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Thursday, October 13, 2022

ASH: Senti Bio's gene circuit CAR-NK cell therapy enhances cancer killing and safety in leukemia models

 Engineered cell therapy has revolutionized the treatment of blood cancers, but precisely selecting the right target to kill off cancer cells while sparing healthy cells has been challenging for some disease types. Now, Senti Bio has promising early data that a CAR-NK (natural killer) cell therapy developed from the biotech’s gene circuit platform could solve that problem—and provide an off-the-shelf option—in acute myeloid leukemia (AML).

Senti uses a technology dubbed “logic-gated gene circuits” to design CAR-NK cells to target AML cells expressing FLT3 OR CD33. In mouse models, the cells improved killing of AML, while a CAR construct that recognizes the endomucin (EMCN) protein steered the immune therapy away from healthy cells. Senti will report the findings at the American Society of Hematology (ASH) annual meeting.

Taking a page from the computation and electronic areas, Senti uses logic-gated gene circuits to build CAR-NK cells that can identify more than one target to either activate the therapy or go silent. The technology could come in handy for designing CAR cell therapies for AML, Senti's scientists figured. That's because the disease lacks a single target antigen that’s adequately expressed across both AML leukemic stem cells and immature leukemic blast cells. In addition, none of the known targets for AML are unique to the blood cancer, according to Senti.

Senti, a 2018 Fierce Biotech Fierce 15 winner, is combining the FLT3 OR CD33 gate gene circuit with one called the EMCN NOT gate in an off-the-shelf CAR-NK cell therapy dubbed SENTI-202. The company is now optimizing the design and targets a first-in-human clinical trial application with the FDA in 2023, Brian Garrison, Ph.D., a director of research at Senti, told Fierce Biotech Research via email. 

For the OR gate part, Senti engineered an activating CAR construct to connect snippets of antibodies that could recognize FLT3 and CD33, which are expressed in AML cells. The CD33 component would enable targeting of primarily blast cells, while the FLT3 part would turn CAR-NK cells against leukemic stem cells, which are critical to a potentially curative treatment, Garrison explained. By targeting two tumor-associated antigens, the OR gate limits the probability that the engineered CAR-NK cells will fail to recognize different cancer cells.

In lab dishes, the FLT3 OR CD33 CAR-NK cells outperformed single-target CAR-NKs against FLT3 or CD33 at killing off cancer in several leukemia cell lines. The novel CAR-NK cells “demonstrated significant cytotoxicity against primary AML patient samples and significantly reduced tumor burden and improved mouse survival” in AML mouse models carrying cancer xenografts, Senti researchers said in an abstract. 

In one patient xenograft model, all control mice had died from disease by day 64, while all rodents that got the CAR-NK cells were still alive, Garrison said.

“We believe that our strategy of concurrently targeting FLT3 and CD33 will result in a more robust synergistic anti-tumor effect, leading to a more durable remission with decreased risk of relapse due to single antigen escape,” the Senti team wrote.

For the NOT gate component, which is designed to reduce off-target toxicity, the team picked EMCN, a surface antigen expressed on up to 76% of healthy hematopoietic stem cells but not on AML cells. The team made an inhibitory CAR with the ability to suppress immune activity.

One of the EMCN-specific inhibitory CAR configurations protected up to 67% of cells that expressed both FLT3 and EMCN from FLT3-targeted activating CAR in lab dishes.

The researchers also mixed FLT3 cells with or without EMCN expression to mimic healthy cells and AML cells. The NOT logic-gated CAR-NK cells preferentially killed the FLT3 cells without EMCN, they found.

Lastly, the researchers combined the OR gate and the NOT gate and added a proprietary IL-15 platform that could improve CAR-NK cell persistence and create a more durable antitumor response, Garrison explained.

In lab dishes, the full SENTI-202 circuit protected about half of healthy blood cells from CAR-NK toxicity while showing the same killing activity as CAR-NK cells without the NOT gate did. Based on decades of bone marrow transplant experiences in the field, Garrison suggested, experts believe that protecting about 10% to 20% of hematopoietic stem cells is likely sufficient to provide clinical benefits.

Senti Bio is the brainchild of a team of prominent scientists in biomedical engineering, including Massachusetts Institute of Technology researchers Tim Lu, M.D., Ph.D., and Jim Collins, Ph.D.

The gene circuit technology has attracted the interest of Big Pharma companies. In January, the company raised $105 million in a series B round led by Bayer’s venture capital arm.

The SENTI-202 CAR-NK readout at the ASH meeting marks the first complete proof-of-concept data set for Senti Bio’s OR gate and NOT gate gene circuits, and the data support the idea that the technology may enable “enhanced broader-spectrum cancer targeting while limiting off-tumor toxicity,” Garrison said in a statement.

SENTI-202 is one of the first programs to emerge from Senti’s platform. The company is also developing SENTI-301, which is designed to target GPC3 for treating liver cancer, along with SENTI-401, a CAR-NK cell therapy being developed for colorectal cancer.

https://www.fiercebiotech.com/research/senti-bio-s-gene-circuit-car-nk-cell-therapy-enhances-cancer-killing-and-safety-leukemia

To outrun inflation, people are making big (and easy) changes to their habits

 Rattled by the rise in the cost of living in recent months, millions of people have been taking action to conserve their cash

We never were the same after last summer.

Stubbornly high inflation rates in recent months and several interest rate hikes by the U.S. Federal Reserve are impacting consumer behavior. That's according to company earnings reports, market-data analytics and consumer surveys.

Inflation reached 8.2% in September on the year, the Bureau of Labor Statistics said Thursday, clinging to a four-decade high. Most economists expected a September inflation rate of 8.1% year-over-year, after August's 8.3% annual increase.

The cost of living increased 0.4% from August to September. But the "core" numbers that strip away volatile food and energy costs rose 0.6% month to month when Wall Street forecasters were expecting a 0.4% rise.

Ahead of the market open Thursday, futures for the Dow Jones Industrial Average , S&P 500 and Nasdaq Composite all plunged after the hot inflation numbers.

Rattled by the rise in the cost of living in recent months, millions of people have already been taking action to conserve their cash, according to recent McKinsey & Co. report that explored the ways people are trading down.

"Whether it's at gas pumps or in grocery stores, people across the United States have been feeling a pinch in their pocketbooks this summer," it said. "Inflation is the highest it's been in decades, and consumers are worried and jittery."

With inflation at a 40-year high, McKinsey said, "The mood has turned darker. Thirty percent of our respondents say they are feeling pessimistic, and that we may be headed toward one of the worst recessions we've ever seen."

Inflation has become a stark -- if bleak -- reality for some people, especially when shopping for food -- like this California woman who told MarketWatch that she buys less vegetables, or freezes them to get more bang for her buck.

Once consumers have made up their minds that inflation is a problem, and it's here to stay, they're less likely than economists to change their minds, said Carlo Pizzinelli, an economist at the International Monetary Fund's research department.

"Consumers also tend to disagree on the outlook for inflation more than experts do, they change their view less often, and they often rely on a few key products they consume regularly -- such as coffee and gasoline -- to extrapolate changes in the overall cost of living," he wrote in this research paper.

Consumers are changing their behavior

-- Three quarters of consumers said they were engaging in some sort of deal-seeking: 60% were adjusting the quantity of what they were buying. That means either opting for large amounts at lower unit prices or smaller amounts.

Some retailers appear to be reaping the benefits: Costco Wholesale (COST) -- which can sell groceries in bulk in addition to a $1.50 hot dog and soda combo -- just had a strong September, with comparable sales rising 8.5% from the same point last year.

-- 44% of people told McKinsey they were delaying purchases on non-essential items. Lower-income shoppers tended to single out certain groceries, home improvement, footwear and apparel as the items bound for a pause.

-- More than one-third (37%) of McKinsey's respondents said they were switching retailers for lower prices or discounts. They are also eyeing lower prices from generic brands and using 'buy now pay later' programs, McKinsey noted.

Some retailers have already been rolling out bargains. In late September, Nike (NKE) announced price-cutting efforts to help get off-season clothing out of warehouses, and executives at the athletic apparel giant expected rivals to do the same.

During an August earnings call, Dollar General (DG) CEO Todd Vasos said a more diverse range of customers from income levels of $100,000 and up. "We really are encouraged in seeing, a younger consumer, a little bit more affluent," he said.

-- Three quarters of consumers are taking a dim view of discretionary spending, according to a separate survey carried out last September by Numerator, a consumer markets and analytics firm.

Many people already know where they are planning to cut back -- starting with dining out, travel, electronics, plus toys and games -- as they are learning to live with feelings of insecurity that rising prices bring.

Earnings season will give economists a better insight those feelings. Third quarter earnings results are also set to start rolling out Friday, giving another look at customer spending -- and whether companies are maintaining their profit margins.

https://www.morningstar.com/news/marketwatch/20221013367/the-mood-has-turned-darker-desperate-to-outrun-inflation-people-are-making-big-and-easy-changes-to-their-habits-you-can-too

Ultragenyx upped to Buy from Neutral by Guggenheim

 Target $50

https://finviz.com/quote.ashx?t=RARE&p=d

Private Equity 'Gambit' Squeezes Excessive ED Charges From Routine Births

 Elizabeth Huffner thinks it is obvious: A full-term, healthy pregnancy results in a birth.

"When your due date has come and gone, you're expecting a baby any minute," Huffner said. So she was surprised to discover she was an "unknown accident" — at least from a billing standpoint — when she went to the hospital during labor. Her bill included a charge for something she said she didn't know she'd ever entered: an obstetrics emergency department.

That's where a doctor briefly checked her cervix, timed her contractions, and monitored the fetal heartbeat before telling her to go home and come back later. The area is separated from the rest of the labor-and-delivery department by a curtain. The hospital got about $1,300 for that visit — $530 of it from Huffner's pocket.

In recent years, hospitals of every stripe have opened obstetrics emergency departments, or OBEDs. They come with a requirement that patients with pregnancy or postpartum medical concerns be seen quickly by a qualified provider, which can be important in a real emergency. But it also means healthy patients like Huffner get bills for emergency care they didn't know they got.

"It should be a cautionary tale to every woman," said Huffner, of Rockford, Illinois.

Three of the four major companies that set up and staff OBEDs are affiliated with private equity firms, which are known for making a profit on quick-turnaround investments. Private equity has been around for a long time in other medical specialties, and researchers are now tracking its move into women's health care, including obstetrics. These private equity-associated practices come with a promise of increased patient satisfaction and better care, which can help the hospital avoid malpractice costs from bad outcomes.

But private equity also is trying to boost revenue. Dr. Robert Wachter, chair of the Department of Medicine at the University of California-San Francisco, calls the private equity encroachment into medicine "worrisome."

"Hospitals will do what they can do to maximize income as long as they're not breaking the rules," Wachter said. "And it sounds like that's sort of what they're doing with this ER gambit."

Surprising Bills

KHN reviewed the bills of a dozen patients in five states who said they were hit with surprise emergency charges for being triaged in an OBED while in labor. That included a woman in Grand Junction, Colorado, who said she felt "gaslit" when she had to pay $300 in emergency charges for the care she received in the small room where they confirmed she was in full-term labor. And in Kansas, a family said they were paying $400 for the same services, also rendered in a "very tiny" room — even though HCA Healthcare, the national for-profit chain that runs the hospital, told KHN that emergency charges are supposed to be waived if the patient is admitted for delivery.

Few of the patients KHN interviewed could recall being told that they were accessing emergency services, nor did they recall entering a space that looked like an emergency room or was marked as one. Insurance denied the charges in some cases. But in others families were left to pay hundreds of dollars for their share of the tab — adding to already large hospital bills. Several patients reported noticing big jumps in cost for their most recent births compared with those of previous children even though they did not notice any changes to the facilities where they delivered.

Three physicians in Colorado told KHN that the hospitals where they work made minimal changes when the institutions opened OBEDs: The facilities were the same triage rooms as before, just with a different sign outside — and different billing practices.

"When I see somebody for a really minor thing, like, someone who comes in at 38 weeks, thinks she's in labor, but she's not in labor, gets discharged home — I feel really bad," said Dr. Vanessa Gilliland, who until recently worked as a hospitalist in OBEDs at two hospitals near Denver. "I hope she doesn't get some $500 bill for just coming in for that."

The bills generated by encounters with OBEDs can be baffling to patients.

Clara Love and Dr. Jonathan Guerra-Rodríguez, an intensive care unit nurse and an internist, respectively, found a charge for the highest level of emergency care in the bill for their son's birth. It took months of back-and-forth — and the looming threat of collections — before the hospital explained that the charge was for treatment in an obstetrics emergency department, the triage area where a nurse examined Love before she was admitted in full-term labor. "I don't like using hyperbole, but as a provider I have never seen anything like this," Guerra-Rodríguez said.

Patients with medical backgrounds may be more likely than other people to notice these unusual charges, which can be hidden in long or opaque billing documents. A physician assistant in North Carolina and an ICU nurse in Texas also were shocked by the OBED charges they faced.

Figuring out where OBEDs even are can be difficult.

Health departments in California, Colorado, Massachusetts, and New York said they do not track hospitals that open OBEDs because they are considered an extension of a hospital's main emergency department. Neither do professional groups like the American Hospital Association, the American College of Obstetricians and Gynecologists, and the Joint Commission, which accredits health care programs across the country.

Some hospitals state clearly on their websites that they have an OBED. A few hospitals state that visiting their OBED will incur emergency room charges. Other hospitals with OBEDs don't mention their existence at all.

Origins of the OBED Concept

Three of the main companies that set up and staff OBEDs — the OB Hospitalist Group, or OBHG; TeamHealth; and Envision Healthcare — are affiliated with private equity firms. The fourth, Pediatrix Medical Group, formerly known as Mednax, is publicly traded. All are for-profit companies.

Several are clear about the revenue benefits of opening OBEDs. TeamHealth — one of the country's dominant ER staffing companies — is owned by private equity firm Blackstone and has faced criticism from lawmakers for high ER bills. In a document aimed at hospital administrators, TeamHealth says OBEDs are good for "boosting hospital revenues" with "little to no structural investment for the hospital." It markets OBED success stories to potential customers, highlighting hospitals in California and South Florida where OBEDs reportedly improved patient care — and "produced additional revenue through OB-ED services." OBHG, which staffs close to 200 OBEDs in 33 states, markets a scoring tool designed to help hospitals maximize charges from OBEDs and has marketed its services to about 3,000 hospitals.

Staffing companies and hospitals, contacted by KHN, said that OBEDs help deliver better care and that private equity involvement doesn't impede that care.

Data from Colorado offers a window into how hospitals may be shifting the way they bill for triaging healthy labor. In an analysis for KHN, the Center for Improving Value in Health Care found that the share of uncomplicated vaginal deliveries that had an emergency department charge embedded in their bills more than doubled in Colorado from 2016 to 2020. It is still a small segment of births, however, rising from 1.4% to 3.3%.

Major staffing companies are set up to charge for every single little thing, said Dr. Wayne Farley. He would know: He used to have a leadership role in one of those major staffing companies, the private equity-backed Envision, after it bought his previous employer. Now he's a practicing OB-GYN hospitalist at four OBEDs and a consultant who helps hospitals start OBEDs.

"I've actually thought about creating a business where I review billings for these patients and help them fight claims," said Farley, who thinks a high-level emergency charge makes sense only if the patient had serious complications or required a high level of care.

Proponents of OBEDs say converting a triage room into an obstetrics emergency department can help pay for a hospital to hire 24/7 hospitalists. In labor and delivery, that means obstetric specialists are available purely to respond to patients who come to the hospital, rather than juggling those cases with clinic visits. Supporters of OBEDs say there's evidence that having hospitalists on hand is safer for patients and can reduce unnecessary cesarean sections.

"That's no excuse," said Dr. Lawrence Casalino, a physician and health policy researcher at Weill Cornell Medicine. "To have people get an emergency room charge when they don't even know they're in an emergency room — I mean, that doesn't meet the laugh test."

But Dr. Christopher Swain, who founded the OB Hospitalist Group and is credited with inventing the OBED concept, said that having round-the-clock hospitalists on staff is essential for giving pregnant patients good care and that starting an OBED can help pay for those hospitalists.

Swain said he started the nation's first OBED in 2006 in Kissimmee, Florida. He said that at early adopter hospitals, OBEDs helped pay to have a doctor available on the labor-and-delivery floor 24/7 and that hospitals subsequently saw better outcomes and lower malpractice rates.

"We feel like we fixed something," Swain said. "I feel like we really helped to move the bar to improve the quality of care and to provide better outcomes."

Swain is no longer affiliated with OBHG, which has been in private equity hands since at least 2013. The company has recently gone so far as to present OBEDs as part of the solution to the country's maternal mortality problem. Hospitals such as an Ascension St. Joseph's hospital in Milwaukee have echoed that statement in their reasons for opening an OBED.

But UCSF's Wachter — who coined the term "hospitalist" and who generally believes the presence of hospitalists leads to better care — thinks that reasoning is questionable, especially because hospitals find ways to pay for hospitalists in other specialties without engineering new facility fees.

"I'm always a little skeptical of the justification," Wachter said. "They will always have a rationale for why income maximization is a reasonable and moral strategy."

Private Equity's Footprint in Women's Health Care

Farley estimates that he has helped set up OBEDs — including Colorado's first in 2013 — in at least 30 hospitals. He's aware of hospitals that claim they have OBEDs when the only change they've made is to have an OB-GYN on site round-the-clock.

"You can't just hang out a shingle and say, 'We have an OBED.' It's an investment on the part of the hospital," he said. That means having, among other things, a separate entrance from the rest of the labor-and-delivery department, clear signage inside and outside the hospital, and a separate waiting room. Some hospitals he has worked with have invested millions of dollars in upgrading facilities for their OBED, he said.

Private equity firms often promise more efficient management, plus investment in technology and facilities that could improve patient care or satisfaction. In some parts of health care, that could really help, said Ambar La Forgia, who researches health care management at the University of California-Berkeley and is studying private equity investment in fertility care. But La Forgia said that in much of health care, gauging whether such firms are truly maintaining or improving the quality of care is difficult.

"Private equity is about being able to extract some sort of value very quickly," La Forgia said. "And in health care, when prices are so opaque and there's so much lack of transparency, a lot of those impacts on the prices are eventually going to fall on the patient."

It's changing circumstances for doctors, too. Dr. Michelle Barhaghi, a Colorado obstetrician, said OBEDs may make sense in busy, urban hospitals with lots of patients who did not get prenatal care. But now they're cropping up everywhere. "From a doctor standpoint, none of us want these jobs because now we're like a resident again, where we have to see every single patient that walks through that door," said Barhaghi, rather than triaging many cases on the phone with a nurse.

Still, private equity is continuing its advance into women's health care.

Indeed, Barhaghi said private equity came knocking on her door earlier this year: Women's Care Enterprises, backed by private equity company BC Partners, wanted to know whether she would consider selling her practice. She said "no."

https://www.medscape.com/viewarticle/982400

Treatments From China: What Data Are Needed and Who Decides?

 I'm David Kerr, professor of cancer medicine at University of Oxford.

I've been really interested in the tit-for-tat argument that's going on between the FDA and other commentators and its Chinese regulatory equivalent. This all circles around the recent biologics license application from a company that was marketing an immune checkpoint inhibitor called sintilimab.

They've done a trial in non–small cell lung cancer comparing sintilimab vs chemotherapy. The trial outcome was positive, but it was done completely within China.

The regulatory package was put forward to the FDA, but it was turned down. There are a number of different factors around endpoints, standards of care, insufficient pharmacokinetic data, and competitiveness. Do we need any more immune checkpoint inhibitors, given the relatively large number that have been approved already?

Perhaps the most telling point was that the study was conducted only in Chinese patients. This led to an interesting discussion among US and Chinese key opinion leaders and the regulatory authorities.

It does represent a really interesting challenge because until relatively recent times, China was the recipient of innovative Western medicines. The Chinese authorities, depending on the drug, the size of the benefit, and so on, might have required a bridging study or some form of crossover.

If they felt that the disease was etiologically different in China, they may require a separate, additional randomized trial to demonstrate the new benefits. That was the case with a drug that was marketed for treatment of hepatocellular cancer, which one could argue is manifestly different in Eastern Asia than it is in the West.

In these days of globalization, we're used to multicenter trials in which big pharma recruit patients from around the world and then do some subgroup analysis to see if the hazard ratios are the same and are independent of ethnicity.

Of course, that can generate some really interesting hypotheses, as was the case in terms of endothelial growth factor receptor (EGFR) inhibitors for the treatment of lung cancer that spawned studies looking at EGFR mutants that are responsive to these drugs and were more common in Eastern Asian populations.

Back to the immune checkpoint inhibitors. There are no data that I know of that suggest any major differences in ethnic handling of these drugs in terms of the pharmacokinetics. The response rates in drugs that have moved from West to East seem very similar. The distribution and kinetics of the handling of antibodies is relatively straightforward and doesn't seem to vary in terms of ethnicity.

There's a very interesting debate to be had about it because there are now more innovative medicines in the pipeline from China, which is fantastic. Building on some of the truly innovative sciences coming from there, I think we'll see more drugs coming from East to West.

Clearly, we need to consider very carefully what trial data we require. Would we take a predominantly Chinese study and then look at a small pharmacokinetic study or a crossover study in a relatively small population of Caucasian patients, depending on the etiology of the disease? Would we require additional randomized trials to be undertaken in a Caucasian population for the Chinese medicine coming over?

We need the regulatory authorities to get together. As a community of oncologists, we are very happy to collaborate. We're very happy to have trials that draw participants from around the world in sufficient number for us to look for subtle but sometimes important differences in patterns of toxicity, response rates, and so on. Having globalized cancer trials may well be the answer.

I think we need to see a greater degree of consistency coming from the regulatory authorities around the world as to what information we really require, and above all else, if we have a set of rules, to apply these consistently across any of the new drugs that are coming in.

Have a look at the publication in the Journal of Thoracic Oncology. See what you think. Are we being fair? Is there an ethnic bias creeping in? Is it scientifically sound? I'd be interested in your viewpoint.

For the time being, Medscapers, thanks for listening. Over and out, and ahoy. Thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

https://www.medscape.com/viewarticle/975136

Vitamin D: Recent Findings and Implications for Clinical Practice

 This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital. I'd like to talk with you about the recent research (particularly randomized clinical trials) of vitamin D supplementation and the implications for clinical practice. As a director of the Vitamin D and Omega-3 trial (VITAL), the largest randomized clinical trial in the world, I'm often asked, "How much vitamin D do we need, and should I take a vitamin D supplement?" I want to review the findings from recent randomized clinical trials and the implications for practice.

For a long time, vitamin D has been perceived as a magic bullet, a panacea, and a cure-all for many chronic health conditions such as cancer, cardiovascular disease, diabetes, bone fractures, cognitive decline, and depression. Many of the findings, though, have been from observational studies where a higher blood level of 25-hydroxy vitamin D has been linked to a lower risk for these health conditions.

We know in epidemiology that correlation doesn't prove causation. Other factors could be involved; for example, people who have higher blood levels of vitamin D may have healthier diets, or they may be spending more time outdoors, being physically active and exposed to the sun. Some of these other factors could be lowering their risk.

When the randomized trials began to emerge, in many of these large-scale trials, the findings were generally neutral or null for cardiovascular disease, total cancer, diabetes, cognitive decline, depression, and many other health outcomes, including fracture. So, the question was asked, does this mean that vitamin D is not important to health?

To the contrary, these findings suggest that vitamin D is so essential to health that we need only small to moderate amounts of vitamin D. Vitamin D is very tightly regulated in the body — the metabolism and function of vitamin D. Even small to moderate amounts will meet the requirements for vitamin D and bone health and many other outcomes.

This is what the National Academy of Medicine, US Preventive Services Task Force, and many other professional organizations have advised, that widespread screening for vitamin D deficiency and blanket universal supplementation with vitamin D would not be indicated.

The randomized trials of vitamin D, including the VITAL study, have generally not shown reductions in the major health outcomes. We found two exceptions in VITAL. We saw promising signals, including a 22% reduction in autoimmune conditions (rheumatoid arthritis and psoriasis) and a 17% reduction in advanced (metastatic or fatal) cancers. In meta-analyses of other large-scale randomized trials, the findings were a signal for a reduction in advanced cancers, even with very small doses of vitamin D (400-800 IUs daily). We tested 2000 IUs daily in VITAL.

Overall, it's recommended that small to moderate amounts of vitamin D are adequate, and among the healthy population, most people do not need screening or supplements.

The reduction in autoimmune diseases suggests that vitamin D may play a role in tamping down inflammation. The question has been raised about whether vitamin D is beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID. We are looking at this question in a separate trial called VIVID (Vitamin D for COVID Trial) which tests a higher dose (> 3000 IUs daily) of vitamin D. Those results will be available at the end of this year or early next year.

In other randomized trials of COVID and vitamin D, the results have been mixed and inconsistent, with no clear answer. During the COVID pandemic, I have generally advised that it's reasonable to take 1000-2000 IUs of vitamin D daily as a form of insurance. This dose is known to be very safe. Over 5.3 years in the VITAL trial we saw that a dose of 2000 IUs was very safe.

But it's not essential to take a supplement. And overall, aside from some high-risk groups, most people do not need a supplement. The high-risk groups include patients in nursing homes who may have restricted diets and limited time out of doors. For people with malabsorption conditions such as Crohn's diseaseceliac disease, post–gastric bypass surgery, and those with osteoporosis who are on medications for osteoporosis, it's still quite reasonable to prescribe calcium and vitamin D.

Recommendations for vitamin D in the generally healthy population really should focus on a healthy diet. The United States has a fortified food supply. Vitamin D is added to many foods, dairy products, and cereals, as well as beverages. Natural sources of vitamin D include fatty fish and wild mushrooms.

We should be looking at food labels (which now include vitamin D content) and try to get adequate vitamin D from our diet, and also do our best to spend time outdoors, being physically active, because it is of great benefit to our health. The general principle is that a dietary supplement will never be a substitute for a healthy diet or healthy lifestyle. And those other behaviors really should be the focus at this time.

https://www.medscape.com/viewarticle/982190

Clinics Offer Free Vasectomies, Citing a Surge in Demand

 Denny Dalliance had long worried about what would happen if he fathered a child because his job as a truck driver keeps him away from home most of the week.

But after the U.S. Supreme Court overturned Roe v. Wade in June, the 31-year-old Independence, Missouri, man decided it was time to take action — and jumped at the chance to sign up for a free vasectomy.

"These are grim circumstances under which I made this decision," he said as he drove a load of cardboard boxes through Kansas this week.

The vasectomy he is scheduled to get next month is part of an effort that involves Planned Parenthood and a physician with a mobile vasectomy clinic. Sixty vasectomies will be offered over three days in and outside Planned Parenthood clinics in St. Louis, Springfield and Joplin to uninsured patients during the first week of November amid what the clinics say is a surge in demand for the procedure.

Dr. Esgar Guarin then plans to take his mobile clinic — a vehicle decorated with large images of sperm that his friends have jokingly dubbed the "Nutcracker" — on the road the following week to offer 40 more free vasectomies in several towns across Iowa.

Guarin also plans to offer discounted vasectomies that month at his regular clinic in the Des Moines area.

The efforts are part of World Vasectomy Day, originally a single-day event that now includes a year-round focus and a host of activities in November.

"It's a very particular moment in reproductive rights in the United States. And we need to talk about it," he said, adding that vasectomies are performed far less often than the tubal ligation method of female sterilization, even though they are cheaper, have a shorter recovery time and require local, rather than general, anesthesia.

Guarin, who serves on the medical advisory board for the World Vasectomy Day, helped offer vasectomies last year at the Planned Parenthood in St. Louis to raise awareness about the procedure. The effort was so popular that the decision was made to expand it to other cities even before the toppling of Roe sent demand soaring.

In July alone, the Planned Parenthood of the St. Louis Region and Southwest Missouri performed 42 vasectomies, compared to 10 in the same month last year. Female sterilizations rose to 18 that month from just three in July 2021.

The American College of Obstetricians and Gynecologists has been hearing similar reports from around the country that more patients are seeking tubal ligations. It is too early for any post-Roe national numbers on permanent sterilization, said Laura Lindberg, a professor at Rutgers University's School of Public Health in New Jersey.

Planned Parenthood, for instance, doesn't have national sterilization numbers available for this year yet. However, its national web page has seen a 53% increase in vasectomy information searches over the last 100 days, a spokesperson said.

Data from Google Trends shows that searches about vasectomies briefly spiked after the leak of the draft majority opinion in the Dobbs case but then reached their highest level in the days after the court released its decision in late June.

Dr. Doug Stein, a urological surgeon in the Tampa-St. Petersburg, Florida, area, said patient registrations for his practice tripled immediately after the Dobbs decision, with many patients under the age of 30.

"I think everybody is busier since the Dobbs decision," said Stein, who co-founded World Vasectomy Day.

Dr. Arnold Bullock, a St. Louis urologist who does about 35 vasectomies a month said that before the U.S. Supreme Court decision, patients waited about a month for the procedure while the wait now is two to three months.

In Texas, Dr. Koushik Shaw said his Austin Urology Institute saw a spike when Texas enacted a strict abortion law last year and another, larger one after the U.S. Supreme Court decision, so that it's now doing 50% more procedures. He said many are for men who don't want children and saw access to abortion as another option should birth control not work as planned.

"It really pushed family planning to the forefront of people's thoughts," he said of the loss of abortion access.

Lawmakers are responding to the growing demand. A California law that will take effect in 2024 will make vasectomies cheaper by allowing patients with private insurance plans to get the procedure at no additional cost other than what they pay for their monthly premiums.

Dr. Margaret Baum, the medical director of Planned Parenthood of the St. Louis Region and Southwest Missouri, will be partnering with Guarin to provide the free vasectomies. She has been having lots of conversations with patients about permanent sterilization in recent months and said there is a sense of urgency.

"I think people are afraid, No. 1, about abortion not being accessible, which is a very real and legitimate fear and in the reality for a large part of folks in our country. And then I think people are also really afraid that what else might be next," she said.

A vasectomy involves cutting and sealing the tube that carries sperm, preventing it from entering ejaculate fluid. Baum said she chats with patients to keep them calm, sometimes turning on a playlist that includes "Great Balls of Fire" and "The Nutcracker Suite." Most patients are fully recovered in a couple of days.

Dalliance, the truck driver, said he didn't want to thrust the responsibility of birth control on partners anymore, especially with abortions harder to get. His home state of Missouri was among the first in the country with a trigger law in effect to ban abortions at any point in pregnancy.

"I don't want to come off as though I'm like unhappy to be doing this, but this is a situation where my hands kind of got forced with regards to the Roe v. Wade decision," he said.

"I feel like that with the extreme cost involved with having a child in the United States, I kind of got priced out," he said. "And so this is me cashing out my chips as it were. It's the right ethical decision for me, but it's not one that's made lightly."

https://www.medscape.com/viewarticle/982398