Publisher Health

The ability of Mycobacterium tuberculosis (MTB), a serious respiratory infection, to form snake-like cords was first noted nearly 80 years ago. In a study published October 20 in the journal Cell, investigators report the biophysical mechanisms by which these cords form and demonstrate how several generations of dividing bacteria hang together to create these structures that enable resistance to antibiotics.
“Our work clearly showed that cord formation is important for infection and why this highly ordered architecture might be important for pathogenesis,” says senior author Vivek Thacker, who led the work at the Global Health Institute at École Polytechnique Fédérale de Lausannen (EPFL) in Switzerland and is now based at the Department of Infectious Diseases at Heidelberg University in Germany.
The study used a unique combination of technologies to address the role of MTB cord formation. One was a lung-on-chip model, which allowed the researchers to get a direct look at “first contact” between MTB and host cells at the air-liquid interface in the lungs. This revealed that cord formation is prominent in early infection. The researchers also used a mouse model that develops pathologies mimicking human tuberculosis, allowing them to obtain tissue that could be studied using confocal imaging and confirming that cording also occurs early in infection in vivo.
The work yielded several new findings about how these cords interact with and compress the cell nucleus, how this compression affects the immune system and connections between host cells and epithelial cells, and how cord formation affects the alveoli in the lungs. The study also revealed how these cords retain their structural integrity and how they increase tolerance to antibiotic therapy.
“There is an increasing understanding that these mechanical forces influence cellular behavior and responses, but this aspect has been overlooked since traditional cell culture models do not recapitulate the mechanical environment of a tissue,” says Melanie Hannebelle, formerly at EPFL’s Global Health Institute and now at Stanford University. “Understanding how forces at the cellular and tissue level or crowding at the molecular level affects cell and tissue function is therefore important to develop a complete picture of how biosystems work.”
“By thinking of MTB in infection as aggregates and not single bacteria, we can imagine new interactions with host proteins for known effectors of MTB pathogenesis and a new paradigm in pathogenesis where forces from bacterial architectures affect host function,” says Thacker.
Future research will focus on understanding whether cord formation enables new functionality to known effectors of MTB pathogenesis, many of which are located on the MTB cell wall. In addition, it will look at the consequence of tight-packing on the bacteria within the clump and how this may lead to a protective effect against antibiotics.
“Antibiotic therapy is the mainstay of treatment for tuberculosis infections, but therapeutic regimens are long and complicated, with an increasing threat of drug resistance,” says Richa Mishra, the other first author who is currently at EPFL’s Global Health Institute. “There is a recognized need for host-directed therapies or therapies that inhibit specific virulence mechanisms that can shorten and improve antibiotic therapy.”

Researchers are studying the dramatic physical transformation that some insects undergo to give birth to live young.
This includes suppressing their immune systems to accommodate babies, which is something some insects and people have in common. Understanding how these systems work can help improve treatments for fibromyalgia and other immune disorders.
Biologists at the University of Cincinnati were part of an international team examining the complex structural and physiological changes that take place in Hawaii’s beetle-mimic cockroaches, which give birth to live young.
“It’s not just immunology,” co-author and UC College of Arts and Sciences Professor Joshua Benoit said.
Biologists see similar changes in the insect’s trachea, its immune system and the outer layer of its exoskeleton called a cuticle, which transforms to make room for the babies.
The study was published in the journal iScience.
Cockroach mothers not only incubate their babies until they are the equivalent size of a 2-year-old human toddler, but they also feed them a milk-like nutrient they produce through secretory glands.

Women with diets during middle age designed to lower blood pressure were about 17 percent less likely to report memory loss and other signs of cognitive decline decades later, a new study finds.
Led by researchers from NYU Grossman School of Medicine, the new findings suggest that a mid-life lifestyle modification — adoption of the Dietary Approaches to Stop Hypertension, or DASH diet — may improve cognitive function later in life for women, who make up more than two-thirds of those diagnosed with Alzheimer’s disease, the most prevalent form of dementia.
The findings, published online today in the journal Alzheimer’s & Dementia , have implications for the approximately 6.5 million Americans over age 65 diagnosed with Alzheimer’s disease in 2022. That number is expected to more than double by 2060.
“Subjective complaints about daily cognitive performance are early predictors of more serious neurocognitive disorders such as Alzheimer’s,” said Yu Chen, PhD, MPH, professor in the Department of Population Health and senior author of the study. “With more than 30 years follow-up, we found that the stronger the adherence to a DASH diet in midlife, the less likely women are to report cognitive issues much later in life.”
The DASH diet includes a high consumption of plant-based foods that are rich in potassium, calcium, and magnesium and limits saturated fat, cholesterol, sodium, and sugar. Longstanding research shows that high blood pressure, particularly in midlife, is a risk factor for cognitive decline and dementia.
How the Study was Conducted
The investigators analyized data from 5,116 of the more than 14,000 women enrolled in the NYU Women’s Health Study, one of the longest running studies of its kind that examines the impact of lifestyle and other factors on the development of the most common cancers among women, as well as other chronic conditions.

New findings from researchers at UCLA Health suggest that measuring changes in how pupils react to light could help predict recovery from depression and personalize transcranial magnetic stimulation (TMS) treatment of major depressive disorder.
TMS is a safe, non-invasive therapy that uses magnetic fields to stimulate parts of the brain involved in mood regulation. While TMS is proven effective, not all patients respond equally well to the therapy. The ability to predict who will benefit most could allow doctors to better customize and target treatments.
In two recent studies, UCLA scientists found that the pupil’s response to light before treatment correlated with improvements in depression symptoms over the course of therapy. Pupil size reflects activation of the autonomic nervous system, which controls involuntary functions and is negatively impacted in people with depression.
The first study, appearing in the Journal of Affective Disorders, reports on outcomes for 51 patients who underwent daily TMS sessions. Before receiving treatment, researchers measured the patients’ baseline pupillary constriction amplitude, or CA: how much the pupil shrinks when exposed to light. The pupil’s constriction is an indicator of parasympathetic nervous system function. The researchers found a significant association between baseline pupil constriction amplitude and symptom improvement, indicating that a greater constriction amplitude at baseline was associated with a better outcome. In other words, those with larger pupil constriction in response to light at baseline showed greater symptom improvement over their full treatment.
The second study, appearing in Brain Stimulation, went further and compared patients who were treated for depression with one of two common TMS protocols: 10 Hz stimulation and intermittent theta burst stimulation (iTBS). In 10 Hz stimulation, magnetic pulses are delivered at a fixed rate of 10 pulses per second, or 10 Hz, a continuous and relatively high-frequency stimulation. iTBS is a faster form of stimulation with bursts of three pulses at 50 Hz, repeated with short breaks between bursts. This pattern is thought to mimic the natural rhythm of certain brain activities.
The researchers found that people with slower pupillary constriction had significantly greater improvement in depression after 10 sessions if they received iTBS rather than 10 Hz treatment.
“These results suggest we may be able to use a simple test of the pupil to identify who is most likely to respond to electromagnetic stimulation of the brain to treat their depression,” said researcher Cole Citrenbaum, lead author of both studies and a researcher with the TMS Clinical and Research Program at the Semel Institute for Neuroscience and Human Behavior at UCLA.
The researchers propose that measuring pupillary reactivity before starting TMS could eventually help guide treatment selection on an individual basis. “Additionally, we may be able to tailor the frequency of stimulation to the individual patient to maximize their benefit from treatment,” Citrenbaum said. This personalized approach could lead to better outcomes for patients.
“At the present time, about 65% of patients treated with TMS have a substantial improvement in their depression,” said Dr. Andrew F. Leuchter, senior author of both studies and Distinguished Professor of Psychiatry at the Jane and Jerry Semel Institute for Neuroscience and Human Behavior at UCLA. “Our goal is to have more than 85% of patients fully recover from depression. As we better understand the complex brain activity underlying depression, we move closer to matching patients with the treatments that ensure their full recovery. Pupil testing may be one useful tool in reaching this goal.”
The studies add to growing evidence on the benefits of biologically-based personalization in treating major depression. UCLA researchers plan further trials to confirm the value of pupillometry in optimizing transcranial magnetic stimulation.

Johns Hopkins researchers looking to develop a long-acting, injectable malaria preventive using atovaquone have shown in a new study that resistance may not be the challenge scientists thought it was, particularly when using atovaquone as a malaria preventive. Malaria parasites in infected patients being treated with atovaquone tend to develop a resistance to the drug. Because of this, atovaquone by itself is not used as a malaria treatment nor has not been seen as a strong candidate for use as a preventive.
The study, led by a team of researchers at the Johns Hopkins Malaria Research Institute and the Johns Hopkins University School of Medicine, in conjunction with colleagues at the University of Liverpool, was published online October 12 in Nature Communications. The Malaria Research Institute is based at the Johns Hopkins Bloomberg School of Public Health.
In their study, the researchers found that the same genetic mutation that renders malaria parasites resistant to atovaquone in patients also destroys the parasite’s ability to live within mosquito hosts — meaning atovaquone-resistant malaria parasites would not be transmissible. The researchers concluded that atovaquone, despite concerns over resistance, holds promise as a long-acting, injectable “chemical vaccine” that could prevent infection in malaria-endemic areas.
“These findings should reduce concerns about the transmission of atovaquone resistance with atovaquone therapy, particularly when it is used as a chemical vaccine,” says study senior author Theresa Shapiro, MD, PhD, professor of Clinical Pharmacology in the Johns Hopkins University School of Medicine and professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the Bloomberg School.
Malaria continues to be a major global health burden. According to the World Health Organization, the mosquito-borne parasitic disease afflicted nearly a quarter of a billion people in 2021, killing more than 600,000. Researchers generally agree that, despite the impact of insecticides and other malaria control measures, and the recent development of a malaria vaccine, new approaches against this deadly parasitic pathogen are needed.
One new approach, described by Shapiro and colleagues at the University of Liverpool in a 2018 preclinical study, would use an injectable, slow-release formulation of atovaquone to provide vaccine-like protection for weeks at a time. Atovaquone is generally considered safe for long-term use even at higher doses, and has the further advantage that it interrupts the malaria life-cycle in human hosts even at the pre-symptomatic stage, when the parasite is developing in liver cells.
However, when atovaquone is used not as a preventive but as a treatment for symptomatic malaria infection, it often fails due to the emergence of genetically acquired resistance. Shapiro notes that by the time an infection is symptomatic, it involves billions of individual malaria organisms, and in this vast population it is likely that a resistance mutation will appear, if only by random genetic variation. Under atovaquone treatment, parasites with this mutation will come to dominate the infection. Because of the resistance problem, atovaquone is used to treat malaria only in combination with another antimalarial called proguanil.

Researchers at Baylor College of Medicine and the University of Michigan conducted a phase I pilot study to assess the feasibility of using potato starch as a dietary intervention to modify the gut microbiome in bone marrow transplant patients. The study, which appears in the journal Nature Medicine, is the first part of a two-phase ongoing clinical trial evaluating the effect of modifying the microbiome on the incidence of graft-versus-host disease (GVHD), a major complication that develops in up to half the patients who receive a bone marrow transplant and can lead to injury and death.
“The gut microbiome is a community of microbes we all carry inside the body, and its composition and products affect our health,” said senior and co-corresponding author Dr. Pavan Reddy, currently professor and director of the Dan L Duncan Comprehensive Cancer Center at Baylor and previously at the University of Michigan. “Early research from our lab and others showed that a normal gut microbiome and its products change after a bone marrow transplant and that this change contributes to GVHD aggravation. Can we alter the progression of GVHD by modifying the microbiome?”
Previous pre-clinical data from the Reddy lab demonstrated that butyrate, a compound produced by healthy intestinal bacteria when they digest resistant potato starch, a form of starch that people cannot digest, was significantly decreased in the gut of mice experiencing GVHD. Restoring butyrate levels by increasing intestinal butyrate-producing bacteria reduced experimental acute GVHD severity and mortality.
“Having more butyrate in the gut is helpful for healing the intestine, and therefore beneficial for alleviating GVHD,” Reddy said. “Previous studies have also shown that in healthy people, potato starch also promotes an increase in butyrate-producing bacteria and intestinal levels of butyrate.”
These findings led the researchers to investigate whether increasing intestinal butyrate-producing bacteria and intestinal butyrate levels in bone marrow transplant patients would reduce or prevent the progression of GVHD.
“We began by assessing in the current study whether it was safe and practical for 10 patients undergoing a bone marrow transplant at the University of Michigan to take a food supplement made from resistant potato starch for more than 100 days and whether this would change the products of the gut bacteria that live in the stomach and intestine in a way that could possibly prevent GVHD after transplant,” said first and co-corresponding author Dr. Mary Riwes, clinical assistant professor in medical oncology, internal medicine and hematology at the University of Michigan’s Rogel Cancer Center.
The goal was that 60% or more of the patients would take 70% or more of the potato starch doses. “Our findings surpassed our expectations,” Reddy said. “We found that more than 80% of the patients took 84% of the doses with no negative side effects, suggesting that it is safe and feasible for most patients to regularly take the food supplement. We also found that butyrate levels in the stools were significantly higher in the participants that took potato starch than in those that did not, as we had seen both in mice and healthy adults.”
“In the next part of the study, currently open at the University of Michigan and soon to open at a second site at Baylor College of Medicine, we will determine whether taking potato starch will indeed result in less GVHD after transplant,” Riwes said.

Artificial intelligence (AI) — of ChatGPT fame — is increasingly used in medicine to improve diagnosis and treatment of diseases, and to avoid unnecessary screening for patients. But AI medical devices could also harm patients and worsen health inequities if they are not designed, tested, and used with care, according to an international task force that included a University of Rochester Medical Center bioethicist.
Jonathan Herington, PhD, was a member of the AI Task Force of the Society for Nuclear Medicine and Medical Imaging, which laid out recommendations on how to ethically develop and use AI medical devices in two papers published in the Journal of Nuclear Medicine. In short, the task force called for increased transparency about the accuracy and limits of AI and outlined ways to ensure all people have access to AI medical devices that work for them — regardless of their race, ethnicity, gender, or wealth.
While the burden of proper design and testing falls to AI developers, health care providers are ultimately responsible for properly using AI and shouldn’t rely too heavily on AI predictions when making patient care decisions.
“There should always be a human in the loop,” said Herington, who is assistant professor of Health Humanities and Bioethics at URMC and was one of three bioethicists added to the task force in 2021. “Clinicians should use AI as an input into their own decision making, rather than replacing their decision making.”
This requires that doctors truly understand how a given AI medical device is intended to be used, how well it performs at that task, and any limitations — and they must pass that knowledge on to their patients. Doctors must weigh the relative risks of false positives versus false negatives for a given situation, all while taking structural inequities into account.
When using an AI system to identify probable tumors in PET scans, for example, health care providers must know how well the system performs at identifying this specific type of tumor in patients of the same sex, race, ethnicity, etc., as the patient in question.
“What that means for the developers of these systems is that they need to be very transparent,” said Herington.

Pregnant people who gained more than the now-recommended amount of weight had a higher risk of death from heart disease or diabetes in the decades that followed, according to new analysis of 50 years of data published in The Lancet and led by researchers from the Perelman School of Medicine at the University of Pennsylvania. The group studied a large national data set that stretched from when a person gave birth through the next five decades, assessing mortality rates to show the potential long-term effects of weight gain in pregnancy. Higher risk of death was found for all weight groups studied — including those defined as underweight, normal weight, or overweight prior to their pregnancies — but no increase in risk was uncovered among those who had been obese.
“We hope that this work leads to greater efforts to identify new, effective, and safe ways to support pregnant people in achieving a healthy weight gain,” said the study’s lead author, Stefanie Hinkle, PhD,an assistant professor of Epidemiology and Obstetrics and Gynecology at Penn. “We showed that gaining weight during pregnancy within the current guidelines may protect against possible negative impacts much later in life, and this builds upon evidence of the short-term benefits for both maternal health and the health of the baby.”
As in their previous work showing links between complications in pregnancy and higher death rates in the following years, Hinkle and her colleagues — who included members of Penn’s departments of Biostatistics, Epidemiology and Informatics, and Obstetrics and Gynecology, as well as the Intramural Research Program of the National Institute of Child Health and Human Development — examined data from the Collaborative Perinatal Project. This project catalogued data from a racially diverse cohort of people who gave birth in the 1950s or 1960s and linked their records to mortality data that ran through 2016, approximately 50 years later. The researchers analyzed information from more than 45,000 people that included their body mass indices (BMI), weight changes over pregnancy, and compared these data to modern recommendations. Those numbers were then linked first to deaths of any cause, then to deaths by cardiovascular- or diabetes-related causes.
Modern recommendations for weight gain during pregnancy were set in 2009 and are linked directly to a person’s weight at the start of their pregnancy. They range from 28 to 40 pounds for people considered “underweight” by BMI standards to 11 to 20 pounds for those considered “obese.” In the present day, almost half of those who are pregnant gain more weight than recommended.
Approximately 39 percent of the people in the cohort had died by 2016, and the death rate increased in correlation with pre-pregnancy BMI — those with the lowest BMI died at a lower rate than those with the highest BMI.
Among those who were “underweight” before pregnancy but gained more than the (now) recommended amount of weight, the risk of death related to heart disease climbed by 84 percent. Among those considered to be of “normal” weight before their pregnancy (which was roughly two-thirds of the cohort), all-cause mortality rose by nine percent when they gained more weight than recommended, with their risk of heart disease-related death climbing by 20 percent. Finally, those considered “overweight” had a 12 percent increased risk of dying if they gained more weight than is now recommended, with a 12 percent increase in their risk of diabetes-related death.
The study found no correlation between high weight gain during pregnancy and subsequent deaths among those in the obese range. While their study wasn’t designed to look into that specific point, Hinkle said that it’s possible this group’s already-elevated death rate could have had a bearing on this finding.
Weight gain during pregnancy doesn’t happen in a vacuum, as health care access, nutrition, and stress can all play a significant factor in it. But now that they have a better picture of the long-term risks associated with unhealthy gains, Hinkle and her colleagues hope to find more that will help address the issue.
“We are committed to delving deeper into the various factors that can affect pregnant individuals’ ability to achieve healthy weight gain during pregnancy,” Hinkle said. “Our team is dedicated to exploring the social, structural, biological, and individual aspects that play a role in this process.”
This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development.

A first-of-its kind hormone replacement therapy that more closely replicates the natural circadian and ultradian rhythms of our hormones has shown to improve symptoms in patients with adrenal conditions. Results from the University of Bristol-led clinical trial are published today [20 October] in the Journal of Internal Medicine.
Low levels of a key hormone called ‘cortisol’ is typically a result of conditions such as Addison’s and Congenital Adrenal Hyperplasia. The hormone regulates a range of vital processes, from cognitive processes such as memory formation, metabolism and immune responses, through to blood pressure and blood sugar levels. When low, it can trigger symptoms of debilitating fatigue, nausea, muscle weakness, dangerously low blood pressure and depression. Although rare, these adrenal conditions require lifelong daily hydrocortisone replacement therapy.
Although existing oral hormone replacement treatment can restore cortisol levels, it is still associated with an impaired quality of life for patients. Scientists believe this is because the current treatment does not mimic the body’s normal physiological timing, missing cortisol’s anticipatory rise and lacking its underlying ultradian and circadian rhythms.
The new ‘Pulsatility’ therapy, the culmination of ten years research by the Bristol team, is designed to deliver standard hydrocortisone replacement to patients via a pump which replicates more closely cortisol’s natural rhythmic secretion pattern. The pulsatile subcutaneous pump has now revealed promising results in its first clinical trial.
Twenty participants aged 18 to 64 years with adrenal insufficiency conditions were assessed during the double-blinded PULSES six-week trial and treated with usual dose hydrocortisone replacement therapy administered either via the pump or the standard three times daily oral treatment.
While only psychological and metabolic symptoms were assessed during the trial, results revealed the pump therapy decreased fatigue by approximately 10%, improved mood and increased patient energy levels by 30% first thing in the morning — a key time frame when many patients struggle. Patient MRI scans also revealed alteration in the way that the brain processes emotional information.
Dr Georgina Russell, Honorary Lecturer at the University’s Bristol Medical School, and the lead author, explained: “Patients on cortisol replacement therapy often have side effects which makes it difficult for them to lead normal lives. We hope this new therapy will offer greater hope for the thousands of people living with hormone insufficiency conditions.”
Stafford Lightman, a neuroendocrinology expert and Professor of Medicine at Bristol Medical School: Translational Health Sciences (THS), and the study’s joint lead author, added: “Besides reduction in dosage, cortisol replacement has remained unchanged for many decades. It is widely recognised that current replacement therapy is unphysiological due to its lack of pre-awakening surge, ultradian rhythmicity, and post dose supraphysiological peaks. The new therapy clearly shows that the timing of cortisol delivery- in line with the body’s own rhythmic pattern of cortisol secretion — is important for normal cognition and behaviour.

Consistently sleeping less than five hours a night might raise the risk of developing depressive symptoms, according to a new genetic study led by UCL (University College London) researchers.
Historically, poor sleep has been seen as a side effect of mental ill health, but this study found that the link between sleep and mental illness is more complex.
The study, published in the journal Translational Psychiatry, analysed data from people with an average age of 65 and found short sleep was associated with the onset of depressive symptoms.
Lead author Odessa S. Hamilton (UCL Institute of Epidemiology & Health Care) said: “We have this chicken or egg scenario between suboptimal sleep duration and depression, they frequently cooccur, but which comes first is largely unresolved. Using genetic susceptibility to disease we determined that sleep likely precedes depressive symptoms, rather than the inverse.”
For the study, the researchers used genetic and health data from 7,146 people recruited by the English Longitudinal Study of Ageing (ELSA), a nationally representative population study in England.
They found that people with a stronger genetic predisposition to short sleep (less than five hours in a given night) were more likely to develop depressive symptoms over 4-12 years, but that people with a greater genetic predisposition to depression did not have an increased likelihood of short sleep.
Senior author Dr Olesya Ajnakina (UCL Institute of Epidemiology & Health Care and the Institute of Psychiatry, Psychology & Neuroscience at King’s College London) said: “Short and long sleep durations, along with depression, are major contributors to public health burden that are highly heritable. Polygenic scores, indices of an individual’s genetic propensity for a trait, are thought to be key in beginning to understand the nature of sleep duration and depressive symptoms.”
The researchers assessed the strength of genetic predisposition among the ELSA participants using findings from previous genome-wide association studies that have identified thousands of genetic variants linked to a higher likelihood of developing depression and short or long sleep.