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  • The path to a better tuberculosis vaccine runs through Montana

    The path to a better tuberculosis vaccine runs through Montana

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    A team of Montana researchers is playing a key role in the development of a more effective vaccine against tuberculosis, an infectious disease that has killed more people than any other.

    One effort is underway at the University of Montana Center for Translational Medicine. The center specializes in improving and creating vaccines by adding what are called novel adjuvants. An adjuvant is a substance included in the vaccine, such as fat molecules or aluminum salts, that enhances the immune response, and novel adjuvants are those that have not yet been used in humans. Scientists are finding that adjuvants make for stronger, more precise, and more durable immunity than antigens, which create antibodies, would alone.

    Eliciting specific responses from the immune system and deepening and broadening the response with adjuvants is known as precision vaccination. “It’s not one-size-fits-all,” said Ofer Levy, a professor of pediatrics at Harvard University and the head of the Precision Vaccines Program at Boston Children’s Hospital. “A vaccine might work differently in a newborn versus an older adult and a middle-aged person.”

    The ultimate precision vaccine, said Levy, would be lifelong protection from a disease with one jab. “A single-shot protection against influenza or a single-shot protection against covid, that would be the holy grail,” Levy said.

    Jay Evans, the director of the University of Montana center and the chief scientific and strategy officer and a co-founder of Inimmune, a privately held biotechnology company in Missoula, said his team has been working on a TB vaccine for 15 years. The private-public partnership is developing vaccines and trying to improve existing vaccines, and he said it’s still five years off before the TB vaccine might be distributed widely.

    It has not gone unnoticed at the center that this state-of-the-art vaccine research and production is located in a state that passed one of the nation’s most extreme anti-vaccination laws during the pandemic in 2021. The law prohibits businesses and governments from discriminating against people who aren’t vaccinated against covid-19 or other diseases, effectively banning both public and private employers from requiring workers to get vaccinated against covid or any other disease. A federal judge later ruled that the law cannot be enforced in health care settings, such as hospitals and doctors’ offices.

    In mid-March, the Bill & Melinda Gates Medical Research Institute announced it had begun the third and final phase of clinical trials for the new vaccine in seven countries. The trials should take about five years to complete. Research and production are being done in several places, including at a manufacturing facility in Hamilton owned by GSK, a giant pharmaceutical company.

    Known as the forgotten pandemic, TB kills up to 1.6 million people a year, mostly in impoverished areas in Asia and Africa, despite its being both preventable and treatable. The U.S. has seen an increase in tuberculosis over the past decade, especially with the influx of migrants, and the number of cases rose by 16% from 2022 to 2023. Tuberculosis is the leading cause of death among people living with HIV, whose risk of contracting a TB infection is 20 times as great as people without HIV.

    “TB is a complex pathogen that has been with human beings for ages,” said Alemnew Dagnew, who heads the program for the new vaccine for the Gates Medical Research Institute. “Because it has been with human beings for many years, it has evolved and has a mechanism to escape the immune system. And the immunology of TB is not fully understood.”

    The University of Montana Center for Translational Medicine and Inimmune together have 80 employees who specialize in researching a range of adjuvants to understand the specifics of immune responses to different substances. “You have to tailor it like tools in a toolbox towards the pathogen you are vaccinating against,” Evans said. “We have a whole library of adjuvant molecules and formulations.”

    Vaccines are made more precise largely by using adjuvants. There are three basic types of natural adjuvants: aluminum salts; squalene, which is made from shark liver; and some kinds of saponins, which are fat molecules. It’s not fully understood how they stimulate the immune system. The center in Missoula has also created and patented a synthetic adjuvant, UM-1098, that drives a specific type of immune response and will be added to new vaccines.

    One of the most promising molecules being used to juice up the immune system response to vaccines is a saponin molecule from the bark of the quillay tree, gathered in Chile from trees at least 10 years old. Such molecules were used by Novavax in its covid vaccine and by GSK in its widely used shingles vaccine, Shingrix. These molecules are also a key component in the new tuberculosis vaccine, known as the M72 vaccine.

    But there is room for improvement.

    “The vaccine shows 50% efficacy, which doesn’t sound like much, but basically there is no effective vaccine currently, so 50% is better than what’s out there,” Evans said. “We’re looking to take what we learned from that vaccine development with additional adjuvants to try and make it even better and move 50% to 80% or more.”

    By contrast, measles vaccines are 95% effective.

    According to Medscape, around 15 vaccine candidates are being developed to replace the BCG vaccine, and three of them are in phase 3 clinical trials.

    One approach Evans’ center is researching to improve the new vaccine’s efficacy is taking a piece of the bacterium that causes TB, synthesizing it, and combining it with the adjuvant QS-21, made from the quillay tree. “It stimulates the immune system in a way that is specific to TB and it drives an immune response that is even closer to what we get from natural infections,” Evans said.

    The University of Montana center is researching the treatment of several problems not commonly thought of as treatable with vaccines. They are entering the first phase of clinical trials for a vaccine for allergies, for instance, and first-phase trials for a cancer vaccine. And later this year, clinical trials will begin for vaccines to block the effects of opioids like heroin and fentanyl. The University of Montana received the largest grant in its history, $33 million, for anti-opioid vaccine research. It works by creating an antibody that binds with the drug in the bloodstream, which keeps it from entering the brain and creating the high.

    For now, though, the eyes of health care experts around the world are on the trials for the new TB vaccines, which, if they are successful, could help save countless lives in the world’s poorest places.




    Kaiser Health NewsThis article was reprinted from khn.org, a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – the independent source for health policy research, polling, and journalism.

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  • AI model GPT-4 exceeds unspecialized doctors’ ability to assess eye problems

    AI model GPT-4 exceeds unspecialized doctors’ ability to assess eye problems

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    The clinical knowledge and reasoning skills of GPT-4 are approaching the level of specialist eye doctors, a study led by the University of Cambridge has found.

    GPT-4 – a ‘large language model’ – was tested against doctors at different stages in their careers, including unspecialized junior doctors, and trainee and expert eye doctors. Each was presented with a series of 87 patient scenarios involving a specific eye problem, and asked to give a diagnosis or advise on treatment by selecting from four options.

    GPT-4 scored significantly better in the test than unspecialized junior doctors, who are comparable to general practitioners in their level of specialist eye knowledge.

    GPT-4 gained similar scores to trainee and expert eye doctors – although the top performing doctors scored higher.

    The researchers say that large language models aren’t likely to replace healthcare professionals, but have the potential to improve healthcare as part of the clinical workflow.

    They say state-of-the-art large language models like GPT-4 could be useful for providing eye-related advice, diagnosis, and management suggestions in well-controlled contexts, like triaging patients, or where access to specialist healthcare professionals is limited.

    “We could realistically deploy AI in triaging patients with eye issues to decide which cases are emergencies that need to be seen by a specialist immediately, which can be seen by a GP, and which don’t need treatment,” said Dr Arun Thirunavukarasu, lead author of the study, which he carried out while a student at the University of Cambridge’s School of Clinical Medicine

    He added: “The models could follow clear algorithms already in use, and we’ve found that GPT-4 is as good as expert clinicians at processing eye symptoms and signs to answer more complicated questions.

    “With further development, large language models could also advise GPs who are struggling to get prompt advice from eye doctors. People in the UK are waiting longer than ever for eye care.

    Large volumes of clinical text are needed to help fine-tune and develop these models, and work is ongoing around the world to facilitate this.

    The researchers say that their study is superior to similar, previous studies because they compared the abilities of AI to practicing doctors, rather than to sets of examination results.

    “Doctors aren’t revising for exams for their whole career. We wanted to see how AI fared when pitted against to the on-the-spot knowledge and abilities of practicing doctors, to provide a fair comparison,” said Thirunavukarasu, who is now an Academic Foundation Doctor at Oxford University Hospitals NHS Foundation Trust.

    He added: “We also need to characterise the capabilities and limitations of commercially available models, as patients may already be using them – rather than the internet – for advice.”

    The test included questions about a huge range of eye problems, including extreme light sensitivity, decreased vision, lesions, itchy and painful eyes, taken from a textbook used to test trainee eye doctors. This textbook is not freely available on the internet, making it unlikely that its content was included in GPT-4’s training datasets.

    The results are published today in the journal PLOS Digital Health.

    Even taking the future use of AI into account, I think doctors will continue to be in charge of patient care. The most important thing is to empower patients to decide whether they want computer systems to be involved or not. That will be an individual decision for each patient to make.”

    Dr. Arun Thirunavukarasu, lead author of the study

    GPT-4 and GPT-3.5 – or ‘Generative Pre-trained Transformers’ – are trained on datasets containing hundreds of billions of words from articles, books, and other internet sources. These are two examples of large language models; others in wide use include Pathways Language Model 2 (PaLM 2) and Large Language Model Meta AI 2 (LLaMA 2).

    The study also tested GPT-3.5, PaLM2, and LLaMA with the same set of questions. GPT-4 gave more accurate responses than all of them.

    GPT-4 powers the online chatbot ChatGPT to provide bespoke responses to human queries. In recent months, ChatGPT has attracted significant attention in medicine for attaining passing level performance in medical school examinations, and providing more accurate and empathetic messages than human doctors in response to patient queries.

    The field of artificially intelligent large language models is moving very rapidly. Since the study was conducted, more advanced models have been released – which may be even closer to the level of expert eye doctors.

    Source:

    Journal reference:

    Thirunavukarasu, A. J., et al. (2024) Large language models approach expert-level clinical knowledge and reasoning in ophthalmology: A head-to-head cross-sectional study. PLOS Digital Health. doi.org/10.1371/journal.pdig.0000341.

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  • Study suggests a promising new approach to understanding autism

    Study suggests a promising new approach to understanding autism

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    Autism spectrum disorder has yet to be linked to a single cause, due to the wide range of its symptoms and severity. However, a study by University of Virginia researchers suggests a promising new approach to finding answers, one that could lead to advances in the study of other neurological diseases and disorders.

    Current approaches to autism research involve observing and understanding the disorder through the study of its behavioral consequences, using techniques like functional magnetic resonance imaging that map the brain’s responses to input and activity, but little work has been done to understand what’s causing those responses.

    However, researchers with UVA’s College and Graduate School of Arts & Sciences have been able to better understand the physiological differences between the brain structures of autistic and non-autistic individuals through the use of Diffusion MRI, a technique that measures molecular diffusion in biological tissue, to observe how water moves throughout the brain and interacts with cellular membranes. The approach has helped the UVA team develop mathematical models of brain microstructures that have helped identify structural differences in the brains of those with autism and those without.

    “It hasn’t been well understood what those differences might be,” said Benjamin Newman, a postdoctoral researcher with UVA’s Department of Psychology, recent graduate of UVA School of Medicine’s neuroscience graduate program and lead author of a paper published this month in PLOS: One. “This new approach looks at the neuronal differences contributing to the etiology of autism spectrum disorder.”

    Building on the work of Alan Hodgkin and Andrew Huxley, who won the 1963 Nobel Prize in Medicine for describing the electrochemical conductivity characteristics of neurons, Newman and his co-authors applied those concepts to understand how that conductivity differs in those with autism and those without, using the latest neuroimaging data and computational methodologies. The result is a first-of-its-kind approach to calculating the conductivity of neural axons and their capacity to carry information through the brain. The study also offers evidence that those microstructural differences are directly related to participants’ scores on the Social Communication Questionnaire, a common clinical tool for diagnosing autism.

    What we’re seeing is that there’s a difference in the diameter of the microstructural components in the brains of autistic people that can cause them to conduct electricity slower. It’s the structure that constrains how the function of the brain works.”

    Benjamin Newman, postdoctoral researcher with UVA’s Department of Psychology

    One of Newman’s co-authors, John Darrell Van Horn, a professor of psychology and data science at UVA, said, that so often we try to understand autism through a collection of behavioral patterns which might be unusual or seem different.

    “But understanding those behaviors can be a bit subjective, depending on who’s doing the observing,” Van Horn said. “We need greater fidelity in terms of the physiological metrics that we have so that we can better understand where those behaviors coming from. This is the first time this kind of metric has been applied in a clinical population, and it sheds some interesting light on the origins of ASD.”

    Van Horn said there’s been a lot of work done with functional magnetic resonance imaging, looking at blood oxygen related signal changes in autistic individuals, but this research, he said “Goes a little bit deeper.” 

    “It’s asking not if there’s a particular cognitive functional activation difference; it’s asking how the brain actually conducts information around itself through these dynamic networks,” Van Horn said. “And I think that we’ve been successful showing that there’s something that’s uniquely different about autistic-spectrum-disorder-diagnosed individuals relative to otherwise typically developing control subjects.”

    Newman and Van Horn, along with co-authors Jason Druzgal and Kevin Pelphrey from the UVA School of Medicine, are affiliated with the National Institute of Health’s Autism Center of Excellence (ACE), an initiative that supports large-scale multidisciplinary and multi-institutional studies on ASD with the aim of determining the disorder’s causes and potential treatments. 

    According to Pelphrey, a neuroscientist and expert on brain development and the study’s principal investigator, the overarching aim of the ACE project is to lead the way in developing a precision medicine approach to autism. 

    “This study provides the foundation for a biological target to measure treatment response and allows us to identify avenues for future treatments to be developed,” he said.

    Van Horn added that study may also have implications for the examination, diagnosis, and treatment of other neurological disorders like Parkinson’s and Alzheimer’s.

    “This is a new tool for measuring the properties of neurons which we are particularly excited about. We are still exploring what we might be able to detect with it,” Van Horn said.

    Source:

    University of Virginia College and Graduate School of Arts & Sciences

    Journal reference:

    Newman, B. T., et al. (2024) Conduction velocity, G-ratio, and extracellular water as microstructural characteristics of autism spectrum disorder. PLOS ONE. doi.org/10.1371/journal.pone.0301964.

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  • Greenspace exposure boosts gut and skin microbiota health, study finds

    Greenspace exposure boosts gut and skin microbiota health, study finds

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    In a recent review article published in the journal Environmental International, researchers conducted a systematic review of observational and interventional studies evaluating the relationship between greenspace exposure and human microbiota across various anatomical sites.

    They found that greenspace exposure is associated with increased diversity and altered composition of gut and skin microbiota, potentially leading to healthier profiles, while evidence for the effect on oral, nasal, and ocular microbiota remains inconclusive.

    Study: Greenspace and human microbiota: A systematic review. Image Credit: Kateryna Kon / ShutterstockStudy: Greenspace and human microbiota: A systematic review. Image Credit: Kateryna Kon / Shutterstock

    Background

    In recent years, research has increasingly focused on the potential health benefits of greenspace exposure, including mental well-being and reduced disease risk.

    Although findings are mixed, human microbiota, crucial for immune function and metabolic health, may be influenced by greenspace. Understanding this relationship could elucidate mechanisms behind greenspace’s health effects.

    About the study

    A systematic review aimed to synthesize observational and interventional evidence on greenspace’s impact on human microbiota diversity and composition across various populations, exposures, and outcomes, seeking to clarify existing knowledge gaps and inform public health interventions and policies.

    The methods involved scoping previous reviews and formulating search strategies for databases, with specific criteria for study selection based on Population, Exposure, Comparator, Outcome, and Study (PECOS) principles.

    Two investigators conducted searches, screened records, and extracted data independently. They assessed the risk of bias, with evidence synthesis following guidelines for systematic reviews without meta-analyses; the certainty of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework.

    Findings

    After several rounds of screening, the qualitative synthesis included 20 articles from 35 countries, including Finland, Canada, the United States, China, the Netherlands, the United Kingdom, India, and Australia.

    Half the studies followed cross-sectional designs, one was a cohort study, and the remaining followed interventional designs, including two randomized controlled trials.

    Observational studies utilized objective metrics like Normalized difference vegetation index (NDVI), greenspace percentage, or binary variables sourced from satellite images or land maps, ensuring precise greenspace exposure allocation. Interventional studies involved activities such as rubbing hands with soil, engaging in park activities, or greening kindergartens for varying durations.

    The 20 studies investigated microbial communities in various human body sites: gut (13 studies), skin (10 studies), oral cavity (5 studies), nasal cavity (5 studies), and ocular region (1 study).

    Amplicon sequencing targeting the 16S ribosomal ribonucleic acid (rRNA) gene was common, with pipelines like Quantitative Insights Into Microbial Ecology (QIIME), Mothur, or Usearch used for bioinformatic analysis. Outcomes included alpha diversity, beta diversity, and relative abundance of taxa.

    The included studies were assessed for the risk of bias, with three rated as “serious” due to confounding bias. Four studies had a “probably high” risk from other sources, like inappropriate statistical approaches. Small sample sizes compromised reliability in some intervention studies.

    Overall, studies suggested that greenspace exposure is associated with higher alpha diversity, altered overall compositions, and changed relative abundances of taxa in the human gut microbiota, as reported by 12 out of 13 studies, including both cross-sectional and interventional designs.

    Cross-sectional studies revealed varied associations of greenspace exposure with alpha diversity, beta diversity, and specific taxa abundances. Interventional studies suggest positive impacts on alpha diversity and specific taxa abundance following greenspace interventions.

    From the 10 studies examining the relationship between greenspace exposure and human skin microbiota. Cross-sectional and interventional studies reveal positive associations between greenspace and skin microbiota alpha diversity, altered compositions, and changes in taxa abundances.

    Observational studies highlighted associations with forest and agricultural land cover, while interventions show increased alpha diversity and altered compositions with greenspace activities.

    Several studies investigated the link between greenspace exposure and human microbiota in oral, nasal, and ocular cavities. Mixed findings were observed. Oral microbiota studies showed increased richness with nearby greenspace, while nasal microbiota studies reported inconsistent results.

    Ocular microbiota showed no significant association with green space. Interventional studies suggested that greenspace activities might positively affect nasal microbiota diversity.

    The certainty assessment of evidence on greenspace and human microbiota varied across body sites. Initial ratings were high or moderate but downgraded to moderate or low due to imprecision and inconsistent results. Overall, the certainty of evidence for greenspace and microbiota in all body sites was assessed as very low.

    Conclusions

    The systematic review assessed 20 studies on greenspace exposure and human microbiota, predominantly in Europe and North America. Evidence suggests that greenspace exposure increases gut and skin microbiota diversity, favoring beneficial bacteria over pathogens.

    However, study heterogeneity, design limitations, and biases were noted. Findings generally align with previous reviews but offer a more comprehensive evaluation. Mechanisms include exposure to diverse environmental microbes, reduced air pollutants, and lifestyle improvements.

    Further longitudinal and intervention studies are recommended, considering various greenspace aspects, participant characteristics, and microbiota functionality.

    Journal reference:

    • Greenspace and human microbiota: a systematic review. Zhang, Y., Zhou, G., Wang, L., Browning, M.H.E.M., Markevych, I., Heinrich, J., Knibbs, L.D., Zhao, T., Ding, Y., Chen, S., Liu, K., Dadvand, P., Dong, G., Yang, B. Environment International (2024). DOI: 10.1016/j.envint.2024.108662, https://www.sciencedirect.com/science/article/pii/S0160412024002484

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  • Penn State study examines how a person’s telomeres are affected by caloric restriction

    Penn State study examines how a person’s telomeres are affected by caloric restriction

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    Penn State researchers may have uncovered another layer of complexity in the mystery of how diet impacts aging. A new study led by researchers in the Penn State College of Health and Human Development examined how a person’s telomeres -; sections of genetic bases that function like protective caps at the ends of chromosomes -; were affected by caloric restriction.

    The team published their results in Aging Cell. Analyzing data from a two-year study of caloric restriction in humans, the researchers found that people who restricted their calories lost telomeres at different rates than the control group -; even though both groups ended the study with telomeres of roughly the same length. Restricting calories by 20% to 60% has been shown to promote longer life in many animals, according to previous research.

    Over the course of human life, every time a person’s cells replicate, some telomeres are lost when chromosomes are copied to the new cell. When this happens, the overall length of the cell’s telomeres becomes shorter. After cells replicate enough times, the protective cap of telomeres completely dissipates. Then, the genetic information in the chromosome can become damaged, preventing future reproduction or proper function of the cell. A cell with longer telomeres is functionally younger than a cell with short telomeres, meaning that two people with the same chronological age could have different biological ages depending on the length of their telomeres. 

    Typical aging, stress, illness, genetics, diet and more can all influence how often cells replicate and how much length the telomeres retain, according to Idan Shalev, associate professor of biobehavioral health at Penn State. Shalev led the researchers who analyzed genetic samples from the national CALERIE study -; the first randomized clinical trial of calorie restriction in humans. Shalev and his team sought to understand the effect of caloric restriction on telomere length in people. Because telomere length reflects how quickly or slowly a person’s cells are aging, examining telomere length could allow scientists to identify one way in which caloric restriction may slow aging in humans.

    “There are many reasons why caloric restriction may extend human lifespans, and the topic is still being studied,” said Waylon Hastings, who earned his doctorate in biobehavioral health at Penn State in 2020 and was lead author of this study. “One primary mechanism through which life is extended relates to metabolism in a cell. When energy is consumed within a cell, waste products from that process cause oxidative stress that can damage DNA and otherwise break down the cell. When a person’s cells consume less energy due to caloric restriction, however, there are fewer waste products, and the cell does not break down as quickly.” 

    The researchers tested the telomere length of 175 research participants using data from the start of the CALERIE study, one year into the study and the end of the study after 24 months of caloric restriction. Approximately two-thirds of study participants participated in caloric restriction, while one-third served as a control group.

    During the study, results showed that telomere loss changed trajectories. Over the first year, participants who were restricting caloric intake lost weight, and they lost telomeres more rapidly than the control group. After a year, the weight of participants on caloric restriction was stabilized, and caloric restriction continued for another year. During the second year of the study, participants on caloric restriction lost telomeres more slowly than the control group. At the end of two years, the two groups had converged, and the telomere lengths of the two groups was not statistically different.

    This research shows the complexity of how caloric restriction affects telomere loss. We hypothesized that telomere loss would be slower among people on caloric restriction. Instead, we found that people on caloric restriction lost telomeres more rapidly at first and then more slowly after their weight stabilized.”


    Idan Shalev, associate professor of biobehavioral health at Penn State

    Shalev said the results raised a lot of important questions. For example, what would have happened to telomere length if data had been collected for another year? Study participants are scheduled for data collection at a 10-year follow-up, and Shalev said that he was eager to analyze those data when they become available.

    Despite the ambiguity of the results, Shalev said there is promise for the potential health benefits of caloric restriction in humans. Previous research on the CALERIE data has demonstrated that caloric restriction may help reduce harmful cholesterol and lower blood pressure. For telomeres, the two-year timeline was not sufficient to show benefits, but those may still be revealed, according to Shalev and Hastings.

    Three of Shalev’s trainees, Hastings, current graduate student Qiaofeng Ye and former postdoctoral scholar Sarah Wolf, led the research under Shalev’s guidance.

    Hastings said the opportunity to lead this study was critical to his career.

    “I was recently hired as an assistant professor in the Department of Nutrition at Texas A&M University, and I will begin that work in the fall semester,” Hastings said. “Prior to this project, I had limited experience in nutrition. This project literally set the course of my career, and I am grateful to Dr. Shalev for trusting me with that responsibility.”

    Calen Ryan and Daniel Belsky of Columbia University Mailman School of Public Health, Sai Krupa Das of Tufts University, Kim Huffman and William Kraus of Duke University School of Medicine, Michael Kobor and Julia MacIsaac of University of British Columbia, Corby Martin and Leanne Redman of Pennington Biomedical Research Center and Susan Racette of Arizona State University College of Health Solutions all contributed to this research.

    The National Institute on Aging funded this research.

    Source:

    Journal reference:

    Hastings, W. J., et al. (2024). Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIETM 2 trial analysis. Aging Cell. doi.org/10.1111/acel.14149.

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  • Opioid dependence in Scotland remains high but largely stable, study shows

    Opioid dependence in Scotland remains high but largely stable, study shows

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    Opioid dependence in Scotland remains high but largely stable, according to a new University of Bristol-led analysis published in Addiction today [18 April] and by Public Health Scotland. The study is the first to estimate the number of people dependent on opioid drugs (such as heroin), and who are in or could benefit from drug treatment, among Scotland’s population since 2015/2016 estimates were published.

    Scotland has one of the highest rates of drug-related deaths in Europe, with the number of these more than doubling between 2011 and 2020. At 250-300 per million population in 2021-22, Scotland’s rate of drug-related deaths was sixteen times higher than the average in the European Union and on par with rates in North America. As part of the response to the public health emergency in drug-related deaths, the Scottish Government-commissioned study sought to understand whether the number of people with opioid dependence among its general publication is also increasing.

    To predict how many people aged 15 to 64 years old are opioid dependent, researchers from Bristol’s National Institute for Health and Care Research Health Protection Research Unit (NIHR HPRU) in Behavioural Science and Evaluation applied a statistical modelling technique using data from Public Health Scotland’s Scottish Public Health Drug Linkage Programme, including information on people in drug treatment called opioid agonist treatment (OAT – primarily methadone and buprenorphine) and data on opioid-related mortality and hospital admissions.

    In these new estimates, researchers found the prevalence of opioid dependence in Scotland to have been relatively stable between 2014/15 to 2019/20, with 47,100 people estimated to be opioid-dependent in 2019/20 – which is 1.3 per cent of the adult population aged 15-64.

    While there was weak evidence of a small reduction in the total number of people with opioid dependence since 2014/15, the extent of any change was estimated to be small (-0.07 per cent or -2,000 people). There was evidence that the population of people with opioid dependence were ageing, with estimates of the number of people aged 15 to 34 years old reducing by 5,100 and the number aged 50 to 64 years old increasing by 2,800 between 2014/15 and 2019/20.

    The research team also estimated that over 60 per cent of the population of people who were opioid-dependent received OAT at least once during 2019/20 and nearly 75 per cent had been in drug treatment in the last five years.

    Dr Hayley Jones, Associate Professor in Medical Statistics in the Bristol Medical School: Population Health Sciences (PHS), lead author and developer of the method (Multi-Parameter Estimation of Prevalence) used in Scotland, said: “This is the first time that trends in the prevalence of people with opioid dependence have been produced in Scotland, showing the value of and making the most of the high-quality linked data sets that are available there.

    “The method can be used to update the estimates in future, and can be applied in other countries that create comprehensive records of people in drug treatment and link these to data on drug-related harms.”

    Importantly, our estimates suggest the substantial increase in drug-related deaths in Scotland is not due to increases in the underlying population of people with opioid dependence but because of increases in the risk of death experienced by people with opioid dependence in Scotland.”


    Professor Matt Hickman, co-first author and director of the NIHR HPRU at the University of Bristol

    Professors Sharon Hutchinson and Andrew McAuley, co-authors and lead researchers at Glasgow Caledonian University, explained: “We showed that exposure to drug treatment in Scotland is high compared to many countries worldwide. The challenge in Scotland and rest of UK, however, is to retain people in drug treatment for longer and to determine what other interventions are required to effect change at the population level – and bring down the number of drug-related deaths.”

    The public health surveillance study, commissioned by the Scottish Government, is a collaboration between Public Health Scotland, the University of Bristol, and Glasgow Caledonian University.

    Source:

    Journal reference:

    Markoulidakis, A., et al. (2024) Prevalence of opioid dependence in Scotland 2015–2020: A multi-parameter estimation of prevalence (MPEP) study. Addiction. doi.org/10.1111/add.16500.

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  • Study reveals long-term consequences of atrial fibrillation

    Study reveals long-term consequences of atrial fibrillation

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    The lifetime risk of atrial fibrillation (a heart condition that causes an irregular and often abnormally fast heart rate) has increased from one in four to one in three over the past two decades, finds a study from Denmark in The BMJ today.

    And among those with the condition, two in five are likely to develop heart failure over their remaining lifetime and one in five encounter a stroke, with little or no improvement in risk evident over the 20 year study period.

    As such, the researchers say stroke and heart failure prevention strategies are needed for people with atrial fibrillation.

    Atrial fibrillation is estimated to affect 18 million people in Europe by 2060 and 16 million people in the US by 2050. In the English NHS alone, more new cases of atrial fibrillation are diagnosed each year than the four most common causes of cancer combined, and direct expenditure on atrial fibrillation has reached £2.5 billion.

    Once atrial fibrillation develops, patient care has primarily focused on the risk of stroke, but other complications such as heart failure and heart attack have yet to be fully explored.

    To address this knowledge gap, researchers analysed national data for 3.5 million Danish adults with no history of atrial fibrillation at age 45 or older to see whether they developed atrial fibrillation over a 23 year period (2000-22).

    All 362,721 individuals with a new diagnosis of atrial fibrillation during this time (46% women and 54% men) but with no complications, were subsequently followed until a diagnosis of heart failure, stroke or heart attack.

    Potentially influential factors such as history of high blood pressure, diabetes, high cholesterol, heart failure, chronic lung and kidney disease, family income and educational attainment, were also taken into account.

    The results show that the lifetime risk of atrial fibrillation increased from 24% in 2000-10 to 31% in 2011-22. The increase was larger among men and individuals with a history of heart failure, heart attack, stroke, diabetes, and chronic kidney disease. 

    Among those with atrial fibrillation, the most common complication was heart failure (lifetime risk 41%). This was twice as large as the lifetime risk of any stroke (21%) and four times greater than the lifetime risk of heart attack (12%).

    Men showed a higher lifetime risk of complications after atrial fibrillation compared with women for heart failure (44% vs 33%) and heart attack (12% vs 10%), while the lifetime risk of stroke after atrial fibrillation was slightly lower in men than women (21% vs 23%).

    Over the 23-year study period, there was virtually no improvement in the lifetime risk of heart failure after atrial fibrillation (43% in 2000-10 vs 42% in 2011-22) and only slight (4-5%) decreases in the lifetime risks of any stroke, ischaemic stroke, and heart attack after atrial fibrillation, which were similar among men and women. 

    This is an observational study, so no firm conclusions can be drawn about cause and effect, and the authors acknowledge that they may have missed patients with undiagnosed atrial fibrillation. Nor did they have information on ethnicity or lifestyle factors, and say results may not apply to other countries or settings.

    But despite these caveats, they conclude: “Our novel quantification of the long term downstream consequences of atrial fibrillation highlights the critical need for treatments to further decrease stroke risk as well as for heart failure prevention strategies among patients with atrial fibrillation.”

    Interventions to prevent stroke have dominated atrial fibrillation research and guidelines during this study period, but no evidence suggests that these interventions can prevent incident heart failure, say UK researchers in a linked editorial.

    They call for alignment of both randomized clinical trials and guidelines “to better reflect the needs of the real-world population with atrial fibrillation” and say this robust observational research “provides novel information that challenges research priorities and guideline design, and raises critical questions for the research and clinical communities about how the growing burden of atrial fibrillation can be stopped.”

    Source:

    Journal reference:

    Vinter, N., et al. (2024). Temporal trends in lifetime risks of atrial fibrillation and its complications between 2000 and 2022: Danish, nationwide, population based cohort study. BMJ. doi.org/10.1136/bmj-2023-077209.

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  • New research pinpoints key pathways in prostate cancer’s vulnerability to ferroptosis

    New research pinpoints key pathways in prostate cancer’s vulnerability to ferroptosis

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    In a recent review published in the journal Nature Reviews Urology, researchers examined the molecular mechanisms and metabolic processes that drive ferroptosis — a form of cell death that plays a significant role in prostate cancer. They also connected pathways involved in ferroptosis to the metabolic reprogramming that occurs in prostate cancer cells to highlight potential avenues of targeted therapeutic interventions.

    Perspective: Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Image Credit: MattL_Images / Shutterstock

    Perspective: Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Image Credit: MattL_Images / Shutterstock

    Background

    Although the five-year survival rate in cases of localized prostate cancer is very promising (greater than 99%), metastasis or the prostate cancer progressing to the castration-resistant form of prostate cancer reduces the five-year survival rate to between 30% and 40%. Furthermore, while treatment options such as radiotherapy, chemotherapy, immunotherapy, and second-generation androgen receptor-signaling inhibitors can be used to treat advanced prostate cancer, these therapies only increase the survival rate by two to three years. Understanding the underlying mechanisms of prostate cancer can help improve and initiate early treatment.

    Recent research has found that a pathway of regulated cell death, called ferroptosis, plays a significant role in the development of prostate cancer. Ferroptosis differs from the other forms of cell death, such as autophagy, apoptosis, and necrosis, in that it is iron-dependent and is driven by lipid peroxide build-up. Studies have found that the suppression of ferroptosis is linked to tumor pathogenesis, especially in prostate cancer.

    Ferroptosis

    Ferroptosis does not have the typical characteristics of apoptosis, such as the condensation of chromatin, apoptotic body formation, and cytoskeletal breakdown. Neither does it show the hallmarks of necrosis and autophagy, such as the swelling of organelles and the formation of the autophagosomes, respectively.

    During ferroptosis, the mitochondrial size and cristae of the cells reduce, and the membrane density increases. Additionally, the polyunsaturated fatty acids that are part of the phospholipid membrane form peroxides. The lipid peroxidation could be initiated due to oxidation from iron overload, the mitochondria, or the production of reactive oxygen species due to iron. The lipid peroxidation process results in widespread damage and oxidative injury, leading to cell death.

    Cells contain various intrinsic systems to circumvent lipid peroxidation and ferroptosis. The classical method involves the use of glutathione and glutathione peroxidase 4 to decrease the levels of lipid hydroperoxides, preserving the integrity of the phospholipid bilayer and preventing ferroptosis. Inhibition of ferroptosis can also occur through ferroptosis suppressor protein 1 or dihydroorotate dehydrogenase.

    Ferroptosis and cancer

    Given the association between ferroptosis and polyunsaturated fatty acids, cancer cells, which undergo substantial metabolic reprogramming and produce reactive oxygen species, are especially susceptible to ferroptosis. Cells in malignant tumors have higher energy and iron demands, which increases their susceptibility to ferroptosis. Prostate cancer cells depend on lipid metabolism for their high energy requirements, which causes the fatty acid metabolism in prostate cancer cells to be dysregulated.

    Furthermore, factors such as lipid metabolism gene upregulation, rewiring of the oxidative phosphorylation metabolism, and increased tricarboxylic acid flux have been observed in both early and late-stage prostate cancer cells. These processes could increase the intracellular reactive oxygen species burden, promote lipid peroxidation, and cause perturbations in iron homeostasis.

    The review discussed various mechanisms through which the susceptibility of cancer cells to ferroptosis could be exploited as potential treatment avenues for advanced cancers. Targeting the defense mechanisms that inhibit ferroptosis is a promising approach. Studies have suggested that targeting the glutathione peroxidase 4 inhibition mechanism could induce ferroptosis in cancer cells that do not respond to other treatment options.

    Research also indicated that dihydroorotate dehydrogenase was not the primary ferroptosis inhibitor in cancer cells, and therefore, targeting dihydroorotate dehydrogenase might not be as effective as deletion of ferroptosis suppressor protein 1.

    Furthermore, these studies highlighted the need to thoroughly understand the pitfalls and benefits of the various mechanisms to induce ferroptosis. Knockout studies in murine models revealed that glutathione peroxidase 4 was essential in various other processes and required for survival, while knocking out ferroptosis suppressor protein 1 resulted in no developmental changes, suggesting the latter to be a preferable method to induce ferroptosis.

    This comprehensive review provided a detailed discussion of the various metabolic processes that could be exploited to make cancer cells vulnerable to ferroptosis. These methods included modulating the balance between mono- and polyunsaturated fatty acids, de-novo lipogenesis, de-novo synthesis of polyunsaturated fatty acids, and β oxidation. The researchers also expanded on the role of iron, cystine, glutamate, and glutathione metabolism in ferroptosis.

    Conclusions

    To summarize, the review provided an in-depth view of the regulated cell death process of ferroptosis, the factors that make cancer cells susceptible to ferroptosis, and its importance in prostate cancer therapy. They discussed the pathways through which ferroptosis is suppressed in cancer cells and the metabolic mechanisms that must be targeted to induce ferroptosis in prostate cancer cells selectively.

    Journal reference:

    • Anh, H., Dominic, A., Lujan, F. E., Senthilkumar, S., Bhattacharya, P. K., Frigo, D. E., & Subramani, E. (2024). Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Nature Reviews Urology. DOI: 10.1038/s41585024008699, https://www.nature.com/articles/s41585-024-00869-9

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  • Global disease burden study highlights COVID-19 impact and health inequities

    Global disease burden study highlights COVID-19 impact and health inequities

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    Rates of early death and poor health caused by HIV/AIDS and diarrhea have been cut in half since 2010, and the rate of disease burden caused by injuries has dropped by a quarter in the same time period, after accounting for differences in age and population size across countries, based on a new study published in The Lancet. The study measures the burden of disease in years lost to early death and poor health. The findings indicate that total rates of global disease burden dropped by 14.2% between 2010 and 2019. However, the researchers found that the COVID-19 pandemic interrupted these downward trends: rates of disease burden increased overall since 2019 by 4.1% in 2020 and by 7.2% in 2021. This is the first study to measure premature death and disability due to the COVID-19 pandemic globally and compare it to other diseases and injuries. 

    The study reveals how healthy life expectancy, which is the number of years a person can expect to live in good health, rose from 61.3 years in 2010 to 62.2 years in 2021. Pinpointing the factors driving these trends, the researchers point to rapid improvements within the three different categories of disease burden: communicable, maternal, neonatal, and nutritional diseases; non-communicable diseases; and injuries. Among communicable, maternal, neonatal, and nutritional diseases, the burden of disease declined for neonatal disorders (diseases and injuries that appear uniquely in the first month of life), lower respiratory infections, diarrhea, malaria, tuberculosis, and HIV/AIDS between 2010 and 2021, ranging from reductions of 17.1% for neonatal disorders to 47.8% for HIV/AIDS. In the category of non-communicable diseases, disease burden from stroke dropped by 16.9%, while disease burden from ischemic heart disease fell by 12.0% during this period. 

    For injuries, the years of healthy life lost due to road injuries was slashed by nearly a quarter (22.9%), while disease burden from falls was reduced by 6.9%. Progress in reducing disease burden varied by countries’ Socio-demographic Index – a measure of income, fertility, and education – underscoring inequities. For example, the burden of disease due to stroke dropped by 9.6% from 2010 to 2021 in countries with the lowest Socio-demographic Index, but it declined faster – by 24.9% – among countries with higher Socio-demographic Index. 

    Our study illuminates both the world’s successes and failures. It demonstrates how the world made huge strides in expanding treatment for HIV/AIDS and combatting vaccine-preventable diseases and deaths among children under 5. At the same time, it shows how COVID-19 exacerbated inequities, causing the greatest disease burden in countries with the fewest resources, where health systems were strained and vaccines were difficult to secure. Governments should prioritize equitable pandemic preparedness planning and work to preserve the momentum that we’ve seen in improving children’s health.” 


    Dr. Alize Ferrari, Affiliate Associate Professor at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Honorary Associate Professor at the School of Public Health at the University of Queensland, and co-first author of the study

    The research presents updated estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. The GBD 2021 study analyzes incidence, prevalence, years lived with disability (years lived in less-than-ideal health), and disability-adjusted life years (lost years of healthy life) at global, regional, national, and subnational levels. It presents estimates of health and health loss in age-adjusted rates and total rates per 100,000 people. The study provides globally comparable measures of healthy life expectancy and is the first study to fully evaluate burden of disease amid the first two years of the COVID-19 pandemic. COVID-19 was the single leading cause of disease burden worldwide in 2021, accounting for 7.4% of total disease burden globally. 

    The study also examined how the COVID-19 pandemic affected males and females differently. The researchers found that males were more likely than females to die of COVID-19; the age-standardized disease burden rate for COVID-19 among males was nearly twice that of females. However, the secondary effects of the COVID-19 pandemic, including long COVID and mental disorders, hit females hardest. For example, females were twice as likely as males to develop long COVID. Depression, which increased sharply during the pandemic, was most likely to affect females between ages 15 and 65. Looking at differences between age groups, COVID-19 caused the most disease burden in older adults. For COVID-19, adults 70 years and older had more than double the levels of disease burden compared to adults between the ages of 50 and 69. 

    The study highlights not only the diseases and injuries that cut life short and cause poor health, and how the burden of disease from different causes has changed over time, but also examines how these patterns differ across countries and regions. “In essence,” the authors write, the study “provides a comprehensive toolkit to inform and enhance decision-making processes across various levels of governance and practice.” 

    GBD 2021 shines a light on the different causes of disease burden, showing which ones have improved and which are stagnating or worsening. It also tallies the number of years that people are living healthy lives. Healthy life expectancy rose significantly in 59 countries and territories between 2010 and 2021, with the greatest improvements in countries ranking lowest on the Socio-demographic Index, jumping from 52.2 years in 2010 to 54.4 years in 2021. In contrast, healthy life expectancy showed minimal change among countries in the highest levels of the Socio-demographic Index, decreasing slightly from 68.9 years in 2010 to 68.5 years in 2021. The findings on healthy life expectancy demonstrate that even though people are living longer lives all over the world, they aren’t spending all those years in good health. The researchers found that the main causes of poor health were low back pain, depressive disorders, and headache disorders. 

    “With low back pain, the leading cause of poor health globally, we see that the existing treatments aren’t working well to address it,” said Dr. Damian Santomauro, Affiliate Assistant Professor of Health Metrics Sciences at IHME; Stream Lead at Queensland Centre for Mental Health Research; Adjunct Fellow at the School of Public Health at the University of Queensland; and co-first author of the study. “We need better tools to manage this major cause of global disease burden.” 

    “In contrast, for depressive disorders, we know what can work: therapy, medication, or both in combination for an adequate period of time. However, most people in the world have little or no access to treatment, unfortunately,” he said. “Considering how depression increased dramatically during the COVID-19 pandemic, it’s urgent to ensure that everyone with this disorder can get treatment.” 

    Another way to understand what is making people ill is by looking at which diseases are growing fastest. GBD 2021 reveals that diabetes experienced the most rapid growth among the different causes of poor health, what the researchers call years lived with disability. Age-adjusted years lived with disability due to diabetes rose by 25.9% between 2010 and 2021. Poor health from diabetes increased in every country and territory that the researchers studied. 

    “Diabetes is a major contributor to stroke and ischemic heart disease, which are among the top three causes of disease burden worldwide,” said Dr. Theo Vos, Professor Emeritus at IHME and one of the study’s senior authors. “Without intervention, more than 1.3 billion people in the world will be living with diabetes by 2050. To counter the threat of diabetes, we must ensure that people in all countries can access preventive care and treatment, including to anti-obesity medications, which can lower a person’s risk of developing diabetes.” 

    Source:

    Institute for Health Metrics and Evaluation

    Journal reference:

    GBD 2021 Diseases and Injuries Collaborators., (2024) Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet. doi.org/10.1016/S0140-6736(24)00757-8.

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  • Bidirectional Mendelian randomization uncovers link between plasma metabolites and heart attack risk

    Bidirectional Mendelian randomization uncovers link between plasma metabolites and heart attack risk

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    Myocardial infarction, more commonly known as a heart attack, is a leading cause of death worldwide. Biomarkers called plasma metabolites may play a key role in the physiological pathways involved in myocardial infarctions. Recently published research used a methodological approach called bidirectional Mendelian randomization to understand more about these biomarkers and what they can tell doctors about heart attack risk.

    The research was published in the Journal of Geriatric Cardiology on February 28.

    Bidirectional Mendelian randomization studies represent a robust methodological approach, with numerous advantages not commonly present in traditional research methodologies. These include mitigating the impact of confounding factors on conclusions and exploring reverse causation, thereby providing a more reliable foundation for casual inferences. This study employed a bidirectional Mendelian randomization approach to investigate the relationship between plasma metabolites and myocardial infarction, offering new insights into the early diagnosis and potential treatment of myocardial infarction.”


    Qiang Wu from the Senior Department of Cardiology, the Sixth Medical Center, Chinese PLA General Hospital, Beijing, China

    By using data sets from large-scale genome-wide association studies, researchers were able to cast a wide net to try and understand more about the role plasma metabolites play in myocardial infarction. The data source included 461,823 individuals of European descent. Of those, 20,917 individuals had myocardial infarction and 440,906 individuals did not. A total of 24,172,914 single nucleotide polymorphisms were identified in that data set to be associated with myocardial infarction. Bidirectional Mendelian randomization narrows down this large amount of data and determines the relationship between plasma metabolites and myocardial infarction.

    This analysis uncovered 198 unique plasma metabolites that were identified to have a significant association with myocardial infarction, of which 14 plasma metabolites had a direct relationship with myocardial infarction risk. “We identified 14 plasma metabolites associated with myocardial infarction, of which 8 plasma metabolites were linked to a decreased risk and 6 plasma metabolites were linked to an increased risk, underscoring the complicated nature of metabolic pathways influencing heart attack risk,” said Dong-Hua LI from Department of Cardiovascular Medicine, Minzu Hospital of Guangxi Zhuang Autonomous Region, Guangxi, China. “The robustness of our findings was strengthened by the application of bidirectional Mendelian randomization, enabling a thorough exploration of causality.” 

    Of the 14 plasma metabolite biomarkers identified in this study, 13 plasma metabolite biomarkers had never been identified as potential biomarkers associated with myocardial infarction before. These biomarkers offer a new option for developing diagnostic tests, routine screenings, and treatments for heart attack.

    Looking to next steps, researchers are hoping to learn more about the mechanisms of these plasma metabolites and how they are related to myocardial infarction. For example, there were 8 plasma metabolites that were associated with a decreased risk of myocardial infarction and researchers speculate that anti-inflammatory properties associated with metabolites are at play, reducing oxidative stress in the body. However, additional research is needed to confirm this hypothesis.

    “Timely detection using metabolic signatures could usher in a new era of preventive cardiology, where interventions are tailored to an individual’s metabolic profile. Furthermore, understanding the metabolic underpinnings of myocardial infarction will contribute to the development of point-of-care diagnostic tools, providing rapid and accessible assessments. Thus, the findings of the study can revolutionize clinical practice by enabling early and precise diagnoses, ultimately causing more effective and tailored treatment strategies,” said Qiang SU from Department of Cardiology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Guangxi, China.

    Other contributors include Jing-Sheng LAN, You-Yi HUANG, Lan-Jin WU, Zhi-Qing QIN, and Ying HUANG from Minzu Hospital of Guangxi Zhuang Autonomous Region in Guangxi, China; Shuo CHEN and Xin HAO from Chinese PLA General Hospital in Beijing, China; and Wan-Zhong HUANG, Ting ZENG, and Hua-Bin SU from Jiangbin Hospital of Guangxi Zhuang Autonomous Region in Guangxi, China.

    The Guangxi Natural Science Foundation, the Key Research and Development Program of Guangxi, and the Chongzuo Science and Technology Bureau Planning Project funded this research.

    Source:

    Tsinghua University Press

    Journal reference:

    Li, D.-H., et al. (2024). Plasma metabolites and risk of myocardial infarction: a bidirectional Mendelian randomization study. Journal of Geriatric Cardiology. doi.org/10.26599/1671-5411.2024.02.002.

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