 3D space within the hydrogel. Hence, a postseeding approach was then applied to fabricate the cardiac patches. Compared to the cell-laden samples, the hiPSC-CMs seeded on the patches showed significantly higher proliferation and beating rate. The attached hiPSC-CMs exhibited spontaneous contractions along the fibers on day 3 (movie S2). Moreover, the immunostaining images revealed robust F-actin, -actinin, Cx43, and cTnI expression of hiPSC-CMs on the printed patches (Fig. 2G). After 7 days of culture, the hiPSC-CMs began to form aggregation structures atop the printed fibers and began to contract synchronously across the entire patches, indicating electrophysiological coupling of the cells (Fig. 2H). Moreover, the beating rate of the hiPSC-CMs on the printed patch was notably similar to that of the monolayer hiPSC-CMs on the seeded well plate (Fig. 2I).

According to previous studies, human mesenchymal stromal cells (hMSCs) have been widely used in coculture with cardiomyocytes and endothelial cells to improve cell viability, myogenesis, angiogenesis, cardiac contractility, and other functions due to their paracrine activity (34, 35). Hence, a triculture of hiPSC-CMs, human endothelial cells (hECs), and hMSCs was performed to fabricate the vascularized cardiac patches. The analysis of cell tracker staining was conducted to investigate the distribution of different cells in the triculture and to optimize the cell ratio in the triculture system based on the calculated fluorescent value. The results demonstrated that when the initial ratio of seeded cells was 4:2:1, the resultant cellular proportion of hiPSC-CMs, hECs, and hMSCs was ~ 30, ~40, and ~30%, respectively, at confluency, which falls within the range of the cellular composition [25 to 35% cardiomyocytes, 40 to 45% endothelial cells, and ~30% supporting cells (i.e., fibroblasts, smooth muscle cells, hematopoietic-derived cells, and others)] of the human heart (Fig. 3A) (36, 37). After 7 days of culture, the printed construct showed a uniform cell distribution and longitudinal alignment of the cells along the fiber direction (Fig. 3B and fig. S3). Autofluorescence images of green fluorescent proteintransfected (GFP+) hiPSC-CMs on day 7 indicated that the cardiomyocytes exhibited an increased proliferation rate on the patches, as compared to initial seeding on day 1, and were able to generate spontaneous contractions (Fig. 3C and fig. S4). After 7 days of culture, fluorescent image analysis of CD31 [platelet endothelial cell adhesion molecule-1 (PECAM-1)] stained patches revealed that the wave-patterned patch had a higher density of capillary-like hEC distribution along the fibers when compared to the mesh control (Fig. 3D). In our previous studies, we found that the beam-scanning laser is able to cure the ink for the macroarchitectural formation together with the aligned microstructure present on the printed fibers (16). Hence, the hECs were easily grown along the fiber direction. Moreover, the iPSC-CMs exhibited an excellent contraction-relaxation behavior along the fibers in the wave-patterned patches, potentially allowing for a local mechanical stimulation on the fiber resident cells, which can help to improve the growth and distribution of hECs. In addition, immunostaining analysis of the cTnI and the marker von Willebrand factor (vWf) indicated that our wave-patterned patches contained a dense network of vascular cells interwoven with hiPSC-CMs distributed over the printed fibers, and the ratio of hiPSC-CMs and hECs was largely retained with 45% hiPSC-CMs (Fig. 3, E and F). Furthermore, it has been well established that the electrical activity at the cardiomyocyte membrane is controlled by ion channels and G proteincoupled receptors, which are usually actuated by calcium transients (38). The electrophysiological profiles of the cardiac patches demonstrated the generation of typical calcium oscillation waveforms and synchronous beating along with the printed fibers across the entire patches after 3 days (Fig. 3G). Over the next 7 days of culture, the amplitudes of calcium transients gradually increased to a stable state, suggesting the establishment of excellent functional contraction-relaxation and electrophysiological behaviors (Fig. 3, H and I).

Cell distribution of tricultured hiPSC-CMs (green), hECs (red), and hMSCs (blue) on the cardiac patches using cell tracker staining after (A) 1 day of confluence and (B) 7 days of culture. Scale bars, 200 m. (C) Autofluorescence 3D images of GFP+ hiPSC-CMs on the wave-patterned patch on day 1 and day 7. Scale bars, 100 m. (D) Immunostaining of capillary-like hEC distribution (CD31; red) on the hydrogel patches. Scale bars, 200 m. Immunostaining (3D images) of cTnI (red) and vascular protein (vWf; green) on the (E) wave-patterned and (F) mesh-patterned patches. Scale bars, 200 m (3D image) and 20 m (2D inset). Calcium transients of hiPSC-CMs on the hydrogel patches recorded on (G) day 3 and (H) day 7. (I) Peak amplitude of the calcium transients of hiPSC-CMs on the mesh- and wave-patterned patches on day 3, day 7, and day 10 (means SD, n 30 cells, *P < 0.05).

To enhance the effectiveness of our design, a custom-made bioreactor consisting of a dynamic flow device and a mechanical loading device was constructed to provide a physiologically relevant environment, which could incorporate both mechanical strain and hydrodynamics (Fig. 4A) (39). The patches were compressed in the radial direction using positive pressure between the piston and stationary polydimethylsiloxane (PDMS) holder to yield a mechanical loading, which mimics the contractile behavior of the in vivo human heart (fig. S5A). During the dual mechanical stimulation (MS), the applied force was stored in the patch as strain energy, which was then responsible for returning the patch to its original shape. The out-of-plane loading (bending) determines the stretch and recovery of the fibers, while the fluid shear stress regulates cellular orientation (Fig. 4B). Both were applied to the patches and transferred onto the cells to improve the vascularization and myocardial maturation of the resident cells.

(A) Schematic illustration of a custom-made bioreactor to apply dual MS for the maturation of engineered cardiac tissue. PMMA, polymethylmethacrylate. (B) Both the out-of-plane loading and fluid shear stress applied to the patches. (C) Immunostaining of cTnI (red) and vWf (green) on the wave-patterned patch under MS condition (+MS) versus nonstimulated control (MS). Scale bars, 50 m. (D) Immunostaining of the -actinin (green) and Cx43 (red) on the wave-patterned patch under MS condition (+MS) versus nonstimulated control (MS). Scale bars, 20 m. (E) Cross-sectional immunostaining of the sarcomeric structure (Desmin; green) and vascular CD31 (red) on the patches under MS condition (+MS). Scale bars, 50 m. (F) The beating rate of hiPSC-CMs on the printed patches under MS condition (+MS) versus nonstimulated control (MS) on day 14 (means SD, n 6, *P < 0.05). BPM, beats per minute. Relative gene expression of (G) myocardial structure [myosin light chain 2 (MYL2)], (H) excitation-contraction coupling [ryanodine receptor 2 (RYR2)], and (I) angiogenesis (CD31) on the patches under MS condition (+MS) versus nonstimulated control (MS) on day 1, day 7, and day 14 (means SD, n 9, *P < 0.05, **P < 0.01, and ***P < 0.001).

After 2 weeks of dynamic culture, we observed a higher expression of mature cardiomyogenic cTnI and angiogenic vWf in MS samples and more longitudinally aligned vascular cells, when compared to the nonstimulated control (Fig. 4C and fig. S5, B and C). In addition, the patches exhibited enhanced sarcomere density and junctions, as identified by the -actinin and Cx43 expression of the hiPSC-CMs (Fig. 4D and fig. S5, D and E). Cross-sectional images illustrated that the high density of cell assemblies on the wave-patterned patches was evident under MS conditions and these assemblies exhibited a higher expression of desmin and CD31 markers compared to the mesh control (Fig. 4E). This suggests that the specific design of the cardiac patch was able to impede the mechanical force against material deformation in our dynamic system to support repeatable stretch cycles and decrease the negative effect on the cells. Moreover, the assembled hiPSC-CM fibers on the cardiac patch spontaneously and synchronously contracted along with the fiber direction (Fig. 4F and movie S3). However, the entire patch did not exhibit in-plane contraction or macroscopic movement itself due to the high mechanical resistance of the hydrogel material. In general, it was observed that the wave-patterned patch was capable of stretching to a physiologically relevant fiber pattern compared to the mesh design, which could improve cell guidance and elongation along the fiber direction.

Consistent with the immunostaining results, the expression of cardiac-related genes, including genes associated with sarcomeric structure, excitation-contraction coupling, and angiogenesis, was significantly increased on day 14 compared to day 7. These results suggest that there was an increase in maturation of the iPSC-CMs on the printed patches over time (Fig. 4, G to I, table S1, and fig. S6). After the application of the MS, the expression of the MYL2 (myosin light chain 2) and RYR2 (ryanodine receptor 2) genes were significantly increased in our wave-patterned patches on day 14, as compared to the mesh control. This demonstrates that our specific patch design can enhance iPSC-CM contractile and electrical function under MS. Moreover, the angiogenic CD31 gene was also considerably up-regulated on the wave-patterned patches with perfusion culture. In general, the gene expression on day 14 was up to 28-fold higher compared to day 1, and an average of 5.5-fold increase in the expression of maturation genes was observed with the MS condition as compared to the nonstimulated groups. This observation provides further evidence that significantly enhanced cardiac maturation is achievable on the printed patches when specific structural design and physiologically relevant culture conditions are combined.

Having used the dynamic culture system to enhance the maturation of hiPSC-CMs in vitro, we further investigated the vascularization and myogenic maturation of the printed cardiac patches in vivo. Ischemia-reperfusion (I/R) is a major contributor to the myocardial damage resulting from MI in humans (40). Murine models of I/R injury provide an effective means to simulate clinical acute or chronic heart disease for cardiovascular research (41, 42). Hence, a chronic MI model with I/R injury was created to assess the functional effects of cardiac patch implantation (43, 44). The cellularized and acellular patches were implanted onto the epicardium of immunodeficient nonobese diabetic severe combined immunodeficient gamma (NSG) mice and were assessed for long-term development 4 months after implantation. Compared to the classic MI model, our I/R injury model produced a shortened recovery time, less inflammation, and higher survival rates. The patches (4-mm diameter by 600-m thickness in size) were entirely positioned over the infarcted (ischemia) site of the mouse hearts (Fig. 5, A and B, and movie S4). To assess the direct interaction (structure and cells) between the patch and the host epicardium, we did not apply fibrin glue. After 3 weeks of implantation, optical images showed that the cellularized patches had a firm adhesion to the epicardium regardless of the contractile function of the heart (Fig. 5C). Hematoxylin and eosin (H&E) assessment confirmed the robust epicardial engraftment of the cell-laden patches, which contained high-density cell clusters after 3 weeks (Fig. 5D). Fluorescent images also showed that the GFP+ hiPSC-CMs (green) maintained higher viability after 3 weeks of implantation (Fig. 5E). The immunofluorescence analysis of cTnI and vWf illustrated the existence and development of hiPSC-CMs and hECs on the cellularized patches in the treated region with time. The image results showed that many vascular cells were found spanning the interface of the patch and myocardium and expanded within the myocardial patch (Fig. 5F).

(A) Optical image of surgical implantation of the patch. (B) Optical image of a heart I/R MI model after 4 months. (C) Optical image of the implanted cellularized patch at week 3, exhibiting a firm adhesion (inset). (D) H&E image of the cellularized patch at week 3, demonstrating the cell clusters with a high density (yellow arrowhead). Scale bar, 400 m. (E) Fluorescent image of (GFP+) iPSC-CMs on the patch at week 3, showing a high engraftment rate (yellow arrowhead). Scale bar, 100 m. (F) Immunostaining of cTnI (red) and vWf (green) on the cellularized patch at week 3. Scale bar, 100 m. (G) H&E images of mouse MI hearts without treatment (MI) and with cellularized patch (MI + patch) at week 10. Infarct area after MI (yellow circles). Scale bars, 800 m. (H) Cardiac magnetic resonance imaging (cMRI) images of a mouse heart with patch at week 10. Left (spin echo): the position of the heart and implanted patch. Right (cine): the blood (white color) perfusion from the heart to the patch. Photo credit: Haitao Cui, GWU.

After 10 weeks of implantation, H&E staining results showed that the infarct sizes of the patch groups (~3.8 0.7%) were smaller than the MI-only control (~8.4 1.1%), suggesting that the patch can provide mechanical support to effectively prevent LV remodeling (Fig. 5G and fig. S7A). The images and videos of the cardiac magnetic resonance imaging (cMRI) demonstrated that the implanted patch was able to contract and relax with the heartbeat of the mouse and also confirmed its excellent structural durability along with evident blood perfusion from the heart to the patch (Fig. 5H and movie S5). Fluorescent images also showed that the GFP+ hiPSC-CMs (green) maintained higher viability after 10 weeks of implantation (fig. S7B). hiPSC-CMs with cTnI+-expressing capillaries (vWf+) were observed in the patches, where the lumen structure of neovessels was also clearly visible (Fig. 6A). Together, these results indicated that epicardially implanted patches exhibited robust survival and vascularization in vivo. Moreover, a high density of capillaries identified by human-specific CD31 expression was observed within the cellularized patches, suggesting that the implanted hECs and hMSCs increased the vessel formation throughout the patch in vivo (Fig. 6B).

(A) Immunostaining of cTnI (red) and vWf (green) on the cellularized patch at week 10. Scale bar, 800 m. Border of the heart (white dashed line) and capillary lumen (white arrow). Scale bar (enlarged), 100 m. (B) Immunostaining of human-specific CD31 (red) on the cellularized patch at week 10, showing the generated capillaries by hECs. Scale bar, 800 m. Border of the heart (white dashed line). Scale bar (enlarged), 100 m. (C) Immunostaining of cTnI (red) and vWf (green) on the cellularized patch for 4 months, showing the increased density of the vessels. Scale bar, 800 m. Border of the heart (white dashed line) and capillary lumen (white arrow). Scale bar (enlarged), 100 m. (D) Quantification of capillaries with vWf staining data for 10 weeks and 4 months (means SD, n 6, *P < 0.05 and **P < 0.01). (E) Immunostaining of human-specific CD31 (red) on the cellularized patch for 4 months. Scale bar, 800 m. Border of the heart (white dashed line). Scale bar (enlarged), 100 m. (F) Immunostaining of -actinin (green) and human-specific CD31 (red) on the cellularized patch at month 4. Scale bars, 50 m.

By 4 months, H&E staining results showed a higher cell density and smaller infarct area (~5.6 1.5%) in the cellularized patch compared to the acellular patch and MI groups (~14.3 2.3%; fig. S7C). The GFP+ fluorescent results demonstrated that the hiPSC-CMs retained high engraftment rates (fig. S7D). Similar to what was observed at 10 weeks, the cellularized patch had a strong integration within the epicardium, whereas the cell-free patch had a weak adhesion by month 4. In addition, the cMRI images also illustrated that the implanted patch had an excellent connection with the mouse heart (fig. S7E). The positive expression of mature cTnI further indicated the presence of advanced structural maturation of the hiPSC-CMs in the treated region, and the capillaries were also substantially identified by the vWf staining in the cell-laden patch groups (Fig. 6C). The images also demonstrated more progressive implant vascularization with a 1.5-fold increase in blood vessel density after 4 months of implantation, when compared to cell-free controls (Fig. 6D). The data were counted by five randomly selected fields in each heart. However, the fraction of humanized vessels was not significantly increased, as identified by the human-specific CD31 staining (Fig. 6E). Therefore, the increased vascularization and vascular remodeling in vivo likely originated from the host vessel ingrowth as opposed to the implanted human vessels at the initial stage of implantation. However, differing from the in vitro results, the cross-sectional images of the implants did not exhibit substantial sarcomeric structure (identified by -actinin) when compared to the native cardiac tissue (Fig. 6F). It can be observed that the cell aggregation in the vertical direction showed a disordered assembly and 3D stacking behavior. Overall, these results demonstrated that the printed patches underwent progressive vascularization, largely remained on the epicardial surface of the LV over the 4-month implantation period, and effectively covered all of the infarcted area. Cardiac function was also evaluated at different time points after injury via cMRI assessments. The LV ejection fraction of all patch groups (~64.1 3.5%) was higher than the MI-only group (~56.1 1.5%); however, there was no difference observed between the cellularized patch group and the cellular group.

MI is a leading cause of morbidity and mortality worldwide. The hiPSC-CMs provide a potentially unlimited source for cardiac tissue regeneration, as they are able to recapitulate many of the physiological, structural, and genetic properties of human primary cardiomyocytes and heart tissue (13). Current methods for the treatment of MI largely involve injecting cardiomyocytes directly into the epicardial infarct zone; however, because of the limited engraftment capacity of the injected cardiomyocytes, injection therapies are not fully satisfactory in restoring cardiac functionality (13). Several studies have been performed with hiPSC-CMs to generate functional cardiac tissue constructs using tissue engineering techniques (7, 10). However, the physiological features of hiPSC-CMs are more sensitive to the physicochemical and bioactive properties of the scaffolds in which they reside. Compared to synthetic polymers, natural polymer-based hydrogels can provide a more favorable matrix for the growth and differentiation of cardiomyocytes (7). However, limitations of structural design and manufacturing techniques, as well as the low mechanical strength and weak processability of hydrogel-based patches, still make their clinical application challenging.

As a proof of concept, a physiologically adaptable 4D cardiac patch, which recapitulates the architectural and biological features of the native myocardial tissue, has been printed using a beam-scanning SL printing technique. The smart patches provided mechanical support, a physiologically tunable structure, and a suitable matrix environment (elasticity and bioactivity) for cell implantation. Successful vascularization of the patches allowed for the continued metabolic demand of hiPSC-CMs and permitted them to remain both viable and functional throughout the in vivo study. Robust engraftment and development of the implanted patches were further confirmed using a more clinically relevant and mechanically realistic environment. The study results showed that the anisotropic mechanical adaption of the printed patches improved the maturation of cardiomyocytes and vascularization in vitro under MS. After implantation into the murine MI model, the printed patches exhibited high levels of in vivo cell engraftment and vascularization.

In a previous study, an engineered auxetic design was developed to give a cardiac patch a negative Poissons ratio, providing it with the ability to conform to the demanding mechanics of the heart (31). Here, we further propose and develop a 4D physiologically adaptable design for a cardiac patch, which includes hierarchical macro- and microstructural transformations attuned to the mechanically dynamic process of the beating heart. Therein, a physiological adaptation is evident in the response of cells (or genes) to the microenvironmental change. Similarly, the adaptive responses of the resident cells on the scaffolds to replicate the native microenvironment are crucial for the in vivo integration of engineered tissue with and the host tissue after implantation. In addition, a highly biomimetic in vitro culture system was developed with dynamic perfusion and mechanical loading to enhance cardiac maturation. Overall, the current work has several unique features: (i) a greatly improved mechanical stretchability of the hydrogel patches; (ii) a triculture of hiPSC-CMs, hMSCs, and hECs, which is necessary to obtain a complex cardiac tissue; (iii) an application of in vitro dual MS by which to improve cardiac maturation; and (iv) in vivo long-term development of the printed patches in a murine chronic MI model to evaluate the potential therapeutic effect.

Although several studies have shown that cell transplantation can greatly improve cardiac function in the MI model, no substantial evidence supporting these improvements in cardiac function was found in the current study. In the MS culture studies, it was observed that the entire patch did not exhibit in-plane contraction. The high mechanical resistance of the hydrogel could be a reason as to why the patches did not significantly enhance cardiac function in vivo. Moreover, as is known, the implanted human cardiomyocytes exhibit different beating frequencies and other biological features within the host mouse heart (13, 45, 46). Hence, integrated functional repair was not observed in this study. Differing from the hypothesis of the functional enhancement, the in vivo results revealed that the enhanced cardiomyogenesis and neovascularization of humanized patches did not significantly improve the cardiac function of the MI mice. The patches provided cellularized niche conditions so that most of the implanted cardiomyocytes were alive, although they still exhibited immature 3D sarcomeric organization. Moreover, the neovascularization effects of the cell-laden patches at the infarct region were also confirmed, suggesting that paracrine effects appear to be a major contributing factor. Although there was a lack of functional integration between humanized patches with the hearts of the host mice, the printed patches exerted no adverse effects on the host cardiac function or vulnerability to arrhythmias. The cell transplantation improved the cellularized environment in the infarct area by, at least in part, promoting angiogenesis and increasing cell retention. The multiple cell transplantation with a high density of hiPSC-CMs retention in the murine MI model suggests that this goal may have been at least partially achieved. While applying humanized grafts to infarcted rodent hearts would likely confirm the paracrine effects, large animal studies are warranted to further evaluate the therapeutic efficacy toward a potential clinical use.

In the future, a physiologically relevant large animal study, such as a porcine or nonhuman primate MI model, will serve as a more realistic means to study cardiac patch engraftment (42, 46). Moreover, developments in advanced printing techniques will enable the development of thick, scale-up ready myocardial tissue, which will play a prominent role in the ultimate success of clinical cardiac engineering therapies. In general, the developed cardiac patch has a great potential to provide a desired therapeutic effect on the in vitro maturation and in vivo retention of hiPSC-CMs, based on the previously unidentified engineering design and manufacturing process.

These studies were designed to evaluate the concept of a 4D cell-laden cardiac patch with physiological adaptability as a potential method for the treatment of MI. To evaluate this technology, we tricultured hiPSC-CMs, hMSCs, and hECs to obtain a complex cardiac tissue and also applied in vitro dual MS to replicate the physiologically relevant conditions for the improvement of regenerated myocardial function. A 4-month in vivo study was conducted to assess the performance of our 4D cell-laden cardiac patches, where the animals were randomly assigned to different experimental groups before the experiments. The sample size and power calculation were determined on the basis of our experience with the experimental models and the anticipated biological variables. Typically, the power is 0.8, and the significance level is 0.05 when the effect size is determined by the minimum sample difference divided by the SD (GPower 3.1). All experiments were blinded and replicated. The sample sizes and replicates are shown in the figure legends.

Ten grams of gelatin (type A, Sigma-Aldrich) was dissolved in 100 ml of deionized water with stirring at 80C. Next, 5 ml of methacrylic anhydride was added dropwise into the gelatin solution. After reaction at 80C for 3 hours, the reactant was dialyzed in deionized water for 5 days at 40C to remove any excess methacrylic acid. The GelMA solid product was finally obtained through lyophilization. The ink solutions consisted of GelMA [with concentrations of 0, 5, 10, 15, or 20 weight % (wt %)], 1 wt % 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959, photoinitiator), and PEGDA (Mn = 700; Sigma-Aldrich; with concentration of 0, 5, 10, 15, and 20 wt %). Solutions were prepared using a 1 phosphate-buffered saline (PBS) solution.

Our 3D computational myocardium model was programmed on the basis of DTI results and was simplified to the basic geometry to replicate the fiber orientation of the native myocardium. The wave (or hexagonal) microstructure was configured with different diameter fibers and fiber angels between each layer, while the mesh microstructure served as a control. To optimize the fiber design, wave or mesh architectures with side lengths of 100, 200, and 400 m and internal angles () of 30, 45, and 60 between each layer were designed with two, four, and eight layers, respectively. All cardiac construct models were saved as .stl files, processed using the Slic3er software package, and were transferred to the 3D printer. Representative CAD models of the constructs were calculated and predicted for surface area, porosity, and other structural characteristics.

Printed cardiac patches were manufactured using our customized table-top beam-scanning SL printer, which is based on the existing Printrbot rapid prototyping platform. This system consists of a movable stage and a 110-m fiber optic-coupled solid-state ultraviolet (355 nm) laser mounted on an X-Y tool head for three-axis motion. The laser scans and solidifies the top layer of ink in a reservoir, and a movable platform lowers the construct further into the ink, covering it with the next material layer. For this study, the effective spot size of the emitted light was 150 50 m and had an energy output of ~20 uJ at 20 kHz. The ability to alter the frequency of the pulsed signal facilitates power control at the material surface ranging from 40 to 110 mW.

Different stacked architectures with fiber widths of 100, 200, and 400 m; fill densities of 20, 40, and 60%; and fiber angels of 30, 45, and 60 between each layer were manufactured with two, four, and eight layers, respectively. The printing accuracy of the patterns was quantified by the mean trajectory error (Et) compared to the designed shape. Et=1ni=0n(x(i)xt(i))2+(y(i)yt(i))2, where n 20 is the number of data points collected. Compressive and tensile mechanical properties were measured with an MTS criterion universal testing system equipped with a 100-N load cell (MTS Systems Corporation). For compressive testing, the printed patches (2 cm by 2 cm) having different microstructures were placed on the tester. The crosshead speed was set to 2 mm/min, and Youngs modulus was calculated from the linear region of the compressive stress-strain curves. For the tensile testing, the samples were mounted on to custom-made copper hooks affixed to the tester and were pulled at a rate of 1 mm/min to a maximum strain of 20%. Youngs modulus was calculated from the linear portion of the tensile stress-strain curve. In addition, the representative uniaxial tensile stress-strain plots for the latitudinal and longitudinal specimens of myocardial constructs were used to evaluate the anisotropic mechanical properties. The swelling behavior was evaluated by quantifying the weight gain after equilibrium swelling. The printed samples were immersed in PBS at 37C for 7 days. The swelling ratios of hydrogel matrices were calculated as equilibrium mass swelling ratio (SR). SR = (wt w0)/w0 100%, where w0 is the original weight of printed samples and wt is the equilibrium weight of samples after swelling.

hiPSC-CMs and GFP+ hiPSC-CMs were cultured in cardiomyocyte basic medium using the same protocol developed by our collaborators at the NHLBI (33). hECs (human umbilical vein endothelial cells; Thermo Fisher Scientific) were cultured in endothelial growth medium consisting of Medium 200 and low-serum growth supplement. hMSCs (harvested from normal human bone marrow, Texas A&M Health Science Center, Institute for Regenerative Medicine) were cultured in mesenchymal stem cell growth medium consisting of minimum essential medium, 20% fetal bovine serum, 1% l-glutamine, and 1% penicillin/streptomycin. All experiments were performed under standard cell culture conditions (in a humidified, 37C, 95% air/5% CO2 environment) with hECs and hMSCs of six cell passages or less.

After the patches were printed, iPSC-CMs, hECs, and hMSCs with different ratios were seeded on the patch constructs (the surface of the patch was precoated with a thin layer of Matrigel, Corning). The tricultured cardiac patches were maintained in the mixed medium at a 1:1:1 ratio for further characterization and in vitro cell study. hECs and hMSCs were prestained with CellTracker Orange CMRA Dye and CellTracker Blue CMAC Dye (Molecular Probes) and were then seeded onto the constructs. After 1, 3, and 7 days of coculture, cells were imaged using a Zeiss 710 confocal microscope. Cell proliferation on days 1, 3, and 7 were quantified using a cholecystokinin-8 solution [10% (v/v) in medium; Dojindo]. After 2 hours of incubation, the absorbance values were measured at 570 and 600 nm on a photometric plate reader (Thermo Fisher Scientific). The spreading morphology and arrangement of hMSCs and hECs were characterized using the double staining of F-actin (red, Texas Red; 1:200) and nuclei [blue, 4,6-diamidino-2-phenylindole dihydrochloride (DAPI), Thermo Fisher Scientific; 1:1000].

A customized bioreactor system consisting of a mechanical loading device and a dynamic flow device was used to culture our cell-laden constructs. The dynamic flow device is composed of four parts: a perfusion chamber, a flow controller, a nutrient controller, and a gas controller (5% CO2/95% air). The culture medium was perfused through the constructs using a digital peristaltic pump (Masterflex, Cole-Parmer) over the whole experimental period, which facilitated the efficient transfer of nutrients and oxygen. A shear stress was set at 10 dynes/cm2 (which is within the range of the shear stress observed in microcirculation), and a flow rate of 8.4 ml/min was selected (the viscosity of medium is ~7.8 104 Ns/m2) (47, 48). A PDMS holder was used to both firmly mount the patches within a polymethylmethacrylate chamber and to maintain the patch structure during cell culturing and MS to prevent undesired movement and damage. The patches were compressed at the speed of 60 times/min in the radial direction using positive pressure between the piston and the stationary holder to yield the mechanical force. The calculated (preload) contractile force per unit area was ~50 mN/mm2 along the fiber direction to match those in the native cardiac tissue. The cardiac constructs were placed in the bioreactor system and incubated at 37C for 7 and 14 days.

After 1 and 2 weeks of culture, cellular functions including cardiomyogenesis and angiogenesis were assessed using an immunofluorescence method. After the predetermined period, the cell-laden constructs were fixed with formalin for 20 min. The samples were permeabilized in 0.1% Triton X-100 for 15 min and were then incubated with a blocking solution [containing 1% bovine serum albumin, 0.1% Tween 20, and 0.3 M glycine in PBS] for 2 hours. The cells were then incubated with primary antibodies at 4C overnight. After incubation with primary antibodies, secondary antibodies were introduced to the samples in the dark for 2 hours at room temperature, followed by incubation with a DAPI (1:1000) solution for 5 min. All images were obtained using the confocal microscope, and protein quantifications were performed using ImageJ (49). In addition, the immunostaining analysis was performed with sliced fragments that were cut with a cryostat microtome. The primary antibodies that were used for our study were purchased from Abcam and included anti-actinin (1:500), antihuman-specific CD31 (human-specific PECAM-1; 1:500), anti-desmin (1:1000), anti-Cx43 (1:1000), anti-cTnI (1:500), and anti-vWf (1:1000). The secondary antibodies were purchased from Thermo Fisher Scientific and included anti-mouse Alexa Fluor 594 (1:1000) and goat anti-rabbit Alexa Fluor 488 (1:1000).

To evaluate the functional beating behavior, iPSC-CMs were observed and recorded using the inverted microscope and confocal microscopy. The Ca2+ that triggers contraction comes through the sarcolemma and plays an important role in excitation-contraction coupling of the heart beating. After the predetermined period, intracellular calcium transients were recorded under the fluorescent microscope at a wavelength of 494 nm over 30 to 120 s. Movies were analyzed with an ImageJ software to measure the fluorescence intensities for two to eight regions of interest (F) and for three to eight background regions (F0) per acquisition.

The cardiac tissue constructrelated gene expression was analyzed by a real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) assay. Specifically, myocardial structure [cTnI (TNNI3), cTnT (TNNI2), MYL2, MYL7, myosin heavy chain 6 (MYH6), MYH7, and -actinin 2 (ACTN2)], excitation-contraction coupling (calsequestrin 2, RYR2, phospholamban, sodium/calcium exchanger 1, and adenosine triphosphatase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2), and angiogenic genes (vWf and CD31) were studied to detect the cardiomyocyte and vascular maturation processes in the constructs. The primers that were used are shown in the Supplementary Materials (table S1). Briefly, the total RNA content was extracted using TRIzol reagent (Life Technologies). The total RNA purity and concentration were determined using a microplate reader [optical density at 260/280 nm within 1.8 to 2.0). The RNA samples were then reverse-transcribed to complementary DNA using the Prime Script RT Reagent Kit (Takara). RT-PCR was then performed on the CFX384 Real-Time System (Bio-Rad) using SYBR Premix Ex Taq according to the manufacturers protocol. The gene expression levels of the target genes were normalized against the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase. The relative gene expression was normalized against the control group to obtain the relative gene expression fold values, which were calculated via the 2Ct method.

The in vivo development of the printed cellularized constructs was evaluated using a xenograft model of transplantation into 6-week-old NSG mice. All the animal experiments were approved by the Institutional Animal Care and Use Committee of the NHLBI. A method of random and blinded group allocation was applied to our animal experiments. The murine model with chronic MI was created via an I/R procedure to analyze implanted cell development, remodeling, and infarction treatment for 4 months. The printed cellularized patches (4-mm diameter by 600-m thickness in size) were prepared in sterile conditions and were surgically implanted into the LV ischemic area of each NSG mouse through a limited left lateral thoracotomy. The acellular patch and MI-only groups served as controls. At different time points after implantation, cMRI was performed to visualize the beating heart and to evaluate the structural/functional parameters, which included the ejection fraction, end-systolic volume, end-diastolic volume, stroke volume, and cardiac output, among others. Last, animals were euthanized, and the specimens, along with the adjacent tissues, were collected for further examination.

Histology was used to qualitatively examine the samples at different time points and included the examination of cellular cytoplasm, red blood cells, and cell distributions. The samples were fixed in formalin, processed, and were embedded in optimal cutting temperature compound for cryosection histology. The samples were cut into 5- to 10-m slides. The mean infarct size was also calculated through the histologic studies. The infarct size was expressed as the percentage of the affected myocardial area (necrosis + inflammatory tissue) in all myocardial areas analyzed, with infarct area % = infarct area 100/total myocardial area. Immunostaining was used to evaluate the in vivo cardiomyogenesis and angiogenesis of the implants. The antibodies were used in a manner similar to the in vitro study. The number of neovessels, including sprouted capillaries, was counted per section, and a total of five sections per sample were analyzed. All of the slide analyses were performed using the ImageJ software.

All data are presented as the means SD. A one-way analysis of variance (ANOVA) with Tukeys test was used to verify statistically significant differences among groups via Origin Pro 8.5, with P < 0.05 being statistically significant (#, *P < 0.05; ##, **P < 0.01; ###, ***P < 0.001).

Acknowledgments: We would like to thank J. Zou and Y. Lin (IPSC core, NHLBI) for providing hiPSC-CMs and S. Anderson (Animal MRI core, NHLBI) for carrying out the MRI analysis. Funding: We also thank American Heart Association Transformative Project Award, NSF EBMS program grant #1856321, and NIH Directors New Innovator Award 1DP2EB020549-01 for financial support. Author contributions: H.C., C.L., Y.H., and L.G.Z. conceived the ideas and designed the experiments. H.C., X.Z., and S.-j.L. conducted the in vitro experiments. H.C., Y.H., C.L., Z.-x.Y., and H.S. carried out animal experiments. H.C., C.L., T.E., Y.H., Z.-x.Y., S.Y.H., M.B., M.M., J.P.F., and L.G.Z. performed data analysis and prepared the manuscript. Competing interests: A patent application describing the approach presented here was filed by H.C., L.G.Z., and Y.H. (US 62/571,684; PCT/US20 18/055707). The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional information related to this paper may be requested from the authors.

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4D physiologically adaptable cardiac patch: A 4-month in vivo study for the treatment of myocardial infarction - Science Advances

Recommendation and review posted by Bethany Smith

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. This approval is based on data from the Phase 2 KEYNOTE-629 trial, in which KEYTRUDA demonstrated meaningful efficacy and durability of response, with an objective response rate (ORR) of 34% (95% CI, 25-44), including a complete response rate of 4% and a partial response rate of 31%. Among responding patients, 69% had ongoing responses of six months or longer. After a median follow-up time of 9.5 months, the median duration of response (DOR) had not been reached (range, 2.7 to 13.1+ months).

Cutaneous squamous cell carcinoma is the second most common form of skin cancer, said Dr. Jonathan Cheng, vice president, clinical research, Merck Research Laboratories. In KEYNOTE-629, treatment with KEYTRUDA resulted in clinically meaningful and durable responses. Todays approval is great news for patients with cSCC and further demonstrates our commitment to bringing new treatment options to patients with advanced, difficult-to-treat cancers.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

Data Supporting Approval

The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC enrolled in KEYNOTE-629 (NCT03284424), a multi-center, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. The major efficacy outcome measures were ORR and DOR as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

Among the 105 patients treated, 87% received one or more prior lines of therapy and 74% received prior radiation therapy. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC and 31% had both locally recurrent and metastatic cSCC. The study population characteristics were: median age of 72 years (range, 29 to 95); 71% age 65 or older; 76% male; 71% White; 25% race unknown; 34% Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 and 66% ECOG PS of 1.

KEYTRUDA demonstrated an ORR of 34% (95% CI, 25-44) with a complete response rate of 4% and a partial response rate of 31%. Among the 36 responding patients, 69% had ongoing responses of six months or longer. After a median follow-up time of 9.5 months, the median DOR had not been reached (range, 2.7 to 13.1+ months).

Patients received KEYTRUDA 200 mg intravenously every three weeks until documented disease progression, unacceptable toxicity or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed every six weeks during the first year and every nine weeks during the second year.

Among the 105 patients with cSCC enrolled in KEYNOTE-629, the median duration of exposure to KEYTRUDA was 5.8 months (range, 1 day to 16.1 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with cSCC were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer (NSCLC) treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (11%).

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

Continued here:
FDA Approves Merck's KEYTRUDA (pembrolizumab) for the Treatment of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) that...

Recommendation and review posted by Bethany Smith

Menopause starts 12 months after the last menstrual period or when menstruation has stopped because of a clinical reason, such as removal of the ovaries, and symptoms may include hot flashes, sleep disturbances, urinary problems, and vaginal dryness.1

In 2017, the North American Menopause Society updated its 2012 Hormone Therapy Position Statement based on new evidence of the benefits versus risks.2 The 2017 position statement discussed that hormone replacement therapy (HRT) provides the most benefit for women younger than 60 years within 10 years of menopause onset and no treatment contraindications.2 This patient population can be treated for vasomotor symptoms, such as hot flashes. However, the risks of HRT may outweigh the benefits for women 60 years and older or those more than 10 or 20 years from menopause onset.2 These patients may have a greater risk of coronary heart disease, dementia, stroke, and venous thromboembolism.2 Pharmacists can play an important role in educating patients about HRT, as well as recommending pharmacotherapy based on age and medical history.

COUNSELING PEARLS, TREATMENT OPTIONS Unopposed estrogen should only be given to women who have had a hysterectomy.2 Combined estrogen-progestin therapy is recommended for women with an intact uterus to prevent endometrial cancer.2 Patients should use HRT for the shortest duration possible at the lowest dose for symptom management.2 Evidence suggests that the risk of breast cancer with HRT may depend on dose, duration of use, and regimen.2 Systemic HRT is not recommended in breast cancer survivors, as there is an increased risk of recurrence.2

There are various HRT options, which include systemic and vaginal estrogen treatments. Estrogen-only medications include a variety of dosage forms, such as gels, injections, oral, patches, vaginal creams and rings (figure2,3). Examples include estradiol (Alora), estradiol (Climara), estradiol (Divigel), and estradiol acetate (Femring).3 Common adverse effects may include breast tenderness, fluid retention, hair loss, headaches, and nausea. The genitourinary syndrome of menopause, which includes vaginal burning, dryness, and irritation, may be treated with low-dose topical vaginal estrogens, which are generally considered safe, as there is little systemic absorption.2 Progestin therapy is not needed with low-dose vaginal estrogen, but there is a lack of randomized trial information available beyond 1 year.2

Combination estrogen-progestin medications include oral and patch dosage forms, such as estradiol/drospirenone (Angeliq), estradiol/levonorgestrel (Climara Pro), and estradiol/norethindrone acetate (Activella).3 Common adverse effects include bloating, breast tenderness, fluid retention, hair loss, headaches, nausea, and vomiting. Conjugated estrogens/bazedoxifene (Duavee) is a combination estrogen-hormone medication.3 Bazedoxifene is an estrogen agonist/antagonist, also known as a selective estrogen receptor modulator, which can protect against endometrial hyperplasia without the need for progestin.2 Bazedoxifene therapy may result in an increased risk of venous thromboembolism like estrogen does, so it is important to counsel patients about the signs and symptoms of blood clots.3

The North American Menopause Society recommends avoiding the use of compounded bioidentical hormones, because of the risk of overdosing or underdosing and a lack of efficacy and safety studies.2 Also, salivary hormone testing to determine the dose is unreliable, because of differences in hormone pharmacokinetics and absorption.2 The FDA does not have evidence that compounded bioidentical hormones are safe and effective.4

Pharmacists should educate patients about the risks of using compounded bioidentical hormones. FDA-approved bioidentical HRT, including estradiol and estrone, is monitored and regulated for safety and efficacy.2

HRT AND DEMENTIA There has been mixed evidence as to whether HRT has a protective effect or increases the risk of dementia. One observational study found an increased risk of Alzheimer disease in patients taking systemic HRT.5 The results of a 12-year population-based study showed that longer HRT use, especially in older women, was associated with higher cognitive status later in life.6 Also, individuals initiating HRT within 5 years of menopause had higher cognitive scores than those starting HRT 6 or more years later.6 There is ongoing research known as the Kronos Early Estrogen Prevention Study that is evaluating the effects of HRT and normal aging on cognitive performance, imaging markers of Alzheimer disease, and brain structure in women who participated in the original Kronos Early Estrogen Prevention Study trial.7 This is a follow-up study evaluating these women 13 years after enrollment. Additionally, the study participants were randomized to receive oral or transdermal estrogen treatments or a placebo within 3 years of menopause.7 Because this study is more robust, it may shed more light on the effect of HRT on dementia.

REFERENCES

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Hormone Replacement Therapy Most Benefits Women Under 60 - Pharmacy Times

Recommendation and review posted by Bethany Smith

LAWRENCE COSENTINO

There should have been a banquet. Then came the coronavirus.

Each year, at Pride Week, City Pulse honors up to eight people from greater Lansing who have advanced the well being of the LGBTQ community.

Its fitting that this years Inclusion Awards focus on health.

In former years, legal and political advances in the LGBTQ community have taken center stage. This year, as a deadly virus tears through the world and leaves economic catastrophe in its wake, the mental and physical resilience of our most vulnerable populations is being tested as never before. Six of our eight 2020 awardees are dedicated to improving the mental or physical health of their LGBTQ clients or patients.

Transgender people, especially trans people of color, still experience stress, anxiety, violence and a range of unacceptable health outcomes. Many of this years awardees are deeply involved in the push to bring the best health care, and the latest information, to people in the community, through their own clinics and practices and networks like Queering Medicine.

Although we cant have an awards banquet this year, our community is still seeded with outstanding people who deserve recognition people who are doing everything they can to help the LGBTQ community keep body and soul together.

To be considered for an award, a person must be nominated by a colleague, friend, admirer or supporter. Our editorial board narrowed the nominees to eight, which wasnt easy.

The shadow of the pandemic loomed over every awardee in one way or another. Two of this years awardees, Isabella Copeland and Colleen Kelley, were chosen by virtue of their ability to create or host safe spaces where LGBTQ people could gather to socialize, be entertained or discuss various aspects of their lives.

Social life, for gay and straight alike, is still on hold, but we long for the return of welcoming places like Gone Wired Caf, which plans to reopen in July, and LGBTQ gatherings like Queers Who Brunch and Thought Club, two of Copelands many projects.

Another striking thing about this years awardees is that some of them have only been in the Lansing area for a couple of years or so, but have made a disproportionate impact in that short time. The reputation of Michigans capital city as a welcoming place for LGBTQ people, and the growing strength, resilience and mutual support of the LGBTQ community here, is drawing energetic, enthusiastic young people who are working toward another growth spurt of equality and justice for all, pandemic or no pandemic.

Isabella (Izzy) Copeland

A live burlesque show at the do-gooding Allen Neighborhood Center, a place most people associate with fresh veggies, tai chi and healthy cooking classes, brought the concept of Pure Lansing to sublime heights last Dec. 7.

Some performers were queer, some were black and they were big, organizer Isabella Copeland said with a laugh. She could see from some visitors faces that it was their first experience with traditional burlesque.

To have these amazing fat rolls and feathers in their faces I could see their brains just expand, Copeland said. It was pure joy, electric energy, positivity through the roof. I was high off of that for days.

The show was part of Queers Who Brunch, a series of get-togethers showcasing LGBTQ life and just one of the many events Copeland has helped to organize in the two years since she moved to Lansing.

When her partner came to MSU to study clinical psychology, Copleand didnt know anybody in Lansing. She resolved to build her own community and host the kind of meaningful social events she herself would want to attend.

Im pretty sure I could go the rest of my life without small talk, she said.

Gatherings like Thought Club, a monthly cocktail hour, and a monthly reading group featuring the poetry of queer women of color have had a major impact on the citys cultural life, bringing hundreds of people together for thoughtful discussions, poetry readings and other events that fill a crying need in the LGBTQ community.

Copeland credits Phiwa Langeti, founder and director of the Salus Center (Lansings LGBTQ resource hub) and man about town Lorenzo Lopez, a highly visible local advocate for Latinx and LGBT people, for ushering her into the world of queer Lansing.

Both of them welcomed me with open arms and taught me about what Lansing has to offer, which is amazing, she said.

The groups allow space for deep conversations.

We talk about things you might not bring up to a stranger sitting next to you at the bar, she said.

Its about depth, concepts that queer people experience, especially queer people of color. That is unique and rare.

Copeland is trying to keep the camaraderie via Zoom and other virtual events, including a virtual dance party, but she admits its just not the same.

Things are going to look different, and thats OK, too, she said. And this is not the end for me. I have other ideas.

Jessica Heselschwerdt

A few years ago, a patient told East Lansing physician Jessica Heselschwerdt she was transgender and requested hormone treatment.

I never learned how to do that in medical school or in my residency, Heselschwerdt said. But I did learn how to take care of post-menopausal women with hormones, and men with low testosterone, treating them with hormones.

Heselschwerdt told the patient she could either go to an endocrinologist or give her a little time to study up and do the treatment herself.

She wanted me to go on this journey with her, Heselschwerdt said. She went on line to research the subject and consulted colleagues.

I learned a lot about disparities, barriers to care, she said. I thought it was really terrible and wanted to help.

Heselschwerdt grew up in Jackson, went to medical school at Wayne State and interned in Austin, Texas. Shes always loved the idea of caring for families from birth to death, but theres a strong note of activism in her love of family practice.

I knew the medical system is not great and I wanted to be a supportive person in a system that frequently isnt, she said.

She cited a recent survey finding that about 23% of transgender people postponed medical care because of discrimination, 33% postponed care because they couldnt afford it and 33% reported a negative experience with health care.

Up to one half of transgender people reported having to teach their doctor about transgender care, which is totally not their job, Heselschwerdt said. It should be the other way around.

She runs into some persistent misconceptions when she teaches students about doing physical exams and other aspects of caring for LGBTQ patients. She has also lectured on the subject for several residency programs in the region and at conferences such as the Michigan Academy of Family Physicians.

Doctors who havent learned about this think that its hard, its complicated and its something they cant do, but its very doable, she said. There are guidelines out there.

Someday, she hopes, helping transgender patients will be a routine part of every physicians bag.

Sending patients to a specialist is just another barrier, she said. We know our patients best and they have the most access to us, so we primary care doctors should be doing this.

Colleen Kelley

Colleen Kelley has been involved in political action and activism for over 30 years, but her 15 years as owner of The Avenue Caf were like graduate study.

Ive learned and grown so much as a person from the examples of members of the community, she said.

Kelley is the embodiment of the inclusive, welcoming east side spirit.

The variety of events The Avenue has hosted over the years is staggering: hip-hop, punk rock, belly dancing, jazz, city planning brainstorm sessions, charity events, political campaign launches, drag shows anything that makes people feel good, improves their lives, furthers a good cause or stirs up a beautiful ruckus.

The cafs scope and business model have changed a lot since Kelley bought the former camping supply store at 2021 E. Michigan Ave. and christened it Gone Wired Caf in 2005.

It started as a coffee shop and cybercafe, but after the 2008 recession, student traffic began to dry up. It was clear to Kelley that her business model wouldnt sustain a place that large.

That really tested my survival, she said. It was tremendously difficult.

She put in a generously proportioned bar to make the establishment recession resistant and made many other changes that took about four years in all to finish.

Typically, she deflects the credit for turning an old camping supply store into a critical community gathering place.

The activists creating neighborhoods that are dedicated to inclusivity that has been true for about 50 years around here, maybe longer, she said. We didnt create the environment of inclusivity.

She said The Avenue has made it through the spring lockdown all right. Careful plans are under way to reopen, probably in June.

We have such a large space that even half capacity is still a lot of people, and we just want to make sure that when we reopen, its safe to do so, she said.

A 16th birthday bash is tentatively set for Aug. 1, although it might be bumped to Oct. 1.

Kelley thinks of The Avenue as a work in progress and feels the same way about herself.

The most important part has been being really vulnerable about where I needed to grow to be a more inclusive person, she said. What Ive learned from the culture of the community is that being a person who strives toward inclusivity isnt something you arrive at. Its a constant journey.

Jae Puckett

Is the news making you sick? Youre not alone. Jae Puckett is hip deep in a massive study showing a direct link between social and political shifts and changes in health for transgender people.

Last year, Puckett drove around Michigan and interviewed transgender people across the state. Many of them had never participated in a study before.

Busting out of academia and meeting people where they are is a big priority for Puckett, an assistant professor of psychology at MSU and an out gender-queer advocate.

Pucketts findings are dispiriting. Most trans people reported spikes in stress after the 2016 election. Nearly 90 percent reported increased fear, social uneasiness and anxiety and 80 percent reported increased exposure to hate speech.

The social climate is shaped by leadership, and without changes, well continue to see oppression of trans people grow, Puckett said. Its important to see people who are supportive and affirming of the trans community come into leadership positions.

This fall and beyond, as the 2020 election arrives, the groundbreaking study will track the link between shifting political winds and public health.

We will have data to show you what peoples experiences were like before the upcoming election, during it and after it, Puckett said.

After three years as an assistant professor at the University of South Dakota, Puckett fled to MSU two years ago.

It was very hard to live in South Dakota, as a trans person, and as a queer person, Puckett said. Its very isolated, and there arent a lot of supports. Every year there was a piece of legislation targeting the trans population in some way.

Puckett has taken on many roles at MSU, including teaching a class of 300 students, supervising a sexual and gender minority clinic with low-cost services and working with the Queering Medicine project to make information more accessible to the LGBTQ community.

Puckett is determined to right some historic wrongs.

The field of psychology has a very negative history when it comes to LGBTQ people, a history of stigmatizing and pathologizing, Puckett said. There are still clinical psychiatrists who try to repair or cure LGBTQ people, which is very harmful, Puckett said.

If you cant even go to the doctor without being discriminated against, that has implications for your health, Puckett said. We need to do some critical self-reflection.

Nicholas (Nick) Royal

About 10 years ago, Nicholas Royal came out to his father. They had some long and difficult conversations.

Flash forward to late 2019, when Royal got a nudge from his supervisor at MSUs Office for Institutional Equity. A youth detention center in Eaton County was looking for someone to train the staff on how to interact with queer and trans residents, and Royal had already done similar training at MSU.

How often do we get a youth facility in rural Michigan wanting to make sure theyre doing well for their trans students? Royal said. Its the first time Ive experienced it.

Royal found that Juvenile Division director Amanda Pollard and her staff were keenly receptive to his message.

It was wonderful for me on so many levels, Royal said. They were ready to learn and we were ready to teach them.

Nick has opened eyes, educated minds and brought real change to our corner of the world, Pollard said.

It gets better.

Joe Royal, a career law enforcement officer, is the probation supervisor for the 15th District Court in Ann Arbor and Nicks father.

His son had spent years working with queer and trans youth. Royal senior had decades of experience with youth detention facilities. It was only logical for father and son to work together on the training program.

I think about coming out to my dad 10 years ago, and the worry that comes with that, and the conversations weve had since then, Royal said. I really got to see it come to fruition.

Royal proudly watched his father dive into research with colleagues in the justice system on how best to serve trans and queer youth.

Hes talking about the intersection of sexual identity and gender identity and race in a way he wouldnt have 10 years ago, Royal said.

These days, Royal bears the formidable title of civil rights investigator at MSUs Office of Institutional Equity.

I feel like I have to soften it, calling on the phone, he said. Hey, Im with OIE, I just want to talk.

He looks into claims of stalking, dating violence, sexual assault, rape and sexual harassment, discrimination based on membership in classes protected by Title VII and MSU, which at Michigan State, post-Larry Nassar, is interesting work, he said.

Mauricio (Jimmy) Franco

Mauricio Jimmy Franco is a leader in a 2-year-old group called Queering Medicine, a grassroots coalition aimed at helping LGBTQ people take their health care into their own hands.

Franco, a fourth-year medical student at MSU, wants ordinary LGBTQ people to have access to the latest scientific research and health practices.

Compiling a directory of LGBTQ-friendly providers is a small part of that work. Queering Medicine already has ties that extend all over the county, from MSUs College of Human Medicine to the Salus Center and the Ingham County Health Department.

Through the Ingham County Health Departments Ryan White Program, Queering Medicine collected masks, disinfecting supplies and other hard-to-get items to pass on to immune-compromised people in the LGBT community.

Hes also a part of Queering Medicines Mythbusters group, digesting a weeks worth of COVID-19 information a daunting task in itself and boiling it down to essentials.

It was really important for us to lean in to the pandemic and figure out a way to leverage our access to information, he said. What is the virus actually doing? What do you need to do to keep someone safe? What do these terms actually mean?

When hes not studying or taking on some new task for Queering Medicine, he takes a minute or two to count his blessings.

Im a queer, Latinx person from Los Angeles with a large family that has supported me along the way, he said. In the grand scheme of things, Im quite lucky to be able to say that my biggest challenge is adapting to changes in medical school during the pandemic.

It helps that his house is within walking distance of Sparrow Hospital.

My walk home from the hospital allows me to kind of digest the day and the patients that I saw, he said. A garden and a dog named Gizmo help him wind down.

I try to spend as much time as I can with my husband, he said. This year, Franco plans to apply for a residency in pediatrics and infectious diseases at Sparrow.

Were fortunate to be able to live in Lansing and to have a community, he said. Its been nice, coming from out of state, creating roots here and meeting so many wonderful people.

Beth Sanford

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To your health - City Pulse

Recommendation and review posted by Bethany Smith

Lead 'OncoMimics' candidate EO2401 planned to start first clinical trials for Glioblastoma and Adrenal Tumors during mid-2020

PARIS and CAMBRIDGE, Massachusetts, June 25, 2020 /PRNewswire/ -- ENTEROME SA, a clinical-stage biopharmaceutical company leveraging its unique knowledge of the microbiome-immunoinflammation axis to develop next-generation therapeutics, today announces a new financing totaling 46.3 million ($52.6million) to progress the clinical development of its therapeutic pipeline, including the first clinical trials of EO2401, a novel 'OncoMimic' cancer immunotherapy.

As part of this financing, Enterome has closed a Series E round with new investors including SymBiosis, LLC, a microbiome-focused investment vehicle, and Takeda Pharmaceutical Company Limited. Existing Enterome investors Seventure, Health for Life Capital, Principia, Omnes Capital and Nestl Health Science also participated in the round. In addition, Enterome has made a first drawdown from a loan facility provided by the European Investment Bank (EIB) under a 2018 agreement.

Enterome will use the funds primarily to progress EO2401, an innovative, off-the-shelf immuno-oncology candidate, into the clinic in two cancer indications. The two Phase 1/2 clinical studies in glioblastoma and adrenal tumors, respectively, are planned to start during mid-2020. EO2401 is the first clinical candidate derived from Enterome's first-in-class OncoMimics platform.

OncoMimics are microbiome-derived peptide antigens that closely mimic antigens expressed by tumor cells; they are selected based on their ability to trigger the rapid activation of memory T-cells that respond to gut bacteria and to direct a targeted cell-killing immune response against the tumor. EO2401 combines three OncoMimics present in aggressive cancers such as glioblastoma and adrenal malignancies.

Enterome expects its second OncoMimic candidate, EO2463, a new multi-peptide cancer immunotherapy, to enter the clinic in 2021 for the treatment of B-cell malignancies (lymphomas and leukaemias).

Enterome is also pursuing the development of its proprietary, next-generation EndoMimics platform, which is designed to produce a new generation of biologics with high potency and unique tolerability. These novel peptide/protein therapeutics are being developed for unmet medical needs in metabolic and inflammatory diseases.

Enterome's lead EndoMimic candidate, EM101, is a human hormone mimetic produced by commensal bacteria. It is currently in pre-clinical development as a potential novel therapy for inflammatory bowel disease (IBD).

Enterome will continue to invest in developing its world-leading Metasecretome technology, of which both the OncoMimics and EndoMimics platforms are key components.

Pierre Belichard, Chief Executive Officer of Enterome, said: "We are extremely pleased to have completed this significant financing round, which represents an attractive balance of dilutive and non-dilutive funds. The financing will be used to progress EO2401, the first targeted immunotherapy generated from our unique OncoMimics platform. This platform capitalizes on the well-described, constant interaction between the microbiome and the immune system, resulting in a pool of memory T cells directed against specific commensal bacterial antigens that we have identified. We have discovered that some of these antigens bear striking similarity to those present on multiple cancer types and can induce a targeted, anti-tumor response hence 'OncoMimics'. We are exploiting this internal discovery to develop highly effective, off-the-shelf immunotherapies against cancers with significant unmet medical need. We look forward to starting the clinical development of this exciting new immunotherapy soon."

Enterome will also use the proceeds to support its global partner Takeda Pharma to deliver proof-of-concept clinical data with EB8018 (sibofimloc/TAK-018), an oral FimH blocker for the treatment of Crohn's disease.

"Takeda's participation in this fundraising round builds on our long-standing productive collaboration with Enterome which is focused on the clinical development of sibofimloc, an oral FimH blocker for the treatment of Crohn's disease," said Asit Parikh, M.D., Ph. D., Head, Gastroenterology Therapeutic Area Unit at Takeda.

About Enterome

Enterome is a world leader in the discovery and development of novel pharmaceuticals based on its unrivalled understanding of the interaction between the gut microbiome and the immune system (the 'microbiome-immunoinflammation axis'). Enterome is leveraging this expertise to develop a pipeline of clinical and pre-clinical candidates (small molecules, proteins and peptides) with a focus on cancer, autoimmune, inflammatory and metabolic diseases.

Enterome has two unique platforms that are generating highly promising drug candidates:

These highly productive platforms have been created using Enterome's world-leading Metasecretome technology, which gives it an unrivalled ability to generate precision drugs by using the natural reservoir of thousands of safe and tolerized effector proteins that are produced by the gut bacteria.

Enterome's most advanced drug candidate is EB8018 (also referred to as sibofimloc/TAK-018), which selectively blocks the virulence factor FimH, is advancing through clinical trials in Crohn's disease. EB8018 has been partnered with Takeda globally, with Enterome retaining a significant profit share in the US.

Enterome is headquartered in Paris (France) with operations in Boston (US) and is backed by leading venture capital investors.

http://www.enterome.com

Contacts EnteromePierre Belichard, CEOTel. +33 1 75 77 27 87media@enterome.com

Media Relations Mark Swallow / Sylvie Berrebi / David DibleCitigate Dewe RogersonTel. +44 207 638 9571enterome@citigatedewerogerson.com

Investor RelationsMelody CareyRx Communications GroupTel. +1 917 322 2571mcarey@rxir.com

View original content:http://www.prnewswire.com/news-releases/enterome-completes-46-3-million-52-6-million-financing-to-progress-the-clinical-development-of-its-therapeutic-pipeline-301083315.html

SOURCE Enterome

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Enterome Completes 46.3 Million ($52.6 Million) Financing to Progress the Clinical Development of Its Therapeutic Pipeline - BioSpace

Recommendation and review posted by Bethany Smith

As a transgender woman, Wanda Batista has long known the pain of receiving inadequate and non-affirming medical care. "Every doctor I went to would freak out," Batista says. "They didn't know what to do with me." Sometimes, she says, doctors would quickly transfer her case to another medical provider but her new doctor would have no more knowledge or experience working with transgender clients than the last. And so the cycle continued. Batista would ask for help and be met with question marks. She'd have to buy her hormone treatments on the black market, putting her life in danger. "You wouldn't even know what you were getting back then," she says.

Batista's experience is infuriating, but sadly by no means unique. Recent research shows that the biggest barrier transgender people face when receiving healthcare is the lack of providers who understand the unique needs this population faces. This, along with other barriers including discrimination and income inequality, makes it harder for transgender people to access quality care. It's important that all members of the LGBTQ+ community receive quality, compassionate care from providers who affirm and understand their patients' experiences.

Batista found that care at Callen-Lorde Community Health Center, a federally-qualified health center (FQHC) in New York City. Such centers are "safety nets to provide primary medical care in medically underserved areas or to medically underserved communities," explains Callen-Lorde's Executive Director, Wendy Stark. Though there are 1,000 such centers across America, Callen-Lorde is unique in that it specializes in providing clinically and culturally competent care to LGBTQ+ communities who are not bound by a geographic area, Stark says. People travel from all five of New York City's boroughs and even from other states to utilize Callen-Lorde's culturally competent services. And they get the best possible healthcare regardless of insurance status or ability to pay.

"There's still a lack of knowledge and understanding of LGBTQ+ health issues particularly around trans health in the medical community," Stark says. "LGBTQ+ health is not required in medical school, and there is often very little, if any, training. In many cases, it's the patient educating the provider on their health needs, whether it be hormones, or interventions like PrEP. We do our part by providing hundreds of competency and sensitivity trainings at other healthcare facilities and to clinicians-in-training, but it barely scratches the surface when you look at the country as a whole."

Photo courtesy Wanda Batista

Callen-Lorde's mission isn't just to offer medical care. "The staff at the center also work to build trust with patients who have been discriminated against or experienced stigma or trauma, especially in medical settings," Stark says. One of the biggest challenges the center faces is working with LGBTQ+ youth who have been ostracized from their families of origin and have deep mistrust of institutions, medical and otherwise. "But on the other side of that coin," Stark says, "is that Callen-Lorde builds lasting trust and community while empowering patients to invest in their health and wellness."

For Wanda Batista, the center provided more than just compassionate and empowering care. It offered her the hope and tools she needed to envision and create a new way of life for herself. During her first visit, Batista says, a doctor told her that she could be connected to a transgender provider who understood what she was going through that she could receive services without fear of being judged or misgendered.

"It was like a breath of fresh air," Batista says. "You dealt with people that had encountered your situation. They knew about everything that you had gone through. They knew where to lead you, and if they didn't, they'd find it for you."

Callen-Lorde, Batista says, became a safe haven for her. Before, she had felt like she was all alone. "Before, I really didn't have anywhere to go, except go to a clinic, get tested. That's about all I knew," Batista says. "I didn't know I needed a liver test. Or that I needed to check my blood work. That I needed to make sure that all these hormones I'm taking are actually beneficial to me and for my body."

Today, Batista is at a point in her life that she couldn't have imagined years ago. Not only is she a successful businesswoman, but she is vice chair on the community board at Callen-Lorde. And she works to spread awareness of the center's services every day. "I let people know that we're here to help you in any shape, way or form," Batista says. "There's not a question Callen-Lorde won't find an answer to."

Batista's trajectory is emblematic of the work that Callen-Lorde does. Carl Gaines also came to Callen-Lorde as a client around 2002. He had only recently moved to New York City after being diagnosed with HIV. Like many young people who move to the city, he knew he needed healthcare as soon as possible, but he hadn't lined up a job and didn't have insurance. And he couldn't focus on other areas of his life relationships, friendships, employment until he knew that his health was in good hands.

Gaines knew he was in the right place the moment he walked through the door. He could tell this was a place where he'd be accepted and where staff would go above and beyond to ensure he had all the tools he needed to keep his health in top shape. "To sit in the waiting room and see the wide spectrum of other clients, that definitely helped instill a sense of community and belonging," he says. "That was really important to me, particularly in the beginning."

Today, Gaines still visits Callen-Lorde for his medical care. He also sits on the center's board of directors. As part of the communications team at Capital One, Gaines is also a driving force behind the partnership between the financial institution and the health center.

"Capital One believes in bringing your whole self to work," Gaines says, "so part of the reason that I feel comfortable talking about my experiences at Callen-Lorde is because I know that I'll be supported within my work community. We also believe in supporting our community, and access to healthcare is a key component of any thriving community."

Capital One has made donations and contributions to Callen-Lorde in honor of Pride Month and in support of the health center's important work. Capital One promotes the center's life-saving work through volunteer activities that give employees the opportunity to learn more about that work firsthand. They sponsored events like Callen-Lorde's Rainbow Run, a virtual 5k this past May that encouraged associates to get out and exercise for a good cause.

For the seventeenth consecutive year, Capital One has received a perfect score on the Human Rights Campaign Foundation's Corporate Equality Index (CEI), designating them as one of the Best Places to Work for LGBTQ+ Equality. Their "Out Front" Business Resource Group enables associates to show up for the LGTBTQ+ community in meaningful ways like through volunteer events and educational opportunities, supporting LGBTQ+ owned business and nonprofits that serve the community.

"So many patients tell us 'I don't know where I'd be without you,'" Wendy Stark, Callen-Lorde's Executive Director, says. "We need to be there for them, and people like them who have nowhere else to turn. We made a commitment to our communities to be there when they need us, where they need us."

Read more:
This LGBTQ health center is changing lives - Upworthy

Recommendation and review posted by Bethany Smith

If theres one star that emerges from this pandemic, it might not just be Dr. Anthony Fauci but vitamin D.This nutrient has been making headlines during the COVID-19 crisis, namely because emerging research showsa link between vitamin D deficiency and the worst of COVID-19 cases.Thats spurred the public to starttakinghuge doses of D supplements, but doctors warn that this can causeother health complications from nausea to kidney failure. While vitamin D can never replace your need to practice physical distancing and wear a mask, we found out: How much D is the right amount, and can you get it from sunshine, or do you need a daily supplement? Here is the scoop on your D needs.

Vitamin D is making headlines because your body needs it and can't get enough of it on a normal diet. Vitamin D is a hormone-like, fat-soluble vitamin responsible for regulating your bodys uptake and use of calcium, promoting bone mineralization, and supporting a healthy immune function, says Whitney English, M.S., R.D.N., dietitian, and NASM certified personal trainer in Los Angeles.

While calcium absorption is one of its biggest roles, so, too, is the role it plays in the immune system, and for that, vitamin D does two things, adds Elroy Vojdani, M.D., functional medicine pioneer and founder of Regenera Medical in Los Angeles.

First, it boosts the "innate immune system," which is your bodys built-in primary defense against bacterial infections and viruses. Secondly, it enhances the function of dendritic cells, which chomp up bacteria and viruses and present them to be added to the immune system in a processcalled adaptive immune function, which creates antibodies to new threats.

Overall, vitamin D, which is known as a signaling hormone, will boost immune function in the first line of defense and then balance the immune system overall, Vojdani says. This is one reason people with optimal vitamin D status have fewer viral and bacterial infections, English adds. It's also why those with deficiency end up in the worst position when a new virus such as COVID-19 comes along since their immune systemsgo into overdrive trying to fight it off.

Humans are designed to produce vitamin D in their bodies by absorbing sunlight. Yet whether you should seek to get unprotected sun exposure is a controversial and complicated topic, says Vojdani, since different skin tones need different amounts of sun to get enough D, and we know that prolonged exposure can lead to skin cancer.

TheInstitute of Medicinerecommends that adults up to 70 years of age get 600 IU and older people get800 IU.However, watch out for supplements that deliver multiples of that amount since taking too much D can cause kidney stones and other toxicity in the body.

And while you can get vitamin D from food, theamount in most food is inadequate to make up the recommended dose. Very few foods naturally contain vitamin D, English says. With the exception of UV-treated mushrooms and fortified plant milk, vitamin D is found in egg yolks, cheese, cod liver oil, beef liver, and fatty fish like tuna, salmon, sardines, herring, and mackerel. Yet the amount of vitamin D in these foods is quite small, and of course, if you're following a plant-based diet, these foods wont be on your menu.

That leaves supplements as the bestviable option. Vitamin D supplements are just as effective at raising blood levels of active vitamin D as food or sunshine, English says.

Given vitamin Ds impact on the immune system, it makes sense that its snagged headlines through this pandemic. Vitamin D represents an inexpensive and potentially powerful way to help balance the immune system and boost its function, and it has particular application with COVID-19, Vojdani says.

The reasons for the confusion lies in a fact that a lackof D causes the body to go into what's known as immunity overdrive:By analyzing publicly available patient data from around the globe,VadimBackman and his team at Northwesterndiscovered a correlation between vitamin D levels and cytokine stormthe hyperinflammatory condition caused by an overactive immune system that causes severe damage to the lungs and respiratory distress that can lead to death.

Observational studies seem to agree that theres a risk if you have a deficiency. Patients with vitamin D deficiency are more likely to suffer from serious cases of the illness, English says, adding that this doesnt mean that taking supplementary vitamin D when your levels are optimal will result in any added benefit. Too much vitamin D can lead to toxicity, which at the extreme can lead to calcification of the heart and blood vessels.

Figuring out how to tackle your vitamin D needs starts with knowing what your vitamin D status is. Thats why you should get your vitamin D levels checked (its a simple blood test) to determine if youre getting enough D from sunlight and your diet, English says.

While theres controversy about optimal vitamin D blood levels, Vojdani believes the general population should be somewhere between 40 and 60 nanograms per milliliter (ng/mL). Somebody with an autoimmune disease or an individual who might have problems defending against viruses should shoot for 60 to 80 ng/mL, but anything above 100 or 120 ng/mL is too high. If youre low, your doctor will most likely recommend a supplement and then recheck your levels in a few weeks.

Because vitamin D deficiency is so widespread, even in sunny spots like southern Californiait means low levels arenotdueto lack of sunlight, Vojdani says its reasonable to supplement, especially during the COVID-19 pandemic. As we make our way to the other end of this pandemic, vitamin D3 should maintain itself as a staple supplementation for the majority of people because I dont think this is our last rodeowith a viral pandemic, he says.

English recommends choosing a supplement with a dosage in line with the RDA which is 600 to 800 IU per day and avoiding high-dose supplements of over 2000 IU. Choose D3 over D2 "Most studies show D3 is more effective at raising blood levels of calcifediol, the active form of vitamin D, Vojdani says. So look for vegan-friendly D3 derived from lichen, a type of microorganism, versus sheepskin.

So what about sunlight? Excessive sun exposure can up your risk of skin cancer, and while these experts recommend supplementation over sunlight, youll have to weigh your risks.

If youre light-skinned and have a significant family history of skin cancer, or have already had it once, you should avoid sun exposure, Vojdani says.For people with darker skin or who have a low risk for skin cancer-that doesnt mean sunning yourself is risk-free. Although obtaining vitamin D through sunshine is how the body is designed, humans are different than they used to be, he adds. People are living longer, and because skin cancer is a cumulative risk, the more you are exposed, the more your lifetime risk goes up.

No matter how you get Vitamin D, just remember that it isnt a silver bullet against experiencing complications from the COVID-19 virus. The best way to avoid COVID-19 is by following safety guidelines, especially by wearing protective face coverings and social distancing, English says.

More here:
Here's the Right Level of Vitamin D to Protect You from COVID-19 - The Beet

Recommendation and review posted by Bethany Smith

Global Endometriosis Therapies Market Research Report Cover Covid-19 Impact

The Endometriosis Therapies market research report fabricated by Brand Essence Market Research is an in-depth analysis of the latest trends persuading the business outlook. The report also offers a concise summary of statistics, market valuation, and profit forecast, along with elucidating paradigms of the evolving competitive environment and business strategies enforced by the behemoths of this industry.

Download Premium Sample of the Report: https://industrystatsreport.com/Request/Sample?ResearchPostId=12189&RequestType=Sample

Endometriosis Therapies Market unveils a succinct analysis of the market size, regional spectrum and revenue forecast about the Endometriosis Therapies market. Furthermore, the report points out major challenges and latest growth plans embraced by key manufacturers that constitute the competitive spectrum of this business domain.

Therapies used totreat endometriosisinclude: Hormonal contraceptives. Birth control pills, patches and vaginal rings help control the hormones responsible for the buildup ofendometrialtissue each month.In this report, 2018 has been considered as the base year and 2019 to 2025 as the forecast period to estimate the market size for Endometriosis Therapies.

This report studies the global market size of Endometriosis Therapies, especially focuses on the key regions like United States, European Union, China, and other regions (Japan, Korea, India and Southeast Asia).

This study presents the Endometriosis Therapies production, revenue, market share and growth rate for each key company, and also covers the breakdown data (production, consumption, revenue and market share) by regions, type and applications. history breakdown data from 2014 to 2019, and forecast to 2025.

In this study, the years considered to estimate the market size of Endometriosis Therapies are as follows:

History Year: 2014-2018 Base Year: 2018 Estimated Year: 2019 Forecast Year 2019 to 2025

For top companies in United States, European Union and China, this report investigates and analyzes the production, value, price, market share and growth rate for the top manufacturers, key data from 2014 to 2019.

In global market, the following companies are covered:

AbbVie Eli Lilly AstraZeneca Bayer Astellas Pharma Meditrina Pharmaceuticals Pfizer Neurocrine Biosciences Takeda Pharmaceutical

Market Segment by Product Type

Hormonal Contraceptives Gonadotropin-releasing Hormone (Gn-RH) Agonists Progestin Therapy Aromatase Inhibitors

Market Segment by Application

Hospital Clinic Other

Key Regions split in this report: breakdown data for each region.

United States China European Union Rest of World (Japan, Korea, India and Southeast Asia)

Endometriosis Therapies market report consists of the worlds crucial region market share, size (volume), trends including the product profit, price, value, production, capacity, capability utilization, supply, and demand. Besides, market growth rate, size, and forecasts at the global level have been provided. The geographic areas covered in this report:North America (United States, Canada and Mexico), Europe (Germany, France, UK, Russia and Italy), Asia-Pacific (China, Japan, Korea, India and Southeast Asia), South America (Brazil, Argentina, Colombia etc.), Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria and South Africa).

This research study involved the extensive usage of both primary and secondary data sources. The research process involved the study of variofactors affecting the industry, including the government policy, market environment, competitive landscape, historical data, present trends in the market, technological innovation, upcoming technologies and the technical progress in related industry, and market risks, opportunities, market barriers and challenges. Top-down and bottom-up approaches are used to validate the global market size market and estimate the market size for manufacturers, regions segments, product segments and applications (end users). All possible factors that influence the markets included in this research study have been accounted for, viewed in extensive detail, verified through primary research, and analyzed to get the final quantitative and qualitative data. The market size for top-level markets and sub-segments is normalized, and the effect of inflation, economic downturns, and regulatory & policy changes or other factors are not accounted for in the market forecast. This data is combined and added with detailed inputs and analysis from BrandEssenceResearch and presented in this report.

After complete market engineering with calculations for market statistics; market size estimations; market forecasting; market breakdown; and data triangulation, extensive primary research was conducted to gather information and verify and validate the critical numbers arrived at. In the complete market engineering process, both top-down and bottom-up approaches were extensively used, along with several data triangulation methods, to perform market estimation and market forecasting for the overall market segments and sub segments listed in this report. Extensive qualitative and further quantitative analysis is also done from all the numbers arrived at in the complete market engineering process to list key information throughout the report.

The study objectives are:

To analyze and research the Endometriosis Therapies statand future forecast in United States, European Union and China, involving sales, value (revenue), growth rate (CAGR), market share, historical and forecast. To present the key Endometriosis Therapies manufacturers, presenting the sales, revenue, market share, and recent development for key players. To split the breakdown data by regions, type, companies and applications To analyze the global and key regions market potential and advantage, opportunity and challenge, restraints and risks. To identify significant trends, drivers, influence factors in global and regions To analyze competitive developments such as expansions, agreements, new product launches, and acquisitions in the market

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To gain insightful analyses of the market and a comprehensive understanding of the impact of COVID-19 is likely to have on the Endometriosis Therapies Market during the forecast period between 2020 and 2026, and its commercial landscapeTo learn about the market strategies that are being adopted by your competitors and other leading companiesTo understand the future outlook and prospects of the Endometriosis Therapies Market post COVID-19To keep you abreast with the strategies used by other players in theTo understand the changes in rules and regulations in variocountries during COVID-19 and its possible effects on the market in the future.

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We publish market research reports & business insights produced by highly qualified and experienced industry analysts. Our research reports are available in a wide range of industry verticals including aviation, food & beverage, healthcare, ICT, Construction, Chemicals and lot more. Brand Essence Market Research report will be best fit for senior executives, business development managers, marketing managers, consultants, CEOs, CIOs, COOs, and Directors, governments, agencies, organizations and Ph.D. Students.

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Endometriosis Therapies Market Size Advanced Technologies & Growth Opportunities in Global Industry By 2025 Cole Reports - Cole of Duty

Recommendation and review posted by Bethany Smith

For those who struggle to remember taking their birth control pill on time, the birth control shot may sound like a desirable alternative. With the shot, you only have to think about birth control four times a year. As long as you're comfortable with injections, it may be a contraceptive to consider.

The birth control shot, Depo-Provera, is an injection of progestin, one of the hormones found in birth control pills. It was approved by the US Food and Drug Administration in 1992 and remains the only approved birth control shot in the US today.

According to the US Department of Health and Human Services, the shot prevents pregnancy "by keeping the ovaries from releasing eggs. It also causes cervical mucus to thicken and the lining of the uterus to thin. This keeps sperm from reaching and fertilizing an egg."

The shot is given every 12-14 weeks, or four times a year. As long as you get the shot on time, it's 99% effective at preventing pregnancy, says Kari Braaten, MD, the medical director of the Fish Center for Women's Health at Brigham and Women's Hospital. The 1% chance of pregnancy is attributed to human error for example, not getting the shot on time. By comparison, the pill is only 91-93% effective.

The shot releases progestin into your bloodstream, and, like the pill, it works by suppressing your natural ovulation. But unlike the pill, the shot is a single dose once every three months, rather than a daily dose.

"Because it's one dose, it can only last so long," says Braaten, adding that at approximately 14 weeks, hormone levels become low enough that some women can have their natural ovarian function return to normal, and with that comes ovulation and fertility.

"So we know, based on the studies that have been done, that no women are at risk of pregnancy in the 12- to 14-week window," says Braaten.

Health care providers will often give the first shot within seven days of starting your period to ensure you're not pregnant when injected. For those who don't get the initial injection during their period, they should use a backup method of birth control in the following seven to 10 days.

Generally, you have to visit a doctor's office to get the shot. However, there is a subcutaneous, or under-the-skin, injection you can give yourself called Depo-Subq Provera 104. However, due to low demand, it is less readily available than Depo-Provera and not covered by many insurance carriers.

Common side effects of the birth control shot include:

Many women also don't get their period while taking the shots. And, after one year, about 50% of women have no bleeding, Braaten explains. But, that's perfectly normal and safe.

"The reason why people don't get a period is because the lining of the uterus that normally has to shed does not build up when you have that hormonal influence from the shot," Braaten says. "You don't bleed because there's just nothing to come out."

The average weight gain amongst those who experience this side effect is approximately five pounds, according to the American College of Obstetricians and Gynecologists. Yet, Braaten says there's a lot of variability. "Some women gain a lot more weight, and some women do not gain any weight."

In fact, the birth control shot is the only contraceptive method proven to make women gain weight. While doctors are still unsure what causes the large variation in weight gain while using the shot, they do know it's probably a result of underlying genetic variations.

If you'd like to get pregnant within the next year, this birth control method may not be for you. Experts say it could take 10 months or more to get pregnant after stopping the shots.

Braaten says the earliest return to ovulation is about 16 weeks, "but for many women the effect of the birth control lasts for much longer, and normal ovarian function doesn't return for quite a bit longer."

The birth control shot should also be avoided if you have certain medical conditions including:

Many forms of hormonal birth control, including the shot, are not recommended for women with breast cancer, as breast cancers can be hormonally responsive. This means the cancer cells grow in response to estrogen or progesterone. Speak with your doctor if you have breast cancer to determine which method of birth control is best for you.

People with liver disease should also avoid the shot. "Hormones are processed or metabolized in the liver, so people with severe liver disease are not allowed to have any hormones," Braaten says.

Women with a history of heart attack or stroke are not advised to use Depo-Provera, according to Mayo Clinic. In general progesterone-only contraceptives are not associated with blood clots, stroke, or heart disease. But because the injection is a slightly higher dose it's best to err on the side of caution, says Braaten.

A downside of the shot is that the injection suppresses your natural estrogen levels. Women with underlying bone loss rely on estrogen to bolster their bone density. Therefore, Braaten says those who are at risk for bone loss should not use Depo-Provera.

People who have the condition hypothalamic amenorrhea, or don't regularly get a period because of low-body fat percentage, also shouldn't get the shot. Braaten says that's because they don't produce enough estrogen on their own so they should opt for an estrogen-containing contraceptive.

Depo-Provera has a warning on its packaging saying that the product might increase the risk of osteoporosis and shouldn't be used for more than two years.

This warning was added after multiple studies showed a strong correlation between the shot and loss of bone density. Researchers said the reason was likely because the active ingredient in the shot, called medroxyprogesterone, can decrease the calcium stored in bones.

However, in 2005 the World Health Organization brought together experts to review the effects of hormone contraception on bone health. They concluded there should be no restriction on the use or duration of the birth control shot in women ages 18-45.

"They also concluded that among females younger than 18 years and women older than 45 years, the advantages of using DMPA [depot medroxyprogesterone acetate] generally outweigh the theoretic safety concerns regarding fracture risk," the American College of Obstetricians and Gynecologists states.

Additional research has shown that the shot is safe to use for longer periods of time and that bone density returns as soon as the Depo-Provera is discontinued. In fact, a 2007 review published in Contraception found bone density returned to normal as early as 24 weeks after stopping use and persisted.

Ultimately, Braaten says the shot is safe to use for more than two years. "There are a lot of women who fear this warning about bone loss and are told that they can't be on it for more than two years," Braaten says. "One of the important messages is there is not for healthy women a time limitation on how long you can stay on it if it is the best method for you."

While you do have to remember your quarterly shot, the injection is less time consuming than daily birth control pills.

Some women favor the birth control shot because it doesn't interrupt sex meaning, no more worrying about condoms or diaphragms. They also may experience fewer cramps and lighter periods, or possibly none at all.

"It can provide very good bleeding control for people who have problems with heavy periods," Braaten says.

Furthermore, the shot only contains progesterone, while other contraceptive methods like the pill usually contain additional hormones, like estrogen. So this progesterone-only option is ideal for women with medical conditions that can't use combined contraception that contains estrogen, like the ring or patch, says Braaten.

With any birth control, there are risks and benefits. So talk to your doctor about the best method for you.

Excerpt from:
What you should know about the birth control shot before trying it - Insider - INSIDER

Recommendation and review posted by Bethany Smith

Fatty foods, dairy, and sweetened treats can raise the risk of acne in adults.

A study by French researchers found that foods such as milk chocolate or sugary drinks could trigger acne in adults.

The results of our study appear to support the hypothesis that the Western diet (rich in animal products and fatty and sugary foods) is associated with the presence of acne in adulthood, the authors wrote.

More than 24,000 adults in France took part in the study. They were asked to keep a 24-hour dietary record over a 2-week period.

The participants were asked to note everything they ate and drank as well as the amounts consumed.

The researchers concluded that fatty, dairy-based, and sugary foods can trigger an acne outbreak.

Drinking five glasses a day of either milk or a sugary drink increased risk of acne by more than 50 percent.

One portion of fatty foods such as french fries or a sugary food like a doughnut increased the risk of acne by 54 percent, the researchers reported.

Dr. Joseph Zahn, an assistant professor of dermatology at George Washington University in Washington, D.C., says the study results arent surprising.

The fact that fatty foods, sugary foods (those foods that are high glycemic), as well as dairy foods (particularly low fat dairy) cause acne doesnt surprise me in the least, Zahn told Healthline.

There have been a number of studies in the recent past which have suggested this particular link, and many of my patients have personally noted acne flares when eating such foods, he said.

Though the exact reasons arent clear at this time, the current school of thought regarding why these particular foods may cause acne to flare is that they may play a role in regulating certain hormones, such as insulin or androgens, which we already know cause acne to flare, Zahn explained.

The researchers suggest a diet high in sugar as well as the consumption of milk causes a rise in levels of circulating insulin.

This, in turn, stimulates cell production while also inhibiting cell death, promoting inflammation and the development of acne.

In addition, an increase in insulin levels also encourages the production of hormones that produce sebum, which can cause acne.

Insulin is a hormone secreted by our pancreas to address glucose levels in our blood. It would make sense that having a high sugar diet or one that is processed would affect insulin levels and other hormones within our bodies as well, some of which also apparently regulate acne, said Dana Hunnes, PhD, a senior dietitian at the University of California Los Angeles Medical Center.

Dairy has its own innate hormones, estrogens, progesterones, likely even some testosterone (as even human females produce some testosterone) that is likely exacerbating our own endogenous hormones and increasing the likelihood of a breakout, Hunnes told Healthline.

Study participants who reported having current acne consumed significantly more milk, sugary beverages, milk chocolate, and fast foods than the participants who reported never having acne.

The group with current acne also ate significantly less meat, vegetables, and dark chocolate.

Lauri Wright, PhD, an assistant professor in public health at the University of South Florida, says if dairy foods trigger an individuals acne, they can find their calcium elsewhere.

Dairy is an important source of calcium and protein, and generally can be a part of a healthy diet. If individuals with acne find dairy to be a trigger food, they can substitute nut milks instead, Wright told Healthline.

She argues that more research needs to be done to determine a diet that could help prevent acne, but she says cutting back on sugar is a good place to start.

​A diet low in sugar and saturated/trans fats is protective against many diseases. For health, limiting sugar and saturated/trans fats while incorporating healthy fats, lean meats, whole grains with a foundation of fruits and vegetables is optimal, she said.

Milk chocolate increased the risk of an acne outbreak by 28 percent, while dark chocolate was linked to a 10 percent reduction in the risk.

Experts say theres some truth to the claim that chocolate can cause breakouts.

Milk chocolate contains whey, a milk-derived protein. Intake of whey protein has been associated with increased levels of acne. Some individuals will be more sensitive to whey, dairy, and sugar (no matter the amount) than others. When we look at the composition of chocolate, it also contains sugar, Kristin Kirkpatrick, a registered dietitian and manager of wellness nutrition services at the Cleveland Clinic Wellness Institute in Ohio, told Healthline.

Zahn agrees that people can respond differently to foods like chocolate, and not everyone will experience acne if they eat it.

Acne can be flared by many different foods, and each person has their own unique triggers. Im not surprised that some people flare in response to milk chocolate or any kind of chocolate, he said.

We just arent sure yet what part of the food causes the outbreak, if its the food itself or a secondary effect of the food, such as increasing levels of certain hormones, Zahn added.

Zahn says acne in adults appears to be on the rise, although the reasons why are yet to be determined.

Its possibly related to rising amounts of stress, fluctuating hormone levels, or new medications, or even other reasons we dont fully understand yet, he said. Its a common problem, and many adults aged 30 to 50 still have acne.

Excerpt from:
Adult Acne Is Real: Here Are the Foods That Can Cause It - Healthline

Recommendation and review posted by Bethany Smith

The Maryland Stem Cell Research Commission (The Commission) recently announced over $7M in Maryland Stem Cell Fund (MSCF) grant awards for its second round of 2020 MSCF fund recipients. The MSCF, which is a program of the Maryland Technology Development Corporation (TEDCO), has awarded $157M in funding to BioHealth Capital Region (BHCR) companies seeking to accelerate stem cell research, therapies and commercialization of products since 2007.

The $7M in new funding follows MSCFs announcement in September 2019 of over $1.3M in grants for the first cohort of 2020 recipients, bringing the total 2020 MSCF award tally to approximately $8.3M for the year. The financial awards are delivered across a wide range of areas, including clinical, commercialization, validation, launch, discovery, and post-doctoral fellowships. The first cohort of funding included three commercialization and two validation awards; the second, larger recipient pool included one clinical, one commercialization, one validation, four launches, 11 discovery, and five post-doctoral awards.

Notable BHCR MSCF recipients included:

Dr. Luis Garza of Johns Hopkins University (JHU) received a clinical grant to support clinical trials for his autologous volar fibroblast injection into the stump site of amputees. The trials are exploring ways to make the skin where a prosthetic limb meets the stump site tougher and less irritable to the wearer. Skin irritation is a major issue for those with prosthetic limbs and is often a cause for individuals to stop wearing their prosthesis.

Vita Therapeutics, a company that spun out of JHU, was awarded a 300K MSCF grant to support the commercialization of the companys satellite stem cell therapy for limb-girdle Muscular Dystrophy. According to the National Organization for Rare Disorders (NORD), Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Vita Therapeutics is led by CEO Douglass Falk, who is a JHU alum.

Jamie Niland, VP of Baltimore, Marylands Neoprogen Inc. received part of $892,080K in funding that was part of MSCFs first 2020 grant round. Jamie is the son of Bill Niland, Neoprogens current CEO and the former leader of Baltimore, Maryland life science community anchor Harpoon Medical, which was acquired by Edwards Scientific in 2017. The award was for Neoprogens neonatal cardiac stem cells for the heart tissue regeneration program.

Dr. Brian Pollok of Rockville, Marylands Propagenix, Inc., was also the recipient of a commercialization award for his Apical Surface-Outward (ASO) airway organoids, which is a potential novel cell system for drug discovery and personalized medicine. Propagenix develops innovative new technologies that address unmet needs in epithelial cell biologyfor applications in life science research as well as in precision diagnostics, and next-generation therapeutics such as immune-oncology, tissue engineering, and regenerative medicine, according to the companys website.

In addition, Dr. Ines Silva, R&D Manager of REPROCELL, USA received an MSCF commercialization grant for its work on building a commercial neural cell bank from patient-derived induced pluripotent stem cells. REPROCELL was founded in Japan in 2003 and acquired BioServe in Beltsville, Maryland in 2014.

Dr. Sashank Reddy, the founder of JHU startup LifeSprout and Medical Director, Johns Hopkins Technology Ventures Johns Hopkins University, received a portion of the $1,334,462 distributed for launch grants in 2020. The grant will go to support the launch of regenerative cell therapies for soft tissue restoration. LifeSprout recently closed a $28.5M seed round.

Past MSCF grant recipients include Frederick, Marylands RoosterBio, Inc. and Theradaptive, Inc., and Baltimore, Marylands Gemstone Biotherapeutics and Domicell, Inc., among others.

TEDCOs MSRF program continues to lend its deep support and ample funding to build and grow Marylands burgeoning and exciting regenerative medicine industry. Well be keeping a close eye on these companies as they grow and make future contributions to the thriving BHCR biocluster.

Steve has over 20 years experience in copywriting, developing brand messaging and creating marketing strategies across a wide range of industries, including the biopharmaceutical, senior living, commercial real estate, IT and renewable energy sectors, among others. He is currently the Principal/Owner of StoryCore, a Frederick, Maryland-based content creation and execution consultancy focused on telling the unique stories of Maryland organizations.

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Over $8M in 2020 Stem Cell Funding Awards Continue to Fuel Marylands Leading Cell Therapy Industry - BioBuzz

Recommendation and review posted by Bethany Smith

The Autologous Stem Cell Based Therapies Market globally is a standout amongst the most emergent and astoundingly approved sectors. This worldwide market has been developing at a higher pace with the development of imaginative frameworks and a developing end-client tendency.

Autologous Stem Cell Based Therapies market reports deliver insight and expert analysis into key consumer trends and behaviour in marketplace, in addition to an overview of the market data and key brands. Autologous Stem Cell Based Therapies market reports provides all data with easily digestible information to guide every businessmans future innovation and move business forward.

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The worldwide Autologous Stem Cell Based Therapies market is an enlarging field for top market players,

The key players covered in this studyRegeneusMesoblastPluristem Therapeutics IncU.S. STEM CELL, INC.Brainstorm Cell TherapeuticsTigenixMed cell Europe

Market segment by Type, the product can be split intoEmbryonic Stem CellResident Cardiac Stem CellsUmbilical Cord Blood Stem Cells

Market segment by Application, split intoNeurodegenerative DisordersAutoimmune DiseasesCardiovascular Diseases

Market segment by Regions/Countries, this report coversUnited StatesEuropeChinaJapanSoutheast AsiaIndiaCentral & South America

The study objectives of this report are:To analyze global Autologous Stem Cell Based Therapies status, future forecast, growth opportunity, key market and key players.To present the Autologous Stem Cell Based Therapies development in United States, Europe and China.To strategically profile the key players and comprehensively analyze their development plan and strategies.To define, describe and forecast the market by product type, market and key regions.

In this study, the years considered to estimate the market size of Autologous Stem Cell Based Therapies are as follows:History Year: 2014-2018Base Year: 2018Estimated Year: 2019Forecast Year 2019 to 2025For the data information by region, company, type and application, 2018 is considered as the base year. Whenever data information was unavailable for the base year, the prior year has been considered.

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This Autologous Stem Cell Based Therapies report begins with a basic overview of the market. The analysis highlights the opportunity and Autologous Stem Cell Based Therapies industry trends that are impacted the market that is global. Players around various regions and analysis of each industry dimensions are covered under this report. The analysis also contains a crucial Autologous Stem Cell Based Therapies insight regarding the things which are driving and affecting the earnings of the market. The Autologous Stem Cell Based Therapies report comprises sections together side landscape which clarifies actions such as venture and acquisitions and mergers.

The Report offers SWOT examination and venture return investigation, and other aspects such as the principle locale, economic situations with benefit, generation, request, limit, supply, and market development rate and figure.

Quantifiable data:-

Geographically, this report studies the top producers and consumers, focuses on product capacity, production, value, consumption, market share and growth opportunity in these key regions, covering North America, Europe, China, Japan, Southeast Asia, India

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Finally, the global Autologous Stem Cell Based Therapies market provides a total research decision and also sector feasibility of investment in new projects will be assessed. Autologous Stem Cell Based Therapies industry is a source of means and guidance for organizations and individuals interested in their market earnings.

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Insight on the Growth of Autologous Stem Cell Based Therapies Market Growth with Challenges, Standardization, Competitive Market Share and Top Players...

Recommendation and review posted by Bethany Smith

LOS ANGELES, United States: QY Research has recently published a report, titled Global Autologous Stem Cell Based Therapies Market Size, Status and Forecast 2020-2026. The market research report is a brilliant, complete, and much-needed resource for companies, stakeholders, and investors interested in the global Autologous Stem Cell Based Therapies market. It informs readers about key trends and opportunities in the global Autologous Stem Cell Based Therapies market along with critical market dynamics expected to impact the global market growth. It offers a range of market analysis studies, including production and consumption, sales, industry value chain, competitive landscape, regional growth, and price. On the whole, it comes out as an intelligent resource that companies can use to gain a competitive advantage in the global Autologous Stem Cell Based Therapies market.

Key companies operating in the global Autologous Stem Cell Based Therapies market include , Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM CELL, INC., Brainstorm Cell Therapeutics, Tigenix, Med cell Europe, Autologous Stem Cell Based Therapies

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Segmental Analysis

Both developed and emerging regions are deeply studied by the authors of the report. The regional analysis section of the report offers a comprehensive analysis of the global Autologous Stem Cell Based Therapies market on the basis of region. Each region is exhaustively researched about so that players can use the analysis to tap into unexplored markets and plan powerful strategies to gain a foothold in lucrative markets.

Global Autologous Stem Cell Based Therapies Market Segment By Type:

, Embryonic Stem Cell, Resident Cardiac Stem Cells, Umbilical Cord Blood Stem Cells Autologous Stem Cell Based Therapies

Global Autologous Stem Cell Based Therapies Market Segment By Application:

, Neurodegenerative Disorders, Autoimmune Diseases, Cardiovascular Diseases

Competitive Landscape

Competitor analysis is one of the best sections of the report that compares the progress of leading players based on crucial parameters, including market share, new developments, global reach, local competition, price, and production. From the nature of competition to future changes in the vendor landscape, the report provides in-depth analysis of the competition in the global Autologous Stem Cell Based Therapies market.

Key companies operating in the global Autologous Stem Cell Based Therapies market include , Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM CELL, INC., Brainstorm Cell Therapeutics, Tigenix, Med cell Europe, Autologous Stem Cell Based Therapies

Key questions answered in the report:

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TOC

1 Report Overview1.1 Study Scope1.2 Key Market Segments1.3 Players Covered: Ranking by Autologous Stem Cell Based Therapies Revenue1.4 Market by Type1.4.1 Global Autologous Stem Cell Based Therapies Market Size Growth Rate by Type: 2020 VS 20261.4.2 Embryonic Stem Cell1.4.3 Resident Cardiac Stem Cells1.4.4 Umbilical Cord Blood Stem Cells1.5 Market by Application1.5.1 Global Autologous Stem Cell Based Therapies Market Share by Application: 2020 VS 20261.5.2 Neurodegenerative Disorders1.5.3 Autoimmune Diseases1.5.4 Cardiovascular Diseases1.6 Study Objectives1.7 Years Considered 2 Global Growth Trends2.1 Global Autologous Stem Cell Based Therapies Market Perspective (2015-2026)2.2 Global Autologous Stem Cell Based Therapies Growth Trends by Regions2.2.1 Autologous Stem Cell Based Therapies Market Size by Regions: 2015 VS 2020 VS 20262.2.2 Autologous Stem Cell Based Therapies Historic Market Share by Regions (2015-2020)2.2.3 Autologous Stem Cell Based Therapies Forecasted Market Size by Regions (2021-2026)2.3 Industry Trends and Growth Strategy2.3.1 Market Top Trends2.3.2 Market Drivers2.3.3 Market Challenges2.3.4 Porters Five Forces Analysis2.3.5 Autologous Stem Cell Based Therapies Market Growth Strategy2.3.6 Primary Interviews with Key Autologous Stem Cell Based Therapies Players (Opinion Leaders) 3 Competition Landscape by Key Players3.1 Global Top Autologous Stem Cell Based Therapies Players by Market Size3.1.1 Global Top Autologous Stem Cell Based Therapies Players by Revenue (2015-2020)3.1.2 Global Autologous Stem Cell Based Therapies Revenue Market Share by Players (2015-2020)3.1.3 Global Autologous Stem Cell Based Therapies Market Share by Company Type (Tier 1, Tier 2 and Tier 3)3.2 Global Autologous Stem Cell Based Therapies Market Concentration Ratio3.2.1 Global Autologous Stem Cell Based Therapies Market Concentration Ratio (CR5 and HHI)3.2.2 Global Top 10 and Top 5 Companies by Autologous Stem Cell Based Therapies Revenue in 20193.3 Autologous Stem Cell Based Therapies Key Players Head office and Area Served3.4 Key Players Autologous Stem Cell Based Therapies Product Solution and Service3.5 Date of Enter into Autologous Stem Cell Based Therapies Market3.6 Mergers & Acquisitions, Expansion Plans 4 Market Size by Type (2015-2026)4.1 Global Autologous Stem Cell Based Therapies Historic Market Size by Type (2015-2020)4.2 Global Autologous Stem Cell Based Therapies Forecasted Market Size by Type (2021-2026) 5 Market Size by Application (2015-2026)5.1 Global Autologous Stem Cell Based Therapies Market Size by Application (2015-2020)5.2 Global Autologous Stem Cell Based Therapies Forecasted Market Size by Application (2021-2026) 6 North America6.1 North America Autologous Stem Cell Based Therapies Market Size (2015-2020)6.2 Autologous Stem Cell Based Therapies Key Players in North America (2019-2020)6.3 North America Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)6.4 North America Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 7 Europe7.1 Europe Autologous Stem Cell Based Therapies Market Size (2015-2020)7.2 Autologous Stem Cell Based Therapies Key Players in Europe (2019-2020)7.3 Europe Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)7.4 Europe Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 8 China8.1 China Autologous Stem Cell Based Therapies Market Size (2015-2020)8.2 Autologous Stem Cell Based Therapies Key Players in China (2019-2020)8.3 China Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)8.4 China Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 9 Japan9.1 Japan Autologous Stem Cell Based Therapies Market Size (2015-2020)9.2 Autologous Stem Cell Based Therapies Key Players in Japan (2019-2020)9.3 Japan Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)9.4 Japan Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 10 Southeast Asia10.1 Southeast Asia Autologous Stem Cell Based Therapies Market Size (2015-2020)10.2 Autologous Stem Cell Based Therapies Key Players in Southeast Asia (2019-2020)10.3 Southeast Asia Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)10.4 Southeast Asia Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 11 India11.1 India Autologous Stem Cell Based Therapies Market Size (2015-2020)11.2 Autologous Stem Cell Based Therapies Key Players in India (2019-2020)11.3 India Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)11.4 India Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 12 Central & South America12.1 Central & South America Autologous Stem Cell Based Therapies Market Size (2015-2020)12.2 Autologous Stem Cell Based Therapies Key Players in Central & South America (2019-2020)12.3 Central & South America Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)12.4 Central & South America Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 13 Key Players Profiles13.1 Regeneus13.1.1 Regeneus Company Details13.1.2 Regeneus Business Overview13.1.3 Regeneus Autologous Stem Cell Based Therapies Introduction13.1.4 Regeneus Revenue in Autologous Stem Cell Based Therapies Business (2015-2020))13.1.5 Regeneus Recent Development13.2 Mesoblast13.2.1 Mesoblast Company Details13.2.2 Mesoblast Business Overview13.2.3 Mesoblast Autologous Stem Cell Based Therapies Introduction13.2.4 Mesoblast Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.2.5 Mesoblast Recent Development13.3 Pluristem Therapeutics Inc13.3.1 Pluristem Therapeutics Inc Company Details13.3.2 Pluristem Therapeutics Inc Business Overview13.3.3 Pluristem Therapeutics Inc Autologous Stem Cell Based Therapies Introduction13.3.4 Pluristem Therapeutics Inc Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.3.5 Pluristem Therapeutics Inc Recent Development13.4 US STEM CELL, INC.13.4.1 US STEM CELL, INC. Company Details13.4.2 US STEM CELL, INC. Business Overview13.4.3 US STEM CELL, INC. Autologous Stem Cell Based Therapies Introduction13.4.4 US STEM CELL, INC. Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.4.5 US STEM CELL, INC. Recent Development13.5 Brainstorm Cell Therapeutics13.5.1 Brainstorm Cell Therapeutics Company Details13.5.2 Brainstorm Cell Therapeutics Business Overview13.5.3 Brainstorm Cell Therapeutics Autologous Stem Cell Based Therapies Introduction13.5.4 Brainstorm Cell Therapeutics Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.5.5 Brainstorm Cell Therapeutics Recent Development13.6 Tigenix13.6.1 Tigenix Company Details13.6.2 Tigenix Business Overview13.6.3 Tigenix Autologous Stem Cell Based Therapies Introduction13.6.4 Tigenix Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.6.5 Tigenix Recent Development13.7 Med cell Europe13.7.1 Med cell Europe Company Details13.7.2 Med cell Europe Business Overview13.7.3 Med cell Europe Autologous Stem Cell Based Therapies Introduction13.7.4 Med cell Europe Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.7.5 Med cell Europe Recent Development 14 Analysts Viewpoints/Conclusions 15 Appendix15.1 Research Methodology15.1.1 Methodology/Research Approach15.1.2 Data Source15.2 Disclaimer15.3 Author Details

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Trending: Autologous Stem Cell Based Therapies 2020: Global Size, Supply-Demand, Product Type and End User Analysis To 2026 - Weekly Wall

Recommendation and review posted by Bethany Smith

Abstract

Cardiovascular disorders are still the primary cause of mortality worldwide. Although intramyocardial injection can effectively deliver agents to the myocardium, this approach is limited because of its restriction to needle-mediated injection and the minor retention of agents in the myocardium. Here, we engineered phase-transition microneedles (MNs) coated with adeno-associated virus (AAV) and achieved homogeneous distribution of AAV delivery. Bioluminescence imaging revealed the successful delivery and transfection of AAV-luciferase. AAVgreen fluorescent proteintransfected cardiomyocytes were homogeneously distributed on postoperative day 28. AAVvascular endothelial growth factor (VEGF)loaded MNs improved heart function by enhancing VEGF expression, promoting functional angiogenesis, and activating the Akt signaling pathway. The results indicated the superiority of MNs over direct muscle injection. Consequently, MNs might emerge as a promising tool with great versatility for delivering various agents to treat ischemic myocardial disease.

The American Heart Association has stated that cardiovascular disease (CVD) is the primary cause of mortality worldwide, leading to more than 17.3 million deaths per year; the number of deaths is estimated to exceed 23.6 million by 2030 (1). Thus, all potential treatment strategies to preserve left ventricle (LV) function by limiting infarct expansion and alleviating adverse remodeling are currently being investigated (2). To date, various injectable agents, including biomaterials, cells, genes, and proteins (37), have been studied and shown to have various advantages. Direct intramyocardial delivery of agents through myocardial transfection in the ischemic regions where vascular delivery procedures were excluded and the systemic administration of vectors might pose potential hazards following the procedures of myocardial revascularization was suitable (8). However, the effects of intramyocardially delivered therapeutics are restricted to the site of injection (911). Another major drawback is the minor myocardial retention of injected agents. Previous reports have demonstrated that few injected cells are retained in injured hearts, which is one of the principal reasons for the failure of cell therapy for myocardial repair (12, 13). On the other hand, all body tissues can be exposed to drugs if they accidently enter the left ventricular cavity, which can reduce therapeutic efficacy and contribute to unexpected results. Therefore, the current limitations associated with this strategy must be mitigated. Cardiac gene transfer has been considered to be a promising therapeutic tool in the field of cardiology (14, 15). Adeno-associated virus (AAV)9, a serotype with high cardiac tropism, persistent transgene expression, and low pathogenicity, has also been applied for cardiac gene therapy (16). Transgenic expression of AAVs starts from 5 to 7 days after administration, and remarkably elevated viral transfection efficiency is achieved at weeks 2 to 3. Delivered vectors continue to express their transgenes for 6 to 12 months in vivo (17, 18). AAV-mediated gene expression in vivo declines with time due to promoter shutoff and loss of AAV-transduced cells and AAV particles (19).

Microneedles (MNs) are an array of small needles, up to 1 mm in length, that provide secure channels for the passage of therapeutic substances (2, 20), especially macromolecules, without causing skin injury or pain; these macromolecules include nucleic acids in the form of genes (21), vaccines (22), and proteins (2325). The precise and efficient transfusion and homogeneous distribution of therapeutic agents delivered via MNs make MN-mediated delivery a promising new administration method for ischemic heart disease (IHD) treatment. In this study, we fabricated phase-transition MNs (PTMs) and studied their properties as well as their safety and practicality for experimental application. A schematic illustrating the overall study design using AAV-harboring MNs (MN-AAV) is shown in Fig. 1A. Figure 1B represents our practice for the application of MNs to deliver therapeutic agents via endoscopy assisted microthoracotomy surgery. A series of endoscopic images demonstrate the in vivo application of MNs to deliver therapeutic agents to the rat heart as shown in Fig. 1C. MNs loaded with fluorescent fluorescein isothiocyanate (FITC)labeled AAV (MN-FITC-AAV) and AAV containing the luciferase coding sequence (MN-AAV-LUC) enabled successful therapeutic agent delivery and gene transfection of target heart regions. AAVgreen fluorescent protein (GFP)loaded MNs (MN-AAV-GFP) enabled fine distribution of AAV particles, presenting an advantage over direct injection (DI), after which positive cells were limited in location to the injection site in vivo. Thus, MN-AAV, which allow agents to be burst-released, can achieve even distributions of agents at the target myocardium rather than confining the agents to the site of administration. Heart performance and histological examinations showed that MNs loaded with AAV vectorencoding vascular endothelial growth factor gene (MN-AAV-VEGF) could improve cardiac function, reduce scar size, ameliorate adverse remodeling, and elevate myocardial perfusion in a rat model of myocardial infarction (MI). MN-mediated gene therapy showed distinct superiority over DI and may therefore provide an alternative, minimally invasive therapeutic option for heart diseases.

(A) Ischemic hearts were administered MN-AAV with the assistance of a customized apparatus. The MNs swelled following application; consequently, the therapeutic agents were burst-released into precise regions to ameliorate cardiac dysfunction through angiogenic effects. (B) Diagram of our practice for the application of the MNs to rat heart via endoscopy assisted microthoracotomy surgery. (C) A series of endoscopic images demonstrating the application of MNs for delivery of therapeutic agents to a rat heart. Scale bars, 600 m. Photo credits: Hongpeng Shi, Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

The fabrication process of the MN patches is shown schematically in fig. S1. The prototype MN-AAV patch was 6 mm in diameter and contained 44.75 1.28 needle tips with base widths of 334 22.88 m, spacing of 465.3 39.51 m, and heights of 850 3.25 m as shown in the scanning electron microscopy (SEM) image (Fig. 2A). The representative stress-strain curves are shown in Fig. 2B (left). Uniaxial tensile tests showed that the MNs had a Youngs modulus of 13.13 1.34 MPa, while the MN-AAV had a Youngs modulus of 12.28 0.80 MPa. The Youngs modulus of the MN group was higher than that of the MN-AAV group; however, this difference was not significant (P > 0.05) (Fig. 2B). Both the MN and MN-AAV had higher moduli than the native myocardium (modulus, several tens of kilopascal), indicating that the stiffness of the MNs with or without AAV loading was sufficient to penetrate the soft myocardium.

(A) SEM images of MNs. (B) Representative stress-strain curves between the group of MNs with AAV (MN-AAV) or MNs without AAV. The histograms represent the comparison test of the two groups. n = 4 patches in each group. (C) Transitions between the dried and swollen states of the MNs. The histograms show the fold changes in MN volume between the dried and swollen stages (n = 8 MN tips, randomly selected from three patches). Photo credits: Hongpeng Shi, Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. (D) Release kinetics of MN-AAV. (E) Fluorescent images (scale bars, 500 m) and magnified images (scale bars, 250 m) indicating MNs surface-coated with FITC-AAV (green) particles and MNs without loading of FITC-AAV. (F) The three-dimensional (3D) construction images of MN-FITC-AAV. All data are reported as the means SD. NS, not significant.

The swelling capacity of the MN bodies was monitored, and volume expansion was measured and calculated using a previously published method. The mean base diameter of the swollen MN bodies among three patches was 670.5 81.63 m, 678.9 89.17 m, and 683.4 67.31 m. The mean height of the swollen MN bodies was 1704 56.75 m, 1701 73 m, and 1705 66.63 m. Measurements of total recorded MN tips in height and base diameter were 1704 64.89 m and 677.6 78.93 m, respectively, which were significantly greater than those of the MN bodies in the initial state. The transitions between the dried and swollen states of MNs are shown in Fig. 2C. Swelling led to an 8.3-fold variation, indicating that the MN tips exhibited a high swelling ratio.

Quantification of AAV release into supernatant collected after incubation at predetermined time points indicated a burst release model. A schematic of the experimental procedures performed to collect the released AAV fluid is provided in fig. S2. As shown in Fig. 2D, burst release led to increased initial AAV delivery, as follows: 90.93% of the virus was released in a 2-s period, while 92.42% of the virus was released in a 5-s period, and slower release followed the initial rapid release. Almost complete release was achieved by 24 hours. The titers of elution fluid released from MN-AAV (n = 3) were determined by real-time polymerase chain reaction (PCR), which indicated that 4.93 1010 vector genomes (vg) of AAV were loaded in each MN array. We also loaded greater amounts of AAV (the quantity of loaded AAV achieved 1011 vg) with three gradient quantities (1, 1.5, and 2; n = 4 patches in each group). The amounts of loaded AAV were calculated to be 3.14 1011 vg, 5.04 1011 vg, and 6.03 1011 vg, respectively; the fold differences of these groups were 1-, 1.69-, and 2.02-folds, respectively. Consequently, we could control the quantity of loaded vectors in each MN array by varying the amount of AAV solutions added. Furthermore, MNs exhibited outstanding drug-loading capacity.

To confirm AAV binding, we performed a critical examination of virus labeling with FITC dyes. As expected, compared with the control MNs without FITC-AAV, the AAV-loaded MNs revealed a strong fluorescence signal on the surface of the MN bodies (Fig. 2E, left and middle). Conversely, a specific fluorescence signal was absent in the control MN group (Fig. 2E, right). Ortho view (fig. S3) of a confocal laser scanning micrograph of z-stack images visualizes the MN tip as transverse section (x-y) and lateral section (x-z and y-z) views. The three-dimensional (3D) images generated by confocal microscopy confirmed that FITC-labeled AAV was successfully coated on the surface of the MN bodies (Fig. 2F). The fluorescence intensity of the fluorescent images acquired by confocal microscopy at the middle of MN bodies (400 m from the base) was measured and compared among 11 randomly selected MNs in one patch. The average optical was measured using Image-Pro Plus software to evaluate the fluorescence intensity. The fluorescence intensity was 0.1127 0.0233 with a little variation among the MNs. In addition, the intensity analysis at the middle of MN bodies among three MN patches (8 or 11 MNs were randomly selected from each patch) was measured and compared. No differences were observed among three patches (0.1127 0.0233 versus 0.1156 0.0254 versus 0.1084 0.0279, all P > 0.05 in the multigroup comparisons) (fig. S4A).

A schematic of the cell culture procedures is provided in Fig. 3A. The released vectors were tested for their infectious capacity and transgene expression in human embryonic kidney (HEK) 293 cells by flow cytometry and fluorescence microscopy. After a 3-day incubation, the distribution of GFP-positive cells was determined using fluorescence microscopy (Fig. 3B). Flow cytometry analysis revealed that 5.14% of the cells were transduced by the supernatant released from MN-AAV2-GFP (Fig. 3C). A comparison analysis of the GFP-positive cells indicated that the percentage of positive cells was significantly different between the MN-AAV2-GFP and normal control (NC) groups (P = 0.0045). We evaluated the efficiency of AAV9 transduction into HEK 293 cells between virus-containing MNs subjected to a freeze-thaw process (MN-AAV-FT) and those not subjected to a freeze-thaw process (MN-AAV-NFT). There was no difference between the MN-AAV-FT and MN-AAV-NFT groups (the relative percentage of the transduction efficiency was 97.2% versus 100%) (fig. S5).

(A) Schematic of the cell culture experimental procedures performed to investigate the cell infectivity of released AAV. (B) Representative fluorescent images of GFP-positive cells in the MN-AAV-GFP group captured under a confocal microscope. Scale bars, 100 m. DAPI, 4,6-diamidino-2-phenylindole. (C) Qualification and comparison of GFP-positive cells between normal 293 cells and AAV-GFP transfected cells as detected by flow cytometry. SSC-A, side-scatter area; FSC-A, forward-scatter area. (D) Representative images of crystal violetstained migratory human umbilical vein endothelial cells (HUVECs) on the porous membranes of Transwell inserts among the three groups and histograms of the numbers of migrated cells. Five random fields were selected for the statistical analysis. All data are reported as the means SD. **P < 0.01 and ****P < 0.0001.

The angiogenic effect of AAV-VEGF was evaluated in vitro. Endothelial cell migration is of great importance in neovessel formation; therefore, the influence of the AAV-VEGFtransfected H9C2 cell culture supernatant on human umbilical vein endothelial cell (HUVEC) migration was assessed. The assay indirectly proved that the H9C2 cells infected by MN-AAV-VEGF released vectors could secrete VEGF into the culture supernatant, which strongly stimulated HUVEC migration [179.8 6.76 per high-power field (HPF) in the H9C2-VEGF group] compared to that observed in the AAV-GFPinfected H9C2 cells (79.2 8.53 per HPF in the H9C2-GFP group, P < 0.0001) and the NC H9C2 group (80.8 9.34 per HPF, P < 0.0001; Fig. 3D).

Figure 4A briefly illustrates the procedures used to demonstrate successful AAV delivery and gene transfection mediated by MN-AAV in vivo. The precise region of the rat heart that received the methylene blueloaded MNs was imaged and dissected. A customized vacuum apparatus was used for the implantation of MN patch (Fig. 1A and movies S1, S2, and S3). As shown in Fig. 4B and movies S3 and S4, the epicardium with puncture spots and the myocardium were stained by the released dyes. Similarly, MN- FITC-AAV were used to further confirm the successful insertion of the MNs. Fluorescent images of the horizontal and vertical sections of the LV wall indicated the penetration of the MNs, which resulted in an even distribution of agents (Fig. 4C, middle) compared to the distribution in the DI group (Fig. 4C, left). The fluorescence intensity in horizontal sections of rat hearts (Fig. 4C, middle) after MN-FITC-AAV administration (n = 3 animals; 15 puncture points were analyzed in each fluorescent image) was measured, and no significant differences were observed (0.1324 0.0172 versus 0.1289 0.0207 versus 0.1337 0.0212, all P > 0.05 in the multigroup comparisons), confirming the uniformity of AAV loading (fig. S4B). In the transverse plane of the LV following MN-FITC-AAV application (Fig. 4C, right), the penetration depth of MNs into the LV wall was approximately 1000 m.

(A) Schematic illustrating the study design, involving the MN application in this section. (B) Confirmed insertion of methylene blueloaded MNs into the myocardium. The black arrow denotes an area of methylene bluestained myocardium. Photo credits: Hongpeng Shi, Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. (C) Representative fluorescent and hematoxylin and eosin (HE) images of LV walls that received DI of FITC-AAV and MN-FITC-AAV. The LV wall was cryosectioned horizontally (n = 3 animals per group; scale bars, 500 m) or transversely (scale bars, 400 m) for the MN-FITC-AAVtreated hearts. The dashed line denotes the shape of MN-FITC-AAV following application. (D) Representative echocardiographic images and left ventricular function parameters between the MN and NC groups. The data are presented as the means SD; n = 3 animals per group. (E) Representative images of bioluminescence (n = 5 animals per group) and Western blot (WB) assay results (n = 3 animals per group) 4 weeks following MN application. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. (F) Representative fluorescence micrographs showing the spatial distribution of GFP-positive cells (green) in the MN-AAV-GFP and DI-AAV-GFP groups at day 28. Cardiomyocytes were identified by anti-cTnT (cardiac troponin T) antibodies (red); nuclei were stained with DAPI (blue). n = 5 animals per group. Scale bars, 200 m. Separated and merged distribution data of fluorescent signals between the MN-AAV-GFP and DI-AAV-GFP groups are presented. All data are reported as the means SD.

Inflammatory staining was performed on sections from hearts subjected to MN-AAV and DI-AAV treatments to reveal signs of tissue inflammation. Normal rats were used as controls. We quantified CD68-positive inflammatory cell infiltration and found that the tissue densities of CD68-positive cells were indistinguishable among the three groups (P > 0.05) (fig. S6). In addition, we examined the heart performance of rats that underwent MN administration, which also confirmed the safety of the MN patch. The echocardiographic results indicated that MN application did not induce any functional impairment. Ejection fraction (EF), fractional shortening (FS), left ventricular systolic inner diameter (LVIDs), and left ventricular diastolic inner diameter (LVIDd) values were recorded and compared to those of normal rats (all P > 0.05) (Fig. 4D).

To trace the expression of luciferase delivered by MN-AAV-LUC in living animals 4 weeks after MN-AAV administration, we applied a noninvasive small animal bioluminescence imaging system with high sensitivity. As shown in Fig. 4E (top), the AAV-LUC vectors transfected the target myocardium, resulting in high levels of luciferase expression in the heart, while no bioluminescence signals were detected in NC rats. In addition, proteins were extracted from the MN-AAV-LUC and NC groups, and an antifirefly luciferase antibody was used to detect the expression in Western blot (WB) assays (Fig. 4E, bottom), which indicated successful AAV delivery into and transfection of the myocardium.

To characterize the distribution of gene expression mediated by MN patches or DI, we analyzed rats that were subjected to gene delivery with AAV vectors encoding a GFP reporter gene. GFP-positive cells were detected in the anterior wall of the LV. The distribution of gene expression following the MN application was marked by an almost even distribution (Fig. 4F, top). In contrast, in the DI group, as described in previously published studies, the transfected cardiomyocytes were mainly confined to the site of the injection (Fig. 4F, middle). The distribution of fluorescent signals at five randomly selected horizontal lines in the fluorescent images was measured by ImageJ software (ImageJ 1.47v, National Institutes of Health). The results were plotted and fitted with OriginPro 8.5 software (OriginLab Corp., Northampton, MA, USA). The fluorescent signals were scattered evenly in the MN-AAV-GFP group, while in the DI-AAV-GFP group, the signals were confined to a specific region (Fig. 4F, bottom). The merged images of the two groups vividly demonstrated the variation in the distributions. No GFP-positive cells were found in the organs of lungs, kidneys, liver, or skeletal muscles, as shown in fig. S7. As indicated by representative in vivo images, no luciferase signals were observed in the defined organs, as shown in Fig. 4E (top).

To assess variations in cardiac function, we measured EF, FS, LVIDs, and LVIDd by echocardiography 2 days after left anterior descending coronary artery (LAD) ligation (baseline data) and 4 weeks after MN application (end point data). The study design for the AAV-VEGF treatment via MNs is illustrated in Fig. 5A. The parameters of the four groups (the MI, MI + MN, MI + DI-VEGF, and MI + MN-VEGF groups) measured at baseline did not differ significantly, indicating equivalent heart performance (fig. S8). Twenty-eight days after MN application, the rats with MI that received MN-VEGF had the greatest EF and FS values and the smallest LVIDs and LVIDd values (Fig. 5B and fig. S9A). EF was improved in the MN-AAV-VEGF group compared with the DI-AAV-VEGF (36.10 5.25% versus 30.29 2.10%, P = 0.042), MI (36.10 5.25% versus 24.28 4.34%, P = 0.0003), and MI + MN (36.10 5.25% versus 24.03 5.87%, P = 0.0002) groups. The MI + MN-VEGF group showed greater FS (18.28 2.97%) than the DI-AAV-VEGF group (15.04 1.05%, P = 0.0034), the MI + MN group (11.76 3.05%, P = 0.0002), and the MI group (11.93 2.27%, P = 0.0002). LVIDd and LVIDs in the MN-AAV-VEGF group were significantly lower than those in the MI group (LVIDd, 9.12 1.09 mm versus 10.55 0.69 mm, P = 0.0179; LVIDs, 7.59 1.01 mm versus 9.33 0.81 mm, P = 0.0048). The absolute changes in heart function (EF and FS) are shown in Fig. 5B. The MI and MI + MN groups showed significantly worse cardiac function in terms of the two parameters than the DI-AAV-VEGF and MI + MN-VEGF groups (EF, 18.77 2.36% in the MI group versus 6.07 4.63% in the MI + MN-VEGF group, P < 0.0001; FS, 9.97 1.25% in the MI group versus 3.14 2.48% in the MI + MN-VEGF group, P < 0.0001). Compared with the DI-AAV-VEGF, MI, and MI + MN groups, the MN-AAV-VEGF group showed a lack of significant change in cardiac function. Thus, MN-mediated VEGF expression improved cardiac function.

(A) Schematic illustrating the study design involving MN-AAV-VEGF application and improvement of injured heart function. (B) Representative echocardiographic images of the experimental groups 4 weeks following MN application. Left ventricular function parameters (EF, FS, LVIDs, and LVIDd) and absolute changes in heart function (EF and FS) were also measured and compared among the three groups. n = 6 animals per group. (C) Representative Massons trichromestained myocardial sections 4 weeks after MN-AAV-VEGF application. The scar areas and infarct sizes were quantified on the basis of Massons trichromestained images. Scale bars, 1 mm. (D) Identification of collagens via picrosirius red staining among the three groups. Scale bars, 1 mm. Representative polarized light images of the picrosirius redstained sections were subjected to polarized light microscopy. Scale bars, 100 m. Histograms showing the comparisons of collagen content and the type I/type III collagen ratios among the three groups. Right: Representative fluorescence micrographs identifying type I collagen (green) and type III collagen (red); the nuclei were stained with DAPI (blue). n = 3 animals per group. Scale bars, 500 m. All data are reported as the means SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.

The infarction size and scar area were measured according to our previously described methods (26). Massons trichrome staining and magnified images revealed the morphology and fibrosis of heart tissues (Fig. 5C and fig. S9B). Compared to those in the MI and MI + MN groups (10.04 0.94 mm2 and 9.92 1.54 mm2, respectively), the scar areas (Fig. 5C, bottom) in the MI + MN-VEGF group (7.02 0.85 mm2) and the MI + DI-VEGF group (8.47 0.82 mm2) were effectively controlled by MN-VEGF application (fig. S9B). There were significant differences between the MI + MN-VEGF group and the control group (MI + MN-VEGF versus MI, P = 0.0004; MI + MN-VEGF versus MI + MN, P = 0.0006; MI + MN-VEGF versus MI + DI-VEGF, P = 0.049). In addition, the infarct size (Fig. 5C, bottom) was not different between the MI (71.27 8.37%) and MI + MN (68.86 3.25%) groups (P = 0.6187). The infarct size was reduced in the AAV-VEGFtreated groups (56.48 5.64% in the MI + DI-VEGF group and 46.17 10.68% in the MI + MN-VEGF group) (P < 0.0001 in the MI + MN-VEGF group compared with the MI group, P = 0.0002 in the MI + MN-VEGF group compared with the MI + MN group, and P = 0.00458 in the MI + MN-VEGF group compared with the MI + DI-VEGF group).

Picrosirius red staining combined with polarization microscopy was used to examine collagen fibers and to quantitatively determine their levels and types in scars in the four groups (Fig. 5D, left, and fig. S9C). Type I collagen was identified by yellow or red staining, and type III collagen was indicated by green staining under polarized light. The total collagen content in the infarcted region was similar among the groups, indicating no difference in collagen deposition (61.42 10.24% in the MI group, 58.97 11.83% in the MI + MN group, 60.16 3.86% in the MI + DI-VEGF group, and 58.97 11.83% in MI + MN-VEGF group, all P > 0.05). Moreover, the ratio of type I to type III collagen (type I/type III) was increased in the MI and MI + MN groups (3.63 3.79% versus 2.99 4.64%, P > 0.05). However, the ratio in the MI + MN-VEGF group (1.11 1.24%) was lower than those in the MI and MI + MN groups (P < 0.05). The ratio in the MI + DI-VEGF group (1.89 1.44%) was slightly higher than that in the MI + MN-VEGF group; however, this difference was not statistically significant (P = 0.2254). In addition, costaining of sections with type I (green) and type III (red) collagen antibodies was used for visualization of the collagen types (Fig. 5D, right, and fig. S9C).

To investigate the angiogenic and arteriogenic effects of MN-VEGF in the border zone and infarction region, we used antibodies against von Willebrand factor (vWF) and -smooth muscle actin (SMA) to stain endothelial cells and vascular smooth muscle cells, respectively. Tubular structures stained by fluorescent antibodies were identified as vessels. The capillary density was estimated on the basis of the vWF-positive vessels per HPF, and the arterial density was evaluated on the basis of SMA-positive vessels per HPF using the data collected at 4 weeks. The mature index was quantified as the ratio of SMA-positive vessels to the total number of vessels (27). As illustrated in Fig. 6B and fig. S9D, in the infarction region, the capillary density in the MI group was identical to that in the MI + MN group (8.33 1.51 per HPF versus 8.33 1.97 per HPF, P > 0.05). However, the value in the MI + MN-VEGF group (39.67 11.15 per HPF) significantly differed from that in the MI (P < 0.0001), MI + MN (P < 0.0001), and MI + DI-VEGF (25.83 5.19 per HPF, P = 0.0011) groups. Regarding the capillary density in the border zone, no difference was found between the MI and MI + MN groups (14.17 1.72 per HPF in the MI group and 14.17 2.40 per HPF in the MI + MN group, P > 0.05). The capillary density in the MI + MN-VEGF group was 72.67 13.46 per HPF (P < 0.0001 compared to those in the MI and MI + MN groups and P = 0.0002 compared to that in the MI + DI-VEGF group). The arterial density was compared as shown in Fig. 6B and fig. S9D. Compared to the MI + MN-VEGF group (38.83 9.77 per HPF, all P < 0.0001), the MI and MI + MN groups (3.83 1.72 per HPF in the MI group and 3.67 1.03 per HPF in the MI + MN group, P > 0.05) showed decreases of 90% in the infarction region. In addition, the arterial density of the MI + MN-VEGF group was significantly higher than that of the MI + DI-VEGF group (24.50 4.85 per HPF, P = 0.0012). In the border region, the arterial density was 6.67 2.50 per HPF in the MI group and 7.17 2.23 per HPF in the MI + MN group (P > 0.05). In the MI + MN-VEGF group, the arterial density was 66.83 12.86 per HPF (P < 0.0001 compared to those in the MI and MI + MN groups and P = 0.0025 compared to that the MI + DI-VEGF group). As shown in Fig. 6B and fig. S9D, the mature index in the infarction region was 36.55 11.60% in the MI group and 37.40 10.53% in the MI + MN group, with no difference between the two groups. In the MI + MN-VEGF group, the value was 86.3 1.67%, which was better than that in the MI (P < 0.0001), MI + MN (P < 0.0001), and MI + DI-VEGF (83.88 5.41%, P > 0.05) groups. No significant difference in the mature index was observed between the MI + MN-VEGF (85.20 4.46%) and MI + DI-VEGF (84.53 6.24%, P > 0.05) groups. The mature index in the MI + MN-VEGF group was markedly greater than that in the MI (39.97 13.85%) and MI + MN (41.73 9.23%) groups (all P < 0.0001). No significant differences in serum VEGF levels were detected at various time points between the MN-VEGF and MI groups (all P > 0.05) (Fig. 6C). The samples were measured in duplicate.

(A) Representative immunofluorescent images of vWF (green) and SMA (red) in the tissues of the infarction and border region showing increased vessel density in the MN-AAV-VEGF group compared with those in the other two groups. n = 3 animals per group. Scale bars, 50 m. Vessels are indicated by white triangles. (B) Quantification of capillary density, arterial density, and the mature index among the three groups in the infarction and border regions. (C) VEGF levels were detected by enzyme-linked immunosorbent assay (ELISA) in serum from the MI + MN-VEGF and MI groups. n = 3 animals per group. (D) Representative WB results for VEGF, VEGF receptor (VEGFR), phosphoinositide 3-kinase (PI3K), Akt, phosphorylated Akt (p-Akt), and caspase-9 in heart homogenates from the MI + MN-VEGF and MI groups. n = 3 animals per group. The bar graphs show the quantified protein levels. All data are reported as the means SD. *P < 0.05 and ****P < 0.0001.

The binding of VEGF to VEGF receptor 2 (VEGFR2) leads to the activation of diverse intracellular extracellular signaling pathways. WB analysis (Fig. 6D) showed that VEGF and VEGFR2, the high-affinity receptor of VEGF, were significantly up-regulated (all P < 0.05). The Akt and phosporylated Akt protein levels in AAV-treated hearts were significantly higher than those in non-AAVtreated MI hearts (all P < 0.05). The protein level of phosphoinositide 3-kinase (PI3K) in the MI + MN-VEGF group was increased, although the difference was not significant (P > 0.05). The level of the proapoptotic protein caspase 9 was significantly decreased in the MI + MN-VEGF group (P < 0.05).

CVD is the primary cause of mortality worldwide (28). Intramyocardial injection of therapeutic agents is a treatment strategy for patients suffering from this disease (29). Although local injection is a commonly used administration method to deliver agents to the myocardium, the effects are inevitably restricted to the injection site (911), which is attributed to the localized high concentrations of the agents. In addition, unlike in other organs, the injected agents can be extruded from the myocardium due to continuous dynamic muscle contraction. As reported in the published literature, a primary obstacle to cell therapy is the extremely low rate of myocardial retention after intramyocardial injection (13). It has been reported that almost 5 to 15% of intramyocardially injected cells are retained within the myocardium (30, 31); thus, only a fraction of injected cells contribute to therapeutic benefit. Development of new types of instruments and technologies to overcome this disadvantage is desperately needed. Figure S10 represents our vision for the clinical translation of MNs, in which MNs will be used to deliver therapeutic agents via a small thoracic incision to decrease the risk of infection induced by open-heart surgical procedures. Different from traditional approach of gene delivery, we developed an MN-AAV to deliver target gene into the myocardium. Coronary artery revascularization [percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG)] is an established therapeutic intervention. However, myocardial revascularization for ischemic regions with small coronary arteries remains a challenge in clinical practice. Gene therapy to improve vascular perfusion of those ischemic regions might be a promising alternative choice, especially for patients with IHD who are not candidates for PCI or CABG. In addition, because of the poor gene transfer efficiency in the myocardium and the inability of the therapy to target ischemic myocardium, the transduction efficiency was reduced. Thus, delivering MNs via less invasive surgeries repeatedly might improve the efficiency of gene transfection.

Angiogenic gene therapy for IHD is a promising option for the treatment of MI (32, 33). VEGF is important for the development and differentiation of the vascular network, with favorable preclinical evidence showing that it notably increases perfusion, improves tissue metabolism, improves cardiac function, and provides cardiac protection. However, intracoronary administration of VEGF protein has not yielded much clinical success (34). The principal limitation of administration of this protein is the short half-life of exogenous proteins in target tissue, which reduces the therapeutic benefit (35). To prolong the effects of angiogenic cytokines, recombinant plasmid DNA and viral vectors can be used, which allow for the consistent replication of the VEGF gene and maintain long-lasting protein expression in transfected cells. A series of studies have demonstrated improvement in rodent and large-animal (dog, sheep, and pig) models of ischemia and infarction following gene therapy with VEGF (3638). Similar results were obtained in our study. MN-AAV-VEGF ameliorated cardiac dysfunction in a rat model of MI. Therefore, the application of proangiogenic substances may be a new treatment option for patients with IHD. However, the results have not been very promising except for safety; follow-up conducted for over 10 years has indicated that there are no significant transgene or vector-related side effects (39).

On the other hand, previously published research has reported that high levels of circulating VEGF in acute MI can induce acute cor pulmonale, resulting in increased mortality (40). Unregulated and continuous expression of VEGF has been reported to lead to angioma formation at the site of injection (33, 41). However, in the future, cardiomyocyte-targeted viruses and improved gene transfection efficiency may enable the delivery of AAV vectors at low starting doses through repeated administration to control the expression of angiogenic factors. Furthermore, the side effects caused by VEGF overexpression might be ameliorated by regulation of gene expression, such as through gene switching, and other therapeutic approaches, such as antiangiogenic therapy using anti-VEGF antibodies. The management of angiogenic factor expression in both serum and target regions is important for enhancing the local therapeutic efficiency of this method and decreasing possible adverse effects (32). Consequently, careful application-specific consideration is warranted when selecting a processing strategy that minimizes unwanted responses.

To overcome difficult obstacles associated with the DI mode of agent administration, we fabricated MN-AAV to deliver the VEGF gene to rat hearts, which led to optimal distribution and local therapeutic efficiency. In addition, the coated vectors instantly penetrated into the myocardium, thus improving the retention of the delivered drugs, which indicated a better therapeutic effect in the MI + MN-VEGFtreated group than in the MI + DI-VEGF group. No significant differences in VEGF levels were detected at various time points between the MI + MN-VEGF and MI groups (Fig. 6C), similar to the results of experiments using large-animal models (32). In addition, no GFP or luciferase expression was detected in other organs (fig. S7 and Fig. 4E).

Versatile MN patches were fabricated according to our previously reported method (20) and were eventually machined into the desired sizes to achieve various characteristics, including sufficient strength to penetrate the target myocardium (Fig. 4B), water-swelling capacity (Fig. 2C), high drug-loading capacity, drug-loading uniformity (fig. S4), and therapeutic burst release kinetics (Fig. 2D). The phase transition capability allows efficient drug diffusion from a drug reservoir through a polymeric matrix with predictable accuracy (42). Researchers have long sought to control and overcome the burst release of agents during the application of MNs (43). However, this shortcoming was effectively used to deliver agents to the myocardium in this study. The intrinsic properties of the MNs and the modified AAV harboring approach resulted in a unique kinetic profile characterized by enhanced AAV delivery with predictable accuracy and early burst release kinetics. Extended release behavior in vitro was detected and confirmed by the AAV tilter assay (Fig. 2D). Combined with in vivo studies (Figs. 5 and 6), AAV-VEGFloaded MN can effectively ameliorate cardiac functions, reduce the scar size, and elevate myocardial perfusion in rat MI model, which suggested that MN-mediated gene delivery to targeted heart regions. Considering that we developed an MN-AAV to deliver gene vectors to repair injured myocardium and the isolated rat heart will suffer various pathophysiologic alterations after being removed from the living body, it is hard to simulate the complicated situations in the body by using Franz diffusion cells. Consequently, the release experiment by using Franz diffusion cell involved heart tissue is not conducted in our study. In addition, researchers have reported that the drug release results obtained using phosphate-buffered saline (PBS) and Franz diffusion cell were comparable (4446), indicating that these two experiments may be equivalent in representing the release profile of MNs. Regarding AAV loading, specific fluorescence imaging was absent in the control MNs, conversely, the surfaces of the` MN-FITC-AAV revealed a strong fluorescence signals (Fig. 2E), and the fluorescence intensity of MNs was identical among different patches, indicating the uniformity of drug loading in the MNs. In addition, the 3D images constructed by confocal microscopy confirmed that FITC-AAV was successfully and uniformly coated onto the surfaces of the MN bodies (Fig. 2F).

Hematoxylin and eosin (HE) staining of sections from hearts subjected to MN treatment revealed no signs of tissue necrosis, as shown in the representative sections. Although the wound area was relatively larger, the pinhole produced by each MN was quite small, and the tissue around each pinhole was not damaged (Fig. 4C). These results demonstrated that the wounds on the hearts might be acceptable and might self-heal after a period of time. Whether application in the hearts of large animals will result in any damage needs to be further studied. The inflammatory staining of the heart sections and the unaffected performance of the hearts treated with the MNs further confirmed the safe application of MNs (Fig. 4D and fig. S6). Previous research has suggested that MNs serve as channels connecting the patch and the host myocardium. For example, MN-loaded cardiac stem/stromal cells can secrete paracrine elements to treat injured hearts with good biocompatibility in rats (2). The spatial distribution of gene transfer mediated by MNs was also evaluated in this study. GFP-positive cells were detected and well distributed in the anterior wall of the LV after MN treatment (Fig. 4F, top). In contrast, in the DI group (Fig. 4F, middle), as described in previously published studies, the transfected cardiomyocytes were confined to the site of the injection (9, 10). MNs mediated gene delivery to the myocardium with a fine distribution and strong targeting precision. Analysis of MN-FITC-AAV and methylene bluestained MNs further confirmed the successful delivery of the released dyes and AAV particles into the myocardium with a homogeneous distribution (Fig. 4, B and C, and movies S3 and S4). The composite image of the in vivo imaging results also confirmed the targeted delivery of and transfection with the AAV-LUC vectors (Fig. 4E).

Given the safety and good distribution of MNs, we investigated the practicability of MN-mediated delivery of therapeutic agents, namely, AAV-VEGF, to the myocardium to treat injured hearts. First, the angiogenic effect of AAV-VEGF was tested in vitro. The HUVEC migration assay indicated that the culture medium of VEGF-transfected H9C2 cells had a powerful influence on the migration of HUVECs (Fig. 3D). The stimulation is an important step in neovessel formation (47). Then, MN-VEGF was used to treat the injured hearts. The echocardiographic results revealed significantly higher EF and FS values and significantly lower LVIDs and LVIDd values in the MN-VEGF group than in the DI-VEGF group and the other two control groups (Fig. 5B and fig. S9A), indicating functional improvement. No significant differences were observed in cardiac function between the MI and MI + MN groups. Significant decreases in the scar area and infarct size were observed in the MI + MN-VEGFtreated group, which showed outcomes superior to those in the three control groups (Fig. 5C). The increased expression of type I and type III collagen in infarcted zones has been suggested to protect hearts from remodeling and dilation (48). Although the differences among the four groups in total collagen content were not statistically significant, the ratio of type I to type III collagen was greater in the control groups than in the MI + MN-VEGFtreated group (Fig. 5D and fig. S9C), showing that the application of MN-VEGF modified the composition of collagen in the infarct scars (predominantly favoring type III collagen). Type III collagen confers elasticity and increases compliance (48), which might lead to the improvement of heart function.

Several studies have reported that VEGF expression improves cardiac function through the induction of angiogenesis (32, 49). Similar results were obtained in our study. As illustrated in Fig. 6A, compared with those in the control groups, the capillary and arterial densities in the scar tissue and border region were significantly increased in the MI + MN-VEGF group, which exhibited an elevated mature index. As previously reported, various signaling pathways, including the PI3K/Akt kinase pathway, were activated by the binding of VEGF to VEGFR, which can preserve cardiac performance (50). Consistent with the results from WB analysis of heart homogenates, the levels of many prosurvival proteins and a few proapoptotic proteins significantly differed in MI + MN-VEGFtreated hearts compared to MI hearts at 4 weeks after MN-VEGF application, indicating that signal transduction pathways were activated by the overexpression of VEGF (Fig. 6D).

This study has several limitations. First, the therapeutic effects of MN-VEGF were evaluated for 4 weeks in this study. In the future, longer time points should be used to determine the roles of MN-VEGF in regulating cardiac function. Second, to further broaden the clinical application of MNs, in vivo studies with large-animal models incorporating MN administration via minimally invasive surgery should be investigated.

In summary, we developed an AAV-loaded MN patch and showed that transepicardial permeation resulted in a homogeneous distribution of agents against direct local intramyocardial injection (after which the agents were confined to the site of injection). Our present study supports the practicality, safety, and versatility of MNs for delivery of therapeutic agents via minimally invasive surgery. This is a proof of concept study supporting translation to clinical applications.

The MNs were prepared according to our previously described method (20). These MNs are made of polyvinyl alcohol (PVA) and are not degradable. They will swell and dissolve after 6 months. The PVA can form microcrystalline domains as cross-linking junctions to produce a PTM patch. The PTM achieves highly efficient delivery of drugs and carriers without depositing the needle tip materials into the body. Briefly, patches were prepared with an air-permeable but water-impermeable mold. A vacuum was applied to the back to suck the aqueous PVA solutions into the holes within the mold. Then, a freeze-thaw process was conducted to form microcrystalline domains to enhance the mechanical strength of the MNs. Drying and punching processes were used after detaching the MNs from the molds (fig. S1). The mechanical properties of the MNs with or without AAV loading were assessed by a universal testing machine (MTS Echo, Exceed 40, USA) equipped with Test Suite TW software and a 100-N loading cell (51). In the compression assay, every patch was compressed to a strain of 20% at a rate of 10 mm/min with an initial load of 0.01 N. The compressive modulus was automatic calculated according to the GB/T 1041-2008/B/0 standard in the machine program. The differential strain (2 1) was 0.0025. A series of modulus was calculated at each point with strain of 0 to 20% and then was linearly fitted to obtain compressive modulus (n = 4 patches in each group). For testing and comparison of the swelling capability of the MNs, MN patches were immersed in PBS and incubated at 37C for at least 1 day until completely swelled; then, the MNs were photographed and measured. At least three measurements were taken, and mean values were reported. The fold change in the tip volume, which was based on the presumption of a conical shape, was calculated to reveal the phase-transition capability of MNs (52).

MN patches of the desired size (6 mm in diameter) were obtained with a punch. The patches were pierced through enlarged Parafilm (Parafilm M laboratory film) membranes (53). AAV9 vectors with cytomegalovirus (CMV) promoters containing the gene sequence for VEGF165 (AAV-VEGF) or GFP (AAV-GFP) alone were constructed by Shanghai GeneChem Co. Ltd. (Shanghai, China). An AAV9 vector with a CMV promoter containing the gene sequence for LUC (AAV-LUC) and an AAV2 vector with a CMV promoter containing the gene sequence for GFP (AAV2-GFP, which was used to assess the efficiency of transgene expression in vitro) were constructed by Hanbio (Shanghai, China). The AAV-containing solutions (~5 1010 vg) were dispensed to the patches and absorbed by the MN bodies. After completely drying in a customized low-temperature dryer, the film was peeled. The MN-AAV was used in in vitro and in vivo studies.

AAV was labeled with FITC (Thermo Fisher Scientific) according to a labeling protocol and a published paper (54). A Slide-A-Lyzer dialysis cassette (Slide-A-Lyzer Dialysis Cassette Kit, Invitrogen; 3.5K molecular weight cutoff, 3 ml) was applied to separate the unconjugated dyes. The yield of FITC conjugate was coated and immobilized onto the surfaces of the MNs with the aid of the intrinsic absorption capacity conferred by the phase-transition characterization.

MN patches were affixed to the inner caps of 1.5-ml Eppendorf microcentrifuge tubes filled with PBS. The tubes were inverted and incubated in a thermostatic shaker (37C with shaking at 100 rpm). The elution fluid was centrifuged to draw the solution from the cap to the base of the tube at 300g and collected at 2 s, 5 s, 10 s, 60 s, 100 s, 2 min, 6 min, and 1 day. Equal quantities of AAV were also detected as NCs. A scheme of these procedures is provided in fig. S2. In the published literature, real-time PCR has been applied to determine AAV titers (55). A real-time PCR assay of serial dilutions of plasmid vector standards and collected samples was performed in a Roche LC96 machine. The samples were preincubated at 95C for 3 min and then subjected to 40 cycles of 94C for 30 s (denaturation), 62C for 30 s (annealing), and 72C for 30 sec (amplification). The data were recorded as cycle threshold (Ct) values. Ct values are linearly correlated with the copy numbers of the templates in the exponential phase (55). The formula of the standard curve between the Ct value and the viral genome copy number was acquired from the standard samples. The titers of the released vectors in the samples were calculated according to the formula. The cumulative percentages of released vectors at different time intervals were calculated by dividing the values of the AAV quantity in the control group. The detection of each sample was performed in triplicate. In addition, the assay was repeated three independent experiments, and the mean values of each time point were used for graph plotting (Fig. 2D).

HEK 293 cells were cultured in Dulbeccos modified Eagles medium (Gibco, 11965092) supplemented with 10% fetal bovine serum (Gibco, 10270-106) and 1 penicillin-streptomycin (Gibco, 15070-063). Subconfluent 293 cells were seeded on the bottoms of the wells (Transwell culture inserts, pore size of 8 m; Corning, 3422). Virus-containing MNs (n = 3, each MN patch contained ~5 1010 vg AAV2-GFP) were placed on the filter inserts and incubated in medium for 1 hour (Fig. 3A). The percentages of 293 cells transfected by the released AAV2-GFP vectors were determined by flow cytometry of 10,000 cells (Beckman Coulter). In addition, mounted 293 cells grown on cleaned coverslips in cell culture dishes were imaged using fluorescence microscopy. We evaluated the transduction efficiency of MN-AAV before and after the freeze-thaw process. Subconfluent 293 cells were seeded on the bottoms of the wells. Virus-containing MNs (subjected and not subjected to the freeze-thaw process; n = 5 in each group) were placed on the filter inserts. After a 3-day incubation, the percentages of GFP-positive cells were determined by flow cytometry.

The culture supernatants of H9C2-VEGF cells transfected with released AAV-VEGF vectors and control groups (NC H9C2 cells and AAV-GFP transfected H9C2 cells) were collected. For migration assays, HUVECs (1 105 cells) in 200 l of culture medium without serum were added to Transwell inserts (Transwell culture inserts, pore size of 8 m; Corning, 3422), and 800 l of culture supernatant from each of the three groups was added to the lower Transwell chamber. The HUVECs were cultivated in a cell culture incubator for 20 hours. The cells were then fixed in methanol and stained with crystal violet solution (0.5%) at room temperature for 30 min. Cotton swabs were used to remove nonmigrated cells. The experiment was performed in triplicate. The transmigrated cells were photographed (200 magnification) with a Nikon Digital Sight DS-U2 (Nikon, Tokyo, Japan) camera attached to an Olympus BX50 microscope (Olympus Optical Co. Ltd., Tokyo, Japan). The total migrated HUVECs were quantified in five randomly selected HPFs. The HUVECs were purchased from the Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences. The H9C2 cells were purchased from the American Type Culture Collection (CRL1446, cardiac myoblasts from rats).

Sprague-Dawley rats (male, 200 to 250 g) were obtained from the Shanghai Laboratory Animal Center. All procedures used in the study conformed to the Guide for the Care and Use of Laboratory Animals and were under the supervision of the Shanghai Jiao Tong University Institutional Animal Care and Use Committee. The Sprague-Dawley rats were anesthetized through intraperitoneal injection of pentobarbital sodium (30 mg/kg) and intubated with cannulas connected to a rodent ventilator. We previously applied MN patches to the skin by pressing with a thumb (at a force of 2.0 to 2.5 kg) (20). However, exertion of this heavy pressure to fix MNs on rat hearts while they are beating at 500 beats/min is difficult. Thus, a customized apparatus that operates via a principle similar to that of off-pump coronary aortic bypass grafting stabilizers (which provide stability during coronary revascularization surgery in patients suffering from CVD) was used for MN implantation (Fig. 1, A and C, and movies S1 and S3). The customized apparatus was a cylindrical conducting cavity with a backing plate. The inner and outer diameters were 9.2 and 10.3 mm, respectively. The inside cavity was 2.2 mm in height. An orifice (2.7 mm in diameter) was located in the center of the backing plate and was attached with a suction tube to a suction source. The MNs were attached to the backing plate with adhesive tape. There was a small gap (1.0 mm) between the hard backing of the MNs and the backing plate to ensure the patency of the cavity. When suction was provided, the targeted myocardial region entered the cavity of the customized apparatus. Consequently, MNs were passively and completely inserted into the soft myocardium. After stopping the supply of suction, the MNs detached from the backing plate and were maintained on the surface of the epicardium for 6 min. The negative pressure was ~8 kPa (~60 mmHg) at the time of MN application. The suction intensity (~400 mmHg) applied to immobilize beating hearts during coronary artery bypass surgery is clinically safe and does not cause myocardial damage (56). In the DI group, 50 l (~5 1010 vg) of AAV-GFP and AAV-VEGF, the same quantity of virus as that used in the MN-AAV group was injected into the left anterior wall in three equal aliquots using a 27-gauge needle via three injections into the predesignated area (57). The success of LAD ligation, which was used to induce the MI model, was confirmed by regional cyanosis of the anterior LV and an increase in the ST segment in the electrocardiogram (26). MN and MN-VEGF were implanted following MI. Echocardiographic measurements were taken for the four groups (the MI, MI + MN, MI + MN-VEGF, and MI + DI-VEGF groups) 2 days and 4 weeks after surgery. Isoflurane anesthesia was used to perform standard transthoracic echocardiography using an ultrasound imaging system (Vevo 2100 Imaging System, Visual Sonics, Toronto, ON, Canada). To assess cardiac function, echocardiographic data, including EF, FS, LVIDs, and LVIDd values, were collected and analyzed.

Methylene blue and FITC-AAVloaded MNs were used to confirm the insertion of the MNs following application to target heart regions in vivo. For analysis of MN insertion, the delivery of methylene blue and FITC-AAV to precise regions of the heart was assessed by observing and quantifying the puncture spots in the epicardium and heart sections. MN-AAV-LUC were applied to the left anterior wall in normal rats and detected by an in vivo fluorescence imaging system after 4 weeks. The luciferase activity in the region of interest was analyzed after intraperitoneal injection of the XenoLight d-Luciferin - K+ Salt bioluminescent substrate and detection with an in vivo bioluminescence imaging system (IVIS Spectrum, PerkinElmer, Waltham, MA, USA) 10 min after the injection of substrate.

We compared the myocardial tissue density of CD68a pan-macrophage marker-positive macrophages among the MN-AAV, DI-AAV, and NC groups 7 days after the AAV vectors were delivered to the myocardium. In addition, cardiac function was measured in the rats that received the MNs, and normal rats were used as controls.

LV walls transfected with AAV-GFP and other rat organs, including the kidneys, lungs, liver, and skeletal muscles, were harvested at the end of the functional experiments, embedded, and frozen in Tissue-Tek optimum cutting temperature compound. Then, the walls were cryosectioned horizontally at an 8-m thickness, and 4% paraformaldehyde was applied to fix the heart samples for 3 days at 4C. The fixed tissues were embedded in paraffin and sectioned at a thickness of 4 m. The sections were placed onto slides and used for picrosirius red, HE, Massons trichrome, and immunofluorescence staining. WB assays were performed with standard WB techniques, as previously described (58), and the antigen-antibody reactions were visualized by enhanced chemiluminescence (Thermo Fisher Scientific, Rockford, IL, USA). The antibodies used in the current study are shown in table S1. Quantification was performed by densitometry. Independent experiments were repeated in triplicate. The tissue sections were stained with primary antibodies and then incubated with fluorescent secondary antibodies. The fluorescent images were acquired under a Zeiss LSM 700 confocal microscope or a fluorescence microscope.

For analysis of variations in serum VEGF, blood samples were collected from the MI and MI + MN-VEGF groups 0, 1, 2, 3, and 4 weeks after LAD ligation. The levels of serum VEGF were detected with an enzyme-linked immunosorbent assay (ELISA) kit for human VEGF (R&D Systems) according to a standard protocol and the manufacturers specifications. The samples were measured in duplicate.

Statistical analysis was performed using IBM SPSS software version 23.0. The data are presented as the means SD. The P values were calculated using one-way analysis of variance (ANOVA) with post hoc least significant difference multiple comparison tests to compare four groups or Students t test to compare two groups. The criterion of statistical significance was set at P < 0.05 (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001).

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: Funding: This work was supported by grants from the National Natural Science Foundation of China (81671832, 81571826, and 81690262), the Natural Science Foundation of Shanghai (18ZR1401900), the Shanghai Municipal Education CommissionGaofeng Clinical Medicine Grant Support (826158), and the Shanghai Municipal Key Clinical Specialty Construction Project. Author contributions: H.S. and T.X. contributed equally to this work. H.S., T.X., T.J., F.W., X.Y., and Q.Z. designed the research. H.S., T.X., C.J., S.H., Q.Y., and Y.Y. performed the cellular and animal experiments, analyzed the data, and drafted the paper. D.L. and Z.Y. performed the test of mechanical properties. Q.Z., X.Y., F.W., and T.J. directed and supervised the study. All authors contributed to the scientific discussions, data interpretation, and the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Microneedle-mediated gene delivery for the treatment of ischemic myocardial disease - Science Advances

Recommendation and review posted by Bethany Smith

The world is increasingly becoming aware of the various kinds of damages that the SARS-CoV-2 can cause. However, researchers from Virginia Tech have found that the relatively harmless Adenovirus can cause heart conditions, which can be as life-threatening as the one induced by COVID-19.

According to the first-of-its-kind study, adenovirus can hamper the electrical signaling pathways between cells in the heart and also impair the ability of the cell to make new communication channels. The scientists exposed heart cells to the virus and learned of the potent effects it had on them.

"This is the first time we're putting this human virus on human heart cells to see what it does in the context of infected heart muscle cells. That's the real power of this," James Smyth, lead author of the study, said.

Adenoviruses belong to a class of common viruses that cause infections in the lining of the lungs, eyes, nervous system, and urinary tract. They often give rise to coughs, fever, pink eye, and sore throats, among others. While it generally affects children, all are prone to it.

The communication between heart muscles takes place through channels called gap junctions. They are formed by proteins known as connexins. Creating a bridge between two cells, gap junctions leads to the sharing of electrical signals that aid in the rhythmic contraction of the heart muscle cells. However, gap junctions can also alert neighboring cells about viral attacks.

Through the study, the researchers intended to demonstrate that the virus hijacks gap junctions, and when it does, it can decrease the production of connexin43(a component of a gap function). This in turn interrupts the electrical system that enables regular functioning of the heart, leading to arrhythmias (irregular heartbeat), and in extreme cases, cardiac death.

The researchers designed a diagnostic technique that employed pluripotent stem cell derived-cardiomyocytes, which are skin cells that have been made to convert to heart cells. The adenovirus was then applied to the cardiomyocytes and the resulting interactions were observed.

As expected, the virus hijacked the gap junctions in order to facilitate its own replication. However, the scientists also observed something that they had not anticipated. It was noted that two distinct processes were being carried out by the virus and that it inflicted dual damage to the cell's capacity to communicate with their neighbors. "Firstly, it was rapidly closing existing channels, and secondly it was shutting down the cells' ability to make new ones," explained Patrick Calhoun, co-author of the study.

Another aspect that caught the eye of the authors was the manner in which the virus prevented the creation of connexin43 and the formation of gap junctions. A protein pathway that is conventionally associated with the making of fresh connexin, was instead made to suppress its production by the virus. "We might learn something very new about the molecular biology there that's causing that switch," Smyth said

Smyth admits that the research is bound by the limitations of extending the results to a living heart while the experiment was conducted in vitro. However, highlighting the potential value of the findings, he asserted, "Fundamental studies provide the footing for the translational research that discovers therapeutics and diagnostic methods that improve people's health."

Going beyond the sheer understanding of viral infection, the research, Calhoun emphasized, can generate new therapeutic interventions for diseased hearts. "We're essentially learning from adenovirus to find the most efficient ways to stop, rather than cause, arrhythmias," he stressed.

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Scientists Find This Relatively Harmless Virus Can Attack and Damage Human Heart - International Business Times, Singapore Edition

Recommendation and review posted by Bethany Smith

Personalized cancer test developer ArcherDX is walking away from plans to take itself public and into the arms of genetic testing company Invitae.

Earlier this month, ArcherDX announced it was filing for a $100 million Nasdaq IPObut instead it will reap a deal worth $1.4 billion, counting upfront cash, Invitae shares and future milestone payments. The two companies plan to integrate their genomics, tumor profiling and liquid biopsy technologies through one, overarching service.

"From the beginning, Invitae's goal has been to aggregate the world's genetic tests into a single platform in service of our mission to bring comprehensive genetic information into mainstream medicine. Today, we take another major step forward in that effort, Invitae co-founder and CEO Sean George said in a statement.

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The transaction begins with $325 million in cash plus 30 million shares of Invitae common stock; an additional 27 million shares are linked to milestones. The move has been approved by the boards of both companies and is expected to close within several months, the companies said.

To help carry the acquisition, Invitae has set up a strategic financing with over $400 million in commitments from investors, led by Perceptive Advisors. Invitae has agreed to sell $275 million of stock in a private placement at $16.85 a share, supported by Casdin Capital, Deerfield Management, Driehaus Capital Management, Farallon, PBM Capital, Redmile Group, Rock Springs Capital, Soleus Capital and an unnamed institutional investor.

RELATED: ArcherDX expands co-marketing, in vitro diagnostics partnerships with Illumina

Invitae has also secured a credit facility for up to $200 million with Perceptive Credit Opportunities Funds. Following the deals announcement, Invitaes stock rose nearly 50% from about $18 to over $26 a share.

We are thrilled to unite with Invitae to form the leading hub for precision oncology, diagnostics, therapy optimization and monitoring, with an opportunity to accelerate both patient care and shareholder value," said ArcherDXs co-founder and CEO Jason Myers.

ArcherDX currently counts over 325 unique products in its research services catalog and is developing in vitro cancer diagnostics with FDA submissions slated for later this year. The companys Stratafide DX and Personalized Cancer Monitoring efforts have both received breakthrough device designations from the agency.

ArcherDX also recently launched separate collaborations with AstraZeneca and Bristol Myers Squibb to apply its minimal residual disease assays to the drugmakers clinical cancer research.

RELATED: Invitae to buy DNA-counseling chatbot developer Clear Genetics for $50M

Together, the two companies aim to offer research and clinical trial support to biopharma companies as well as biomarker identification and companion diagnostic development while providing test reports, consultations and genetic counseling through Invitaes central laboratory.

"Integrating all aspects of cancer genetics can transform care for patients and the flexibility that comes from both centralized and decentralized capabilities will uniquely position Invitae to meet the needs of customers worldwide," said George. "By joining together, we will unite world-class capabilities in the hands of a talented team with complementary expertise and strong brands in service of a shared goal to improve healthcare for patients."

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ArcherDX drops IPO plans in favor of a $1.4B takeover by Invitae - FierceBiotech

Recommendation and review posted by Bethany Smith

Direct-to-consumer Genetic Testing Market 2020: Inclusive Insight

Direct-to-consumer Genetic Testing: Market Shares, Strategies, and Forecasts, Worldwide, 2017 to 2026 report is based on comprehensive analysis conducted by experienced and professional experts. The report mentions, factors that are influencing growth such as drivers, restrains of the market. The report offers in-depth analysis of trends and opportunities in the Direct-to-consumer Genetic Testing Market. The report offers figurative estimations and predicts future for upcoming years on the basis of the recent developments and historic data. For the gathering information and estimating revenue for all segments, researchers have used top-down and bottom-up approach. On the basis of data collected from primary and secondary research and trusted data sources the report offers future predictions of revenue and market share.

The Leading Market Players Covered in this Report are: 23andMe, MyHeritage, LabCorp, Myriad Genetics, Ancestry.com, Quest Diagnostics, Gene By Gene, DNA Diagnostics Center, Invitae, IntelliGenetics, Ambry Genetics, Living DNA, EasyDNA, Pathway Genomics, Centrillion Technology, Xcode, Color Genomics, Anglia DNA Services, African Ancestry, Canadian DNA Services, DNA Family Check, Alpha Biolaboratories, Test Me DNA, 23 Mofang, Genetic Health, DNA Services of America, Shuwen Health Sciences, Mapmygenome, Full Genomes.

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Impact of Covid-19 in Direct-to-consumer Genetic Testing Market: The utility-owned segment is mainly being driven by increasing financial incentives and regulatory supports from the governments globally. The current utility-owned Direct-to-consumer Genetic Testing are affected primarily by the COVID-19 pandemic. Most of the projects in China, the US, Germany, and South Korea are delayed, and the companies are facing short-term operational issues due to supply chain constraints and lack of site access due to the COVID-19 outbreak. Asia-Pacific is anticipated to get highly affected by the spread of the COVID-19 due to the effect of the pandemic in China, Japan, and India. China is the epic center of this lethal disease. China is a major country in terms of the chemical industry.

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Company Market Share Top Market Strategies Company Profiles

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Diagnostic Screening, Prenatal, Newborn Screening, and Pre-Implantation Diagnosis, Relationship Testing

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North America (United States, Canada and Mexico) Europe (Germany, France, UK, Russia and Italy) Asia-Pacific (China, Japan, Korea, India and Southeast Asia) South America (Brazil, Argentina, etc.) Middle East & Africa (Saudi Arabia, Egypt, Nigeria and South Africa)

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To analyze competitive developments such as Expansions, Agreements, New Product Launches, And Acquisitions in the Market.

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To strategically analyze each submarket with respect to individual Growth Trend and Their Contribution to the Direct-to-consumer Genetic Testing Market.

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(2020-2026) Direct-to-consumer Genetic Testing Market: Business Size| Strategies| Opportunities| Future Trends| Top Key Players| Market Share and...

Recommendation and review posted by Bethany Smith

Everlywell COVID-19 Home Collection Test kit

Startup Disrupts Medical Testing Industry

Sometimes, to disrupt an industry, you need an outsider's perspective. Other than being a dissatisfied consumer, Julia Cheek had no expertise in healthcare. Trying to find out why she was experiencing debilitating fatigue, doctors ordered a battery of tests. Even with good insurance, she still had to pay more than $2,000. Fortunately, it turned out she had easily treatable vitamin and hormone deficiencies. There had to be a better way, she thought. And, that better way could be used during the coronavirus pandemic.

The technology to do biological testing at home has existed for more than a decade think DNA genetic testing like Ancestry and 23andMe but no one had thought to use it for medical tests. Cheek launched Austin-based Everlywell in 2015 to provide at-home lab testing kits and digital results within just days for things such as cholesterol, food sensitivity, fertility, STDs, and thyroid problems.

Even though she had a Harvard MBA, as a woman and solo founder of a healthtech company, she was ignored by venture capitalists. "What I learned is that it only takes one 'yes,'" said Cheek. Helping to get people to say "yes" was the fact that the company had significant market traction generating $250,000 in sales per month.

An angel investor, Craig Barrett, and a micro venture capital firm, SoGal Ventures, invested in the first quarter of 2017. She landed a $1 million loan at 8% plus help with sales and marketing for a 5% stake from Shark Tank investor Lori Greiner in November 2017. Sales doubled overnight, said company spokesperson. Christina Song. In April of 2019, the company received $50 million in venture capital led by Goodwater Capital. The capital round also included Highland Capital Partners and NextGen Venture Partners. In March 2020, Everlywell was recognized as the third fastest-growing company in Texas, by Inc. 5000. Thanks in large part to Greiner's knowledge of brick and mortar retail, in the two years since her involvement, Cheek announced on a recent Shark Tank update segment that Everlywell's sales have grown from $2.5 million in sales annually to $65 million.

Spotting The Potential For A Pandemic Early

Everlywell's Chief Medical and Scientific Officer, Frank Ong, MD, had been in Asia when SARS broke out in 2002-2003. He understood the risks posed by the new coronavirus identified at the end of 2019. On a business trip in January 2020, he and Cheek discussed his fears that COVID-19 could develop into a pandemic. By February, it was clear the virus was spreading and testing was not keeping pace. "That's when we got into gear," said Ong.

With over 250,000 CLIA-certified labs in the U.S., Cheek saw an opportunity to increase the United States' capacity to do COVID-19 testing as well as to limit exposure to the coronavirus and reduce the potential overload of healthcare facilities through home sample collection. For Everlywell, increasing lab testing capacity wasn't a pivot. It was in line with its values of providing easy and convenient testing. Even though the startup wasn't profitable, the board gave Cheek a quick thumbs up for a $1 million initiative to help smaller labs be FDA compliant.

On March 8, 2020, the company announced a $1 million development incentive to any certified laboratories who fulfilled requirements set by the Federal Drug Administration (FDA) and Everlywell to prioritize the development of a COVID-19 diagnostic test. "The money would help small labs get proper testing up and running," said Ong. This would help home testing to become an essential part of the national response.

Earlier in March 2020, a couple of other companies started selling at-home COVID-19 tests for consumers. Everlywell announced the launch of an at-home sample-collection kit that it believed was permitted under an FDA policy. The FDA stopped everyone because it said it had not yet authorized any self-administered tests at home. The false start was due to confusion in the interpretation of FDA guidelines. The good news was that the FDA did see the public health value in the tests and wanted to work with companies.

If At First You Don't Succeed Try, Try Again

Everlywell worked with the FDA to secure an Emergency Use Authorization (EUA) for its kits before sending any to consumers. EUA allows the FDA to help strengthen the nation's public health protections against chemical, biological, radiological, and nuclear (CBRN) threats by facilitating the availability and use of medical countermeasures (MCMs) needed during public health emergencies. Without the EUA, Ong's experience was that it took 1 1/2 to 2 years for FDA approval. Under the EUA and with Ong's knowledge of aggregating clinical trial research, including data from studies from the Bill & Melinda Gates Foundation and UnitedHealth Group, showing self-collected specimens could remain stable through the mail.

Everlywell COVID-19 Home Collection Test Kit

Everlywell's COVID-19 Test Home Collection Kit became the first stand-alone sample collection kit to be granted an EUA by the FDA. Everlywell's offering is unique because its sample kit is independent of any specific testing lab. It can work with a variety of labs to potentially provide a broader testing footprint.

"The authorization of a COVID-19 at-home collection kit that can be used with multiple tests at multiple labs not only provides increased patient access to tests but also protects others from potential exposure," Dr. Jeffrey Shuren, director of the FDA's Center for Devices and Radiological Health, said in a statement. "Today's [May 15] action is also another great example of public-private partnerships in which data from a privately funded study was used by industry to support an EUA request, saving precious time as we continue our fight against this pandemic."

For now, Everlywell charges for its home test but makes no profit. However, the company is working with insurance companies to get the test covered and with Congress to make the test free.

During the eight weeks Ong was working with the FDA on approval for the company's COVID-19 test, Everlywell implemented work-from-home procedures and cut all discretionary spending. It also provided tests to healthcare and frontline workers.

How can you put together the team and the resources to help you overcome hurdles?

Read more from the original source:
How The FDA Cut Bureaucratic Red Tape To Make Coronavirus Home Testing Available - Forbes

Recommendation and review posted by Bethany Smith

Home / More Lifestyle / Narnia, the two-faced cat, fathers kittens that match his two facesmore-lifestyleUpdated: Jun 24, 2020 17:04 ISTNarnias face is split in the middle perfectly, and the mystery behind what caused this makes him all the more special.(@AmazingNarnia/Instagram)

Narnia, a 3-year-old cat with a rare genetic trait that gives him his characteristic half grey and half white face, lives in Britain with his owner, Stephanie Jiminez, a cat breeder. After proper genetic testing, it was discovered that Narnia is not a chimera, a genetic anomaly that results in an extra X chromosome in the early stages of his development. Narnias face is split in the middle perfectly, and the mystery behind what caused this makes him all the more special. He also has electric blues eyes that are very rare in black cats.

In the early days of March, Narnia fathered a whole litter of adorable kittens, a few of which have been adopted. Many of Narnias children have his devastatingly good looks and similar to his litter born in May 2019, this one has a perfect representation of both his halves too!

Kittens Renesme and Roswell are copies of each half of Narnia and have Narnias hypnotic blue eyes and we cannot stop gushing about them.

Narnia has a verified account on Instagram where he features in various avatars, including Batman. He can also be found online via his Facebook and YouTube pages.

Narnia and his adorable family have certainly taken over the hearts of people all around the world. He is set to receive another bunch of kittens by the end of June. This adorable miracle of a family is sure to make you smile during these trying times.

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Narnia, the two-faced cat, fathers kittens that match his two faces - Hindustan Times

Recommendation and review posted by Bethany Smith

The first big leader to livestream a message to the virtual World Health Assembly on 18 May was supposed to be Cyril Ramaphosa, president of South Africa and chairman of the African Union, but something went wrong with the feed. Xi Jinping went first instead. We saw the president of China seated behind a highly polished table, in front of a mural showing rosy dawn creeping over the Great Wall. He promised billions of dollars to fight Covid-19 and invoked planet Earth, our common home. When the virus appeared in China, he said, his country had acted with openness, transparency, and then responsibility. Emmanuel Macron was next, bobbing and rubbing his hands as he spoke of humanitys fundamental right to health. Moon Jae-In, the president of South Korea, spoke of solidarity; Angela Merkel popped up to tell us wanly that the World Health Organisation was a good thing.

The assembly is the annual meeting of the member states that fund and supervise the WHO. The opening session of this years assembly, forced online by the worldwide lockdown, was anchored from WHO headquarters in Geneva. We were led on a claustrophobic internet tour of ministerial offices and oppressively large desks in three dozen world capitals, some of the speeches crackling and fuzzy, until, just after Canada and just before Honduras, we cut to Alex Azar, the emissary from the United States, sent to put Xi and the WHO in their place. He sat in front of a blank blue screen in rimless glasses and a light grey suit, his hair slicked down 1950s-style, bearing an uncomfortable resemblance to the late Donald Pleasence.

It took Azar, Donald Trumps health secretary and a one-time pharmaceutical industry lobbyist and executive, less than three snippy minutes to deliver his bosss message. The pith was the astounding charge that Xi and the director-general of the WHO, Tedros Adhanom Ghebreyesus, were to blame for the severity of the pandemic. We must be frank about one of the primary reasons this outbreak spun out of control, Azar said.

There was a failure by this organisation to obtain the information that the world needed, and that failure cost many lives In an apparent attempt to conceal this outbreak, at least one member state made a mockery of their transparency obligations, with tremendous costs for the entire world. We saw that WHO failed at its core mission of information-sharing and transparency, when member states do not act in good faith.

It was clear that the member state was China. Trump had been trolling the WHO for weeks, accusing it of being a tool of China if it hadnt actively helped China cover up the outbreak, it had at least helped China cover up the cover-up. Trump likes to present the World Health Organisation and the World Trade Organisation as two arms of a global system captured by China to take advantage of big-hearted, deep-pocketed American naivety. Again and again in April, he returned bitterly to the WHOs disapproval of border closures as a way to contain epidemics. On 14 April, he froze US funding for the organisation.

At the end of March, the death tolls in China and the US were about the same, a little above three thousand. Two weeks later, when Trump was claiming in the Rose Garden that China and the WHO between them had raised the worldwide caseload by a factor of twenty, the number of dead in China had barely budged: the epidemic there was under control. In the US, more than 23,000 had perished. By the time of Azars address to the assembly barely a month later, the Chinese toll had crept up to 4638, and was flat, while Americas dead numbered nearly ninety thousand, and the figure was still rising.

That night in America it was already first light in Geneva Trump tweeted a letter laying out his accusations against the WHO, threatening to quit the organisation if it didnt perform an unspecified act of repudiation of China by the middle of June. He didnt wait that long. On 29 May, as part of another broad spectrum attack on China, he announced that the US would be pulling out of the WHO. China, he said, has total control over the World Health Organisation, despite only paying $40 million per year compared to what the United States has been paying, which is approximately $450 million a year.

The Trump dmarche, both the letter and the later statement of intent to quit, seemed extraordinary: for its timing (an attack on the worlds public health agency in the midst of a once in a century global pandemic); for the easily disproved fake evidence it cited (the letter opened with a claim that the Lancet had warned of the virus spreading in China in 2019 it hadnt); and, circumstantially, for the transparency of Trumps real motivation (to shift the blame for his weak handling of the crisis less than six months before the presidential election). In a way, the episode was extraordinary, a notable moment in the coarsening of the US governments diplomatic voice under Trump. But it was also in keeping with a pattern in the management of global disease, a pattern that goes back long before Trump, and long before the WHO was founded in 1948. There is a recurrent Euro-American fear that infection will leak in from elsewhere on the planet, and a recurrent desire to build barriers against it. The pattern connects to the American dread of being subjected to anything resembling a world government. And it alternates between two ideals of healthcare: the tech model, in which health is seen as a set of individual problems to be fixed by intensive, preferably one-time scientific interventions (wipe out malaria with genetically modified mosquitoes!), and the communal model, in which health is deemed a rolling project of social reform, endless and universal, low-tech and labour-intensive, inseparable from questions of housing, poverty, sanitation, education, inequality, diet and work.

Disease knows no borders, we were told in speech after speech at the assembly: we must work together. But what does this mean? Can the WHO be the means to marshal a collective global effort, or is it doomed to cloak the reality that, in fact, there is very little solidarity between nations? Trumps intervention in May didnt help the WHO, and American withdrawal from the organisation would be a hard blow, but some version of the letter was expected, and there must have been a measure of relief among national governments that the US president had sucked from the gathering all the media attention that might otherwise have been directed at wider failures of co-operation. Far from increasing pressure on China, whose initial response to the appearance of the new virus was certainly not open, transparent and responsible, Trumps eagerness to turn hysterically on the WHO itself actually eased the pressure on Xi Jinping at a time when, as we later learned, he was busy planning the suppression of democracy in Hong Kong.

Britains health secretary, Matt Hancock, delivered its message to the assembly. He spoke perkily, as if everything in his country was under control. In fact Britain is the country which, given its relative wealth and long warning time, has failed most grievously to protect its people against the first onslaught of the virus. Its failure lay primarily in its neglect of the low-tech, low-cost, labour-intensive public health methods and community mobilisation that successfully prevented disease in low-income countries: universal lockdowns, self-isolation, masking, quarantine and tracing by people, not apps of all those whom sick people have been in contact with. Yet in his short video message Hancock was speaking the old language of Americans and Europeans, coming up with a tech solution in this case, a vaccine that doesnt yet exist to the worlds problems. Im proud that the UK is leading this work, he said, that were the biggest donor to the global effort to find a vaccine, and that UK research efforts are leading the way. Hancocks wasnt the only speech at the assembly to prompt the thought that before there can be solidarity, a little humility would help.

Towards the end of 1826, Alexander Pushkin was playing chess with a friend who, as he put it, knew a lot of the kinds of thing they study in universities while we were learning to dance. The friend checkmated Pushkin with his knight and remarked: Cholera morbus is at our borders, and in five years, itll be here. Like most of his peers Pushkin knew almost nothing about the disease, which was endemic in Asia but unfamiliar to Europeans. Four years later, in 1830, he went to his fathers estate near Nizhny Novgorod for what he thought would be a few weeks business. He ended up caught in a harsh and futile lockdown against the cholera epidemic that spread from Georgia and Astrakhan to European Russia that autumn.* Pushkin enjoyed the most artistically productive three months of his life; Russia was paralysed by a pandemic regime that sanctioned the shooting of quarantine violators and triggered a series of violent uprisings.

The disease spread to Finland and Poland. It was in Vienna by August 1831. From there it reached the German ports and travelled on to England, Ireland and France. This first incidence of cholera in Europe, with its horrible symptoms of constant diarrhoea and vomiting, is the novel pandemic that haunts Middlemarch. All the world is in apprehension about the cholera pestilence, which, indeed, seems advancing towards us with a frightful, slow, unswerving consistency, Thomas Carlyle wrote as the disease entered Britain through Sunderland. Eventually it killed 52,000 in Britain alone. Our other plagues were home-bred, and part of ourselves, an anonymous English doctor wrote:

We had a habit of looking on them with a fatal indifference, indeed, inasmuch as it led us to believe that they could be effectually subdued. But the cholera was something outlandish, unknown, monstrous; its tremendous ravages, so long foreseen and feared, so little to be explained, its insidious march over whole continents, its apparent defiance of all the known and conventional precautions against the spread of epidemic disease, invested it with a mystery and a terror which thoroughly took hold of the public mind, and seemed to recall the memory of the great epidemics of the middle ages.

The pandemic of the 1830s wasnt the first great cholera outbreak of modern times. That had occurred a few years earlier, in British-ruled India, where a million or more people died. The prevailing attitude among the British in India one which subsequently spread, with cholera, to the Euro-American world was that cholera was of India and Indians, transmitted by means of deplorable Indian habits, from which innocent Europeans and Americans had to be protected. Yet what turned cholera from a series of restricted outbreaks among Hindu pilgrims in India into a global pandemic was the international movement of British troops and British merchant ships, which spread the illness across the subcontinent and on to Central Asia, Africa and the Middle East.

One way of protecting Europe from cholera, in other words, would have been for Europeans to avoid establishing rapacious and intrusive global empires. But they had established them. There was much European hand-wringing in the 19th century over the perilous sanitary consequences, to Europe, of the grand imperial transport projects for which Europe was largely responsible. The Suez Canal, according to a recent history of the WHO by Marcos Cueto, Theodore Brown and Elizabeth Fee, made Europeans feel dangerously close to India. In 1900 the fear was the imminent completion of a railway line linking Berlin to Mecca, seen as a cholera hotbed.

Cholera, which returned to Europe repeatedly during the 19th century, was the subject of the first International Sanitary Conference in Paris in 1851. At intermittent meetings over the next three decades, against opposition from shipping interests, a system of marine quarantine was set up. Cholera receded as a threat, but plague and yellow fever were resurgent; a yellow fever outbreak killed as many as twenty thousand in the south-eastern US in 1878. In December 1907, 13 countries mainly European, but including Brazil, Egypt and the US set up the first embryonic global health agency, the Paris-based Office International dHygine Publique (OIHP), to share information about epidemics between member states (a similar organisation, for the Americas only, had been set up a few years earlier). Whatever humanitarian intentions the OIHP had were clouded by the racist implementation of quarantine rules. Prevailing attitudes, Cueto, Brown and Fee write, meant holding individuals, communities or nations (usually non-Caucasian) responsible for epidemics, an attitude that reinforced the cultural dimensions of European imperialism. Arab pilgrims were thus commonly portrayed as vectors of cholera yellow fever was thought to be carried by immigrants from the Caribbean and bubonic plague by immigrants from China. The unspoken goal of the OIHP was not the improvement of the health of the worlds people but the protection of certain favoured nations from the grandes maladies pidmiques originating primarily in less favoured ones.

In 1923 the OIHP gained a rival in the League of Nations Health Organisation (LNHO), based, like the League of Nations itself, in Geneva. The OIHP was abolished in 1946, its reputation destroyed after being folded into the Nazi-Vichy administrative system during the Second World War. In the spring of 1945, a conference was held in San Francisco to set up the United Nations. It hadnt originally been scheduled to discuss a separate body for health, but a Chinese medic and diplomats son called Szeming Sze managed to push it onto the agenda, where it was overwhelmingly endorsed. Three years later, the WHO came into being. Each member state, regardless of size or wealth, would appoint three delegates to the World Health Assembly, which would elect the director-general, who would run the WHOs day to day operations with a staff of international civil servants. A group of experts chosen by the assembly would mediate between the director-general and member countries.

Raymond Gautier, the Swiss medical director of the LNHO who drafted a plan for a successor agency in 1943, had imagined an organisation that would be able to enforce health rules with sanctions against countries that didnt comply, but this never happened. The WHO has never had the power to compel a reluctant member nation. Its funding and staffing were small 254 in 1949 and its competencies both vague and potentially limitless. It had the remit to be the worlds watchman for infectious disease outbreaks, but it also had a stirring constitution written in the language of social justice, a Magna Carta for health that declared health a universal human right, and defined it as a state of complete physical, mental and social well-being not merely the absence of disease or infirmity. The WHO was obliged to do some concrete tasks, such as gathering epidemiological data and standardising the technical vocabulary of medicine. At the same time it was open to initiatives not only from countries desperate for help with hospitals or sanitation but from philanthropists keen to give it.

The organisations logo is the snake-twined staff of Asclepius against a map of the world, an arcane signifier that avoids commitment to any particular one of the organisations three priorities. Should the prime symbol instead be a syringe, to proclaim the power to solve ill-health, disease by disease, with technological fixes? Or should it be two hands clasped, to represent ill-health as the problem of a lack of social solidarity? Or a watchtower, to symbolise vigilance and defence against the menace of spreading infection? The Bill & Melinda Gates Foundation is the second biggest contributor, after the US government, to the WHOs $2.4 billion budget. Gates is a believer in the tech fix. I believe we are on the verge of taking historic steps to reduce disease in the developing world, he told the World Health Assembly in 2005. What will make it possible to do something in the 21st century that weve never done before? Science and technology. The same philosophy was expounded a hundred years ago by the Rockefeller Foundations International Health Division, founded in 1913, which by 1933 was paying the salaries of half the staff of the LNHO. Tech fixes have had striking successes the elimination of smallpox, a WHO-choreographed triumph but also failures, notably the abortive effort to eradicate malaria in the 1950s and 1960s.

That failure, and the growing sense of the iniquity of importing Euro-American medical models into former colonies that couldnt afford to run them or to scale them up, were the primary concerns of a joint WHO-Unicef conference on primary healthcare held at Alma-Ata in Soviet Kazakhstan in 1978. The conference ended with a declaration calling for community-level public health and better public services for everyone in developing countries. The declaration is a foundation text for those, like Tedros, the current director-general, who reckon theres little point in saving a child from dying of malaria if theyre going to be killed by bad sanitation or lack of education. People should not die because they are poor, Tedros observed after his election a remark that might be taken as trite were it not for the great number of political movements in the world who live by the implicit premise that, actually, its their fault if they do.

Over the decades the US government has veered between the syringe and the watchtower. For much of the WHOs existence it has put immense expertise and resources into global healthcare, from a mixture of motives humanitarian, scientific, influence-seeking, image-boosting, or to support its medical industries. The US has provided some of the WHOs most dynamic figures, notably Jonathan Mann, who led the organisations response to the spread of Aids in the 1980s. In narrative fiction and non-fiction, a stock figure has emerged: the brave, principled, maverick American researcher who leaves the safety of the homeland to plunge into the world of foreign disease. The real-life archetype, who appears in two bestselling books from 1994, Richard Prestons The Hot Zone and Laurie Garretts The Coming Plague, is the medical researcher Joe McCormick. Here he is, in Garretts version, being asked by the WHO in 1979 to fly from the Atlanta headquarters of the US Centres for Disease Control and Prevention (CDC) to Sudan to investigate an Ebola outbreak:

McCormick hastily gathered supplies and the first assistant he could get his hands on Dr Roy Baron. Within a matter of hours, the pair were on board a flight to Khartoum, and McCormick was giving Baron a rapid-fire lesson on Ebola, Sudan, field operations and self-protection.

Joe tugged at his dark brown goatee with anticipatory excitement, relishing a second chance to crack the mysteries of Ebola.

If the US does pull out of the WHO and there is considerable scepticism that it will, even if Trump wins a second term it wouldnt be the first country to quit a UN organisation. The Soviet Union left the WHO in 1949, taking its Eastern European satellites with it, returning only in 1956 after the death of Stalin. Britain twice followed the US out of Unesco at the end of the last century. The suspicion that international organisations are stalking horses for world government is near the surface of American politics. The US declined to join the League of Nations; the US (along with China, India and Russia) is not party to the International Criminal Court; alone among member states, the US demanded at the WHOs founding that it should be allowed to withdraw unilaterally with a years notice. Even if the US does leave, it wont cut off aid to global health programmes. Theyre too valuable for leveraging power and supporting the domestic pharmaceutical industry. When Azar addressed the assembly in May he took care to say that the US doesnt begrudge setting aside $9 billion to fight Covid-19 around the world. The question is whether the US can really afford to undermine the WHOs watchtower role as the early warning system, data clearing house and resource co-ordinator for pandemics; and what it will mean for the health security of the rest of the world if one part of the globe goes silent. After decades when it seemed that high-income countries no longer had much to fear from epidemics, a succession of novel viruses has appeared: HIV, Ebola, Sars and now Covid-19. Trumps preoccupation with borders, immigration and, lately, cordons sanitaires is a throwback to the early days of the OIHP and the fear of cholera, when the emphasis was on the need to establish a disease barrier between civilisation and barbarity. Under Trump the US is no longer moving between the syringe and the watchtower; it is a riled-up bald eagle with a bottle of pills in one set of talons and a roll of razor wire in the other. His position is that the US can and must do without WHO watchkeeping because, in respect of Wuhan, thats exactly the role in which the agency has already failed. The truth is rather different.

Wuhan is one of the great cities of China, bigger than any European city apart from Moscow, but I knew nothing about it before the outbreak. I know a little more now, but my own city, the pre-Covid London of midwinter 2019, has become a remote, fantastical place. I look back at the first week of December. S. and I had just moved into a new house. Her sister came to stay. A friend came over to cook us coq au vin; he was in our kitchen for hours. I went to the pub with my family, and stood close to strangers at the bar. Nobody was masked. I watched the highlights of the Liverpool-Everton game. Tens of thousands of people roared from the terraces. We checked out a primary school for our son. Dozens of unmasked parents trooped into classrooms filled with children and unmasked teachers. Nobody washed their hands. It was my birthday; we got a babysitter; we met friends at a restaurant in Soho. Black cabs and Ubers seeded Frith Street with revellers. The boozing-rooms roared. Unmasked waiters leaned in. The skies were full of planes, underground and overground trains full of people. And at this time, somewhere in a great city in China whose name held no meaning for me, was an individual with a bad cough who was going to stop it all.

A WHO bulletin on 12 January said, citing the Chinese authorities, that the first patient reported symptoms on 8 December. An article in the Lancet in January by 29 Chinese medical professionals, including doctors from Wuhan, said the first symptoms in a patient appeared a week before that, on 1 December. In its first public statements the Wuhan Municipal Health Commission was adamant all the cases were linked to the local seafood market, and that there was no evidence of human to human transmission. But the Lancet article reported that only two-thirds of the patients could be linked to the market, and that the 1 December case could not. Nor were any links found between that case and any other cases; none of patient ones family ever showed symptoms.

Patient one, in other words, probably wasnt patient zero. To be honest, we still do not know where the virus came from, one of the lead authors of the Lancet article, Bin Cao, wrote in an email to Science magazine. In March the Hong Kong-based South China Morning Post, citing leaked Chinese government data, suggested that the first identifiable case was actually in mid-November. In May Gao Fu, head of the Chinese Centre for Disease Control and Prevention (CCDCP), said no trace of the virus had been found in any animal samples from the market. Adding to the origin mystery are reports of early cases, or possible cases, in other countries. A retrospective test of a sample from a recovered pneumonia patient in France, who was swabbed on 27 December, came back positive for Covid-19. The patient hadnt travelled abroad. The late Andy Gill, a member of the band Gang of Four, fell ill with what seemed to be pneumonia after coming back from a tour of China in November. The band didnt gig in Wuhan, but did visit Beijing, Shanghai and Guangzhou. Gill died at St Thomass Hospital in London in February. His widow, Catherine Mayer, wrote on her blog that one of the specialists treating him told her there was a real possibility that Andy had been infected by Sars-CoV-2.

The first known cases in Wuhan were scattered between a number of hospitals. According to an account on the website of the Chinese National Health Commission, on 27 December, an unspecified private genetic testing company alerted staff at Wuhans Tongji Hospital that a sample from one of its pneumonia patients had tested positive for coronavirus RNA. Staff at Tongji called another hospital, Jinyintan, which had a specialist infectious disease unit, asking if the patient could be transferred there. Instead of alerting the national CCDCP, local officials kept the information within Wuhan and Hubei province. On 29 December, a senior specialist at Jinyintan, Huang Chaolin, was asked by local officials to investigate seven patients with inexplicable lung conditions at a third hospital, Hubei Provincial. What Chaolin found was worrying enough to prompt the transfer of the patients to Jinyintan in ambulances designed to prevent the leakage of potentially contaminated air.

A fourth hospital, Wuhan Central, had admitted a worker from the seafood market with an unusually intractable fever on 16 December. A sample of fluid from his lungs was sent to the Guangzhou-based firm Vision Medicals for genetic analysis on 22 December. According to an investigation by the Chinese business news site Caixin Global, Vision Medicals found, as early as 27 December, an alarming similarity to the deadly Sars coronavirus that killed nearly eight hundred people between 2002 and 2003. Instead of sending a written report to Wuhan Central, Vision Medicals conveyed the news by phone. In an interview with the Chinese magazine People, subsequently removed from its website, the head of the A&E department at Wuhan Central, Ai Fen, said the consultant looking after the patient had told her: That persons diagnosis is coronavirus.

The same day, a new patient was brought in to Central Hospital with the same unusual symptoms. Samples from his lungs were sent off for testing to another lab, CapitalBio of Beijing. At noon on 30 December, Ai was watching a CT scan of yet another pneumonia patient linked to the seafood market when a former classmate, now at Tongji, sent her a screenshot of a WeChat exchange warning against visiting the market because there are lots of people with high fever. He asked whether this was true. Ai sent him a clip of the video of the lungs of her latest patient. Four hours later, Ai got a copy of the 27 December lab report. This time the coronavirus finding was printed on the page. After alerting her superiors, she drew a red circle round the part of the report identifying Sars coronavirus in the patient, photographed it, and sent the image to a group of medical friends and colleagues. It quickly spread online. Among the doctors who pushed the report on Chinese social media in those first hours on 30 December, eight were later punished by local security services for putting out false information, including the ophthalmologist Li Wenliang, who would later die of Covid-19. Ai was bawled out by her bosses for spreading rumours and bringing the hospital into disrepute.

Whether because of the unofficial warning Ai put out on the Chinese language internet, or because theyd been planning to do it anyway, local health officials issued a red alert that night, warning all local hospitals to be on the lookout for unusual pneumonia cases. That alert quickly joined Ais picture of the lab report on social media. A journalist from China Business News saw the posts and got confirmation of the story from Wuhans health committee. The next day, New Years Eve, a team from the National Health Commission arrived from Beijing to investigate. News organisations around the world, from the South China Morning Post to the Daily Mail, reported on a mysterious pneumonia-like illness in Wuhan that had infected 27 people. Although no one had died, and Wuhan health officials assured everyone that all the cases seemed to be linked to the now closed seafood market and there was no sign of human to human transmission, Hong Kong began to put its well-laid epidemic contingency plans into action.

On 2 January, the WHO activated its incident management system, and on 5 January, issued its first bulletin. By this time there were 44 cases. Reliant on the Wuhan authorities for information, the WHO bulletin repeated its insistence that there was no evidence of significant human to human transmission of the disease, although it didnt dismiss the danger: The occurrence of 44 cases of pneumonia requiring hospitalisation clustered in space and time, it stated, should be handled prudently.

For all the impression China can give of being a monolithic state with a clear top to bottom chain of command, it seems to have taken the national authorities the best part of the first three weeks of January to get to grips with what the local authorities in Wuhan had been in denial about. The WHO, dependent on the information China chose to share, took a reputational hit. As it turns out, it was already known in Wuhan in late December that it was extremely likely inter-human transmission of the virus was taking place, and that the connection with the seafood market was shaky. In an interview in April with CGTN, Chinas international state TV service, Zhang Jixian, the head of respiratory medicine at Hubei Provincial Hospital, explained that her first three Covid-19 cases, admitted on 26 and 27 December, were members of the same family, parents and son, living together. None had any connection to the market. At the time Zhang had made clear her opinion on whether human to human transmission was taking place by immediately ordering masks and other protective gear for herself and her team.

Yet well into the third week of January the official information coming out of China remained that there was no sign of human to human transmission, and the WHO, with no evidence to the contrary, sent out the same message. On 12 January the WHO relayed the Chinese line that, fantastically, no new cases had been detected for nine days. (We now know that, just among medical personnel, seven caught the disease in that period.) According to an article in the New York Times, citing a leaked diagnostic guide that has since been taken down from the internet, officials in Wuhan ruled on 3 January that local doctors couldnt designate a patient as suffering from the new coronavirus unless there was some connection to the seafood market. On 14 January Science quoted Xu Jianguo of the CCDCP: It is a limited outbreak. If no new patients appear in the next week, it might be over.

China was praised by some, including Tedros, for the speed with which its scientists sequenced the genome of Covid-19 and shared it with the world. The first sequence was posted on 11 January by researchers from Fudan University in Shanghai: Japan and Germany came up with tests in less than a week. But had China built on the work done by its private genetics labs in December it could have sequenced and made public the genome even earlier. Instead, according to Caixin, on 1 January private testing companies were ordered by local authorities in Wuhan to stop all testing and destroy any samples they had. Two days later the National Health Commission issued a similar blanket order, muzzling private labs. Shi Zhengli, of the Wuhan Institute of Virology, who in 2005 proved the link between the Sars virus and bats, claims that she sequenced Sars-CoV-2 in less than four days. The information could have been sent around the world on 2 January, making it possible for other countries to start work on tests more than a week earlier, but China sat on it.

At a press conference in April, Michael Ryan, the WHOs emergencies chief, revealed that the WHO had first learned of the outbreak not from the Chinese authorities but from ProMED, a non-profit network of observers who scan the internet for disease reports. One of ProMEDs spotters drew the attention of a ProMED editor in Brooklyn to the first social media posts from Wuhan on the morning of 31 December, China time. Ryan hinted strongly that the Chinese government didnt give the WHO the formal response required by the International Health Regulations until the last possible minute, that is, 48 hours after it was requested.

Recordings of WHO meetings obtained by the Associated Press show how frustrated its leadership was in private. Recalling the Sars outbreak of 2003, Ryan told colleagues: This is exactly the same scenario, endlessly trying to get updates from China about what was going on. WHO barely got out of that one with its neck intact. By 8 January, when the Wall Street Journal reported that China had sequenced the viral genome, Ryan was seething: Were two to three weeks into an event, we dont have a laboratory diagnosis, we dont have an age, sex or geographic distribution, we dont have an [epidemic] curve.

On 14 January Maria Van Kerkhove, head of the WHOs emerging diseases section, said that limited human to human transmission was possible, but it is very clear right now that we have no sustained human to human transmission. Not until 20 January, three and a half weeks after Zhang Jixian masked up at Hubei Provincial Hospital, did China concede that human to human transmission of the virus was taking place. By this time Wuhans hospitals were swamped with hundreds of coronavirus patients, protective equipment was in short supply, and medical staff were dying; the disease had spread to Guangdong, Beijing and Shanghai; and cases had turned up in Thailand, Japan, Korea and the United States.

Before the outbreak, the most popular destinations for travellers from Wuhan were the first three of those countries, along with Taiwan, Singapore, Malaysia and Australia. All of them mindful of previous viruses that originated in China, particularly the original Sars reacted quickly to the first news of Covid-19. Working on the assumption that human to human transmission was possible, if not likely, they began screening passengers at airports, set up systems to trace the contacts of anyone who was infected and, as soon as the viral genome sequence was made available, started to test. In many of these places, mask culture was already a thing. So far, all these countries have weathered the first wave of the virus well. Even relatively wealthy countries the ones that later suffered the worst death tolls, notably Britain and the US seemed in the beginning to be doing the right thing: treating the epidemic as if it might be a highly infectious disease that could spread from person to person, whatever China was saying. In this they were following WHO advice: it never said that human to human transmission was ruled out, only that there was no evidence. Rather belatedly, on 17 January, the CDC began screening flights from Wuhan; Britain followed suit five days later, and so did Italy at about the same time.

One of the paradoxes of the Covid-19 story is that the US, Britain and other European countries began to lose control of the situation soon afterwards, at the very moment China stopped being the bad citizen of global health and instead became an examplar. On 23 January, just before the great annual travel rush of the Spring Festival, China locked down Wuhan, a city of 11 million people. Soon afterwards it began its epic campaign to speed-build new isolation hospitals to quarantine thousands of coronavirus patients. On 30 January, shortly after Tedros flew to Beijing to meet Xi Jinping, the WHO declared Covid-19 a public health emergency of international concern, but by that time the scale of Chinas response spoke more eloquently than any WHO official declaration could of the disaster that was unfolding.

Much of the subsequent US criticism of the WHO, and of Tedros in particular, stems from this period, when the director-general was effusive in his praise for China and ignored the countrys early blunders and secretiveness. The speed with which China detected the outbreak, isolated the virus, sequenced the genome, and shared it with WHO and the world are very impressive, and beyond words, he said. So is Chinas commitment to transparency and to supporting other countries. In many ways, China is actually setting a new standard for outbreak response. Occasionally Tedross eagerness to give credit to China led him unwittingly to repeat things that turned out to be untrue, such as when he said, on 23 January, that the outbreak had been detected because the Chinese government, post-Sars, put in place a system specifically to pick up severe lower respiratory infections. It was that system that caught this event. Such a system, elaborate and seemingly foolproof, did exist but the authorities in Wuhan still managed to bypass it. The actual system that picked up the event was concerned citizens on social media.

In part, Tedros was perceived to be over-praising China because the rest of the worlds media were still picking over the chaos and deception of the early weeks; the first signs of Chinas fightback seemed from the outside, as one Italian put it later, like science fiction. But much of the resentment at Tedross warm words for China was based on a misunderstanding of WHOs role and powers. Lacking any means to force countries to give it information, but desperately needing to get it, it is obliged to fall back on consensus, persuasion and flattery in other words, diplomacy. The half-hearted cover-up by Wuhans local health officials showed what happens, on a national scale, when leaders fear humiliation. Theirs were not the actions of people who expected to be rewarded for the speedy delivery of bad news. You have to keep positive incentives for countries to report, Devi Sridhar, a professor of global public health at Edinburgh University, said. If there are negative incentives WHO comes out and grabs a headline saying They did it badly what other countries are ever going to come forward and report when they have an outbreak going on?

By February, when a WHO fact-finding mission toured China along with a group of Chinese specialists, Chinas campaign to suppress the virus was in full swing. The official report produced afterwards makes disconcerting reading. On the one hand, it ignores the clumsy deceits of Chinas first few weeks. On the other, it spells out what China had gone on to do, the things we now know countries like Britain, Italy, Spain and the US could have and should have copied in time to stop the outbreak gaining a foothold. Across the country China mobilised tens of thousands of contact tracers nine thousand in Wuhan alone. It pioneered the use of lockdowns to break the transmission chain. And it created a system of mass monitoring and diagnosis to identify and isolate as many cases as possible.

Well within the time-frame to make a meaningful difference in Britain, the US, Brazil or Italy, the WHO began energetically promoting the Chinese approach of suppressing the virus, rather than mitigating it. Bruce Aylward, the Canadian who led the non-Chinese group on the WHO mission, said when he returned at the end of February that governments preparing to let the epidemic simply wash over them had lost before they started and needed to change their mindset. He said he doubted whether the Chinese could suppress a previously unknown virus without drugs or a vaccine, but added that they have taken very standard and what some people think of as old-fashioned public health tools and applied these, with a rigour and innovation of approach, on a scale that weve never seen in history. They have taken case finding, contact tracing, social distancing, movement restriction, and used that approach to try and stop a new emergent respiratory-borne pathogen. There was, of course, a lot of technology in the Chinese effort. While British conspiracists were torching mobile phone masts in the belief they were the source of the virus, China was using its 5G network to give ultra-fast wireless data links to contact tracing teams in remote rural areas.

Even as the UK and US ended up, late in the day, chasing something like the Chinese approach, with its emphasis on public health and communal effort, Donald Trump and Boris Johnson were stressing a different route to pushing back Covid-19: the tech fix. With Johnson, its been ventilators, prospective vaccines, phone apps and antibody tests. Trump speaks of undiscovered vaccines too, but also returns to conspiracy medicine: the idea of an already existing pill that makes you well, or an ordinary household substance that those in the know can use, like one of those clickbait remedies on a website sidebar Doctors Dont Want You to Know about This One Simple Trick to Beat Covid.

The divide between communal health advocates and tech fixers represents a deeper choice: between actions that aim to help an individual, so may indirectly help everyone, and actions that aim to help everyone, so may indirectly help the individual. Lockdown requires each individual to accept personal constraints for the sake of the community, even when they are not themselves ill. In theory, the tech fix can be for everyone, too, but because it is a thing to be obtained, rather than a constraint to abide by, it comes trailing issues of priority, price, privilege, exclusivity: what device, what pill, what treatment, what test can I get for myself, my family, my friends, to protect them?

The WHO has sometimes leaned towards the tech interventionists, but in Tedros Adhanom Ghebreyesus, the organisation has found a leader from the community health tradition. He doesnt share the transactional, individualistic, Trumpian view of medicine and his election was bound to create tension at a time when the American nationalist right was already disposed to see the WHO as a project aligned with its ideological enemies. Even before the pandemic they saw Tedros as Chinas man. The US has never really been at peace with the WHO. I mean its not a new thing, Seye Abimbola, editor of the journal BMJ Global Health, told me in a call from Sydney. Theres always been a history of some kind of suspicion that its socialism.

As head of the WHO, Tedros represents many firsts: the first black director-general, the first African, the first not to be a medical doctor, the first to come from one of the five large countries India, Nigeria, Democratic Republic of Congo, Bangladesh and Ethiopia where half the worlds extremely poor people live. He was born and grew up in Asmara, in what is now Eritrea, at that time the Red Sea coast of Ethiopia. His parents came from further south, in Ethiopias Tigray region. While he was a small child, Emperor Haile Selassie still sat on the throne; his schooldays were during the Marxist-Leninist regime of Mengistu and the Derg; while he was at university in Asmara, studying biology, many Tigrayans and Eritreans were fighting an insurgency against Mengistu. After graduating Tedros worked for a while at the Ethiopian health ministry, before being awarded a WHO scholarship to study for a masters in immunology at the London School of Hygiene and Tropical Medicine. His time in London in the early 1990s coincided with a change of power in Ethiopia when a coalition of rebels, with Tigrayan insurgents in the forefront, overthrew Mengistu. When he went back, still in his early thirties, he drew attention in the Euro-American world for his research into malaria in Tigray. He earned a PhD in public health from Nottingham University and in 2005, just as the Ethiopian economy under the late Meles Zenawi, a former Tigrayan insurgent leader, was beginning its extraordinary decade of East Asia-inspired economic growth, he became the countrys health minister.

Tedros took control of a radical programme of public health reform that Zenawi and his allies had brought into national government from their experience running rebel provinces with zero resources. It was community-centred and woman-centred, and as much about education as doling out pills. The first phase was one years health training for thirty thousand high-school graduates, most of them women, who were then deployed in pairs to villages across the country. Tedros led the creation of a network called the Health Transformation Army, which aimed to designate one member of every family as a good health advocate. When the Lancet interviewed Tedros in Addis Ababa in 2011, he cited as an inspiration the Alma-Ata declaration of 1978 and its revolt against the tech-fix world of the shiny hospital. Our focus is primary healthcare, he said. We really want to be helping communities help themselves by expanding public health services in villages What we are saying to the world even to the developed countries primary healthcare is the answer. The programme showed remarkable results. From the time of Mengistus overthrow to 2015, child mortality was cut by two thirds, maternal mortality by 71 per cent, HIV infections by 90 per cent and malaria deaths fell by 73 per cent.

Tedros became director-general of the WHO in 2017, after a difficult period as Ethiopias foreign minister. He was the beneficiary of the WHOs first open leadership election; previously the choice had been made in backroom stitch-ups orchestrated by countries with deep pockets. In 2017 the system was changed to one country, one vote. Theresa Mays administration put a lot of effort and resources into backing a British candidate, the WHO insider David Nabarro; its thought he was also the Trump teams choice. The campaign became quite ugly Tedros was accused by critics of downplaying a cholera outbreak in Ethiopia and of complicity in repression there but the mud failed to stick. He got the African support, Abimbola said. Having got Africa, the only thing you needed to get was China, and if you can get China and Africa youve won the election. So he got China and also got Chinas people, to put it indelicately, and then he won it.

The Alma-Ata declaration was made not only in reaction to the failure of the WHOs attempt to eradicate malaria but was part of a turn towards the idealised glow of Mao-era Chinas barefoot doctor programme. The spirit of the barefoot doctors haunted Tedross work in Ethiopia and haunts, perhaps, the villages of Hubei in the era of Covid-19; it isnt surprising he found Chinas coronavirus campaign congenial. The Health Transformation Army, I was told by Sarah Vaughan, who came to know Tedros in the course of thirty years research in Ethiopia, was basically a kind of health extension programme using women through a classic party cell mobilisation system, a one to five system, where one woman would have five followers and each of them would have another five followers. And the idea was a sort of triangle with the party in the vanguard, the state providing the resources and the technical people, and the population mobilised, so it was a sort of inclusive consensus, everybody behind the Great Leap Forward. Tedros was put in as the internationally acceptable face of a system which was delivering outcomes in a way that pleased the donor community, but it was using the party political structure to do that. It was a totalitarian system in the technical sense of the word a benign dictatorship to engineer better community health.

Vaughan described Tedros as a technocrat without an ideological bone in his body. I wondered whether his apparent surprise at the horror in the Euro-American world that greeted his appointment of Robert Mugabe as a goodwill ambassador quickly rescinded was simply the reaction of a man whose lifelong habit has been to isolate health work from all other forms of politics. This attitude might sound cynical, or naive, but it could just as well be seen as a rebuke to the neoliberal idea that democracy, in the shallow sense of elections, and minimal barriers to trade are sufficient in themselves to allow low-income countries to prosper. Before Alma-Ata, before Maos barefoot doctors, there was Britains National Health Service which Tedros has also eulogised, along with other European manifestations of communally-funded medicine. He was elected on a platform that included getting a billion more people enrolled in universal health coverage.

The true significance of Tedross election, and of Trumps attack on the WHO and China, may be as markers of how radically the world has changed since the WHO was founded, and of the refusal of the nationalist Euro-American right to accept that change. In 1950, Europeans and Americans constituted more than a quarter of the worlds population; now they make up less than 14 per cent. The combined population of just two African countries, Ethiopia and Nigeria, is almost as large as the population of the US. In 1950, two-thirds of the world economy was Euro-American; now it is less than two-fifths. Abimbola told me of the groundswell of noise from educated Africans that had propelled Tedros to the director-generals post. There are hundreds of thousands of us, he said. Mostly middle-class, low or middle-income-country people who have the time, the attention, the resources, the exposure and the scepticism to see what is wrong, and to be willing to spell it out.

At the beginning of the coronavirus epidemic it was gravely expected that the Euro-American countries would hold firm, with their sophisticated healthcare systems based around high-tech hospitals, while the disease would cut a terrible swathe through Africa. The question of solidarity, or the lack of it, would come down to how much or how little the rich countries were willing to give the less well-off. So far it hasnt happened that way. The formerly colonised countries, with their thinly resourced health systems, have been spared the worst; it is the old colonisers, with their ventilators and ECMO machines, that have suffered. Senegal has had far fewer deaths than France, the Democratic Republic of Congo far fewer than Belgium, Kenya far fewer than Britain.

That may yet change. More remarkable is the way the epidemic has exposed a lack of solidarity within Western countries themselves. The debate about the path of global health improvements the balance between individualistic tech fixes and community health turns out to be meaningful within countries as well. Nowhere has this been clearer than in Britain, where the expectation each winter is that hospitals will struggle to treat the surge of frail old people; the elderly are pushed back into under-scrutinised private care homes, or into a community care and public health system whose budget to help them has been cut to the bone. When the virus came, this dynamic intensified. Tens of thousands of old people were sent home or into residential care without being tested for coronavirus. They infected others. Many died. The Alma-Ata declaration, with its advocacy of community healthcare and wariness of high-tech hospitals that poorer countries cant maintain, has found a grotesque echo in Britain, where despite efforts at reform, politicians and public remain complicit in the fantasy that healthcare equates to hospitals, doctors, drugs and machines, and community, meanwhile, has become a euphemism for Youre on your own.

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James Meek The Health Transformation Army: What can the WHO do? LRB 2 July 2020 - London Review of Books

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The family of a Santa Clarita teen with Batten disease, a fatal degenerative genetic disorder, is pleading with the community for help after suddenly learning that scheduled life-saving research had been halted, and is now being faced with an urgent need for additional fundraising support.

Affectionately known as Sebi, Sebastian Velona was born in 2003, and was a perfectly happy, healthy young boy with a big heart for the first several years of his life, according to his mother, Teri Hughes Fox.

He would also have the biggest heart and just want to hug everyone, Teri said. He just felt like, if you had a boo-boo, if you had a scrape, if you were crying, if youre hurt, if youre sad He felt he could hug people and heal them with his hugs.

Then, in October of 2007, four-year-old Sebi and his family were on vacation in Hawaii when tragedy struck.

He collapsed in the hallway going back to the room after having a fun day swimming in the pool, Teri said. He collapsed and had his first seizure. We thought he was dying. We didnt know what was wrong. He was turning blue. He was shaking. It was just horrible.

When the family returned home, a series of tests were unable to find any cause for Sebastians seizure, and a neurologist deemed it a one-off fever seizure.

Six months later, he had a second seizure. At that point, Sebi was diagnosed with epilepsy.

That was just the worst word at that time Id ever heard, Teri said. Our world changed.

After that came years of trial and error with medications, some of which came with side effects that further endangered Sebis health. Some medications resulted in mood swings and outbursts of anger, where others caused him to suffer more than 10 seizures in a day.

Eventually, Sebis doctors discovered a cocktail of three medications that managed to control his seizures, but the problems were just beginning.

When he was six, Sebi began to lose his vision, eventually being diagnosed with retinitis pigmentosa, a degenerative eye disease that will eventually cause him to lose his sight entirely.

He was at school learning to read and all of a sudden, overnight, it seemed like he couldnt see what was on the page, Teri said. It was fuzzy, he couldnt read it. There was something wrong.

It was at this time that Sebis family began to notice other issues developing in his behavior. He became clumsier and his speech began to slur. His parents insisted that there was something else at work, and obtained a DNA test to narrow down the cause of Sebis health issues in order to get him treatment.

Im thinking: Its not just retinitis pigmentosa and epilepsy. Theyre not separate issues where my son is just developing all these horrific diseases, Teri said. Theres something else wrong, everything about him is different, everything is changing and unless a doctor sees you every day, they dont see what were talking about.

After months of waiting, Sebi was diagnosed with CLN8 Batten disease in 2012. Batten disease is a disorder that primarily affects the nervous system, leading to neurological impairment, including developmental regression, seizures, blindness, behavior changes and dementia, according to health officials.

Teri described Batten disease as similar to a juvenile form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs disease. The two conditions share many of the same symptoms.

The condition occurs in an estimated two-to four-in-100,000 live births in the United States, according to the National Institute of Neurological Disorders and Stroke (NINDS).

His parents immediately set to work to advocate on behalf of their child, working hard to raise the $3.5 million that would be needed in order to fund life-saving gene therapy research for Sebi and other children with CLN8. They founded the Sebastian Velona Foundation (SVF) to help raise the necessary funds.

Over the past several years, the family has advocated for gene therapy for their son after discovering successful forms of gene therapy to battle CLN6, another form of the disease.

In 2018, Senator Scott Wilk, R-Santa Clarita, sponsored a bill that designated the first weekend in June as Batten Disease Awareness Week. Wilk was made aware of the deadly disease and the need for more awareness after Chris Velona, Sebis father, traveled to Sacramento and sought out support for his son, as well as the thousands of other children and their families who have been affected by the disease.

Unfortunately, due to Food and Drug Administration (FDA) guidelines and other safety regulations, it has taken more than three years to reach the point where gene therapy research is able to take place. The SVF partnered with Columbus, Ohio-based Nationwide Childrens Hospital, which had placed gene therapy on the map according to Teri.

Nationwides Childrens Hospitals gene therapy program was bought by another company, before eventually being acquired by Amicus Therapeutics approximately 18 months ago.

Unfortunately for us because of the regulations, and the changing of the companies and the acquisitions, were kind of confused as to where were at, Teri said. Its really slowed us down.

The gene therapy is now in the process of being transferred back to Nationwide Childrens Hospital in order to complete the process and bring the result to human trials as quickly as possible.

Although Nationwide Childrens Hospital is more than willing to perform the research, they simply do not have the budget available to fund the project. The funding for the final stretch of research instead falls to the Velona family, with a price of at least $500,000.

We need to raise $500,000 and we need to do it yesterday, Teri said. We need to do this now and get the word out there, that there are so many with Batten disease that we could help with this gene therapy. As the pioneer, its going to get less expensive to bring this treatment to the masses.

According to Teri, the gene therapy treatment can not only halt the progression of the disease, but also save Sebis life as well as the lives of others affected by it. Without treatment, it is highly likely that within a few years at most, his condition will progressively deteriorate until he is unable to speak, see, walk, or even eat, until he would eventually die.

Teri worries that all families can do is wait for funds and treatment, knowing that waiting will only worsen their childs condition and quality of life.

We dont have the time to wait if he gets any worse we dont want to leave him in a state where its not a good quality of life, she said.

According to his mother, as of early June, Sebi is barely able to see, his speech is muddled and often unrecognizable, his cognitive thinking has deteriorated, and his physical and motor skills have so declined that he is unable to write or walk unaided. He is deteriorating on a daily basis, she said.

This is my son, he was fine, it just happened so fast, Teri said. Now were scrambling, kicking down any door, looking for anyone that will hear us, listen to us. We cant just watch our son deteriorate and die. Im not a good mom if I sit there and do nothing.

The news about new funding and the delays in gene therapy comes just as Sebi lost one of his grandfathers to COVID-19 in April, a death that has been devastating for him, according to his mother.

Hes very frustrated and sad. He keeps asking When is the gene therapy? asking me It was going to be soon, where is it? Teri said. Its my job to take care of him and fix him, and I cant fix him. So its hard.

Teri says that her 16-year-old son understands what is happening to him and why he cant go to school or get a drivers license like other teens his age, but he keeps a positive outlook through the difficulties he experiences every day, and even attempts to comfort her whenever the frustration becomes too much to handle.

He has an amazing attitude he wants to help people with his hugs, she said. If he saw me crying right now he would lose it, and be hugging me, and petting me and telling me, Mom its going to be okay, Im going to get gene therapy.

Although his body is failing him, it is Sebis good attitude about the situation that helps motivate his family, according to his mother.

He is so positive in his outlook that he makes me a better mom. Im not allowed to get down, or cry, or get frustrated, or kick and scream, Teri said. Im mad this gene therapy is taking so long. But Im so grateful that we have this opportunity to actually get a treatment

After receiving funding for gene therapy treatment, Teri and the SVF plan to continue helping other children with CLN8 around the world, and to help others with rare diseases.

Everyone deserves a chance, she said. The disease can be stopped by one injection, replacing the good gene with the bad gene. It baffles me.

In a literal race against time, the doctors at National Childrens Hospital and the Velona family remain dedicated to making sure that the gene therapy goes to trial before it is too late to save Sebastian and the other children like him.

Im not going to let my baby go that way, we need to fight, we need to raise money, its worth everything, Teri said. I know there are so many amazing charities out there, but you can actually save some childrens lives right now.

To support gene therapy research for Sebi, or to learn more about the SVF, click here.

KHTS FM 98.1 and AM 1220 is Santa Claritas only local radio station. KHTS mixes in a combination of news, traffic, sports, and features along with your favorite adult contemporary hits. Santa Clarita news and features are delivered throughout the day over our airwaves, on our website and through a variety of social media platforms. Our KHTS national award-winning daily news briefs are now read daily by 34,000+ residents. A vibrant member of the Santa Clarita community, the KHTS broadcast signal reaches all of the Santa Clarita Valley and parts of the high desert communities located in the Antelope Valley. The station streams its talk shows over the web, reaching a potentially worldwide audience. Follow @KHTSRadio on Facebook, Twitter, and Instagram.

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Family Of Dying Santa Clarita Teen Pleads With Community For Donations To Fund Life-Saving Treatment - KHTS Radio

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Botond Roska, a Hungarian neurobiologist researching in Switzerland, will receive the Krber Foundations prestigious award, the Krber European Science Prize, which recognizes a single European scientist each year, alternating between life sciences and physical sciences. The Hungarian physician, one of the worlds leading experts in the study of vision and the retina, is to be awarded for his work that revolutionised ophthalmology.

According to the website of the Krber Foundation, the Hungarian neurobiologist Botond Roska has set himself the goal of restoring sight to the blind. Roska and his research group in Switzerland investigate how various cell types in the visual system extract visual information from the environment. Based on molecular mechanisms, they have designed novel gene therapies for restoring vision in genetic forms of blindness. The scientist has carried out pioneering work to identify approximately one hundred different cell types in the retina and their complex interplay in signal processing.

The Krber European Science Prize honors outstanding and excellent scientists working in Europe. The prize is awarded to research projects that show great potential for possible application and international impact. In the last ten years alone, the Krber Prize winners included six scientists who were later awarded the Nobel Prize.

Roska is now working on making these fundamental insights beneficial for patients and using gene therapies to alleviate or cure their diseases. A genuine breakthrough was achieved by reprogramming a cell type in the eye, enabling it to take over the function of defective light receptor cells. He was thus able to make blind retinas light-sensitive again and clinical trials with blind people have already begun.

Hungarian-born Researcher Awarded for Helping People Regain Their Sight

In 2019, Roska was awarded the Louis-Jeantet Prize for Medicine for the discovery of basic principles of visual information processing and the development of therapeutic strategies, such as gene therapy, to restore vision in retinal disorders. He is also the first Hungarian to earn the Bressler Prize for his vision-restoring therapy, and the Alden Spencer Prize for understanding the vision process.

Later last year, President Jnos der decorated the neurobiologist with the Hungarian Saint Stephen Order on August 20th, Hungarys national holiday. der referred to Roska as a doctor who does not treat patients but enables others to heal through his research.

August 20 Saint Stephen Order Goes to Outstanding Neurobiologist Botond Roska

The father of the world-renowned researcher was electrical engineer Tams Roska, founder of the research of neural networks in Hungary. Botond Roska, although first studying cello at the Liszt Ferenc Academy of Music in Budapest, had to give up his music career because of an injury. He later received his medical degree from Semmelweis University, a PhD in neurobiology from the University of California, Berkeley, and studied genetics and virology at Harvard University. Roska currently works in Basel, Switzerland as co-director of the Institute of Ophthalmology Basel (IOB).

The Krber European Science Prize 2020 will be presented to Roska on7 September in the Great Festival Hall of Hamburg City Hall.

featured photo: Nomi Bruzk/MTI

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Hungarian Neurobiologist Botond Roska to Receive This Year's Krber European Science Prize - Hungary Today

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