Archive for the ‘Hormone Clinic’ Category

Conference Call and Webcast Today at 8:30 a.m. ET

MALVERN, Pa., Nov. 08, 2019 (GLOBE NEWSWIRE) -- Ocugen, Inc., (NASDAQ: OCGN), a clinical stage biopharmaceutical company focused on discovering, developing and commercializing a pipeline of innovative therapies that address rare and underserved eye diseases, today reported financial highlights for the third quarter of 2019 and a business update.

This is an exciting time for Ocugen as weve completed our merger and are now a publicly traded company, commented Shankar Musunuri, PhD, MBA, Chairman, CEO and Co-Founder of Ocugen. We are focused on advancing our clinical and preclinical programs, which includes completing enrollment in our Phase 3 clinical trial of OCU300, our product candidate that has received orphan drug designation from the FDA and is being developed for the treatment of ocular graft versus host disease (oGVHD) and furthering our IND-enabling studies for OCU400, our first gene therapy product candidate with two distinct orphan drug designations. We believe our new strategic partnership with CanSinoBIO will be instrumental in accelerating the progress of our modifier gene therapy platform closer to the clinic. We are working to meet several milestones over the course of the next few years that we believe will continue to add value to Ocugen shareholders.

Third Quarter 2019 and Recent Highlights:

Third Quarter 2019 Financial Highlights

Conference Call and Webcast Details

The Company has scheduled a conference call and webcast for8:30 a.m. ETtoday to discuss the financial and recent business highlights. Ocugen's senior management team will host the call, which will be open to all listeners. There will also be a question and answer session following the prepared remarks.

The call can be accessed by dialing (844) 987-9316 (domestic) or (602) 563-8454 (international) and providing the conference ID 9979278. To access a live audio webcast of the call on the Investors section of the Ocugen website, please click here. A replay of the webcast will be archived on Ocugens website for approximately 45 days following the call.

About Ocugen, Inc.Ocugen, Inc. is a clinical stage biopharmaceutical company focused on discovering, developing and commercializing a pipeline of innovative therapies that address rare and underserved eye diseases. The Company offers a robust and diversified ophthalmology portfolio that includes novel gene therapies, biologics, and small molecules and targets a broad range of high-need retinal and ocular surface diseases. Ocugen is leveraging its groundbreaking modifier gene therapy platform to address genetically diverse inherited retinal diseases (IRDs) and dry AMD, based on nuclear hormone receptor genes NR2E3 (OCU400) and RORA (OCU410), respectively. OCU400 has received two orphan drug designations (ODD) targeting two distinct IRDs. Ocugen is also developing novel biologic therapies for wet-AMD, diabetic macular edema and diabetic retinopathy (OCU200), as well as for retinitis pigmentosa (OCU100). The Companys late-stage Phase 3 trial for patients with ocular graft versus host disease (oGVHD)(OCU300) leverages Ocugens patented OcuNanoE Ocugens ONE Platform technology to enhance the efficacy of topical ophthalmic therapeutics. OCU300 is the first and only therapeutic with ODD for oGVHD, providing certain regulatory and economic benefits. For more information, please visit http://www.ocugen.com.

Cautionary Note on Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, which are subject to risks and uncertainties. We may, in some cases, use terms such as predicts, believes, potential, proposed, continue, estimates, anticipates, expects, plans, intends, may, could, might, will, should or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the Companys current expectations. These and other risks and uncertainties are more fully described in our periodic filings with the Securities and Exchange Commission (the SEC), including the risk factors described in the section entitled Risk Factors in our Registration Statement on Form S-3 (File No. 333-234127) and our Registration Statement on Form S-4 (Reg. No. 333-232147), as amended, filed with the SEC by Ocugen, Inc. (f/k/a Histogenics Corporation) . Any forward-looking statements that the Company makes in this press release speak only as of the date of this press release. The Company assumes no obligation to update forward-looking statements contained in this press release whether as a result of new information, future events or otherwise, after the date of this press release.

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Corporate Contact:Ocugen, Inc.Kelly Beckkelly.beck@ocugen.com+1 484-328-4698

Media Contact:LaVoieHealthScienceEmmie Twomblyetwombly@lavoiehealthscience.com+1 857-389-6042

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Ocugen Provides Business Update and Third Quarter 2019 Financial Highlights - Yahoo Finance

Share on PinterestA new U.K. blood test is one of several tests aiming to detect cancer early. Getty Images

Theres a new blood test that aims to detect breast cancer. Its one of many attempts to create an effective early detection method.

The test could pinpoint breast cancer up to 5 years before a person shows clinical signs of the disease, according to researchers from the University of Nottingham in the United Kingdom.

The test evaluates the bodys immune response to the substances tumor cells produce.

Cancer cells make antigens that cause the body to make antibodies known as autoantibodies. The test looks for the presence of autoantibodies against tumor-associated antigens (TAAs).

The team was able to make a panel that looked for autoantibodies against 40 antigens that are known to be associated with breast cancer.

Additionally, they looked at 27 antigens or TAAs that werent known to be linked with breast cancer.

The research was presented at the 2019 National Cancer Research Institute (NCRI) Cancer Conference.

To assess the test, the researchers collected blood samples from 90 people with breast cancer when they received their diagnosis. They then compared those samples with blood samples from 90 people without breast cancer.

We were able to detect cancer with reasonable accuracy by identifying these autoantibodies in the blood, Daniyah Alfattani, a PhD student in the group, said, speaking at the conference.

The results of our study showed that breast cancer does induce autoantibodies against panels of specific tumor-associated antigens, Alfattani said.

Test accuracy improved in the panels that had more TAAs. A panel of five TAAs correctly detected breast cancer in 29 percent of samples.

Additionally, in the control group, researchers detected 84 percent of people as not having cancer. A panel of seven TAAs found cancer in 35 percent of samples and no cancer in 79 percent. The panel of nine TAAs identified cancer in 37 percent of people with cancer and 79 percent in people without cancer.

The researchers are hoping to improve the accuracy of the test. They hope it can evolve into a test that could offer an easy way to detect the disease in an early stage. Next, theyll test the panel with nine TAAs on 800 people.

If funded and evaluated completely, the test could be available in about 4 to 5 years, the researchers said.

Theres been a lot of interest in early cancer detection via blood tests, and more research keeps coming in looking at different approaches, says Dr. Len Lichtenfeld, interim chief medical and scientific officer for the American Cancer Society.

People have known about TAAs for many years. The U.K. test needs more data, but its an example of taking another approach to try to identify cancer through blood, he told Healthline.

Two interesting aspects of the research are that it looked at the bodys response to early stage cancer compared to cancer proteins or DNA shed by a tumor.

It also used a panel that looked at different markers instead of just one, explains Muhammed Murtaza, MD, PhD, assistant professor at Mayo Clinic and TGen, a nonprofit research organization.

These are promising results, but it is still too early to tell how the test will perform across breast cancer subtypes and stages, Murtaza told Healthline.

Stefan H. Bossmann, PhD, is a distinguished professor at Kansas State University and was part of a team that developed blood test technology that looked at cancer-related enzymes in blood.

He told Healthline about some of the ways to detect cancer in blood. These include looking for circulating tumor DNA or RNA, tumor cells, epigenetic markers, TAAs, and proteases and kinases (enzymes).

Another blood test for breast cancer in testing claims to be able to detect 15 different biomarkers (microRNA and methylation markers) in the blood, spotting metastatic and recurring cancers at an early stage, as well as small tumors.

That test may also be used for long-term monitoring to gauge treatment efficacy and is meant to complement other screening methods. It may be out later this year in European markets, according to reports.

Another blood test for early cancer detection, CancerSEEK, is a liquid biopsy test aimed at detecting multiple types of cancer by looking at circulating DNA. It recently obtained venture capital funding.

Early stage cancers shed very small amounts of most biomarkers into blood, making the pursuit for early detection tests fraught with challenges, Murtaza says.

There is not a blood test method yet that is used clinically for early detection, said Dr. Natalie Berger, assistant professor at Icahn School of Medicine at Mount Sinai.

There are multiple subtypes of breast cancer, and to detect these cancers through a blood test may not be a one-size-fits-all approach, Berger said.

Different antigens may be needed to detect hormone receptor-positive breast cancer compared to HER2-positive breast cancer or triple-negative breast cancer, Berger explains.

There are also differences between breast cancer in premenopausal and postmenopausal women as well as differences in people with a familial risk. Those factors may affect the sensitivity and specificity of these tests.

Imaging is superior at this time, but a blood test may be complementary or even the standard of care in the future, Berger said.

Another challenge of detecting cancer in blood is being able to detect enough of a cancer indicator, whatever it may be. Tests have to be accurate. They also need to show that they improve outcomes as well, Lichtenfeld says.

He says more data is needed to see whether the U.K. test will be effective at spotting breast cancers early.

This is an exciting development, but we have to see how it performs in larger studies, Berger added.

Though theres not a blood test for breast cancer thats truly effective and meets the needs of the larger population, developments are moving in that direction, Lichtenfeld says.

We will get there, he added.

More:
How Close Are We to a Blood Test for Breast Cancer? - Healthline

PLAN-LES-OUATES Nov 8, 2019 (Thomson StreetEvents) -- Edited Transcript of Obseva SA earnings conference call or presentation Thursday, November 7, 2019 at 1:00:00pm GMT

* Timothy M. Adams

SVB Leerink LLC, Research Division - MD of Biopharma & Generics and Senior Analyst

* Biren N. Amin

* Edward D. Marks

H.C. Wainwright & Co, LLC, Research Division - Research Analyst

* Kennen B. MacKay

Ladies and gentlemen, thank you for standing by, and welcome to the ObsEva Third Quarter 2019 Financial and Business Update and IMPLANT4 Trial Results Conference Call. (Operator Instructions) Please be advised that today's conference is being recorded. (Operator Instructions)

I would now like to hand the conference over to your speaker, Mr. Mario Corso. You may begin.

Thank you, operator. This is Mario Corso, Senior Director, Investor Relations at ObsEva. Good morning or afternoon to our listeners, and welcome to today's call.

ObsEva issued 2 press releases this morning, one disclosing Phase III results from the IMPLANT4 clinical trials of nolasiban in women undergoing embryo transfer following in-vitro fertilization and the other the disclosure of our third quarter 2019 financial results and business update. On today's call, I'm joined by Ernest Loumaye, our Co-Founder and Chief Executive Officer; Jean-Pierre Gotteland, our Chief Scientific Officer; Wim Souverijns, our Chief Commercial Officer; Tim Adams, our Chief Financial Officer; and Beth Garner, our Chief Medical Officer.

During today's call, ObsEva management will be making forward-looking statements, including, but not limited to, statements relating to financial results and trends; the process and timing of anticipated future development of ObsEva's product candidates; our oxytocin receptor antagonist, nolasiban; our gonadotropin-releasing hormone receptor antagonist, linzagolix; and our prostaglandin F2 alpha receptor antagonist, ObE022.

These forward-looking statements will include comments about expected clinical trial results and regulatory pathways in the U.S., Europe and Asia as well as the therapeutic and commercial potential of ObsEva's products.

These forward-looking statements are based on ObsEva's current expectations and the inherently involve risks and uncertainties. ObsEva's actual results and the timing of events could differ materially from those anticipated in such forward-looking statements. Risks and uncertainties include, without limitation, those related to ObsEva's development programs; clinical trial time lines and results; the uncertain clinical development process including adverse events; the success cost and timing of all development activities in clinical trials; the market potential for ObsEva's product candidates; the accuracy of ObsEva's estimates regarding expenses, capital requirements and the need for financing; and other risks detailed in the Risk Factors and elsewhere in ObsEva's filings with the U.S. Securities and Exchange Commission, including a 6-K report for the 3 months ended September 30, 2019, to be filed on or around November 11, 2019, as well as other reports filed on Form 6-K and 20-F.

ObsEva undertakes no obligation to update any forward-looking statements as a result of new information, future events or changes in expectations, except as required by law.

I will now turn the call over to Ernest Loumaye, our Chief Executive Officer.

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Ernest Loumaye, ObsEva SA - Co-Founder, CEO & Director [3]

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Thank you, Mario. Today, we disclosed results of the Phase III IMPLANT4 trials of nolasiban in women undergoing embryo transfer following in-vitro fertilization. We are surprised and obviously, very disappointed that the trial did not meet its primary end point. The 10 weeks pregnancy rate for women receiving nolasiban was 40.5%. This is a rate of 39.1% for women on placebo with a p-value of 0.745.

As to safety, nolasiban was well tolerated. No difference between placebo and nolasiban were observed. As this result did not confirm the positive results observed in our first Phase III trials of nolasiban, we have decided to discontinue the current development program for nolasiban in IVF. However, we will assess whether there is potential for nolasiban in other indications.

We remain fully committed to continuing the development of our innovative pipeline, focused on addressing unmet needs in women's health and pregnancy. We are focusing our effort and resource on the 4 ongoing Phase III trials of linzagolix for uterine fibroids and endometriosis and our Phase II program for OBE022 for the treatment of acute preterm labor.

We have very important data results for both of this compound this quarter is a PRIMROSE 2 trials of linzagolix in heavy menstrual bleeding due to uterine fibroid and an interim update in 60 patients from the prolonged trial of OBE022 in preterm labor. We consider both of this compound to be potentially best-in-class and look forward to sharing prior results soon.

PRIMROSE 2 recruited approximately 500 women with heavy menstrual bleeding or HMB due to uterine fibroids. It is a standard primary end point of reduction in HMB, as measured by the alkaline hematin method. The trial includes a low dose of linzagolix, 100-milligram without add-back therapy and a high-dose 200 milligram, including add-back therapy. Importantly, we are the only company developing a dose without add-back therapy for the uterine fibroids indication, which we believe is a critical point of differentiation of targeting the large and diverse U.S. patient population.

The 100-milligram dose achieved a response rate in the range of 40% to 50% without clinically significant impact on BMD, bone mineral density. We believe this provides a differentiation needed to be competitive in the market as none of the other generation antagonist under development can offer a way to control symptoms without requiring exogenous hormone through add-back therapy to mitigate bone loss.

Therefore, this could be the de facto first-line dose with our highest dose option, 200-milligram with add-back would be available for patients not responding to the lower dose.

Additionally, we expect a readout of 6 months data for PRIMROSE 1, second Phase III trial in uterine fibroids in the second quarter of next year.

With approximately 5 -- 4 million women in the U.S. diagnosed and treated, we believe that the unmet needs in uterine fibroids is tremendous. Oral contraceptives are often an ineffective treatment option to reduce menstrual bleeding. Generation antagonist are primary used short term as [alternative to] surgery. And surgery is costly and invasive. In addition, as we mentioned in our previous call, the EDELWEISS 2 and 3, the 3 trials assessing the efficacy and safety of linzagolix in women with endometriosis-associated pain are well underway, both in the U.S. and Europe.

Similarly to uterine fibroids, we are developing both a partial suppression, first-line option without add-back therapy as well as a full suppression option with add-back therapy. For the Phase IIa PROLONG study of OBE022 in pregnant women from 24 to 34 weeks of gestation experience in preterm labor, we expect an interim update in 60 patients later this quarter.

Following the open-label Part A of the trial concludes earlier this year, we have seen an acceleration in the randomization [AbbVie] of the trial in recent months, which compared treatment with atosiban alone versus OBE022 added to atosiban. The trial IDMC is scheduled to conduct its second review soon now in 60 patients versus 30 earlier this year.

In addition to safety, we will receive information on any initial efficacy signal that OBE022 may be able to prolong pregnancy compared to atosiban alone, but are not conducting statistical or futility analysis at this interim time point as previously mentioned.

Importantly, the unmet medical needs is likely greater in preterm labor than any other area that we are pursuing with 500,000 annual case in both Europe and in the U.S. and exceedingly high-medical risk to the mother and baby as well as financial cost for neonatal intensive care unit and clinic care that amounts to billions of dollars annually.

In conclusion, we regret not being able to improve outcome with nolasiban for women undergoing IVF. Due to our multi-asset strategy, we have the opportunity to develop 2 potentially best-in-class innovative assets, one of which is in late-stage Phase III. We continue to believe we have the right strategy of building a portfolio of promising assets, addressing significant unmet need in the field of women health.

I will now turn the call over to our CFO, Tim Adams, for a brief financial review. Tim?

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Timothy M. Adams, ObsEva SA - CFO [4]

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Thank you, Ernest, and good morning, everyone. I would like to spend a few minutes outlining third quarter results and our updated financial outlook.

Our net loss for the third quarter 2019 was $27.6 million or $0.63 per share. This compares with a net loss of $18.6 million or $0.42 per share for the third quarter of 2018. The year-over-year increase in net loss was largely attributed to increased spending on the clinical development for nolasiban and linzagolix.

Research and development expenses were $21.9 million for the third quarter of 2019 versus $15.9 million for the third quarter of 2018. This increase resulted from the expansion and continued progress with the clinical trial development for nolasiban and linzagolix.

G&A expense in the third quarter of 2019 was $4.9 million as compared to $3.1 million for the third quarter of 2018. This increase is primarily attributed to higher staff costs and precommercial activities for nolasiban.

Our cash balance as of September 30, 2019, was $91 million as compared to $138.6 million at year-end 2018. Of note, the 9/30 cash balance includes the first $25 million loan from our credit facility with Oxford Finance.

Cash used in operations during the third quarter was $26.9 million, reflecting continued spending in support of our pipeline. We also made a $5 million milestone payment to our partner, Kissei, related to the start of the Phase III EDELWEISS trials in endometriosis. Based upon our year-to-date spend and preliminary revisions to our nolasiban and precommercial spend, we now estimate our full year 2019 cash investment to be between $96 million and $99 million. This is less than our previous estimate of $105 million to $110 million cash used for 2019.

And finally, a quick update on the revised cash runway. Based on the $91 million of cash at September 30, our preliminary revised spending plans and assuming we draw another $25 million on the Oxford loan, our updated cash runway can fund our operations into the first quarter of 2021. We remain committed to the continued development of our innovative pipeline, and we will continue to invest appropriately with 4 Phase III trials ongoing for linzagolix and a Phase II trial for OBE022.

With that, operator, we can now take questions.

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Questions and Answers

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Operator [1]

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(Operator Instructions) And our first question comes from Kennen Mackay with RBC Capital Markets.

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Kennen B. MacKay, RBC Capital Markets, Research Division - Co-Head of Biotechnology Research [2]

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I was hoping, maybe this morning, you could help us understand a little bit around the potential to reduce R&D spend? And how much sort of the current run rate in R&D is coming from IMPLANT4 or spend on the IVF program? I think that would be incredibly helpful going forward. And then I was just wondering on any additional clarity in terms of how much of the -- you have remaining following the quarter or as of today? And again, share the disappointment in the IGF results -- IVF results.

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Timothy M. Adams, ObsEva SA - CFO [3]

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Kennen, it's Tim. Let me start with that. So we will not pursue the IMPLANT3 trial for nolasiban, which was scheduled for the U.S. market. I think we have shared with investors previously that, that trial was much more expensive than what we saw with IMPLANT4 over in Europe. So we will see a significant savings in nolasiban because we're not going forward within IMPLANT3. There are some additional CMC costs and some other things related to the program that we won't incur. So that will be the primary component.

When the financials come out back in the MD&A, you will see the detail of the R&D spend for this quarter was approximately $22 million. The lion's share of that goes to linzagolix. It was a little bit over $14 million. So roughly 2/3 plus, then our additional staff costs. So the run rate in the third quarter for nolasiban was approximately $3 million. But again, that was at the tail end of IMPLANT4 and before IMPLANT3 really got started. So again, our plans for revision are preliminary. This has all come at us very quickly. Certainly, the disappointment of the results.

And then I think your second question related to the Oxford loan. So it's a $75 million facility. And there were 3 tranches. The first tranche of $25 million was drawn back in August when we signed the deal with Oxford. The second tranche was subject to positive results from nolasiban that we will not be drawing. And then the third tranche is available to us mid next year upon the readout of the -- of both PRIMROSE 1 and 2. So we have to wait for that second PRIMROSE to read out before we control that third tranche of $25 million.

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Operator [4]

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And our next question comes from Ami Fadia with SVB Leerink.

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Ami Fadia, SVB Leerink LLC, Research Division - MD of Biopharma & Generics and Senior Analyst [5]

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Obviously, I share your disappointment on the nolasiban data. Can we -- can you help us sort of remind us on the linzagolix data that's expected before the year-end? Maybe remind us what we're looking for in the data? And how confident you are in this study being positive? And secondly, with the discontinuation of the nolasiban program, what are your thoughts around the OBE022 study and your development plans around that?

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Ernest Loumaye, ObsEva SA - Co-Founder, CEO & Director [6]

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Yes, Fadia. For the linzagolix PRIMROSE trial, you are well aware that it's a responder rate analysis in terms of heavy menstrual bleeding. That means that -- but it's a proportion of patients achieving a bleeding below 80 milliliter over a period of 28 days at the end of the treatment. So the generation antagonists are usually leading to a responder rate around 70% of the subjects, and we expect with our high dose add-back therapy to be around 70% of responder. For the low dose, we are the only one to have. We have no figure in February, but indirect evidence. It goes in the endometriosis population, the 100-milligram dose led to an amenorrhea rate of 55%. But if you extrapolate that to the fibroid population and there a reason to do that, that means that it should be above 55% because, indeed, amenorrhea, I mean, no bleeding and patient between 80 milliliter and 0 bleeding will still be responder. However -- so I think we are comfortably waiting for this data. Now we are a little bit conservative, and we are setting it as an objective between 40% and 50% because -- and I will ask Wim to justify that, why is it even a 40% is important in this population?

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Wim Souverijns, ObsEva SA - Chief Commercial Officer [7]

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Yes, thanks, Ernest. So Ami, the reason why that number comes up is that we try to assess from what point on would a drug that has an option to control symptoms without the use of add-back become commercially relevant. And as soon as we hit the 40% to 50%, there will be a significant opportunity for us to capture market share because, first of all, there is a segment of women that physiologically is not able to take or should not take add-back therapy, with a high BMI, [vis-a-vis] diabetes, cardiovascular complications, you're supposed not to take hormone replacement therapy. So if you hit a 40% response rate, 40%, 50%, one in two, you would respond. Those women definitely would be a key target for us.

And then on top of that, in terms of market expansion, the second segment are those women that technically could take add-back therapy, but really have expressed a preference of not to take exogenous hormones. And so that is the -- I would say, in the second wave of a commercial launch with the second segment of patients that we could go after. If we are below 30%, it becomes much harder to justify a commercial opportunity there. But as of 40%, 50%, we think there is definitely a value for us.

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Ami Fadia, SVB Leerink LLC, Research Division - MD of Biopharma & Generics and Senior Analyst [8]

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And if I could just follow-up, what percent of the target patient population falls within that segment of high BMI, cardiovascular risk, et cetera?

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Ernest Loumaye, ObsEva SA - Co-Founder, CEO & Director [9]

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We don't have a figure on that. But what is clear that, when we compare our EDELWEISS population, which is about 32, the endometriosis versus the fibroids, the fibroids is on average 42 years old, and that's a tranche of age where you have more hypertension, insulin -- glucose intolerance, obesity and so forth. So -- but we cannot give a precise figure. And maybe, Wim, you can help us with that...

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Wim Souverijns, ObsEva SA - Chief Commercial Officer [10]

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Yes, we're actually -- Ami, we're actually running currently research to assess that, to actually get a qualitative number behind that. But as Ernest said, there is definitely a population, significant population in that age group that will fall in that category.

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Elizabeth Ijeoma Onyemelukwe Garner, ObsEva SA - Chief Medical Officer [11]

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The prevalence of fibroid is also much higher in African-American women who are more likely to be having those conditions.

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Ernest Loumaye, ObsEva SA - Co-Founder, CEO & Director [12]

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Yes. Thank you, Elizabeth. Yes.

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Ami Fadia, SVB Leerink LLC, Research Division - MD of Biopharma & Generics and Senior Analyst [13]

See original here:
Edited Transcript of OBSV.O earnings conference call or presentation 7-Nov-19 1:00pm GMT - Yahoo Finance

Alex McCall, a trans student from Brighton, hit the headlines in March 2019 when he criticized the NHS for not allowing Trans people equal access to fertility treatment.

Alex wants to freeze his eggs before he undergoes full transition treatment as he fears that hormone treatment may leave him infertile. His application for egg freezing was turned down by the NHS after the Brighton and Hove Clinical Commissioning Group stated that its decision was fair and in-line with other groups.

Currently studying at Newcastle University, 22-year-old Alex is now trying a new route to fulfill his dream of being able to have a family in the future. He said,

Next week, I will go back to my GP to ask them for a new Individual Funding Request. Last year I got my hopes up and I was devastated to hear the result.

Alex has since had a second consultation with Dr James Barrett, lead clinician at the Gender Identity Clinic in London. Alex was delighted to find out that there may be some hope for his request to be accepted by May 2020.

I was told that I could apply for funding again. Apparently by May 2020 the case against the NHS may be withdrawn and a compromise could be reached. If a Trans person was refused funding without good reason, then they may be able to take the matter to court.

If this is the case, then this may affect the future of fertility rights for the Trans community. However Alex is understandably cautious, saying,

Im always feeling in limbo. I went into the clinic last year with the mindset of having to let go of my hopes of having biological children in the future. Sometimes, I dont want to ride that roller-coaster.

Sam Hall, a GP and Chair of The Clare Project, is himself a Trans man and parent of three. He feels that Trans males should not rely on egg freezing as the only way to make a family. He explains,

Taking hormones does not necessarily deprive you of having a family. Many Trans men have already managed to get pregnant and have families by using their own eggs.

Sam, who runs the regular Brighton TMP social night for the Trans community, is concerned that Transgender teenagers are now feeling under extra pressure to choose between egg freezing and start their transitioning treatment, when it not necessarily a choice that they will need to make.

Click here for more information on The Clare Projects regular TNB nights

Photo: Alex with sisters Danielle and Sarah Cornish-Spencer DongPei Yu

If youd like to see more articles like this, please support our Crowdfunder and help us keep community journalism alive.

Read more:
Trans student still hopeful for fertility treatment on the NHS - Brighton Journal

Therapies used to treat endometriosis include: Hormonal contraceptives. Birth control pills, patches and vaginal rings help control the hormones responsible for the buildup of endometrialtissue each month

Access Report Details at: https://www.themarketreports.com/report/global-endometriosis-therapies-market-by-manufacturers-regions-type-and-application-forecast

Market share of global Endometriosis Therapies industry is dominate by companies like AbbVie, Eli Lilly, AstraZeneca, Bayer, Astellas Pharma, Meditrina Pharmaceuticals, Pfizer, Neurocrine Biosciences, Takeda Pharmaceutical and others which are profiled in this report as well in terms of Sales, Price, Revenue, Gross Margin and Market Share (2017-2018).

With the help of 15 chapters spread over 100 pages this report describe Endometriosis Therapies Introduction, product scope, market overview, market opportunities, market risk, and market driving force. Later it provide top manufacturers sales, revenue, and price of Endometriosis Therapies, in 2017 and 2018 followed by regional and country wise analysis of sales, revenue and market share. Added to above, the important forecasting information by regions, type and application, with sales and revenue from 2019 to 2024 is provided in this research report. At last information about Endometriosis Therapies sales channel, distributors, traders, dealers, and research findings completes the global Endometriosis Therapies market research report.

Market Segment by Regions, regional analysis covers:

North America (USA, Canada and Mexico)

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

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

South America (Brazil, Argentina, Columbia, etc.)

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

Market Segment by Type, covers:

Hormonal Contraceptives

Gonadotropin-releasing Hormone (Gn-RH) Agonists

Progestin Therapy

Aromatase Inhibitors

Market Segment by Applications, can be divided into

Hospital

Clinic

Other

Purchase this premium research report at: https://www.themarketreports.com/report/buy-now/1501936

Table of Contents

1 Market Overview

2 Manufacturers Profiles

3 Global Endometriosis Therapies Market Competitions, by Manufacturer

4 Global Endometriosis Therapies Market Analysis by Regions

5 North America Endometriosis Therapies by Countries

6 Europe Endometriosis Therapies by Countries

7 Asia-Pacific Endometriosis Therapies by Countries

8 South America Endometriosis Therapies by Countries

9 Middle East and Africa Endometriosis Therapies by Countries

10 Global Endometriosis Therapies Market Segment by Type

11 Global Endometriosis Therapies Market Segment by Application

12 Endometriosis Therapies Market Forecast (2019-2024)

13 Sales Channel, Distributors, Traders and Dealers

14 Research Findings and Conclusion

15 Appendix

Ask your report related queries at: https://www.themarketreports.com/report/ask-your-query/1501936

Continued here:
Global Endometriosis Therapies Market Status and Outlook (2014-2024): Shared in a Latest Research available at TMR - Market Research Writeup

CHICAGO In a cohort of adults who received a thyroid function test during hospitalization, most did not have a thyroid disease and those who did generally had mild conditions, according to findings presented at the annual meeting of the American Thyroid Association.

Ruaa Al-Ward

Thyroid function tests are very frequently ordered in the hospitalized patients, Ruaa Al-Ward, MD, a hospital medicine senior associate consultant at Mayo Clinic in Rochester, Minnesota, told Endocrine Today. When abnormal, they are likely related to established diagnosis of thyroid disorders. However, in patients with no prior history of thyroid disorder, thyroid abnormalities resolved in two-thirds of the cases upon follow-up, therefore observation should be considered for the majority of these patients.

Al-Ward and colleagues analyzed data from 116 adults (mean age, 63.8 years; 50% women) who received a thyroid function test between January 2018 and January 2019 at Mayo Clinic. An abnormal test was required for all participants as was a lack of thyroid disorder history, although the researchers noted that risk factors for such disorders were present in 32% of the cohort.

Researchers identified thyroid disease in 35 of patients, with 31 having hypothyroidism and 23 having minimally elevated thyroid-stimulating hormone. Among the total cohort, 82% had a TSH level between 4.3 mIU/L and 10 mIU/L, 9.4% had a TSH level of more than 10 mIU/L and 7.7% had a TSH level below 0.2 mIU/L. According to the researchers, an arrythmia accounted for 22% of the tests, whereas 39% of requests came from ED providers who the researchers labeled as the group that most commonly ordered tests.

Although it is widely known that acute illness can affect thyroid function test, TSH is still commonly ordered. Physicians should keep in mind that, most of the time, thyroid testing is normal and not the explanation for the patients problem, and when the abnormalities are present they tend to be mild and they resolve during follow-up without any specific thyroid intervention, Al-Ward said. Thyroid testing should only be pursued when there is a high likelihood of thyroid disease. by Phil Neuffer

Reference:

Al-Ward R, et al. Poster 340. Presented at: 89th Annual Meeting of the American Thyroid Association; Oct. 30-Nov. 3, 2019; Chicago.

Disclosure: Al-Ward reports no relevant financial disclosures.

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Thyroid function tests frequently yield no evidence of thyroid disease - Healio

The Fulton County Health Department has scheduled the following health clinics and services.

CANTON The Fulton County Health Department has scheduled the following health clinics and services. Please call the number listed with each service for an appointment or more information.

Maternal child health: Health screenings, WIC nutrition education and supplemental food coupons for women, infants and children. To make an appointment or for more information call 647-1134 (ext. 254). For Astoria clinic appointments call 329-2922.

Canton - Clinic - Monday, Nov 4 - 8-4 - Appt needed

Canton - WIC Nutrition Education - Tuesday, Nov 5 - 8-4 - Appt needed

Canton - Clinic/Immunizations - Tuesday, Nov 5 - 4-7 - Appt needed

Canton - Clinic/Immunizations - Wednesday, Nov 6 - 8-4 - Appt needed

Astoria - Clinic, WIC Nutrition Educ. - Wednesday, Nov. 6 - 9-3 - Appt needed

Canton - Clinic - Thursday, Nov 7 - 8-4 - Appt needed

Adult Health Immunizations: Various vaccines are available. There is a fee for immunization administration. Medicaid cards are accepted. To make an appointment or for more information call 647-1134 (ext. 254).

Canton - Immunizations - Tuesday, Nov 5 - 4-7 - Appt needed

Canton - Immunizations - Wednesday, Nov 6 - 8-4 - Appt needed

Other times available by special arrangement at Canton, Cuba and Astoria.

Blood Lead Screening: Blood lead screenings are available for children ages one to six years. A fee is based on income. To make an appointment or for more information call 647-1134 (ext. 254). For Astoria appointments call 329-2922.

Canton - Clinic - Wednesday, Nov 6 - 8-4 - Appt needed

Family Planning: Confidential family planning services are available by appointment at the Canton office for families and males of child-bearing age. Services provided include physical exams, pap smears, sexually transmitted disease testing, contraceptive methods, pregnancy testing, education and counseling. Services are available to individuals of all income levels. Fees are based on a sliding fee scale with services provided at no charge to many clients. Medicaid and many insurances are accepted. After hours appointments are available. To make an appointment or for more information call the 647-1134 (ext. 244). *Program funding includes a grant from the US DHHS Title X.

Pregnancy testing: Confidential urine pregnancy testing is available at the Canton and Astoria offices. This service is available to females of all income levels. A nominal fee is charged. No appointment is needed. A first morning urine specimen should be collected for optimal testing and brought to the health department. Services are provided on a walk-in basis on the following days each week:

Canton: Every Wednesday & Thursday, 8-3:30 (for more information call 647-1134 ext. 244)

Astoria: Every Wednesday, 9-2:30 (for more information call 329-2922)

Womens Health: A womens clinic for pap tests, clinical breast examinations and vaginal examinations is available by appointment. There is a nominal fee for this service. Medicaid cards are accepted. Financial assistance is available for a mammogram. Cardiovascular screenings may be available to age and income eligible women. To make an appointment or for more information call 647-1134 (ext. 244).

Mammograms: Age and income eligible women may receive mammograms at no charge. Speakers are available to provide information to clubs and organizations. For more information or to apply for financial assistance, call 647-1134 (ext. 254).

Mens Health: Prostate specific antigen (PSA) blood tests are available for men for a fee. To make an appointment or for more information call 647-1134 (ext. 224).

Sexually Transmitted Disease (STD) Clinic: Confidential STD and HIV testing services are available by appointment to males and females at the Canton office. Services include physical exams to identify STDs, a variety of STD testing, HIV testing, education, counseling, medications and condoms. There is a nominal fee for services. Services are available to individuals of all income levels. Medicaid cards are accepted. To make an appointment or for more information call 746-1134 (ext. 224).

HIV Testing and Counseling: Confidential HIV testing and counseling services are available by appointment through the sexually transmitted disease (STD) clinic at the Canton office. To make an appointment or for more information call 647-1134 (ext. 224).

Tuberculosis (TB) Testing: TB skin tests are available at no charge by appointment. To make an appointment or for more information call 647-1134 (ext. 254).

Blood Pressure Screenings: The Fulton County Health Department provides blood pressure screenings at no charge on a walk-in basis during the following times:

Cuba - Screening - Monday, Nov 4 - 8-12 - Walk in

Astoria - Screening - Wednesday, Nov 6 - 9-12 - Walk in

Health Watch Wellness Program: The Health Watch Program provides low cost lab services. Through this program adults can obtain venous blood draws for a variety of blood tests. Blood tests offered without a doctors order Comprehensive Metabolic Panel (CMP), Complete Blood Count (CBC), Lipid Panel, Prostate Specific Antigen (PSA) test, Hepatitis C test, and Thyroid Stimulating Hormone (TSH). A wide variety of blood tests are also available with a doctors order. There is a charge at the time of service. To make an appointment or for more information call 647-1134 (ext. 254).

Canton - Clinic - Monday, Oct. 28 - 8-12 - Appt needed

Dental Services: The Dental Center offers a variety of basic dental services to children and adults. An appointment is needed. Medicaid and Kid Care cards are accepted. To make an appointment or for more information call 647-1134 (ext. 292).

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Health Department announces services for the week of Nov 4 - Orion Gazette

What is diabetes?

Diabetes is a lifelong health condition in which the bodys levels of blood glucose and the hormone insulin are out of balance. Symptoms include increased thirst, increased frequency of passing urine, and fatigue. There are two main forms:

Type 1, in which the body doesnt produce enough insulin.

Type 2, where either the body doesnt produce enough insulin, or the bodys cell no longer react to the insulin produced.

An inability to produce insulin, or use it effectively, results in raised levels of blood sugar (hyperglycaemia). If present over a prolonged period, hyperglycaemia is associated with damage to organs and tissue within the body including the heart, blood vessels, nerves, kidney and eyes.

The risk factors for Type 1 diabetes are still being researched, but several have been identified for the commonest form, Type 2. These include a family history of the disease, being overweight, physical inactivity, and unhealthy eating.

What is a podiatrist?

A podiatrist is an important part of a team of health professionals who manage complications associated with diabetes. Diabetes can affect circulation, nerve sensation (feet go numb or tingly), skin health, healing of wounds, and fighting infections. If you have no other complications with your diabetes, an annual foot exam can help detect problems early. Pressure points that turn into calluses, can result in foot ulcerations and infections.

Ingrown or fungal toenails, can lead to infections as well. Some patients require foot care every 2-3 months, to avoid problems with their feet, and closely monitor for problems.

Podiatrists can assess shoes, and even prescribe shoes and orthoses for your feet. They will help prevent the complications, along with accommodating deformities like hammertoes and bunions. If you have had a wound of some kind on your foot, it can also be prevented from recurring.

How does diabetes link to podiatry?

Foot complications in diabetes are common, accounting for more hospital admissions than any other diabetic complication. Foot ulcers present as one of the most significant pathologies, and are associated with neuropathy (nerve damage), and/or peripheral arterial disease (poor circulation). These greatly increase the risk of amputation, with up to 80 per cent of amputations attributed to foot ulceration.

The prognosis for individuals with ulceration and amputation is poor, with a five year mortality rate of 43-55 per cent, and up to 74 per cent respectively. Podiatrists play a leading role in the management of ulceration.

They provide treatments, including wound debridement, dressing and pressure relief. It has been suggested that 80 per cent of amputations are potentially preventable, through the provision of well structured, quality care.

Why is

awareness important?

The consequences of diabetes manifest slowly over a period of time. As a result, by the time they occur, it is too late, and the focus of treatment is the prevention of ulceration, and the subsequent fallouts.

It is why patient education is so important from the outset, and should be an ongoing process. Optimising blood glucose control is key; by providing regular foot checks, it can be reinforced, serving as a warning to those who are developing the complications.

Every person with diabetes, should pay careful attention to the systems of the body that can be affected directly and adversely These are the cardiovascular system, the renal system (kidneys), the eyes, and feet. It is recommended that every patient with diabetes have at least an annual check on all of these systems.

As far as the feet are concerned, people with diabetes can have severe, even life-threatening foot problems. This can happen because of a snowball effect the disease can have on the circulatory and nervous systems of the body. Essentially, diabetes can cause:

decreased foot blood flow

decreased healing potential

decreased infection fighting capability

numbness of the feet

These problems can all come together in a diabetic foot, causing drastic results.

It is entirely possible, for example, that a diabetic could step on a nail, and being numb, not even be aware.

Then follows a severe infection (which the person may not be able to fight), decreased healing potential, decreased blood flow, and problems can spiral quickly.

Often this patient may not even realise he/she stepped on a nail for a few days; by then, a severe infection has set in, and the problem is serious.

Every diabetic should have a podiatrist, whom those with numbness in the feet, should see on a regular basis each year. These problems are preventable, and are not inevitable. Regular check-ups with your podiatrist can prevent problems; as well, nail and callus trimming can be done, if you cannot manage same at home.

November is World Diabetes Month, so stay tuned, and look out for varied topics.

Your feet mirror your general health . . . cherish them!

Leana Huntley is a UK trained Podiatrist attached to Almawi Limited The Holistic Clinic, and Clinical Director-Fit Feet, Special Olympics Trindad and Tobago. E-mail: info@almawiclinic.com or visit the website at http://www.almawiclinic.com.

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Diabetes and podiatry...the connection | Features Local - Trinidad & Tobago Express Newspapers

SEATTLE, Oct. 31, 2019 /PRNewswire/ RareCyte announces an addition to the RarePlex Staining Kit product line, enabling customers to evaluate HER2 and ER expression on circulating tumor cells (CTCs) in their own laboratory. HER2 and ER are biomarkers that direct treatment recommendations for invasive breast cancer, and liquid biopsy offers a blood-based method to evaluate biomarker expression for insight into receptor status, response to treatment, and potentially therapy selection in clinical research.The RarePlex HER2/ER CTC Panel Kit includes all the reagents necessary for immunofluorescent detection of CTCs along with HER2 and ER expression. When combined with the RareCyte platform for CTC analysis, the RarePlex HER2/ER CTC Panel Kit enables the first blood-to-result breast-specific CTC assay deployable in customer laboratories.The HER2/ER Panel Kit was validated based on rigorous requirements set to clinical standards with guidance from CLIA and industry experts. Tad George, PhD, Sr. VP of Biology R&D at RareCyte noted Our approach to CTC assay development and validation is centered on creating deployable products that combine the sensitivity, specificity, and precision required for multi-center trials, not only for CTC enumeration but also for classifying CTCs based on their biomarker phenotypes.Dr. Minetta Liu, MD, Professor and Research Chair in the Department of Oncology at Mayo Clinic recently presented her work with the HER2/ER CTC Panel Kit at the Advances in Circulating Tumor Cells Conference in Corfu, Greece. Our early work with this assay has revealed interesting patterns of HER2/ER expression that vary widely across patients. Efforts will now focus on defining thresholds for HER2 and ER positivity that are specific to CTCs. This platform will facilitate important investigations into the clinical significance of CTC heterogeneity relative to standard tissue-based definitions of HER2 positive and/or hormone receptor positive advanced breast cancer.The HER2/ER Panel Kit is available for purchase and more information on the HER2/ER Panel Kit and the RareCyte platform is available at rarecyte.com.RareCyte products are for research use only. Not for use in diagnostic procedures.About RareCyte, Inc.RareCyte offers next generation instruments, consumables and reagents for the analysis and capture of rare cells from blood and tissue, enabling its foundational liquid biopsy and tissue analysis platform. The company has deep experience in developing advanced precision life science systems used in cutting-edge labs worldwide. Our customers perform innovative research, bring new therapeutics to market, and perform a wide-range of single cell applications in oncology, prenatal testing, and infectious disease. For more information about RareCyte, visit rarecyte.com.

FOX28 Spokane

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RareCyte expands liquid biopsy offering with the release of a HER2/ER breast cancer CTC Panel Kit - FOX 28 Spokane

AUSTIN (KXAN) Many people are looking forward to an extra hour of sleep with the time change Sunday morning as daylight saving comes to an end. However, others may begin to feel the effects of Seasonal Affective Disorder.

Seasonal Affective Disorder (SAD), also know as seasonal depression, is a type of depression that occurs around the same time every year, usually in late fall, and can go through the end of winter when the days become longer again.

While less common, SAD can also occur in the spring and summer time as well.

According to Help Guide, fall and winter SAD symptoms can include low self-esteem, appetite and weight changes, difficulty concentrating and changes in sleeping pattern.

The National Institute of Mental Healthsays women are four times more likely to experience SAD symptoms then men. Living far from the equator, family history of depression and young age can also be risk factors.

While the exact causes of SAD are unknown, researchers have found some biological cues. People with SAD may have trouble regulating serotonin, overproducing the hormone melatonin and lack of vitamin D.

Mayo Clinicsays treatment for SAD can include anything from light therapy to meditation to taking vitamin D supplements.

Remember to set your clocks back and take time to understand how the changing of seasons might lead to changes in your mood.

For more information go toThe National Institute of Mental Health.

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The time changes on Sunday, but your mood might be changing too - WKRG News 5

DEAR DOCS: I was a cigarette smoker for 30 years until my doctor told me that I needed to quit immediately. So I started vaping. It sure made it easy to walk away from tobacco. But can I use nicotine vapes safely?

DEAR JORDAN: The reason it was easy to go from cigarette to vape is because you were substituting one nicotine source for another. And thats no way to reduce your health risks.

Nicotine is an addictive drug that is associated with increased risk of cardiovascular, respiratory and gastrointestinal disorders, decreased immune response, harm to reproductive health and DNA mutation that leads to cancer. Plus, the American Heart Association says that vapers who think vaping nicotine can help them stop using cigarettes are likely to continue smoking cigarettes while they vape thats called dual use.

Vaping anything has never been safe. The only studies that say theres no harm associated with e-cigarettes are those funded by the vaping (tobacco) industry. The Altria Group (formerly Philip Morris of Marlboro and Virginia Slims fame) recently acquired a 35% stake in Juul. Its an old, familiar bag of tricks. Remember the 50s ad slogan that said, More doctors smoke Camels than any other cigarette?

The Centers for Disease Control and Prevention has reported that as of this writing more than 1,080 people have developed lung illnesses and at least 19 people have died from vaping. Those numbers could be just the tip of the iceberg. Lung damage from vaping isnt associated only with THC; nicotine also has been a cause. According to Mayo Clinic doctors, vaping-induced lung injury looks like a toxic chemical exposure, a toxic chemical fume exposure or a chemical burn injury. Thats because vaping is a delivery system for flavorings, ultrafine particles, heavy metals and volatile organic compounds.

So go to http://www.heart.org and type in 5 Steps to Quit (it includes vaping). For more comprehensive program, talk to your doctor.

DEAR DOCS:: Ive been waking up grumpy lately, and I dont know why. Im usually fine by midday. What can I do when I wake up to set myself up for a good mood in the morning?

DEAR CHONDRA: Lots of people wake up feeling grumpy at least a couple of days a week. In fact, one shower company in Great Britain did a survey and found that 6 out of 10 Brits wake up in a bad mood. The shower companys solution? Take a shower!

Well, we agree, but to maintain that good mood throughout the morning and rest of the day, you need to provide your body with the nutrition it needs to smoothly regulate your hormones, gut function and brain power. That means eating a nutritious breakfast. Your best bet is to put together a protein- and fiber-filled first meal of the day.

A great choice is oatmeal, muesli or granola (100% whole grains) with nonfat yogurt and lots of strawberries, blueberries and/or raspberries. Whole grains digest slowly and steadily raise levels of your feel-good hormone serotonin. They also help to keep your blood sugar stable, which improves mood.

Fresh berries deliver polyphenols, which can help you moderate your stress response and improve heart health. For variety, you can try grapefruit, oranges and melons (honeydew and cantaloupe).

Low-fat yogurt can deliver about a third of your daily requirement for calcium, which is good for your blood pressure and (along with magnesium) can have an anti-anxiety effect.

You might also try these foods that deliver mood-enhancing benefits: whole-wheat avocado toast; an egg-white omelet with vegetables; a green smoothie; or almond oatmeal. All those recipes and more are available at sharecare.com or doctoroz.com.

Other mood enhancers: Go to bed an hour earlier and get up an hour earlier. Get plenty of physical activity (sex counts); thatll stimulate the release of oxytocin, which increases your happiness. All these choices may help you see a turnaround in your morning mood.

Mehmet Oz, M.D., is host of The Dr. Oz Show. Mike Roizen, M.D., is chief wellness officer and chairman of Wellness Institute at Cleveland Clinic. Email questions to youdocsdaily@sharecare.com.

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Drs. Oz & Roizen: Respiratory effects of vaping; foods to keep you happy all day - The Union Leader

This transcript has been edited for clarity.

Good morning, everyone. I'm Dr Kathy Miller from Indiana University, and I'm here to tell you a story.

On a good day, God made a mixture of passion, determination, and smarts, and he called that mixture Bernie. Those of us in the breast cancer world know that Bernie can only mean Dr Bernard Fisher, who left us not long ago after 101 amazing years on this earth.

Very early in my training, I remember asking a mentor why breast cancer seemed like it had advanced faster than colon cancer or lung cancer. Was it that the biology of the disease was more favorable? Did we have an easier tumor? He laughed and said, "Maybe, but really it's because we have Bernie."

What he meant is that we had Berniewe had a surgeon who was passionate about research.

Bernie was famous for reminding us all that in God we trust; everybody else has to have data. You don't assume things that you can proveyou get the data. For Bernie, the data often started in the basic laboratory but continued into the clinic.

He was passionate about the role of clinical research and challenging the surgical dogma that had existed for 50 years. Only someone with incredible smarts, determination, and passionthat force of naturewould have been able to mount those early studies, gradually moving from radical mastectomy to modified radical mastectomy to lumpectomy to sentinel node biopsy.

Bernie was an early champion of the role of systemic therapy, making us all recognize that breast cancer was not a local disease to be solved by more and more extensive local therapy.

He also challenged us to think about prevention. That's an insight that came from those early studies when they realized that hormone therapy also reduced contralateral breast cancers, as well as distant recurrence and overall survival. That's why we're here today.

Bernie certainly did not work in isolation. He was joined by equally smart and passionate medical oncologists. He was clearly bolstered by statisticians who recognized the need for much larger clinical trials to be appropriately powered in order to find clinically relevant differences on which we could build.

But all of those people needed Bernie. We were all so much the richer for having known him, and for having benefited from his wisdom, passion, determination, and smarts.

Please take a moment to remember Bernie. Look around and see all of the things that wouldn't be here today or would have taken longer to get here had we not had Bernie as one of our early champions.

Kathy D. Miller, MD, is associate director of clinical research and co-director of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University. Her career has combined both laboratory and clinical research in breast cancer.

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Remembering Bernie: An Early Champion in Breast Cancer - Medscape

When it comes to finding an effective adult acne treatment, youve likely tried every lotion, potion, and serum out there. But it also helps to get to the root of the problem. In other words, to really treat your adult acne, you may need to understand what causes it in the first place.

Because, honestly, theres nothing more disappointing than waiting until your 20s to finally have clear skin and then learning the hard way that bad breakouts dont necessarily end when your teenage years do. Coming to terms with adult acne is difficultbut rest assured, youre not the only adult dealing with zits.

Knowing whats causing your pimples can help you clear up your skin and keep breakouts at bay. Keep reading to learn some of the most common adult acne causesand the best ways to treat these stubborn breakouts.

At the root of all acne is a clogged pore. Your pores, which are the opening that surrounds each hair follicle, are an important part of your skin because they also house your sebaceous glands.

These glands secrete sebum (oil) through the pore opening, which helps keep your skin soft and protected. But if the pore gets clogged by dirt, dead skin cells, excess oil, and possibly bacteria, youve got a recipe for a pimple.

Sometimes, just taking better care of your skin by cleansing or exfoliating regularly can be enough to prevent acne. For many others, though, the situation is more complicated. And, especially when youre an adult, trying to figure out whats causing your acne can get pretty frustrating.

Fluctuation in hormones, such as before ones menstrual cycle, is the main cause, dermatologist Julia Tzu, M.D., of Wall Street Dermatology, tells SELF.

This issue usually rears its ugly head in the form of deep (painful) cystic acne around the chin, neck, and back, dermatologist Rebecca Kazin, M.D., of the Washington Institute of Dermatologic Laser Surgery and the Johns Hopkins Department of Dermatology, tells SELF.

Cysts are pockets of pus that form deep in the skin, SELF explained previously. Theyre notoriously stubborn to treat because topical treatments dont usually have much of an effect. And because theyre so deep, they are more likely to cause scarring if popped.

Because your hormones naturally fluctuate at certain points in your life, the American Academy of Dermatology (AAD) explains, hormone-related acne is most likely to pop up:

We know that chronic stress can play a huge role in skin issues like acne, and its strongly suspected that the hormone cortisol may be responsible for the link.

When youre stressed, your adrenal gland releases cortisol, Neal Schultz, M.D. a New York Citybased dermatologist, tells SELF, and recent research also suggests that its produced locally in hair follicles and different types of skin cells. Although its commonly referred to as the stress hormone, cortisol is actually an important compound that helps regulate a ton of different bodily processes, including the immune system, digestive system, and neurological systems affecting your mood. Its levels naturally fluctuate over time (even within a single day).

But when you experience stressespecially chronic stresscortisol can start working overtime, causing issues with those bodily processes, including messing with your skin. Research suggests it may contribute to acne by creating a favorable environment for bacteria-driven inflammatory acne.

You may not have considered the effect that your environment has on your skinespecially the dirt and UV radiation outside. Air pollution just puts this layer of crap on your face, Dr. Schultz says, especially if you live in a city.

However, experts still dont totally understand how pollution can contribute to acne. Obviously, having excess dirt and grime on your face can increase your chances of getting clogged pores, so removing that stuff via a consistent cleansing routine is definitely helpful. But can exposure to UV rays or chemicals in the air actually damage your skin? Or cause acne?

Well, we know that UV exposure increases your risk for skin cancer and premature signs of aging, like fine lines and dark spots. And its possible for sun exposure to cause acne because it dries out the skin, leading to excess oil production in an effort to compensate. Thats why its always important to wear a broad-spectrum sunscreen with at least 30 SPF basically every day. Itll help prevent adult acne and help protect your face in general.

If you have oily or combination skin and are prone to breakouts, you should be using skin-care products labeled oil-free, noncomedogenic, or water-based, Dr. Schultz says. Products like these are less likely to clog your pores.

Try a light or gel-based moisturizer like Simple Light Hydrating Moisturizer, $4; CeraVe Facial Moisturizing Lotion, $12; or Tatcha the Water Cream, $68.

Overwashing your face can make acne worse, Dr. Kazin explains. Although some people with especially dry or sensitive skin find that they only need to cleanse once a day, most of us should be cleansing twice a day with a gentle cleanser. Cleansing any more than that is usually too much and can just dry out skin, which can cause [it] to produce more oil to overcompensate, Dr. Kazin says.

Gentle cleansers like Cetaphil Gentle Skin Cleanser, $14; SkinCeuticals Gentle Cleanser, $35; or Dermalogica Ultracalming Cleanser, $62, wont aggravate your skin. Additionally, some people find that cleansing balms or oils like Biore Makeup Remover Cleansing Oil, $8; DHC Deep Cleansing Oil, $28; Boscia MakeUp-BreakUp Cool Cleansing Oil, $32; or Then I Met You Living Cleansing Balm, $38, remove makeup more effectively and help their skin feel more moisturized than traditional cleansers.

Additionally, exfoliating too often or with products that are too harsh can damage skin and exacerbate acne. The type of exfoliating you should be doing and how frequently you should be doing it (if at all) depends on your skin type and your major skin concerns. But in general, experts recommend going with the gentler chemical exfoliants (products containing ingredients like lactic acid, glycolic acid, or salicylic acid) over scrubs or brushes, which are considered manual or physical exfoliants.

Experts also recommend exfoliating no more than three times per week for most people. If you have more dry or sensitive skin, just exfoliating once a week or every other week may be plenty for you.

For gentle exfoliating products, check out Paulas Choice the Unscrub, $29; Tatcha the Rice Polish, $65; or Benton Aloe BHA Toner, $19.

Weve all heard that some ridiculously long list of foods like chocolate, fried foods, pizza, caffeine, or dairy can cause acne. But, Dr. Schultz says, theres no conclusive proof that our dietary choices make a huge difference in the severity of acne.

Still, everyones skin is different and some people really do notice that their skin reacts badly after they eat certain foods. So the guiding rule here is to pay attention to your skin, and if you feel like it helps to avoid certain foods, you can try to cut them out. That said, planning out any major dietary changesespecially ones involving eliminating foodsis something thats best done with the guidance of your doctor or an R.D., so consider chatting with your derm before swearing off dairy.

In some cases, adult acne could be a symptom of another health condition, the AAD says.

For instance, one common hormone-related condition that results in acne is polycystic ovary syndrome (PCOS), a condition that causes symptoms such as irregular periods, facial hair, and weight gain. But PCOS is also known to cause hormonal acne thanks to the abnormal hormonal fluctuations it can cause.

Additionally, medications such as corticosteroids, lithium, or androgens can cause acne as a side effect, the Mayo Clinic says. So if you have any conditions that are being managed with those drugs, youre more likely to get acne.

If you think your acne might be due to an underlying health issue or medication, its especially important to check in with a dermatologist to figure out whats actually going on.

If a close relative has dealt with adult acne, you may be predisposed to having it too, according to the AAD. Part of that is because some things about your skin have genetic factors, like the size and visibility of your pores.

These genetic factors may be out of your control, but you *can* change your skin-care regimen to make sure youre giving your skin the best chance. That means knowing your skin type and using products and steps that work with your skin, possibly with the help of a dermatologist and prescription acne treatments.

The first and most important thing to to do when tackling acne is to make sure you have an arsenal of products with science-backed ingredients at your disposal. Remember that not every product or ingredient is going to work for everyone, and many of these products need to be used consistently for a few weeks before theres any noticeable change in your skin. So take it slowbut be persistent. And if youre not seeing any results or you cant find products that dont irritate your skin, talk to a dermatologist for some guidance and, maybe, a prescription treatment.

Here are the ingredients to look for:

Salicylic acid is a beta-hydroxy-acid (BHA), a kind of chemical exfoliant. It works by dissolving the bonds between dead skin cells. Salicylic acid is also particularly helpful when treating acne because its oil-soluble, which allows it to work its unclogging magic deeper in your oily pores than other chemical exfoliants.

Find it in: A ton of over-the-counter cleansers, spot treatments, and masks. For most people, its gentle enough to use on your whole facepossibly even daily. To start with, try a salicylic acidcontaining cleanser like Neutrogena Oil-Free Acne Wash, $10, or Dermalogica Breakout Clearing Foaming Wash, $20. When youre ready for toners and serums, check out La Roche-Posay Effaclar Clarifying Solution Acne Toner With Salicylic Acid, $15; Paulas Choice 2% Skin Perfecting BHA Liquid Exfoliant, $30; or SkinCeuticals Blemish and Age Defense Serum $92.

Glycolic acid is an alpha-hydroxy acid (AHA), another type of chemical exfoliant.

Find it in: Cleansers, serums, and peels. Pay attention to the concentration of glycolic acid in a given product as this will clue you in to how strong it will be. As the concentration gets higher, the product will be more powerful, but also more sensitizing. So if youre a beginner, start at the lower end of the spectrum with products like Pixi Glow Tonic, $30; Mario Badescu Glycolic Acid Toner, $18; or First Aid Beauty Facial Radiance Pads, $32. If you want something stronger, check out The Ordinary Glycolic Acid 7% Toning Solution, $9, or Juice Beauty Green Apple Peel, $42.

Lactic acid is yet another chemical exfoliant, an AHA. But lactic acid is known to be gentler than other types of chemical exfoliants, so its a good place to start if youre new to exfoliating treatments.

Find it in: Lactic acid is often paired with other acids in serums, toners, and peels, which means you could still be exposed to a more intense acid without realizing. But you can find lactic acid on its own in The Ordinary Lactic Acid 5% + HA 2% Superficial Peeling Formulation, $7; PCA Skin Facial Wash, $33; and the cult-favorite Sunday Riley Good Genes All-in-One Lactic Acid Treatment, $158.

Polyhydroxy acids (PHAs), which includes gluconolactone and lactobionic acid, are another class of chemical exfoliants and are generally considered to be the most gentle. If you have very dry or sensitive skin, or youve had bad reactions to other chemical exfoliants in the past, you should consider using a PHA.

Find it in: Lots of exfoliating peels, masks, and creams, such as Dr. Jart Dermaclear Micro Milk Peel, $42; Glow Recipe Avocado Melt Sleeping Mask, $45; and Cosrx PHA Moisture Renewal Power Cream, $25.

Benzoyl peroxide works by actually killing the acne bacteria while exfoliating the pores at the same time. Its not as gentle as the chemical exfoliants, so be careful when using it and make sure to moisturize.

Find it in: A classic derm recommendation, PanOxyl facial wash, comes in both lower-strength and higher-strength versions. But benzoyl peroxide is also found in many lotions and spot treatments, often paired with a chemical exfoliant like salicylic acid. Check out SkinMedica Acne Treatment Lotion, $56; Glo Skin Beauty Clear Skin Spot Treatment, $26; and PCA Skin Acne Cream, $30.

Sulfur doesnt have as much research behind it for acne as some of the other options on this list, but it is often a recommended treatment for acne-like bumps related to rosacea.

Find it in: Mainly spot treatments and face masks, like Murad Clarifying Mask, $40; Peter Thomas Roth Sulfur Cooling Mask, $52; Sunday Riley Saturn Sulfur Acne Treatment Mask, $55; and First Aid Beauty Anti-Redness Serum, $36.

Azelaic acid is another rosacea/acne crossover medication thats great at clearing the bumps sometimes seen in rosacea as well as pimples. As SELF explained previously, the exact mechanism by which azelaic acid works isnt totally understood. But we do know its effective.

Find it in: Azelaic acid is available in a few prescription forms, but its also present in over-the-counter products at lower concentrations. For concentrated options, check out The Ordinary Azelaic Acid Suspension 10%, $8, and Paulas Choice 10% Azelaic Acid Booster, $36. But azelaic acid is also included alongside other acne-treating ingredients in Ren Ready Steady Glow Daily AHA Tonic, $35, and PCA Skin Acne Gel, $50.

Retinoids are vitamin A derivatives, including retinol, retinal (retinaldehyde), and retinoic acid. They come in over-the-counter options (usually the active ingredient is retinol in these) and stronger prescription versions. Topical retinoids are fortunately one of the most effective treatments for acne and also happen to be a highly effective anti-aging ingredient, Dr. Tzu notes.

The biggest downside is theyre harsh and can sometimes be too much for sensitive skin, especially when youre first starting to use them. Thats why its important to use them just a few days a week at first, to always moisturize effectively, and to be extremely diligent about wearing sunscreen when using a retinoid.

Find it in: Retinol is available in many over-the-counter products, and thats generally the best place to start, because retinoids can be irritating. There are really a ton of retinol products out there, so check out these dermatologist-recommended options. If you want to try something stronger, you can opt for Differin (adapalene), $29, which used to be prescription-only but is now available over-the-counter. For more severe or stubborn acne, talk to a dermatologist about getting a prescription retinoid.

Exfoliation is the most important thing you can do on a regular basis to be fighting acne both in terms of preventing it and treating it, Dr. Schultz says. Whether you choose to use a chemical or physical exfoliant, know that this step will help prevent breakouts by keeping your pores clear and helping to remove any clogs you currently have.

If your skin can handle it, glycolic acid is Dr. Schultzs go-to ingredient, and he suggests using leave-on products or masks rather than cleansers, which will only stay on your skin for a short amount of time.

That said, be careful not to exfoliate too often, which can result in irritated, flaky, dry skin. Between one and three times a week is plenty for most people, but your skin may be able to take more or less than that depending on your individual skin type and concerns.

Spot treatments are key for treating a pimple ASAP, especially ones containing benzoyl peroxide, which work by killing the bacteria thats often responsible for acne. It can be a little harsh, though, so those with sensitive skin should be careful with it.

Try this classic spot treatment: Neutrogena On-the-Spot Acne Treatment, which contains benzoyl peroxide, heavy-duty action.

As we mentioned, pimples form when a pore gets clogged with dirt, oil, and dead skin cells. If bacteria are also present, the pimple might get inflamed, meaning it becomes red, swollen, and painful. Not all pimples are inflamed, but those that are tend to be extra unpleasant to deal with. So finding ways to calm them down while treating the root of the problem is essential.

If you have inflamed acne, look for products that contain soothing ingredients (like colloidal oatmeal, aloe, or centella asiatica) alongside acne-fighting ingredients, like salicylic acid.

Depending on the root cause(s) and severity your acne, you may find that topical treatments dont cut it. For instance, hormonal acne is fueled by internal processes that cant really be tamed with external medications.

In that case, your dermatologist may recommend an oral medication. Medications that manipulate hormonal levels, such as oral contraceptives and spironolactone, are helpful in curbing hormonal chin and lower face outbreaks, Dr. Tzu says. Additionally, oral retinoids like isotretinoin (formerly Accutane) are considered the big dermatological guns when fighting acne. Ask your derm about what might work for you.

When it comes to cystic acne, topical treatments are unlikely to cut it. And because those big, painful zits are so deep in the skin, theyre more likely to leave a scar if you pick and prod at them than other types of acne. The only way to reduce it quickly is to drain it, and thats not a DIY deal, Dr. Schultz warns.

One option, if you have access to a dermatologist, is to get a cortisone shot to deal with a stubborn cyst. Cortisone shots are the true spot treatments for painful cystic acne lesions, Dr. Tzu says.

There are ways to deal with them at home, though, by applying a warm or cold compress (whichever feels better to you), applying a small amount of over-the-counter hydrocortisone cream to calm the inflammation, and just waiting it out.

Related:

Originally Appeared on Self

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8 Causes of Adult Acneand How to Actually Treat It - Yahoo Lifestyle

Defeating severe obesity is healthy for moms and babies alike.

LOS ANGELES (PRWEB) November 01, 2019

An October 16 article on WebMD reported on a recent study finding that obese women who undergo weight loss surgery before becoming pregnant decrease health risks to themselves and their babies. Los Angeles-based weight loss surgery specialists Dr. Feiz and Associates says that the research demonstrates that defeating obesity with the help of a weight-loss procedure is an overall boon to a patients health as well as her offsprings.

The weight loss clinic says its no secret that when individuals struggling with obesity lose significant amounts of weight, their overall health and quality of life increases. Common conditions that are linked to obesity include type 2 diabetes, high blood pressure, and heart disease. The clinic adds that all of these conditions can not only shorten individuals life expectancy but also affect the quality in which they are able to live out those years. The problem, of course, is that defeating obesity is a lot easier said than done.

While natural weight loss through proper diet and exercise is theoretically a simple matter of consuming fewer calories than one burns, there are a number of reasons why bariatric surgery appears to be necessary for the large majority of patients to defeat severe obesity. Dr. Feiz and Associates says that one reason involves the reality that obese individuals tend to produce higher amounts of a hormone called ghrelin, which spurs our desire to eat. As dieters begin losing weight, however, it gets worse because the production of the hormone increases ever further the body is essentially preparing for a famine that is never going to come. The result is nagging feelings that are essentially identical to hunger and very difficult to ignore.

The clinic says that reducing ghrelin production is part of why such procedures as a sleeve gastrectomy have proven so powerful. The original premise of the procedure was simply to reduce the size of the stomach to make overeating uncomfortable and reduce the appetite. Over time, however, it became clear that removing roughly 75%-85% of the stomach also removes the area of the body that might be most responsible for ghrelin production. Thus, patients are discouraged from overeating while being less bothered by the feelings that make them want to overeat in the first place.

Dr. Feiz and Associates note that its crucial for prospective patients to realize that undergoing a weight loss procedure will not automatically fix all of their weight-related health issues and they still have to work at changing their relationship with food. The clinic says that with the aid of a weight loss procedure, however, reducing significant amounts of weight through diet becomes much easier to accomplish.

Readers who would like to learn more about Dr. Feiz and Associates and their weight loss services can call 310-855-8058 or visit the clinics website at https://www.drfeiz.com.

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Weight Loss Surgery Benefits by Bolstered by Research into Bariatric Procedures and Childbirth, Says Dr. Feiz and Associates - PR Web

Your waistline has been gradually expanding through the years. You feel sluggish and tired, sometimes even on waking up. What could be the problem? A slow metabolism could be the culprit. But while gaining weight and feeling fatigued could be signs of slow metabolism, its important to know that medically induced slow metabolism is quite rare. In most cases, slow metabolism is caused by poor diet, lack of sleep, or lack of physical exercise.What is metabolism?Simply put, metabolism is how your body turns calories into energy. When someone says they have a slow metabolism, they mean that their body holds on to calories, causing unwanted weight gain. Often, when people talk about metabolism, theyre referring to their metabolic rate -- which is the number of calories your body burns in a period of time.People have different metabolic rates depending on factors such as sex, genetics, age, diet and physical activity. You can get a resting metabolic rate (RMR) test at a specialised clinic to accurately determine your metabolic rate.Here are some hidden medical reasons for slow metabolism:1. You have too much cortisol

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Why you are gaining weight despite doing all the right things - The Standard

SEATTLE, Oct. 31, 2019 /PRNewswire/ -- RareCyte announces an addition to the RarePlex Staining Kit product line, enabling customers to evaluate HER2 and ER expression on circulating tumor cells (CTCs) in their own laboratory. HER2 and ER are biomarkers that direct treatment recommendations for invasive breast cancer, and liquid biopsy offers a blood-based method to evaluate biomarker expression for insight into receptor status, response to treatment, and potentially therapy selection in clinical research.

The RarePlex HER2/ER CTC Panel Kit includes all the reagents necessary for immunofluorescent detection of CTCs along with HER2 and ER expression. When combined with the RareCyte platform for CTC analysis, the RarePlex HER2/ER CTC Panel Kit enables the first blood-to-result breast-specific CTC assay deployable in customer laboratories.

The HER2/ER Panel Kit was validated based on rigorous requirements set to clinical standards with guidance from CLIA and industry experts. Tad George, PhD, Sr. VP of Biology R&D at RareCyte noted "Our approach to CTC assay development and validation is centered on creating deployable products that combine the sensitivity, specificity, and precision required for multi-center trials, not only for CTC enumeration but also for classifying CTCs based on their biomarker phenotypes."

Dr. Minetta Liu, MD, Professor and Research Chair in the Department of Oncology at Mayo Clinic recently presented her work with the HER2/ER CTC Panel Kit at the Advances in Circulating Tumor Cells Conference in Corfu, Greece. "Our early work with this assay has revealed interesting patterns of HER2/ER expression that vary widely across patients. Efforts will now focus on defining thresholds for HER2 and ER positivity that are specific to CTCs. This platform will facilitate important investigations into the clinical significance of CTC heterogeneity relative to standard tissue-based definitions of HER2 positive and/or hormone receptor positive advanced breast cancer."

The HER2/ER Panel Kit is available for purchase and more information on the HER2/ER Panel Kit and the RareCyte platform is available at rarecyte.com.

RareCyte products are for research use only. Not for use in diagnostic procedures.

About RareCyte, Inc.

RareCyte offers next generation instruments, consumables and reagents for the analysis and capture of rare cells from blood and tissue, enabling its foundational liquid biopsy and tissue analysis platform. The company has deep experience in developing advanced precision life science systems used in cutting-edge labs worldwide. Our customers perform innovative research, bring new therapeutics to market, and perform a wide-range of single cell applications in oncology, prenatal testing, and infectious disease. For more information about RareCyte, visitrarecyte.com.

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RareCyte expands liquid biopsy offering with the release of a HER2/ER breast cancer CTC Panel Kit - Daily Record-News

Abbie Duggar is having a rough time. The 27-year-old, who is expecting her first child with husband John David Duggar, 29, has been battling severe morning sickness, the dad-to-be told Us Weekly. He called the experience scary.

Abbie who is due early next year was diagnosed with hyperemesis gravidarum, John David explained. Its a type of serious morning sickness that causes extreme nausea and vomiting. It can lead to dehydration, weight loss, and can sometimes requires hospitalization.

It hit her hard, and she was down for probably seven weeks with severe morning sickness, he told the magazine. She got diagnosed with hyperemesis gravidarum, and she was hospitalized a couple times. We made multiple visits to the ER for dehydration. She couldnt eat, pretty much, or drink, or anything. So she was actually on IVs and had IVs at home. So that was a pretty scary time.

While Abbies illness was alarming, John David stepped up to care for his wife and make sure she was as comfortable as possible.

I keep her water filled up, and her snacks for her, the Counting On star explained. I keep her eating and just comfortable. Anything I can get for her, I try to. I run to the store, [get] whatever she needs, just keep her as comfortable as possible when shes feeling bad.

Abbie says shes been grateful for her husbands help. Hes cooked for me. Hes cleaned. Hes just been an angel, she said.

Hyperemesis gravidarum affects fewer than 3% of pregnant women, according to WebMD. Many people had never heard of it until 2012, when the royal family revealed that Kate Middleton was suffering from the condition during her pregnancy with Prince George. The duchess had to be admitted to the hospital for treatment. She experienced the condition again during her second and third pregnancies.

Since then, a number of celebrities have opened up about their struggle with the condition. Amy Schumers hypermesis was so serious she had to be hospitalized.

I have hyperemesis and it blows, the comedian wrote on Instagram. Very lucky to be pregnant but this is some bullsh*t!

Amber Rose also experienced the extreme nausea and vomiting associated with the condition. Im tired and I just want to barf all day. Its just not fun. But its totally worth it, she said in an Instagram video.

Doctors arent entirely sure what causes hyperemesis gravidarum, though it might be related to changes in hormone levels, according to the Cleveland Clinic. Symptoms usually begin in the first trimester and include vomiting multiple times per day, losing a significant amount of weight, dizziness and lightheadness, and dehydration.

Women whove experienced the condition describe not being able to keep down most food, being unable to get out of bed, and feeling so awful they considered ending the pregnancy.

Treatment for hyperemesis gravidarum can include anti-nausea medications, intravenous fluids, and ginger. Some women may need to be hospitalized if the condition is severe.

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'Counting On': Pregnant Abbie Duggar Is Battling the Same Condition That Afflicted Kate Middleton - Showbiz Cheat Sheet

Pictured here is the logo for the University of California San Francisco (UCSF) medical center ... [+] embedded into the wall of a building in the Mission Bay neighborhood of San Francisco, California, July 11, 2018. (Photo by Smith Collection/Gado/Getty Images)

Imagine that you are at work and thirsty. How easy is it to get a soda or some other sugary drink? Not too easy? Easy? Very easy? Open-your-eyes-and-it-will-be-in front-of-you-easy?

How then might this affect your chances of drinking a sugary drink rather than water and how might this affect your health?

Well, a study just published in JAMA Internal Medicine showed what happened after a big employer banned the sales of sugar-sweetened beverages. Significant changes occurred and, spoiler alert, things didnt go to waist.

The big employer was the University of California, San Francisco (UCSF), which is the second-largest employer in San Francisco and the fourth-largest in the Bay Area with over 24,000 employees, according to UCSF. As part of the UCSF Healthy Beverage Initiative, the mega-medical center has banned the sales of all sugary drinks across all of their venues since November 1, 2015. After that date, no cafeteria, no vending machine, no food truck, no restaurant, and no store on a UCSF campus could sell sodas or any other drink with added sugar. Not in a box, not with a fox, not with a mouse, there was no such drinks sold in the house.

It can be common to find cans of soda being sold at healthcare facilities. Photographer: Carla ... [+] Gottgens/Bloomberg

Now this didnt mean that UCSF employees had to smuggle sodas in brown paper bags into their workplaces and pretend that they were drinking very brownish water. People could still bring whatever non-alcoholic drinks they wanted onto the UCSF campus. They could also step out of their immediate workplaces into the surrounding neighborhoods to buy sugary beverages. Because, after all, how many times have you heard a person complain about not being able to find soda in a major American city?

Therefore, before this sales ban went into effect, a research team at UCSF (Elissa S. Epel, PhD, Alison Hartman, Laurie M. Jacobs, PhD, Cindy Leung, ScD, MPH, Michael A. Cohn, PhD, Leeane Jensen, MPH, Laura Ishkanian, MPH, Janet Wojcicki, PhD, MPH, Ashley E. Mason, PhD, Robert H. Lustig, MD, MSL, Kimber L. Stanhope, PhD,MS, RD, and Laura A. Schmidt, PhD, MSW, MPH) thought that this would be a great opportunity to measure the impact of such a workplace ban. As Epel, first author of the study, a health psychologist, and Professor in the UCSF Department of Psychiatry said, Many hospitals have recently been implementing bans on selling sugar-sweetened beverages, but no one had really evaluated the effects on consumption and health.

The research team recruited 214 UCSF employees for the study that began on July 28, 2015, about three months before the ban had gone into effect. All of the study participants had to be regular sugar-sweetened beverage drinkers, consuming at least 360 mL or 12 fluid ounces a day. Thats the size of an average aluminum beverage can.

At the start of the study, the research team interviewed and examined each participant, taking a bunch of measurements. Physical measurements included each participants height, weight, waist-to-hip ratio, waist circumference, and sagittal diameter. Your sagittal abdominal diameter (SAD) has nothing to do with how much of a Sagittarius you are or how sad you happen to be. It is the distance from the small of your back to your upper abdomen, which gives a sense of how much fat that you may have in your gut.

The team also asked each participant how many sugar-sweetened beverages he or she consumed each day and did blood tests to assess each participants level of insulin sensitivity. Insulin is the hormone normally secreted by your pancreas that helps regulate sugar in your body and sugar move from your bloodstream into the your cells.

Additionally, the researchers randomly chose half of the participants to undergo a motivational intervention. This motivational intervention wasnt quite like the live in a van down the river Chris Farley as Matt Foley speech from Saturday Night Live. Instead, health educators interviewed each selected participant at the beginning of the study. During this fifteen-minute encounter, the educator quantified the amount of sugar that the participant was drinking each day and provided guidance and educational materials on how to reduce sugar intake. The intervention also included five minute follow-up phones calls one week after the initial interview and one month and six months following the beginning of the sales ban. The motivational intervention was similar to the interventions used to make people aware of the dangers of alcohol dependence.

By the way, this Kasier Permanente video, which was not part of the study, shows how much sugar sugary drinks can have:

How sweet then were the results of the study? Well, just ten months after the ban had started, the average daily consumption of sugar-sweetened beverages had gone down from 1050 mL (or 35 fluid ounces) to 540 mL (or 18 fluid ounces) per participant. That was a 510-mL (or 17 fluid ounces or almost a can-and-a-half) drop, which amounted to a 48.6% decrease. The participants who had received the motivational intervention experienced on average a greater drop (762 mL, 25.4 fluid ounces, or two cans worth) than those who had not (246.0 mL or 8.2 fluid ounces).

Thats not all folks. Those who had decreases in daily sugar-sweetened beverage consumption also tended to have decreases in their insulin resistance as measured by lab tests. Insulin resistance is not a political movement but is a situation in which the cells in your body begin ignoring what insulin is trying to do. With insulin resistance, the cells in your muscles, fat, and liver essentially say, bye Felicia, when insulin says take up some sugar from the blood. As a result, your blood sugar levels begin creeping upwards, which can be a major step towards badness such as developing fatty liver disease or diabetes.

Then theres the waist from this study or rather waists. The average waistline measurements decreased by 2.1 cm. Again, just 10 months after the ban had started, noticeable loosening of pants or similar garments occurred in a number of participants. Thats big, or rather less big.

Epel explained that the study period was too short to see significant changes in weight but abdominal fat is sensitive to sugar intake, and we saw significantly reduced waist lines.

Of note, significant decreases in waist sizes occurred among not only those who were in the obesity or overweight categories but also those who fell into the lean category, which was having a body mass index (BMI) less than 25. This was a reminder that even though you may appear lean or skinny, looks can be deceiving. It also matters how much fat you may have sitting in your abdomen.

Ten months is significant because it was long enough for each participant to go through different seasons, as much as seasons exist in San Francisco. The research team wanted to make sure that any observed changes were sustained and not just typical fluctuations that may occur throughout the year. In fact, the observed changes persisted through not just 10 months but 12 months after the ban had begun.

Of course, 12 months is not 15 months, which is not two years, which is not a decade. So, yes, the study did have its limitations and could not tell you if the changes were sustainable over several years. The study also did not track what concurrently happened with other habits such as eating and exercise. Moreover, different workplaces can be quite different, so the question remains: would such a ban have the same effects elsewhere.

Schmidt, the senior author of the study and a Professor of Health Policy at UCSF, did say that their team has started a controlled study in Sutter Health, a large health care system in the Bay Area, that will address some of these limitations and help better nail down the mechanisms involved. So stay tuned.

Nonetheless, this is yet more evidence that your work environment really matters. This is not surprising, since you do spend on average a third of your time at work, maybe more if you are a doctor or a doctor going through training. What you are exposed to at work can really affect what you eat and drink. After all, you are still like a baby in that you tend to put whats close to you into your mouth. The food and beverages that are around you comprise whats called your food and beverage environment.

In fact, changing the beverage environment at work could have a spill-over effect as well, so to speak. People in the study really drank less sugar-sweetened beverages, not just at work, said Epel. They were making equal reductions at home and at work.

Schmidt likened removing soda from workplaces to taking cigarettes out of workplace vending machines. Schmidt is certainly not the first person to find similarities between sugary beverages and tobacco. A number of people have called sugar the new tobacco, including the authors of aCMAJ (Canadian Medical Association Journal) commentary. As I have written previously for Forbes, a report from Vital Strategiesraised concerns that soda companies are using the same marketing strategies that Big Tobacco companies have used.

Sugar does have at least one thing in common with nicotine, it can be addictive. Epel included the following video on food addiction on her UCSF Aging, Metabolism, and Emotion Research website:

Addiction is one reason why sugar exposure at work can affect what you consume at home. As Epel explained, there is deeply ingrained moral ethic of personal responsibility. While theoretically that sounds good, the reality is our brain is vulnerable to addiction. We need to help people be well by creating the right environments. In other words, you are what you are exposed to every day.

Speaking of exposure, marketing is another possible cause of such spill-over effects. If you are exposed to soda is great messages at work, that could potentially influence what you buy elsewhere. No matter how hard you try to separate work life from home life, influences invariably will bubble over in both directions.

While some other healthcare institutions, such as the Cleveland Clinic, the University of Michigan Health System, the Baylor Health Care System, and the Geisinger Clinic, have instituted sugar-sweetened beverage sales bans as well, there are still many healthcare institutions that continue to pour some sugar on their employees. Schmidt pointed out that institutions arrange pouring rights with soda companies. The institutions will then co-brand and market sugar-sweetened beverages. This could be money-makers for institutions, making them more likely to continue to go with the flow.

To re-purpose the words of Alanis Morissette, isnt it ironic for healthcare institutions to help sell sugar-sweetened beverages? After all, many such beverages have no demonstrated nutritional value over water and are in essence liquid sugar, in the words of Epel. As Epel related, you have institutions that are training people to be health professionals and employing people to treat patients but at the same time are serving them sugary beverages.

Its not as if employees at UCSF resisted the ban. Rather, UCSF employees appreciated the care for their health. They were very positive about the ban. In fact, the only people who expressed any concerns were some visitors who didnt understand the culture and wanted to buy sugar-sweetened beverages during their visit, according to Epel.

Of course, healthcare employers arent the only employers that could institute such a ban. Schmidt referred to such bans as low-hanging fruit, as opposed to low-hanging sugar-sweetened fruit drinks. Policy changes such as soda taxes have run into political obstacles. Having employers change their food and beverage environments is a way of getting around such obstacles.

Indeed, employers could have lots of incentive to make such changes. Studies such as one published in a 2014 issue of JAMA Internal Medicine have linked excess sugar consumption to a variety of health problems including obesity, diabetes, cardiovascular disease, cancer, and early death, even for those who fall into the normal weight category. What employers then would want their employees to be as sick as possible? Schmidt pointed out that if you can avert new cases of illness, you can save a lot of money.

The fact that UCSF not only instituted the ban but also provided financial support for the study suggests that employers could help lead the way in curbing sugar-sweetened beverage consumption. Employers may want to pore through this UCSF study before they decide about pouring rights and what to essentially pour on their employees.

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UCSF Banned Sugary Drink Sales, Here Is What Happened Next - Forbes

SAN DIEGO, Oct. 30, 2019 /PRNewswire/ -- Eurofins Discovery, a leading partner to drug discovery and development scientists, today announced a Founding Partner sponsorship agreement with BioLabs San Diego. The agreementprovides support for BioLabs, San Diego's premium wet lab and shared office facilities for early stage life science entrepreneurs and offers resident companies access to Eurofins Discovery's global expertise in products and services to fast-track their development programs in therapeutics, diagnostics, and life science tools.

Eurofins Discovery provides a specialized portfolio that is critical to driving drug programs through the early phases from target discovery to the clinic. Christina Shasserre, SVP of Eurofins Discovery, comments, "Our group has been recognized for over 40 years as the industry leader providing researchers with the largest and most technically deep portfolio for drug discovery. This portfolio was built by the same kind of pioneers that we are looking to foster in the BioLabs facilities. By sharing our significant expertise in drug discovery and offering products and services through our global laboratory network, we hope to accelerate the time it takes to discover innovative therapies and technologies."

Eurofins Discovery and BioLabs will work together to develop a new BioLabs-managed site that will promote the thriving startup community in San Diego. It will be equipped specifically for therapeutic, diagnostic and life science technology companies and will capitalize on the Eurofins Discovery team's high-quality, actionable insights in pre-clinical strategy and scientific research across the drug discovery continuum."We are excited by this opportunity to partner with BioLabs San Diego and work with companies developing first-in-class therapeutic tools and products," says Justin Mika, SVP of Strategy and Business Development for Eurofins Discovery and General Manager of Eurofins DiscoverX Services. "Eurofins Discovery is committed to working with early stage companies to provide turn-key solutions for the drug discovery, screening and life science markets. In addition, some of our team members are sharing the space at the BioLabs San Diego Towne Centre facility to support closer engagement and collaboration with company founders and scientists daily. We look forward to helping entrepreneurs improve the productivity and effectiveness of their research so they can get their innovative products to market more quickly and cost-efficiently."

Adam Milne, vice president of operations for BioLabs says he welcomes Eurofins Discovery as a Founding Sponsor. "The leadership of Eurofins Discovery is committed to serving companies that benefit from the BioLabs San Diego co-working space model, which provides shared wet lab and office facilities and a suite of services. We see the potential to develop further program offerings like the Eurofins-BioLabs Innovation Center with Eurofins Discovery as we work collaboratively to help member companies that are developing therapeutics, diagnostics and life sciences tools get to proof of concept and move to the next stage of product development."

Abegale Colmenar, site director for BioLabs San Diego, says, "We appreciate the support from Eurofins Discovery for our work to create a vibrant community for the most promising life sciences startups. The added benefit of their global industry knowledge will be a plus for our member companies, and a demonstration of the value that BioLabs offers startups that want to scale and grow."

Eurofins Discovery will partner with BioLabs in its 2 San Diego locations in the University Town Centre (UTC) area. BioLabs, San Diego at Campus Pointe by Alexandria offers flexible and fully equipped co-working space designed for early stage companies needing access to shared workstations and wet lab space. BioLabs, San Diego - Towne Centre is designed for entrepreneurs seeking office space, as well as for early-stage companies that want the benefits of being part of BioLabs' creative innovation ecosystem but do not require the full wet-lab facilities offered at Campus Pointe.

For further informationwww.eurofinsdiscoveryservices.com http://www.eurofins.com

About Eurofins DiscoveryEurofins Discovery, a business operating under the Eurofins BioPharma Services division, has supported Drug Discovery research for over 40 years. Eurofins is recognized as the industry leader for providing drug discovery researchers the largest and most diverse portfolio of standard and customin vitrosafety & pharmacology assays and panels for drug screening and profiling. In addition toin vitrosafety pharmacology strengths, we also offer a broad portfolio of over 3500 drug discovery services and 1800 products. These includein vitroassays, cell-based phenotypic assays, safety pharmacology and efficacy, ADME toxicology, medicinal chemistry design, synthetic chemistry, and custom proteins and assay development capabilities. We support a variety of drug discovery targets such as GPCRs, Kinases, Ion Channels, Nuclear Hormone Receptors and other proteins & enzymes. The Eurofins Discovery capabilities, expertise, knowledge and skill sets enable the company to provide clients the benefit of being able to work with a single outsourcing provider (CRO) for all their drug discovery programs.

About BioLabs and BioLabs San Diegowww.BioLabs.iotwitter:@BioLabSD and @BioLabs

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Abstract

Leber congenital amaurosis (LCA), one of the leading causes of childhood-onset blindness, is caused by autosomal recessive mutations in several genes including RPE65. In this study, we performed CRISPR-Cas9mediated therapeutic correction of a disease-associated nonsense mutation in Rpe65 in rd12 mice, a model of human LCA. Subretinal injection of adeno-associated virus carrying CRISPR-Cas9 and donor DNA resulted in >1% homology-directed repair and ~1.6% deletion of the pathogenic stop codon in Rpe65 in retinal pigment epithelial tissues of rd12 mice. The a- and b-waves of electroretinograms were recovered to levels up to 21.2 4.1% and 39.8 3.2% of their wild-type mice counterparts upon bright stimuli after dark adaptation 7 months after injection. There was no definite evidence of histologic perturbation or tumorigenesis during 7 months of observation. Collectively, we present the first therapeutic correction of an Rpe65 nonsense mutation using CRISPR-Cas9, providing new insight for developing therapeutics for LCA.

Leber congenital amaurosis (LCA) is a hereditary retinal degenerative disease that leads to childhood-onset blindness (1). Among the genes causing LCA, CEP290, GUCY2D, CRB1, and RPE65 are those most frequently mutated. In particular, about 6% of LCA cases are caused by mutations in RPE65 (2). To date, no substantial treatments or cures for LCA have been developed, except for voretigene neparvovec (Luxturna, Spark Therapeutics), which is approved by the U.S. Food and Drug Administration (FDA). This approach is based on RPE65 gene delivery by adeno-associated virus (AAV) to the retina in patients who lack the functional RPE65 protein (35). On the basis of preclinical studies performed in RPE65 null dogs (6, 7) and mice (8, 9), initial clinical trials tested the adverse events and therapeutic outcomes of AAV containing the human RPE65 complementary DNA (cDNA) (35). Although normal vision was not achieved, these trials showed that subretinal injection of AAV had an acceptable local and systemic adverse event profile and improved visual function (10). Nevertheless, because gene therapy cannot totally correct the mutated sequence and has a limitation in the cargo size of the AAV (~4.8 kb) when AAV is used, there are still unmet needs in the gene therapy area for broader clinical application.

CRISPR-Cas9 is a genome editing tool that can lead to the insertion of genes or the deletion of mutations (1115) by homology-directed repair (HDR) or by nonhomologous end joining (NHEJ), respectively. Although the frequency of HDR is generally lower than that of NHEJ, the ability of HDR to correct pathogenic mutations permanently has great potential for curing various genetic disorders (1618). For example, intravenously infused AAV expressing the Cas9 machinery and the donor DNA reversed the disease-causing mutation and rescued the disease phenotypes in two different mouse models of metabolic diseases (1618).

In this context, we hypothesized that CRISPR-Cas9 could represent another therapy for LCA and tested the therapeutic outcomes of CRISPR-Cas9mediated HDR in rd12 mice, a model of human LCA that bears a disease-associated premature stop codon in Rpe65. We used CRISPR-Cas9 technology to correct the nonsense mutation in this model and found that HDR and in-frame NHEJ in response to CRISPR-Cas9mediated DNA cleavage led to the recovery of retinal functions and protection from retinal degeneration. The results from this proof-of-concept study demonstrate the feasibility of our approach and imply that CRISPR-Cas9mediated HDR could be expanded to other ophthalmologic diseases in which HDR might be needed.

To use CRISPR-Cas9 technology to treat LCA, we first screened single guide RNA (sgRNA) sequences targeting Rpe65 exon 3 in the region that corresponds to the C-to-T nonsense mutation locus using mouse embryonic fibroblasts (MEFs) from rd12 mice (fig. S1A). Of nine potential candidates tested, the TS4 sgRNA was selected for further studies because it generated double-strand break (DSB) at the nearest locus from the premature stop codon and resulted in highly efficient insertion or deletion (indel) rates, as determined by targeted deep sequencing when transfected with SpCas9 protein as riboneucleoprotein (RNP) complex (fig. S1B). Next, we examined the correction frequencies by HDR induced by the TS4 sgRNA and Rpe65 donor in rd12 MEFs. Synonymous mutations were introduced into the donor sequence to prevent cleavage of the donor itself or recleavage of the repaired Rpe65 locus after correction (Fig. 1, A and F). Single-stranded oligodeoxynucleotide (ssODN) was used as an Rpe65 donor and induced correction in a range of 3 to 6% (Fig. 1, B, C, and F). When NHEJ was analyzed by deep sequencing, TS4 sgRNAmediated indels were dominated by deletions, and approximately one-fourth of the mutations corresponded to in-frame indels (Fig. 1, D and E). Among the in-frame indels, one-codon deletions accounted for 5.6% of the total reads (Fig. 1F). Because the in-frame indels could result in the removal of the premature Rpe65 stop codon from rd12 mice, we suggest that NHEJ-mediated editing might also contribute to the therapeutic effects of CRISPR-Cas9. These data indicate that we identified an optimized sgRNA sequence for therapeutic, CRISPR-Cas9mediated genome editing to treat LCA.

(A) A schematic drawing of Rpe65 in rd12 MEF. Red text, sequence of the premature stop codon; orange arrow, TS4 sgRNA target sequence; blue text, protospacer adjacent motif (PAM). (B) TS4 sgRNAinduced indel frequencies measured by targeted deep sequencing (n = 4). ssODN dose (in microgram scale) are indicated in parenthesis. (C) Correction frequencies in the rd12 mutation measured by targeted deep sequencing (n = 4). (D) The mean values of the number of deep sequencing reads in different categories show the pattern of indels induced by the TS4 sgRNA (n = 4). Of the total reads, about 61% contain deletions. Ins, insertion; Del, deletion; WT, wild type. (E) Mean percent values of different types of in-frame and out-of-frame indels induced by the TS4 sgRNA (n = 4). 3N, one codon; 3N + 1, one codon + 1 nucleotide; 3N + 2, one codon + 2 nucleotides. (F) Nucleotide sequences showing types of editing induced by the TS4 sgRNA and 1.5 g of ssODN in rd12 MEF (n = 4). Violet triangle, position of the DSB induced by the TS4 sgRNA; red text, sequences of the stop codon in rd12 MEF; blue text, PAM sequences; green text, synonymous mutations in the donor template; underlined sequences, nucleotides encompassing the premature stop codon and their corresponding amino acid sequences. Error bars indicate SEM. **P < 0.01; ***P < 0.001 by Kruskal-Wallis test with Dunns multiple comparison test.

To evaluate the therapeutic efficacy of CRISPR-Cas9mediated editing of the Rpe65 nonsense mutation in a disease model, we changed one nucleotide in TS4 to design the TS4rd12 sgRNA, which perfectly matches the sequence of the Rpe65 exon 3 mutation locus in rd12 mice. All required editing components were incorporated into two separate AAVs (AAV-SpCas9 and AAV-TS4rd12 sgRNA-Rpe65-donor, hereafter referred to as AAV-TS4rd12-donor), and in vivo delivery was carried out using the dual AAV system (Fig. 2A). We optimized the ratio of AAV components by varying their concentrations to obtain maximized genome editing results. A low dose [a total of 2 1010 vector genomes (vg) per eye] or high dose (a total of 2 1011 vg per eye) of AAVs was administered via subretinal injection into 3-week-old rd12 mice. After 4 weeks of AAV treatment, the targeted region of Rpe65 was analyzed by deep sequencing using cells from the retina and retinal pigment epithelium (RPE). Subretinal injection resulted in indel rates in the retina and RPE that reached ~20% but varied depending on various parameters (Fig. 2, B and C). Low-dose subretinal injection induced low and high indel rates in the retina and RPE, respectively. This result indicates that subretinal AAV administration is more efficient in the RPE versus the retina; this conclusion was further verified by the finding of a higher AAV copy number per diploid cell (Fig. 2D and fig. S2) in the RPE. Because a previous study showed that the use of a high (10:1) ratio of sgRNAs and donor to Cas9 induced a further increase in the frequency of a correction in a mouse model of liver disease (18), an excessive amount of AAV-TS4rd12-donor relative to AAV-SpCas9 (AAV-SpCas9:AAV-TS4rd12-donor ratio of 0.1:1.9) was tested, but it resulted in a lower frequency of indels in both tissues after subretinal administration (Fig. 2, B and C). Collectively, these data suggest that subretinal delivery is an efficient method of inducing in vivo Rpe65 editing and that the Cas9-to-sgRNA ratio is critical for optimized editing.

(A) A schematic drawing of the dual AAV strategy for CRISPR-Cas9mediated therapeutic correction of the nonsense mutation in Rpe65 in rd12 mice. The premature stop codon in Rpe65 (red text) is generated by a C-to-T mutation in exon 3. The U6 and EFS promoters in the AAV vector were used to express the sgRNA together with the donor template and SpCas9, respectively. Green text, synonymous mutations in the donor template. Therapeutic gene correction could be derived from HDR-mediated precise correction (HDR) or in-frame NHEJ (Inf-NHEJ). (B and C) Indel frequencies measured by targeted deep sequencing in the retina (B) and RPE (C) of rd12 mice at 4 weeks after injection of high-dose (a total of 2 1011 vg per eye) and low-dose (a total of 2 1010 vg per eye) AAV. SpCas9toTS4 sgRNA-Rpe65-donor ratios are indicated in parentheses. (D) Correlation between the indel frequency and AAV copy number per diploid cell (n = 10). A high dose of 1:1 ratio of SpCas9 and TS4 sgRNA-Rpe65-donor was injected subretinally. (E) Frequencies of therapeutic HDR at the site of the C-to-T mutation in the retina and RPE of rd12 mice at 4 weeks after injection. (F) Ratio of HDR to indel frequencies. A high or low dose of SpCas9 and TS4 sgRNA-Rpe65-donor at a 1:1 ratio was injected subretinally (n = 4). (G) Mean values of the number of deep sequencing reads including insertions, deletions, or HDR in AAV-treated RPE (n = 10). A high dose of 1:1 ratio of SpCas9 and TS4 sgRNA-Rpe65-donor was injected subretinally. Rpe65mut, nonedited; Ins, insertion; Out-f-Del, out-of-frame deletion; Inf-Del, in-frame deletion. (H) Nucleotide sequences showing the Rpe65 donor template and changes induced by the TS4 sgRNA in AAV-treated RPE (n = 10). A high dose of 1:1 ratio of SpCas9 and TS4 sgRNA-Rpe65-donor was injected subretinally. Violet triangle, position of the DSB induced by the TS4 sgRNA; red text, sequences corresponding to the premature stop codon in rd12 mice; blue text, PAM sequences; green text, synonymous mutations in the donor template; underlined sequences, nucleotides encompassing the premature stop codon and their corresponding amino acid sequences. *P < 0.05; **P < 0.01; ***P < 0.001 by Kruskal-Wallis test with Dunns multiple comparison test (B, C, and E) and Mann-Whitney U test (F).

Subsequently, we analyzed HDR events near the pathogenic C-to-T mutation in Rpe65 in the retina and RPE after AAV treatment in rd12 mice. HDR events were observed in the RPE but not in the retina (Fig. 2E). Although indel frequencies were comparable between low-dose AAV and high-dose AAVtreated RPE when a 1:1 ratio of AAV-SpCas9 to AAV-TS4-donor was used (Fig. 2C), HDR events were more frequent in the high-dose AAVtreated group (high dose, 1.17 0.31%; low dose, 0.59 0.22%) (Fig. 2E), as similarly observed in the CRISPR-mediated correction of the ornithine transcarbamylase gene in hepatocytes (18). Moreover, analysis of the HDR-to-indel ratio revealed that HDR events were approximately three times more frequent in the high dosetreated group (Fig. 2F). Successful HDR (1.01 0.38%) was also induced by the application of a 0.5:1.5 ratio of AAV-SpCas9 to AAV-TS4-donor (Fig. 2E). It should be noted that most HDR events resulted in a precise correction of the T-to-C mutation, so that the resulting protein sequences were identical to that of wild-type Rpe65 (Fig. 2H). We additionally characterized NHEJ-mediated editing in the RPE and found that in-frame deletions occurred at a frequency of 3.83%; 1.61% were one-codon deletions that resulted in the removal of the premature stop codon in rd12 mice (Fig. 2, G and H). The 1-codon-Del-2 type (CGT-deletion) was also predicted as one of the top three end-joining categories (table S1) by inDelphi, the machine learning model that predicts SpCas9-mediated template-free genome editing (19). In addition, substantial in-frame editing was achieved in human RPE65 with the use of various sgRNAs in human embryonic kidney (HEK) 293 cells, suggesting the clinical potential of our approach (fig. S3, A to C).

To investigate the therapeutic effects of HDR-mediated Rpe65 gene correction in rd12 mice, we performed electroretinography after dark adaptation at 6 weeks and 7 months after subretinal AAV injection (Fig. 3A). AAV treatment led to the recovery of Rpe65 expression in RPE cells at 6 weeks after injection (Fig. 3B). Furthermore, AAV treatment resulted in increased Rpe65 gene expression in RPE cells at 7 months after injection (Fig. 3C). In electroretinography, rd12 mice demonstrated severely attenuated dark-adapted light responses compared with age-matched normal C57BL/6 mice (20). In contrast, there were definite responses to bright stimuli (0 dB) by which both rod and cone responses are provoked after dark adaptation in the AAV-treated rd12 mice at 6 weeks after the subretinal injection (Fig. 3, D to F, and fig. S4), whereas there were no responses to dim stimuli (25 dB) (fig. S5). The electrical responses were maintained up to 7 months after the initial injection (Fig. 3, G and H). The estimated a- and b-wave amplitudes were 21.2 4.1% and 39.8 3.2% of those of normal C57BL/6 mice. These functional recoveries were accompanied by anatomical changes in which HDR-mediated Rpe65 gene correction prevented the loss of neuronal cells in the outer nuclear layer of the retina in rd12 mice (Fig. 3, I and J).

(A) Overview of animal experiments. Time points for subretinal injection and electroretinography are indicated. P0, postnatal day 0; ERG, electroretinography; w, weeks. (B) RPE65 protein expression in the RPE layer of rd12 mice at 6 weeks after the injection. Scale bar, 10 m. (C) The relative expression of Rpe65 mRNA in the RPE cells of rd12 mice at 7 months after the injection (n = 4). (D) Representative electroretinographic responses to bright stimuli (0 dB) after dark adaptation from normal C57BL/6 and rd12 mice at 6 weeks after the injection. (E to H) Amplitudes of electroretinographic responses to bright stimuli (0 dB) after dark adaptation (n = 4). (E and G) Amplitudes of the a-wave at 0 dB at 6 weeks (E) and 7 months (G) after the injection. (F and H) Amplitudes of the b-wave at 0 dB at 6 weeks (F) and 7 months (H) after the injection. (I) Representative hematoxylin and eosin (H&E) images of retinal tissues from rd12 mice at 7 months after the injection. Scale bar, 20 m. (J) The number of layers of outer nuclear layer nuclei in rd12 mice at 7 months after the injection (n = 4). Normal, C57BL/6; rd12, rd12 mice without treatment; rd12-AAV, rd12 mice treated with subretinal injection of a high dose of 1:1 ratio of SpCas9 and TS4 sgRNA-Rpe65-donor. *P < 0.05; **P < 0.01; ***P < 0.001 by Kruskal-Wallis test with Dunns multiple comparison test. DAPI, 4,6-diamidino-2-phenylindole; GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer.

To globally characterize potential off-target sites recognized by the TS4rd12 sgRNA, we performed Digenome-seq, a genome-wide unbiased off-target detection method (21), using genomic DNA from rd12 mice. This analysis showed several potential off-target sites (Fig. 4A). We validated the 29 potential off-target sites with the highest Digenome-seq cleavage scores using targeted deep sequencing. Six genomic loci were shown to be actively targeted by the TS4rd12 sgRNA in the retina of rd12 mice (Fig. 4B), and these off-target sites were consistently found to be targeted in the RPE (Fig. 4C). All of the active off-target sites are located in intronic or intergenic regions (table S2). In a subsequent off-target analysis for all 33 homologous sites that differed from the TS4rd12 sgRNA sequence by up to three nucleotides, no meaningful indel mutations were observed at the predicted genomic loci in AAV-treated rd12 mice (fig. S6). In addition, there was no definitive evidence of histologic perturbation or tumorigenesis for 7 months in these mice (Fig. 4D).

(A) Genome-wide Circos plot showing in vitro cleavage sites in the rd12 mouse genome in the absence (gray) or in the presence (blue) of TS4 sgRNA. On-target cleavage is indicated by the red arrow. (B) Targeted deep sequencing results for the top 29 Digenome-seq candidates in AAV-treated retina (n = 3). Nucleotides in red and orange indicate sequences that are mismatched relative to the on-target site, and nucleotides in blue indicate PAM sequences. (C) Reanalysis of the active off-targets by targeted deep sequencing in AAV-treated RPE (n = 3). (D) Representative whole mount of RPE tissues from rd12 mice at 7 months after treatment with or without the dual AAV system encoding SpCas9 and the donor template. Scale bar, 10 m.

In this study, we deployed CRISPR-Cas9mediated HDR as a new treatment for LCA. We showed that dual AAVmediated delivery of CRISPR-Cas9 and an Rpe65 donor sequence can lead to the correction of a disease-causing mutation in Rpe65 and an improvement in retinal function in a mouse model of LCA. In addition to this improvement, our study showed a level of functional recovery that exceeds the measured gene correction level. The results are provocative because in postmitotic cells, HDR events are generally known as rare. However, our observations are supported by recent studies showing CRISPR-Cas9mediated HDR events in postmitotic neurons (22) and muscles (23). Our results are also supported by previous studies in which CRISPR-Cas9 treatment for certain autosomal recessive diseases, such as Duchenne muscular dystrophy (23) and retinitis pigmentosa (24), resulted in functional improvement beyond the level expected from the gene correction frequency. Together, these results suggest that HDR can be activated in these postmitotic cells and that therapeutic outcomes exceeding that expected from the editing level could be achieved in some cases.

Gene therapy works by using viruses as a means of overexpressing wild-type copies of defective, disease-associated genes. For instance, Luxturna, the FDA-approved gene therapy for LCA, uses AAV2 to express functional RPE65 to replace the mutant, LCA-associated RPE65 protein. Different types of viruses, such as lentivirus and retrovirus, can also be used for gene therapy, but AAV is clinically validated (35, 25, 26). Although AAV is very attractive for gene therapy because it does not integrate into the host genome, its limited cargo packaging capability hinders its application in many cases. Therefore, for some ocular diseases such as Stargardt disease or Usher syndrome, which require the delivery of large DNA fragments, our approach using CRISPR-Cas9mediated HDR could be suitable therapeutically. In addition, because the desired wild-type sequence can be introduced at the genomic site where the gene should exist, replacing the mutant sequence by HDR, the HDR-corrected cells can express the introduced genes at the endogenous level. In this study, CRISPR-Cas9 was randomly introduced into the eye by subretinal injection in rd12 mice because mice lack a macula, the center and core of vision in humans. The injection resulted in a frequency of gene correction of nearly 3% by HDR and in-frame NHEJ (Fig. 2, E, F, and H) and led to substantial improvement in electroretinography measurements (Fig. 3, D to H). We expect that these results in mice can be further improved in human patients with LCA because ophthalmologists can selectively perform subretinal injection near the macular area, enabling focused editing around this structure to achieve even more restoration of vision.

The deep sequencing in our study provides a detailed description of the types of indels generated and the extent of off-target mutations produced, which was extensive. Although the active off-target sites that we detected were within intronic or intergenic regions, this level of off-target effects could undermine the therapeutic potential of our approach using CRISPR-Cas9mediated genome editing. As the first study to use CRISPR-Cas9 to treat LCA, we used wild-type SpCas9, the conventional and most commonly used form of Cas9. To reduce the frequency of off-target mutations, high-fidelity versions of Cas9 [HFCas9, eCas9, HypaCas9 (27), SniperCas9 (28), or self-targeting AAV (29)] or inducible-editing (30) could be tried as an alternative. We tested SniperCas9 (28), a high-fidelity version of SpCas9 that was developed by our group in the C2C12 cell line. We found that SniperCas9 was associated with a significant reduction in indel frequencies at the off-target sites recognized by SpCas9 (fig. S7). In addition, SniperCas9 showed comparable activity against the mRosa26 target, indicating that its low level of off-target effects does not come at the expense of on-target activity. These results suggest that various approaches might be tried to reduce off-target mutations in further studies. In addition, the off-target mutations detected in this study might not be found in the clinic because of differences between the human and mouse genomes. Moreover, it is noteworthy that there were no definite morphological changes in the RPE at 7 months after the subretinal injection, suggesting that the off-target mutations do not exert definite harmful effects (Fig. 4D).

In conclusion, we provide a new, CRISPR-Cas9based approach for treating LCA. To our knowledge, no previous reports have shown in vivo HDR-mediated correction in animal models of ophthalmologic diseases. Our permanent therapeutic genome editing approach could be used alone, or together with gene therapy or protein therapy, to treat LCA.

MEFs were maintained in Dulbeccos modified Eagles medium (DMEM) supplemented with glucose (4.5 g/liter), 4 mM glutamine, 1 mM sodium pyruvate, 10% fetal bovine serum, penicillin (100 U/ml), and streptomycin (100 mg/ml). RNPs and 120-mer ssODN were transfected using Neon Transfection following the manufacturers procedures (Life Technologies). Briefly, 2.5 105 cells were mixed with materials for transfection and were subjected to electrical shock using 10-l tips on the Neon system for 30 ms at 1350 V for one pulse. Five days after transfection, the cells were harvested, and genomic DNA was extracted using a DNeasy Blood and Tissue kit (Qiagen). For transfections of HEK293 cells, cells were seeded at 2 105 cell per well into 24-well plates the day before transfection. One microgram of plasmids encoding human optimized SpCas9 and sgRNA was mixed with 2 l of Lipofectamine 2000 (Invitrogen) in 200 l of Opti-MEM, left for 20 min, and then added to cells that had reached 70% confluence in 500 l of DMEM. After overnight incubation, the medium was replaced with 500 l of fresh medium, and genomic DNA was extracted after 5 days of transfection.

Eight-week-old male C57BL/6 mice and mating pairs of rd12 mice (stock no. 005379, the Jackson laboratory) were purchased from Central Laboratory Animal and maintained under a 12-hour dark-light cycle. rd12 mice were mated with each other to produce offspring with a homozygous mutation in the Rpe65 gene. All animal experiments were performed following guidelines from the Association for Research in Vision and Ophthalmology statement for the use of animals in ophthalmic and vision research and approved by Institutional Animal Care and Use Committees of both Seoul National University and Seoul National University Hospital.

To quantify indel frequency, on-target and off-target regions were amplified by polymerase chain reaction (PCR) from genomic DNA extracted from transfected cells, retina, or RPE using the primer sets summarized in table S2. To quantify HDR frequencies, PCRs were first performed from genomic DNA (50 ng) using primers outside of the Rpe65-homology arm, after which products were further amplified to generate amplicons for deep sequencing. The produced amplicons were barcoded during subsequent PCR with Illumina TrueSeq adaptors. The products were purified with a PCR purification kit (Geneall) and were then pooled in equimolar ratio. The final libraries were paired-end sequenced using the Illumina Miseq platform according to the manufacturers protocol. Indel frequencies were quantified using Cas-Analyzer (www.rgenome.net) (31). Quantification of specific patterns such as in-frame or out-of-frame indels, one-codon deletions, and precise HDR were determined by manual counting.

Potential off-target sites were identified using an in silico tool, Cas-OFFinder (32). Mouse genomic sites containing up to 3base pair (bp) mismatches were considered as off-target sites and further confirmed by targeted deep sequencing using the primers shown in table S3.

Genomic DNA was purified from the retina of rd12 mice with a DNeasy Tissue kit (Qiagen) according to the manufacturers instructions. Genomic DNA (8 g) was incubated with purified Cas9 protein (100 nM) and sgRNA (300 nM) in a reaction volume of 400 l for 8 hours at 37C in a buffer [100 mM NaCl, 40 mM tris-HCl, 10 mM MgCl2, and bovine serum albumin (100 g/ml; pH 7.9)]. Digested genomic DNA was purified again with a DNeasy Tissue kit (Qiagen) after RNase A (50 g/ml) was added to remove sgRNA. To check targeted in vitro DNA cleavage, digested genomic DNA was mixed with 2 SYBR Green Master Mix and analyzed by real-time quantitative PCR (qPCR) using forward primer 5-GGACATTCTACATATGAATCCAGG-3 and reverse primer 5-TAACATTCTCAGGTGGCTGTGCAA-3. The fraction of target sites that were cleaved was measured using the comparative CT method (33).

For Digenome-seq, genomic DNA (1 g) was sonicated to produce fragments in the 400- to 500-bp range using the Covaris system (Life Technologies) and blunt ended using End Repair Mix (Thermo Fisher). Fragmented DNA was ligated with adapters to produce libraries, which were then subjected to whole-genome sequencing (WGS) using a HiSeq X Ten Sequencer (Illumina) at Macrogen. WGS was performed at a sequencing depth of 30 to 40, and the DNA cleavage score was calculated using a previously published scoring system (34).

Sequences of the elongation factor 1a short (EFS) promoter and human optimized SpCas9 with a nuclear localization signal, hemagglutinin (HA) tag, and bovine growth hormone poly-A tail were synthesized and subcloned into an AAV2 inverted terminal repeat (ITR)based plasmid using Not I restriction sites. For the other AAV vector, sequences of the U6 promoter, TS4 sgRNA, and Rpe65 donor were also synthesized and subcloned into the AAV2 ITRbased plasmid using the same restriction sites. In the Rpe65 donor sequences, five nucleotides were substituted without causing codon changes to prevent possible TS4 sgRNAmediated cleavage and to precisely distinguish knocked-in sequences from endogenous genomic sequences. Recombinant AAV particles were produced using a helper adenovirus-free packaging system. Briefly, HEK293 cells were cotransfected with pAAV-ITR-EFS-SpCas9 or pAAV-ITR-TS4rd12-sgRNA-Rpe65-donor, AAV9-capsid plasmid, and helper plasmid. After 3 days of transfection, the cells were lysed and the virus particles were purified by iodixanol gradient ultracentrifugation and concentrated to obtain titers greater than 1013 vg/ml.

After deep anesthesia, AAV9-SpCas9 and AAV9-TS4 sgRNA-Rpe65-donor (a total of 2 1010 or 2 1011 vg in 1 l of phosphate-buffered saline) were mixed and injected into the subretinal space of the mouse eye through the vitreous cavity using a customized Nanofil syringe with a 33-gauge blunt needle (World Precision Instrument) under an operating microscope (Leica), as previously described (35).

qPCR to determine the AAV genome copy number was performed using genomic DNA extracted from the retina or RPE. After measuring the genomic DNA concentration using a Quantus fluorometer together with the Quantifluor Dye system (Promega), 50 ng of genomic DNA was subjected to qPCR analysis using an AAVpro titration kit (Takara). Thermocycling conditions were as follows: 95C, 2 min followed by 35 cycles of 95C, 5 s; 60C, 30 s. The number of AAV genome copies was calculated against a standard curve. The number of diploid mouse cells was calculated using a conversion factor of ~1.6 104 diploid cells per 100 g of genomic DNA.

Mice were dark adapted for over 16 hours. After deep anesthesia, pupils were dilated with an eye drop containing phenylephrine hydrochloride (5 mg/ml) and tropicamide (5 mg/ml). Full-field electroretinography was performed using the universal testing and electrophysiologic system 2000 (UTAS E-2000, LKC Technologies). The scotopic responses were recorded with a flash of 0 dB at a gain of 2 k using a notch filter at 60 Hz and were bandpass filtered between 0.1 and 1500 Hz. The amplitudes of the a-wave were measured from the baseline to the lowest negative-going voltage, whereas the peak b-wave amplitudes were estimated from the trough of the a-wave to the highest peak of the positive b-wave.

At 6 weeks after AAV-mediated delivery of SpCas9 and TS4 sgRNA-Rpe65-donor, paraffin blocks were prepared from enucleated eyes. Thin sections were immunostained with anti-HA antibody (1:1,000; cat. no. 3F10, Roche) and anti-Rpe65 antibody (1:1,000; cat. no. sc-73616, Santa Cruz Biotechnologies), followed by treatment with Alexa Fluor 488 or 594 immunoglobulin G (IgG; 1:500; Thermo Fisher). Nuclear staining was performed using 4,6-diamidino-2-phenylindole dihydrochloride (Sigma-Aldrich). The slides then were observed under a fluorescence microscope (Leica).

Total RNA was isolated using TRI Reagent (Molecular Research Center) from RPE cells of rd12 mice at 7 months after AAV-mediated delivery of SpCas9 and TS4 sgRNA-Rpe65-donor. cDNAs were prepared with a High-Capacity RNA-to-cDNA Kit (Thermo Fisher). Real-time PCR was performed with the StepOnePlus Real-Time PCR System (Thermo Fisher) using TaqMan Fast Advanced Master Mix (Thermo Fisher) with Gene Expression Assays (Thermo Fisher) for gene expression analyses. Product IDs of the gene expression assays for genes are as follows: for Rpe65, Mm00504133_m1; for Gapdh, Mm99999915_g1; and for Rn18s, Mm03928990_g1. The relative expression levels of the Rpe65 gene were normalized to those of Gapdh and Rn18s. All procedures were performed in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments guidelines.

At 7 months after AAV-mediated delivery of SpCas9 and TS4 sgRNA-Rpe65-donor, paraffin blocks were prepared from enucleated eyes. Thin sections were then prepared for hematoxylin and eosin (H&E) staining.

At 7 months after AAV-mediated delivery of SpCas9 and TS4 sgRNA-Rpe65-donor, RPE-choroid-scleral complexes were prepared from enucleated eyes. Then, the complexes were immunostained with antiZO-1 antibody (5 g/ml; cat. no. 61-7300, Thermo Fisher), followed by treatment with Alexa Fluor 594 IgG (1:500; Thermo Fisher). Nuclear staining was performed using 4,6-diamidino-2-phenylindole dihydrochloride (Sigma-Aldrich). The slides then were observed under a fluorescence microscope (Leica).

All group results are expressed as means SEM, if not stated otherwise. Statistical significance as compared to untreated controls is denoted with * (P < 0.05), ** (P < 0.01), and *** (P < 0.001) in the figures and figure legends. Statistical analyses were performed using GraphPad PRISM 5, and the specific tests are mentioned in the figure legends.

Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/10/eaax1210/DC1

Fig. S1. Screening of sgRNAs targeting the Rpe65 gene in rd12 MEFs.

Fig. S2. Delivered AAV copies between retina and RPE.

Fig. S3. Analysis of human RPE65 editing.

Fig. S4. Electroretinographic responses to bright stimuli (0 dB) after dark adaptation from normal C57BL/6 and rd12 mice at 6 weeks after the injection (n = 4).

Fig. S5. Electroretinographic responses to dim stimuli (25 dB) after dark adaptation from normal C57BL/6 and rd12 mice at 6 weeks after the injection.

Fig. S6. Analysis of TS4 sgRNA off-target effects.

Fig. S7. Comparison of off-target frequency between wild-type SpCas9 and SniperCas9.

Table S1. Summary of predictions at the target site with sgRNA by the inDelphi approach.

Table S2. Active off-target sites.

Table S3. Primers used in this study.

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

Acknowledgments: We thank J. K. Lee (ToolGen Inc.) for the gift of SniperCas9-expressing vector. Funding: This research was supported by the Ministry of Food and Drug Safety (17172MFDS213), the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (2017M3A9B4061406), the Bio and Medical Technology Development Program of the National Research Foundation funded by the Korean government, MSIP (NRF-2015M3A9E6028949 and 2017M3A9B4062654 to Je.H.K.), the Creative Materials Discovery Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2018M3D1A1058826 to Je.H.K.), the Development of Platform Technology for Innovative Medical Measurements funded by the Korea Research Institute of Standards and Science (KRISS-2018-GP2018-0018 to Je.H.K.), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A3A04004741 to D.H.J.). J.M.L. was supported by the Korea Bio Grand Challenge program through the National Research Foundation of Korea funded by the Ministry (NRF-2018M3A9H3020844) and BioYouCell. Author contributions: D.H.J. drafted the manuscript and performed/analyzed the animal experiments. D.W.S. drafted the manuscript and performed/analyzed the genome editing experiments. C.S.C. and S.W.P. performed the animal experiments. U.G.K. and K.J.L. performed the genome editing experiments. K.L. and Ji.H.K. edited the manuscript. D.K. performed the Digenome-seq. S.K. and J.-S.K. revised the manuscript. Je.H.K. and J.M.L. designed the study and revised the manuscript. Competing interests: D.W.S., U.G.K., K.J.L., and S.K. are employed by ToolGen. J.M.L. was formerly employed by ToolGen. D.W.S., U.G.K., J.M.L., D.H.J., and Je.H.K. are inventors on a patent application related to this work filed by ToolGen Inc., Seoul National University Hospital, and Seoul National University R&D Foundation (KIPO no. 10-2018-0115678 and PCT no. PCT/KR2018/011522, filed on 28 September 2018). The authors declare no other competing interests. Data 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 are available from authors upon request.

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CRISPR-Cas9mediated therapeutic editing of Rpe65 ameliorates the disease phenotypes in a mouse model of Leber congenital amaurosis - Science Advances

DALLAS, Texas, October 29, 2019 (LifeSiteNews) LifeSiteNews has obtained a certified copy of the complete ruling in the case of seven-year-old James Younger, whose mother wanted him to undergo a gender transition against his fathers wishes.

Mr. Jeffrey Younger was fighting to prevent his ex-wife Dr. Anne Georgulas from transitioning James into Luna. The custody battle over James and his twin, Jude, garnered national attention after initially being ignored by the mainstream media. LifeSiteNews and The Texan were the only news outlets present for the entire trial.

Judge Kim Cooks ultimately ruled that Dr. Georgulas will not be able to transition the child into a girl without Mr. Youngers consent, and placed a gag order on both parents preventing either of them from talking about the case with media until James and Jude turn 18.

Judge Cooks made it clear she was not happy with the media attention the case received, and Dr. Georgulas lawyers brought up Mr. Youngers speaking to the media. He said he felt the public had a right to know what was going on in the medical field.

Judge Cooks did not uphold the jurys ruling that the current order be modified to provide one of the parents with sole managing conservatorship. She ruled that Mr. Younger and Dr. Georgulas will be joint managing conservators. They will both need to agree on all medical, dental, and psychological/psychiatric care. If a counselor determines it is appropriate, Mr. Younger will be granted 50/50 custody in January or June 2020. Judge Cooks also mandated family counseling for the entire family.

Judge Cooks is the same judge who, in 2017, awarded Dr. Georgulas the exclusive right, after notifying the Father, to consent to psychiatric and psychological treatment of the children and the exclusive right, after notifying the Father, to consent to medical, dental, and surgical treatment involving invasive procedures.

The court also mandated counseling to address specifically outlined issues and issued an injunction against the parents making disparaging remarks regarding the other parent in the presence of the children or in the childrens listening.

Judge Cooks gave the amicus attorney, Mr. Stacy Dunlop, the power to make medical decisions for the boys if Mr. Younger and Dr. Georgulas cannot agree.

If the parents cannot come to an agreement, they will make an appointment with Stacy Dunlop, the Parenting Coordinator, who will resolve the dispute by making a decision on behalf of the parents if they still disagree, the ruling says.

Specifically on medical, psychological, psychiatric, and dental issues, Mr. Dunlop will resolve the dispute by making a decision on behalf of the parents if they still disagree after discussing the disagreement with Stacy Dunlop.

Dr. Georgulas has the exclusive right to the services and earnings of the children, and the exclusive right to receive child support.

The ruling also outlines the courts 68 findings. The court found that there has been no abuse, neglect, or family violence by either parent to the children or from one parent towards the other. The court found, the mother made no request to surgically or chemically transition the childs sex or to chemically castrate the child.

Evidence presented in court indicated Dr. Georgulas had referrals to the GENECIS transgender childrens clinic. Dr. Georgulas also testified that she consulted with the GENECIS clinic about James. Dr. Georgulas expert witnesses testified about the alleged benefits of affirming transgenderism in children, including the use of puberty blockers and cross-sex hormones.

The court found that, the State of Texas has no compelling interest to justify such interference as to entering Orders requiring the Father to affirm Luna and honor her [sic] choices, both inside and outside the home. In other words, Mr. Younger will not be forced to use female pronouns to refer to his son.

One of the court findings highlighted a statement from Dr. Albritton, the custody evaluator, that Dr. Georgulas was over and above affirming. The court also found that the Mother has exceeded the scope of the exclusive rights and duties provided in the prior order.

The ruling also said that the state has not mandated the transition of James directly: No Texas judge or Texas court nor the 255th family court of appeal has ordered the chemical castration, puberty blockers, hormone blockers, or any transgnder reassignment surgery on this child.

Gov. Greg Abbott, Sen. Ted Cruz, and Rep. Dan Crenshaw all of Texas and many conservative leaders weighed in on the case after it went viral.

Sen. Rand Paul, R-KY, tweeted: We dont let kids drink alcohol til 21. People want to move smoking age to 21. But we will allow a 7 year old to have his life and body altered like this? This is child abuse and the state should side with the father who is trying to protect the child.

The certified copy of the ruling can be read HERE.

Follow all LifeSiteNews coverage of the James Younger case here.

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Here are the important details of the James Younger verdict (FULL RULING) - Lifesite

The eating pattern means the clock, not your body, dictates when you eat. TanyaJoy/Getty Images

The trend:

When it comes to Dorsey's fasting style, the CEO chooses to eat one time daily at 6:30 p.m., at which point he'll consume a protein (either fish, chicken, or steak) and some vegetables (an arugula or spinach salad, asparagus, or Brussels sprouts). Then he'll have a dessert of mixed berries or dark chocolate, which he consumes before 9 p.m.

On weekends, Dorsey fasts until Sunday evening. When he breaks his fast, he'll have bone broth and some red wine, though Dorsey didn't specify how often he consumes alcohol.

"It really has increased my appreciation for food and taste because I'm deprived of it for so long during the day," Dorsey told fitness authorBen Greenfield in April during an episode of Greenfield's podcast.

Dorsey's approach isn't the only way to go about intermittent fasting though. There are four popular types, according to the Cleveland Clinic, including a twice-weekly fast and a time-restricted method where a dieter eats only between 11 a.m. and 7 p.m., or between or noon and 8 p.m.

The science behind it:

Some research suggests intermittent fasting can help with weight loss better than restricting overall calories while eating throughout the day.

At the same time, research has found people have trouble sticking to intermittent fasting for the long term compared to other weight-loss plans.

According to the Cleveland Clinic, intermittent fasting isn't entirely proven as a helpful diet, but it does work for some people if they learn how to incorporate it into their lives without feeling deprived.

When it comes to Dorsey's more extreme style of fasting, some professionals see it as disordered eating. And, doing it over a long period of time could be especially detrimental to mental and physical health.

"Humans are mammals that need certain amounts of food and fluid to maintain our physiological [functions] and energy to do things we want to do in the world," Dr. Jennifer Gaudiani, an internal-medicine doctor who specializes in eating disorders, previously told Business Insider.

"When people undercut their need for food with radical under-eating, the body doesn't care about the reasoning. It is just going react to save your life," Gaudiani said.

That reaction will include feelings of mental sharpness because the body is trying to determine when and where from it will get its next meal, according to Gaudiani, which could explain Dorsey's mention of increased mental acuity during the Greenfield interview.

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7 health trends Silicon Valley tech bros are obsessed with, from dopamine fasting to the keto diet - INSIDER

Texas governor Greg Abbott(Brendan McDermid/Reuters)

Texas Governor Greg Abbott announced Wednesday night that the Texas Attorney Generals Office and the Texas Department of Family and Protective Services are looking into a case involving a custody battle over a seven-year-old boy who is said to be transgender by his mother.

On Tuesday, a Texas jury denied Jamess father, Jeff Youngers, request for sole conservatorship, ruling that he must continue parenting with Jamess mom, who has been encouraging Jamess social transition against his fathers wishes.

Jamess mother, Dr. Anne Georgulas, who is a pediatrician, separated from Younger several years ago after James and his brother were born, and was given exclusive rights and duties, while Youngers custody rights were limited.

Georgulas has said that seven-year-old James began to show signs of identifying as a girl when he asked for a girls toy from McDonalds, began imitating the female characters from Disneys Frozen, and started asking to wear dresses.

After being referred to a LGBT family therapist, Georgulas was advised to begin affirming James by calling him Luna, as well as socially transitioning him at school. Medical records presented by the boys pediatrician list James as Luna Younger, female, and included a recommendation to visit GENecis clinic at Childrens Hospital Center, which offers hormone therapy and puberty suppression.

Georgulas legal team has brought several therapists and counselors as witnesses, all of whom testified that James told them that he was a girl and wanted to be called Luna.

Younger has contended in court that James is happy to present as a boy when they are together, referring to himself as James and wearing male clothing.

He has also argued that the situation violates one of the two requirements for gender dysphoria in the DSM-V, the current manual used by the American Psychiatric Association. In addition to displaying characteristics related to gender expression, such as clothes, pronouns, etc., the patient must display distress. Witnesses who testified in the case including those who diagnosed James with gender dysphoria said that he has not displayed any such distress, according to the Texan.

Conservatives, including Texas Senator Ted Cruz, voiced their concerns about the case on Twitter ahead of Abbotts announcement.

Georgulas legal representation told the Daily Caller in a statement Wednesday that a completely distorted and untrue version of events in this case has been circling the media . . . The pleadings in this case are available online, including, but not limited to, the Courts prior annulment proceedings and the numerous findings of fraud that the Court made in this case against Mr. Younger.

The lawyers said that Georgulas case is being viciously attacked and threatened by complete strangers based on false and untrue statements.

The judge presiding over the case is expected to read the final ruling and order on Thursday, which may force Younger to call his son Luna, and attend classes on transgenderism. He could also be barred from taking his son outside the home dressed as a boy.

On Thursday, Judge Kim Cooks ruled that Jeff Younger is entitled to a say in his sons gender-transition process.

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Texas Gov. Announces Investigation Into Custody Battle Over Boys Gender Transition - National Review

An incomplete miscarriage is when a person experiences bleeding and severe cramping and may pass some pregnancy tissue at home. When an ultrasound is done, the gestational sac may not be visible, but there may remain pregnancy tissue. In that case, treatment options to remove the remaining tissue will be discussed. A complete miscarriage means all of the tissue has been passed and an ultrasound reveals no tissue remains in the uterus. This scenario would not require additional medical treatment because the uterus has fully released all pregnancy tissue.

After 20 weeks, pregnancy loss is no longer officially considered a miscarriage. But White believes that stillbirth, ectopic pregnancies, and molar pregnancies belong in the discussion.

Stillbirth is the birth of an infant who has died in the womb after surviving at least 20 to 28 weeks. Ectopic pregnancy is when an egg implants outside the uterus, usually in the fallopian tube. Molar pregnancy is when the fetus never grows and theres hypergrowth of the placenta. In all of these cases, the pregnancy ends before term, often risking the mothers health.

The first signs of miscarriage are spotting and cramps. Anytime you experience spotting, especially if youre spotting before your first ob-gyn appointment, its important to call your doctor. I would never tell a patient bleeding or spotting in pregnancy is normal. Its not uncommon, but its not normal, says McConnell. You may notice that any symptoms you might have had with pregnancylike exhaustion, tender breasts, and nauseadisappear.

If your pregnancy hasnt been confirmed by an ultrasound, a doctor will take one to ensure the bleeding doesnt indicate an ectopic pregnancy. If you dont yet have an ob-gyn or your doctors office is closed, go to the emergency room to have an ultrasound done. Its possible that at some point you will miscarry on your own [before an appointment], says White. Thats the hard thing. Sometimes youll be in a position to know its happening, and other times it starts on its own and you end up passing tissue before you can even get in to see your doctor.

Miscarriages dont always happen on their ownmost of the time they require medical treatment. Depending on timing, necessity, and cost, youll have one of three treatment options: expected management, medication, or a surgical procedure.

Opting for expected management is essentially letting nature run its course, giving your body the space to expel the fetal tissue on its own. This can take weeks80% of people will pass the pregnancy tissue within eight weeks of the cervix's being open, according to White.

With this method you will most likely experience heavy bleeding and severe cramping; your doctor may recommend ibuprofen or acetaminophen to mitigate the pain. (In pregnancy, acetaminophen is typically the only medication approved, but if youre miscarrying, its safe to take other pain-relieving medications.) Expected management means you can miscarry at home, which may make it more comfortable.

If you decide to have your miscarriage at home but dont want the limbo of waiting for your body to miscarry naturally, your doctor may prescribe you a medication called misoprostol, one of the medications commonly referred to as the abortion pill. You will still experience bleeding and cramping, but the miscarriage would take place within one to two weeks.

The third option is the quickest: a dilation and curettage procedure, also called a D&C. In this procedure the doctor will dilate the cervix to manually remove the tissue from the uterus. General or local anesthesia is given for the procedure, and spotting and light cramping may persist for a few days after.

The physical side of recovery can take up to three weeks. After a treatment its common to bleed for two to three weeks and experience cramping over the first 48 hours, with it calming down in the following days. Your doctor may say the pregnancy is over, but when youre still managing symptoms for two to three weeks, it may not feel like it, White says. I tell people if you push it too hard [with work or exercise], you may increase your bleeding. Its okay, but it might make you uncomfortable and want to slow it down. See how your body reacts and then slowly ramp it up.

In general, your menstrual cycle should return within six weeks, and hormonal changes, like pregnancy acne, should balance out within three months. If you experience ongoing heavy bleeding or severe cramping, you should contact your doctor immediately.

As far as trying to conceive again, White recommends waiting two weeks, to be on the conservative side. You dont always feel like having sex, but at the same time having sex can also be really life-affirming, she says.

The aftermath of miscarriage, like grief itself, is different for everyone. Some people are ready to try again soon after, and others, like me, bury their grief for months. The absolute last thing a person experiencing miscarriage needs is someone telling them how to feel. Theres no right or wrong way to move forward.

Rachel Wells is a writer based in Nashville, covering the intersection of reproductive rights, mental health, and sexual violence. Follow her on Twitter @rachelwells and on Instagram @rachelwells1.

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Miscarriage Signs, Causes & Treatment: What to Expect - Glamour

I was a cigarette smoker for 30 years until my doctor told me that I needed to quit immediately. So I started vaping. It sure made it easy to walk away from tobacco. But can I use nicotine vapes safely? Jordan B., Milwaukee

The reason it was easy to go from cigarette to vape is because you were substituting one nicotine source for another. And that's no way to reduce your health risks.

Nicotine is an addictive drug that is associated with increased risk of cardiovascular, respiratory and gastrointestinal disorders, decreased immune response, harm to reproductive health and DNA mutation that leads to cancer. Plus, the American Heart Association says that vapers who think vaping nicotine can help them stop using cigarettes are likely to continue smoking cigarettes while they vape that's called "dual use."

Vaping anything has never been safe. The only studies that say there's no harm associated with e-cigarettes are those funded by the vaping (tobacco) industry. The Altria Group (formerly Philip Morris of Marlboro and Virginia Slims fame) recently acquired a 35% stake in Juul. It's an old, familiar bag of tricks. Remember the '50s ad slogan that said, "More doctors smoke Camels than any other cigarette"?

The Centers for Disease Control and Prevention has reported that as of this writing more than 1,080 people have developed lung illnesses and at least 19 people have died from vaping. Those numbers could be just the tip of the iceberg. Lung damage from vaping isn't associated only with THC; nicotine also has been a cause. According to Mayo Clinic doctors, vaping-induced lung injury "looks like a toxic chemical exposure, a toxic chemical fume exposure or a chemical burn injury." That's because vaping is a delivery system for flavorings, ultrafine particles, heavy metals and volatile organic compounds.

So go to http://www.heart.org and type in "5 Steps to Quit" (it includes vaping). For more comprehensive program, talk to your doctor.

I've been waking up grumpy lately, and I don't know why. I'm usually fine by midday. What can I do when I wake up to set myself up for a good mood in the morning? Chondra B., Chicago

Lots of people wake up feeling grumpy at least a couple of days a week. In fact, one shower company in Great Britain did a survey and found that six out of 10 Brits wake up in a bad mood. The shower company's solution? Take a shower!

Well, we agree, but to maintain that good mood throughout the morning and the day that follows you need to provide your body with the nutrition it needs to smoothly regulate your hormones, gut function and brain power. That means eating a nutritious breakfast. Your best bet is to put together a protein- and fiber-filled first meal of the day.

A great choice is oatmeal, muesli or granola (100% whole grains) with nonfat yogurt and lots of strawberries, blueberries and/or raspberries. Whole grains digest slowly and steadily raise levels of your feel-good hormone serotonin. They also help to keep your blood sugar stable, which improves mood.

Fresh berries deliver polyphenols, which can help you moderate your stress response and improve heart health. For variety, you can try grapefruit, oranges and melons (honeydew and cantaloupe).

Low-fat yogurt can deliver about a third of your daily requirement for calcium, which is good for your blood pressure and (along with magnesium) can have an anti-anxiety effect.

To mix up your morning menu, you might also try these foods that deliver mood-enhancing benefits: whole-wheat avocado toast; an egg-white omelet with vegetables; a green smoothie; or almond oatmeal. All those recipes and more are available at sharecare.com or doctoroz.com.

Other mood enhancers: Go to bed an hour earlier and get up an hour earlier. Get plenty of physical activity (sex counts); that'll stimulate the release of oxytocin, which increases your happiness. All these choices may help you see a turnaround in your morning mood.

Mehmet Oz, M.D. is host of "The Dr. Oz Show," and Mike Roizen, M.D. is Chief Wellness Officer and Chair of Wellness Institute at Cleveland Clinic. Email your health and wellness questions to Dr. Oz and Dr. Roizen at youdocsdaily@sharecare.com.

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Oz & Roizen: The respiratory effects of vaping - Online Athens