Publisher Health

Fresh insights into how our bodies interact with the microbes living in our guts suggest that a two-drug combination may offer a new way to treat inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.
The potential treatment pathway emerges from a study led by experts at Cincinnati Children’s published online March 28, 2023, in the Journal of Experimental Medicine. Co-first authors were Garrett Overcast, PhD, and Hannah Meibers, BS. Corresponding author was Chandrashekhar Pasare, DVM, PhD, Division of Immunobiology and co-director, Center for Inflammation and Tolerance.
The research team conducted numerous experiments to learn about how immune cells located in the lining of the intestine detect and respond to microbes and relay important signals to gut epithelial cells. When the signaling networks between immune cells and epithelial cells function correctly, the immune system can live in harmony with friendly bacteria residing in the gut.
Acting in unhealthy concert
When microbe-to-cell signals get scrambled — by genetic mutations or other causes such as damage to the intestinal epithelium — the immune system can either fail to react or can over-react, which can lead to inflammatory bowel disease (IBD).
This study reveals that microbes are detected by cells of the immune system located in the intestines. These immune cells deliver signals to induce a protein called IL-1. This increases levels of another protein called IL-22, which in turn, begins acting in concert with IL-1 to activate the IL-1 receptor (IL-1R) expressed on intestinal epithelial cells. Activation of IL-1R induces ROS gene activity in addition to other genes that recruit inflammatory cells to the tissue. This chain reaction drives an excessive inflammatory response that can damage the intestine, the researchers say.
“The pathogenic role that IL-22 appears to play in inflammatory responses — due to its synergy with IL-1R signaling — had not been made clear previously,” Pasare says. “We believe this may help explain why past treatments for IBD that focused only on inhibiting IL-1? activity had mixed results. We believe that a combined blockade of both IL-22 and IL-1R could serve as a more promising treatment for IBD.”
What’s next?
Some monoclonal antibodies that can inhibit IL-22 or IL-1R have been evaluated in clinical trials for various auto-immune conditions. The research team is interested in exploring whether existing products can be safely used in combination therapy or whether developing new treatments that target the two pathways would be more effective.
Cincinnati Children’s co-authors for this publication also included Emily Eshleman, PhD, Irene Saha, PhD, Lisa Waggoner, MS, Krupaben Patel, BS, David Haslam, MD, Theresa Alenghat, VMD, PhD, and Kelli VanDussen, PhD; and Viral Jain, MD, University of Alabama at Birmingham.

Cancer is not incurable anymore. Nevertheless, according to statistics released by Statistics Korea last year, cancer remained the primary cause of mortality in Korea in 2021. This highlights the ongoing struggle against cancer, which demands effective prevention measures as well as timely diagnosis and prompt intervention through effective treatment. However, the question remains whether it is feasible to provide treatment promptly upon diagnosis.
A POSTECH research team led by Professor Young Tae Chang (Department of Chemistry) and Research Professor Nam-Young Kang (Department of Convergence IT Engineering) collaborated with researchers at A*STAR in Singapore to determine the ability of fluorescent probe for tumor-initiating cell yellow (TiY) to stain the cells responsible for tumor growth and simultaneously suppress the growth of those cells. The empirical data of the research was published in the journal Theranostics, which covers treatment, diagnosis, and personalized medicine.
In their previous study, the research team developed fluorescent probe TiY with the ability to selectively identify and detect tumor-initiating cells (TICs), much like a fluorescent highlighter. Building upon this accomplishment, the team has conducted research aimed at exploring the potential of TiY for cancer treatment.
In the present study, the team observed changes in cancer stem cells in response to different concentrations of TiY. The team obtained cancer stem cells from patients with lung cancer and transplanted them into mice for experimental purposes. In order to evaluate the therapeutic effects of TiY staining, the team gradually increased the dose of TiY administered to the mice via intravenous injection in their tests.
When exposed to a low concentration, TiY has been demonstrated to have the ability to stain cancer stem cells. However, as the concentration of TiY increases, it exhibits the remarkable ability to effectively inhibit the growth of cancer stem cells, leading to their substantial destruction. This selective targeting and treatment are made possible by the mechanism of TiY molecules, which have the capacity to selectively bind themselves to vimentin, a muscle-specific protein that is a component of the cytoskeleton of cancer stem cells, thus allowing TiY to specifically target and inhibit these cells of growth.
Current cancer treatments often fail to achieve complete tumor removal, as cancer cells can be metastasized to other organs or recur. Given the challenge, TiY presents a promising approach to cancer treatment as it can facilitate both diagnosis and treatment in a single step
This study was conducted with the support from the Ministry of Science and ICT, the Ministry of Education, the Mid-career Researcher Program of the National Research Foundation of Korea, the Institute of Basic Science, and the NMRC in Singapore.

Scientists have demonstrated for the first time that, globally, the association between antibiotic consumption and antimicrobial resistance (AMR) between human and animals goes both ways.
The findings, published in The Lancet Planetary Health, reveal that using antibiotics in animals is associated with AMR in humans and using antibiotics in humans is associated with AMR in animals.
The study highlights the urgent need for an integrated, cross-domain strategy to tackle the spread of AMR, focusing on social development, poverty reduction and enforcing tighter rules on the use of antibiotics.
Kasim Allel, lead author and Associate Research Fellow in Infectious Disease Epidemiology at the London School of Hygiene & Tropical Medicine (LSHTM) said: “AMR is a ‘wicked problem’ as conflicting priorities exist amongst an intricate web of stakeholders.
“A robust, cross-disciplinary and-species approach for AMR surveillance and control, which is not limited to a human-centred perspective, should be embraced among decision-makers and local governments for better planetary health.”
AMR is a major threat to global health, with resistant bacteria responsible for 1.27 million deaths in 2019.

Incorrect use of antibiotics (which include antibiotics, antivirals and antifungals) is a key driver of the spread of AMR. Rising demands for animal-based food and products, as well as intricate and interlinked socioeconomic and environmental factors, are also highly influential.
In this study, an international team of researchers, including from LSHTM, investigated links between the global consumption of antibiotics and rates of AMR in humans and food-producing animals around 2018. The authors also considered the influence of socioeconomic, health and environmental risk factors.
As predicted, overall, greater consumption of antibiotics in animals is associated with an increased rate of AMR in food-producing animals, with higher rates of human consumption of antibiotics increasing the risk of AMR in humans.
However, the paper also uniquely revealed a global bi-directional relationship between humans and animals. Namely, greater consumption of antibiotics by animals is associated with an increased risk of AMR in human pathogens (defined as critical priority by the World Health Organization), while greater human consumption of antibiotics increases the risk of AMR in animals.
Despite recording low levels of antibiotic consumption, low- and middle-income countries, notably in Asia (such as Bangladesh, China and India), had the highest rates of AMR in food-producing animals, suggesting that antibiotic consumption may be a secondary risk factor to the spread of AMR in certain areas of the world.

Socioeconomic factors, such as income inequality or death rates due to unsafe hygiene practices or heart problems, also increased rates of AMR in humans.
Consistent with previous research, these findings highlight that factors that typically reflect lower socioeconomic status are associated with an increased likelihood of AMR in humans. The authors argue that this further emphasises the importance of strong governance and anti-corruption within a ‘One-Health’ context, which emphasises the interdependency between animals, humans and the environment.
The team conclude that reducing antibiotic consumption alone will not be enough to fight the global spread of AMR. Instead, they state that integrated control methods focused on reducing poverty and supporting social development will be needed to prevent the transmission of resistance between humans and animals.
They also emphasise the importance of strengthening surveillance efforts, especially in low-and middle-income countries, and ensuring that livestock surveillance for AMR in particular, mirrors surveillance in humans.
Laith Yakob, senior author and Taught Programme co-Director of the Faculty of Infectious and Tropical Diseases at LSHTM said: “This bidirectionality in antibiotic consumption and resistance among humans and livestock uncovered by our analysis offers novel opportunities for mitigating resistance. For example, it highlights the potential for targeting single One-Health components with interventions but having system-wide impacts.
“Designing interventions around this holistic picture of resistance will be essential in tackling what has rapidly become one of the biggest threats to global health.
“Going forward, we recommend tighter country policies and regulations on antibiotic use and prescription among animals and humans, as well as improved governance, transparency and accountability, particularly among countries with the highest disease burdens.”

Women are more likely than men to develop Alzheimer’s disease (AD), with women making up two-thirds of the population living with AD. A new study, led by Mass General Brigham researchers, sheds light on the relationship between the risk of Alzheimer’s disease and age of menopause and use of hormone therapy (HT). The results, published in JAMA Neurology, indicate that early age at menopause may be a risk factor for AD dementia, but that women who were prescribed HT around the age of menopause onset did not show increased risk.
“HT is the most reliable way to ameliorate severe menopause symptoms, but over the last few decades, there has been a lack of clarity on how HT affects the brain,” said corresponding author Rachel Buckley, PhD, of the Department of Neurology at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system. “We found that the highest levels of tau, a protein involved in Alzheimer’s disease, were only observed in hormone therapy users who reported a long delay between age at menopause onset and their initiation of hormone therapy. The idea that tau deposition may underlie the association between late hormone therapy intervention and Alzheimer’s disease dementia was a huge finding, something that hadn’t been seen before.”
Premature menopause, defined as menopause that occurs spontaneously before the age of 40 or due to surgical intervention before the age of 45, has been associated with increased risk of AD dementia. HT improves many severe symptoms related to menopause and has been hypothesized to also prevent cognitive impairment. However, two decades ago, the seminal Women’s Health Initiative (WHI) study found that HT use was associated with a nearly two-fold higher incidence of dementia compared to a placebo among women aged 65 years and older, possibly due to the initiation of HT many years after menopause onset. To better understand these findings, Buckley and colleagues used positron emission tomography (PET) neuroimaging to study how the presence of two proteins involved in AD dementia, ?-amyloid and tau, related to age at menopause and HT use. While previous studies examined symptoms of cognitive decline in menopausal women, few investigations analyzed the biological factors underlying these changes, which may be at play in determining risk of Alzheimer’s disease.
“When it comes to hormone therapy, timing is everything,” said co-author JoAnn Manson, MD, MPH, DrPH, one of the lead investigators of the WHI and chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. “Our previous findings from the WHI suggested that starting HT early in menopause, rather than late initiation, provides better outcomes for heart disease, cognitive function, and all-cause mortality — and this study suggests that the same is true for tau deposition.”
The researchers used data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), one of the few longitudinal studies on AD dementia that includes detailed information on menopause and HT use as well as PET neuroimaging. They analyzed PET scans from 292 cognitively unimpaired adults to determine levels of amyloid and tau in seven regions of the brain. Tau, which is known to be present in greater quantities in women compared to men in these brain regions, was the primary focus of the investigation, as its presence may offer insight into the sex-specific aspects of AD dementia and the risks that post-menopausal women may experience, even before they begin to display symptoms of cognitive decline.
As expected, women had greater levels of tau compared to men of the same age, especially in cases where they also had elevated ?-amyloid. But the researchers also found that the association between abnormal levels of ?-amyloid and tau was much stronger in women who had earlier menopause onset, even after adjusting for known causes of premature menopause, such as smoking and oophorectomy, and even genetic risk factors for AD dementia. Notably, tau levels were high in the entorhinal and inferior temporal regions, which are located close to the memory-center of the brain and are known to be involved in the progression of AD dementia. Given that many women who undergo premature menopause use HT, the researchers examined whether HT use was associated with ?-amyloid and tau. While they did confirm this association, they observed that late initiation of HT — five years or more after menopause — drove this relationship. Many women in the late-HT-initiation group began HT close to a decade after menopause.
Going forward, the researchers are continuing to study sex-specific risk factors for AD dementia by analyzing biological signatures, including sex hormones, in blood plasma and on the X-chromosome. They are also continuing to engage in efforts to understand the unique role that tau plays in women compared to men, its impact on the brain, and why earlier menopause and late HT initiation may be associated with increased tau, even in cognitively unimpaired women.
“Up to 10 percent of women experience premature or early menopause, and our findings suggest that earlier age at menopause may be a risk factor for AD dementia,” said first author Gillian Coughlan, PhD, of the MGH Department of Neurology. “Hormone therapy can have negative effects on cognition, but only if initiated several years after age at menopause. These observational findings support clinical guidelines that state hormone therapy should be administered close to menopause onset, but not several years after.”

A North Carolina State University-led study found it is possible to retrieve forensically relevant information from human DNA in household dust. After sampling indoor dust from 13 households, the researchers were able to detect DNA from household residents over 90% of the time, and DNA from non-occupants 50% of the time. The work could be a way to help investigators find leads in difficult cases.
Specifically, the researchers were able to obtain single nucleotide polymorphisms, or SNPs, from the dust samples. SNPs are sites within the genome that vary between individuals — corresponding to characteristics like eye color- that can give investigators a “snapshot” of the person.
“SNPs are just single sites in the genome that can provide forensically useful information on identity, ancestry and physical characteristics — it’s the same information used by places like Ancestry.com — that can be done with tests that are widely available,” says Kelly Meiklejohn, assistant professor of forensic science and coordinator of the forensic sciences cluster at NC State. Meiklejohn is corresponding author of the study.
“Because they’re single sites, they’re easier to recover for highly degraded samples where we may only be able to amplify short regions of the DNA,” Meiklejohn says. “Traditional DNA analysis in forensics amplifies regions ranging from 100 to 500 base pairs, so for a highly degraded sample the large regions often drop out. SNPs as a whole don’t provide the same level of discrimination as traditional forensic DNA testing, but they could be a starting place in cases without leads.”
Meiklejohn and her team recruited 13 diverse households and took cheek swabs from each occupant along with dust samples from five areas within each home: the top of the refrigerator; inside the bedroom closet; the top frame of the front door; a bookshelf or photo frame in the living room; and a windowsill in the living room.
Utilizing massively parallel sequencing, or MPS, the team was able to quickly sequence multiple samples and target the SNPs of interest. They found that 93% of known household occupants were detected in at least one dust sample from each household. They also saw DNA from non-occupants in over half of the samples collected from each site.
“This data wouldn’t be used like traditional forensic DNA evidence — to link a single individual to a crime — but it could be useful for establishing clues about the ancestry and physical characteristics of individuals at a scene and possibly give investigators leads in cases where there may not be much to go on,” Meiklejohn says. “But while we know it is possible to detect occupants versus non-occupants, we don’t know how long an individual has to stay in a household before they leave DNA traces in household dust.”
The researchers plan to address the question of how much time it takes for non-occupants to be detected in dust in future studies. Meiklejohn sees the work as being useful in numerous potential investigative scenarios.
“When perpetrators clean crime scenes, dust isn’t something they usually think of,” Meiklejohn says. “This study is our first step into this realm. We could see this being applied to scenarios such as trying to confirm individuals who might have been in a space but left no trace blood, saliva or hair. Also for cases with no leads, no hit on the national DNA database, could household dust provide leads?”
The work appears in the Journal of Forensic Sciences and was supported by funding from the NC State College of Veterinary Medicine. NC State Senior Vice Provost for University Interdisciplinary Programs Rob Dunn, NC State research associates Melissa Scheible and Laura Boggs, and Darrell Ricke of the Massachusetts Institute of Technology’s Lincoln Labs also contributed to the work.

The spread of the Ebola-like virus has claimed lives but could be a crucial chance to test a vaccine — if supplies and researchers are mobilized in time.Two concurrent outbreaks of the Marburg virus, a close cousin of Ebola that can kill as many as 90 percent of the people it infects, are raising critical questions about the behavior of this mysterious bat-borne pathogen and global efforts to prepare for potential pandemics.Marburg, a hemorrhagic fever, is rare: Just a handful of outbreaks have been reported since the virus was identified in 1967. But a steady uptick in occurrences in Africa in recent years is raising alarm.Marburg causes high fever, vomiting, diarrhea and, in the most severe cases, bleeding from orifices. It spreads between people via direct contact with the blood or other bodily fluids of infected people and with surfaces and materials such as clothing contaminated with these fluids. One of the two outbreaks, in Tanzania in East Africa, seems to have been brought under control, with just two people left in quarantine. But in the other, in Equatorial Guinea on the west coast, spread of the virus is ongoing, and the World Health Organization said last week that the country was not being transparent in reporting cases.There are no treatments or vaccines for Marburg, but there are some candidates that have shown promise in Phase 1 clinical trials. However these candidates must be tested in active outbreaks to prove they work, and so far, no vaccine supplies have been delivered to test in the current outbreaks.“The moment an outbreak is detected there should be a mechanism of moving in quickly,” said Dr. John Amuasi, the head of the global health department at Kwame Nkrumah University of Science and Technology in Ghana who investigated a Marburg outbreak in that country last year.The W.H.O. and others are good at rapid response to control the spread of a virus, he said, but lack a similarly swift response for research. It requires ready-to-ship stockpiles of the vaccine candidates and researchers equipped to operate without putting additional strain on an already struggling health system; neither currently exists. The W.H.O. says it has drafted a research protocol that can be applied in these outbreaks and to any other filovirus — the family that includes Marburg and Ebola — and it has been scrambling for more than a month to get trials underway, working against a ticking clock.If outbreak response works well — isolating cases and tracing contacts — the epidemic will quickly be controlled, which seems to be the case in Tanzania. If the response doesn’t go as well (as in Equatorial Guinea), there are fears of a widespread outbreak and a redoubled need for vaccination.When an Ebola outbreak began in Uganda in September 2022, the strain that rapidly claimed lives was one for which there was no vaccine, but, similarly, there was a strong candidate waiting a chance to be tested. Researchers announced plans to try it in Uganda. But the outbreak was over by the time the vaccine doses arrived.The outbreaks in Equatorial Guinea and Tanzania are the first ever reported in either country. The outbreak in Equatorial Guinea began in January. The government has reported the deaths of nine people with confirmed Marburg virus disease and the deaths of another 20 people linked to the confirmed cases who were not tested but are considered probable cases.The government of Equatorial Guinea has released limited information about the outbreak, and the W.H.O. has said there are likely undetected chains of transmission and that not all the known cases have a clear connection to each other, suggesting a wider spread than previously thought.“W.H.O. is aware of additional cases, and we have asked the government to report these cases officially to W.H.O.,” Dr. Tedros Adhanom Ghebreyesus, the agency’s director, said last week.The outbreak in Tanzania was first reported in March. Five people with confirmed Marburg infections have died there, including a health care worker.No new cases have been reported in Tanzania for two weeks but the Marburg incubation period is 21 days, so the outbreak is considered active.“This is the hard part, with people in isolation, waiting through the days,” said Kheri Issa, the Tanzania Red Cross manager for Marburg viral disease response, in a telephone interview from the Kagera area where the disease broke out.The W.H.O. said both outbreaks pose regional risks: Equatorial Guinea has porous borders with Cameroon and Gabon, and so far the cases have appeared in geographically diffuse parts of the country. In Tanzania, the Kagera region has busy borders with Uganda, Rwanda and Burundi.These outbreaks follow one in Ghana last year and in Guinea the year before — a marked shift from the sporadic occurrences in previous years. Dr. Amuasi said better tracking was likely contributing to what appeared to be a rise in cases. As part of the response to the Covid-19 pandemic, he said, every African country improved its PCR testing capacity and infectious disease surveillance, which means Marburg is being diagnosed more frequently.But that suggests there may have historically been more of the virus circulating among humans than has been thought, Dr. Amuasi said, and the way it sickens people may be different than has been understood.Dr. Nancy Sullivan, the director of the National Emerging Infectious Diseases Laboratories at Boston University, said she believes climate change, and the way it is shifting human and animal behavior, is driving an actual increase in cases. “We’re impinging much more on reservoirs” of the virus, she said.Dr. Sullivan designed the Marburg vaccine candidate farthest along in development when she worked with the National Institute of Allergy and Infectious Diseases. It showed safety and immune response in a Phase 1 clinical trial, and the Sabin Vaccine Institute, a nonprofit organization based in Washington that promotes global vaccine development, is continuing the testing process.The Sabin Institute said it has 600 doses of the vaccines in vials and ready to use and plans for an eventual stockpile of 8,000 by the end of this year. Dr. Sullivan said 600 doses would be enough to start a ring vaccination trial of those at risk in Tanzania and Equatorial Guinea.But the W.H.O. has yet to announce operational details for a trial of this or three other vaccine candidates. Transporting the doses into the country is just one challenge; a trial would require a principal investigator from the outbreak country, legal agreements with the vaccine makers and regulatory approval. Equatorial Guinea has a notoriously opaque government that has been under the control of President Teodoro Obiang Nguema Mbasogo and his family for more than 30 years.Without committed resources and preapproved trial protocols, filovirus outbreaks will keep happening with little progress on interventions that could stop them, Dr. Amuasi said.

A requirement that states keep people on Medicaid during the coronavirus pandemic has come to an end, and 15 million people could lose their coverage as a result.KANSAS CITY, Mo. — In a closet-sized windowless office, Kialah Marshall maintains an Excel spreadsheet with a prosaic title, “Medicaid Unwinding,” the source material for a mind-numbing routine.Five days a week, she and a group of co-workers in a poor section of Kansas City, Missouri’s largest city, call 75 to 100 Medicaid recipients from a list of about 19,000 who receive care at Swope Health, a federally funded network of health clinics. Their assignment is straightforward: warning those patients that they could lose their health insurance for the first time in at least three years.“Medicaid is on the line,” Ms. Marshall, once a recipient herself, said in that cramped office last week, describing how she delivers the potentially dire news.As of Saturday, state officials around the country could begin removing people from Medicaid who no longer qualify — something they had been prohibited from doing under a provision in a coronavirus relief package passed by Congress in 2020.That package offered states additional federal funding in exchange for guaranteeing that recipients of Medicaid, a joint federal-state program that serves low-income people, would retain their health coverage during the pandemic. In part because of that policy, the nation’s uninsured rate reached a record low early last year.Medicaid and the Children’s Health Insurance Program have ballooned to cover roughly 90 million people, or more than one in four Americans — up from about 70 million people at the start of the pandemic. The guaranteed coverage amounted to an extraordinary reprieve for patients, preserving insurance for millions of vulnerable Americans and sparing them the hassles of regular eligibility checks.The federal government has estimated that about 15 million people will lose coverage in the coming months, including nearly seven million people who are expected to be dropped from the rolls even though they are still eligible. Nearly half of those who lose coverage will be Black or Hispanic, according to federal projections.The changes in eligibility could lead to more people signing up for private coverage through the Affordable Care Act’s marketplaces, where some people who lose Medicaid coverage will be eligible for free plans.But hundreds of thousands of people could end up in the so-called coverage gap in states that have not expanded Medicaid under the Affordable Care Act, with incomes too low for subsidized coverage through those marketplaces but too high to qualify for Medicaid.In Missouri, state officials have warned that as many as 200,000 people may lose coverage.Arin Yoon for The New York TimesThe speed and mechanics of what Ms. Marshall and state and federal health officials are calling the “unwinding” will vary by state. A majority of them plan to take 12 to 14 months to complete the eligibility verifications, with many states beginning to remove people from Medicaid rolls by late spring or early summer. Only five states — Arizona, Arkansas, Idaho, New Hampshire and South Dakota — were expected to begin axing people from Medicaid this month, according to the federal government.Some state officials have argued that the program is merely retreating to its intended size and shape. “We’ll be able to go back in there and say, ‘OK, do you belong? Do you not belong?’” Gov. Michael L. Parson of Missouri, a Republican, said in February.Annual eligibility checks can save states money by relieving their Medicaid programs of spending on participants who no longer qualify for coverage. But they often result in a cycle that health policy experts call churn, or when people eligible for Medicaid lose their insurance in the confusing, intimidating bureaucracy of enrollment verification, then eventually re-enroll.“Those people don’t have anywhere else to go,” said Jennifer Tolbert, an associate director of the Program on Medicaid and the Uninsured at the Kaiser Family Foundation. She added that the consequences would be severe for people with chronic health conditions for whom a week or a month without insurance could be especially risky.Researchers have found that most people who lose Medicaid coverage often go without insurance for some period of time, while about four in 10 regain Medicaid coverage within a year.In Missouri, where state officials have warned that as many as 200,000 people may lose coverage, the unwinding could result in a boom-and-bust cycle.The state expanded Medicaid under the Affordable Care Act during the pandemic, resulting in more than 300,000 new adults with coverage. It now has about 1.5 million Medicaid recipients, half of whom are children.That growth makes the state a proverbial canary in the coal mine for the rest of the country during the unwinding, said Timothy McBride, a health policy expert at Washington University in St. Louis and the former chair of an oversight committee for the state’s Medicaid program. He pointed to a controversial period in 2018 and 2019, when officials used a new process for verifying Medicaid eligibility to remove over 100,000 people from the rolls, many of them children. That led to complaints of unjust removals.“Have we learned lessons from that period?” Dr. McBride asked.Medicaid eligibility rules vary by state. They can depend on a family’s income, whether someone is raising a child and whether a person has a disability. Millions of children and pregnant women benefit from the program.For states, tracking down those who are on Medicaid will be daunting, experts say. Some people will have moved, and some will have died. Phone numbers will have changed, making some people hard to reach. Others will be earning more, making them ineligible for coverage.Researchers at the Kaiser Family Foundation and the Georgetown University Center for Children and Families found different strategies among states, some of them with spottier technology that could hinder efficient re-enrollment. Most states, the researchers found, were using databases from other government programs, such as food stamps or Social Security, to verify eligibility for Medicaid automatically and save people the hassle of filling out paper forms. Missouri has adopted that strategy.Tamika Reliford helps patients with insurance enrollment at Swope Health. Almost half of Swope’s patients are covered by Medicaid or the Children’s Health Insurance Program.Arin Yoon for The New York TimesThe so-called continuous enrollment policy requiring that Medicaid recipients retain their coverage was initially set to end with the expiration of the public health emergency for the pandemic, which the Biden administration is planning to allow to lapse in May. But before the administration announced its plans to end the emergency, a spending package that Congress passed in December separated the Medicaid policy from the emergency declaration and established an April 1 starting point for the unwinding.When lawmakers set that date, they attached guardrails to encourage states to undertake the work gradually. The legislation mandates that states report data monthly to the Department of Health and Human Services on how many people have been taken off Medicaid. It also allows the department to intervene if a state does not comply with federal requirements.Missouri is starting with people whose coverage would be up for renewal in June, a group of about 100,000. The state is leaning on managed care organizations to work with Medicaid recipients on renewals, but the effort required of the state is still immense. Kim Evans, the official overseeing the Medicaid unwinding in Missouri’s Department of Social Services, said she had about 1,200 government workers available to help.Those whose status the state is still uncertain about after automatic checks will be mailed letters early next month, and they will have until the end of June to complete renewal forms. If they miss that deadline, they will lose their insurance, but they can still challenge the decision and be re-enrolled if state officials determine them to be eligible.Ms. Evans called the work an “all-out assault” to reach people who might otherwise slip through the cracks.Sidney D. Watson, a health law professor at Saint Louis University, said the unwinding could be particularly damaging to the many seasonal agricultural workers in rural stretches of the state, like in the Ozarks. “Everyone is on high alert here,” she said, adding that Medicaid coverage among those seasonal workers was important to keeping smaller hospitals and clinics running.Clinics like Swope Health are especially critical to warning Medicaid recipients about the unwinding policy, since their doctors and other health providers often know people affected by the policy change. Swope has run radio ads and placed billboards in and around Kansas City, which have increased calls from Medicaid recipients inquiring about how to preserve their insurance, said Tamika Reliford, one of Ms. Marshall’s co-workers who helps patients with their coverage.Derrick Smith was one of the hundreds of thousands of adults who secured Medicaid coverage when Missouri expanded the program under the Affordable Care Act.Arin Yoon for The New York TimesAlmost half of Swope’s roughly 40,000 patients are covered by Medicaid or the Children’s Health Insurance Program, meaning the clinics rely on Medicaid funds. “We still have to employ the providers, the nurses and administrators here to do the hard work,” said Jeron Ravin, Swope’s chief executive.For some Swope patients unaware of the unwinding, it takes a lucky encounter. Unable to get Medicaid to cover his eye-drop prescription for glaucoma in recent weeks, Derrick Smith learned something more important when he asked Swope for help: He could eventually lose his coverage altogether.Checking Mr. Smith’s Medicaid status, Ms. Reliford noticed he had moved, making him vulnerable to missing a mailing about the unwinding if one was sent to his previous address. Mr. Smith had not heard about the eligibility check.“I was real close on it,” he said sheepishly while visiting a Swope clinic last week, adding that losing his insurance would have been an “easy mistake” for him to make.Mr. Smith was one of the hundreds of thousands of adults who secured Medicaid coverage when Missouri expanded the program under the Affordable Care Act during the pandemic. But like others who gained coverage that way, he will be getting his first glimpse of annual scrutiny of his eligibility.Ms. Marshall, the Swope employee working through the Medicaid spreadsheet, said she worried about sending patients into a state of “frantic panic” when she reaches them to warn about the possibility of losing coverage. “This is something that a person needs,” she said, “for their family, for their children.”

Missing crucial doses of medicines and vaccines could become a thing of the past thanks to Rice University bioengineers’ next-level technology for making time-released drugs.
“This is a huge problem in the treatment of chronic disease,” said Kevin McHugh, corresponding author of a study about the technology published online in Advanced Materials. “It’s estimated that 50% of people don’t take their medications correctly. With this, you’d give them one shot, and they’d be all set for the next couple of months.”
When patients fail to take prescription medicine or take it incorrectly, the costs can be staggering. The annual toll in the United States alone has been estimated at more than 100,000 deaths, up to 25% of hospitalizations and more than $100 billion in healthcare costs.
Encapsulating medicine in microparticles that dissolve and release drugs over time isn’t a new idea. But McHugh and graduate student Tyler Graf used 21st-century methods to develop next-level encapsulation technology that is far more versatile than its forerunners.
Dubbed PULSED (short for Particles Uniformly Liquified and Sealed to Encapsulate Drugs), the technology employs high-resolution 3D printing and soft lithography to produce arrays of more than 300 nontoxic, biodegradable cylinders that are small enough to be injected with standard hypodermic needles.
The cylinders are made of a polymer called PLGA that’s widely used in clinical medical treatment. McHugh and Graf demonstrated four methods of loading the microcylinders with drugs, and showed they could tweak the PLGA recipe to vary how quickly the particles dissolved and released the drugs — from as little as 10 days to almost five weeks. They also developed a fast and easy method for sealing the cylinders, a critical step to demonstrate the technology is both scalable and capable of addressing a major hurdle in time-release drug delivery.

“The thing we’re trying to overcome is ‘first-order release,'” McHugh said, referring to the uneven dosing that’s characteristic with current methods of drug encapsulation. “The common pattern is for a lot of the drug to be released early, on day one. And then on day 10, you might get 10 times less than you got on day one.
“If there’s a huge therapeutic window, then releasing 10 times less on day 10 might still be OK, but that’s rarely the case,” McHugh said. “Most of the time it’s really problematic, either because the day-one dose brings you close to toxicity or because getting 10 times less — or even four or five times less — at later time points isn’t enough to be effective.”
In many cases, it would be ideal for patients to have the same amount of a drug in their systems throughout treatment. McHugh said PULSED can be tailored for that kind of release profile, and it also could be used in other ways.
“Our motivation for this particular project actually came from the vaccine space,” he said. “In vaccination, you often need multiple doses spread out over the course of months. That’s really difficult to do in low- and middle-income countries because of health care accessibility issues. The idea was, ‘What if we made particles that exhibit pulsatile release?’ And we hypothesized that this core-shell structure — where you’d have the vaccine in a pocket inside a biodegradable polymer shell — could both produce that kind of all-or-nothing release event and provide a reliable way to set the delayed timing of the release.”
Though PULSED hasn’t yet been tested for months-long release delays, McHugh said previous studies from other labs have shown PLGA capsules can be formulated to release drugs as much as six months after injection.

In their study, Graf and McHugh showed they could make and load particles with diameters ranging from 400 microns to 100 microns. McHugh said this size enables particles to stay where they are injected until they dissolve, which could be useful for delivering large or continuous doses of one or more drugs at a specific location, like a cancerous tumor.
“For toxic cancer chemotherapies, you’d love to have the poison concentrated in the tumor and not in the rest of the body,” he said. “People have done that experimentally, injecting soluble drugs into tumors. But then the question is how long is it going to take for that to diffuse out.
“Our microparticles will stay where you put them,” McHugh said. “The idea is to make chemotherapy more effective and reduce its side effects by delivering a prolonged, concentrated dose of the drugs exactly where they’re needed.”
The crucial discovery of the contactless sealing method happened partly by chance. McHugh said previous studies had explored the use of PLGA microparticles for time-released drug encapsulation, but sealing large numbers of particles had proven so difficult that the cost of production was considered impractical for many applications.
While exploring alternative sealing methods, Graf noticed that trying to seal the microparticles by dipping them into different melted polymers was not giving the desired outcome. “Eventually, I questioned whether dipping the microparticles into a liquid polymer was even necessary,” said Graf, who proceeded to suspend the PLGA microparticles above a hot plate, enabling the top of the particles to melt and to self-seal while the bottom of the particles remained intact, “Those first particle batches barely sealed, but seeing the process was possible was very exciting.”Further optimization and experimentation resulted in consistent and robust sealing of the cylinders, which eventually proved to be one of the easier steps in making the time-released drug capsules. Each 22×14 array of cylinders was about the size of a postage stamp, and Graf made them atop glass microscope slides.
After loading an array with drugs, Graf said he would suspend it about a millimeter or so above the hot plate for a short time. “I’d just flip it over and rest it on two other glass slides, one on either end, and set a timer for however long it would take to seal. It just takes a few seconds.”
This work was supported by the Cancer Prevention and Research Institute of Texas (RR190056), the National Institutes of Health (EB031495, EB023833) and the National Science Foundation (1842494, 2236422).

Have you ever been so hungry that you become angry, otherwise known as “hangry?” New research by Adam Rosenthal, PhD, assistant professor in the Department of Microbiology and Immunology, has found that some bacteria cells get hangry too, releasing harmful toxins into our bodies and making us sick.
Rosenthal and his colleagues from Harvard, Princeton and Danisco Animal Nutrition discovered, using a recently developed technology, that genetically identical cells within a bacterial community have different functions, with some members behaving more docile and others producing the very toxins that make us feel ill.
“Bacteria behave much more different than we traditionally thought,” said Rosenthal. “Even when we study a community of bacteria that are all genetically identical, they don’t all act the same way. We wanted to find out why.”
The findings, published in Nature Microbiology, are particularly important in understanding how and why bacterial communities defer duties to certain cells — and could lead to new ways to tackle antibiotic tolerance further down the line.
Rosenthal decided to take a closer look into why some cells act as “well-behaved citizens” and others as “bad actors” that are tasked with releasing toxins into the environment. He selected Clostridium perfringens — a rod-shaped bacterium that can be found in the intestinal tract of humans and other vertebrates, insects, and soil — as his microbe of study.
With the help of a device called a microfluidic droplet generator, they were able to separate, or partition, single bacterial cells into droplets to decode every single cell.

They found that the C. perfringens cells that were not producing toxins were well-fed with nutrients. On the other hand, toxin-producing C. perfringens cells appear to be lacking those crucial nutrients.
“If we give more of these nutrients,” postulated Rosenthal, “maybe we can get the toxin-producing cells to behave a little bit better.”
Researchers then exposed the bad actor cells to a substance called acetate. Their hypothesis rang true. Not only did toxin levels drop across the community, but the number of bad actors reduced as well. But in the aftermath of such astounding results, even more questions are popping up.
Now that they know that nutrients play a significant role in toxicity, Rosenthal wonders if there are particular factors found in the environment that may be ‘turning on’ toxin production in other types of infections, or if this new finding is only true for C. perfringens.
Perhaps most importantly, Rosenthal theorizes that introducing nutrients to bacteria could provide a new alternative treatment for animals and humans, alike.
For example, the model organism Clostridium perfringens is a powerful foe in the hen house. As the food industry is shifting away from the use of antibiotics, poultry are left defenseless from the rapidly spreading, fatal disease. The recent findings from Rosenthal et al. may give farmers a new tool to reduce pathogenic bacteria without the use of antibiotics.
As for us humans, there is more work to be done. Rosenthal is in the process of partnering with colleagues across UNC to apply his recent findings to tackle antibiotic tolerance. Antibiotic tolerance occurs when some bacteria are able to dodge the drug target even when the community has not evolved mutations to make all cells resistant to an antibiotic. Such tolerance can result in a less-effective treatment, but the mechanisms controlling tolerance are not well understood.
In the meantime, Rosenthal will continue to research these increasingly complex bacterial communities to better understand why they do what they do.

Is our brain able to regenerate? And can we harness this regenerative potential during aging or in neurodegenerative conditions? These questions sparked intense controversy within the field of neuroscience for many years. A new study from the Netherlands Institute for Neuroscience shows why there are conflicting results and proposes a roadmap on how to solve these issues.
The notion of exploiting the regenerative potential of the human brain in aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing or restoring brain function, especially given the current lack of effective therapeutic strategies in neurodegenerative disorders like Alzheimer’s disease. The question of whether the human brain does possess the ability to regenerate or not has been at the center of a fierce scientific debate for many years and recent studies yielded conflicting results. A new study from Giorgia Tosoni and Dilara Ayyildiz, under the supervision of Evgenia Salta in the laboratory of Neurogenesis and Neurodegeneration, critically discusses and re-analyzes previously published datasets. How is it possible that we haven’t yet found a clear answer to this mystery?
Previous studies in which dividing cells were labeled in postmortem human brain, showed that new cells can indeed arise throughout adulthood in the hippocampus of our brain, a structure that plays an important role in learning and memory, and is also severely affected in Alzheimer’s disease. However, other studies contradict these results and cannot detect the generation of new brain cells in this area. Both conceptual and methodological confounders have likely contributed to these seemingly opposing observations. Hence, elucidating the extent of regeneration in the human brain remains a challenge.
New state-of-the-art technologies
Recent advances in single-cell transcriptomics technologies have provided valuable insights into the different cell types found in human brains from deceased donors with different brain diseases. To date, single-cell transcriptomic technologies have been used to characterize rare cell populations in the human brain. In addition to identifying specific cell types, single-nucleus RNA sequencing can also explore specific gene expression profiles to unravel full the complexity of the cells in the hippocampus.
The advent of single-cell transcriptomics technologies was initially viewed as a panacea to resolving the controversy in the field. However, recent single-cell RNA sequencing studies in human hippocampus yielded conflicting results. Two studies indeed identified neural stem cells, while a third study failed to detect any neurogenic populations. Are these novel approaches — once again — failing to finally settle the controversy regarding the existence of hippocampal regeneration in humans? Will we eventually be able to overcome the conceptual and technical challenges and reconcile these -seemingly- opposing views and findings?

Technical issues
In this study, the researchers critically discussed and re-analyzed previously published single-cell transcriptomics datasets. They caution that the design, analysis and interpretation of these studies in the adult human hippocampus can be confounded by specific issues, which ask for conceptual, methodological and computational adjustments. By re-analyzing previously published datasets, a series of specific challenges were probed that require particular attention and would greatly profit from an open discussion in the field.
Giorgia Tosoni: ‘We analyzed previously published single-cell transcriptomic studies and performed a meta-analysis to assess whether adult neurogenic populations can reliably be identified across different species, especially when comparing mice and humans. The neurogenic process in adult mice is very well characterized and the profiles of the different cellular populations involved are known. These are actually the same molecular and cellular signatures that have been widely used in the field to also identify neurogenic cells in the human brain. However, due to several evolutionary adaptations, we would expect the neurogenesis between mice and humans to be different. We checked the markers for every neurogenic cell type and looked at the amount of marker overlap between the two species.’
‘We found very little, if no, overlap between the two, which suggests that the mouse-inferred markers we have been long using may not be suitable for the human brain. We also discovered that such studies require enough statistical power: if regeneration of neuronal cells does happen in the adult human brain, we expect it to be quite rare. Therefore, enough cells would need to be sequenced in order to identify those scarce, presumably neurogenic populations. Other parameters are also important, for example the quality of the samples. The interval between the death of the donor and the downstream processing is critical, since the quality of the tissue and of the resulting data drops over time.’
Reproducibility is key
Dilara Ayyildiz: ‘These novel technologies, when appropriately applied, offer a unique opportunity to map hippocampal regeneration in the human brain and explore which cell types and states may be possibly most amenable to therapeutic interventions in aging, neurodegenerative and neuropsychiatric diseases. However, reproducibility and consistency are key. While doing the analysis we realized that some seemingly small, but otherwise very critical details and parameters in the experimental and computational pipeline, can have a big impact on the results, and hence affect the interpretation of the data.’
‘Accurate reporting is essential for making these single-cell transcriptomics experiments and their analysis reproducible. Once we re-analyzed these previous studies applying common computational pipelines and criteria, we realized that the apparent controversy in the field may in reality be misleading: with our work we propose that there may actually be more that we agree on than previously believed.’