Publisher Health

To design drugs that stall the growth of aggressive cancers, it helps to know the structures of the proteins that are revving the cancers’ engines.
In a series of three papers published in Proceedings of the National Academy of Sciences, Scripps Research scientists have illuminated the three-dimensional structure of phosphoinositide 3-kinase alpha (PI3Kα), a protein often mutated in cancer cells. Moreover, the research team shed light on how that structure changes with the cancer-associated mutations, paving the way for drugs that could target only the mutated versions.
“We hope that these detailed structural findings lead to the discovery of drugs that affect cancer cells but not healthy cells,” says senior author Peter Vogt, PhD, a professor in the Department of Molecular Medicine at Scripps Research. “That could potentially eliminate the side effects associated with current PI3Kα drugs.”
PI3Kα plays a central role in cell survival and growth. In healthy cells, the protein is flipped on and off as needed. But in numerous types of cancer — including breast, colorectal, endometrial and brain — mutations in PI3Kα make it active all the time, encouraging the unchecked growth of the tumors. Current drugs that aim to put the brakes on PI3Kα bind to a section of the protein that rarely changes between healthy and mutated versions; this means all the PI3Kα in the body is shut off. Because of that, these PI3Kα inhibitors carry a long list of side effects and toxicities.
“To solve this problem, you have to make inhibitors that only recognize the mutated versions of PI3Kα,” says Vogt. “But to do that, you need structural information about what differentiates mutated, overactive PI3Kα from normal PI3Kα.”
This is no easy feat: PI3Kα is a particularly flexible, “wiggly” protein, so it’s difficult to get a single snapshot of its structure. Vogt’s group, however, discovered that when PI3Kα was bound to one of the existing inhibitors, it became more stable. In PNAS papers published in November 2021 and September 2022, they used a type of imaging technique known as cryogenic electron microscopy (cryo-EM) to work out the three-dimensional structure of PI3Kα. With this knowledge, they first examined the structure of PI3Kα attached to the inhibitor. Then, to visualize the protein without the inhibitor, they used cross-linking molecules to attach different parts of PI3Kα to itself, stabilizing the most flexible parts of the protein.
More recently, the research team used the same cryo-EM toolbox to piece together the structure of two mutated versions of PI3Kα often found in cancer cells. That work, published last month in PNAS, showed how some segments of the mutated PI3Kα resemble the activated form of PI3Kα.
“There are quite dramatic structural changes,” says Vogt. “And in the end, the changes essentially mimic the normal activated form of the protein, with the only difference being that it’s always in this active structure.”
The findings point toward ways to use drugs to shut off this always-on version of PI3Kα in cancer cells, without turning off healthy PI3Kα. The key, Vogt says, is that the drugs will need to bind to a different part of the PI3Kα protein than where the existing PI3Kα inhibitors bind — a part that varies structurally between the healthy and mutated versions of the protein.
His lab group is following-up on this research with additional studies revealing how current drugs change the structure of PI3Kα.
In addition to Vogt, authors of the studies, “Cryo-EM structures of PI3Kα reveal conformational changes during inhibition and activation,” “Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα,” and “Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα,” include Su Yang, Jonathan R. Hart, Lynn Ueno and Alexandra Quezada of Scripps Research.
The work at Scripps Research was supported by funding from the National Cancer Institute (R35 CA197582 and R50 CA243899).

An inflammatory molecule called LIGHT, appears to be the cause of life-threatening airway damage in patients with severe asthma. According to the new research from scientists at La Jolla Institute for Immunology (LJI), therapeutics to stop LIGHT (which is related to tumor necrosis factor) could reverse airway and lung damage in patients — and potentially offer a long-term treatment for asthma.
“This is a very, very significant finding,” says LJI Professor Michael Croft, Ph.D., senior author of the new study and member of the LJI Center for Autoimmunity and Inflammation. “This research gives us a better understanding of the potential of therapeutic targeting of LIGHT and what we might do to relieve some of the symptoms and some of the inflammatory features seen in patients who have severe asthma.”
This research was published recently in the Journal of Allergy and Clinical Immunology. The study included experiments with both mouse and human tissues and was spearheaded by LJI Instructor Haruka Miki, M.D., Ph.D.
Croft’s team has studied LIGHT for more than a decade. The LIGHT protein is a type of inflammatory “cytokine” produced by the immune system’s T cells. T cells normally fight disease, but in asthma, T cells overreact to environmental triggers and flood the airways with LIGHT and other inflammatory cytokines. Researchers have developed therapies to block the activity of some of the other harmful cytokines made by T cells, but these therapies aren’t effective for many with severe asthma.
LIGHT can be found elevated in the sputum of asthmatic patients with severe disease, and Croft’s previous work showed that LIGHT is essential in a process called tissue “remodeling,” where the lungs and airways grow thicker following an asthma attack. These thicker airways can leave a person with long-term breathing problems.
“Current treatments for asthma are mainly to suppress symptoms and subdue allergic inflammation. No treatment has been developed to fundamentally cure asthma,” says Miki. “Even when inflammation is suppressed by current treatments, underlying airway hyperresponsiveness and airway tissue changes (airway remodeling) often remain, especially in severe asthma.”
Even though they knew LIGHT was involved in this remodeling, the researchers did not know whether LIGHT directly affects the smooth muscle tissue that lines the major airways of the lungs. These cells increase in number and size in moderate and severe asthmatics, which is thought to be a primary cause of loss of lung function.

During infections, the hematopoietic system switches from normal to emergency mode. This improves the defense against the pathogens. Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now found an epigenetic switch in blood stem cells and progenitor cells of mice that can trigger the switch from one mode to the other.
If the emergency program of hematopoiesis starts up in the body, this signals an alarm state of the immune system and serves two different purposes: Compared to hematopoiesis in “normal mode,” the emergency program results in increased replenishment of immune cells that are consumed during infections or inflammations. In addition, the emergency program puts the entire immune system into a pre-activation that helps clear infections more quickly.
Characteristic of the emergency program are, for example, an increased division rate of blood stem cells and a shift in the balance of mature white blood cells in favor of myeloid cells (macrophages and granulocytes). Normally, the emergency program is triggered by typical molecular components of pathogens or by pro-inflammatory messenger substances such as certain interferons.
But what happens in the blood stem cells and progenitor cells? Is there a cellular switch that triggers the emergency program? Scientists led by Nikolaus Dietlein and Hans-Reimer Rodewald of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) targeted a specific epigenetic modification, abbreviated H2Bub1. It is involved in switching on genes that are activated by interferon as a result of a viral infection and that are important for the defense against infection. The modification, which attaches to the packaging proteins of the DNA, the histones, is removed again by the enzyme USP22.
Could H2Bub1 and USP22 be the sought-after switch that triggers the emergency program in the blood stem cell? The researchers led by Rodewald investigated this in mice in whose blood stem cells USP22 was genetically switched off. In these animals, the emergency program of hematopoiesis with all its key features ran without any detectable infection or increased interferon levels.
The genetically modified animals were better able to fight off infection with the bacterium Listeria monocytogenes than normal mice. In addition, important scavenger cells in their blood, neutrophil granulocytes, were more successful at engulfing bacteria.
As expected, the genetic material in the blood cells of the gene-modified animals also had significantly more of the epigenetic H2Bub1 modifications. “The increased H2Bub1 level seems to be the alarm button that puts the immune system on standby. In particular, this puts the innate immune defense, which is especially important during initial contact with a pathogen, into heightened defense alert,” says Nikolaus Dietlein, first author of the current publication. USP22, which removes the H2Bub1 modification, terminates the alert in normal animals.
H2Bub1 and USP22 are also found in human cells and, according to current research, perform comparable functions there to those in mice. Hans-Reimer Rodewald says: “In mice, we were able to show that an epigenetic modification improves the defense against infection. However, how the loss of USP22 affects human hematopoietic stem and progenitor cells is still unknown and should now be investigated. Inhibition of USP22 by drugs could possibly one day help to improve the immune defense against pathogens. So far, however, this is currently still unproven and needs to be tested in further studies.”

Using new gene mapping methods, researchers have found connections between atopic dermatitis (eczema) in dogs and several regions of the genome. Some of the genes identified coincide with genes linked to similar problems in humans. The filaggrin gene region, for example, which is regarded as the most powerful risk factor for atopic eczema in humans, has now also been linked to this disease in Labrador retrievers.
The findings are reported in a new study produced by the dog genetics group at Uppsala University and the Swedish University of Agricultural Sciences, which has been conducting research in this field for more than ten years in cooperation with colleagues in Switzerland, the United Kingdom and the United States.
Genome sequencing became possible in the early-2000s. Since then, canine genome sequencing has proved invaluable for researchers seeking to understand the human genome.
Dogs have lived alongside humans for tens of thousands of years and suffer from similar diseases, including immunological diseases such as atopic dermatitis (allergic eczema). Studying dog disease genetics, using ordinary blood samples, can also be a way to obtain clues to the causes of the corresponding human diseases.
Dogs and humans affected by atopic eczema have much in common as regards medical symptoms and the early onset of the disease, as well as in histopathological terms with similar immune cell infiltration in the skin. The disease has a complex genetic background in both species and is also influenced by environmental factors.
“It’s vital that atopic eczema is correctly diagnosed by careful elimination of other potential non-allergic causes of the patient’s symptoms, followed by a positive allergy test,” says Kerstin Bergvall, veterinarian in charge and specialist in dermatology who has been involved in the research from the start.
With gene mapping technology steadily advancing, new methods have recently emerged for mapping complex diseases. In the study now published in the journal Communications Biology, the researchers used one methodology to capture multiple associated genetic risk variants and another to discover disease variants ‘hidden’ in the genome because of artificially (i.e. humanly) selected characteristics.
“The new methods make it possible to find new risk factors that have become common in the specific breed, perhaps because of the selection for other characteristics,” says Katarina Tengvall, researcher at Uppsala University and first author of the study. “The candidate genes identified here are important for both the nature of the skin barrier and the immune defence, as expected in atopic eczema.”
The study shows several overlaps, or correspondences, with genes associated with human atopic dermatitis. One particularly striking finding now made by the researchers in this study is that the genetic region containing the filaggrin gene, which is regarded as the most powerful genetic risk factor for atopic eczema in humans, is a risk factor in dogs as well.
“This highlights the value of canine studies of genetic diseases that also affect humans. A better understanding of the disease mechanisms may ultimately lead to better therapies for dog and human alike,” says Kerstin Lindblad-Toh, Professor of Comparative Genomics and senior author of the study.
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Materials provided by Uppsala University. Note: Content may be edited for style and length.

Despite advances in technology and availability, one of the best ways for parents and health care providers to prevent or help stop adolescent substance use is still an old-fashioned conversation, according to a new Viewpoint published in the November issue of The Lancet Child & Adolescent Health. The piece, written by a team of University of Rhode Island trainees under Prochaska Endowed Professor Sarah Feldstein Ewing, stresses that relying on detection through informal observation — as parents and providers have commonly done with alcohol and tobacco use — is quickly becoming a thing of the past. The paper provides health care professionals and parents concrete steps for screening, detection and intervention.
The past decade has seen a global surge in adolescent use of e-cigarettes/vaping, cannabis, and prescription opioids not-taken-as-prescribed. This surge has been aided, in some cases, by entirely new methods of substance use and delivery — such as cannabis edibles and vaping — as well as youths’ lower perceptions of harm, and/or greater accessibility. These substances have “invisible symptoms” to adults and, in turn, can be much harder-to-detect by parents, caregivers, and health care providers.
“What is so different today than in past generations is that parents and providers could really rely on what we traditionally think of as obvious signs to tell if kids were using. Did they come home smelling like cigarettes or cannabis? Is there alcohol on their breath? Are they slurring their speech?” said Feldstein Ewing. “While some of these things still work, where we run into trouble today is that, more and more, the substances that kids are using are just not as easy to spot. And, the signs are not as conspicuous as they once were.”
This is especially concerning when it comes to the still-developing adolescent brain. While the ways in which these substances affect the brain are under ongoing investigation, there is evidence to suggest that their use during adolescence may adversely affect long-term neural and behavioral development. Also, because their use can be hard to identify by adults, youth may be more likely to transition from experimentation to heavier, hazardous use in a manner that is often undetected by providers or caregivers until there is a substantial impact on school, work, or their personal or family relationships.
In addition to her position as a professor of psychology within URI’s College of Health Sciences, Feldstein Ewing is a child/adolescent clinician with over two decades experience working in adolescent substance use prevention and treatment.
“Families would come to me for treatment for youth engaged in heavy substance use and say, ‘I didn’t even know my kid was using.’ Parents are having a hard time and now that many states are making cannabis legal for recreational use, I think parents and providers are really feeling at a loss to navigate this,” she said.
The Viewpoint is primarily geared toward adolescent health care providers who are in a unique position to assist in detection as well as facilitating access to treatment services, due to their recurring appointments with young people. But, says Feldstein Ewing, parents and caregivers may also find the recommendations helpful. Opening the lines of communication with young people can provide adolescents a platform in which to discuss current life concerns, including substance use. One straightforward way that parents or caregivers can do this, she says, is by increasing the frequency of family dinners.
“It’s definitely hard today — families are busy with work, school, sports and other activities. But the point is, if that can be a place where you are seeing and connecting with your kids every day, it will be easier to notice small changes in behavior or other patterns. It doesn’t even have to be a dinner, it can also take the form of drives or walks — if you provide a forum to talk about ‘regular stuff’ it will be easier for them and for you to bring these things up.”
Provider use of well-validated substance use screening tools, specific for adolescents, is recommended as part of the framework — as is active listening and the use of open-ended questions. Providers may also be able to communicate things that parents can’t, such as the risks and potential longer-term effects associated with such substances. By the same token, adolescents may be more likely to open up to providers in the patient-provider context. Parents and providers may find that asking about peer use can provide helpful insights while being perceived as less intrusive to young people.
“The most important part of all this is that this is new territory — and that’s OK. The things we have done historically no longer translate well for these new forms of substances, so we need to readjust. Providers and parents often do not feel comfortable discussing topics like substance use because they are not sure what to do if teens say, ‘Yes , we are using’,” said Feldstein Ewing. “But when it comes down to it, even though we often think about teens as spending most of their time with their friends, parents still have the biggest influence on their teen’s behavior. So knowing where they are, who they are hanging out with, and being open to having these sometimes scary conversations on a consistent basis is important. And, providers have a critical role to play in supporting kids and families.”
Feldstein Ewing is Director of URI’s Adolescent Neuroscience Center for Health Resilience, which focuses on adolescent translational approaches, increasing understanding of the links between basic biological mechanisms — like the brain — and effective treatments for reducing adolescent health risk behaviors. Several of Feldstein Ewing’s trainees contributed to the piece, including lead author, Genevieve Dash, M.S., at the University of Missouri; as well as Karen Hudson, M.C.R., at URI; and her URI graduate students Emily Kenyon, Emily Carter, and Diana Ho.

Northwestern University researchers have discovered a previously unknown mechanism that drives aging.
In a new study, researchers used artificial intelligence to analyze data from a wide variety of tissues, collected from humans, mice, rats and killifish. They discovered that the length of genes can explain most molecular-level changes that occur during aging.
All cells must balance the activity of long and short genes. The researchers found that longer genes are linked to longer lifespans, and shorter genes are linked to shorter lifespans. They also found that aging genes change their activity according to length. More specifically, aging is accompanied by a shift in activity toward short genes. This causes the gene activity in cells to become unbalanced.
Surprisingly, this finding was near universal. The researchers uncovered this pattern across several animals, including humans, and across many tissues (blood, muscle, bone and organs, including liver, heart, intestines, brain and lungs) analyzed in the study.
The new finding potentially could lead to interventions designed to slow the pace of — or even reverse — aging.
The study will be published on Dec. 9 in the journal Nature Aging.

A fast, needle-free malaria detection tool developed by a University of Queensland-led team could help save hundreds of thousands of lives annually.
Malaria is usually detected by a blood test, but scientists have devised a method using a device that shines a beam of harmless infrared light on a person’s ear or finger for five-to-10 seconds, it collects an infrared signature that is processed by a computer algorithm.
International team leader, Dr Maggy Lord from UQ’s School of Biological Sciences, said the technology would revolutionise how malaria is fought globally.
“Currently it’s incredibly challenging to test large groups of people, such as the population of a village or town — you have to take blood from everyone and mix it with a reagent to get a result,” Dr Lord said.
“But with this tool we can find out very quickly whether a whole village or town is suffering from, or carrying, malaria.
“The technique is chemical-free, needle-free and detects malaria through the skin using infrared-light — it’s literally just a flash on a person’s skin and it’s done.

Published1 hour agoSharecloseShare pageCopy linkAbout sharingImage source, Dean BurnsBy Rachel RussellBBC NewsThe grandmother of a four-year-old girl who was fighting for her life in hospital with strep A says she is starting to get better.Camila Rose Burns was put on a ventilator at Liverpool’s Alder Hey Children’s Hospital after falling ill.Fifteen UK children have now died after invasive strep A infections since September.Most strep A infections are mild, but more severe invasive cases – while still rare – are rising.Experts say cases are higher than normal this year because of increased social mixing after Covid.Strep A cases expected to level off soon – doctorGPs say parents need clearer strep A adviceWhat is strep A and how dangerous is it?Dawn Burns said her granddaughter Camila was making progress after being initially taken to hospital in Bolton last weekend when her father Dean Burns found her hallucinating.She told Radio 4’s Today programme: “She gradually came off the different meds… when we first got there the consultant said she was the illest child in the UK and she was as close to death as you could be without actually dying – that’s what he said to us. “She was on absolutely tons of support meds, ventilator, dialysis et cetera. But slowly and surely, she managed to pull it round.”Prof Kamila Hawthorne, of the Royal College of GPs, added on the programme that children who have had chicken pox are more likely to get strep A or scarlet fever, which is one of many types of infections caused by strep a.She later advised: “If a child has temperature over 39C (102.2F) and their behaviour is changing we are more than happy to see them.”‘No antibiotic shortage’Prof Sir Andrew Pollard, chairman of the Joint Committee on Vaccination and Immunisation (JCVI), also told Radio 4 on Friday that he is not aware of any “national shortage” in antibiotics to treat strep A.He said: “I can’t tell you about supply chain issues but my understanding is that overall we do have plenty of antibiotics.”Of course, you could have a local situation where there’s a shortage, but I’m not aware of any national shortage, particularly given that this bug is treatable with one of our oldest antibiotics, penicillin, and it’s always sensitive to penicillin, so it should be perfectly treatable when it’s recognised.”Ms Burns also advised parents to look out for signs of the infection as she said Camila had originally complained of having pain in the top left hand corner of her chest, but a doctor said it was likely due to her pulling a muscle. Image source, Dean BurnsEarlier this week, Camila’s father Dean Burns told parents who had any concerns about their children’s health to “scoop them up” and to get checked. He added Camila’s family were “hoping and praying for a miracle so that she heals and comes back to us”.Hanna Roap, a primary school pupil from Penarth, Vale of Glamorgan, in Wales, is among the children who have died from strep A, with her family saying their hearts had been “broken into a million pieces”.Public Health Wales said on Friday that levels of strep A were now similar to 2016, despite having doubled in recent weeks.And leading paediatrician Dr Ray Nethercott added cases of strep A in Northern Ireland are expected to level off within weeks.The UK Health Security Agency has said there is no current evidence that a new strain is circulating and that the rise in cases is more likely because of high amounts of circulating bacteria and increased social mixing.What is Strep A?Image source, BSIP/Getty ImagesGroup A streptococcal (GAS) infection is caused by strains of the streptococcus pyogenes bacteriumThe bacteria can live on hands or the throat for long enough to allow easy spread between people through sneezing, kissing and skin contactMost infections cause mild illnesses such as “strep throat” or skin infectionsIt can also cause scarlet fever and in the majority of cases this clears up with antibioticsOn rare occasions the bacteria can get deeper into the body – including infecting the lungs and bloodstream. It is known as invasive GAS (iGAS) and needs urgent treatment as this can be serious and life-threatening You can read more about Strep A here.More on this storyStrep A: What is strep A and what are the symptoms?17 minutes agoGPs say parents need clearer strep A advice18 hours agoCall for awareness after eighth strep A child death3 days agoGirl’s family devastated by Strep A death6 days ago

Published1 hour agoSharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesBy Antoinette RadfordBBC NewsYoung people in France will have free access to condoms from January, in a bid to minimise the spread of sexually transmitted infections (STIs).The French president announced the new health measure on Thursday at an event for young people’s health.Emmanuel Macron said young people would be able to collect them from pharmacies, and described the move as a “small revolution in contraception”.In 2020 and 2021 France experienced a 30% national increase in STI rates.The new measure comes alongside other health initiatives targeting the spread of STIs and improving access to contraception. In 2018 the French government started reimbursing the costs of condoms to individuals, if purchased in a pharmacy with a prescription from a doctor or midwife.Earlier this year the government made contraception free for all women up to 26 years old – a move that affected three million women. Contraception had previously been free for women and girls 18 or younger.Mr Macron added in a tweet that Thursday’s announcement comes alongside other health measures. They include free emergency contraception for all women in pharmacies, and free STI screenings without a prescription, except HIV, to those under the age of 26.More on this storyWarning online STI tests aren’t meeting standards14 AprilLessons in pleasure boost good safe sex14 February

CASCADE, Idaho — It was 3 a.m. at the 10-bed hospital near the River of No Return, and by every measure, Ella Wenrich should have been dead.Gastrointestinal bleeding had sent her hemoglobin level — typically above 12 — down to 3.3, and she needed an enormous blood transfusion at a larger medical center. But amid a surge in Covid cases, every major facility within 400 miles refused to take her. The smallest hospital in Idaho was, once again, on its own.The doctor woke the sheriff and sent him barreling north in his pickup truck with a cardboard box lined with ice packs and a mission to bring back blood. Ms. Wenrich, 83, known as Ms. Ella, needed seven units. The rush paid off and she survived. She worries the hospital that saved her may not.For 46 million Americans, rural hospitals are a lifeline, yet an increasing number of them are closing. The federal government is trying to resuscitate them with a new program that offers a huge infusion of cash to ease their financial strain. But it comes with a bewildering condition: They must end all inpatient care.The program, which invites more than 1,700 small institutions to become federally designated “rural emergency hospitals,” would inject monthly payments amounting to more than $3 million a year into each of their budgets, a game-changing total for many that would not only keep them open but allow them to expand services and staff. In return, they must commit to discharging or transferring their patients to bigger hospitals within 24 hours.The government’s reasoning is simple: Many rural hospitals can no longer afford to offer inpatient care. A rural closure is often preceded by a decline in volume, according to a congressional report, and empty beds can drain the hospital’s ability to provide outpatient services that the community needs.But the new opportunity is presenting many institutions with an excruciating choice.“On one hand, you have a massive incentive, a ‘Wow!’ kind of deal that feels impossible to turn down,” said Harold Miller, the president of the nonprofit Center for Healthcare Quality and Payment Reform. “But it’s based on this longstanding myth that they’ve been forced to deliver inpatient services — not that their communities need those services to survive.”Nurses at Cascade Medical Center vacuum, clean toilets and scrub down the blood-splattered emergency room after each trauma patient. A father walks his daughter and wife into the emergency room at dusk following a sledding accident. Tight on space, Cascade Medical Center converted an ambulance bay into a CT imaging suite.Medical staff members organize supplies in a patient room used for storage.Some rural health care providers and health policy analysts say the officials behind the rule are out of touch with the difficulties of transferring rural patients. Bigger hospitals — bogged down with Covid surges, pediatric R.S.V. patients and their own financial woes — are increasingly unwilling to accept transferred patients, particularly from small field hospitals unaffiliated with their own systems.There are also blizzards, downed cattle fences and mountain pass roads that close for months at a time.“I really want to give this policy a chance to work well,” said Katy Kozhimannil, director of the University of Minnesota Rural Health Research Center. But gambling with transfers could mean that “some of the most extremely remote and marginalized communities could end up with no care at all — and that’s what we were trying to avoid in the first place.”Over 180 rural hospitals have closed in the United States since 2005, according to a recent analysis, with a record 19 closings in 2020 alone. Then, the trend seemed to pivot toward a brighter future: In 2021, the number plummeted to just two.“The total margins look great, but behind them, there’s a sad reality,” said Carrie Cochran-McClain, the chief policy officer of the National Rural Health Association. More than $15 billion in pandemic-era federal aid was injected into rural hospitals to keep them open. On Dec. 31, most of it will expire.Now, labor expenses per patient are up more than a third, and payment rates are lagging. Over 600 rural hospitals — 30 percent of the total — are at risk of shuttering. More than 200 could close within three years, according to a study by the Center for Healthcare Quality and Payment Reform. In 10 states, at least 40 percent of rural hospitals are in danger: In Kansas, 16 could close within three years; in Mississippi, 24.When rural hospitals close, it is medically and economically devastating for communities. They have supported one in every 12 rural jobs and contributed to about $220 billion in economic activity per year, according to the American Hospital Association. A community’s population typically shrinks soon thereafter.A Covid test was transported to an improvised laboratory in the parking lot of Cascade Medical Center. Tight on space, the staff has turned to shipping containers.Shelby Hallan, a registered nurse, worked with Alison Zeller, a physical therapist, to help patient Jack Sides stand up in his room at Cascade.Tom Reinhardt, the chief executive at Cascade, had previously led the much larger St. Alphonsus Neighborhood Hospital just outside Boise. After he broke his leg hiking and sought care in Cascade, he wanted to join the team.The new federal program is designed to mitigate that threat. Struggling hospitals that convert themselves to rural emergency hospitals will receive monthly payments of $272,866, with increases based on inflation each year. They will also receive higher Medicare reimbursements than larger hospitals.The new option takes effect on Jan. 1.A spokeswoman for the Centers for Medicare and Medicaid Services said that the “prohibition” on inpatient services was set by Congress in an appropriations act for 2021 and that the agency’s role was “to enforce such requirements.”During the mandatory comment period, members of the public suggested exceptions for labor and delivery patients; the agency responded: “Since this is a statutory requirement we do not have the ability to make exceptions.”The office of Senator Charles E. Grassley, Republican of Iowa, who is one of the lawmakers behind the program, said in a November statement, “The goal is to preserve patient access to emergency medical care in rural areas that can no longer support a fully operational inpatient hospital.”Cascade Medical Center, where Ms. Wenrich was treated, seems like exactly the type of hospital that federal officials had in mind.This former lumber mill community is home to less than a thousand people, but the hospital serves patients from across 2,800 square miles; patients travel up to eight hours round trip from homes without addresses. “About 12 miles past Yellow Pine,” one said; “middle fork of the Salmon River — can’t get there by road,” another described.Here, where deer graze on a helipad and nurses ventilate patients by hand, resourcefulness has long been the drumbeat of the operation. The 11,000-square-foot center houses an emergency room, lab and radiology unit, and primary care clinic, as well as sections for mental health counseling and physical therapy. Space is so tight, the staff keeps the CT scanner in the ambulance garage. Doctors treat patients in a shipping container in the driveway.Because of budget constraints at the hospital, which is open day and night, every day of the year, there are just two physicians, who trade shifts. A cardiologist and a podiatrist visit once a month; radiology technologists rotate in for a week at a time. The nurses vacuum the hallways, clean the toilets and scrub down the blood-splattered emergency room after each trauma patient. The staff eats family-style lunches off a single sheet pan.“We play eight-man football with a nine-person roster,” said Tom Reinhardt, the hospital’s chief executive, who smiles widely and often pauses midsentence to readdress his listener by name.Shane Cusic and Chad Kreider, both nurses, folded laundry during the night shift at Cascade.Like many small rural hospitals, Cascade Medical Center’s future seems uncertain. Significant federal funds are available if the hospital decides to shift away from inpatient care.In central Idaho, the rural town of Cascade has a median age that is 20 years higher than the state’s. Residents are often admitted for chronic conditions like congestive heart failure.Mr. Reinhardt had previously led the much larger St. Alphonsus Neighborhood Hospital just outside Boise. After he broke his leg hiking and sought care in Cascade, he told his wife to let him know when she was ready to retire from the city. He wanted to join the team.“It’s the neatest job I’ve ever had,” he said. “And we do have an IT department,” he joked. “His name is Craig.”Small rural facilities like Cascade don’t enjoy revenue from lucrative procedures like heart and joint surgeries, which medical systems often capitalize on to increase cash flow. The hospital is operating at a loss of around 20 percent for the third year in a row.If Cascade Medical Center were to become a rural emergency hospital, it would lose payments from both inpatients and swing beds — the total was more than $624,000 in 2021 — and services those patients would have used, such as lab tests and X-rays. But for a hospital with a total revenue of just $7.3 million in 2021, the new $3.2 million annual payments could still put it significantly ahead. That could allow it to offer colonoscopies, cataract surgeries and other services that many residents go without.“The math gets harder and harder,” Mr. Reinhardt said. “It would be irresponsible for me to not take this option to the board.”But in rural towns like Cascade, general inpatient services are at the core of the community’s needs. Residents are routinely admitted for chronic conditions like congestive heart failure; others need rehabilitation after accidents before they can return to isolated houses to live on their own.Ashley Thompson, 70, was admitted overnight with a pulmonary embolism before he could be transferred to a specialist in Boise. Ron Wise, 78, who came on a recent morning to get a flu shot from the nurse, Bradi (who is his granddaughter), has repeatedly received inpatient care for heart failure and came in once for internal bleeding after he fell off the roof of his barn.“If it weren’t for the good Lord and this hospital, I wouldn’t be here — clear as that,” he said.Dan Rosbrugh spent five days at Cascade Medical Center recovering from pancreatitis. If the hospital ended inpatient care and larger ones in Boise were full, residents like Mr. Rosbrugh and his wife, Lynn, would have to go out of state for care.This former lumber mill community is home to less than a thousand people, but the hospital serves patients from across 2,800 square miles. Here, dozens of deer often linger in the parking lot and on the helipad.Dr. Katie Camarata, the physician who cared for Ella Wenrich, in one of the few inpatient rooms at Cascade Medical Center.Michael Hanson for The New York TimesEven intensive-care patients who belong in special units are dependent on Cascade. One recent diabetic ketoacidosis patient was kept alive at Cascade because the Life Flight helicopter from Boise couldn’t navigate through thick fog. Another patient, who was having a heart attack, was denied a transfer to Saint Luke’s in Boise because Cascade is not part of the hospital’s system, but doctors treated her successfully at Cascade.During Covid surges, Dr. Katie Camarata, the physician who cared for Ms. Wenrich, stayed up overnight with critically ill patients, calling hospital systems in surrounding states. All seven refused the transfers. Eventually, the Cascade staff created their own negative-pressure rooms so it could keep highly infectious patients in-house without infecting others.Providing inpatient care “comes down to a moral decision,” said Dan Rosbrugh, 75, who was admitted to Cascade in October with pancreatitis pain he called “worse than my broken leg in Vietnam.” He stayed for five days. When he could eat again, his doctor, Dr. Ron Ellsworth, drove to the D9 Grocery to buy him pudding.Some hospitals have already made the decision to accept the government’s offer. St. Margaret’s Health in Illinois told community members that it would convert one of its two hospitals, which are less than four miles apart, into a rural emergency one but keep the other full service. Sturgis Hospital in Michigan was struggling to operate on a loan when it learned of the new designation and said it would convert.Others plan to forgo it. Chief executives at Ouachita County Medical Center in Camden, Ark.; Southern Inyo Hospital in Lone Pine, Calif.; and Comanche County Hospital in Coldwater, Kan., said that ending inpatient services would be untenable for their elderly populations.Tim Reeves, the chief executive of the 16-bed Bucktail Medical Center in Renovo, Pa., ruled out conversion because, in the case of another pandemic surge, there would be “nowhere to transfer my patients anymore.”In 2021, Bucktail’s financial margin for patient services was negative 43 percent.“Am I going to lose some revenue? Possibly,” he said. “But is it more important to provide the services needed? That’s the position we’re taking.”In Cascade, the decision doesn’t seem so simple. Perhaps a hospital without inpatient services is better than no hospital at all.After Ms. Wenrich’s husband died suddenly, she broke her ankle and then came down with pneumonia. Ms. Wenrich is legally blind, and there is no nursing home or assisted living in the county. It was the Cascade staff that came to her tiny trailer home to transport her — 42 miles, through the canyon fog, across Rainbow Bridge and into the CT scanner in the ambulance garage to check her lungs for fluid.She stayed there for almost a week.The hospital is open day and night, every day of the year, but there are just two physicians who trade shifts.