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The F.D.A. authorized a breath-based test made by a small Texas company, which said it hoped that mobile sites could use the device.Coronavirus infections might soon be flagged with a puff of exhaled breath, after the Food and Drug Administration authorized the first breath-based Covid-19 test in the United States on Thursday.The emergency use authorization of the InspectIR Covid-19 Breathalyzer is a meaningful milestone in the yearslong quest to develop more breath-based diagnostics, as well as innovative new tests for Covid, experts said. And it is likely to be the first of many similar breath-based Covid tests, experts said.“I think this is a really exciting development for the entire field of breath analysis,” said Cristina Davis, the associate vice chancellor of Interdisciplinary Research and Strategic Initiatives at the University of California, Davis, who has been developing her own coronavirus test. “This is a huge step forward.”But breath tests still pose real-world challenges, and this particular device has several practical limitations, scientists said. The machine required to conduct the tests is large — about the size of a carry-on suitcase — and can only be used by trained operators supervised by health care professionals.And many devices would be needed for wide-scale screening, given that each machine can process only about 20 samples an hour, according to InspectIR Systems, a small, five-person company based in Frisco, Texas.The company cited high accuracy rates for its tests, but some experts said they wanted to examine the data underlying its application to the F.D.A. before endorsing this test method.In addition, many health care settings and mobile test sites where the devices may be used have already adopted other kinds of rapid tests, which are now widely available. InspectIR’s officials said that final pricing plans had not yet been set.It could take 10 to 12 weeks for the first devices to hit the market, John Redmond, a co-founder of InspectIR Systems, said on Friday. The company said it planned to produce about 100 devices a week, according to the F.D.A., but it was not immediately clear when production would reach that level. “We’ve been thinking about these types of tests for the entire pandemic, and we were kind of waiting for the first one” to be authorized, said Dr. Wilbur Lam, a pediatric hematologist and bioengineer at Emory University and the Georgia Institute of Technology and an expert on Covid tests.“The devil is in the details to really determine how useful this thing will be,” he said.Many diseases cause physiological changes that alter the compounds we exhale, and there has long been interest in developing breath tests for a wide range of illnesses, from lung cancer to liver disease.When the pandemic began, numerous research teams began trying to identify unique chemical patterns in the breath of Covid patients, and many scientists and companies have been developing breath-based coronavirus tests, which could be used to rapidly and noninvasively screen large groups of people for the virus.Some Covid breath tests have already been tested in pilot programs or authorized for use in other countries, but the InspectIR Breathalyzer would be the first to hit the market in the United States.To use the device, patients blow into a cardboard straw attached to a chemical analyzer. “It’s a chemistry lab in a box,” Mr. Redmond said. The machine then analyzes the levels of five volatile organic compounds, or V.O.C.s, that together make up a “breath print” of Covid, Mr. Redmond said. (InspectIR said it could not disclose what the five compounds are.) Results are delivered within three minutes, the company said.“That’s really fast and pretty impressive,” said Nathaniel Hafer, a molecular biologist and testing expert at UMass Chan Medical School.Expanding the types of samples that can be used to detect the virus is “really valuable,” he added. “Not everybody can provide a nasal sample very easily.”Other countries have authorized breathalyzer tests for the coronavirus, and others are in development in the U.S.via InspectIR SystemsIn a company-sponsored study of 2,409 asymptomatic people, the breathalyzer had a sensitivity of 91 percent, meaning that of the people who tested positive for the virus on a P.C.R. test, the device flagged 91 percent of them as presumptive positives, according to documents released by the F.D.A. It had a specificity of 99 percent, meaning it did not detect any signs of the virus in 99 percent of those who received a negative result from a P.C.R. test.Susan Butler-Wu, a clinical microbiologist at the Keck School of Medicine of the University of Southern California, said that she wanted to see more independent data on the device’s performance and more details on precisely what compounds it was detecting.“The use of V.O.C.s is not well developed for the diagnosis of infection,” she said. “I would not feel comfortable using it for diagnosing patients without getting some more real-world data.”Certain foods and substances can throw off breath tests, scientists noted. And the instructions for the InspectIR Breathalyzer specify that people should not eat, drink or use any tobacco products in the 15 minutes before taking the test. Those who test positive should also have the result confirmed with a P.C.R. or other similar test, the company says.Indeed, the most promising way to use breath tests is as a quick screening tool — a more accurate version of not-very-reliable temperature screens that became common during the pandemic, Dr. Lam said. “They don’t really give you a diagnosis,” he said, referring to breath tests. “They give you a biochemical pattern that is consistent with the disease.”InspectIR hopes to lease the analyzers to other businesses, including health care facilities and companies that run mobile or pop-up testing sites. They could be used to test travelers at airports or workers in an office building, the co-founders said, adding that there has already been interest from professional sports leagues and companies in the travel industry.“Anywhere that they’re doing a nasal swab more than once a day, we’re a great fit,” said Tim Wing, a co-founder of the company.The device’s pricing has not yet been finalized, but the co-founders said on Friday that they hope to be able to offer licenses or subscriptions that translate to a cost of about $10 to $12 per test.“Yesterday was a huge domino for us,” Mr. Wing said on Friday, the day after the device was authorized. “Not all this stuff is ready to go, is defined yet.”The company said that it had raised $2.7 million to date and that Pfeiffer Vacuum would be its initial manufacturing partner.

He transformed a small company into a corporation focused on providing health insurance under government programs. It now insures 25 million people.Michael F. Neidorff, who built the Centene Corporation from a small Milwaukee health plan into the nation’s largest insurer for the government’s Medicaid program and a stalwart of the Obamacare markets, died on April 7 in St. Louis. He was 79.His family said the cause was an infection.Mr. Neidorff indicated in December that he would retire as chief executive in 2022, and he took a medical leave of absence in February. Centene, which is headquartered in St. Louis, appointed Sarah London, who had been vice chairwoman, as its chief executive in March.When Mr. Neidorff joined Centene as chief executive in 1996, the insurer, then known as Coordinated Care, offered a single health plan and had $40 million in sales. Over the next 25 years, he transformed it into a corporation that focused on providing health insurance under government programs like Medicaid and Medicare. Centene now provides coverage to 25 million people and had $126 billion in revenues last year.“The company he built provides health care for nearly one in 15 vulnerable Americans,” Ms. London said in a statement.Under Mr. Neidorff’s leadership, Centene chose to concentrate on government-sponsored insurance through Medicaid for low-income individuals and Medicare for older people and the disabled.“Michael was very clever from a strategic standpoint,” said Dr. J. Mario Molina, the former chief executive of Molina Healthcare, one of Centene’s main rivals. Early on, he said, Mr. Neidorff recognized that fewer people were likely to be insured through their employer while “the government programs were growing,”When a new market for insurance was created under the Affordable Care Act — the federal law, known as Obamacare, that helps provide private insurance to people who do not qualify for Medicaid but who are not covered by their employers — Mr. Neidorff positioned Centene as a major provider of low-cost plans. He persevered even after many large insurers lost money and stopped offering coverage.“He stayed with Obamacare in the exchanges when many of the other companies pulled out,” Ana Gupte, a former Wall Street analyst who now runs her own advisory company, recalled.“They grew remarkably in Obamacare,” she said. “They took advantage of the fact that other companies were risk averse and exiting.”When state officials and government regulators were concerned that some counties in the United States would be left without a carrier willing to sell insurance under the Affordable Care Act, Mr. Neidorff agreed to provide coverage in some of those markets, said Jesse Hunter, a former chief strategy officer for Centene, and “there was never any hesitation.”“We want to help out where we are able to,” Mr. Neidorff told The New York Times in 2017.He was born in 1942 in Altoona, Pa., to A. Harvey Neidorff, a physician, and Shirley Rubin Neidorff, a nurse. He had considered going into medicine but decided instead to major in political science at Trinity University in San Antonio. He later earned a master’s degree from St. Francis College in Brooklyn.He is survived by his wife, Noémi; his brother, Robert; his sister, Susan Neidorff Reinglass; and his son, Peter. His daughter, Monica Neidorff, died in 2021.Mr. Neidorff had worked for a unit of UnitedHealthcare when he was recruited to be chief executive of Coordinated Care, the small managed-care company that would become Centene. “It was obvious they needed a complete change,” said Robert Ditmore, a longtime Centene board member who was involved in the company.Mr. Neidorff expanded aggressively into the Medicaid market, despite concerns about whether it would be a successful venture. “I had questions about Medicaid; is it going to work?” Mr. Ditmore said. But, he added, Mr. Neidorff persuaded him: “It was obviously a big market, so we said let’s go for it.”Mr. Neidorff took the company public in 2001. In 2016, he acquired a California insurer, Health Net, which offered private plans for another government program, Medicare.When the Affordable Care Act provided an opportunity to sell low-cost private insurance through the state markets set up by the federal government, Mr. Ditmore recalled, Mr. Neidorff was eager to become a major player, despite uncertainty about how insurers should price their policies in the new market. “He kept pushing for it,” Mr. Ditmore said. “He was a bulldog with a bone in his mouth.”Mr. Neidorff made several key acquisitions to add to Centene’s depth. In 2020 he bought WellCare, a Florida Medicare Advantage insurer. This year the company completed the purchase of Magellan Health, which specialized in providing mental health benefits.Centene’s stock price had underperformed in recent years, and the company found itself under pressure from an activist investor, Politan Capital Management. In December, the company agreed to change the composition of its board, and Mr. Neidorff announced that he would retire as chief executive in 2022.He was also active in philanthropy. He was chairman of the National Urban League’s board of trustees and a board member of the St. Louis Symphony Orchestra, the Opera Theater of Saint Louis and the Manhattan School of Music, among other organizations. Last September, he donated $25 million to Trinity for the Michael F. Neidorff School of Business.

A research group at Karolinska Institutet in Sweden has analysed how certain immune cells known as innate lymphoid cells (ILCs) develop into mature cells that play a part in inflammatory bowel disease (IBD). The findings could pave the way for more effective treatments against IBD, a disease that causes considerable suffering and that is linked to an increased risk of colorectal cancer. The results are published today in the journal Science Immunology.
Inflammatory bowel disease (IBD) is characterised by a chronic inflammation of the gut mucosa that is thought to increase the risk of colon cancer. The disease often debuts before middle age with symptoms such as abdominal pain and weight loss. The cause is unknown but genetical, environmental and immunological factors are all believed to play a role. As a large group of IBD patients do not respond to available treatments, there is a great need for new knowledge about the mechanisms driving the disease.
ILCs are lymphocytes, a family of immune cells, found in the mucosa where they form part of the immune system and maintain tissue function, such as the production of mucous. Previous research has shown that ILCs change function during inflammation, making them a promising target for IBD treatment.
In the present study, the researchers isolated ILCs from the tonsils and gut tissue of patients who had undergone resection surgery or endoscopic examination. A total of 48 patients were involved in the study, 31 of whom had IBD. The ILCs were then examined in detail, both immediately after isolation and after cell culture.
The results show that a subgroup of ILCs constitute a pre-stage of mature ILCs and accumulate in the intestinal mucosa of patients with IBD. Factors in the gut environment can then influence the metabolism of the immature ILCs, stimulate increased cell division and production of cytokines, including IL-22, which helps to protect the intestinal tissue.
“The function of ILCs changes during inflammation and therefore ILCs represent a promising therapeutic target for conditions like inflammatory bowel disease,” says the study’s first author Efthymia Kokkinou, doctoral student at the Department of Medicine, Huddinge at Karolinska Institutet. “Insight into how these cells develop from immature cells into mature cells in tissue helps us understand how they influence tissue function or inflammation in mucosa and how they can be manipulated for therapeutic purposes.
The research group now hopes to study if the presence and properties of immature intestinal ILCs can predict responses to medical drugs, particularly those containing the active substances ustekinumab, infliximab and tofacitinib, which are currently used to treat Crohn’s disease and ulcerative colitis, two of the most common IBDs.
“These studies are important since the right choice of effective treatment can reduce both personal suffering and societal costs,” says Jenny Mjösberg, associate professor at the same department at Karolinska Institutet and the study’s senior author.
The study was mainly financed through an ERC starting grant and by the Erling-Persson Foundation, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation and Karolinska Institutet.
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Therapies based on engineered immune cells have recently emerged as a promising approach in the treatment of cancer. Compared to traditional drugs, engineered immune cells are more precise and sophisticated in their ability to detect and eliminate cancer cells.
But despite their promise, cell-based therapies still face important limitations, including toxicity and the possibility that they could attack healthy cells. In addition, scientists don’t have a good handle on how to modify existing therapeutic cells to expand their applications or better control their activity.
To overcome these limitations, researchers at Gladstone Institutes and UC San Francisco (UCSF) undertook a systematic analysis of the molecular building blocks used to engineer therapeutic cells. Their work, reported in the journal Cell, resulted in a comprehensive rule book for the design of therapeutic cells with improved specificity and safety, and for the eventual customization of cell-based therapies.
“We have identified principles that should greatly facilitate the engineering of therapeutic cells with greater sensitivity, accuracy, and safety than was possible before,” says Kole Roybal, PhD, an associate professor in the Department of Microbiology and Immunology at UCSF, an affiliate investigator at Gladstone Institutes and core member of the Gladstone-UCSF Institute of Genomic Immunology, a Parker Institute for Cancer Immunotherapy investigator, and the study’s senior author. “Our work will provide biomedical researchers with a toolkit for directing a range of cell-based therapies to their intended targets and for programming their therapeutic activities.”
Building a Better Receptor
At the core of most therapeutic cells is a molecule called a receptor. Receptors are large proteins that straddle the cell’s outer membrane. Their outer portion recognizes a specific target (for instance a protein on the surface of a cancer cell) and their inner portion tells the cell what to do upon recognizing this target. One way to engineer a therapeutic cell is to insert in a cell — often an immune cell called a T cell — a synthetic receptor made by piecing together fragments of known receptors.

A University of Illinois at Urbana-Champaign research team has discovered a way to produce a special class of molecule that could open the door for new drugs to treat currently untreatable diseases.
Open the household medicine cabinet and you will likely find organic derivatives of ammonia, called amines. They are one of the most prevalent structures found in medicines today. More than 40 percent of drugs and drug candidates contain amines, and 60 percent of those amines are tertiary, so named for the three carbons that are bonded to a nitrogen.
Tertiary amines are found in some of the most impactful human medicines, including antibiotics, breast cancer and leukemia drugs, opioid pain medications, antihistamines, blood thinners, HIV treatments, antimigraine medications and more. They increase a drug’s solubility and can trigger its key biological functions.
Despite the prevalence of this special class of molecules in medicines today, much of the functional potential of tertiary amines likely remains untapped.
That’s because the traditional process of making them requires specific, controlled conditions that inherently limit the discovery of new tertiary amines, which could potentially treat a wide range of currently untreatable diseases.
Now, an Illinois research team led by Lycan Professor of Chemistry M. Christina White and graduate students Siraj Ali, Brenna Budaitis, and Devon Fontaine have discovered a new chemical reaction, a carbon-hydrogen amination cross-coupling reaction, that creates a faster, simpler way of making tertiary amines without the inherent limitations of classic methods. The researchers believe this could also be used to discover new reactions with nitrogen.

Patients seeking treatment for depression who have lower income and education and those who are members of minority populations tend to have worse treatment outcomes even when receiving equal access to treatment, according to new research from the University of Cincinnati.
Led by Jeffrey Mills, PhD, and Jeffrey Strawn, MD, the UC cross-college collaborative research was recently published in the journal Psychiatric Services.
Strawn, professor in the Department of Psychiatry and Behavioral Neuroscience in UC’s College of Medicine and a UC Health adolescent psychiatrist, said that previous research has concluded that people seeking treatment for depression with lower income and less education have worse outcomes because of a lack of access to quality health care, but it is hard to isolate socioeconomic factors as they are often intertwined.
The research team analyzed data from a very large clinical trial known as CO-MED that enrolled 665 patients seeking treatment for depression. In the randomized trial, all patients had the same access to treatment without differences due to health insurance or income.
Study results
After controlling for sex, age and treatment type following 12 weeks of antidepressant medication treatment in the study, the team’s analysis found patients who were non-white improved 11.3% less compared to white patients. Those who were unemployed saw 6.6% less improvement compared to employed patients. Compared to patients in the 75th percentile of income distribution, patients having income at the 25th percentile reduced improvement by 4.8%.

Patients with cancers stemming from non-reproductive organs, such as bladder and liver cancer, have striking discrepancies in incidence, progression, response to treatment and survival outcomes depending on their sex. In almost all cases, male patients have worse prognoses and outcomes. This phenomenon has puzzled the scientific community for decades.
A study published today in Science Immunology and led by researchers in the Pelotonia Institute for Immuno-Oncology (PIIO) at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC — James) examined the differences in intratumoral immune responses between male and female cancers of non-reproductive origin
The focus of this research was the T cell immune response to malignancy, a key determinator of outcomes in cancer, and an important target that has contributed to the renaissance of cancer immunotherapy seen in recent years. The study reported a landmark finding that describes how male sex hormones contribute to cancer-related sex bias via the modulation of CD8+ T cells — a population of cells often referred to as cancer “killer” cells, which mediate adaptive immunity and are critical for mounting an anti-tumor response.
“Collectively, these findings highlight androgen-mediated promotion of CD8+ T cell dysfunction in cancer and suggest broader implications for therapeutic development to address sex disparities in health and disease,” said the study’s senior corresponding author Dr. Zihai Li, cancer immunologist, medical oncologist and founding director of the PIIO at OSUCCC — James.
Androgens are sex hormones more highly present in males. This study revealed that CD8+ T cells from cancers in male subjects, including human patients and mice, are more likely to have characteristics of a weakened anti-tumor immune function, also known as “exhausted” T cells. Androgen signaling promotes the progenitor exhausted CD8+ T cell phenotype via modulating expression of TCF1, a master regulator of CD8+ T cell function.
“Androgen-mediated promotion of CD8+ T cell dysfunction results in faster tumor growth and worsened outcomes, and targeting of this signaling cascade holds a crucial key to improving current cancer immunotherapies,” said Li, who is also a professor in the Ohio State College of Medicine.
This work was made possible because of the unique collaborations happening in Ohio State’s Pelotonia Institute for Immuno-Oncology. Founded in 2019, the PIIO is a comprehensive bench-to-bedside research initiative focused on harnessing the body’s immune system to fight cancer at all levels — from prevention to treatment and survivorship. The institute is centered on systems and translational immuno-oncology and supported by immune monitoring and discovery as well as immuno-informatics.
The PIIO was established through a $102 million pledge from OSUCCC — James and Pelotonia. Founded in 2008, Pelotonia was established with the objective to fund innovative cancer research, and has raised over $236 million for cancer research.
Additional financial support for the study came from the National Institutes of Health, Prostate Cancer Foundation, Canadian Institutes of Health Research and Hollings Cancer Center.
Other study authors include Hyunwoo Kwon, Johanna Schafer, No-Joon Song, Satoski Kaneko, Anqi Li, Tong Xiao, Anjun Ma, Carter Allen, Komal Das, Lei Zhou, Brian Riesenberg, Yuzhou Chang, Payton Weltge, Maria Velegraki, David Oh, Lawrence Fong, Qin Ma and Debasish Sundi, as well as co-corresponding authors Drs. Xue Li (Cedars-Sinai Medical Center) and Dongjun Chung (OSUCCC — James).

Smoking dominates other factors, including amount of wealth, in shortening lifespan, reports a study by researchers at Georgetown University and the University of California, Riverside.
“Our results suggest that even if wealth has a causal effect on mortality, it cannot compete with the impact of smoking. If you want to live longer, you better avoid the cancer sticks,” said corresponding author Dana Glei, a senior research investigator at Georgetown University’s Center for Population and Health.
The new study finds that the percentage of Americans surviving from age 65 to 85 was 19 percentage points higher for someone with at least $300,000 in wealth than for those with no assets. But there was a 37 percentage point difference between those who never smoked and current smokers. Due to how the data was collected, wealth was measured in 1995 dollars. $300,000 is the equivalent of $558,000 today.
The wealth-related disparity in mortality was larger than the disparities by education, occupation, income, or childhood socioeconomic status. But smoking made the greatest difference among all factors.
“Our finding further confirmed that smoking shortens our lives and that abstaining from smoking might be cheaper and more effective for living longer,” said Chioun Lee, an assistant professor of sociology at UC Riverside.
Glei, along with Lee and Maxine Weinstein, a professor at Georgetown University, used data from 6,320 participants in the Midlife in the United States, or MIDUS, study funded by the National Institute on Aging to examine the effects of childhood socioeconomic status, education, occupation, income, wealth, and smoking history on mortality for adults aged 20-92 years old.
In fully adjusted models — which also controlled for age, sex, race, marital status, health insurance coverage, employment status, and numerous health-related measures — the researchers found that wealth outpaced all other measures of socioeconomic status associated with living past age 65. Mortality declined at higher levels of wealth, but wealth above $500,000 (in 1995 dollars) yielded no further mortality benefit. This amount is the equivalent of more than $925,000 today.
“We already know having a good education, a well-paid job, and extra savings are critical factors that help us live longer and stay healthier. Among education, occupation, income, and wealth, we found that wealth seems to be most important for longevity. However, beyond a certain amount, additional wealth may not yield extra years of life,” said Lee.
For smokers, however, the picture was much grimmer. Above age 65, the mortality rate among current smokers was three times higher than never-smokers. Former smokers had significantly lower mortality than current smokers, but slightly higher mortality than never-smokers.
“Health care practitioners cannot modify their patient’s wealth, but they should continue to discourage smoking. Wealth may be associated with longevity, but just don’t smoke,” said Glei.
The open-access paper, “Assessment of mortality disparities by wealth relative to other measures of socioeconomic status among us adults,” is published in Jama Network Open.

Gut microbiota by-products circulate in the bloodstream, regulating host physiological processes including immunity, metabolism and brain functions. Scientists from the Institut Pasteur (a partner research organization of Université Paris Cité), Inserm and the CNRS have discovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt appetite and body temperature accordingly. These findings demonstrate that a direct dialog occurs between the gut microbiota and the brain, a discovery that could lead to new therapeutic approaches for tackling metabolic disorders such as diabetes and obesity. The findings are due to be published in Science on April 15, 2022.
The gut is the body’s largest reservoir of bacteria. A growing body of evidence reveals the degree of interdependence between hosts and their gut microbiota, and emphasizes the importance of the gut-brain axis. At the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS)[1], immunobiologists from the Microenvironment and Immunity Unit (Institut Pasteur/Inserm), and microbiologists from the Biology and Genetics of the Bacterial Cell Wall Unit (Institut Pasteur/CNRS/Inserm)[2] have shared their expertise to investigate how bacteria in the gut directly control the activity of particular neurons in the brain.
The scientists focused on the NOD2 (nucleotide oligomerization domain) receptor which is found inside of mostly immune cells. This receptor detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that variants of the gene coding for the NOD2 receptor are associated with digestive disorders, including Crohn’s disease, as well as neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. This was revealed by the consortium of scientists in the new study.
Using brain imaging techniques, the scientists initially observed that the NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular, in a region known as the hypothalamus. They subsequently discovered that these neurons’ electrical activity is suppressed when they come into contact with bacterial muropeptides from the gut. “Muropeptides in the gut, blood and brain are considered to be markers of bacterial proliferation,” explains Ivo G. Boneca, Head of the Biology and Genetics of the Bacterial Cell Wall Unit at the Institut Pasteur (CNRS/Inserm). Conversely, if the NOD2 receptor is absent, these neurons are no longer suppressed by muropeptides. Consequently, the brain loses control of food intake and body temperature. The mice gain weight and are more susceptible to developing type 2 diabetes, particularly in older females.
In this study, the scientists have demonstrated the astonishing fact that neurons perceive bacterial muropeptides directly, while this task was thought to be primarily assigned to immune cells. “It is extraordinary to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions such as body temperature, reproduction, hunger and thirst,” comments Pierre-Marie Lledo, CNRS scientist and Head of the Institut Pasteur’s Perception and Memory Unit.
The neurons thus appear to detect bacterial activity (proliferation and death) as a direct gauge of the impact of food intake on the intestinal ecosystem. “Excessive intake of a specific food may stimulate the disproportionate growth of certain bacteria or pathogens, thus jeopardizing intestinal balance,” says Gérard Eberl, Head of the Microenvironment and Immunity Unit at the Institut Pasteur (Inserm).
The impact of muropeptides on hypothalamic neurons and metabolism raises questions on their potential role in other brain functions, and may help us understand the link between certain brain diseases and genetic variants of NOD2. This discovery paves the way for new interdisciplinary projects at the frontier between neurosciences, immunology and microbiology, and ultimately, for new therapeutic approaches to brain diseases and metabolic disorders such as diabetes and obesity.
[1] This research unit is also known as the “Genes, Synapses and Cognition Laboratory” (Institut Pasteur/CNRS). Paris Brain Institute (CNRS/Inserm/Sorbonne Université/AP-HP) also contributed to these findings.
[2] The CNRS unit’s name is the “Integrative and Molecular Microbiology Unit” and the Inserm unit’s name is the “Host-Microbe Interactions and Pathophysiology Unit” (Institut Pasteur/CNRS/Inserm).
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In people with immune thrombocytopenia (ITP), the body produces destructive antibodies against platelets in the blood, which increases the risk of bruising, bleeding, hospitalization, death, fatigue, and an impaired quality of life. A drug called rilzabrutinib has generated promising safety and efficacy results in a recent international multi-center phase 1-2 ITP trial led by investigators at Massachusetts General Hospital (MGH). The findings, which are published in the New England Journal of Medicine, pave the way for more advanced clinical trials.
Research has shown that cells called macrophages are primarily responsible for destroying antibody-coated platelets in ITP, and an enzyme called Bruton kinase is critical to their function. Although an inhibitor of Bruton kinase that was approved to treat a common form of leukemia decreases macrophage activity and raises platelets counts in patients with both leukemia and ITP, the drug, called ibrutinib, also inhibits the function of platelets, which reduces its efficacy in ITP.
Oral rilzabrutinib was developed as a new type of Bruton kinase inhibitor that reduces macrophage activity and the production of anti-platelet antibodies but does not affect the function of platelets. “We hypothesized that rilzabrutinib would be effective in both reducing the antibody attacking the platelets as well as minimizing the rate of platelet destruction by the macrophages,” says lead author David J. Kuter, MD, DPhil, who is the program director of Hematology at MGH and a professor of Medicine at Harvard Medical School.
In the 60-patient trial that involved a range of rilzabrutinib doses, all treatment-related adverse events were minor and transient. At a median follow-up of approximately 5.5 months of treatment, 24 of the 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose experienced a significant platelet response. The median time to develop a healthy platelet count was 10.5 days. Among patients who experienced a platelet response, the average percentage of weeks in which they had a healthy platelet count was 65%. The dose of 400 mg twice daily was identified as the dose for further testing.
Importantly, the patients in this study had already tried multiple therapies, and their disease were considered highly refractory to treatment. A major phase 3 clinical trial is currently underway at many sites, including MGH, to test the effectiveness of rilzabrutinib in patients with ITP that is less refractory to other medications.
“If the findings of our study are borne out in other studies, rilzabrutinib may provide a rapid rise in platelet count and a sustained increase to a safe platelet count number, which could thereby minimize bleeding, and the drug could conceivably make the antibody causing the disease to disappear,” says Kuter. “What is impressive is that this drug lacks major negative effects that have been historically associated with this class of medications. We saw no increased risk of bleeding, infection, liver dysfunction, or intolerance by patients.”
Additional study authors include Merlin Efraim, MD, Jiri Mayer, MD, Marek Trne?ný, MD, Vickie McDonald, MD, Robert Bird, MB, BS, Thomas Regenbogen, MD, Mamta Garg, MD, Zane Kaplan, MD, Nikolay Tzvetkov, MD,?Philip Y. Choi, MD, A.J. Gerard Jansen, MD, Milan Kostal, MD,?Ross Baker, MD, Jaromir Gumulec, MD, Eun-Ju Lee, MD,?Ilona Cunningham, MD, Isaac Goncalves, MD, Margaret Warner, MD, Ralph Boccia, MD, Terry Gernsheimer, MD, Waleed Ghanima, MD, Olga Bandman, MD, Regan Burns, BA, Ann Neale, BS, Dolca Thomas, MD, Puneet Arora, MD, Beiyao Zheng, PhD, and Nichola Cooper, MD.
This work was supported by Sanofi.