Publisher Health

Findings from a new study conducted by a team of researchers at Dartmouth’s Geisel School of Medicine and published in the journal mBio, reflect the important role that the gut microbiome (communities of bacteria) plays in the airway health of persons with cystic fibrosis.
Cystic fibrosis is an inherited disease that causes sticky, thick mucus to build up in the lungs and other organs, causing persistent infections that can be deadly. Until relatively recently, CF microbiology research has largely been focused on microorganisms in the lungs since most CF-related deaths have been due to respiratory complications.
But interest in the CF gut microbiome and its influence on the health of organs like the lungs has grown as the role of the gut microbiome in broader health outcomes has become more apparent.
For George O’Toole, PhD, and his colleagues at the Dartmouth Cystic Fibrosis Research Center(DartCF), the journey to better understand the gut-lung connection began more than 10 years ago, as part of a collaboration with physician-scientist Juliette Madan, MD, MS, who studies children with CF at Dartmouth Hitchcock Medical Center (DHMC).
“One of the key observations that Dr. Madan made early on was that, surprisingly, the best predictor of how a kid’s airway would function actually turned out to be the microbes in their gut rather than the microbes in their airway,” explains O’Toole, the Elmer R. Pfefferkorn, PhD, Professor of Microbiology and Immunology at Geisel and anchor author on the study. “We also had noticed that kids with CF were depleted for Bacteroides, a microbe known to be important in programming gut function and the immune system early in life.”
The findings prompted them to do some experiments in which they were able to show that secreted products from these Bacteroides strains could reduce inflammation in gut-derived cell lines grown in the lab. In further experiments, they were able to narrow down the molecule that was important for that process — a short-chain fatty acid known as propionate.
To reinforce their hypothesis, the team did experiments in mice with the same CF mutation as humans which showed that those mice that had Bacteroides introduced into their guts had less inflammation in their blood and airways after being exposed to Pseudomonas aeruginosa — a common bacterium in CF infections — than other similar mice that were not given Bacteroides. Importantly, a Bacteroides variant that could not make propionate could not reduce inflammation.
“We think this establishes the idea that changes in the gut are causing a reprogramming of the immune system in such a way that the body isn’t as sensitive to subsequent airway infections, so you don’t have as much disease burden,” says O’Toole. “The other exciting finding is that this actually provides, we think, a proof of concept that probiotics could be beneficial to kids with CF, so it could have important implications for treatments.”
O’Toole is quick to credit his colleagues at Geisel and at DHMC for their contributions to the study, which in addition to Madan’s clinic involved three labs in the CF Center and utilized microbiology experiments, tissue culture work, and animal studies. The Bliska, Cramer, and Ross groups at Geisel contributed to this study.
“There were a lot of moving parts to this project, so we needed a lot of help to get it all done,” he says. “We’re grateful, not only for the expertise that people provided but also for their willingness to participate. The culture of collaboration is core at DartCF, I think, to the success of our group and this is just a nice example of that.”

Blockage of arterial blood vessels caused by atherosclerosis is largely responsible for heart attacks and strokes, which are the most common causes of death worldwide. The complex mechanisms that lead to pathological changes in the arteries are not yet fully understood. An international research team led by the Medical University of Vienna and the University Hospital of Würzburg has now made important progress in understanding this disease and identified potential new approaches for early detection and therapy. The results of the study were recently published in the scientific journal Nature Cardiovascular Research.
Researchers already know that specialised cells called macrophages are central to the development of atherosclerosis. These cells play a critical role in the formation of so-called plaques, which narrow or block the arteries and can lead to dangerous complications — above all heart attacks and strokes. However, the exact mechanisms of how macrophages function in this process are not yet fully understood.
In the search for the solution to this puzzle, Christoph Binder and Florentina Porsch from MedUni Vienna’s Department of Laboratory Medicine, in collaboration with Clément Cochain, Alma Zernecke and Marie Piollet from the University Hospital of Würzburg, took a closer look at the protein TREM2. TREM2 (TREM = Triggering Receptor Expressed on Myeloid Cells) controls the activity of macrophages and therefore has a potential influence on the development of atherosclerosis. The study results indicate that TREM2 plays an important role in the formation of unstable plaques, which are particularly susceptible to rupture and thus increase the risk of heart attacks and strokes. By regulating the survival of so-called foam cells, which are particularly common in atherosclerotic plaques, and by promoting the degradation and removal of damaged or dying cells, TREM2 helps to limit the formation of these dangerous plaques.
Important insight into complex mechanisms
The evidence obtained in the study that the treatment of mice prone to atherosclerosis with a specific antibody against TREM2 was able to reduce the formation of these unstable plaques is particularly promising. TREM2 thus emerges as a new therapeutic target for stabilising plaques, which could prevent heart attacks and strokes. In addition, the researchers were able to establish a link between a soluble form of this protein (“sTREM2”) and the progression of atherosclerosis. TREM2 could therefore not only enable new approaches for the treatment of the disease but also serve as a potential biomarker for early detection. “Our results provide an important insight into the complex mechanisms of atherosclerosis and open up new avenues for the development of effective therapies,” the researchers summarise the relevance of their work in the run-up to further studies.

A new study published in the American Journal of Obstetrics & Gynecology, published by Elsevier, challenges the prevailing view on the maternal death rate in the United States. The findings show that the rates of maternal death were stable between 1999-2002 and 2018-2021, instead of the dramatic upward trends previously reported by the National Vital Statistics System (NVSS), Centers for Disease Control and Prevention (CDC). Additionally, the study indicates that direct obstetric causes of death declined over the last 20 years.
To determine whether the reported maternal death rates are accurate, a team of researchers took a deep dive into the underlying data and looked at the factors driving the increase, namely, changes in obstetric factors, maternal chronic conditions, and surveillance issues (i.e., changes in data collection methods). Maternal deaths refer to those occurring during pregnancy, childbirth, or the postpartum period from conditions directly related to pregnancy or those exacerbated by pregnancy and birth (accidental and incidental deaths in pregnancy are not included in the maternal death definition).
Lead author K.S. Joseph, MD, PhD, Department of Obstetrics and Gynaecology, University of British Columbia and the Children’s and Women’s Hospital and Health Centre of British Columbia; and School of Population and Public Health, University of British Columbia, said “Our study showed that maternal mortality rates were low and stable between 1999-2002 and 2018-2021, which is very different from the high rates and dramatic increases reported by the NVSS in recent years. We found that exclusive reliance on the pregnancy checkbox on death certificates, without corroboration from the cause-of-death information, led to an overestimation of maternal mortality rates by the NVSS in 2018-2021.”
Researchers examined all deaths in the US between 1999 and 2021 using an approach that enables greater accuracy in how maternal deaths are identified and classified in the mortality database. The study uncovered several indications that the pregnancy checkbox was responsible for misclassifying nonmaternal and incidental deaths in pregnancy as maternal deaths. These included a 46-fold increase in maternal deaths among women with malignant neoplasms (which likely represent incidental deaths in pregnancy and not maternal deaths). Also, a substantially higher proportion of maternal deaths identified by the pregnancy checkbox had a single entry in the cause-of-death section, which requires a listing of all the immediate, intermediate, contributory, and underlying causes of death (thus suggesting a less thorough approach to death certification).
Although the pregnancy checkbox was introduced on death certificates in 2003 to improve identification of maternal death, its use between 2003 and 2017 was associated with some substantial errors. A detailed investigation by the National Center for Health Statistics (NCHS), CDC showed that the checkbox was erroneously ticked in many cases, leading to misclassification and overestimation of maternal death. For example, hundreds of decedents, 70 years of age and older (including 147 women aged 85 years and older in 2013), were certified as pregnant at the time of death or in the year prior. The NCHS concluded that the entire increase in maternal mortality in the US between 2003 and 2017 was due to the pregnancy checkbox. In response, NCHS made specific changes regarding pregnancy checkbox use for deaths from 2018 onwards but NVSS reports show that maternal mortality rates have continued to increase (nearly doubling from 2018 to 2021).
Roberto Romero, MD, DMedSci, Editor-in-Chief for Obstetrics of the American Journal of Obstetrics & Gynecology (AJOG), and Chief of the Pregnancy Research Branch of NICHD, NIH, stated, “Accurate assessment of the number and causes of maternal death is an important priority for countries and healthcare policymakers. Improving maternal mortality surveillance is key to formulating plans to improve maternal health. Comparisons of the rate of maternal death among countries should be interpreted with great caution because the methods of surveillance and accuracy differ. The article by Dr. Joseph and a distinguished group of epidemiologists and obstetricians published in AJOG calls attention to the need to improve surveillance in the United States and to thoughtful interpretation of reported statistics.”
Co-author Justin S. Brandt, MD, Director of the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, NYU Grossman School of Medicine, notes, “By not relying on the pregnancy checkbox, our approach avoided the misclassification that has given the false impression of increasing maternal mortality rates in the US. Identifying maternal deaths by requiring mention of pregnancy among the multiple causes of death shows stable maternal mortality rates and declines in maternal deaths from direct obstetric causes.”
The research team previously published a study on maternal mortality in the US in 2017, which also showed stable rates of maternal mortality from 1999 to 2014. As mentioned, their results were subsequently validated by a detailed investigation carried out by the NCHS and published in January 2020.

Although the study’s findings contradict the mainstream narrative of high and rising rates of maternal death in the US, the results are consistent with changes in maternal characteristics and improvements in obstetric practice. For instance, the increase in maternal deaths due to specific placental complications (i.e., placenta accreta spectrum disorder) observed in their study is consistent with increases in deliveries to women with a previous cesarean delivery. Similarly, the reduction in maternal deaths due to hypertensive disorders in pregnancy (i.e., preeclampsia/eclampsia), blood clot embolism (i.e., thromboembolism), and infection (i.e., puerperal sepsis) is consistent with advances in the obstetric management of these conditions.
The study also showed a reduction in overall maternal mortality, and especially in maternal deaths from direct obstetric causes among non-Hispanic Blacks, which is encouraging. However, the disproportionately high rate of maternal death among Non-Hispanic Blacks in 2018-21 and the persistent racial/ethnic disparities are concerning, as is the small increase in direct obstetric deaths among non-Hispanic Whites.
Co-author Cande Ananth, PhD, MPH, MD, Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences; Cardiovascular Institute of New Jersey and Department of Medicine; and Environmental and Occupational Health Sciences Institute, Rutgers, Robert Wood Johnson Medical School; and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, elaborates, “Our analysis suggests that people who are Black remain at much higher risk of dying due to pregnancy complications compared with people who are White. The continuing disparities in maternal mortality rates are concerning and deserve strategic and focused efforts to combat structural racism and designed to address chronic conditions disproportionately represented in this subpopulation.”
The study provides important insights into cause- and race/ethnicity-specific maternal mortality and provides suggestions for the appropriate use of the pregnancy checkbox on death certificates. The authors hope that these findings will serve as the evidentiary basis for clinical and public health initiatives for reducing maternal mortality.

Researchers at the National Institutes of Health (NIH) have discovered that symptoms of attention-deficit/hyperactivity disorder (ADHD) are tied to atypical interactions between the brain’s frontal cortex and information processing centers deep in the brain. The researchers examined more than 10,000 functional brain images of youth with ADHD and published their results in the American Journal of Psychiatry. The study was led by researchers at NIH’s National Institute of Mental Health (NIMH) and National Human Genome Research Institute.
Luke Norman, Ph.D., a staff scientist in the NIMH Office of the Clinical Director, and colleagues analyzed brain images supplied by more than 8,000 youth with and without ADHD sourced from six different functional imaging datasets. Using these images, the researchers examined associations between functional brain connectivity and ADHD symptoms.
They found that youth with ADHD had heightened connectivity between structures deep in the brain involved in learning, movement, reward, and emotion (caudate, putamen, and nucleus accumbens seeds) and structures in the frontal area of the brain involved in attention and control of unwanted behaviors (superior temporal gyri, insula, inferior parietal lobe, and inferior frontal gyri).
While neuroscience researchers have long suspected that ADHD symptoms result from atypical interactions between the frontal cortex and these deep information-processing brain structures, studies testing this model have returned mixed findings, possibly due to the small nature of the studies, with only 100 or so subjects. Researchers suggest that the smaller studies may not have been able to reliably detect the brain interactions leading to the complex behaviors seen in ADHD.
The findings from this study help further our understanding of the brain processes contributing to ADHD symptoms — information that can help inform clinically relevant research and advancements.

Are sleeping pills the only solution for insomnia? Not according to Flinders University’s Dr Alexander Sweetman, who says that using self-guided digital behavioural therapy is an alternative solution that should be considered.
Despite a wealth of evidence supporting the effectiveness of cognitive behavioural therapy for insomnia (CBTi), access to this ‘first line’ treatment is extremely limited due to a shortage of CBTi trained psychologists.
In Australia, approximately 90 per cent of primary care patients with insomnia are managed with sleeping pills while only 1 per cent are referred to psychologists for CBTi.
To increase accessibility to CBTi and reduce the reliance on sleeping pills, sleep experts at Flinders University and the University of Western Australia designed and tested the effectiveness of a self-guided digital CBTi program called ‘Bedtime Window’ to treat insomnia.
“We tested a new CBTi program in people with insomnia symptoms throughout Australia and found it very easy to use, delivering significant and sustained improvements in sleep, daytime function and mental health,” says Dr Alexander Sweetman, who led the latest research published today in Frontiers in Sleep.
“We know that CBTi improves insomnia, mental health and quality of life and we want to see more people accessing this treatment because it can reduce the need for sleeping pills or other interventions which may not tackle long-term sleep problems,” he says.
Insomnia and obstructive sleep apnoea (OSA) are the two most prevalent sleep disorders and frequently co-occur. Approximately 30-40 per cent of people with insomnia have co-morbid OSA however most people with OSA remain undiagnosed and untreated.

“People with co-morbid insomnia and sleep apnoea (COMISA) generally have worse sleep, daytime function, mental health, physical health, productivity and quality of life when compared to people with neither sleep disorder, and often when compared to people with either insomnia-alone or OSA-alone,” says Dr Sweetman.
“Recent studies found that people with COMISA experience a 50-70 per cent increased risk of mortality over 10-20 years of follow-up, compared to people with neither condition.
“Given the high prevalence and adverse health risks of COMISA, it is vital that we develop and implement an effective evidence-based management approach for this condition,” he says.
“To increase CBTi access for people with COMISA, we developed the self-guided interactive digital CBTi program that is appropriate for people with insomnia-alone and COMISA and compared its effectiveness between people with insomnia-alone, versus comorbid insomnia and high-risk sleep apnoea.”
62 adults with insomnia symptoms used ‘Bedroom Window’ over an 18-month period and reported significant and sustained improvements in symptoms of insomnia and associated mental health symptoms.
“The program is designed for people with insomnia-alone and COMISA. Each weekly session lasts for approximately 20-30 minutes and includes short videos, images and text-based information,” he says. “Treatment components include psychoeducation, stimulus control therapy, sleep restriction therapy, relaxation therapy, cognitive therapy and sleep hygiene information.
“The program includes algorithms that continuously assess for symptoms of sleepiness and alertness and provides tailored and interactive recommendations to treat insomnia without worsening levels of daytime sleepiness.
“The positive results of our study highlight the potential to investigate the effectiveness, safety and acceptability of this digital CBTi program in people with a confirmed diagnosis of OSA, before increasing access to people with COMISA throughout the health system,” adds Dr Sweetman.

A largescale new study has found that some people whose genetics are linked to the common iron overload condition haemochromatosis have substantially greater levels of liver, musculoskeletal and brain disease than previously reported, especially at older ages.
Haemochromatosis causes a build-up of iron in the body which can cause harm to joints and organs — although the extent of this harm is unclear, especially in older ages. The new research, led by a team at the University of Exeter and supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre, found higher levels of disease plus greater mortality in males, especially after age 65.
Published in BMJ Open, the research analysed data from more than 450,000 European Ancestry participants in UK Biobank, over a 13 year follow-up, making it the largest-scale study to look at disease outcomes linked to haemochromatosis. For the first time, the team provided data on clinical outcomes up to the age of 80 years on people who carry genes linked to haemochromatosis, providing insight into how the condition affects older age groups, including those who were undiagnosed at baseline.
Dr Janice Atkins, Senior Research Fellow at the University of Exeter and study co-author, said: “Haemochromatosis is the most common genetic disorder in people of Northern European ancestry, yet we are still learning the extent to which it causes harm. Our study is the most comprehensive to date and reveals higher levels of death and organ and joint damage than previously known, including liver disease and joint replacements.”
In UK Biobank, 2,902 people (0.6 % of participants) had two copies of the genetic variant (C282Y) which mean they are at risk of the condition. Of these people, who had a mean age of 57, only a small proportion were diagnosed with haemochromatosis at the start of the study- 12% of males and 3.4% of females.
By the times males with the two genetic variants had reached the age of 80, the study found that 33.1% had died, compared to 25.4% without thevariants. The study also found that 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there was higher delirium, non Alzheimer’s dementia, and Parkinson’s disease in those with the two gene variants.
In females by age 80, those with both genetic variants had higher levels of liver disease (8.9% vs 6.8%), joint replacements and delirium.

Haemochromatosis is more common in males, and particularly affects white people of Northern European ancestry. An estimated 175,000 men of European ancestry in the UK have the two gene variations that cause haemochromatosis. The disorder is known as the “Celtic curse” because it is particularly prevalent in Celtic bloodlines.
Reliable tests are available to identify those at risk — blood tests for measuring iron levels and genetic testing. Symptoms can include feeling tired all the time, muscle weakness and joint pains, meaning it is often misdiagnosed as the usual signs of ageing. Once diagnosed, the condition is easily treated by a process similar to donating blood several times a year, to lower iron levels. The blood can be donated to the NHS transfusion service once iron levels have reduced enough.
Professor David Melzer, who leads the research team, said: “These findings highlight the need for earlier diagnosis of iron overload, as many people with the high risk genetic variants are currently diagnosed too late to prevent organ damage. The condition can be picked up with a simple blood iron test, and it is encouraging that more and more GPs are aware of the need to test for iron overload. The research results also contained very good news for people with the milder genetic variants (called C282Y/H63D and H63D homozygotes), with no excess of fatigue, liver fibrosis, diabetes or arthritis, adding to the evidence that these variants are benign. Of course, some people with these variants will unfortunately have fatigue, liver fibrosis, arthritis or diabetes, but this happens at the same rate as people without these gene variants and underlines the need to investigate the other causes of these conditions too.”
Study co-author Dr Jeremy Shearman, Consultant Hepatologist and Gastroenterologist at South Warwickshire University NHS Foundation Trust, said: “This important data supports the long-held belief that we should be using targeted genetic testing more consistently to make an earlier and more accurate diagnosis of haemochromatosis. It is a common condition here in the UK and can be easily treated to avoid serious harm.”

Many children announce their arrival in the delivery room with a piercing cry. As a newborn automatically takes its first breath, the lungs inflate, the blood vessels in the lungs widen, and the whole circulatory system reconfigures itself to life outside the womb. This process doesn’t always go to plan, however. Some infants — particularly those who are very sick or born prematurely — suffer from pulmonary hypertension, a serious disorder in which the arteries to the lungs remain narrowed after delivery or close up again in the first few days or weeks after birth. This constricts the flow of blood to the lungs, reducing the amount of oxygen in the blood.
Prompt diagnosis and treatment improve prognosis
Severe cases of pulmonary hypertension need to be detected and treated as rapidly as possible. The sooner treatment begins, the better the prognosis for the newborn infant. Yet making the correct diagnosis can be challenging. Only experienced paediatric cardiologists are able to diagnose pulmonary hypertension based on a comprehensive ultrasound examination of the heart. “Detecting pulmonary hypertension is time-consuming and requires a cardiologist with highly specific expertise and many years of experience. Only the largest paediatric clinics tend to have those skills on hand,” says Professor Sven Wellmann, Medical Director of the Department of Neonatology at KUNO Klinik St. Hedwig, part of the Hospital of the Order of St. John in Regensburg in Germany.
Researchers from the group led by Julia Vogt, who runs the Medical Data Science Group at ETH Zurich, recently teamed up with neonatologists at KUNO Klinik St. Hedwig to develop a computer model that provides reliable support in diagnosing the disease in newborn infants. Their results have now been published in the International Journal of Computer Vision.
Making AI reliable and explainable
The ETH researchers began by training their algorithm on hundreds of video recordings taken from ultrasound examinations of the hearts of 192 newborns. This dataset also included moving images of the beating heart taken from different angles as well as diagnoses by experienced paediatric cardiologists (is pulmonary hypertension present or not) and an evaluation of the disease’s severity (“mild” or “moderate to severe”). To determine the algorithm’s success at interpreting the images, the researchers subsequently added a second dataset of ultrasound images from 78 newborn infants, which the model had never seen before. The model suggested the correct diagnosis in around 80 to 90 percent of cases and was able to determine the correct level of disease severity in around 65 to 85 percent of cases.
“The key to using a machine-learning model in a medical context is not just the prediction accuracy, but also whether humans are able to understand the criteria the model uses to make decisions,” Vogt says. Her model makes this possible by highlighting the parts of the ultrasound image on which its categorisation is based. This allows doctors to see exactly which areas or characteristics of the heart and its blood vessels the model considered to be suspicious. When the paediatric cardiologists examined the datasets, they discovered that the model looks at the same characteristics as they do, even though it was not explicitly programmed to do so.
A human makes the diagnosis
This machine-learning model could potentially be extended to other organs and diseases, for example to diagnose heart septal defects or valvular heart disease.
It could also be useful in regions where no specialists are available: standardised ultrasound images could be taken by a healthcare professional, and the model could then provide a preliminary risk assessment and an indication of whether a specialist should be consulted. Medical facilities that do have access to highly qualified specialists could use the model to ease their workload and to help reach a better and more objective diagnosis. “AI has the potential to make significant improvements to healthcare. The crucial issue for us is that the final decision should always be made by a human, by a doctor. AI should simply be providing support to ensure that the maximum number of people can receive the best possible medical care,” Vogt says.

Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients — especially glucose and oxygen — to activate all neuronal functions. Now, a study led by the University of Barcelona and the Bellvitge Biomedical Research Institute (IBIDELL) reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system.
According to the study, featured on the cover of the journal JCI Insight, the TDP-43 protein is also critical in maintaining the integrity of the blood-brain barrier, which prevents toxins and pathogens from reaching the central nervous system.
The project is led by Professor Eloi Montañez, from the Faculty of Medicine and Health Sciences of the University of Barcelona and IDIBELL, and involves teams from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB), the Josep Carreras Leukaemia Research Institute, and the National Centre for Genomic Analysis (CNAG-CRG).
What is the role of the TDP-43 protein in the vascular system?
The TDP-43 protein is a key factor in nervous system function and neuronal plasticity. It is a DNA- and RNA-binding protein that regulates gene expression, and its dysfunction has been associated with various neurodegenerative disorders.
Although much progress has been made recently in understanding the functions of TDP-43 in neurons, its exact role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis) and vascular function was not yet known.
“The study reveals for the first time that TDP-43 is essential for the formation and stability of blood vessels in the central nervous system, and for the integrity of the blood-brain barrier,” says Professor Montañez, from the UB’s Department of Physiological Sciences.

The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signalling pathways. For example, the integrin signalling pathway that regulates the interaction of cells with the extracellular matrix and the signalling carried out by the transcription factor β-catenin.
“In the study, we found that TDP-43 deficiency alters the extracellular matrix that surrounds blood vessels and reduces β-catenin signalling in endothelial cells,” says the researcher. “Thus, mice without endothelial TDP-43 protein show multiple haemorrhages and vascular degeneration in the brain and spinal cord.”
Vascular defects and inflammatory response in neurosciences
The authors also identify TDP-43 in endothelial cells as a potential contributing factor to the vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases.
“Some alterations in the blood vessels of the central nervous system — defects in the integrity of the blood-brain barrier or degeneration of endothelial cells — are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration underlies the origin or progression of various neurological disorders — stroke, diabetic retinopathy — and some neurodegenerative diseases such as Alzheimer’s disease, ALS or LATE (Limbic-predominant age-related TDP- 43 encephalopathy).
The study will help to better understand the molecular mechanisms linking vascular defects and neuroinflammation. “Our goal now is to analyse whether defects in TDP-43 protein function in the endothelium of mature vessels could be involved in ALS or other TDP-43-associated pathologies due to increased vascular permeability or inflammatory processes,” Montañez concludes.

The emergence of drug-resistant bacteria is a global threat to human health, and the development of new antibiotics from scratch is an extremely expensive and time-consuming process. To address this urgent issue, researchers from the University of Kent’s School of Biosciences have combined computational and microbiology laboratory approaches to identify existing drugs that can be repurposed to combat antibiotic-resistant bacterial infections.
This research, which has been published in the Journal of Infectious Diseases, revealed that a class of steroid drugs currently used in hormone replacement therapy (HRT) can also stop the growth of antibiotic-resistant E. coli and effectively kill MRSA. These drugs are particularly good at binding to a protein complex, cytochrome bd, which is important for the growth and survival of a range of disease-causing bacterial species. It is expected that steroids may provide an alternative to conventional antibiotics that are becoming increasingly ineffective.
Dr Mark Shepherd, Reader in Microbial Biochemistry at Kent and the corresponding author on the paper, said: ‘These exciting developments will help to advance research into new antimicrobials, and we are enthusiastic to use our powerful experimental approach to discover drugs that can target other bacterial proteins and combat a wide range of antibiotic-resistant infections.’
The article ‘Steroid Drugs Inhibit Bacterial Respiratory Oxidases and Are Lethal Toward Methicillin-Resistant Staphylococcus aureus’ is published in the Journal of Infectious Diseases (University of Kent: Samantha A. Henry, Calum M. Webster, Mark N. Wass, Gary K. Robinson and Mark Shepherd).

Targeting two brain tumor-associated proteins — rather than one — with CAR T cell therapy shows promise as a strategy for reducing solid tumor growth in patients with recurrent glioblastoma (GBM), an aggressive form of brain cancer, according to early results from the first six patients treated in an ongoing Phase I clinical trial led by researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center. The findings, published today in Nature Medicine, suggest that this “dual-target” approach is an encouraging step toward developing effective, long-lasting therapies for solid tumors like GBM.
“This is the first time CAR T cell therapy with two targets, rather than just one, has been administered to patients with glioblastoma,” said Stephen Bagley, MD, MSCE, an assistant professor of Hematology-Oncology, and Neurosurgery, and principal investigator in the clinical trial. “Our results suggest that this is a step in the right direction, and this method, when delivered through a patient’s spinal fluid, could be the key to developing therapies that outsmart the complicated defense systems of GBM.”
GBM is the most common — and most aggressive — type of cancerous brain tumor in adults. Individuals with GBM usually expect to live 12-18 months following their diagnosis. Despite decades of research, there is no known cure for GBM, and approved treatments — such as surgery, radiation, and chemotherapy — have limited effect in prolonging an individual’s life expectancy. However, even after aggressive treatment, GBM returns in most patients, which is known as recurrent GBM. The median survival rate for recurrent GBM is less than one year.
CAR T cell therapy uses a patient’s own immune system to fight cancer; a patient’s T cells — the white blood cells that find and fight illness and infection in the body — are removed, re-programmed to recognize proteins, or antigens, characteristic of a specific type of cancer, and then returned to the body, where they seek out and destroy these cancer cells. CAR T cell therapy is FDA approved to fight a number of blood cancers, like leukemia, but researchers have struggled to engineer cells to successfully seek out and kill solid tumors, which make up the vast majority of cancer types, including GBM.
“The challenge with GBM and other solid tumors is tumor heterogeneity, meaning not all cells within a GBM tumor are the same or have the same antigen that a CAR T cell is engineered to attack, and every person’s GBM is unique to them, so a treatment that works for one patient might not be as effective for another,” said Bagley. “What’s more, GBM tumors can evade a patient’s immune system, and block immune cells — both engineered CAR T cells, and a patient’s own immune cells — that might otherwise fight the tumor. Our challenge is getting our treatment around the tumor’s defenses so we can kill it.”
In this trial, researchers used a technology developed in the lab of Donald M. O’Rourke, MD, the John Templeton, Jr., MD Professor in Neurosurgery and director of the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center, and scientific advisor to the trial. This technique delivers CAR T cells targeting two proteins commonly found in brain tumors: epidermal growth factor receptor (EGFR), which is estimated to be present in 60 percent of all GBMs, and interleukin-13 receptor alpha 2 (IL13Rα2), which is expressed in over 75 percent of GBMs. While CAR T cell therapy for blood cancers is typically delivered through an IV, researchers administered these dual-target CAR T cells intrathecally, through an injection into the cerebrospinal fluid, so that the engineered cells could reach the tumors more directly in the brain.
MRI scans 24 to 48 hours after dual-target CAR T cells targeting EGFR and IL13Rα2 that were administered revealed reduced tumor sizes in all six patients, and these reductions have been sustained out to several months later in a subset of patients.

“We are energized by these results, and are eager to continue our trial, which will give us a better understanding of how this dual-target CAR T cell therapy affects a wider range of individuals with recurrent GBM,” said
O’Rourke. “This cancer is unique in each individual, so a wider range of patients will help us determine the optimal dose, better understand effects like neurotoxicity, and more firmly establish efficacy.”
A major concern with CAR T cell therapy, especially when delivered to the brain, is neurotoxicity, which occurs when a toxic substance alters the activity of the nervous system, and can disrupt or kill brain cells, called neurons. The researchers report that in all six patients treated with CAR T cell therapy in this trial, neurotoxicity was substantial but manageable.
For more information on CAR T research at Penn Medicine, visit: https://www.pennmedicine.org/cancer/navigating-cancer-care/treatment-types/immunotherapy/what-is-car-t-therapy
For more information on glioblastoma research and clinical trials at Penn Medicine, visit: https://www.pennmedicine.org/brain-tumor
This research is funded by Kite, a Gilead Company, (NCT05168423), and grants from the National Institutes of Health (R35NS116843 and R35NS097370).