What are the emerging opportunities in the Point-of-Care Genetic Testing Market?

Currently, significant business sectors are going through changes. This has prompted huge benefits for a few and misfortunes for other people. To make the most out of the emerging chances, you can exploit the most granted Point-of-Care Genetic Testing market report. It offers nitty-gritty experiences into the market. This will doubtlessly manage their organizations in creating the following move over the impending industry quarters.

It must be noticed that the Point-of-Care Genetic Testing market is encountering unexpected ascent in reception by numerous new players (from MNCs to SMEs). It is because of the way that even with the market turbulences the Global market came out with solid numbers. With the new business running into the market, it is basic to stand apart from the group. The customers can undoubtedly accomplish this utilizing the means referenced in the Point-of-Care Genetic Testing market report.

What type of investigation is done in the Point-of-Care Genetic Testing market report?

Analysis of various socioeconomics for venturing into the market is important as it will hugely affect the development throughout the following coming years. The Point-of-Care Genetic Testing market report is planned subsequent to doing long periods of exploration and the information sifted through in the report was gathered from dependable sources, for example, government sites.

As the market is gigantic, it turns out to be imperative to comprehend the market from its underlying foundations. Get a superior perspective on the Point-of-Care Genetic Testing market through the data referenced in the committed areas of the report. With this, the customers likewise get a perspective on the business structure of the contenders.

What are the reasons that impact the growth of the Point-of-Care Genetic Testing Market?

As of late, the advanced transformation has pushed the associations in changing into a computerized business for coming to the intended interest group present over the globe. The Point-of-Care Genetic Testing market report shares the significance of neighborhood language, partners, and political situation that will drive the Global market higher than ever.

With the best possible comprehension of the Point-of-Care Genetic Testing market, the associations can hop onto the open doors that will bring productive outcomes. The customers can exploit the biggest in-house information base for taking the most effective actions. Likewise, the Point-of-Care Genetic Testing market report has committed segments covering the insights concerning the current market players. With the information on how they function and accomplish their objectives, your business can likewise be formed as needs be.

What type of analysis short-term or long-term is added in the Point-of-Care Genetic Testing Market report?

This is important to sidestep any negative circumstances that may affect the development of the organizations. In addition, the associations need to comprehend Porters five powers that shape the market elements. In the event that the customers wish to add or eliminate the names of the organizations, it tends to be done, to suit the desires for the clients, for accomplishing long-haul objectives. SWOT investigation helps in uncovering the qualities and shortcomings of the business. The PESTLE investigation helps in checking the outer elements that shape the market overall. Subsequently, for making a name in the Point-of-Care Genetic Testing market, it gets important to get thought from both SWOT and PESTLE investigations.

The Point-of-Care Genetic Testing market report likewise brushes over the significance of language and partners for the smooth working of the associations. Thusly, the customers are stacked with data and steps and are prepared to move into the market for accomplishing the ideal objectives.

About Us:

Verified Market Reports is a leading Global Research and Consulting firm servicing over 5000+ customers. Verified Market Reports provides advanced analytical research solutions while offering information enriched research studies. We offer insight into strategic and growth analyses, Data necessary to achieve corporate goals, and critical revenue decisions.

Our 250 Analysts and SMEs offer a high level of expertise in data collection and governance use industrial techniques to collect and analyze data on more than 15,000 high impact and niche markets. Our analysts are trained to combine modern data collection techniques, superior research methodology, expertise, and years of collective experience to produce informative and accurate research.

Contact us:

Mr. Edwyne Fernandes

US: +1 (650)-781-4080UK: +44 (203)-411-9686APAC: +91 (902)-863-5784US Toll-Free: +1 (800)-7821768

Email: [emailprotected]

Read more:
Point-of-Care Genetic Testing Market Size, Analysis, Regional Outlook, Competitive Strategies and Forecasts to 2027 - Cheshire Media

Recommendation and review posted by Bethany Smith

Possible TMI alert: You know that sleepless feeling when youre curled up on your sleeping side and one nostril is so stuffed you cant breathe so you switch to the other side to give it a break then that one stuffs too? Tired of this cycle, I met with Jason Erdan, the head herbalist at Alchemist Kitchen in NYC, a botanical dispensary dedicated to connecting you with the power of plants. to find out the best supplements to fight fall allergies.

The benefit of herbalism is that often one can find a plant based equivalent for manyeven mostallopathic (or Western) remedies with fewer side effects, says Erdan. When it comes to finding relief for allergies, Erdan explains that the first step is to know exactly what youre up against. Seasonal allergies are the bodys immune responses to common allergens entering your system. This results in your body releasing T-cells (parts of the immune system that attack foreign particles) to clean up and remove the invader. This stimulates the inflammatory response and releases histamine, causing allergic symptoms. To find the internal balance to both relieve and prevent these symptoms, Erdan says one has to understand the symptoms, the system, and the individual. Allergies arent coming to me for a consultation, the person that has them is, says Erdan. And they want a personalized plan based on everything from their current habits, exercise routine, supplement regimen, sleep schedule, and diet.

While both over-the-counter and prescribed antihistamines are helpful to combating allergens, they can often come with side effects like drowsiness. Erdans main recommendation for the majority of individuals struggling with seasonal allergies is to consult with ones physician first, and then incorporate adaptogens like ashwagandha, and mushrooms, like reishi, into ones diet.

Why? Ashwagandha is an adaptogen that helps manage stress and inflammation in the body by controlling our cortisol (or stress hormone) and blood sugar levels. This means if the immune system is depressed, this anti-inflammatory, immune-boosting adaptogen enhances the immune response. If the immune system is overactivelike with allergiesit helps to regulate and promote homeostasis (the balance of bodily functions).

Reishi mushrooms (Ganoderma lucidum), known as lingzhi in Chinese, are also high in antioxidants and can act as natures natural antihistamine. They are stimulants that help regulate the Th1 levels, which are responsible for battlingintracellular parasites within the body and inhibiting inflammatory compounds.

Erdan always recommends discussing any large changes with your physician, but he stresses that along with all of the more clinical remedies that we often turn to, the foods that you do and dont eat are a huge contributing factor to combating inflammation of all kinds, especially seasonal allergies. After taking Erdans advice, my ever-present allergy attacks have become more and more sporadic and much less aggressive, and I couldnt be more grateful. So the next time you feel those peskyor in my case, debilitatingallergies coming along, make sure to talk to your doc, but also take a peek at your diet and try to squeeze some adaptogens and healthy mushrooms into your routine.

View original post here:
The Two Things an Herbalist Wants You To Take To Stop Cold-Weather Allergies in Their Tracks - Well+Good

Recommendation and review posted by Bethany Smith

Recent reports suggest that both clinical and genetic risk factors may contribute to COVID-19 susceptibility and severity. Catherine Ball, Chief Scientific Officer of Ancestry, discusses results of the companys COVID-19 Research Study, designed to explore non-genetic and genetic associations with disease outcomes.

ONE OF THE more puzzling aspects of SARS-CoV-2, the causative agent of COVID-19, is that infection can produce a remarkably diverse spectrum of outcomes, ranging from asymptomatic to fatal. In the US, most infections result in mild illness that can be managed at home, yet about 14 percent of cases are hospitalised and approximately five percent are fatal.

Known risk factors for severe COVID-19, as identified by epidemiological studies, include common health conditions such as hypertension, diabetes and obesity as well as older age and male sex. For example, reports of higher susceptibility to and severity of SARS-CoV-2 infections in men could suggest important differences in immune response to the virus in men relative to women.

The growing toll of the COVID-19 pandemic has heightened the urgency of identifying those who are most at risk of infection and severe outcomes

Emerging evidence suggests that genetic variation may contribute to COVID-19 susceptibility and severity. An early genome-wide association study (GWAS) of COVID-19 cases with respiratory failure identified two genetic loci that achieved genome-wide significance: one signal on chromosome 9 near the ABO gene, which determines blood type, and one signal on chromosome 3 near a cluster of genes with known immune function.1 Both genetic signals were later replicated by meta-analyses conducted by the COVID-19 Host Genetics Initiative (HGI), which combines more than 30 individual GWAS. The HGI additionally identified novel associations on chromosome 6, near FOXP4; on chromosome 12, near a gene cluster encoding antiviral restriction enzyme activators; on chromosome 19 near TYK2; and on chromosome 21, near IFNAR2. Multiple studies have also reported evidence of rare-variant associations, though such discoveries have not yet successfully been replicated in independent cohorts.

The growing toll of the COVID-19 pandemic has heightened the urgency of identifying those who are most at risk of infection and severe outcomes; hence, the need for further investigation to assess patterns of susceptibility and severity in large datasets. The Ancestry COVID-19 Research Study, one of the largest studies of infection susceptibility and severity to date, was designed to:

To replicate and discover non-genetic and genetic associations with COVID-19 outcomes, we engaged AncestryDNA adult members in the US a majority of the 18 million individuals in our global network. On 22 April 2020, we issued a 54-question COVID-19 survey intended to assess exposure, risk factors, symptomatology and demographic information that had previously been identified as associated with COVID-19 susceptibility and severity. Within four weeks, more than 500,000 AncestryDNA customers from all 50 states who consented to participate in research responded, including more than 4,700 individuals with COVID-19, as measured by a selfreported positive nasal swab test. All data were de-identified prior to subsequent analyses.

Rates of hospitalisation calculated from the self-reported positive cases in the Ancestry data are consistent with characteristics seen in a CDC data analysis (10 percent of individuals reported hospitalisation in the Ancestry data compared to 14 percent in the CDC dataset). In addition, these data represent a unique view of the US population, including the range of symptoms experienced by those who tested positive for COVID-19 as well as those who have been exposed to SARSCoV-2 but have not experienced any symptoms. From these self-reported outcomes, we assessed susceptibility by comparing those who reported a positive COVID-19 nasal swab test result to those who reported a negative swab test result. We also looked at severity by comparing COVID-19 positive individuals who were hospitalised to COVID-19 positive individuals who were not hospitalised.

We observed significant associations between several risk factors and COVID-19 susceptibility and severity outcomes.2 Given the scale of our database, we were able to account for known exposures to COVID-19 to try to understand potential risk factors not explained by differences in exposures, which has not been accounted for in most other work. We found males were more likely than females to test positive for COVID-19 (odds ratio [OR]=1.36), even among people with the same known exposures to COVID-19 and age. This exposureadjusted result is novel and distinct from previous reports of elevated severity risk in males. Among those who tested positive for COVID-19, males (6.6 percent) were more likely than females (3.9 percent) to report progression to a critical case of the virus, consistent with CDC findings.

People aged 18-29 reported higher exposure to COVID-19 than all other age groups and were at a slightly elevated risk (OR=1.28) for positive diagnosis compared to those aged 50-64, even among people with the same exposure and sex. People aged 65 and older were significantly more likely to be hospitalised (OR=1.60) compared to those aged 50-64, even when accounting for differences in health conditions, obesity and biological sex.

We identified three novel loci indicating genetic associations with COVID-19 outcomes

AfricanAmericans were more likely to develop COVID-19 (OR=1.23) and were also significantly more likely to report progression to a critical case compared to those with European ancestry (OR=2.34), after accounting for health conditions, obesity, age and biological sex. We developed risk models to robustly predict individualised COVID-19 outcomes and were able to accurately predict an individuals susceptibility risk based on self-reported demographics, exposures and symptoms. We trained a peer-reviewed susceptibility model3 on our training cohort and found that our models perform slightly better (Ancestry area under a curve [AUC]=0.94, Litmodel AUC=0.90). We were also able to accurately predict an individuals severity risk based on selfreported demographics, preexisting conditions and symptoms. The severity risk models performed slightly better than previously reported clinical models despite not relying on clinical risk factors (eg, bloodwork), suggesting that selfreported data can be used to accurately assess risk of both susceptibility and severity in lieu of clinical data. We assessed the risk models across different age, sex and genetic ancestry cohorts and we can report reasonably high performance in all cohorts; highlighting the potential utility and generalisability of these models to the broader population. To our knowledge, the assessment by genetic ancestry is the first of its kind in the COVID-19 risk modelling literature.

To explore possible differences in biological response to COVID-19 infection, we analysed both susceptibility and severity outcomes using sex-stratified GWAS and sex-combined meta-analyses to identify genetic determinants associated with COVID-19 susceptibility and severity from more than 500,000 respondents reporting COVID-19 symptoms, outcomes, risk factors and exposures. These analyses included over 2,400 individuals with COVID-19 and 250 hospitalised cases in a cohort of European ancestry individuals.

Importantly, we identified three novel loci indicating genetic associations with COVID-19 outcomes.4 The strongest association was near IVNS1ABP, a gene involved in influenza virus replication, and it was only associated in males. It is unclear why this association is present only in males, though it may provide a clue as to why males appear to be at higher risk of COVID-19 infection, hospitalisation and mortality. We speculate that sex hormones or behavioural differences might trigger different cellular responses to COVID-19 infection in men and in women, and one such difference may involve differential expression of IVNS1ABP. The other two novel loci harbour genes with established roles in viral replication or immunity.

Our results add to a growing body of evidence that individual genetic variation contributes to both susceptibility to COVID-19 and severity of illness. These results also suggest that identification of these genetic risk factors could provide profound insight into why COVID-19 manifests differently in individuals, particularly in men.

This research highlights the value of selfreported epidemiological data at scale to provide public health insights into the evolving COVID-19 pandemic. Further, these survey responses, coupled with genomic data for over 500,000 individuals who have consented to research, provides Ancestry with the unique ability to quickly contribute to the global effort to better understand this disease. We are working to gain a deeper understanding of COVID-19 by investigating genomic and clinical components that influence how people contract and respond to the virus. We know that this information may be useful in the effort to develop treatments, preventatives or vaccines for the disease. In that spirit, we are making a subset of data from this study available to other qualified scientists through the European Genome-phenome Archive (EGA) to help inform their research.

Cathy Ball, PhD has served as Chief Scientific Officer for AncestryDNA, LLC since September 2016. She joined as Vice President of Genomics and Bioinformatics in 2011, helping to establish the companys approach to genetic genealogy leading to the launch of AncestryDNA. Cathy is a genomic scientist who has annotated and mined the genomes of various organisms and created resources to help clinicians, citizens and other scientists exploit and explore genome data. Cathy also led the Stanford Microarray Database, the largest academic database of its kind. She has presented seminars at leading universities and contributes to National Institutes of Health committees. She received a BS in Biology and a PhD in Molecular Biology from the University of California, Los Angeles. Cathy was a post-doctoral fellow at the University of California, Berkeley prior to her research in the Departments of Genetics and Biochemistry at Stanford University School of Medicine.

See more here:
Predicting COVID-19 susceptibility and severity - Drug Target Review

Recommendation and review posted by Bethany Smith

We know from history that traumatic experiences in childhood can have long-lasting effects, impacting both the physical body and our mental health. Research has shown that these stressful experiences in life can also impact the offspring of individuals whom have endured trauma.This contradicts some of the basic underpinnings of genetic hereditary. How can experiences in life affect our gametes the sperm and egg cells which pass on hereditary information through DNA to our offspring? Scientists are focusing on the role that the epigenome plays here.

The epigenome, which regulates gene activity by mechanisms which, put simply, involve "switching on" and "switching off" of genes, can be influenced by biological molecules.

A new study led by Professor Isabelle Mansuy at the University of Zurich's Brain Research Institute explored how circulating factors in the blood communicate with the embryonic precursors of gametes (germ cells) in both animal models and human participants.1Mansuy and colleagues focused their efforts on studying the biological impact of trauma. They found that traumatic experiences in early life cause changes in the blood composition namely metabolites that are passed on to the next generation.

Technology Networks spoke with Mansuy to learn more about the field of epigenetic inheritance, the specifics of the study and the possible impact these data may have on matters of public health.

Molly Campbell (MC): Your new study contributes to a research field known as epigenetic inheritance. For our readers that may be unfamiliar, can you please tell us more about this field of research, and its applications?Isabelle Mansuy (IM): This field of research studies a form of heredity that has hardly been studied before and that involves epigenetic factors. Heredity is classically known as depending on genetics, and our genetic code (or genome), which is transferred from parent to offspring through gametes (reproductive cells: oocyte and sperm cell). This is innate heredity, which is the inheritance of natural or intrinsic traits. But there is also acquired heredity, which is the inheritance of traits acquired during life upon exposure to the environment and life experiences. This form of inheritance depends on the epigenome, which are factors around the DNA sequence that regulate its activity. The applications are broad, and include a better understanding of diseases linked to the environment/experiences such as psychiatric disorders, autoimmune diseases, cardiovascular diseases, cancer, etc whose causes and mechanisms remain poorly known and which have no treatment.

MC: Epigenetic inheritance is a field that has been deemed "controversial" in the past. In your opinion, are attitudes towards the research area changing? IM: Yes, because people realize how fundamental it is, and how it can answer questions that have remained unsolved for a long time, like the complex diseases, the transmission of the effects of life experiences (diet, stress or endocrine disruptors). Also, there is now a lot more evidence for its existence. Many studies and reports now document epigenetic inheritance in various species.

MC: Why did you decide to focus on the effects of trauma specifically in your study?IM: We are neurobiologists interested in brain functions and in the mechanisms of brain diseases, in particular psychiatric disorders. The possibility that adverse experiences in childhood can alter mental and physical health later in life and affect future generations is an extremely important public health issue. It needs to be understood mechanistically to help patients, doctors and the society.

MC: Why did you hypothesize that blood metabolites (an example of circulating factors) carry signals induced by exposure to germ cells? What previous research supported this hypothesis?IM: The hypothesis stems from our observation that many cells and tissues are affected by trauma exposure in early life and that some of the changes are comparable across tissues, suggesting that there is a common inducing factor. It was logical to think of blood since it provides nutrient to all tissues and cells across the body. The fact that blood factors can communicate with germ cells was not known before, it was even deemed impossible mid-19th century by August Weissmann, purely based on a theory he put forward that the soma cannot communicate with the germline (the Weismann barrier). It relied, for instance, on the observation that if you cut the tail of a mouse at each generation, the offspring will never be born with a cut tail. This theory was erroneous from the start but somewhat blocked proper thinking for a long time.

MC: In mice, you found that exposure to trauma upregulated certain metabolic pathways, and that this upregulation was also detected in the male progeny of these mice in adulthood. Can you expand on the metabolic pathways that you analyzed and why, and what the key results were?IM: Some metabolites are up-regulated but others are down-regulated. We analysed all metabolites by mass spectrometry (unbiased method) and observed that lipid metabolism is perturbed with polyinsaturated fatty acids metabolites being increased. We also saw that glucose and insulin are dysregulated.

MC: You also assessed the relevance of these findings in a cohort of children, specifically children from an SOS Children's Village in Lahore, Pakistan. Can you discuss the choice of human sample used in this study? Why is it representative? Are there any potential limitations?IM: The Pakistani cohort was selected to resemble as much as possible our mouse model. The children were separated from their mother after their lost their husband (father). Our mouse model uses unpredictable maternal separation combined with unpredictable maternal stress. It is representative of a severe family trauma. The limitations are that it is a small cohort (25 SOS and 14 controls) however we have now expanded this sample and that we have blood samples from only one time point. Ideally, we would like to follow the children across time. A positive point though is that we have a small group of adult men who were in the SOS village when younger and who do show changes in blood (this data is not published).

MC: How did the results of the human analyses compare to the results you obtained in mice?IM: There are lots of similarities in symptoms of trauma e.g. depression, and in physiological parameters e.g. altered glycemia, dyslipidemia, decreased HDL, etc

MC: What can the data tell us about how trauma is altering metabolic pathways, and why this might be passed on to the next generation?IM: We do not know exactly how trauma alters metabolic pathways, but it is likely by perturbing liver, pancreas, the endocrine system, etc. The effects are systemic, and every tissue is affected. The effects of trauma are passed to the next generation (demonstrated in mice) because germ cells (here sperm) carry molecular alterations e.g. altered RNA populations, that are passed to the embryo upon fertilization with the oocyte.

MC: What clinical applications might this research have?IM: Perhaps the identification of a signature of trauma in blood, saliva and/or sperm which could help diagnostics and treatment monitoring.

MC: Finally, what are your next steps in this research space?IM: Identify the mechanisms responsible for changes in germ cells (male and female) and how these changes are perpetuated/maintained in the offspring.

Professor Isabelle Mansuy was speaking to Molly Campbell, Science Writer for Technology Networks.

Reference:

1. van Steenwyk G, Gapp K, Jawaid A, et al. Involvement of circulating factors in the transmission of paternal experiences through the germline. EMBO J.. 2020;39(23):e104579. doi:10.15252/embj.2020104579.

Visit link:
Exploring the Biological Inheritance of Childhood Trauma - Technology Networks

Recommendation and review posted by Bethany Smith

The Conversation

The world is eagerly awaiting the release of several COVID-19 vaccines, but Brazilian President Jair Bolsonaro is not. Im not going to take it. Its my right, he said in a Nov. 26 social media broadcast. Bolsonaro, who came down with COVID-19 in July, has also criticized face masks. He and his more faithful supporters oppose any suggestion of mandatory coronavirus vaccinations. Vaccine resistance has a long history in Brazil. In November 1904, thousands of people in the city of Rio de Janeiro protested government-mandated smallpox vaccinations in a famous revolt that nearly ended with a coup. Making modern BrazilThe smallpox vaccine had arrived in Brazil almost a century earlier. But the syringes were long, left skin pockmarked and could transmit other diseases such as syphilis. Between 1898 and 1904, only 2% to 10% of Rios population was vaccinated yearly, according to historian Sidney Chalhoub. In 1904, smallpox killed 0.4% of Rio residents a higher percentage of the population than COVID-19s victims in New York City this year.But these were not the only reasons Brazil made vaccinations mandatory in 1904. As part of a modernization plan to attract European immigration and foreign investment, President Rodrigues Alves was committed to eradicating epidemics not just smallpox, but also yellow fever and the bubonic plague.To rid Rio de Janeiro, then the nations capital, of sanitary hazards while opening space for Parisian-style avenues and buildings, hundreds of tenements were demolished between 1903 and 1909. Almost 40,000 people mostly Afro-Brazilians but also poor Italian, Portuguese and Spanish immigrants were evicted and removed from downtown Rio. Many were left homeless, forced to resettle on nearby hillsides or in distant rural areas. Meanwhile, public health agents accompanied by armed police systematically disinfected homes with sulfur that destroyed furniture and other belongings whether residents welcomed them or not. Conspiracy and barricadesPoliticians and military officers who opposed President Alves saw opportunity in the outrage these health initiatives caused. They stoked discontent.With the help of labor organizers and news editors, Alves opponents led a campaign against Brazils public health mandates throughout 1904. Newspapers reported on violent home disinfections and forced vaccinations. Senators and other public figures declared that mandatory vaccinations encroached on peoples homes and bodies.In mid-November of that year, thousands of protesters gathered in public squares to rally against public health efforts. Rio police reacted with disproportionate force, triggering six days of unrest in the city. A racially diverse crowd of students, construction workers, port workers and other residents fought back, armed with rocks, housewares or the tools of their trade, flipping over streetcars to barricade the streets. Meanwhile, behind the scenes, conspirators were mobilizing young military cadets. Their plan: to overthrow Alves government. Their scheme was foiled when the president called upon both the Army and the Navy to contain protesters and detain alleged insurgents. Brazils great vaccine revolt was soon suppressed. The language of rightsAfterward, newspapers portrayed protesters as an ignorant mass, manipulated by cunning politicians. They deemed one of the uprisings popular leaders, Horcio Jos da Silva known as Black Silver a disorderly thug.But Brazils vaccine revolt was more than a cynical political manipulation. Digging into archives, historians like me are learning what really motivated the uprising.The violent and segregationist features of Alves urban plan are one obvious answer. In early 20th-century Brazil, most people women, those who couldnt read, the unemployed couldnt vote. For these Brazilians, the streets were the only place to have their voices heard.But why would they so virulently oppose methods that controlled the spread of disease?Delving into newspapers and legal records, I have found that critics of Brazils 1904 public health drive often expressed their opposition in terms of inviolability of the home, both on the streets and in courts.For elite Brazilians, invoking this constitutional right was about protecting the privacy of their households, where men ruled over wives, children and servants. Public health agents threatened this patriarchal authority by demanding access to homes and womens bodies.Poor men and women in Rio also held patriarchal values. But for them there was more than privacy at stake in 1904. Throughout the 19th century, enslaved Afro-Brazilians had formed families and built homes, even on plantations, carving out spaces of relative freedom from their masters. After slavery was abolished in 1888, many freed Afro-Brazilians shared crowded tenements with immigrants. By the time of Alvess vaccination drive, the poor of Rio had been fighting eviction and police violence for decades. For Black Brazilians, then, defending their rights to choose what to do or not to do with their homes and bodies was part of a much longer struggle for social, economic and political inclusion. Deadly learning experienceFour years after the 1904 revolt, Rio was struck by another smallpox epidemic. With so many people unvaccinated, deaths doubled; almost 1% of the city perished.[Deep knowledge, daily. Sign up for The Conversations newsletter.]It was a deadly learning experience. From then on, Brazilian leaders framed mandatory smallpox, measles and other vaccines as a means to protect the common good, and invested in educational campaigns to explain why. Throughout the 20th century, vaccinations were extremely successful in Brazil. Since the 1990s, 95% of children have been vaccinated, though the numbers are dropping.Today, Brazil is one of the countries hardest hit by the coronavirus pandemic. As in the past, Afro-Brazilians are hurting more than others.By invoking Brazilians individual right not to get vaccinated against COVID-19, President Bolsonaro is ignoring the lessons of 1904 undermining a century of hard work fighting disease in Brazil.This article is republished from The Conversation, a nonprofit news site dedicated to sharing ideas from academic experts. It was written by: Pedro Cantisano, University of Nebraska Omaha.Read more: * COVID-19 is deadlier for black Brazilians, a legacy of structural racism that dates back toslavery * In Brazils raging pandemic, domestic workers fear for their lives and theirjobsPedro Cantisano does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

Read more from the original source:
Man caught breaking into Tom Brady and Gisele Bndchen's Massachusetts mansion - Yahoo News

Recommendation and review posted by Bethany Smith

Following a frustrating year plagued by transport restrictions caused by Covid-19 and tilapia lake virus, Til-Aquarecently decided to branch out from selling live tilapia fry a move that has netted them the first of a new breed of deal this week.

Like many other companies, we are currently confronted with transport issues limited available flights and closed borders due to the coronavirus. The import restrictions that some countries have imposed regarding the tilapia lake virus had already severely limited our current operations. As a result, we decided to change course drastically so as not to lose 25 years of genetic effort: we have put our genetics for sale to interested parties, explains Eric Bink, director of the Dutch firm.

Til-Aquas first deal in the new era has been signed with Gardsfisk, a fast-growing tilapia producer in Sweden. According to Bink, they will need about 3 million tilapia fingerlings for their own company and partners net year, which would make it a very significant deal by European standards.

They will start producing NMT soon and in a few months also YY production. There are several other YY genetic centres to be set up soon (Saudi Arabia, Algeria, Morocco, US, Tanzania) and we are now in advanced negotiations for transferring the YY technology to various parties worldwide, adds Bink.

Despite the radical shift, Bink's plans appear to have been validated.

We believe that transferring our YY technology to countries for local YY production is the best option. These parties would own YY-males and YY-females and would receive the information on how to maintain these lines. With these fish, they can produce their own YY-males; the broodstock that produces NMT [natural male tilapia] offspring. These YY-males can be both used for your own NMT production and distributed to interested parties. [our own] NMT production has since stopped. We will be able to supply our YY-males until the end of December 2020, he adds.

Excerpt from:
The pivot that's helping a tilapia producer cope with covid restrictions - The Fish Site

Recommendation and review posted by Bethany Smith

The Conversation

The world is eagerly awaiting the release of several COVID-19 vaccines, but Brazilian President Jair Bolsonaro is not. Im not going to take it. Its my right, he said in a Nov. 26 social media broadcast. Bolsonaro, who came down with COVID-19 in July, has also criticized face masks. He and his more faithful supporters oppose any suggestion of mandatory coronavirus vaccinations. Vaccine resistance has a long history in Brazil. In November 1904, thousands of people in the city of Rio de Janeiro protested government-mandated smallpox vaccinations in a famous revolt that nearly ended with a coup. Making modern BrazilThe smallpox vaccine had arrived in Brazil almost a century earlier. But the syringes were long, left skin pockmarked and could transmit other diseases such as syphilis. Between 1898 and 1904, only 2% to 10% of Rios population was vaccinated yearly, according to historian Sidney Chalhoub. In 1904, smallpox killed 0.4% of Rio residents a higher percentage of the population than COVID-19s victims in New York City this year.But these were not the only reasons Brazil made vaccinations mandatory in 1904. As part of a modernization plan to attract European immigration and foreign investment, President Rodrigues Alves was committed to eradicating epidemics not just smallpox, but also yellow fever and the bubonic plague.To rid Rio de Janeiro, then the nations capital, of sanitary hazards while opening space for Parisian-style avenues and buildings, hundreds of tenements were demolished between 1903 and 1909. Almost 40,000 people mostly Afro-Brazilians but also poor Italian, Portuguese and Spanish immigrants were evicted and removed from downtown Rio. Many were left homeless, forced to resettle on nearby hillsides or in distant rural areas. Meanwhile, public health agents accompanied by armed police systematically disinfected homes with sulfur that destroyed furniture and other belongings whether residents welcomed them or not. Conspiracy and barricadesPoliticians and military officers who opposed President Alves saw opportunity in the outrage these health initiatives caused. They stoked discontent.With the help of labor organizers and news editors, Alves opponents led a campaign against Brazils public health mandates throughout 1904. Newspapers reported on violent home disinfections and forced vaccinations. Senators and other public figures declared that mandatory vaccinations encroached on peoples homes and bodies.In mid-November of that year, thousands of protesters gathered in public squares to rally against public health efforts. Rio police reacted with disproportionate force, triggering six days of unrest in the city. A racially diverse crowd of students, construction workers, port workers and other residents fought back, armed with rocks, housewares or the tools of their trade, flipping over streetcars to barricade the streets. Meanwhile, behind the scenes, conspirators were mobilizing young military cadets. Their plan: to overthrow Alves government. Their scheme was foiled when the president called upon both the Army and the Navy to contain protesters and detain alleged insurgents. Brazils great vaccine revolt was soon suppressed. The language of rightsAfterward, newspapers portrayed protesters as an ignorant mass, manipulated by cunning politicians. They deemed one of the uprisings popular leaders, Horcio Jos da Silva known as Black Silver a disorderly thug.But Brazils vaccine revolt was more than a cynical political manipulation. Digging into archives, historians like me are learning what really motivated the uprising.The violent and segregationist features of Alves urban plan are one obvious answer. In early 20th-century Brazil, most people women, those who couldnt read, the unemployed couldnt vote. For these Brazilians, the streets were the only place to have their voices heard.But why would they so virulently oppose methods that controlled the spread of disease?Delving into newspapers and legal records, I have found that critics of Brazils 1904 public health drive often expressed their opposition in terms of inviolability of the home, both on the streets and in courts.For elite Brazilians, invoking this constitutional right was about protecting the privacy of their households, where men ruled over wives, children and servants. Public health agents threatened this patriarchal authority by demanding access to homes and womens bodies.Poor men and women in Rio also held patriarchal values. But for them there was more than privacy at stake in 1904. Throughout the 19th century, enslaved Afro-Brazilians had formed families and built homes, even on plantations, carving out spaces of relative freedom from their masters. After slavery was abolished in 1888, many freed Afro-Brazilians shared crowded tenements with immigrants. By the time of Alvess vaccination drive, the poor of Rio had been fighting eviction and police violence for decades. For Black Brazilians, then, defending their rights to choose what to do or not to do with their homes and bodies was part of a much longer struggle for social, economic and political inclusion. Deadly learning experienceFour years after the 1904 revolt, Rio was struck by another smallpox epidemic. With so many people unvaccinated, deaths doubled; almost 1% of the city perished.[Deep knowledge, daily. Sign up for The Conversations newsletter.]It was a deadly learning experience. From then on, Brazilian leaders framed mandatory smallpox, measles and other vaccines as a means to protect the common good, and invested in educational campaigns to explain why. Throughout the 20th century, vaccinations were extremely successful in Brazil. Since the 1990s, 95% of children have been vaccinated, though the numbers are dropping.Today, Brazil is one of the countries hardest hit by the coronavirus pandemic. As in the past, Afro-Brazilians are hurting more than others.By invoking Brazilians individual right not to get vaccinated against COVID-19, President Bolsonaro is ignoring the lessons of 1904 undermining a century of hard work fighting disease in Brazil.This article is republished from The Conversation, a nonprofit news site dedicated to sharing ideas from academic experts. It was written by: Pedro Cantisano, University of Nebraska Omaha.Read more: * COVID-19 is deadlier for black Brazilians, a legacy of structural racism that dates back toslavery * In Brazils raging pandemic, domestic workers fear for their lives and theirjobsPedro Cantisano does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

Visit link:
Man Killed In Hudson Stabbing Identified As New Brighton Man; 2 Persons Of Interest Arrested In Minnesota - Yahoo News

Recommendation and review posted by Bethany Smith

The Conversation

The world is eagerly awaiting the release of several COVID-19 vaccines, but Brazilian President Jair Bolsonaro is not. Im not going to take it. Its my right, he said in a Nov. 26 social media broadcast. Bolsonaro, who came down with COVID-19 in July, has also criticized face masks. He and his more faithful supporters oppose any suggestion of mandatory coronavirus vaccinations. Vaccine resistance has a long history in Brazil. In November 1904, thousands of people in the city of Rio de Janeiro protested government-mandated smallpox vaccinations in a famous revolt that nearly ended with a coup. Making modern BrazilThe smallpox vaccine had arrived in Brazil almost a century earlier. But the syringes were long, left skin pockmarked and could transmit other diseases such as syphilis. Between 1898 and 1904, only 2% to 10% of Rios population was vaccinated yearly, according to historian Sidney Chalhoub. In 1904, smallpox killed 0.4% of Rio residents a higher percentage of the population than COVID-19s victims in New York City this year.But these were not the only reasons Brazil made vaccinations mandatory in 1904. As part of a modernization plan to attract European immigration and foreign investment, President Rodrigues Alves was committed to eradicating epidemics not just smallpox, but also yellow fever and the bubonic plague.To rid Rio de Janeiro, then the nations capital, of sanitary hazards while opening space for Parisian-style avenues and buildings, hundreds of tenements were demolished between 1903 and 1909. Almost 40,000 people mostly Afro-Brazilians but also poor Italian, Portuguese and Spanish immigrants were evicted and removed from downtown Rio. Many were left homeless, forced to resettle on nearby hillsides or in distant rural areas. Meanwhile, public health agents accompanied by armed police systematically disinfected homes with sulfur that destroyed furniture and other belongings whether residents welcomed them or not. Conspiracy and barricadesPoliticians and military officers who opposed President Alves saw opportunity in the outrage these health initiatives caused. They stoked discontent.With the help of labor organizers and news editors, Alves opponents led a campaign against Brazils public health mandates throughout 1904. Newspapers reported on violent home disinfections and forced vaccinations. Senators and other public figures declared that mandatory vaccinations encroached on peoples homes and bodies.In mid-November of that year, thousands of protesters gathered in public squares to rally against public health efforts. Rio police reacted with disproportionate force, triggering six days of unrest in the city. A racially diverse crowd of students, construction workers, port workers and other residents fought back, armed with rocks, housewares or the tools of their trade, flipping over streetcars to barricade the streets. Meanwhile, behind the scenes, conspirators were mobilizing young military cadets. Their plan: to overthrow Alves government. Their scheme was foiled when the president called upon both the Army and the Navy to contain protesters and detain alleged insurgents. Brazils great vaccine revolt was soon suppressed. The language of rightsAfterward, newspapers portrayed protesters as an ignorant mass, manipulated by cunning politicians. They deemed one of the uprisings popular leaders, Horcio Jos da Silva known as Black Silver a disorderly thug.But Brazils vaccine revolt was more than a cynical political manipulation. Digging into archives, historians like me are learning what really motivated the uprising.The violent and segregationist features of Alves urban plan are one obvious answer. In early 20th-century Brazil, most people women, those who couldnt read, the unemployed couldnt vote. For these Brazilians, the streets were the only place to have their voices heard.But why would they so virulently oppose methods that controlled the spread of disease?Delving into newspapers and legal records, I have found that critics of Brazils 1904 public health drive often expressed their opposition in terms of inviolability of the home, both on the streets and in courts.For elite Brazilians, invoking this constitutional right was about protecting the privacy of their households, where men ruled over wives, children and servants. Public health agents threatened this patriarchal authority by demanding access to homes and womens bodies.Poor men and women in Rio also held patriarchal values. But for them there was more than privacy at stake in 1904. Throughout the 19th century, enslaved Afro-Brazilians had formed families and built homes, even on plantations, carving out spaces of relative freedom from their masters. After slavery was abolished in 1888, many freed Afro-Brazilians shared crowded tenements with immigrants. By the time of Alvess vaccination drive, the poor of Rio had been fighting eviction and police violence for decades. For Black Brazilians, then, defending their rights to choose what to do or not to do with their homes and bodies was part of a much longer struggle for social, economic and political inclusion. Deadly learning experienceFour years after the 1904 revolt, Rio was struck by another smallpox epidemic. With so many people unvaccinated, deaths doubled; almost 1% of the city perished.[Deep knowledge, daily. Sign up for The Conversations newsletter.]It was a deadly learning experience. From then on, Brazilian leaders framed mandatory smallpox, measles and other vaccines as a means to protect the common good, and invested in educational campaigns to explain why. Throughout the 20th century, vaccinations were extremely successful in Brazil. Since the 1990s, 95% of children have been vaccinated, though the numbers are dropping.Today, Brazil is one of the countries hardest hit by the coronavirus pandemic. As in the past, Afro-Brazilians are hurting more than others.By invoking Brazilians individual right not to get vaccinated against COVID-19, President Bolsonaro is ignoring the lessons of 1904 undermining a century of hard work fighting disease in Brazil.This article is republished from The Conversation, a nonprofit news site dedicated to sharing ideas from academic experts. It was written by: Pedro Cantisano, University of Nebraska Omaha.Read more: * COVID-19 is deadlier for black Brazilians, a legacy of structural racism that dates back toslavery * In Brazils raging pandemic, domestic workers fear for their lives and theirjobsPedro Cantisano does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

Read the original here:
Something Good: Local Man Celebrates The Holidays And The Steelers - Yahoo News

Recommendation and review posted by Bethany Smith

What Is Cryogenics?

Cryogenics is the study of how materials behave at very low temperatures.

This field of study helps us understand the chemical changes which occur when a substance reaches the lowest possible temperature of -273.

Presently this knowledge has been applied to the field of death care as human bodies are now being frozen in hopes of reanimating them in the future.

About 350 people all over the world have chosen to have their bodies frozen immediately after death.

Lots of paperwork must take place long before death if the cryogenic process is to take place.

Clients must complete all the necessary documentation and make sure funding is in place well ahead of time.

The freezing process must begin within 2-15 minutes after the person has been declared legally dead.

Then the body is packed in ice and injected with chemicals to keep the blood from clotting.

A special machine called a heart-lung resuscitator artificially restores circulation and breathing.

The body is then transported to a long-term care facility for final cooling and perfusion, a process in which the patients blood is slowly and carefully replaced by special substances to protect against ice formation.

They are then slowly cooled to a temperature of -196 and preserved in liquid nitrogen in a special storage unit called a cryostat.

For most of us, this idea seems creepy yet weirdly hopeful at the same time.

It reads like the plot of the most far-fetched science fiction novel.

But is it possible that this science fiction may simply becomescience?

As you can imagine, the issue is by no means simple.

Here are the different schools of thought on whether this is medical science or wishful thinking.

In 2015, the MIT Technology Review published an article debunking cryonics as a false science.

Their main point is that human consciousness is much too complex to recreate.

Even reconstructing the consciousness of a roundworm, a far less complex organism than humans are, remains beyond us.

In addition, we have no evidence that major organs such as the heart and the kidneys could be successfully frozen and thawed.

Promoters of cryonics declare that indeed there are other specimens of life which have been frozen and reanimated.

These include insects, vinegar eels, and even embryos which later became human children.

Recent advances in biology point to the hope that we can do even greater things in the future.

We already know that victims of cardiac arrest can sometimes be saved through lowering body temperature. Who is to say that we couldnt use it to save more people at some later time?

As you can well imagine, there are many misunderstandings about this radical approach to post-death care.

Here we debunk some of these common myths.

Although its true that the process of cryonics involves lowering your bodys temperature substantially, its not at all the same process as simply throwing something in the freezer.

The chemicals placed in your cells (through a process called vitrification) actually protect tissue and organs from freezing.

The goal is simply to slow all molecular movement to a standstill so that the body can be preserved in its original state.

We now understand that death is not an abrupt event. In fact, its a lengthy process which happens in stages.

Medically, a person is declared dead when his/her heart stops beating.

However, life processes continue within cells and tissue until they gradually cease and begin to decay due to the lack of oxygenated blood.

In cryonics, the patient is stabilized before this gradual decay can begin. Tissue and organs are kept viable through artificial means, similar to the emergency procedures employed for cardiac arrest patients.

As with most controversial issues in the medical field, there are some experts who support cryonics and others who do not.

Unfortunately, the credibility of cryonics has been undermined by some bad press and over-sensationalized reporting.

Because of this controversial reputation, there are some scientists who have dismissed the idea without bothering to research it thoroughly.

In spite of this, there are at least 60 prominent scientists who have publicly endorsed cryonics by signing an open letter in support of it.

There is still a considerable amount of work to do to secure legal rights for cryonicists.

In most states, the next of kin has the right to determine what happens to a loved ones body after death. Even if the deceased person has a legal contract with a cryonics facility, their wishes are often undermined by family members who bury or cremate them instead.

However, representatives of cryonics facilities are diligent about going to court to fight for the rights of those with whom they have legal contracts. In many cases, they can even file an injunction to stop an autopsy.

Because this is still a new method, there are still some ethical questions around it which remain unclear.

For example, if the cryonic facility runs out of money or the technology fails, does it still have a duty to care for the patients entrusted to them?

On a more existential level, can we even preserve all the complex components of a persons true identity?

If someone is successfully reanimated 30 years from now, would they be able to function as their true self in a society thats sure to be radically different from what they remember?

These are all questions that the cryonics community still needs to grapple with.

So assuming you want to preserve your body after death for future revival, who can you go to?

There are two reputable American organizations worth looking into if this route holds any appeal for you.

The Cryonics Institute offers an impressive level of stability.

Here are some of the advantages to choosing this company.

The mission of the Cryonics Institute, as stated on their website, is to provide the highest possible quality at the lowest possible cost.

As a non-profit, they are committed to benefiting their members.

The Institute asserts a passionate belief in the possibility of a radical extension of the human lifespan, giving patients a second chance at life, youth and health as expressed in Robert Ettingers 1962 book The Prospect of Immortality.

The Cryonics Institute was founded back in 1976 by Robert Ettinger, the scientist credited with starting the cryonics movement.

Ettinger became a celebrity after the publication of The Prospect of Immortality. He appeared on talk shows and spoke with newspapers and magazines on the topic.

In 2004, vitrification became part of the cryopreservation process, based on the work of researchers Greg Fahy and William F. Rall.

Since their beginning in 1976, the Cryonics Institute has cryopreserved a total of 100 patients who are still successfully preserved at the facility.

The Cryonics Institute is owned by the membership and governed by a board of twelve directors, all of whom demonstrate personal passion for the ideals of immortality that cryonics represents.

They have established a rapid and effective system incorporating the best aspects of emergency medicine and mortuary care.

They have teams of funeral directors specially trained in the science of cryonics. These highly skilled and effective teams can be dispatched anywhere in the world when their services are urgently needed.

Another leader in the newly-emerging field of cryonics, Alcor is a reputable organization to look into if you want to explore the option of cryopreservation.

Here are the things you need to know.

Alcor is a non-profit organization based in Scottsdale, AZ.

Founded in 1972, they specialize in cryonics research and technology.

Members have the ability to use life insurance towards the cost of cryopreservation.

Presently, Alcor is working on technology to preserve the information in the brain which comprises memory and identity.

Alcor has clearly prioritized the five components of their mission as follows:

Maintain the current patients in biostasis.

Place current and future members into biostasis (when and if needed).

Eventually restore all patients in Alcors care to health and reintegrate them into society.

Fund research into developing more cost-effective and reliable means for 1-3 above.

Provide public education as a means of fostering growth to support the goals of 1, 2, 3, 4 above.

As of the end of 2019, Alcor has a total of 177 patients in its care.

129 of these patients are male; 46 of them are female.

Their first suspension was in 1967, carried out while Alcor still went by the name of the Cryonics Society of California.

The most recent was a 77-year-old man who had been a member of Alcor since 2000.

The number of patients in cryonic suspension with Alcor has risen steadily since its founding.

The cost of cryonics can be prohibitive, as it is much more expensive than other deathcare options.

The Cryonics Institute typically charges a one-time cost of $28,000, which can be covered by life insurance. This cost includes storage as well as vitrification perfusion.

For a whole body cryopreservation, Alcor charges $200,000, also payable through a life insurance policy. There is also an option to preserve only the patients head for $80,000.

The practice of cryonics demands a radical reimagining of everything we thought we knew about death.

Maybe death isnt as final as we have always believed.

If this is true, then it opens up a whole new way of thinking about our post-death rituals.

Naturally this leaves us with many questions.

Here are some of the most common questions about cryonics.

As of this writing, no human has yet been revived after their body temperature has been lowered to a level far below freezing.

However, the point of cryonics lies in the hope that technology will eventually advance enough to allow this to happen.

There is an expectation that the field of molecular nanotechnology will discover ways to reverse any damage caused by the cryonics process.

To that end, cryonics patients are cared for until such time as they can be revived safely.

This question is tricky, because there are multiple definitions of dead.

By law, the cryonics process cannot begin until the patient is legally dead.

Usually, a medical professional declares someone legally dead if they have stopped breathing, their heart has stopped beating, or brain activity has ceased due to the removal of life support.

But the philosophy behind cryonics is that we will one day have the ability to resuscitate these patients.

Breathing and blood circulation are restored immediately after legal death so that essential organs continue to function.

For that reason, cryonics patients are not considered dead. Instead, the term cryopreserved is used.

Ideally, the cryonics process should begin as soon as possible after the heart stops beating, usually around one or two minutes and certainly not more than fifteen.

If it takes longer, the process of restoration could pose more of a challenge.

Thats because any decay of the circulatory system can make it more difficult to circulate the chemicals necessary to prevent ice formation.

The most affordable way to fund cryonic suspension is by purchasing a life insurance policy in which you name the cryonics facility as the primary beneficiary.

To do this, you just have to purchase a life insurance policy in an amount sufficient to cover the cost of cryopreservation. Then you make a monthly payment.

Read more from the original source:
Cryonics In 2020 Guide: Will It Replace Burial and Cremation?

Recommendation and review posted by Bethany Smith

hormone clinic, testosterone therapy, bio-identical hormones, growth hormone prescription

At Hormone Logics we believe aging better should be effortless, and with our bioidentical hormone therapy, diet, nutraceutical, and exercise programs, this goal is definitely within reach.

We focus on Individualizing Hormone Therapy for Men and Women specializing in Hormone Replacement for approved indications of Low Testosterone Replacement Therapy for men and Menopause for women. Our Medical Team at Hormone Logics is committed to restoring your health and vitality. While we cannot prevent aging, we can help you manage it so you feel younger, healthier, and more vibrant.

Hormone Logics provides American Hormone Replacement Therapy for Men & Women across the USA including those living in New Jersey and Hudson, NJ County.

Hormone Logics specializes in anti-aging and hormone replacement for men and women in Hudson County, New Jersey. This includes Human Growth Hormone-HGH Therapy, Testosterone Therapy, Hormone Deficiency Education, Therapy for Testosterone Deficiency, Therapy for Erectile Dysfunction, Andropause Therapy, Menopause Therapy, Growth Hormone Deficiency, Peptides for Men & Women, Sermorelin Therapy, Ipamorelin Acetate Therapy, GHRP-6 & GHRP-2 Therapy, CJC-1295 Therapy, BPC-157 Therapy, PT-141 Therapy, Adrenal Imbalances, Insulin Imbalance, Thyroid Functional Imbalance, Medical Weight Loss With HCG, Lipotropic Weight Loss Injections, Fitness & Nutrition Programs, Nutraceuticals & Blood Tests. Hudson, NJ

The rest is here:
Hudson Hormone Replacement Therapy and Anti-Aging in ...

Recommendation and review posted by Bethany Smith

Getting some education on Bio-Identical Hormone Replacement Therapy (BHRT) is important! The question is: How much do you know about your hormones?

The fact remains that most medical professionals do not understand nor do they specifically treat hormone deficiency. Why? Thats a good question to ask. The good news is we are experts in the field of hormone deficiency. Specifically in using Bio-Identical Hormone Replacement Therapy to treat our patients. LoveJoy Hormone Clinic providers (combined) have treated THOUSANDS of patients and performed over 10,000 procedures. That is a lot!

More importantly, we only treat through the combination of scientific (blood analysis) and anicdodal (patient symptoms). Not to mention, we listen to our patients and only provide therapy if they need it.

Sodo a little homework and request our FREE BHRT E-book above. Then, you will be empowered to make the decision to call us for your FREE consultation.

At LoveJoy Hormone Clinic, we get it! We have the solution using bio-identical hormone replacement that lasts months. There are no creams, pills, or shots to take every day or week. We use only the best pellets individually customized for all of our hormone therapy patients. Best yet, our clinic is managed by Joy Melby, NP-C who has performed thousands of hormone replacement procedures. She is classified as an expert in the field of Bioidentical Hormone Replacement.

See original here:
LoveJoy Home | LOVEJOY Hormone Clinic

Recommendation and review posted by Bethany Smith

ByThe Associated Press

December 1, 2020, 5:17 PM

2 min read

LONDON -- Britains High Court ruled Tuesday that children under 16 years old who are considering gender reassignment are unlikely to be able to give informed consent to medical treatment involving drugs that delay puberty.

The ruling said that because of the experimental nature of the drugs, clinics should seek court authorization before starting such treatment, even in cases of teens aged 16 or over.

The case was brought by two claimants against a National Health Service trust that runs the U.K.s main gender identity development service for children. One of the claimants, who was prescribed hormone blockers at 16, argued that the clinic should have challenged her more over her decision to transition to a male.

Tuesdays ruling will protect vulnerable young people, said Keira Bell, who is now 23 and has stopped taking cross-sex hormones. She added that she was delighted to see that common sense has prevailed.

I wish (the judgement) had been made before I embarked on the devastating experiment of puberty blockers. My life would be very different today, she said outside the court.

Hormone blockers are drugs that can pause the development of puberty, and are sometimes prescribed to help children with gender dysphoria by giving them more time to consider their options.

Lawyers for Bell and the other claimant the mother of a 15-year-old autistic girl on the waiting list for treatment said that children going through puberty are not capable of properly understanding the nature and effects of hormone blockers.

They argued that children who start taking hormone blockers are highly likely to later take cross-sex hormones, which they say cause irreversible changes.

Health officials involved in the case argued that taking hormone blockers and later cross-sex hormones were entirely separate stages of treatment.

But on Tuesday, three judges ruled that children under 16 are unlikely to understand and weigh both the immediate and long-term consequences of the treatment to be able to consent to the use of puberty blockers. They said that puberty blocking drugs are a pathway to much greater medical interventions because a vast majority of patients taking the drugs go on to take cross-sex hormones.

The Tavistock and Portman NHS Trust, which runs the gender clinic, said it would seek permission to appeal against the ruling.

The trans childrens charity Mermaids said the ruling was devastating for trans young people in the country.

Read more:
UK court rules against clinic in puberty blocking drugs case - ABC News

Recommendation and review posted by Bethany Smith

Approximately one in 11 persons in the United States has been affected by kidney stones; among those who have experienced a kidney stone, the likelihood of recurrence is high, with up to 50% developing a recurrent stone within 10 years of the first episode. Hyperparathyroidism (PHPT) is evident in approximately 3% to 5% of patients with kidney stones and screening for PHPT is a strategy aimed at reducing the recurrence rate. Patients with kidney stones and PHPT present with hypercalcemia and hypercalciuria, raising the risk for stones by increasing urine supersaturation for calcium oxalate or phosphate.

Guidelines from the American Urological Association and the European Association of Urology call for measurement of serum calcium in patients with kidney stones, followed by the serum parathyroid level (PTH) if there is clinical suspicion for PHPT. It is unknown whether patients with kidney stones receive those recommended screenings in clinical practice. Results of a previous study suggested that fewer than one in four veterans with persistent hypercalcemia treated in the Veterans Health Administration (VHA) were screened for PHPT.

Calyani Ganesan, MD, MS, and colleagues conducted a cohort study to examine the prevalence of PTH testing in veterans with kidney stones and hypercalcemia. The researchers also sought to identify the demographic, geographic, and clinical characteristics of veterans who were more or less likely to receive PTH testing. The study was designed to test the hypothesis that the frequency of PTH testing remains low despite current clinical practice guidelines and that a wide variation in screening practices is not adequately explained by patient-specific or facility-level factors. Results of the study were reported online in JAMA Surgery [doi:10.1001/jamasurg.2020.2423].

The study utilized VHA health records to identify patients with kidney stones and hypercalcemia who received care in one of the 130 VHA facilities across the United States from January 1, 2008, through December 31, 2013. Patients with kidney stones were those with one or more inpatient International Classification of Diseases, Ninth Revision (ICD-9) codes for kidney or ureteral stones, two or more outpatient ICD-9 codes for kidney or ureteral stones, or one or more Current Procedural Terminology codes for kidney or ureteral stone procedures within 1 year. Exclusion criteria included previous screening for PHPT, defined as those with a PTH level measurement between 6 and 30 months prior to the index stone diagnosis.

Data collection occurred from January 1, 2006, to December 31, 2014. Data analysis occurred from June 1, 2009, to January 31, 2020. The primary outcomes of interest were the proportion of patients with a serum PTH level measurement and the proportion of patients with biochemical evidence of PHPT who underwent parathyroidectomy.

A total of 157,539 unique veterans were diagnosed with kidney stones during the study period. Of those, 139,115 had a serum calcium determination within 6 months of their index stone diagnosis, and 7381 had been previously screened with a serum PTH level measurement and were excluded. Following application of exclusion criteria, the final cohort comprised 7561 patients with kidney stones and measured hypercalcemia (n=3938) or albumin-corrected hypercalcemia (n=3623). Mean age of the final cohort was 64.3 years, 94.4% (n=7139) were men, 5.6% (n=422) were women, and 75.0% (n=5673) were white. Patients with hypercalcemia compared with those with normocalcemia (n=124,173) were more likely to have diabetes (39.8% vs 29.5%), impaired kidney function, defined as estimated glomerular filtration rate <45 mL/min/1.73 m2 (36.1% vs 15.1%), osteoporosis (4.4% vs 2.1%), and fractures (7.1% vs 4.2%).

Of the 7561 patients with kidney stones and hypercalcemia, 24.8% (n=1873) completed a serum PTH level measurement around the time of the initial stone diagnosis. In the 3938 patients with measured hypercalcemia, 34.8% (n=1369) completed a serum PHT level measurement; only 13.09% (n=504/3623) of the patients with albumin-corrected hypercalcemia did so. Of the 1873 veterans with PTH testing, 38.3% (n=717) had an elevated PTH level consistent with biochemical PHPT.

Results of multivariable logistic regression models demonstrated that the odds of PTH testing in patients with kidney stones and hypercalcemia were lower with older age (odds ratio [OR], 0.95 per decade; 95% confidence interval [CI], 0.90-1.00) and among patients with a history of metastatic cancer (OR, 0.63; 95% CI, 0.49-0.81). Patients with albumin-corrected hypercalcemia were less likely to complete PTH testing compared with patients with measured hypercalcemia (OR, 0.32; 95% CI, 0.28-0.37).

The odds of PTH testing were higher for patients who visited either a nephrologist or a urologist (OR, 1.56; 95% CI, 1.35-1.81), and much higher for those who visited both a nephrologist and a urologist (OR, 6.57; 95% CI, 5.33-8.10) compared with patients who did not visit a stone specialty clinic during the observation period.

Across the 130 VHA facilities in the United States, the prevalence of PHT testing among the veterans with kidney stones varied between 4.0% and 57.0%. The study researchers examined the composite complexity score assigned to each facility and found no association with PTH testing rate for each facility. None of the individual facility-level variables of the complexity score were associated with PTH testing across the 130 facilities. In a comparison of facilities in the top quartile versus the bottom quartile of the PTH testing, there was an association between PTH testing and the presence of stone specialty care at each facility. There was no association between PTH testing and the mean number of parathyroidectomies performed at each facility.

Study limitations cited by the authors included the high proportion of male participants, using a single definition of PHPT, and the inability to capture medical care for veterans with kidney stones who received care outside the VHA system.

In conclusion, the researchers said, In this cohort study, a generally low rate of PTH testing was found in veterans with kidney stones and hypercalcemia, and extensive variation in PTH testing rates was found across VHA facilities in the United States. More awareness of the level or frequency of elevated serum calcium concentration may be associated with higher rates of PTH testing in patients with kidney stones. Improved screening for PHPT could increase the rates of detection and treatment of PHPT and decrease stone recurrence associated with missed or untreated PHPT.

Takeaway Points

Original post:
Parathyroid Hormone Testing in Veterans with Kidney Stones and Hypercalcemia - DocWire News

Recommendation and review posted by Bethany Smith

Roughly one in four women will have one. You probably know one of them, whether shes told you about it or not. As of 2017, theyre at a record low rate in America, thanks in part to the Affordable Care Acts requirement that birth control is covered by private insurance as out-of-pocket costs. Sixty-one percent of Americans say it should be legal in all cases, but a considerable subsection of them, especially in the South, dont have reliable access to it. Thats right: were talking about abortion and the musicians who are working to preserve access to it.

If youve seen some of your faves posting about the issue on Instagram (Kim Gordon and Karen O doing it caught my eye), youve probably been seeing the work of a New Mexico-based initiative called Noise For Now. They play matchmaker between musicians who want to support reproductive rights, including abortion and local funds. They aim to destigmatize the conversation around abortion. Hence, part of their plan is to ask artists to post about the organization and why access to healthcare for women is essential. Co-founder and President Amelia Bauer moved to the Southwest from New York after the 2016 election and, while trying to find a way to get involved with local reproductive rights organizations, ended up organizing a concert to benefit the National Organization For Women. It outraised all the big donor dinners and galas they had been putting on.

The idea to work as a connector between those with a large audience your favorite musician and small, local abortion funds hits at a targeted play to provide access to reproductive health care that includes abortion to women who are systematically cut off from it. Since 2011, Texas has lost 25 clinics. In the Midwest, 33 clinics have shut down. In the South, its 50. Even after the TRAP (targeted regulation of abortion providers) laws that closed them were largely overturned by the courts, most of those clinics have not reopened. Theres no doubt that in specific regions of America, the right to choose is under attack. Meanwhile, 59 new womens health clinics opened in the Northeast. More and more, having access to reproductive care and abortion is a matter of how much money you have and where you live.

When you have state legislators working against the will of the people, they create barriers to abortion for people without means, Bauer explains. Anyone with means can travel to another state to access abortion if they cant reach it near their home. That means people who work multiple jobs, who cant get time off, who cant afford a plane or bus ticket, who cant afford childcare are left out of access to safe abortion. She notes that in the U.S., where most abortions are performed in clinics, the procedure is extremely safe, while in countries where it has been outlawed and criminalized, it becomes dangerous for women. Thats why Noise For Now focuses on working with funds that support and are run by Black, brown, indigenous, and undocumented people.

For Bauer, her work in New Mexico started with an eye on preserving the access that women in nearby states traveled to get and in making that travel and all the things that go with it, from the time off work to childcare, possible. The current Supreme Court, which leans more conservative than it has in generations, has caused many to worry about stripping away the landmark Roe vs. Wade ruling. It is what guarantees women the right to have an abortion under the Fourteenth Amendment right to privacy, as explained in the majority opinion by Justice Harry Blackmun a lifelong Republican. With the current slate of justices, Bauer predicts the worst, saying, I dont have a crystal ball, but I dont think its very likely it will survive this court.

Amanda Shires is all too aware of the restrictions placed on womens access to reproductive rights. In Tennessee, 96% of the counties have no facilities that provide abortions. The issue is also bleak for women in neighboring Alabama, Kentucky, and Mississippi the latter has only one clinic and three facilities in total where women can obtain an abortion.

Part of the problem is if people are out protesting [clinics], theyre protesting contraceptive services, HIV testing, hormone therapy, treatment for erectile dysfunction, and all kinds of stuff they dont even think about. And cancer screenings. And LGBTQA+ hormone therapy, Shires points out. She later continues, saying, What I try to do is say, to the best I can, is that Im on your side, whatever side of this you choose, in hopes people dont have to walk around feeling alone.

For Shires, who performed at Noise For Nows Voices For Choice event and the Pro Roe Tee Campaign for Planned Parenthood, talking about things is the most effective way to destigmatize them and affect change. It sometimes feels hard to make a change on your own because you cant. If you can align and affiliate and help and take action, then I dont know about you, but it makes me feel like I can sleep a tiny bit better at night, Shires says.

Shires released The Problem near the end of 2020. This song imagines a conversation between a couple discussing abortion, with proceeds benefitting the Yellowhammer Fund. This Alabama-based fund offers financial and logistic support to those in need of abortion in the state. Yellowhammer is also a fund that Noise For Now has supported. Its Executive Director Laurie Bertram Roberts points out that having these conversations in spaces where its typically verboten, namely among the conservative audiences of country music, is part of removing the stigma.

We need to be talking about how we make sure were having these conversions in spaces we may not think are welcoming, but are maybe more welcoming than we think they are, Roberts says and notes that some of the most significant legacies in country music have been all about womens issues.

Amandas song is one is a long legacy of country women artists giving social critique. It goes back to the first women in country music. It goes to Kitty Wells. It goes to Loretta Lynn and The Pill. Even Tammy Wynette singing D-I-V-O-R-C-E. All those things were controversial at the time, but it tells womens stories. Even Martina McBride talking about Independence Day. Those are women telling their stories in a way that made it accessible and acceptable to talk about those subjects.

See the original post:
Noise For Now Connects The Indie Scene To Support Women's Health Care - UPROXX

Recommendation and review posted by Bethany Smith

Medicine is ever-evolving on a daily basis. Keeping track of the changes can be an almost-full-time job.Stacker looked at a number of medical journals and media sources to discover the biggest breakthroughs the year you were born, from 1921 to the current day.

From diseases that have been around for decades, such as diabetes and the flu, to cutting-edge tools like artificial intelligence and 3D printing, explore how medical and scientific professionals continually conduct research and clinical trials to improve the lives of patients. Sometimes advances arent immediately adopted, as with the Pap smearthat wasnt integrated into womens health care for 16 years after it was invented. But other times the path from laboratory to everyday use is much more abbreviated, like with insulin, which was used to treat diabetes only a year after it was discovered.

Another recurring theme in medical history is the repurposing of medicines that have worked for one disease in the past, to see how theyll work with another. A number of drugs and vaccines are being re-explored to manage COVID-19. Not all the heroes of medical research come from a traditional backgroundone was an electric engineer who worked for a major record label. Some were recognized with the highest honors, but others still have little visibility decades after their death. Funding for the research behind the breakthroughs is always a considerationsometimes it comes from foundations and government entities, but other times via donations from individuals and enterprises.

The dark side of medical history shown here includes unethical behavior by researchers in the past, which explains why some in the Black community arent exactly early adopters when it comes to clinical trials and new treatment options.

Advances noted here focus not only on the body, but also the mind. Explore this slideshow to see all the ways that health care has changed over the past century.

You may also like: Countries with the best life expectancy

Read more here:
Medical history from the year you were born - Bryan-College Station Eagle

Recommendation and review posted by Bethany Smith

DARE-BV1 met the primary endpoint of the study and all pre-specified secondary efficacy endpoints; demonstrated significantly greater clinical cure rates compared to placebo

DARE-BV1 has Fast Track and QIDP designations from FDA

New drug application (NDA) submission planned 1H of 2021

SAN DIEGO, Dec. 07, 2020 (GLOBE NEWSWIRE) -- Dar Bioscience, Inc. (NASDAQ: DARE), a leader in womens health innovation, today announced positive topline results from the DARE-BVFREE Phase 3 randomized, double-blinded, placebo-controlled clinical trial evaluating DARE-BV1 in 307 women diagnosed with bacterial vaginosis, a serious condition estimated to affect approximately 21 million women in the United States. DARE-BV1 is an investigational thermosetting bioadhesive hydrogel containing clindamycin phosphate 2% designed as a convenient, one-time vaginally-administered treatment for bacterial vaginosis. The trial met its primary endpoint demonstrating that a single administration of DARE-BV1 was superior to placebo as a primary therapeutic intervention for women diagnosed with bacterial vaginosis.

Based on these topline results, DARE-BV1 delivered clinical cure rate values greater than those of currently marketed FDA-approved products for the treatment of bacterial vaginosis. This successful Phase 3 clinical trial marks another important achievement for Dar. We began 2020 with the announcement of a commercial partnership for Ovaprene with Bayer, marketer of one of the most successful contraceptive products in womens health, and were concluding the year with another exciting milestone, the successful completion of our Phase 3 clinical trial of DARE-BV1 to support an NDA for the treatment of bacterial vaginosis, said Sabrina Martucci Johnson, President and CEO of Dar Bioscience. We believe there is a large unmet need for a more efficacious and convenient, single-dose vaginally-administered product to treat bacterial vaginosis, and we believe DARE-BV1 could become a new front-line treatment option. DARE-BV1 received Fast Track designation from the FDA earlier this year and, based on the topline results of this trial, we plan to file our NDA in the first half of 2021.

Topline Results of the Phase 3 Randomized Clinical TrialDARE-BVFREE randomized 307 women at 32 centers across the United States in a 2:1 ratio to receive a single vaginal dose of DARE-BV1 (N=204) or a single vaginal dose of placebo gel (N=103) to be applied intravaginally within one day of randomization.

The primary endpoint for the study was clinical cure of bacterial vaginosis determined at the final study visit which occurred 21 to 30 days after study drug administration, also referred to as the test-of-cure (TOC) visit, in the modified intent-to-treat (mITT) study population (N=180). In accordance with U.S. Food and Drug Administration (FDA) guidance, the mITT population excludes subjects from the intent-to-treat (ITT) population (N=307) who subsequently demonstrated a positive test result for other concomitant vaginal or cervical infections at baseline.

A single vaginal dose of DARE-BV1 proved statistically superior to placebo at p-value < 0.001 at the TOC visit that occurred 21 to 30 days after study drug administration (primary efficacy endpoint) and also at the assessment visit that occurred 7 to 14 days after study drug administration. DARE-BV1 also demonstrated statistically significant efficacy in all four additional pre-specified secondary efficacy assessments. The clinical cure endpoint results are shown in the following table:

Summary of Clinical Cure Results (mITT Population), p-value < 0.001:

The clinical cure rate at the Day 21-30 visit for the ITT population was similar to that for the mITT population (70.1% for the DARE-BV1 group (N=204) and 36.9% for the placebo group (N=103), p-value < 0.001), demonstrating effectiveness of DARE-BV1 in treating bacterial vaginosis even when other concomitant vaginal or cervical infections were present.

The DARE-BVFREE studys two treatment arms were well balanced in terms of age, race, ethnicity, bacterial vaginosis history, and body mass index (BMI). The ITT population comprised primarily patients aged 15 to 51 years, with a mean age of 34.8 (standard deviation 8.84) and median age of 35. Over 53% of the ITT population qualified as obese (BMI 30.0), with a mean BMI of 31.50 (standard deviation 8.499). In the ITT population, 56.0% of women identified as Black or African American, 41% identified as white and 25.5% identified as of Hispanic or Latino origin (compared to 74.5% as not of Hispanic or Latino origin). In addition, more than 75% of the women in the ITT population reported one or more episodes of bacterial vaginosis diagnosed in the 12 months before they were randomized into the study (76.9% in the DARE-BV1 group and 73.8% in the placebo group).

DARE-BV1 was well-tolerated in the study. There were no early discontinuations due to adverse events (AEs), and the only serious AE occurred in a woman in the placebo group. In the DARE-BV1 group, 15.3% of patients reported AEs that were considered to be possibly, probably or definitely related to study treatment compared to 9.7% of patients in the placebo group.

Only two AEs were reported by more than 2% of patients in the DARE-BV1 arm and at a rate higher than in patients in the placebo arm vulvovaginal candidiasis, commonly called a vaginal yeast infection (17.2% in the DARE-BV1 group and 3.9% in the placebo group), and vulvovaginal pruritus, commonly referred to as vaginal itching (4.4% in the DARE-BV1 group and 1.9% in the placebo group). Over half of the vaginal yeast infections reported in the DARE-BV1 group and exactly half of those reported in the placebo group occurred in patients who exhibited a positive yeast culture prior to dosing.

"We believe these data demonstrate that DARE-BV1 is significantly effective in a representative patient population, including a large proportion of patients who have been previously treated for this infection. Today, about half of the patients treated for bacterial vaginosis experience recurrence of the infection within 12 months of their treatment, and currently marketed FDA-approved products for the treatment of bacterial vaginosis have clinical cure rates in the mid-30% to the high-60% range, said David Friend, PhD, Chief Scientific Officer of Dar Bioscience. If approved, we believe DARE-BV1 will be an important new and convenient one-time vaginally-administered treatment option with the potential to improve clinical outcomes and overall quality of life for women suffering with bacterial vaginosis.

Based on the topline results from the study, Dar expects to have a pre-NDA meeting with the FDA in early 2021 and to submit an NDA during the first half of 2021. DARE-BV1 received both Fast Track and Qualified Infectious Disease Product (QIDP) designations from the FDA for the treatment of bacterial vaginosis. Given these designations, the NDA could be eligible for priority review, which, if granted, could allow for a 2021 PDUFA date, and, assuming approval, an early 2022 commercial launch in the U.S.

About the Phase 3 Study

DARE-BVFREE was a randomized, multicenter, double-blind, placebo-controlled study of a single administration of DARE-BV1 (clindamycin phosphate vaginal gel, 2%) compared to a single administration of placebo vaginal gel (HEC Universal Placebo Gel) for the treatment of bacterial vaginosis. Patients were evaluated during three clinic visits: Day 1 (screening and randomization visit), Day 7-14 (assessment visit), and Day 21-30 (TOC visit). Clinical cure was defined as resolution of the specific clinical signs that comprise the Amsel criteria; specifically, resolution of abnormal vaginal discharge associated with bacterial vaginosis, clue cells less than 20% of total epithelial cells on microscopy, and a negative 10% KOH whiff test. The total study duration was approximately one month for each individual patient.

About Bacterial Vaginosis

Bacterial vaginosis is the most common cause of vaginitis worldwide and is estimated to affect approximately 21 million women in the United States.1,2 Prevalence of bacterial vaginosis among non-white women in the U.S. is higher than among white women (African American 51%, Mexican American 32%, white 23%).2 While there are several therapeutic options for women in the U.S. diagnosed with bacterial vaginosis, currently approved options have relatively insufficient clinical cure rates, require sequential daily administrations or can be otherwise inconvenient for women to use. It is estimated that as many as 50% of women treated for bacterial vaginosis will experience a recurrence within 12 months of their treatment.3

About DARE-BV1

DARE-BV1 is an investigational thermosetting bioadhesive hydrogel containing clindamycin phosphate 2% being evaluated as a one-time, vaginally-administered treatment for bacterial vaginosis.

About Dar Bioscience

Dar Bioscience is a clinical-stage biopharmaceutical company committed to the advancement of innovative products for womens health. The companys mission is to identify, develop and bring to market a diverse portfolio of differentiated therapies that expand treatment options, improve outcomes and facilitate convenience for women, primarily in the areas of contraception, vaginal health, sexual health, and fertility.

Dars product portfolio includes potential first-in-category candidates in clinical development: Ovaprene, a hormone-free, monthly contraceptive intravaginal ring whose U.S. commercial rights are under a license agreement with Bayer; Sildenafil Cream, 3.6%, a novel cream formulation of sildenafil to treat female sexual arousal disorder utilizing the active ingredient in Viagra; DARE-BV1, a unique hydrogel formulation of clindamycin phosphate 2% to treat bacterial vaginosis via a single application; and DARE-HRT1, a combination bio-identical estradiol and progesterone intravaginal ring for hormone replacement therapy following menopause. To learn more about Dars full portfolio of womens health product candidates, and mission to deliver differentiated therapies for women, please visit http://www.darebioscience.com.

Dar may announce material information about its finances, product candidates, clinical trials and other matters using the Investors section of its website (http://ir.darebioscience.com), SEC filings, press releases, public conference calls and webcasts. Dar will use these channels to distribute material information about the company, and may also use social media to communicate important information about the company, its finances, product candidates, clinical trials and other matters. The information Dar posts on its investor relations website or through social media channels may be deemed to be material information. Dar encourages investors, the media, and others interested in the company to review the information Dar posts in the Investors section of its website and to follow these Twitter accounts: @SabrinaDareCEO and @DareBioscience. Any updates to the list of social media channels the company may use to communicate information will be posted on the investor relations page of Dars website mentioned above.

Forward-Looking Statements

Dar cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, or the negative version of these words and similar expressions. In this press release, forward-looking statements include, but are not limited to, statements regarding Dars plans and strategies for regulatory approval and commercialization of DARE-BV1, including expected timing of Dars engagement with the FDA regarding an NDA for DARE-BV1, submission of an NDA for DARE-BV1, FDA review and approval of the NDA, and commercial launch of DARE-BV1 in the U.S. if approved; DARE-BV1s potential importance to and utilization by women with bacterial vaginosis, including its potential ability to improve clinical outcomes and overall quality of life compared to currently available therapeutic options for bacterial vaginosis if approved; and DARE-BV1s commercial potential. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Dars actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, without limitation, risk and uncertainties related to: the risk that topline results from a clinical trial, including the DARE-BVFREE study, are based on Dars preliminary analysis of key efficacy and safety data and, following a comprehensive review of study data, such results may change and topline results may not accurately reflect the complete results from the clinical trial; the risk that the FDA, other regulatory authorities or members of the scientific or medical communities may not accept or agree with Dars interpretation of or conclusions regarding the study data; Dars ability to raise additional capital when and as needed to advance its product candidates and continue as a going concern; the effects of the COVID-19 pandemic on Dars operations, financial results and condition, and ability to achieve current plans and objectives, including the potential impact of the pandemic on the ability of third parties on which Dar relies to assist in the conduct of its business, including its clinical trials, to fulfill their contractual obligations to Dar; Dars ability to develop, obtain regulatory approval for, and commercialize its product candidates; the failure or delay in starting, conducting and completing clinical trials or obtaining FDA or foreign regulatory approval for Dars product candidates in a timely manner; Dars ability to conduct and design successful clinical trials, to enroll a sufficient number of patients, to meet established clinical endpoints, to avoid undesirable side effects and other safety concerns, and to demonstrate sufficient safety and efficacy of its product candidates; the risk that positive findings in early clinical and/or nonclinical studies of a product candidate may not be predictive of success in subsequent clinical and/or nonclinical studies of that candidate; Dars ability to retain its licensed rights to develop and commercialize a product candidate; Dars ability to satisfy the monetary obligations and other requirements in connection with its exclusive, in-license agreements covering the critical patents and related intellectual property related to its product candidates; the risks that the license agreement with Bayer may not become effective and, if it becomes effective, that future payments to Dar under the agreement may be significantly less than anticipated or potential amounts; developments by Dars competitors that make its product candidates less competitive or obsolete; Dars dependence on third parties to conduct clinical trials and manufacture clinical trial material; Dars ability to adequately protect or enforce its, or its licensors, intellectual property rights; the lack of patent protection for the active ingredients in certain of Dars product candidates which could expose its products to competition from other formulations using the same active ingredients; the risk of failure associated with product candidates in preclinical stages of development that may lead investors to assign them little to no value and make these assets difficult to fund; cyber attacks, security breaches or similar events that compromise Dars technology systems or those of third parties on which it relies and/or significantly disrupt Dars business; and disputes or other developments concerning Dars intellectual property rights. Dars forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. For a detailed description of Dars risks and uncertainties, you are encouraged to review its documents filed with the SEC including Dars recent filings on Form 8-K, Form 10-K and Form 10-Q. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Dar undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Investors on behalf of Dar Bioscience, Inc.:Lee RothBurns McClellanEmail: lroth@burnsmc.com+1 212-213-0006

Source: Dar Bioscience, Inc.

Go here to see the original:
Dar Bioscience Announces Positive Topline Results From DARE-BVFREE, a Phase 3 Trial of DARE-BV1 in Patients Diagnosed with Bacterial Vaginosis -...

Recommendation and review posted by Bethany Smith

Touro College of Osteopathic Medicine Middletown student Atif Towheed, Ph.D., is researching the health care provider's role in vaccination

Please can you share a couple of your top findings to date?

One of the most significant findings was the need for more education about vaccination. Respondents said this was a need they had for themselves as well as for their patients. We also confirmed the widespread belief that social media plays a critical role in patients decision-making when it comes to vaccines. Additionally, we learned that practitioners confidence levels in discussing vaccines with patients varied significantly between rural and urban areas, with more confidence in urban settings.

What are some of the key factors that pose barriers to vaccination?

Our research showed that key factors posing barriers to vaccination include lack of education on vaccines, fear of becoming sick after vaccination, parental or patient hesitancy, and safety concerns. There are ways to combat these barriers by increasing awareness through patient-provider interactions, including discussions about the risks and benefits of vaccines during patient interactions on routine visits. Based on these findings, we recommend an education program tiered to target health professionals at various levels of their education and careers.

How did you come to research this topic?

The study was initiated in summer 2019 after a noted outbreak of measles in and around our community. Our team of five includes faculty and students at TouroCOM, Middletown and a representative from the Orange County Department of Health. The work grew out of a discussion about the critical importance of vaccination for preventing illness. Under the supervision of Dr. Stephanie Zeszutek, clinical associate professor in the Department of Primary Care, we considered how vaccines also help lower health care costs, especially given the increasing number of vaccine-preventable diseases in the United States.

Others have looked into the relationship between vaccination rates and the education and views/beliefs of health care providers. How is your study different?

Most studies have focused specifically on patient populations. Although there are reports on health care providers views and beliefs, most of them are limited either to specific vaccines or to examining specific health care provider categories. Our study covers views and perspectives on most of the vaccines available in the U.S. We also have a very diverse survey population of health care workers and students.

Please share your background and how you became interested in science.

I was born and raised in India. My parents are both zoologists - my father is an endocrinologist, and I spent a lot of time in his lab learning from him. My mother is an assistant professor of sericulture (the study of silkworms). Their work made enough of an impression on me that I decided to pursue science; at the same time, I like to interact with people, so medical practice was always in the back of my mind.

After receiving my masters degree in biotechnology in India, I joined a U.N. research lab where I studied viruses, including the now-infamous SARS coronavirus. In 2009, I came to the U.S. to earn my Ph.D. at the University of Pittsburgh School of Medicine, after which I accepted a postdoctoral fellowship at The Childrens Hospital of Philadelphia (CHOP).During these years of research, I studied and evaluated gene therapy for mitochondrial diseases, including a potential treatment for Leber Hereditary Optic Neuropathy, an inherited form of vision loss.

How did you finally end up in medical school and at TouroCOM?

During my research and training, I was always associated with hospitals, collaborating with physicians, and talking about patients. I wanted to interact with patients directly, but the final decision to apply to medical school came when my son was born and suffered birth trauma. His doctor was a DO at CHOP, and her management of his care was holistic and inspiring, leading me to finally apply - and to DO schools. My wife often travels to New York City on business, so we wanted to find a school nearby. I attended an open house at TouroCOM and loved the school and the faculty. Im grateful to TouroCOM for giving me the chance to follow my passion.

See the rest here:
Vaccination in the Era of Covid - Touro College News

Recommendation and review posted by Bethany Smith

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that new data from the pivotal Phase III MURANO and CLL14 studies support the efficacy of fixed-duration, chemotherapy-free Venclexta (venetoclax)-based combinations in certain people with chronic lymphocytic leukemia (CLL) and provide more evidence on the potential value of minimal residual disease (MRD). Data were presented at the all-virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition on Saturday, December 5, 2020.

These results reinforce the long-term value of fixed-duration, chemotherapy-free Venclexta-based combinations in CLL, potentially offering patients a significant period of time without treatment following initial therapy, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. These data also reflect our ongoing commitment to accelerating clinical advancements for patients by exploring the novel endpoint minimal residual disease as a potential predictor of patient outcomes.

Five-year data from the pivotal Phase III MURANO trial continue to show sustained investigator-assessed progression-free survival (PFS) with Venclexta plus Rituxan (rituximab). Data, presented in an oral session, showed:

Data from the Phase III CLL14 study contributes to growing evidence regarding the potential of MRD measurements to predict future outcomes for certain people with previously untreated CLL who were treated with fixed-duration Venclexta plus Gazyva (obinutuzumab):

Exploring novel endpoints, such as MRD, is an important area of development for Genentech, which continues to investigate Venclexta in a robust clinical development program. This includes the Phase III CRISTALLO trial in previously untreated CLL, which uses MRD as a primary endpoint.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States.

*Minimal residual disease (MRD) is a measure of the number of remaining cancer cells. Undetectable MRD (uMRD), sometimes referred to as MRD-negativity, means that no cancer cells could be detected using a specific and highly sensitive test, and is defined as less than one cancer cell in 10,000 leukocytes.

About the MURANO Study

MURANO [NCT02005471] is a Phase III open-label, international, multicenter, randomized study evaluating the efficacy and safety of fixed-duration Venclexta (venetoclax) in combination with Rituxan (rituximab) compared to bendamustine in combination with Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta, patients on the Venclexta plus Rituxan arm received six cycles of Venclexta plus Rituxan followed by Venclexta monotherapy for up to two years total. Patients on the BR arm received six cycles of BR. The study included 389 patients with chronic lymphocytic leukemia, with or without 17p deletion, who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta plus Rituxan or BR. The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About the CLL14 Study

CLL14 [NCT02242942] is a randomized Phase III study evaluating the combination of fixed-duration Venclexta (venetoclax) plus Gazyva (obinutuzumab) compared to Gazyva plus chlorambucil in adult patients with previously untreated chronic lymphocytic leukemia (CLL) and co-existing medical conditions. 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta alongside six-month duration of Gazyva (Arm A) or six-month duration of Gazyva alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva followed by a five-week Venclexta dose ramp-up to help reduce the risk of tumor burden. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints include PFS assessed by independent review committee, minimal residual disease (MRD) status, overall response rate, complete response rate (with or without complete blood count recovery), overall survival, duration of response, event-free survival, time to next CLL treatment, and safety. MRD-negativity, or undetectable MRD, means no cancer can be detected using a specific and highly sensitive test, and was defined as less than one cancer cell in 10,000 leukocytes. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, M.D., University of Cologne.

About CLL

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. In the United States, it is estimated that more than 20,000 new cases of CLL will be diagnosed in 2020. Although signs of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of cancerous cells.

About Venclexta

Venclexta is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States. Together, the companies are committed to research with Venclexta, which is currently being studied in clinical trials across several types of blood and other cancers.

In the United States, Venclexta has been granted five Breakthrough Therapy Designations by the U.S. Food and Drug Administration (FDA): one for previously untreated CLL, two for relapsed or refractory CLL and two for previously untreated acute myeloid leukemia.

Venclexta Indications

Venclexta is a prescription medicine used:

are 75 years of age or older, or have other medical conditions that prevent the use of standard chemotherapy.

It is not known if Venclexta is safe and effective in children.

Important Safety Information

What is the most important information patients should know about Venclexta?

Venclexta can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. The patients doctor will do tests to check their risk of getting TLS before they start taking Venclexta. The patient will receive other medicines before starting and during treatment with Venclexta to help reduce the risk of TLS. The patient may also need to receive intravenous (IV) fluids into their vein.

The patients doctor will do blood tests to check for TLS when the patient first starts treatment and during treatment with Venclexta. It is important for patients to keep appointments for blood tests. Patients should tell their doctor right away if they have any symptoms of TLS during treatment with Venclexta, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Patients should drink plenty of water during treatment with Venclexta to help reduce the risk of getting TLS.

Patients should drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before the first dose on the day of the first dose of Venclexta, and each time a dose is increased.

The patients doctor may delay, decrease the dose, or stop treatment with Venclexta if the patient has side effects. When restarting Venclexta after stopping for 1 week or longer, the patients doctor may again check for the risk of TLS and change the patients dose.

What patients should not take Venclexta?

Certain medicines must not be taken when the patient first starts taking Venclexta and while the dose is being slowly increased because of the risk of increased TLS.

Before taking Venclexta, patients must tell their doctor about all of their medical conditions, including if they:

What to avoid while taking Venclexta:

Patients should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while they are taking Venclexta. These products may increase the amount of Venclexta in the patients blood.

What are the possible side effects of Venclexta?

Venclexta can cause serious side effects, including:

Patients should tell their doctor right away if they have a fever or any signs of an infection during treatment with Venclexta.

The most common side effects of Venclexta when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell count; low platelet count; low red blood cell count; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of arms, legs, hands, and feet.

The most common side effects of Venclexta in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

Venclexta may cause fertility problems in males. This may affect the ability to father a child. Patients should talk to their doctor if they have concerns about fertility.

These are not all the possible side effects of Venclexta. Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at 1-888-835-2555.

Please see the Venclexta full Prescribing Information, including the Medication Guide, for additional Important Safety Information.

Rituxan Indications

Rituxan (rituximab) is a prescription medicine used to treat adults with:

Important Safety Information:

Rituxan can cause serious side effects that can lead to death, including:

What should patients tell their doctor before receiving Rituxan?

Before receiving Rituxan, patients should tell their doctor if they:

What are the possible side effects of Rituxan?

Rituxan can cause serious side effects, including:

TLS can happen within 12 to 24 hours after an infusion of Rituxan. The patients doctor may do blood tests to check for TLS. The patients doctor may give medicine to help prevent TLS. Patients must tell their doctor right away if they have any of the following signs or symptoms of TLS:

The patients doctor will stop treatment with Rituxan if they have severe, serious, or life-threatening side effects.

What are the most common side effects during treatment with Rituxan?

Other side effects include:

These are not all of the possible side effects with Rituxan.

Please see the Rituxan full Prescribing Information, including the Medication Guide, for additional Important Safety Information at http://www.Rituxan.com.

Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Gazyva Indications

Gazyva (obinutuzumab) is a prescription medicine used:

Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that can become serious or life threatening, including:

Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must tell their healthcare provider if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that may become severe or life threatening, including:

The most common side effects of Gazyva in CLL were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

The safety of Gazyva was evaluated based on 392 patients with relapsed or refractory NHL, including FL (81 percent), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (a disease for which Gazyva is not indicated), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen. In patients with follicular lymphoma, the profile of side effects that were seen were consistent with the overall population who had NHL. The most common side effects of Gazyva were infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness, and urinary tract infection.

A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of Gazyva as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86 percent) or marginal zone lymphoma (14 percent). The most common side effects of Gazyva were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please visit http://www.Gazyva.com for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, were investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit http://www.gene.com/hematology.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

Visit link:
Genentech Announces New Data Reinforcing the Long-Term Benefit of Venclexta-Based Combination for People With Relapsed or Refractory Chronic...

Recommendation and review posted by Bethany Smith

Medicare provides coverage options for people with cystic fibrosis who are aged 65 years and older or receive Social Security disability insurance payments.

Cystic fibrosis (CF) is a severe and potentially life threatening disease. People with CF have abnormally thick and sticky mucus that can clog their lungs and make it difficult to breathe.

More than 30,000 people in the United States live with CF, and there is currently no cure.

This article explores Medicare coverage for CF medication and other treatments. It also looks at the costs and the financial assistance that may help.

We may use a few terms in this piece that can be helpful to understand when selecting the best insurance plan:

CF is a hereditary disease that occurs when a person inherits two defective genes one from each biological parent.

It primarily affects the lungs and pancreas, making the mucus in the lungs thicker and stickier than normal. The thick mucus can reduce the effectiveness of a persons airways, leading to infection and inflammation. Over time, CF can lead to respiratory failure.

The abnormal amount of thick mucus also prevents a persons pancreas from releasing digestive enzymes. Without these enzymes, a person cannot absorb nutrients and may become malnourished. The excess mucus can also cause liver disease by blocking the bile duct in the liver.

There are different tests to diagnose CF, and a doctor will screen newborn babies for the condition. The Cystic Fibrosis Foundation (CFF) note that most people receive a diagnosis of the condition by the age of 2 years. Other tests may include a genetic or carrier test, a sweat test, and an evaluation at a healthcare clinic that the CFF have accredited.

Federally funded Medicare is a health insurance program for older people in the U.S. Some people with disabilities also benefit from Medicare.

The program has four parts, each of which offers coverage for some CF-related services:

If someone with CF needs care in an inpatient facility, hospital, or clinic, Medicare Part A covers some of these costs.

For example, if a person needs CF-related treatment, such as a blood transfusion, or a surgical procedure, such as a lung transplant, Part A covers the services. If the person needs hospice or home healthcare, Part A is also the coverage provider.

Learn more about Part A coverage here.

Medicare Part B covers doctors visits, diagnostic and laboratory tests, and other outpatient procedures. If a doctor recommends that a person with CF receive physical therapy, such as pulmonary rehabilitation, Part B covers this service.

Another item that Part B covers is a nebulizer, as long as a doctor has prescribed the device for a medically approved reason, such as CF. Medicare considers a nebulizer to be durable medical equipment (DME). Therefore, it covers 80% of the cost of the equipment and the nebulized CF medications.

Learn more about Part B coverage here.

Private insurance companies provide Medicare Advantage plans as an alternative to original Medicare. Legally, these plans must have the same coverage as original Medicare, and they often also include other benefits, such as prescription drug coverage and dental, vision, and hearing care.

A person enrolled in a Medicare Advantage plan may have to use the plan providers specific network of doctors and hospitals for CF treatment.

Learn more about Medicare Advantage here.

Private insurance companies provide stand-alone Part D plans to people with original Medicare. The plans offer coverage for prescription drugs and cover the cost of regular medication, as long as a doctor has prescribed it.

Part D plans use a formulary that lists the covered drugs. A person can use this online tool to check whether their chosen Plan D plan formulary includes their medication.

Learn more about Part D plans here.

At this time, there is no cure for CF, and treatments aim to help people manage the symptoms and live a healthier life. According to the CFF, there are several options, including medication, nutritional therapies, and fitness routines.

Some of the available options include:

CF transmembrane conductance regulator (CFTR) modulator therapies are newer medications that target the faulty gene causing CF and encourage the correct balance of salt and fluids in the lungs, which thins the mucus.

A doctor may advise a person with CF to have a lung transplant. However, the process includes an evaluation and a significant amount of planning and preparation.

The Food and Drug Administration (FDA) have approved Kalydeco and Orkambi for children with CF who are 2 years of age and older. They have also approved Symdeko for those older than 5 years and Trikafta for those aged 12 years and older.

The cost of CF treatment varies considerably according to the individuals needs. Medicare costs may include premiums, deductibles, copays, and coinsurance.

Most people do not pay a premium for Part A, as long as they have paid Medicare taxes for 40 or more quarters. However, if a person has to pay the premium, the cost in 2021 ranges from $259 to $471.

If a person needs inpatient care in a hospital or clinic, Medicare Part A covers the cost. However, a person must meet the deductible of $1,484 (in 2021) before Medicare contributes. Medicare assesses the deductible per benefit period, which starts when someone enters the hospital and lasts for 60 days.

The Part B basic premium for 2021 is $148.50. A person with an annual income level above $88,000 may have a higher premium, ranging from $207.90 to $504.90.

Part B covers 80% of a persons outpatient healthcare costs.

Advantage plan costs vary depending on several factors, including location, coverage, and a persons age. However, in addition to the plans costs, a person will pay the basic Part B premium.

Learn more about Advantage plan costs here.

Part D costs vary among plans. Monthly premiums are based on income, and Medicare uses the adjusted gross income from a persons tax returns to assess the premium. A person may also pay an adjusted monthly fee.

Learn more about Part D costs here.

Some programs, including Medigap, Medicaid, and Extra Help, may help cover a persons out-of-pocket expenses.

This supplementary insurance helps people pay for some out-of-pocket Medicare expenses, such as copays, deductibles, and coinsurance. Private insurance companies provide 10 Medigap plans with different coverage levels. The costs depend on location and vary among plans.

Learn more about Medigap here.

Medicaid is a government program to assist people with a low income and few resources. The criteria to qualify for the program vary among states.

Learn more about Medicaid here.

Federally funded Medicare Extra Help is sometimes known as Part D low income subsidy. It assists a person on a low income in meeting the costs of Medicare prescription drugs. The Social Security Administration (SSA) oversee the program.

Learn more about Extra Help here.

Cystic fibrosis is an inherited genetic condition that causes lung dysfunction and related issues.

Medicare covers most of the costs of inpatient and outpatient care for CF after a person has met the annual deductible. Medicare Part D and Advantage plans may also cover costs.

The information on this website may assist you in making personal decisions about insurance, but it is not intended to provide advice regarding the purchase or use of any insurance or insurance products. Healthline Media does not transact the business of insurance in any manner and is not licensed as an insurance company or producer in any U.S. jurisdiction. Healthline Media does not recommend or endorse any third parties that may transact the business of insurance.

Read more:
Medicare and cystic fibrosis: Coverage, options, treatments, and costs - Medical News Today

Recommendation and review posted by Bethany Smith

Medicine is ever-evolving on a daily basis. Keeping track of the changes can be an almost-full-time job.Stacker looked at a number of medical journals and media sources to discover the biggest breakthroughs the year you were born, from 1921 to the current day.

From diseases that have been around for decades, such as diabetes and the flu, to cutting-edge tools like artificial intelligence and 3D printing, explore how medical and scientific professionals continually conduct research and clinical trials to improve the lives of patients. Sometimes advances arent immediately adopted, as with the Pap smearthat wasnt integrated into womens health care for 16 years after it was invented. But other times the path from laboratory to everyday use is much more abbreviated, like with insulin, which was used to treat diabetes only a year after it was discovered.

Another recurring theme in medical history is the repurposing of medicines that have worked for one disease in the past, to see how theyll work with another. A number of drugs and vaccines are being re-explored to manage COVID-19. Not all the heroes of medical research come from a traditional backgroundone was an electric engineer who worked for a major record label. Some were recognized with the highest honors, but others still have little visibility decades after their death. Funding for the research behind the breakthroughs is always a considerationsometimes it comes from foundations and government entities, but other times via donations from individuals and enterprises.

The dark side of medical history shown here includes unethical behavior by researchers in the past, which explains why some in the Black community arent exactly early adopters when it comes to clinical trials and new treatment options.

Advances noted here focus not only on the body, but also the mind. Explore this slideshow to see all the ways that health care has changed over the past century.

You may also like: Countries with the best life expectancy

See the rest here:
Medical history from the year you were born - The Elkhart Truth

Recommendation and review posted by Bethany Smith

[Stay on top of transportation news: Get TTNews in your inbox.]

About nine years ago, California-based longhaul truck driver Richard Hall was in for a big surprise when he got his first Department of Transportation medical exam.

You should be in a coma, the medical examiner said, looking at the results of Halls bloodwork. He told me my blood sugar level was 392, and that Im diabetic.

Needless to say Hall, 50, a former physically active construction worker before becoming a truck driver, was shocked. Like many truck drivers, Hall had no idea he was diabetic, or that his blood sugar levels were dangerously high.

Nine years ago, Richard Hall was suprised to learn he had Type 2 diabetes.(Courtesy Hall)

Doctors and diabetes experts say Hall is one of a growing number of truck drivers and Americans in general who either have no clue they have Type 2 diabetes by far the most common form of diabetes or might be ignoring some of the more common signs of the so-called lifestyledisease. Unfortunately, even some drivers who have been diagnosed with diabetes are taking chances by not watching their weight, not eating right and not exercising, according to experts.

Diabetes is a disease in which the bodys ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose-surge in the blood and urine. It can be detected in a urine or blood test, or at home by pricking a finger, putting a drop of blood onto a test strip, and inserting it into a glucose monitor.

Early on, youll feel fine, until one day, boom, your body is going to crash, said Kay Pfeiffer, senior vice president at TrueLifeCare of Brentwood, Tenn., a firm that helps employers and employees wrestle with the impact of diabetes.

Pfeiffer

Medications are a temporary solution, Pfeiffer told Transport Topics. Diabetes not managed, sooner or later, something is going to happen.

For instance, untreated diabetes is one of the leading causes of blindness.

If blood sugar is too high for too long, you run the risk of having damage to the eyes, the kidneys and the heart, said Natalie Hartenbaum, a medical doctor and recognized expert in occupational fitness and truck driver health. Those that cant control their blood sugar will generally end up on insulin.

Hall says diabetes has not interfered with his driving. But he only drives about nine hours a day to avoid getting fatigued.

RELATED: Options Abound for Elevating Drivers Health and Wellness

Because of his diagnosis, Hall was only given a one-year medical card, rather than the two-year card that a healthier diver is typically given after passing a medical exam administered by one of the more than 50,000 certified Federal Motor Carrier Safety Administration examiners. About 43% of drivers have a medical certification of one year or less, according to David Thorpe, a Fayetteville, N.Y., chiropractor who has trained more than 5,000 FMCSA certified medical examiners in his career. Thorpe has focused his medical practice on drivers and occupational medicine for over 30 years.

Thorpe

So why is diabetes such a prominent issue among drivers? The answer is its a stressful job, a lot of time away from home, poor eating habits, drivers are notoriously overweight, and in poor health in general. Plus it's an aging population, Thorpe told TT.

Thorpe said that diabetic drivers can sometimes be managed without drugs, but its not uncommon for them to receive oral medications. Oftentimes they work very well, other times they dont, he said. Even when taking drugs, Type 2 diabetics need to take care of their health, Thorpe said.

Really, we dont know that much about Type 2 diabetes, Pfeiffer said.

The medical experts do know this: There is no cure for Type 2 diabetes. Its a disease that requires those who have it to eat healthy, keep their weight in check, and exercise. You have to get in front of diabetes. You have to have the will to manage diabetes, Pfeiffer, a former hospital nurse, told Transport Topics.

Type 1 diabetics, believed to be only about 5% of the U.S. diabetic population, are dependent on insulin to stay healthy and risk almost certain death if not taking it.

But in a way, Type 2 diabetics have a tougher battle ahead of them because they must radically alter their daily lives.

While about 7% to 10% of the U.S. population is believed to diabetic, a 2014 FMCSA survey of longhaul drivers self-reported higher rates of diabetes for drivers 14.1%. The study also concluded that the prevalence of obesity is more than twice as high (69% vs. 31%) in longhaul drivers as the general population, and the prevalence of morbid obesity is more than twice as high as well (17% vs. 7%).

About 25% of truck drivers over the age of 54 are diabetic, according to numbers compiled by TrueLifeCare.

This past June, an FMCSA-sponsored Virginia Tech Transportation Institute study, Commercial Driver Safety Risk Factors, used data from more than 21,000 drivers to help understand the impact of health and other challenges for those sitting behind the wheel.

While the study concluded that treated diabetic truck drivers are at no greater risk of accidents, it noted that those same treated drivers were 38% more likely to be convicted of a moving violation compared to drivers who do not have diabetes or elevated blood sugar.

The study further concluded that diabetic drivers not being medicated for the disease had a threefold increased crash risk.

Larry Wolfe, retired medical doctor

While there are many good reasons for drivers such as Hall to keep their blood sugar in control, diabetes is an issue for the whole country, not just truck drivers, said Larry Wolfe, a retired medical doctor who specialized in endocrinology nearly his entire career. Wolfe was a staff doctor at the Vanderbilt University Diabetes Center for 10 years.

Its almost an epidemic, he told TT. Truck drivers tend to be obese, dont exercise, they eat wrong, so their diabetes is a real problem to manage, even under the best of circumstances. The major fear always was that they could experience hypoglycemia and lose consciousness while they are driving.

The common signs of Type 2 diabetes include profuse sweating, irritability, a lack of coordination, blurry vision and shaky hands. Ignoring the signs of Type 2 diabetes can lead to ulcers on the feet or legs that can ultimately result in amputations.

Pfeiffer said when some drivers feel symptoms of the disease, they sometimes stop at a convenience store and get a Coke.

Home | Video | Heroes' Photo Gallery

Saluting the men and women of the trucking industry who kept America's essential goods flowing during the coronavirus pandemic.

Heroes: Peter Lacoste | Susan Dawson | James Rogers | Reggie Barrows | Kevin Cooper | Cesar Quintana Moreno

Theyll say to themselves, Ive gotten used to it, she said. But its very, very dangerous.

Thats why Hall, who spends three months at a time away from home hauling dry goods across much of the country in his tractor-trailer, says he tries to eat mostly chicken and fish and avoids sweets to do the best job he can to control his blood sugar. And when he gets home, he visits his doctor.

To get exercise, I even walk around the truck three times to do my pre-trip, Hall said. The last time he checked his blood sugar level, it was 182, a little high, but he has registered up to 249. The American Diabetes Association (ADA) says a normal blood sugar reading for an individual fasting is 100 or lower. If the level is 126 or higher after fasting for eight hours or more, a person could be diabetic.

There also is another problematic issue related to diabetes: It adds costs to an employers bottom line, according to the most recent diabetes report by the Health Care Cost Institute. The per capita annual spend in 2014 for people with diabetes enrolled in employer health plans was $16,021 (combined employer and employee). Thats nearly four times the $4,396 per capita spend for health plan members without diabetes.

How did turkey-to-table change this year? What obstacles were suppliers going through to get turkeys to grocery stores? Join us as we talk with J.J. Smith, President of Valley Proteins, about how staying open-minded and flexible helped his business of delivering turkeys persevere.Hear a snippet, above, and get the full program by going to RoadSigns.TTNews.com.

The ADA states that people with diabetes typically will experience three additional days of absenteeism and have 12 days of lost productivity each year associated with the disease.

Diabetes goes along with the epidemic of obesity, Wolfe said. And unfortunately, we wont be able to get a good handle on the treatment of Type 2 diabetes until we get a handle on how to treat obesity. Thats the real problem that we dont know how to get people to lose weight. If we could, there would be a whole lot less Type 2 diabetes.

Wolfe said a person can have Type 2 diabetes for 10 years and not know it. Since it is possible for drivers to not have symptoms, the easiest thing for some of them to do is deny having the disease. Its a very frustrating practice to take care of truck drivers, he said.

Wolfe added, Its a disease where the patient has to assume a lot of the responsibility for treatment. Its a complicated disease because it requires you to think about it every day of your life. If you dont take it seriously, no doctor in the world is going to help you.

What was really sad for me as a physician was when the poor patient was in the position of having to choose between his health and making a living, Wolfe said.

From a regulatory standpoint, FMCSA relies on a drivers treating physician and the medical examiners to ensure that drivers who take insulin and those who dont take it all have a stable medication and treatment regimen prior to medically qualifying them to get a medical card.

Federal regulations require that insulin-treated diabetics fill out an assessment form in which the drivers treating clinician must attest that the driver has a stable insulin regimen and well-controlled diabetes. The form poses a series of diabetes management-related questions that can aid the medical examiner in deciding if a driver is fit to get behind the wheel.

Hartenbaum

Hartenbaum said she believes that since there are no specific federal guidelines for medical examiners, the so-called best practices used by medical examiners to qualify a driver can vary.

Because of the lack of specific federal guidance, Hartenbaum said she is very concerned that there may be an increased crash risk for diabetics. But it hasnt shown up yet, she said.

FMCSA doesnt monitor medical conditions, Hartenbaum said. They dont monitor sleep apnea, they dont monitor blood pressure, they dont monitor heart disease. They have medical standards and medical guidelines. But its up to the medical examiner to evaluate whether the individual is at risk of sudden or gradual incapacitation due to a medical condition, and whether a study is needed to evaluate that.

Want more news? Listen to today's daily briefing:

See the original post here:
Diabetes: The Bump in the Road for the Longhaul Truck Driver - Transport Topics Online

Recommendation and review posted by Bethany Smith

In 1992 when investigators began testing trastuzumab (Herceptin) in women with HER2-positive breast cancer, many observers predicted failureand they kept on predicting failure throughout the trial process. Even after the FDA approved the drug in 1998, some observers scoffed at the modest survival benefit it had demonstrated to that point and predicted that targeted therapy would never be a major form of cancer treatment. There was a great deal of skepticism about targeted monoclonal antibodies back in the 1990s. People didnt believe that it would be possible to make antibodies that bound specifically to cancer cells or, if it was possible, that the antibodies would kill the cancer cells. Its hard to imagine now, but those first trastuzumab trials I did in the mid-90s were actually controversial, said Howard A. Skip Burris III, MD, president of clinical operations and chief medical officer at Sarah Cannon in Nashville, Tennessee.

It wasnt until the subsequent trials that used trastuzumab in women with early-stage breast cancers, trials that showed a much bigger survival benefit than the trials in metastatic cancers, that everyone saw trastuzumab as a major breakthrough, and many people realized that targeted therapies might proliferate quickly, he said.

There was, of course, reason for skepticism. A small number of successful targeted therapies existed longbefore trastuzumab, but none of them launched a new class of cancer treatments that successfully fought a wide range of tumor types.

Indeed, physicians have known since the 1940s that iodine-131 therapy can selectively target thyroid cancer and that androgen deprivation therapy can selectively target prostate cancer. Hormone deprivation did find one other major use in the 1970s, when tamoxifen (Soltamox) was approved for hormone receptorpositive breastncancer, but neither iodine-131 nor any other elemental radioisotopes have become major treatment types.

Thus, many people doubted that the approval of the first 2 monoclonal antibodies, trastuzumab and rituximab (Rituxan), signified an explosion in new targeted therapies, and if not for rapid advances in genetics, proteomics, and molecular synthesis, the doubters may have been right.

But the 2001 approval of a third novel targeted therapy, imatinib mesylate (Gleevec), turned many skeptics into believers. Unlike trastuzumab and rituximab, imatinib is a small molecule drug, but it is a highly specific inhibitor of tyrosine kinase enzymes that are overactive in a number of cancers that are Philadelphia chromosome positive. It was also obvious, from the very first trials, that imatinib was an incredibly effective treatment, particularly for chronic myelogenous leukemia (CML). A phase 1 trial launched in 1998 reported that the drug caused CML to quickly disappear in the vast majority of patients with early-stage disease, and a 5-year follow-up found that 98% of patients were still in remission.1

Within a decade of trastuzumabs initial approval, the FDA approved another 23 targeted cancer therapies. More than 80 targeted cancer therapies are now available to patients.2

Its been an amazingly rapid proliferation, and its happened because weve made huge technical advances on 2 distinct fronts, Burris said. When trastuzumab arrived, we were still working to sequence one human genome at a cost of many billions of dollars. Systematically analyzing tumors for druggable driver mutations seemed unrealistically expensive, but then, over the course of just a few years, the technology became so much faster and so much cheaper that it was entirely feasible. The other big advance has been on the chemistry side. Pharmaceutical and biotech companies have gotten much better at creating molecules that will bind to their intended targets. Better chemistry has allowed medications to bind to many targets like KRAS that were once considered undruggable.

Monoclonal Antibodies

The first attempt to develop a targeted monoclonal antibody treatment for cancer dates back to 1980, when a team led by Lee Marshall Nadler, MD, treated a patient affected by non-Hodgkin lymphoma with the murine monoclonal antibody AB 89. The treatment, however, did not produce a significant clinical response.3

Several other research groups tested monoclonal antibodies against hematological cancers over the next decade, but none of them worked well enough for FDA approval. In fact, many of these murine formulations induced immune reactions that both created adverse effects and reduced therapeutic half-life.4

The first monoclonal antibody to demonstrate itself safe and effective enough for FDA approval was rituximab, which kills B cells by targeting the surface antigen CD20. The drug, which was first approved in 1997 for B-cell lymphoproliferative disorders, is currently indicated, alone or in various combinations, to treat forms of non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Trastuzumab, which was approved a year later, is a genetically engineered, humanized monoclonal antibody that fights cancer 2 ways. First, it inhibits HER2, a glycoprotein receptor with tyrosine kinase activity that promotes breast cancer cell growth. Second, it induces cancer cell death via antibodydependent cell-mediated cytotoxicity.

Trastuzumab was developed at the University of California, Los Angeles (UCLA) by a team led by Dennis Slamon, MD, PhD. Slamon identified the HER2-positive subtype of breast cancer in the early 1980s, demonstrated that this subtype was particularly deadly and aggressive, and hypothesized that a HER2 inhibitor would extend life. The team spent several years developing drug candidates, and the very first human trials were conducted at UCLA in 1990.

Trastuzumab has since shown significantand often dramaticbenefit when used in a variety of ways against HER2-positive breast cancer. For example, a 2005 trial of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer found that after a median follow-up of one year, 1693 women assigned to the observation group had nearly twice as many events (recurrence, contralateral breast cancer, second nonbreast malignant disease, or death) as the 1694 women assigned to the trastuzumab group.5

In the early 1990s, women with the HER2-positive subtype had an average life expectancy after diagnosis of 3 to 5 years. Today, an estimated 3 million patients have an average life expectancy of 7 to 10 years, thanks largely to receiving trastuzumab.6

The next targeted therapy to reach patients was gefitinib (Iressa), an EGFR tyrosine kinase inhibitor (TKI) approved in 2003 for the treatment of nonsmall cell lung cancer (NSCLC). Studies published the following year showed that a particular subset of patients with EGFR mutation positive NSCLC were far more likely than others to respond to gefitinib7 and a second EGFR TKI approved in 2004, erlotinib (Tarceva).8

The phase 3 trial that led to erlotinibs approval found that only 8.9% of patients responded to the drug and that it increased median overall survival (OS) by just 2 months to 6.7 months,9 but the subgroup analysis found traits ranging from female sex to never smoking to EGFR expression that predicted response.

Later research demonstrated that EGFR TKIs greatly increase survival in patients with EGFR-positive NSCLC. Combination chemotherapy in advanced NSCLC typically results in a median OS of 8 to 12 months and a median progression-free survival (PFS) of 5 to 6 months.10 Among 137 patients with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009, however, median PFS and OS were 12.1 months and 30.9 months, respectively. Twenty patients (14.6%) were 5-year survivors.11

Even though targeted therapies had already proven themselves effective against other tumor types, especially imatinib against CML, a lot of people were still skeptical that they would work against lung cancer, said Paul Bunn, MD, distinguished professor of medicine-medical oncology and the James Dudley Chair in Cancer Research at the University of Colorado School of Medicine in Aurora, Colorado. But the skeptics were quickly silenced. The trial results were pretty convincing.

Shortly after the FDA approved erlotinib, it also approved bevacizumab (Avastin), the first example of another novel form of targeted therapies called antiangiogenics, which are designed to deprive tumors of blood.

Many targeted therapies were conceived long before they were approved, including antiangiogenics. The idea of fighting cancer by starving tumors of blood first occurred to Judah Folkman, MD, in 1963, when he and Fred Becker, MD, were comparing possible substitutes for blood transfusions. During those experiments, the 2 young doctors injected adult mouse melanoma cells into isolated, perfused thyroid glands taken from dogs and noticed that while tumors did form, they never developed blood vessels or grew beyond 2 mm in diameter.12

Other investigators had already made similar observations, but Folkmans efforts to understand his findings led him to complete a few more experiments and then to hypothesize, via a 1971 piece in the New England Journal of Medicine, 13 several very new ideas:

The paper drew such negative response that it quickly made Folkman a pariah.

The approval of bevacizumab in 2004 was a triumph for Folkman, but because he died in 2008, he did not live long enough to see how broadly the use of antiangiogenics would expand. Bevacizumab alone is now approved as monotherapy or in combination with other medications to treat 7 different tumor types,14 and more than a dozen other angiogenesisinhibiting medications have subsequently been approved as cancer treatments.15

Many of them work by binding to VEGF, preventing it from activating the VEGF receptor, and blocking the formation of new blood vessels. The first 2 approved drugs that targeted this pathway were sorafenib (Nexavar), which was approved in 2005, and sunitinib malate (Sutent), which was approved in 2006.16,17

Oddly, an antiangiogenic drug had already been approved for use in most of the world (just not the United States) slightly before Folkman first devised the idea in 1963, but it was approved to treat sleeplessness and morning sickness rather than cancer. That drug, of course, was thalidomide (Synovir, Thalomid), which was later approved to treat multiple myeloma, many decades after the discovery that it causes birth defects.

Molecules that inhibit PARPs, which play a major role in DNA damage repair, were another form of targeted therapy that existed long before FDA approval to treat cancer. PARP-inhibiting substances, such as nicotinamide, have been used for various indications over the decades. In the 1970s, some thought these substances might prime patients for better response to chemotherapy or radiation.18

The FDA, however, did not support a PARP inhibitor for cancer treatment until 2014, when it approved olaparib (Lynparza) for advanced ovarian cancer with a deleterious or suspected deleterious germline BRCA mutation.19 It has since approved more PARP inhibitors, including rucaparib (Rubraca), niraparib (Zejula), and talazoparib (Talzenna) across a wide variety of tumors, including metastatic prostate cancer and certain subtypes of breast cancer (TABLE19-22).20-22

Immunotherapies are another type of targeted cancer treatment that were hypothesized many decades before they were realized. A German physician working in the mid-19th century noticed that tumors tended to regress when cancer patients were infected by erysipelas, so in 1868, he intentionally infected a patient with erysipelas to treat their cancer.23

In the 19th century, the American doctor William Coley began directly injecting tumors with mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens. He reported more than 1000 regressions or cures over the course of his career, but he was poorly esteemed among researchers of the day and his findings were largely ignored.24

The work that laid the foundation for todays immunotherapies took place in 1982, nearly a century after Coleys first efforts at immunotherapy, when James Allison, PhD, and colleagues identified and described tumor-specific antigens in a mouse model of T-cell lymphoma. 25 A year later, they described the first T-cell antigen receptor.

The first immune checkpoint molecule was discovered in 1987 and named CTLA-4. Just one year later, the first CTLA-4blocking antibody was discovered, and in 2011, the first CTLA-4blocking drug, ipilimumab (Yervoy), was approved by the FDA.26

The sheer number of targeted therapies that have been approved in the [past] 20 years is amazing, even if youre just looking at my specialty of lung cancer, said Bunn, who is a past president of the American Society of Clinical Oncology. And thanks to those treatments, along with earlier diagnosis, survival rates have improved considerably, from roughly 4 to 6 months untreated to a year with chemotherapy to 5 years or more with TKIs. But theres still work to be done because neither the TKIs nor the immunotherapies, or anything else, tends to produce complete responses or absolute cures. We need to find things we can pair with TKIs to kill the cancer cells they dont, and there are a large number of combinations that are currently being investigated.

Burris is also excited to see so many new targeted treatmentsand combinations of targeted treatmentsin trials right now. He is particularly optimistic about antibody-drug conjugates, therapies that combine antibodies that bind to tumors with a second agent that attacks the tumor. The most successful such product may be ado-trastuzumab emtansine (Kadcyla), which combines trastuzumab with a cytotoxic drug thats released after the molecule binds to the cancer.

When you see what big pharmaceutical companies are paying to acquire the makers of antibody- drug conjugates, you get a good sense of how promising the technology is, Burris said. The technology for binding the antibody and the cytotoxic agent, for getting the antibody to bind with the tumor, and for releasing the cytotoxic agent at the right time all keep improving. This is a promising strategy for attacking a wide range of tumors that dont have a druggable driver mutation.

References:

1. Druker BJ, Guilhot F, OBrien SG, et al; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J. Med. 2006;355(23):2408-2417. doi: 10.1056/NEJMoa063867

2. Targeted therapies: overview of targeted therapies for cancer. My Cancer Genome. Updated May 27, 2019. Accessed November 2, 2020. https://bit.ly/385txmr

3. Nadler LM, Stashenko P, Hardy R, et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res. 1980;40(9):3147-3154.

4. Dillman RO, Beauregard JC, Halpern SE, Clutter M. Toxicities and side effects associated with intravenous infusions of murine monoclonal antibodies antibodies. J Biol Response Mod. 1986;5(1):73-84.

5. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672. doi:10.1056/NEJMoa052306

6. UCLA oncologist Dennis Slamon wins 2019 Lasker Award for clinical medical research. UCLA newsroom. September 9, 2019. Accessed November 2, 2020. https://bit.ly/2TKzvkt

7. Paez JG, Jnne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. doi:10.1126/science.1099314

8. Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144. doi:10.1056/NEJMoa050736

9. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med. 2005;353(2):123-132. doi:10.1056/NEJMoa050753

10. Schiller JH, Harrington D, Belani CP, et al; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced nonsmall- cell lung cancer. N Engl J Med. 2002;346(2):92-98. doi:10.1056/NEJMoa011954

11. Lin JJ, Cardarella S, Lydon CA, et al. Five-Year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. J Thorac Oncol. 2016;11(4):556-565. doi:10.1016/j.jtho.2015.12.103

12. Folkman J, Long DM Jr, Becker FF. Growth and metastasis of tumor in organ culture. Cancer. 1963;16:453-467. doi:10.1002/1097-0142(196304)16:4<453::aid-cncr2820160407>3.0.co;2-y

13. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186. doi:10.1056/NEJM197111182852108

14. Bevacizumab. National Cancer Institute. October 5, 2006. Updated September 10, 2020. Accessed November 2, 2020. https://bit.ly/2TKcNcn

15. Angiogenesis inhibitors. National Cancer Institute. Updated April 2, 2018. Accessed November 2, 2020. https://bit.ly/325ldQ0

16. Nexavar. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2010. Accessed November 2, 2020. https://bit.ly/360eQid

17. Sutent. Prescribing information. Pfizer Inc; 2011. Accessed November 2, 2020. https://bit.ly/2I0jzbr

18. Clark JB, Ferris GM, Pinder S. Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5-methyl nicotinamide. Biochim Biophys Acta. 1971;238(1):82-85. doi:10.1016/0005-2787(71)90012-8

19. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. FDA. Updated August 17, 2017. Accessed November 3, 2020. https://bit.ly/324l5Ah

20. FDA grants accelerated approval to new treatment for advanced ovarian cancer. News release. FDA. December 19, 2016. Accessed November 3, 2020. https://bit.ly/34Pzsu7

21. Niraparib (Zejula). FDA. Updated May 30, 2017. Accessed November 2, 2020. https://bit.ly/36bQT7J

22. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA. Updated December 14, 2018. Accessed November 2, 2020. https://bit.ly/3jUsp7r

23. Busch W. Aus der Sitzung der medicinischen Section vom 13 November 1867. Berlin Klin Wochenschr. 1868;5:137. (Ger).

24. Dobosz P, Dziecitkowski T. The intriguing history of cancer immunotherapy. Front Immunol. 2019;10:2965. doi:10.3389/fimmu.2019.02965

25. Allison JP, McIntyre BW, Bloch D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J Immunol. 1982;129(5):2293-2300.

26. Yervoy. Prescribing information. Bristol Myers Squibb; 2018. Accessed November 2, 2020. https://bit.ly/2HQsQT7

Follow this link:
A Look Back Prompts Memories of Initial Skepticism for Targeted Agents Shattered by Positive Efficacy Trials - Targeted Oncology

Recommendation and review posted by Bethany Smith

Abstract

Remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic or intrinsic regulators in oligodendroglial biology. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient mouse model to compare induced pluripotent stem cellderived oligodendroglia from MS and healthy donors following engraftment in the developing CNS. We show that the MS-progeny behaves and differentiates into oligodendrocytes to the same extent as controls. They generate equal amounts of myelin, with bona fide nodes of Ranvier, and promote equal restoration of their host slow conduction. MS-progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glia. Thus, MS oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia/glia-glia connections, reinforcing the view that the MS oligodendrocyte differentiation block is not from major intrinsic oligodendroglial deficits.

Remyelination occurs in multiple sclerosis (MS) lesions but its capacity decreases over time (13). Failed remyelination in MS leads to altered conduction followed by axon degeneration, which, in the long run, results in severe and permanent neurological deficits (4). MS lesions may or may not harbor immature oligodendroglia (oligodendrocyte progenitors and pre-oligodendrocytes), with these cells failing to differentiate into myelin-forming cells, suggesting that oligodendrocyte differentiation is blocked (57). So far, the mechanism underlying this block is poorly understood. It may result from adverse environmental conditions or the failed capacity of oligodendrocyte progenitors/pre-oligodendrocytes to migrate or mature efficiently into myelin-forming cells or even a combination of these conditions, all of which may worsen with aging. It has been shown that increasing remyelination either through manipulating the endogenous pool (8, 9) or by grafting competent myelin forming oligodendroglia (10, 11) or both (12) can restore the lost axonal functions, improve the clinical scores, and protect from subsequent axonal degeneration in experimental (13, 14) or clinical (3) settings.

There are multiple ways to investigate the oligodendroglial lineage in disease. Cells can be studied in postmortem tissue sections or purified from postmortem adult human brain for in vitro and transcriptomic/proteomic analysis. In this respect, in vitro experiments highlighted the heterogeneity of the adult human oligodendrocyte progenitor population in terms of antigen and microRNA expression, suggesting that remyelination in the adult human brain involves multiple progenitor populations (15). Moreover, single-cell transcriptomics characterized in detail the heterogeneity of human oligodendroglial cells, emphasizing changes in MS, with some subpopulations expressing disease-specific markers that could play a role in disease onset and/or aggravation (16, 17).

Yet, this MS signature could preexist or be acquired early at disease onset. Moreover, most of these MS postmortem analyses or experimental models cannot overlook the involvement of extrinsic factors such as immune factors that might add more complexity toward understanding the behavior of MS oligodenroglial cells.

Little is known about the biology of the MS oligodendroglial lineage, primarily due to the impossibility, for ethical reasons, to harvest oligodendroglial populations from patients and study the diseased cells and their matching controls in vitro or in vivo after cell transplantation. While cell-cell interactions and cell heterogeneity in diseased conditions generate more complexity when comparing control and pathological samples, the induced pluripotent stem cell (iPSC) technology provides a unique opportunity to study homogeneous populations of human oligodendroglial cells and gain further insights into monogenetic diseases and multifactorial diseases, such as MS. The iPSC technology has unraveled differences in oligodendroglia biology, in Huntingtons disease (18), and schizophrenia (19, 20), indicating that these cells can contribute autonomously to multifactorial diseases outcome. However, so far, little is known about the potential contribution of MS oligodendroglia to failed remyelination. While senescence affects iPSCneural precursor cells (NPCs) derived from patients with primary progressive MS (PPMS) (21), only few preliminary reports alluded to the fate of PPMS (22, 23) or relapsing-remitting (RRMS) (24) iPSC-derived oligodendroglia after experimental transplantation and did not study per se their capacity to differentiate into functional myelin-forming cells. We exploited a robust approach (25) to generate large quantities of iPSCs-derived O4+ oligodendroglial cells from skin fibroblasts (hiOLs) of three RRMS and three healthy subjects, including two monozygous twin pairs discordant for the disease. As a critical feature of the pluripotent-derived cells should be their ability to fully integrate and function in vivo, we compared the capacity of healthy and MS-hiOL derivatives to integrate and restore axo-glial and glial-glial functional interactions after engraftment in the developing dysmyelinated murine central nervous system (CNS). Our data show that in noninflammatory conditions, the intrinsic properties of iPSC-oligodendroglial cells to differentiate, myelinate, and establish functional cell-cell interactions in vivo are not altered in MS, making them candidates of interest for personalized drug/cell therapies as pluripotency maintains MS oligodendroglial cells in a genuine nonpathological state.

Fibroblasts were isolated from three control and three patients with MS and reprogrammed into iPSC. Pluripotent cells were differentiated into NPCs and further into O4+ hiOLs for 12 days in vitro under glial differentiation medium (GDM) conditions as previously described (25). hiOL cells were selected using flow cytometry for O4 before transplantation. Because our aim was to study the intrinsic properties of MS cells, we chose to engraft O4+ hiOLs in the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects.

We first questioned whether MS-hiOLs differed from control-hiOLs wild type (WT) in their capacity to survive and proliferate in vivo. To this aim, we grafted MS- and control-hiOLs in the forebrain of neonatal Shi/Shi:Rag2/ mice. MS cells engrafted (one injection per hemisphere) in the rostral forebrain, spread primarily through white matter, including the corpus callosum and fimbria, as previously observed using control human fetal (11, 26, 27) and iPSC (25, 28) progenitors. With time, cells also spread rostrally to the olfactory bulb and caudally to the brain stem and cerebellum (fig. S1). Examining engrafted brains at 8, 12, and 16 weeks postgraft (wpg), we found that MS-hiOLs expressing the human nuclear marker STEM101 and the oligodendroglial-specific transcription factor OLIG2 maintained a slow proliferation rate at all times (5 to 19% of STEM+ cells), with no difference in Ki67+ MS-hiOLs compared to control (Fig. 1, A and C). Moreover, immunostaining for cleaved Caspase3 at 8 wpg indicated that MS cells survived as well as control-hiOLs (Fig. 1, B and D). Evaluation of the cell density of human cells based on STEM positivity at each stage revealed no significant difference between grafted MS-hiOLs and control cells (fig. S2).

(A and C) Immunodetection of the human nuclei marker STEM101 (red) combined with OLIG2 (green) and the proliferation marker Ki67 (white) shows that a moderate proportion of MS-hiOLs sustains proliferation (empty arrowheads in the insets) following transplantation in their host developing brain, with no significant difference in the rate of proliferation between MS- and control-hiOLs over time. (B and D) Immunodetection of the apoptotic marker Caspase3 (green) indicates that MS-hiOLs survive as well as control-hiOLs 8 wpg. Two-way analysis of variance (ANOVA) followed by Tukeys multiple comparison or Mann-Whitney t tests were used for the statistical analysis (n = 3 to 4 mice per group). Error bars represent SEMs. H, Hoechst dye. Scale bars, 100 m.

Because MS-hiOLs and control cells proliferated and survived to the same extent, we next questioned whether their differentiation potential into mature oligodendrocytes could be affected. We used the human nuclei marker STEM101 to detect all human cells in combination with SOX10, a general marker for the oligodendroglial lineage, and CC1 as a marker of differentiated oligodendrocytes. We found that the number of MS oligodendroglial cells (SOX10+) increased slightly but significantly with time, most likely resulting from sustained proliferation (Fig. 2, A and B). Moreover, they timely differentiated into mature CC1+ oligodendrocytes with a fourfold increase at 12 wpg and a fivefold increase at 16 wpg when compared to 8 wpg and with no difference with control-hiOLs (Fig. 2, B and C).

(A) Combined immunodetection of human nuclei marker STEM101 (red) with CC1 (green) and SOX10 (white) for control (top) and MS-hiOLs (bottom) at 8, 12, and 16 wpg. (B and C) Quantification of SOX10+/STEM+ cells (B) and CC1+ SOX10+ over STEM+ cells (C). While the percentage of human oligodendroglial cells increased only slightly with time, the percentage of mature oligodendrocytes was significantly time regulated for both MS- and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 3 to 4 mice per group). Error bars represent SEMs. *P < 0.05 and ****P < 0.0001. Scale bar, 100 m.

The absence of abnormal MS-hiOL differentiation did not exclude a potential defect in myelination potential. We further investigated the capacity of MS-hiOLs to differentiate into myelin-forming cells. We focused our analysis on the core of the corpus callosum and fimbria. MS-hiOLs, identified by the human nuclear and cytoplasmic markers (STEM101 and STEM121), evolved from a bipolar to multibranched phenotype (Fig. 3A and fig. S3: compare 4 wpg to 8 and 12 wpg) and differentiated progressively into myelin basic proteinpositive (MBP+) cells associated, or not, with T-shaped MBP+ myelin-like profiles of increasing complexity (Fig. 3A and figs. S3 and S4B). Myelin-like profiles clearly overlapped with NF200+ axons (fig. S4A) and formed functional nodes of Ranvier expressing ankyrin G and flanked by paranodes enriched for CASPR (fig. S4B) or neurofascin (fig. S4C), as previously observed with control-hiOLs (25).

(A) Combined detection of human nuclei (STEM101) and human cytoplasm (STEM 121) (red) with MBP (green) in the Shi/Shi Rag2/ corpus callosum at 8, 12, and 16 wpg. General views of horizontal sections at the level of the corpus callosum showing the progressive increase of donor-derived myelin for control- (top) and MS- (bottom) hiOLs. (B) Evaluation of the MBP+ area over STEM+ cells. (C and D) Quantification of the percentage of (C) MBP+ cells and (D) MBP+ ensheathed cells. (E) Evaluation of the average sheath length (m) per MBP+ cells. No obvious difference was observed between MS and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 6 to 14 mice per group). Error bars represent SEMs. *P < 0.05, **P < 0.01, and ***P < 0.001. Scale bar, 200 m. See also figs. S3 and S5.

We further analyzed, in depth, the myelinating potential of MS-hiOLs, applying automated imaging and analysis, which provided multiparametric quantification of MBP as established in vitro (29) for each donor hiOL (three controls and three RRMS) at 4, 8, 12, 16, and 20 wpg in vivo (Fig. 3, B to D). We first examined the MBP+ surface area generated by the STEM+ cell population (Fig. 3B). While MS-hiOLs generated very low amount of myelin at 4 wpg, they generated significantly more myelin at 12, 16, and 20 wpg, with similar findings for control-hiOLs, highlighting the rapid progress in the percentage of myelin producing STEM+ cells in MS group over time. Detailed MBP+ surface area generated by the STEM+ cell population per donor is presented in fig. S5 and shows differences among hiOLs in the control and MS groups, respectively.

We also quantified the percentage of STEM+ cells expressing MBP and the percentage of MBP+ with processes associated with linear myelin-like features, which we called MBP+ ensheathed cells. Both parameters increased significantly with time for control-hiOLs, reaching a plateau at 16 wpg. The same tendency was achieved for MS-hiOLs with no significant differences between the control- and MS-hiOL groups (Fig. 3, C and D).

Myelin sheath length is considered to be an intrinsic property of oligodendrocytes (30). We analyzed this paradigm in our MS cohort at 12 and 16 wpg, time points at which sheaths were present at a density compatible with quantification. For those time points, we found that the average MS MBP+ sheath length was equivalent to that of control with 25.86 0.98 and 27.74 1.52 m for MS-hiOLs and 24.52 1.48 and 27.65 0.96 m for control-hiOLs at 12 and 16 wpg, respectively (Fig. 3F). In summary, our detailed analysis of immunohistochemically labeled sections indicates that MS-hiOLs did not generate abnormal amounts of myelin in vivo when compared to control-hiOLs.

Moreover, the myelinating potential of MS-hiOLs was further validated after engraftment in the developing spinal cord (4 weeks of age). Immunohistological analysis 12 wpg revealed that STEM+ cells not only populated the whole dorsal and ventral columns of the spinal cord with preferential colonization of white matter but also generated remarkable amounts of MBP+ myelin-like internodes that were found on multiple spinal cord coronal sections (fig. S6), thus indicating that their myelination potential was not restricted to only one CNS structure.

The presence of normal amounts of donor MBP+ myelin-like structures in the shiverer forebrain does not exclude potential structural anomalies. Therefore, we examined the quality of MS derived myelin at the ultrastructural level at 16 wpg in the Shi/Shi:Rag2/ forebrain. In the corpus callosum of both MS and control-hiOLs grafted mice, we detected numerous axons surrounded by electron dense myelin, which at higher magnification was fully compacted compared to the uncompacted shiverer myelin (Fig. 4, A to F) (25, 31). Moreover, MS myelin reached a mean g ratio of 0.76 1.15 comparable to that of control myelin (0.75 1.56) (Fig. 4G) and thus a similar myelin thickness. This argues in favor of (i) MS-hiOLs having the ability to produce normal compact myelin and thus its functional normality and (ii) a similar rate of myelination between the two groups and, consequently, an absence of delay in myelination for MS-hiOLs.

(A to F) Ultrastructure of myelin in sagittal sections of the core of the corpus callosum 16 wpg with control-hiOLs (A to C) and MS-hiOLs (D to F). (A and D) General views illustrating the presence of some electron dense myelin, which could be donor derived. (B, C, E, and F) Higher magnifications of control (B and C) and MS (E and F) grafted corpus callosum validate that host axons are surrounded by thick and compact donor derived myelin. Insets in (C) and (F) are enlargements of myelin and show the presence of the major dense line. No difference in compaction and structure is observed between the MS and control myelin. (G) Quantification of g-ratio revealed no significant difference between myelin thickness of axons myelinated by control- and MS-hiOLs. Mann-Whitney t tests were used for the statistical analysis of this experiment (n = 4 mice per group). Error bars represent SEMs. Scale bars, (A and D) 5 m , (B and E) 2 m, and (C and F) 500 nm [with 200 and 100 nm, respectively in (C) and (F) insets].

Myelin compaction has a direct impact on axonal conduction with slower conduction in shiverer mice compared to WT mice (10, 32). We therefore questioned whether newly formed MS-hiOLderived myelin has the ability to rescue the slow axon conduction velocity of shiverer mice in vivo (Fig. 5). As previously performed with fetal glial-restricted progenitors (11), transcallosal conduction was recorded in vivo at 16 wpg in mice grafted with MS- and control-hiOLs and compared with nongrafted shiverer and WT mice. As expected, conduction in nongrafted shiverer mice was significantly slower compared to WT mice. However, axon conduction velocity was rescued by MS-hiOLs and, to the same extent, by control-hiOLs.

(A) Scheme illustrating that intracallosal stimulation and recording are performed in the ipsi- and contralateral hemisphere, respectively. (B) N1 latency was measured following stimulation in different groups of Shi/Shi:Rag2/: intact or grafted with control or MS-hiOLs and WT mice at 16 wpg. MS-hiOLderived myelin significantly restored transcallosal conduction latency in Shi/Shi:Rag2/ mice to the same extent than control-derived myelin (P = 0.01) and close to that of WT levels. One-way ANOVA with Dunnetts multiple comparison test for each group against the group of intact Shi/Shi:Rag2/ was used. Error bars represent SEMs. *P < 0.05. (C) Representative response profiles for each group. Scales in Y axis is equal to 10 V and in the X axis is 0.4 ms.

Rodent oligodendrocyte progenitors and oligodendrocytes can be distinguished by cell stagespecific electrophysiological properties (33, 34). To assess the electrophysiological properties of oligodendroglial lineage cells derived from human grafted control- and MS-hiOLs, red fluorescent protein (RFP)hiOLs were engrafted in the Shi/Shi:Rag2/ forebrain and recorded with a K-gluconatebased intracellular solution in acute corpus callosum slices at 12 to 15 wpg (Fig. 6A). As previously described for rodent cells, hiOLs in both groups were identified by their characteristic voltage-dependent current profile recognized by the presence of inward Na+ currents and outwardly rectifying steady-state currents (Fig. 6B). We found that ~60 and ~44% of recorded cells were oligodendrocyte progenitors derived from MS and control progenies, respectively. No significant differences were observed in the amplitude of Na+ currents measured at 20 mV (Fig. 6D) or steady-state currents measured at +20 mV between MS- and control-derived oligodendrocyte progenitors (Isteady = 236.70 19.45 pA and 262.10 31.14 pA, respectively; P = 0.8148, Mann Whitney U test). We further confirmed the identity of these cells by the combined expression of SOX10 or OLIG2 with STEM101/121 and the absence of CC1 in biocytin-loaded cells (Fig. 6F, top). The remaining recorded cells (MS and control) did not show detectable Na+ currents after leak subtraction and were considered to be differentiated oligodendrocytes by their combined expression of SOX10, STEM101/121, and CC1 in biocytin-loaded cells (Fig. 6F, bottom). The I-V curve of these differentiated oligodendrocytes displayed a variable profile that gradually changed from voltage dependent to linear as described for young and mature oligodendroglial cells in the mouse (33). Figure 6C illustrates a typical linear I-V curve of fully mature MS-derived oligodendrocytes. No significant differences were observed in the amplitude of steady-state currents measured at +20 mV between MS- and control-derived oligodendrocytes (Fig. 6E). Overall, the electrophysiological profile of oligodendrocyte progenitors and oligodendrocytes derived from control and MS was equivalent and showed similar characteristics to murine cells (33, 34).

(A) Schematic representation of the concomitant Biocytin loading and recording of single RFP+ hiOL derivative in an acute coronal brain slice prepared from mice engrafted with hiOLs (control or MS) and analyzed at 12 to 14 wpg. (B and C) Currents elicited by voltage steps from 100 to +60 mV in a control-oligodendrocyte progenitor (B, left) and a MS-oligodendrocyte (C, left). Note that the presence of an inward Na+ current obtained after leak subtraction in the oligodendrocyte progenitor, but not in the oligodendrocyte (insets). The steady-state I-V curve of the oligodendrocyte progenitor displays an outward rectification (B, right) while the curve of the oligodendrocyte has a linear shape (C, right). (D) Mean amplitudes of Na+ currents measured at 20 mV in control and MS iPSCs-derived oligodendrocyte progenitors (n = 8 and n = 9, respectively, for four mice per condition; P = 0.743, Mann-Whitney U test). (E). Mean amplitudes of steady-state currents measured at +20 mV in control and patient differentiated iPSC-derived oligodendrocytes (n = 10 and n = 6 for 3 and four mice, respectively; P = 0.6058, Mann-Whitney U test). (F) A control iPSC-derived oligodendrocyte progenitor loaded with biocytin and expressing OLIG2, STEM101/121, and lacking CC1 (top) and an MS iPSCderived oligodendrocyte loaded with biocytin and expressing SOX10, CC1, and STEM101/121 (bottom). Scale bar, 20 m.

(A) Z-stack identifying a target and connected cell. One single grafted human RFP+ cell (per acute slice) was loaded with biocytin by a patch pipette and allowed to rest for 30 min. The white arrowheads and insets in (A) illustrate biocytin diffusion up to the donut-shaped tip of the human oligodendrocyte processes. Another biocytin-labeled cell (empty yellow arrowhead) was revealed at different morphological level indicating diffusion to a neighboring cell and communication between the two cells via gap junctions. (B and C) Split images of (A) showing the target (B) and connected (C) cell separately at different levels. Immunolabeling for the combined detection of the human markers STEM101/121 (red), OLIG2 (blue), and CC1 (white) indicated that the target cell is of human origin (STEM+) and strongly positive for OLIG2 and CC1, a mature oligodendrocyte, and that the connected cell is of murine origin (STEM-) and weakly positive for OLIG2 and CC1, most likely an immature oligodendrocyte. Scale bars, 30 m. See also fig. S7.

Studies with rodents have reported that oligodendrocytes exhibit extensive gap-junctional intercellular coupling between other oligodendrocytes and astrocytes (35). Whether oligodendrocytes derived from grafted human cells can be interconnected with cells in the adult host mouse brain was not known, and whether MS-hiOLs maintain this intrinsic property was also not addressed. Because biocytin can pass through gap junctions, we inspected biocytin-labeled cells for dye coupling (Figs. 6A and 7, A and B).

We found that two of seven MS-derived oligodendrocytes (~29%) and 5 of 21 control-derived oligodendrocytes (~24%) were connected with a single neighboring cell, which was either human or murine (Fig. 7), except in one case where three mouse cells were connected to the biocytin-loaded human cell. These findings reveal that gap junctional coupling can occur between cells from the same or different species, and MS-hiOLs can functionally connect to other glial cells to the same extent as their control counterparts.

To validate the presence of glial-glial interactions, we investigated whether the grafted hiOL-derived progeny had the machinery to be connected to one another via gap junctions. To this end, we focused on oligodendrocyte-specific Cx47 and astrocyte-specific Cx43 as Cx43/47 channels, which are important for astrocyte/oligodendrocyte cross talk during myelination and demyelination (36, 37). Combined immunolabeling for hNOGOA, CC1, OLIG2, and Cx47 revealed that MS-derived oligodendrocyte cell bodies and processes were decorated by Cx47+ gap junction plaques, which were often shared by exogenous MS-derived oligodendrocytes or by MS and endogenous murine oligodendrocytes (fig. S7A). In addition, colabeling exogenous myelin for MBP and Cx43 identified the presence of several astrocyte-specific Cx43 gap junction plaques between human myelin internodes, highlighting contact points between astrocyte processes and axons at the human-murine chimeric nodes of Ranvier (fig. S7B).

Last, colabeling of hNOGOA, with Cx47 and the astrocyte-specific Cx43, revealed coexpression of oligodendrocyte- and astrocyte-specific connexins at the surface of MS-derived oligodendrocyte cell bodies and at the level of T-shaped myelin-like structures (fig. S7C), thus implying connections between human oligodendrocytes and murine and/or human astrocytes, as a small proportion of the grafted hiOLs differentiated into astrocytes. Immunolabeling for human glial fibrillary acidic protein (GFAP), and Cx43 showed that these human astrocytes were decorated by Cx43+ aggregates, as observed in the host subventricular zone (fig. S8A).

Furthermore, immunolabeling for human GFAP, mouse GFAP, and Cx43 indicated that Cx43+ gap junctions were shared between human and mouse astrocytes as observed at the level of blood vessels (fig. S8B). These data validate interconnections between the grafted-derived human glia (MS and controls) with murine host glial cells and confirm their interconnection with the pan-glial network.

Two main hypotheses have been considered in understanding MS pathology and etiology: the outside-in hypothesis highlighting the role of immune regulators and environmental inhibitors as extrinsic key players in MS pathology and possibly its repair failure or the inside-out hypothesis pointing to the intrinsic characteristics of neuroglia including oligodendroglial cells as the main contributors in the MS scenario. Single-cell transcriptomic analysis revealed the presence of disease-specific oligodendroglia expressing susceptibility genes in MS brains (16) and altered oligodendroglia heterogeneity in MS (17). The question remains open as to whether these altered oligodendroglial phenotypes are acquired in response to the disease environment or whether they reflect intrinsic traits of the MS oligodendroglial population. On the other hand, the whole exome sequencing analysis in 132 patients from 34 multi-incident families identified 12 candidate genes of the innate immune system and provided the molecular and biological rational for the chronic inflammation, demyelination, and neurodegeneration observed in patients with MS (38) and revealed the presence of epigenetic variants in immune cells and in a subset of oligodendrocytes contributing to risk for MS (39).

While none of these hypotheses have been fully proven or rejected, research efforts for a better understanding of this multifactorial disease have continued. Impaired remyelination or oligodendrocyte differentiation block in MS is still considered a potentially disease-relevant phenotype (40, 41). Many histological and experimental studies suggest that impaired oligodendrocyte progenitor to oligodendrocyte differentiation may contribute to limited remyelination in MS, although some reports question the contribution of newly generated oligodendrocytes to remyelination (17, 42, 43). Understanding MS oligodendrocyte biology has been challenging mainly due to the following reasons: (i) oligodendroglial cells are not easily accessible to be studied in vivo; (ii) dynamic remyelination observed in patients with MS, which points to their individual remyelination potential, is inversely correlated with their clinical disability (3), highlighting even more complexity in oligodendrocyte heterogeneity between patients with MS; and (iii) exclusion of the role of immune system players in understanding MS oligodendrocyte biology being inevitable in most of clinical or experimental studies.

In such a complex multifactorial disease, one of the most accessible and applicable approaches to overcome these problems is the generation of large quantities of disease and control oligodendroglia using the iPSC technology, and to investigate their genuine behavior in vivo after engraftment in a B and T cellfree system. Using a very efficient reprogramming method (25), and the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects, we show that MS-hiOLs derivatives survive, proliferate, migrate, and timely differentiate into bona fide myelinating oligodendrocytes in vivo as efficiently as their control counterparts. Nicaise and colleagues reported that iPSC-NPCs from PPMS cases did not provide neuroprotection against active CNS demyelination compared to control iPSC-NPCs (44) and failed to promote oligodendrocyte progenitor genesis due to senescence without affecting their endogenous capacity to generate myelin-forming oligodendrocytes (21, 22). However, their myelinating potential was not evaluated against control cells. Generation of iPSC-oligodendrocyte progenitors from patients with PPMS or RRMS has also been reported by other groups, yet with no evidence for their capacity to become functional oligodendrocytes in vivo (23, 24). Thus, so far, no conclusion could be made regarding the potential impact of disease severity (PPMS verses RRMS) on the functionality of the iPSC-derived progeny.

We compared side by side, and at different time points after engraftment, hiOLs from patients with RRMS and controls including two pairs of homozygous twins discordant for disease. We found no significant difference in their capacity to timely differentiate (according to the human tempo of differentiation) and efficiently myelinate axons in the shiverer mouse in terms of the percentage of MBP+ cells generated, amount of myelin produced, length of MBP+ sheaths, and the ultrastructure and thickness of myelin sheaths. MS-hiOLs also reconstructed nodes of Ranvier expressing nodal components key to their function. We not only verified that the grafted MS-hiOLs derivatives were anatomically competent but also established their functionality at the electrophysiological level using (i) in vivo recordings of transcallosal evoked potentials and (ii) ex vivo recordings of the elicited current-voltage curves of the grafted MS-hiOLs verses controls. Our data show that the grafted MS-hiOLs were able to rescue the established delayed latency of shiverer mice to the same extent as control cells, as previously reported for human fetal glial progenitors grafted in the same model (11). Moreover, at the single-cell level, MS-hiOLderived oligodendrocyte progenitors and oligodendrocytes did not harbor aberrant characteristics in membrane currents compared to control cells ex vivo. Thus, iPSC-derived human oligodendroglial cells shift their membrane properties with maturation as previously observed in vitro (45) and these properties are not impaired in MS.

The absence of differences among control and MS-derivatives might be due to different causes. One might consider that pluripotency induction could by in vitro manipulation, erase cell epigenetic traits and/or reverse cells to an embryonic state, and as a result, modulate their intrinsic characteristics. Yet, several reports have highlighted differences in the behavior of diseased iPSC-derived oligodendrocytes in comparison to those from healthy controls using the same technology in multifactorial diseases such as schizophrenia (19, 20), Huntingtons disease (18), and others (46). In this regard, direct reprogramming of somatic cells into the desired cell type, bypassing the pluripotent stage, could be an attractive alternative. However, so far only mouse fibroblasts have been successfully directly converted into oligodendroglial cells, and with relatively low efficiency (47, 48).

iPSCs were transduced with three transcription factors to generate hiOLs in a fast and efficient way (25). While we cannot rule out that the use of these three transcription factors may have obscured differences between MS and controls, results for controls are quite comparable to our previously published data based on human fetal oligodendrocyte progenitor engraftment in the Shi/Shi:Rag2/ developing forebrain (49) or fetal NPC engrafted in the Shi/Shi:Rag2/ demyelinated spinal cord (50), suggesting that transduction with the three transcription factors does not overly modify the behavior of the grafted human cells. It could also be argued that the absence of differences between control and MS monozygous twins is not surprising given their equal genetic background. Yet, comparing controls with nonsibling MS hiOLS (compare C1 with RRMS2 and RRMS3; C2 with RRMS1, RRMS2, and RRMS3; and C3 with RRMS1 and RRMS2) revealed no defect in myelination for MS cells as well.

Analysis of hiOLs from each donor showed differences within each group. This could result from phenotypic instability, heterogeneity among donors, or disease subtype. Yet, the clinical history of each patient suggests a certain homogeneity among the MS disease phenotype, all being RRMS. In addition, the equal survival and proliferation rates between both groups argue in favor of cell stability. These confounding observations sustain that differences in terms of myelination are most likely due to heterogeneity among individuals rather than phenotypic instability or disease subtype.

While most preclinical transplantation studies have focused on myelination potential as the successful outcome of axo-glia interactions, less is known about the capacity of the grafted cells to fulfill glial-glial interactions in the pan-glial syncytium, which could ensure maintenance of newly generated myelin (51) and cell homeostasis (52). Oligodendrocytes are extensively coupled to other oligodendrocytes and oligodendrocyte progenitors through the homologous gap junctions Cx47 (35). These intercellular interactions between competing oligodendroglial cells influence the number and length of myelin internodes and the initiation of differentiation (53, 54). Oligodendrocytes are also coupled to astrocytes through heterologous gap junctions such as Cx32/Cx30 and Cx47/Cx43 (55). Disruption of oligodendrocytes from each other and from astrocytes, i.e., deconstruction of pan-glial network, has been observed in experimental models of demyelination (unpublished data) and frequently reported in MS and neuromyelitis optica (37, 56, 57). Mutations in Cx47 and Cx32 result in developmental CNS and PNS abnormalities in leukodystrophies (58, 59). Moreover, experimental ablation of Cx47 results in aberrant myelination (60) and significantly abolished coupling of oligodendrocytes to astrocytes (35).

In view of the major role of Cx-mediated gap junctions among oligodendrocytes and between oligodendrocytes and astrocytes during myelin formation (55), we asked whether the MS-hiOL progeny was capable of making functional gap junctions with other glial cells, and integrating into the host panglial network. We show that grafted MS-hiOLs, in common with rodent oligodendrocytes, express Cx47 that was frequently shared not only between the human and murine oligodendrocytes (through Cx47-Cx47) but also in conjunction with the astrocyte Cx43 (via Cx47/Cx43). The dye-coupling study highlighted that MS-hiOLs, similar to control cells, were capable of forming functional gap junctions with neighbor murine or human glial cells, indicating that MS-hiOLs retained the intrinsic property, not only to myelinate host axons but also to functionally integrate into the host pan-glial network. While our study focused mainly on oligodendroglial cells, a small proportion of the grafted hiOLs differentiated into astrocytes expressing Cx43. These human astrocytes were detected associated with blood vessels or the subventricular zone, where they were structurally gap-junction coupled to mouse astrocytes as observed after engraftment of human fetal glial restricted progenitors (61).

Together, our data highlight that human skinderived glia retain characteristics of embryonic/fetal brainderived glia as observed for rodent cells (10). In particular, we show that MS-hiOLs timely differentiate into mature oligodendrocytes, functionally myelinate host axons and contribute to the human-mouse chimeric pan-glial network as efficiently as control-hiOLs. These observations favor a role for extrinsic rather than intrinsic oligodendroglial factors in the failed remyelination of MS. The International Multiple Sclerosis Genetics Consortium after analyzing the genomic map of more than 47,000 MS cases and 63,000 control subjects, implicated microglia, and multiple different peripheral immune cell populations in disease onset (62). Moreover, neuroinflammation appears to block oligodendrocyte differentiation and to alter their properties and thereby aggravate the autoimmune process (63). Furthermore, MS lymphocytes are reported to exhibit intrinsic capacities that drive myelin repair in a mouse model of demyelination (64). On the other hand, a recent study highlighted the presence of disease-specific oligodendroglia in MS (16, 17). However, it should be considered that most of the data in the later were collected using single nuclei RNA sequencing of postmortem tissues from MS or control subjects of different ages that were suffering from other disorders ranging from cancer to sepsis and undergoing various treatment, and so died for different reasons, that may have influenced the type or level of RNA expression by the cells. In addition, the presence of genetic variants that alter oligodendrocyte function in addition to that of immune cells was also found (39). While this oligodendrocyte dysfunction contributes to MS risk factor, whether it is involved in other aspects of MS such as severity, relapse rate, and rate of progression is not yet known.

Numerous factors may cause the failure of oligodendrocyte progenitor maturation comprising factors such as axonal damage and/or altered cellular and extracellular signaling within the lesion environment (65) without neglecting aged-related environmental and cellular changes (40). Although the cells generated in this study are more of an embryonic nature, and did not experienced the kind of inhibitory environment that is present in MS, our data provide valuable findings in the scenario of MS pathology highlighting that RRMS-hiOLs, regardless of major manipulators of the immune system, do not lose their intrinsic capacity to functionally myelinate and interact with other neuroglial cells in the CNS under nonpathological conditions. Whether RRMS-hiOLs or oligodendroglial cells directly reprogrammed from MS fibroblasts would behave similarly well, if challenged with neuropathological inflammatory conditions as opposed to conditions wherein the immune system is intact (presence of T and B cells), or whether they would reflect intrinsic aging properties will require further investigation.

In summary, our findings provide valuable insights not only into the biology of MS oligodendroglia but also their application for cell-based therapy and should contribute to the establishment of improved preclinical models for in vivo drug screening of pharmacological compounds targeting the oligodendrocyte progenitors, oligodendrocytes, and their interactions with the neuronal and pan-glial networks.

We examined side by side the molecular, cellular, and functional behavior of MS hiOLs with their control counterparts after their engraftment in a dysmyelinating animal model to avoid the effect of major immune modulators. We used three MS and three control hiOLs including two monozygous twin pairs discordant for the disease. We performed in vivo studies in mouse with sample size between three to six animals per donor/time point/assay required to achieve significant differences. Numbers of replicates are listed in each figure legend. Animals were monitored carefully during all the study time, and animal welfare criteria for experimentation were fully respected. All experiments were randomized with regard to animal enrollment into treatment groups. The same experimenter handled the animals and performed the engraftment experiments to avoid errors. The data were analyzed by a group of authors.

Shiverer mice were crossed to Rag2 null immunodeficient mice to generate a line of Shi/Shi:Rag2/ dysmyelinating-immunodeficient mice to (i) prevent rejection of the grafted human cells and allow detection of donor-derived WT myelin and (ii) investigate the original behavior of MS-derived oligodendrocytes in a B cell/T cellfree environment. Mice were housed under standard conditions of 12-hour light/12-hour dark cycles with ad libitum access to dry food and water at the ICM animal facility. Experiments were performed according to European Community regulations and INSERM ethical committee (authorization 75-348; 20/04/2005) and were approved by the local Darwin ethical committee.

Fibroblasts were obtained under informed consent from three control and three RRMS subjects including two monozygous twin pairs discordant for the disease. They were reprogrammed into iPSCs using the replication incompetent Senda virus kit (Invitrogen) according to manufacturers instructions. Table S1 summarizes information about the human cell lines used in this study. The study was approved by the local ethical committees of Mnster and Milan (AZ 2018-040-f-S, and Banca INSpe).

Human iPSCs were differentiated into NPC by treatment with small molecules as described (66, 67). Differentiation of NPCs into O4+ oligodendroglial cells used a poly-cistronic lentiviral vector containing the coding regions of the human transcription factors Sox10, Olig2, and Nkx6.2 (SON) followed by an IRES-pac cassette, allowing puromycin selection for 16 hours (25). For single-cell electrophysiological recordings, the IRES-pac cassette was replaced by a sequence encoding RFP. Briefly, human NPCs were seeded at 1.5 105 cells per well in 12-well plates, allowed to attach overnight and transduced with SON lentiviral particles and protamine sulfate (5 g/ml) in fresh NPC medium. After extensive washing, viral medium was replaced with glial induction medium (GIM). After 4 days, GIM was replaced by differentiation medium (DM). After 12 days of differentiation, cells were dissociated by accutase treatment for 10 min at 37C, washed with phosphate-buffered saline (PBS) and resuspended in PBS/0.5% bovine serum albumin (BSA) buffer, and singularized cells were filtered through a 70-m cell strainer (BD Falcon). Cells were incubated with mouse immunoglobulin M (IgM) antiO4-APC antibody (Miltenyi Biotech) following the manufacturers protocol, washed, resuspended in PBS/0.5% BSA buffer (5 106 cells/ml), and immediately sorted using a FACS Aria cell sorter (BD Biosciences). Subsequently, human O4+ hiOLs were frozen and stored in liquid nitrogen. Media details were provided in (25). hiOLS from each donor was assayed individually (no cell mix) and studied as follows for forebrain engraftment: immunohistochemistry (all donors, three to seven mice per time point), electron microscopy (C1 and RRMS1, four mice per donor at 16 wpg), in vivo electrophysiology (C1 and RRMS1, six mice per donor and eight mice per medium at 16 wpg), dye coupling, and ex-vivo electrophysiology (C1-RFP and RRMS3-RFP, six to seven mice per donor at 16 wpg). For spinal cord engraftment: immuno-histochemistry (C1 and RRMS3, 3 and 4 mice respectively at 12 wpg).

RRMS1: Disease duration at biopsy was 11 years. Started on Rebif 22 and switched to Rebif 44 because of relapses. Relapse was treated with bolus of cortisone 20 to 30 days before biopsy and then switched to natalizumab.

RRMS2: Disease duration at biopsy was 16 months. Relapse at disease onset. On Rebif 22 from disease onset until biopsy with no episodes. A new lesion was identified 3 months after biopsy. At the time of biopsy, the patient reported cognitive difficulties, no motor dysfunctions.

RRMS3: Disease duration at biopsy was 15 months. Relapse 6 months before biopsy with dysesthesias and hypoesthesia right thigh and buttock. Active lesion identified by magnetic resonance imaging at day 10. On Rebif smart 44 mcg, 50 days later, and skin biopsy 4 months later. A new gadolinium negative temporal lesion identified 2 months after biopsy and the patient switched to Tecfidera.

To assay hiOL contribution to forebrain developmental myelination, newborn Shi/Shi:Rag2/ pups (n = 148) were cryo-anesthetized, and control and RRMS hiOLs were transplanted bilaterally, rostral to the corpus callosum. Injections (1 l in each hemisphere and 105 cells/l) were performed 1 mm caudally, 1 mm laterally from the bregma, and to a depth of 1 mm as previously described (49, 68). Animals were sacrificed at 4, 8, 12, 16, and, when indicated, 20 wpg for immunohistological studies and at one time point for electron microscopy (16 wpg), ex vivo (12 to 15 wpg), and in vivo (16 wpg) electrophysiology.

To assay the fate of hiOLs in the developing spinal cord, 4-week-old mice (n = 4) were anesthetized by intraperitoneal injection of a mixture of ketamine (100 mg/kg) (Alcyon) and xylazine (10 mg/kg) (Alcyon) and received a single injection at low speed (1 l/2 min) of hiOLs (1 l, 105 cells/l) at the spinal cord thoracic level using a stereotaxic frame equipped with a micromanipulator and a Hamilton syringe. Animals were sacrificed at 12 wpg for immunohistological studies.

Immunohistochemistry. Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 3 to 6 per group, donor and time point) were sacrificed by transcardiac perfusion-fixation with 4% paraformaldehyde in PBS. Tissues were postfixed in the same fixative for 1 hour and incubated in 20% sucrose in 1 PBS overnight before freezing at 80C. Serial horizontal brain and spinal cord cross sections of 12 m thickness were performed with a cryostat (CM3050S, Leica). Transplanted hiOLs were identified using anti-human cytoplasm [1:100; STEM121; Takara, Y40410, IgG1], anti-human nuclei (1:100; STEM101; Takara, Y40400, IgG1), and anti-human NOGOA (1:50; Santa Cruz Biotechnology, sc-11030, goat) antibodies. In vivo characterization was performed using a series of primary antibodies listed in tableS2. For MBP staining, sections were pretreated with ethanol (10 min, room temperature). For glial-glial interactions, oligodendrocyte-specific connexin was detected with anti-connexin 47 (1:200; Cx47; Invitrogen, 4A11A2, IgG1) and astrocyte-specific connexin, with anti-connexin 43 (1:50; Cx43; Sigma-Aldrich, C6219, rabbit), and sections were pretreated with methanol (10 min, 20C). Secondary antibodies conjugated with fluorescein isothiocyanate, tetramethyl rhodamine isothiocyanate (SouthernBiotech), or Alexa Fluor 647 (Life Technologies) were used, respectively, at 1:100 and 1:1000. Biotin-conjugated antibodies followed by AMCA AVIDIN D (1:20; Vector, A2006). Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI) (1 g/ml; Sigma-Aldrich) (1:1000). Tissue scanning, cell visualization, and imaging were performed with a Carl Zeiss microscope equipped with ApoTome 2.

Electron microscopy. For electron microscopy, Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 4 per group) were perfused with 1% PBS followed by a mixture of 4% paraformaldehyde/5% glutaraldehyde (Electron Microscopy Sciences) in 1% PBS. After 2-hour postfixation in the same solution, 100-m-thick sagittal sections were cut and fixed in 2% osmium tetroxide (Sigma-Aldrich) overnight. After dehydration, samples were flat-embedded in Epon. Ultra-thin sections (80 nm) of the median corpus callosum were examined and imaged with a HITACHI 120 kV HT-7700 electron microscope.

Electrophysiological recordings were performed in mice grafted with MS- and control-hiOLs, and compared with nongrafted intact or medium injected Shi/Shi:Rag2/ mice and WT mice 16 weeks after injection (n = 4 to 6 per group) as described (11). Briefly mice were anesthetized with 2 to 4% isoflurane performed under analgesia (0.1 mg/kg buprecare) and placed in a stereotaxic frame (D. Kopf, Tujunga, CA, USA). Body temperature was maintained at 37C by a feedback-controlled heating blanket (CMA Microdialysis). Electrical stimulation (0.1 ms at 0 to 0.1 mA) was applied using a bipolar electrode (FHC- CBBSE75) inserted to a depth of 200 m into the left cortex at 2 mm posterior to bregma and 3 mm from the midline. At the same coordinates in the contralateral hemisphere, homemade electrodes were positioned for recording local field potentials (LFPs) generated by transcallosal electric stimulation. Electrical stimulation and evoked LFPs were performed by the data acquisition system apparatus (Neurosoft, Russia), and signals were filtered at 0.01 to 1 000 Hz. Each response latency (in ms) was measured as the time between the onset of stimulus artifact to the first peak for each animal. A ground electrode was placed subcutaneously over the neck.

Slice preparation and recordings. Acute coronal slices (300 m) containing corpus callosum were made from Shi/Shi:Rag2/ mice grafted with control (n = 7) and RRMS (n = 6) RFP+ hiOLs. They were prepared from grafted mice between 12 and 15 wpg as previously described (69). Briefly, slices were performed in a chilled cutting solution containing 93 mM N-methyl-d-glucamine, 2.5 mM KCl, 1.2 mM NaH2PO4, 30 mM NaHCO3, 20 mM Hepes, 25 mM glucose, 2 mM urea, 5 mM Na-ascorbate, 3 mM Na-pyruvate, 0.5 mM CaCl2, and 10 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2) and kept in the same solution for 8 min at 34C. Then, they were transferred for 20 min to solution at 34C containing 126 mM NaCl, 2.5 mM KCl, 1.25 mM NaH2PO4, 26 mM NaHCO3, 20 mM glucose, 5 mM Na-pyruvate, 2 mM CaCl2, and 1 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2). Transplanted RFP+ hiOLs were visualized with a 40 fluorescent water-immersion objective on an Olympus BX51 microscope coupled to a CMOS digital camera (TH4-200 OptiMOS) and an light-emitting diode light source (CoolLed p-E2, Scientifica, UK) and recorded in voltage-clamp mode with an intracellular solution containing 130 mM K-gluconate, 0.1 mM EGTA, 2 mM MgCl2, 10 mM Hepes, 10 mM -aminobutyric acid, 2 mM Na2-adenosine 5-triphosphate, 0.5 mM Na-guanosine 5-triphosphate, 10 mM Na2-phosphocreatine, and 5.4 mM biocytin (pH 7.23). Holding potentials were corrected by a junction potential of 10 mV. Electrophysiological recordings were performed with Multiclamp 700B and Pclamp10.6 software (Molecular Devices). Signals were filtered at 3 kHz, digitized at 10 kHz, and analyzed off-line.

Immunostainings and imaging of recorded slices. For analysis of recorded cells, one single RFP+ cell per hemisphere was recorded in a slice and loaded with biocytin for 25 min in whole-cell configuration. After gently removing the patch pipette, biocytin was allowed to diffuse for at least 10 min before the slice was fixed 2 hours in 4% paraformaldehyde at 4C. Then, the slice was rinsed three times in PBS for 10 min and incubated with 1% Triton X-100 and 10% normal goat serum (NGS) for 2 hours. After washing in PBS, slices were immunostained for SOX10, CC1, and STEM101/121. Tissues were incubated with primary antibodies for 3 days at 4C. Secondary antibodies were diluted in 2% NGS and 0.2% Triton X-100. Tissues were incubated with secondary antibodies for 2 hours at room temperature. Biocytin was revealed with secondary antibodies using DyLight-488 streptavidin (Vector Laboratories, Burlingame, USA, 1:200). Images of biocytin-loaded cells were acquired either with a Carl Zeiss microscope equipped with ApoTome 2 or a LEICA SP8 confocal microscope (63 oil objective; numerical aperture, 1.4; 0.75-m Z-step) and processed with National Institutes of Health ImageJ software (70).

We adapted the heuristic algorithm from (29) to identify STEM+ MBP+ OLs in tissue sections. The foundations of the quantitative method remained the same. A ridge-filter extracted sheath-like objects based on intensity and segments associated to cell bodies using watershed segmentation. Two additional features adapted the workflow beyond its original in vitro application. First, we added functionality to allow colocalization of multiple fluorescent stains, as we needed to quantify triple positive STEM+/MBP+/DAPI+ cell objects. Second, because oligodendrocyte sheaths are not parallel and aligned in situ as they are in dissociated nanofiber cell cultures, we adapted the algorithm to report additional metrics about MBP production locally and globally that do not rely on the dissociation of sheaths in dense regions.

Cell nuclei were identified using watershed segmentation of DAPI+ regions and then colocalized pixel-wise with STEM+ objects. The DAPI+ nuclei were then used as local minima to seed a watershed segmentation of the STEM+ stain to separate nearby cell bodies. Last, the identified STEM+ cell bodies were colocalized with overlapping MBP+ sheath-like ridges to define ensheathed cells. We reported the area of MBP overlapping with STEM fluorescence in colocalized regions associated with individual cells, as well as the number of single, double, and triple fluorescently labeled cells. In addition, different cellular phenotypes were noted in situ that were then captured with the adapted algorithm. Qualitatively, we observed cells with expansive MBP production without extended linear sheath-like segments that were not observed in previous applications of the algorithm. These cells were denoted as tuft cells, and were quantitatively defined as STEM+/MBP+/DAPI+ cells without fluorescent ridges that could be identified as extended sheath-like objects.

The myelination potential of three control and 3 MS hiOLs was evaluated at 4, 8, 12, 16, and 20 wpg (n = 2 to 7 per line and per time point; n = 6 to 14 per time point). For each animal, six serial sections at 180-m intervals were analyzed. The percentage of MBP+ cells (composed of ensheathed or tuft cells) was evaluated. Total MBP+ area per STEM+ cells and the average length of MBP+ sheaths per MBP+ cells were analyzed.

Cell survival, proliferation, and differentiation in vivo. The number of STEM101+ grafted cells expressing Caspase3, or Ki67, or SOX10 and CC1 was quantified in the core of the corpus callosum at 8, 12, and 16 wpg. For each animal (n = 3 per group), six serial sections at 180-m intervals were analyzed. Cell counts were expressed as the percentage of total STEM101+ cells.

Myelination by electron microscopy. G ratio (diameter of axon/diameter of axon and myelin sheath) of donor-derived compact myelin was measured as previously described (10). Briefly, the maximum and minimum diameters of a given axon and the maximum and minimum axon plus myelin sheath diameter were measured with the ImageJ software at a magnification of 62,000 for a minimum of 70 myelinated axons per animal. Data were expressed as the mean of the maximal and minimal values for each axon for mice from each group (n = 4 mice per group). Myelin compaction was confirmed at a magnification of 220,000.

Data are presented as means + SEM. Statistical significance was determined by two-tailed Mann Whitney U test when comparing two statistical groups, and with one-way or two-way analysis of variance (ANOVA) followed by Tukeys or Dunnetts (in vivo electrophysiology) multiple comparison tests for multiple groups. Because electrophysiological data in brain slices do not follow a normal distribution after a DAgostino-Pearson normality test, we also performed two-tailed Mann-Whitney U test for comparison between groups. Statistics were done in GraphPad Prism 5.00 and GraphPad Prism 8.2.1 (GraphPad Software Inc., USA). See the figure captions for the test used in each experiment.

Acknowledgments: Funding: This work was supported by the Progressive MS Alliance [PMSA; collaborative research network PA-1604-08492 (BRAVEinMS)] to G.M., J.P.A., A.B.-V.E., and T.K., the National MS Society (NMSS RG-1801-30020 to T.K. and A.B.-V.E.), INSERM and ICM grants to A.B.-V.E., the German Research Foundation (DFG CRC-TR-128B07 to T.K.), and the Italian Multiple Sclerosis Foundation (FISM) (project no. Neural Stem Cells in MS to G.M.). M.C.A. was supported by grants from Fondation pour laide la recherche sur la Sclrose en Plaques (ARSEP) and a sub-award agreement from the University of Connecticut with funds provided by grant no. RG-1612-26501 from National Multiple Sclerosis Society. During this work, S.M. was funded by European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). B.G.-D. and M.J.F.L. were supported by the PMSA, PA-1604-08492 and the National MS Society (RG-1801-30020), respectively. B.M.-S. was supported by a Ph.D. fellowship from the French Ministry of Research (ED BioSPC). A.B. and M.C.A. thank respective imaging facilities, ICM Quant and IPNP NeurImag and their respective funding sources Institut des Neurosciences Translationnelles ANR-10-IAIHU-06 Fondation Leducq. Author contributions: Conceptualization: S.M. and A.B.-V.E. Methodology: S.M., L.S., B.M.-S., Y.K.T.X., B.G.-D., M.J.F.L., D.R., L.O., K.-P.K., H.R.S., J.P.A., T.K., G.M., T.E.K., M.C.A., and A.B.V.-E. Formal analysis: S.M., B.M-S., Y.K.T.X., M.C.A., and A.B.-V.E. Writing: S.M. and A.B.V.-E, with editing and discussion from all coauthors Funding acquisition: S.M. and A.B.V.-E. Supervision: A.B.V.-E. Competing interests: T.K. has a pending patent application for the generation of human oligodendrocytes. 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 data related to this paper may be requested from the authors.

Link:
Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo - Science Advances

Recommendation and review posted by Bethany Smith

The Male Hypogonadism Therapy market report provides a detailed analysis of the emerging trends, opportunities, and as well as the challenges in the market. This extensive report sheds light on the latest developments, market drivers, and competitive analysis to help the new entrants and emerging players to make crucial decisions.

Besides this, the market research report presents insights on consumer behavior, regulatory policies, and supply & demand scenario to provide a holistic view of the market. The primitive aim of the report is to represent the critical data and figures of the market concisely and layout top winning strategies to aid industry players to leverage their market position.

Get Free Sample Report + All Related Graphs & Charts: https://industrygrowthinsights.com/request-sample/?reportId=171163

The dedicated research team has included Porters Five Point Force analysis to tailor the Global Male Hypogonadism Therapy Market. They have conducted interviews with industry experts to provide accurate predictions and better insights in a detailed manner. The research report covers the latest advancements that have overhauled the market dynamics while examined the threats which has impacted the overall market.

Key Answers Captured in the Study are

Complete Purchase of Latest Version Global Male Hypogonadism Therapy Market Study with COVID-19 Impact Analysis: https://industrygrowthinsights.com/checkout/?reportId=171163

Important Features that are under offering & key highlights of the report:

Detailed overview of Male Hypogonadism Therapy

Changing market dynamics of the industry

In-depth market segmentation by Type, Application, etc.

Historical, current, and projected market size in terms of volume and value

Recent industry trends and developments

Competitive landscape of Male Hypogonadism Therapy

Strategies of key players and product offerings

Potential and niche segments/regions exhibiting promising growth

A neutral perspective towards Male Hypogonadism Therapy performance

Market players information to sustain and enhance their footprint

Ask for the discount @ https://industrygrowthinsights.com/ask-for-discount/?reportId=171163

Research Objectives

To analyze and forecast the Worldwide Male Hypogonadism Therapy, in terms of value and volume.

Which segment has the potential to gain the highest market share?

To help decision-makers from a new offer perspective and benchmark existing marketing strategy.

Correlate cost structure historical data with key business segments.

Analyze marketing contribution and customer acquisition by up-selling and cross-selling.

Identifying Influencing factors keeping Worldwide Male Hypogonadism Therapy Intense, factored with periodic analysis of CR4 & CR8 concentration ratio & HHI Index.

Important Features that are under offering & key highlights of the report:

1) Does the study cover COVID-19 Impact Analysis and its effect on Growth %?

Yes, the overall industry has seen quite a big impact due to slowdown and shutdown in the production line & supply chain. The study covers a separate qualitative chapter on COVID-19 Impact analysis. Additionally, it also provides before and after the scenario of COVID-19 on sales growth & market size estimation to better analyze the exact scenario of the industry.

2) How companies are selected or profiled in the report?

List of some players that are profiled in the report include:

Eli LillyPfizerAbbVieNovo NordiskMerck KGaAMylanBayerTevaNovartisAbbottRocheEndo InternationalIpsenANI PharmaceuticalsTherapeuticsMDMale Hypogonadism Therap

Usually, we follow NAICS Industry standards and validate company profile with product mapping to filter relevant Industry players, furthermore the list is sorted to come up with a sample size of at least 50 to 100 companies having greater topline value to get their segment revenue for market estimation.

** List of companies mentioned may vary in the final report subject to Name Change / Merger etc.

3) Can we add or profiled a new company as per our needs?

Yes, we can add or profile a new company as per client need in the report, provided it is available in our coverage list as mentioned in answer to Question 1 and after feasibility run, final confirmation will be provided by the research team checking the constraints related to the difficulty of survey.

4) Can we narrow the available business segments?

Yes, depending upon the data availability and feasibility check by our Research Analyst, a further breakdown in business segments by end-use application or product type can be provided (If applicable) by Revenue Size or Volume*.

Male Hypogonadism Therapy market segmentation

The Study is segmented by following Product Type:

ParenteralTransdermalOralOthersMale Hypogonadism Therap

Major applications/end-users industry are as follows:

HospitalsDrugstoresOthers

5) Can a specific country of interest be added? What all regional segmentation covered?

Yes, Country-level splits can be modified in the study as per objectives. Currently, the research report gives special attention and focus on the following regions:

North America [United States, Canada, Mexico], Asia-Pacific [China, India, Japan, South Korea, Australia, Indonesia, Malaysia, Philippines, Thailand, Vietnam], Europe [Germany, France, UK, Italy, Russia, Rest of Europe], South America [Brazil, Argentina, Rest of South America], Middle East & Africa [GCC Countries, Turkey, Egypt, South Africa, Rest of the Middle East & Africa]

** One country of specific interest can be included at no added cost. For inclusion of more regional segment quotes will vary.

Get on the call with our research analyst if you have any particular doubts before buying the report @ https://industrygrowthinsights.com/enquiry-before-buying/?reportId=171163

About Us:

Our reports are more than just research reports to us. They are tools that enable us to maintain long-term relationships with our clients whom we honor and cherish. Our clients business growth is integral for not only them but also us. This is what differentiates us from other market research companies.

At IGI, we provide our expertise and guideline for success. Our team of efficient and experienced researchers and consultants provide progressive market intelligence reports that are accurate, authentic, and in-depth. This empowers the clients to make well-informed decisions.

Moreover, we offer market intelligence studies, ensuring relevant and fact-based research across a range of industries including chemicals and materials, energy, automobile, healthcare, consumer goods, and technology. Our deep understanding of many business environments across industries such as those mentioned above allows us to deliver tailor-made reports.

Contact Us:

Alex MathewsHead of Business DevelopmentPhone No.: +1 909 545 6473Email [emailprotected] Website https://industrygrowthinsights.com Address 500 East E Street, Ontario, CA 91764, United States.

Read this article:
Male Hypogonadism Therapy Market Detailed Analysis Of Current Industry Figures With Forecasts Growth By 2026 - Cheshire Media

Recommendation and review posted by Bethany Smith

Dataintelo, one of the worlds leading market research firms has rolled out a new report on Male Hypogonadism market. The report is integrated with crucial insights on the market which will support the clients to make the right business decisions. This research will help both existing and new aspirants for Global Male Hypogonadism Market to figure out and study market needs, market size, and competition. The report provides information about the supply and demand situation, the competitive scenario, and the challenges for market growth, market opportunities, and the threats faced by key players.

The report also includes the impact of the ongoing global crisis i.e. COVID-19 on the Male Hypogonadism market and what the future holds for it. The pandemic of Coronavirus (COVID-19) has landed a major blow to every aspect of life globally. This has lead to various changes in market conditions. The swiftly transforming market scenario and initial and future assessment of the impact are covered in the report.

Request a sample Report of Male Hypogonadism Market: https://dataintelo.com/request-sample/?reportId=41372

The report is fabricated by tracking the market performance since 2015 and is one of the most detailed reports. It also covers data varying according to region and country. The insights in the report are easy to understand and include pictorial representations. These insights are also applicable in real-time scenarios. Components such as market drivers, restraints, challenges, and opportunities for Male Hypogonadism are explained in detail. Since the research team is tracking the data for the market from 2015, therefore any additional data requirement can be easily fulfilled.

The scope of the report has a wide spectrum extending from market scenarios to comparative pricing between major players, cost, and profit of the specified market regions. The numerical data is supported by statistical tools such as SWOT analysis, BCG matrix, SCOT analysis, and PESTLE analysis. The statistics are depicted in a graphical format for a clear picture of facts and figures.

The generated report is strongly based on primary research, interviews with top executives, news sources, and information insiders. Secondary research techniques are utilized for better understanding and clarity for data analysis.

The Male Hypogonadism Market is divided into the following segments to have a better understanding:

By Application:

Kallmann SyndromeKlinefelters SyndromePituitary DisordersOthers

By Type:

Testosterone Replacement TherapyGonadotropin-Releasing Hormones Therapy

By Geographical Regions:

Ask for Discount on Male Hypogonadism Market Report at: https://dataintelo.com/ask-for-discount/?reportId=41372

The Male Hypogonadism Market industry Analysis and Forecast 20192026 help clients with customized and syndicated reports holding key importance for professionals requiring data and market analytics. The report also calls for market-driven results providing feasibility studies for client requirements. Dataintelo promises qualified and verifiable aspects of market data operating in the real-time scenario. The analytical studies are carried out ensuring client requirements with a thorough understanding of market capacities in the real-time scenario.

Some of the prominent companies that are covered in this report:

Key players, major collaborations, merger & acquisitions along with trending innovation and business policies are reviewed in the report. Following is the list of key players:

Astrazeneca Plc.Merck& Co. Inc.Laboratories GenevrierAllergan Plc.Endo International Plc.Ferring

*Note: Additional companies can be included on request

Reasons you should buy this report:

Dataintelo provides attractive discounts that fit your needs. Customization of the reports as per your requirement is also offered. Get in touch with our sales team, who will guarantee you a report that suits your needs.

Customized Report and Inquiry for the Male Hypogonadism Market Report: https://dataintelo.com/enquiry-before-buying/?reportId=41372

About US:

DATAINTELO has set its benchmark in the market research industry by providing syndicated and customized research report to the clients. The database of the company is updated on a daily basis to prompt the clients with the latest trends and in-depth analysis of the industry.

Our pool of database contains various industry verticals that include: IT & Telecom, Food Beverage, Automotive, Healthcare, Chemicals and Energy, Consumer foods, Food and beverages, and many more. Each and every report goes through the proper research methodology, validated from the professionals and analysts to ensure the eminent quality reports.

Contact Info:

Name: Alex Mathews

Address: 500 East E Street, Ontario,

CA 91764, United States.

Phone No: USA: +1 909 545 6473

Email:[emailprotected]

Website:https://dataintelo.com

Read more:
Male Hypogonadism Market is Expected to Thrive at Impressive CAGR by 2026 & Top Key Players are Astrazeneca Plc., Merck& Co. Inc.,...

Recommendation and review posted by Bethany Smith