Publisher Health

The ADHD medication lisdexamfetamine was associated with the lowest risk of hospitalisation and death in people with amphetamine addiction, when medications generally used among persons with substance use disorders were compared. This is shown in a large registry-based study by researchers at Karolinska Institutet in Sweden in collaboration with the University of Eastern Finland and Niuvanniemi Hospital, published in JAMA Psychiatry.
“Our results suggest that lisdexamfetamine is associated with the best outcomes, and encourage the conduction of randomized controlled trials to explore this further,” says Jari Tiihonen, professor at the Department of Clinical Neuroscience, Karolinska Institutet, and the study’s last author.
Amphetamines are the second most used illicit drugs in the world and amphetamine-related hospitalisations are increasing substantially.
However, there are currently no approved pharmacological interventions available for treating addiction to amphetamine or the variant methamphetamine. Certain medications have shown promising results, but to date, the studies have often been small and convincing evidence is lacking.
In the present study, the researchers investigated the association between generally used medications among persons with substance use disorder and the risk of two primary outcomes in people with amphetamine or methamphetamine use disorder: 1) hospitalisation due to substance use disorder or 2) hospitalisation due to any cause, or death.
The study included nearly 14,000 individuals; all residents aged 16 to 64 years living in Sweden with a registered first-time diagnosis of amphetamine or methamphetamine use disorder from July 2006 to December 2018. Individuals with schizophrenia or bipolar disorder were excluded.

Myocarditis is a complication that can occur in cancer patients treated with immune checkpoint inhibitors. Although the adverse event is rare — affecting less than 1% of patients given the immunotherapy — the mortality rate is nearly 50%. Now, researchers from Vanderbilt-Ingram Cancer Center have identified the mechanism for the deadly heart inflammation.
The researchers discovered that T-cells recognizing the cardiac antigen α-myosin are the mechanism for this complication, setting the framework to identify biomarkers so at-risk patients can be recognized and medical strategies developed for them to tolerate the immunotherapy. Their findings are reported Nov. 16 in Nature.
“In 2016, our research group first described two melanoma patients treated with immunotherapy who developed myocarditis, and performed some early studies linking the activity of T cells in the heart to the condition, work which was published in The New England Journal of Medicine,” said Justin Balko, PharmD, PhD, Ingram Associate Professor of Cancer Research and a co-corresponding author of the study.
“Subsequently, working the Nobel laureate James P. Allison, PhD from MD Anderson Cancer Center in Houston, we helped characterize a mouse model that seemed to replicate what we had observed in patients (published in Cancer Discovery in 2020). Using that same model, together with oncologist Douglas Johnson, MD, MSCI at Vanderbilt and co-corresponding author Javid Moslehi, MD, at UCSF, we were able to pinpoint the mechanism of why it occurs — and importantly — translate this back to patients. This discovery represents the next important step to making these often-effective therapies safer in patients.”
The research team obtained cardiac samples and peripheral blood from three patients who had suffered severe myocarditis after being treated with immune checkpoint inhibitors. These samples were analyzed after the team replicated immunotherapy-related myocarditis in a mouse model. The researchers sequenced individual T cells invading the heart during myocarditis in the mouse models to reconstruct their receptors. These T cell receptors were then screened against peptides to determine specificity. After determination of the specific peptide, the researchers analyzed the human samples and found that the three patients had reactive T cells to this same antigen source — a protein called α-myosin, which is expressed only in heart and skeletal muscles.
“The extension of our findings from the mouse model to human patients was a key part of our work. These results show how useful it is to have a mouse model where you can make an initial discovery and use that to understand something about human disease. Our data show that α-myosin is a disease-relevant autoantigen in patients with immunotherapy-related myocarditis. We hope this mechanistic understanding of this often-deadly complication can pave the way toward making immunotherapy safer for patients,” said the study’s lead author, Margaret Axelrod, PhD, a Vanderbilt Medical Scientist Training Program student who completed her PhD in Balko’s Lab.
Clinicians currently do not have a clear understanding for why immunotherapy-related myocarditis occurs in some patients. Although early treatment with steroids can improve survival chances, a more effective treatment is needed. The study is the first to identify the role of α-myosin in the mechanism of heart complications from immune checkpoint inhibitors. The study is also among the first to identify a candidate autoantigen for an immunotherapy toxicity in humans.
“While autoreactive T cells are the presumed mechanism for many toxicities to immunotherapies, tracing the condition back to a specific T cell receptor (often unique to each patient) and antigen source (drawing from tens to hundreds of thousands of potential antigens in the human body) is a daunting task,” Balko said.
The research received support from the Susan and Luke Simons Directorship, Van Stephenson Memorial Cancer Research Fund, the James C. Bradford Jr. Fund in Melanoma Cancer Research, and grants from the National Institutes of Health.
Vanderbilt researchers who are co-authors of the study are Wouter Meijers, MD, PhD, Elles Screever, Juan Qin, PhD, Mary Grace Carroll, Xiaopeng Sun, Elie Tannous, MD, Yueli Zhang, Ayaka Sugiura, PhD, Brandie Taylor, Ann Hanna, PhD, Kaushik Amancherla, MD, Warren Tai, MD, Jordan Wright, MD, PhD, Susan Opalenik, PhD, Abigail Toren, Jeffrey Rathmell, PhD, P. Brent Ferrell, MD, Elizabeth Phillips, PhD, Simon Mallal, MBBS, and Douglas Johnson, MD, MSCI.

Clostridioides difficile, often referred to as C. difficile or C. diff, is a bacterium that causes severe intestinal illness and, as its name suggests, can be difficult to study and treat. Approximately 1 in 6 patients infected with C. difficile will be reinfected within two months. Yet scientists have not figured out why C. difficileinfection is more difficult to treat in some patients versus others. The human gut is filled with trillions of microbes, and these microbes influence the virulence of various pathogens, but until now, scientists had little understanding of how C. difficile cooperates with the rich collection of microorganisms in the gastrointestinal tract.
In a new study in Nature, researchers at Children’s Hospital of Philadelphia (CHOP) have found that Enterococcus — an antibiotic-resistant, opportunistic pathogen — works together with C. difficile, reshaping and enhancing the metabolic environment in the gut so that C. difficile can thrive.
“When we talk about bacterial infections, we often just think of the pathogen itself, but the ‘bystanders’ in the gut can have a huge impact on the course of infection,” said senior author Joseph P. Zackular, PhD, Investigator and Assistant Professor of Pathology and Laboratory Medicine at Children’s Hospital of Philadelphia. “This study reveals that the coincidence of two pathogenic organisms — Enterococcus and C. difficile — is more than a coincidence; they truly take advantage of each other. Understanding this relationship, as well as other factors that contribute to clinical outcomes of C. difficile infection, is essential for combating this urgent public health challenge.”
Prior studies have shown that adults infected with C. difficile also have high levels of Enterococcus in their gut and that vancomycin-resistant Enterococcus (VRE) frequently co-infects patients with C. difficile. However, the effect of Enterococcus on susceptibility to C. difficile infection and clinical outcomes has not been established.
To further define the association between Enterococcus and C. difficile during infection, the researchers analyzed stool samples from 54 pediatric patients infected with C. difficile. Consistent with studies in adults, the researchers found the stool of these patients had high levels of Enterococcus, as well as a positive correlation between enterococcal and C. difficile burdens.
Having confirmation that enterococci are highly abundant in the gut of children with a C. difficile infection and that this positively correlates with C. difficile burden, the researchers then validated the mechanism of how these two pathogens work together. Using both in vitro and in vivo experimental models, they found that enterococci increase C. difficilevirulence by enhancing its production of toxins.
Then, using data ranging from transcriptomics to metabolomics — that is, the study of the RNA transcripts and metabolites related to these pathogens — the researchers found that enterococcireshape the gut environment, effectively remodeling the house the C. difficile pathogen walks into and making it more conducive for the pathogen to thrive. They found that enterococci use arginine, an amino acid, for energy and that in the process of doing so, the pathogen exports ornithine, another amino acid. Further analysis showed that enterococci modulate levels of arginine and ornithine in the gut during C. difficile infection and that arginine depletion plays a central role in C. difficile virulence.
Finally, the researchers explored whether their findings in the lab correlated with findings in human patients. Analyzing the microbiome of children with C. difficile infection and inflammatory bowel disease (IBD), they found that these children had high levels of fermentable amino acids, including ornithine. They also observed a positive correlation between C. difficile burdens and ornithine, supporting a key role for this amino acid in C. difficile infection.
“Collectively, these data suggest that enterococci and C. difficile interact during C. difficile infection through metabolic cross-talk to support increased colonization, pathogenesis and persistence in the gut,” Dr. Zackular said. “Future research should explore targeting enterococcal metabolism — and the resulting amino acid landscape in the gut — as a way of altering the pathogenesis of C. difficile.”
This work was done in collaboration with researchers at the University of Pennsylvania, University of Florida, Vanderbilt University School of Medicine, University of Virginia, University of Pittsburgh, and University of Minnesota Medical School.
Smith et al. “Enterococci enhance Clostridioides difficile pathogenesis,” Nature, online November 16, 2022, DOI: 10.1038/s41586-022-05438-x.

Preserving and restoring natural habitats could prevent pathogens that originate in wildlife from spilling over into domesticated animals and humans, according to two new companion studies.
The research, based in Australia, found that when bats experience loss of winter habitat and food shortages in their natural settings, their populations splinter, and they excrete more virus. When populations break up, bats move near humans to agricultural and urban areas.
“Pathogen Spillover Driven by Rapid Changes in Bat Ecology,” published Nov. 16 in Nature and combines multiple datasets over 25 years. The data includes information on bat behavior, distributions, reproduction and food availability, along with records of climate, habitat loss and environmental conditions. The study predicts when Hendra virus — an often-fatal illness in humans — spills over from fruit bats to horses and then people.
The researchers found that in years when food was abundant in their natural habitats during winter months, bats emptied out of agricultural areas to feed in native forests, and away from human communities.
A second paper, “Ecological Conditions Predict the Intensity of Hendra Virus Excretion over Space and Time from Bat Reservoir Hosts,” published Oct. 30 in Ecology Letters, used data from the Nature study to reveal ecological conditions when bats excrete more or less virus.
While previous research has shown correlations between habitat loss and occurrence of pathogen spillover, these studies together reveal for the first time a mechanism for such events and provide a method to predict and prevent them.

The answer might seem obvious — that electricity is key to economic growth and other societal benefits like better health. But in the world’s most impoverished regions, where resources to improve livelihoods are scarce, it’s not clear how much better off people are when they have access to electrical power.
Now, however, a new Stanford study published Nov. 16 in the journal Nature uncovers some of the strongest and most direct evidence yet of the extent to which electrification fuels economic growth in the developing world. The research is the first to rely on a pioneering technique recently developed at Stanford that combines satellite imagery and artificial intelligence (AI) to measure and study poverty in ways that were not previously possible.
The study — co-authored by Marshall Burke, an associate professor at the Stanford Doerr School of Sustainabilityand a senior fellow at the Stanford Institute for Economic Policy Research (SIEPR); Nathan Ratledge, a PhD student in environment and resources at the Doerr School; and others — examined the economic impacts of Uganda’s expanding electricity grid.
The researchers found that communities given access to electricity experienced improvements in their economic livelihoods roughly double that of regions without power. They measure livelihood changes based on increases they identify in home construction, appliances, and other tangible assets suggestive of economic wealth.
“We provide first-of-its-kind causal evidence of how electricity access impacts economic well-being at scale across an entire country in Africa,” said Ratledge, the study’s lead author.

Millions of antibiotics are prescribed every year. Although they can be incredibly effective at treating infections, antibiotics usually do not solely target the bacteria that is causing infection. They also kill the harmless bacteria that live in our gut and help us stay healthy. There is evidence that this disruption to the gut microbiome composition can last for up to 2 years after antibiotic treatment. Gastrointestinal symptoms such as diarrhea and bloating are also common side effects of antibiotic use.
Dr Elisa Marroquin, Assistant Professor at Texas Christian University, USA, and co-author of the paper, explained:
“Like in a human community, we need people that have different professions because we don’t all know how to do every single job. And so the same happens with bacteria. We need lots of different gut bacteria that know how to do different things.
“Even though we haven’t come up with a single definition of what is a healthy gut microbiome, one of the constant things we observe in healthy people is that they have a higher level of diversity and more variety of bacteria in the gut.”
Previous studies demonstrated that taking probiotics can reduce gastrointestinal side effects from antibiotics, but there has been debate over whether taking probiotics alongside antibiotics can also preserve the diversity and composition of microbes in the gut. Some healthcare professionals are reluctant to recommend probiotics alongside antibiotics for fear of further altering the delicate balance of microbes in the patient’s gut.
A new paper published in the Journal of Medical Microbiology reveals the first systematic review to assess the effect of taking probiotics alongside antibiotics on the diversity and composition of the human gut microbiome. Authored by researchers from the School of Medical and Health Sciences at Tecnológico de Monterrey, University of Texas and Texas Christian University, the review evaluates trends across 29 studies published over the past seven years.
The authors found that taking probiotics alongside antibiotics can prevent or lessen some antibiotic-induced changes to gut microbiome composition. Probiotics can also help protect species diversity and even restore the populations of some friendly bacteria such as Faecalibacterium prausnitzii, which reduces inflammation and promotes a healthy intestinal barrier.
Dr Elisa Marroquin said: “When participants take antibiotics, we see several consistent changes in some bacterial species. But when treatment was combined with probiotics, the majority of those changes were less pronounced and some changes were completely prevented.
“Considering the human data available up to this point, there does not seem to be a reason to withhold a prescription of probiotics when antibiotics are prescribed.”
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An international team led by Professor Hagai Levine of Hebrew University of Jerusalem’s Hadassah Braun School of Public Health, with Prof. Shanna Swan at the Icahn School of Medicine, Mount Sinai, New York, along with researchers in Denmark, Brazil, Spain, Israel and the USA, published the first meta-analysis to demonstrate declining sperm counts among men from South and Central America, Asia and Africa.
Alarmingly, this study also shows that the decline in sperm counts in North America, Europe, and Australia — reported by this team in 2017 — has continued and even accelerated in the 21st century. Sperm count is not only an indicator of human fertility; it also is an indicator of men’s health, with low levels being associated with increased risk of chronic disease, testicular cancer and a decreased lifespan. The authors say the decline reflects a global crisis related to our modern environment and lifestyle, with broad implications for the survival of the human species.
This latest analysis, with data from 53 countries, was published today in the journal Human Reproduction Update. It includes an additional seven years of data collection (2011-2018) and focuses on sperm count trends among men in regions not reviewed previously, specifically South America, Asia and Africa. The data shows, for the first time, that men in those regions share the significant decline in total sperm counts (TSC) and sperm concentration (SC) seen previously in North America, Europe and Australia. Furthermore, this study shows an accelerated post-2000 decline in TSC and SC globally. As Levine summarized these results, “Overall, we’re seeing a significant worldwide decline in sperm counts of over 50% in the past 46 years, a decline that has accelerated in recent years.”
While the current study did not examine the causes of sperm count declines, Levine pointed to recent research indicating that disturbances in the development of the reproductive tract during fetal life are linked to lifetime impairment of fertility and other markers of reproductive dysfunction. Additionally, Levine explained that “lifestyle choices and chemicals in the environment are adversely affecting this fetal development.”
Time is running out, cautioned Levine. “Our findings serve as a canary in a coal mine. We have a serious problem on our hands that, if not mitigated, could threaten humankind’s survival. We urgently call for global action to promoted healthier environments for all species and reduce exposures and behaviors that threaten our reproductive health.”
Swan stressed that low sperm counts do not only affect men’s fertility, but have serious ramifications for men’s health more generally, and are linked with other adverse trends, termed together as testicular dysgenesis syndrome. “The troubling declines in men’s sperm concentration and total sperm counts at over 1% each year as reported in our paper are consistent with adverse trends in other men’s health outcomes, such as testicular cancer, hormonal disruption, and genital birth defects, as well as declines in female reproductive health. This clearly cannot continue unchecked.”
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Materials provided by The Hebrew University of Jerusalem. Note: Content may be edited for style and length.

Immune checkpoint inhibitors such as Keytruda and Opdivo work by unleashing the immune system’s T cells to attack tumor cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10% to 30% of treated patients experience long-term improvement. In a paper published online today in The Journal of Clinical Investigation (JCI), scientists at Albert Einstein College of Medicine describe findings that could bolster the effectiveness of immune-checkpoint therapy.
Rather than rally T cells against cancer, the Einstein research team used different human immune cells known as natural killer (NK) cells — with dramatic results. “We believe the novel immunotherapy we’ve developed has great potential to move into clinical trials involving various types of cancer,” said study leader Xingxing Zang, M.Med., Ph.D., the Louis Goldstein Swan Chair in Cancer Research and professor of microbiology & immunology, of oncology, of urology, and of medicine at Einstein and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center.
Telling Friend from Foe
The surfaces of immune cells are studded with receptors known as “checkpoint” proteins, which prevent immune cells from straying beyond their usual targets (pathogen-infected cells and cancer cells). When checkpoint receptors on immune cells bind with proteins expressed by the body’s own normal cells, the interaction puts the brakes on a possible immune-cell attack. Diabolically, most types of cancer cells express proteins that bind with checkpoint proteins, tricking immune cells into standing down and not attacking the tumor.
Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit immune-cell/cancer-cell interactions by blocking either the tumor proteins or the immune-cell receptors that bind with tumor proteins. With no brakes to impede them, immune cells can attack and destroy cancer cells.
New Focus on Natural Killer Cells
The limited effectiveness of checkpoint inhibitors prompted Dr. Zang and other scientists to look at checkpoint pathways involving NK cells, which — like T cells — play major roles in eliminating unwanted cells. A cancer-cell protein called PVR soon captured their attention. “We realized that PVR may be a very important protein that human cancers use to hobble the immune system’s attack,” said Dr. Zang.