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  • Machine learning system offers new hope for diagnosis of rare genetic disorders

    Machine learning system offers new hope for diagnosis of rare genetic disorders

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    Diagnosing rare Mendelian disorders is a labor-intensive task, even for experienced geneticists. Investigators at Baylor College of Medicine are trying to make the process more efficient using artificial intelligence. The team developed a machine learning system called AI-MARRVEL (AIM) to help prioritize potentially causative variants for Mendelian disorders. The study is published today in NEJM AI. 

    Researchers from the Baylor Genetics clinical diagnostic laboratory noted that AIM’s module can contribute to predictions independent of clinical knowledge of the gene of interest, helping to advance the discovery of novel disease mechanisms. “The diagnostic rate for rare genetic disorders is only about 30%, and on average, it is six years from the time of symptom onset to diagnosis. There is an urgent need for new approaches to enhance the speed and accuracy of diagnosis,” said co-corresponding author Dr. Pengfei Liu, associate professor of molecular and human genetics and associate clinical director at Baylor Genetics.

    AIM is trained using a public database of known variants and genetic analysis called Model organism Aggregated Resources for Rare Variant ExpLoration (MARRVEL) previously developed by the Baylor team. The MARRVEL database includes more than 3.5 million variants from thousands of diagnosed cases. Researchers provide AIM with patients’ exome sequence data and symptoms, and AIM provides a ranking of the most likely gene candidates causing the rare disease. 

    Researchers compared AIM’s results to other algorithms used in recent benchmark papers. They tested the models using three data cohorts with established diagnoses from Baylor Genetics, the National Institutes of Health-funded Undiagnosed Diseases Network (UDN) and the Deciphering Developmental Disorders (DDD) project. AIM consistently ranked diagnosed genes as the No. 1 candidate in twice as many cases than all other benchmark methods using these real-world data sets. 

    We trained AIM to mimic the way humans make decisions, and the machine can do it much faster, more efficiently and at a lower cost. This method has effectively doubled the rate of accurate diagnosis.”


    Dr. Zhandong Liu, co-corresponding author, associate professor of pediatrics – neurology at Baylor and investigator at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital

    AIM also offers new hope for rare disease cases that have remained unsolved for years. Hundreds of novel disease-causing variants that may be key to solving these cold cases are reported every year; however, determining which cases warrant reanalysis is challenging because of the high volume of cases. The researchers tested AIM’s clinical exome reanalysis on a dataset of UDN and DDD cases and found that it was able to correctly identify 57% of diagnosable cases.

    “We can make the reanalysis process much more efficient by using AIM to identify a high-confidence set of potentially solvable cases and pushing those cases for manual review,” Zhandong Liu said. “We anticipate that this tool can recover an unprecedented number of cases that were not previously thought to be diagnosable.”

    Researchers also tested AIM’s potential for discovery of novel gene candidates that have not been linked to a disease. AIM correctly predicted two newly reported disease genes as top candidates in two UDN cases.

    “AIM is a major step forward in using AI to diagnose rare diseases. It narrows the differential genetic diagnoses down to a few genes and has the potential to guide the discovery of previously unknown disorders,” said co-corresponding author Dr. Hugo Bellen, Distinguished Service Professor in molecular and human genetics at Baylor and chair in neurogenetics at the Duncan NRI.

    “When combined with the deep expertise of our certified clinical lab directors, highly curated datasets and scalable automated technology, we are seeing the impact of augmented intelligence to provide comprehensive genetic insights at scale, even for the most vulnerable patient populations and complex conditions,” said senior author Dr. Fan Xia, associate professor of molecular and human genetics at Baylor and vice president of clinical genomics at Baylor Genetics. “By applying real-world training data from a Baylor Genetics cohort without any inclusion criteria, AIM has shown superior accuracy. Baylor Genetics is aiming to develop the next generation of diagnostic intelligence and bring this to clinical practice.”

    Other authors of this work include Dongxue Mao, Chaozhong Liu, Linhua Wang, Rami AI-Ouran, Cole Deisseroth, Sasidhar Pasupuleti, Seon Young Kim, Lucian Li, Jill A.Rosenfeld, Linyan Meng, Lindsay C. Burrage, Michael Wangler, Shinya Yamamoto, Michael Santana, Victor Perez, Priyank Shukla, Christine Eng, Brendan Lee and Bo Yuan. They are affiliated with one or more of the following institutions: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Al Hussein Technical University, Baylor Genetics and the Human Genome Sequencing Center at Baylor.

    This work was supported by the Chang Zuckerberg Initiative and the National Institute of Neurological Disorders and Stroke (3U2CNS132415).

    Source:

    Baylor College of Medicine

    Journal reference:

    Mao, D., et al. (2024) AI-MARRVEL — A Knowledge-Driven AI System for Diagnosing Mendelian Disorders. NEJM AI. doi.org/10.1056/AIoa2300009.

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  • Landmark study highlights power of vaccination

    Landmark study highlights power of vaccination

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    A major landmark study to be published by The Lancet reveals that global immunization efforts have saved an estimated 154 million lives – or the equivalent of 6 lives every minute of every year – over the past 50 years. The vast majority of lives saved – 101 million – were those of infants.

    The study, led by the World Health Organization (WHO), shows that immunization is the single greatest contribution of any health intervention to ensuring babies not only see their first birthdays but continue leading healthy lives into adulthood.

    Of the vaccines included in the study, the measles vaccination had the most significant impact on reducing infant mortality, accounting for 60% of the lives saved due to immunization. This vaccine will likely remain the top contributor to preventing deaths in the future.

    Over the past 50 years, vaccination against 14 diseases (diphtheria, Haemophilus influenzae type B, hepatitis B, Japanese encephalitis, measles, meningitis A, pertussis, invasive pneumococcal disease, polio, rotavirus, rubella, tetanus, tuberculosis, and yellow fever) has directly contributed to reducing infant deaths by 40% globally, and by more than 50% in the African Region.

    “Vaccines are among the most powerful inventions in history, making once-feared diseases preventable,” said WHO Director-General, Dr Tedros Adhanom Ghebreyesus. “Thanks to vaccines, smallpox has been eradicated, polio is on the brink, and with the more recent development of vaccines against diseases like malaria and cervical cancer, we are pushing back the frontiers of disease. With continued research, investment and collaboration, we can save millions more lives today and in the next 50 years.”

    The study found that for each life saved through immunization, an average of 66 years of full health were gained – with a total of 10.2 billion full health years gained over the five decades. As the result of vaccination against polio more than 20 million people are able to walk today who would otherwise have been paralysed, and the world is on the verge of eradicating polio, once and for all.

    These gains in childhood survival highlight the importance of protecting immunization progress in every country of the world and accelerating efforts to reach the 67 million children who missed out on one or more vaccines during the pandemic years.

    Monumental efforts to increase access to vaccination over five decades

    Released ahead of the 50th anniversary of the Expanded Programme on Immunization (EPI) to take place in May 2024, the study is the most comprehensive analysis of the programme’s global and regional health impact over the past five decades.

    Founded in 1974 by the World Health Assembly, EPI’s original goal was to vaccinate all children against diphtheria, measles, pertussis, polio, tetanus, tuberculosis, as well as smallpox, the only human disease ever eradicated. Today, the programme, now referred to as the Essential Programme on Immunization, includes universal recommendations to vaccinate against 13 diseases, and context-specific recommendations for another 17 diseases, extending the reach of immunization beyond children, to adolescent and adults.

    The study highlights that fewer than 5% of infants globally had access to routine immunization when EPI was launched. Today, 84% of infants are protected with 3 doses of the vaccine against diphtheria, tetanus and pertussis (DTP) – the global marker for immunization coverage.

    Nearly 94 million of the estimated 154 million lives saved since 1974, were a result of protection by measles vaccines. Yet, there were still 33 million children who missed a measles vaccine dose in 2022: nearly 22 million missed their first dose and an additional 11 million missed their second dose.

    Coverage of 95% or greater with 2 doses of measles-containing vaccine is needed to protect communities from outbreaks. Currently, the global coverage rate of the first dose of measles vaccine is 83% and the second dose is 74%, contributing to a very high number of outbreaks across the world.

    To increase immunization coverage, UNICEF, as one of the largest buyers of vaccines in the world, procures more than 2 billion doses every year on behalf of countries and partners for reaching almost half of the world’s children. It also works to distribute vaccines to the last mile, ensuring that even remote and underserved communities have access to immunization services.

    Thanks to vaccinations, more children now survive and thrive past their fifth birthday than at any other point in history. This massive achievement is a credit to the collective efforts of governments, partners, scientists, healthcare workers, civil society, volunteers and parents themselves, all pulling in the same direction of keeping children safe from deadly diseases. We must build on the momentum and ensure that every child, everywhere, has access to life-saving immunizations.”


    Catherine Russell, UNICEF Executive Director

    In 2000, Gavi, the Vaccine Alliance, which includes WHO, UNICEF and the Bill & Melinda Gates Foundation (BMGF) as core founding members, was created to expand the impact of EPI and help the poorest countries in the world increase coverage, benefit from new, life-saving vaccines and expand the breadth of protection against an increasing number of vaccine-preventable diseases. This intensified effort in the most vulnerable parts of the world has helped to save more lives and further promote vaccine equity. Today, Gavi has helped protect a whole generation of children and now provides vaccines against 20 infectious diseases, including the HPV vaccine and vaccines for outbreaks of measles, cholera, yellow fever, Ebola and meningitis.

    “Gavi was established to build on the partnership and progress made possible by EPI, intensifying focus on protecting the most vulnerable around the world,” said Dr Sania Nishtar, CEO of Gavi, the Vaccine Alliance. “In a little over two decades we have seen incredible progress – protecting more than a billion children, helping halve childhood mortality in these countries, and providing billions in economic benefits. Vaccines are truly the best investment we can make in ensuring everyone, no matter where they are born, has an equal right to a healthy future: we must ensure these efforts are fully funded to protect the progress made and help countries address current challenges of their immunization programmes.”

    Immunization programmes have become the bedrock of primary health services in communities and countries due to their far reach and wide coverage. They provide not only an opportunity for vaccination but also enable other life-saving care to be provided, including nutritional support, maternal tetanus prevention, illness screenings and bed net distribution to protect families from diseases like malaria.

    Since the study only covers the health impact of vaccination against 14 diseases, the number of lives saved due to vaccination is a conservative estimate and not a full account of the life-saving impact of vaccines. Societal, economic or educational impacts to health and well-being over the 50 years have also contributed to further reductions in mortality. Today, there are vaccines to protect against more than 30 life-threatening diseases.

    While the HPV vaccine, which protects against cervical cancer in adults, was not included in the study, it is expected to prevent a high number of future deaths as countries work towards increasing immunization targets aimed at eliminating cervical cancer by 2030. New vaccine introductions, such as those for malaria, COVID-19, respiratory syncytial virus (RSV) and meningitis, as well as cholera and Ebola vaccines used during outbreaks, will further save lives in the next 50 years.

    Saving millions more is “Humanly Possible”

    Global immunization programmes have shown what is humanly possible when many stakeholders, including heads of state, regional and global health agencies, scientists, charities, aid agencies, businesses, and communities work together.

    Today, WHO, UNICEF, Gavi, and BMGF are unveiling “Humanly Possible”, a joint campaign, marking the annual World Immunization Week, 24-30 April 2024. The worldwide communication campaign calls on world leaders to advocate, support and fund vaccines and the immunization programmes that deliver these lifesaving products – reaffirming their commitment to public health, while celebrating one of humanity’s greatest achievements. The next 50 years of EPI will require not only reaching the children missing out on vaccines, but protecting grandparents from influenza, mothers from tetanus, adolescents from HPV and everyone from TB, and many other infectious diseases.

    “It’s inspiring to see what vaccines have made possible over the last fifty years, thanks to the tireless efforts of governments, global partners and health workers to make them more accessible to more people,” said Dr Chris Elias, president of Global Development at the Bill & Melinda Gates Foundation. “We cannot let this incredible progress falter. By continuing to invest in immunization, we can ensure that every child – and every person – has the chance to live a healthy and productive life.”

    Source:

    The World Health Organization

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  • High BMI associated with changes in physiological brain pulsations

    High BMI associated with changes in physiological brain pulsations

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    A recent study from the University of Oulu reveals that high body mass index (BMI) is associated with changes in physiological brain pulsations. These pulsations play a crucial role in maintaining brain fluid circulation and the clearance of metabolic waste from the brain.

    The brain exhibits three types of pulsations: cardiac driven by the heartbeat, respiratory linked to breathing cycles and vasomotion related to rhythmic blood vessel oscillations.

    In the latest study by the Oulu Functional Neuroimaging (OFNI) research group at the University of Oulu, it was found that a high BMI particularly intensifies pulsations related to respiration in the brain. At the same time, pulsations caused by arteries in the pituitary gland and hypothalamus region decrease, while arterial vasomotor waves increase slightly.

    The findings suggest that being overweight may disrupt vital metabolic processes and homeostatsis in the brain.

    The study used ultrafast MREG imaging to examine the brain activity of 115 healthy adults at rest. Additional factors such as gender, age, and blood pressure, known to correlate with BMI, were taken into account, enhancing the reliability of the findings. The results indicate that a high BMI significantly impacts brain pulsations throughout the brain.

    Altered pulsations, resulting from overweight, may adversely affect brain health. Researchers emphasize the need for greater consideration of the effects of overweight on the brain in both scientific research and clinical practice.

    Overweight is a risk factor for many brain and cardiovascular diseases. These research findings help us understand how overweight affects brain function and the associated neurological risks. These observations may also help develop new diagnostic tools and treatment methods for conditions such as memory disorders, which are often associated with overweight.”

    Lauri Raitamaa, Doctoral Researcher 

    The study was published in the International Journal of Obesity in March: Raitamaa, L., Kautto, J., Tuunanen, J. et al. Association of body-mass index with physiological brain pulsations across adulthood – a fast fMRI study. Int J Obes (2024). https://doi.org/10.1038/s41366-024-01515-5

    The research was funded by, among others, The Research Council of Finland, the Jane and Aatos Erkko Foundation, and the Finnish Brain Foundation.

    Source:

    Journal reference:

    Raitamaa, L., et al. (2024). Association of body-mass index with physiological brain pulsations across adulthood – a fast fMRI study. International Journal of Obesity. doi.org/10.1038/s41366-024-01515-5.

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  • Therapeutic potential of human umbilical cord-derived mesenchymal stem cells in Crohn’s disease

    Therapeutic potential of human umbilical cord-derived mesenchymal stem cells in Crohn’s disease

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    In a recent study published in eBioMedicine, researchers investigated whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could heal luminal ulcers in Crohn’s disease (CD) patients.

    Study: hUC-MSCs therapy for Crohn’s disease: efficacy in TNBS-induced colitis in rats and pilot clinical study. Image Credit: Lobachad/Shutterstok.comStudy: hUC-MSCs therapy for Crohn’s disease: efficacy in TNBS-induced colitis in rats and pilot clinical study. Image Credit: Lobachad/Shutterstok.com

    Background

    CD is a developing global disease with a poor overall effectiveness rate, posing a considerable therapeutic challenge to health professionals. Current therapies have limitations, and recovery rates are far from expected.

    MSC-based therapy has demonstrated promise as a potential new treatment option for various disorders, including CD of the perianal fistulizing type. However, limited evidence is available on the efficacy of MSCs in treating or healing intestinal ulcers in CD. 

    Human umbilical cord MSCs have acquired popularity due to their immunomodulatory capabilities, simplicity of collection, limitless source of stem cells, low immunological rejection, and lack of tumorigenic features.

    Despite their usefulness in immunological and inflammatory illnesses, there has been no research on using hUC-MSCs locally to heal intestinal ulcers in CD patients.

    About the study

    The present study researchers explored hUC-MSC safety and effectiveness in CD management.

    The researchers used the 4,6-trinitrobenzene-sulfonic acid (TNBS)-inflicted colitis rat model to investigate the effectiveness of hUC-MSC therapy in CD. They calculated the disease activity index (DAI) by adding values for body weight loss, stool consistency, and stool blood.

    The colon macroscopic damage index (CMDI) assessed the level of colonic inflammation. They analyzed colon samples under a microscope to establish histopathological scores (HPS).

    From November 2020 to October 2023, the researchers ran a pilot, open-label clinical study with 17 refractory CD patients. Participants received a local submucosal injection of hUC-MSCs (60 × 106 cells/10 mL) by colonoscopy, followed by an intravenous drip of 1.0 × 106 hUC-MSCs/kg/100 mL the following day.

    The study included individuals aged 18–75 years with moderate-severe CD for ≥3 months, baseline CDAI scores of 220-450, and endoscopic ulcers. They did not respond to conventional or advanced treatment, including immunomodulators and biologics.

    The researchers followed the patients for 24 weeks, measuring laboratory and clinical markers on days 0, week 4, week 8, week 12, and week 24.

    They performed endoscopic assessments at the start of the trial and, after 12 weeks, obtained mucosal specimens from lesion margins for ribonucleic acid (RNA) sequencing. The researchers excluded individuals with a history of pregnancy, CD complications, comorbidities, prior surgery, uncontrolled infections, or cancer in the past five years.

    The team also produced two hUC-MSC in vitro co-cultures using mucosal tissues and the human monocyte cell line THP-1-induced M1 macrophages. Reverse transcription-polymerase chain reaction (RT-PCR) measured inflammatory and intestinal barrier function-related genes.

    In addition, the researchers performed gene ontology (GO) analysis and explored the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment.

    They used enzyme-linked immunosorbent assays (ELISA) to assess the expression of tumor necrosis factor-stimulated gene-6 protein (TSG-6) in hUC-MSC culture supernatants after 48 hours of stimulation with lipopolysaccharide (LPS), interferon-gamma (IFNγ), and TNF-alpha (TNFα) for 48 hours.

    Results

    In preclinical studies, hUC-MSCs raised body weight while decreasing DAI, CMDI, and HPS scores in the TNBS-inflicted colitis murine model, with significant reductions in intestinal mucosal injury, edema, hyperemia, and ulcerations.

    Local and submucosal hUC-MSC injections resulted in intestinal ulcer regression in the study participants.

    Among the subjects, eight (47%) displayed endoscopic responses (a ≥50% improvement in SES-CD scores), and three (18%) demonstrated mucosal healing, with parallel improvements of laboratory and clinical markers without significant side effects.

    Human umbilical cord-derived MSCs increased transcripts associated with intestinal barrier integrity while decreasing those related to inflammatory intestinal mucosal pathways, including TNF-α, interleukin-17 (IL-17), and toll-like receptor (TLR) signaling.

    The treatment dramatically enhanced RNA levels of tight junction proteins [E-cadherin (CDH1), zonula occludens-1 (ZO1), and claudin-1 (CLDN1)] in the intestinal epithelium and intestinal pro-inflammatory genes (TNF-α, IL-1β, and IL-6).

    Furthermore, hUC-MSCs reduced THP1-induced M1 macrophage polarization and messenger RNA (mRNA) expressions of TNF-α, IL-1β, and IL-6.

    MSCs obtained from the human umbilical cord suppressed Janus kinase/signal transducers and activators of transcription (JAK/STAT) phosphorylation in intestinal mucosal cells from Crohn’s disease patients.

    Conclusions

    The study findings showed that submucosal injection of hUC-MSCs by colonoscopy, paired with an intravenous drip, reduced TNBS-inflicted colitis among rats. This technique may treat refractory CD with clinical effectiveness and tolerable risk.

    TSG-6 release may contribute to the therapeutic effect by inhibiting JAK/STAT phosphorylation, reducing M1 macrophage polarization, and improving intestinal barrier function.

    In individuals with moderately or highly active CD, hUC-MSC treatment resulted in clinical remission and the repair of intestinal ulcers.

    The expression of STAT1, M1 macrophage-associated specific markers, and pro-inflammatory factors in the intestinal mucosa dropped considerably following therapy. Further research is required to establish the efficacy of hUC-MSC treatment and investigate the underlying processes of the therapy.

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  • Meta-analysis reveals drivers of antibiotic resistance in infants

    Meta-analysis reveals drivers of antibiotic resistance in infants

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    A meta-analysis of genetic studies analyzing the microbiota (bacteria in the gut) of 1,275 infants from 10 countries finds that cesarean delivery and antibiotic use are driving the increase of antibiotic resistance genes load among infants, according to new research being presented at this year’s ESCMID Global Congress (formerly ECCMID) in Barcelona, Spain (27-30 April).

    The study, by researchers from UiT The Artic University of Norway, highlights the urgent need for more research on targeted interventions to reduce antibiotic resistance in infants. They speculate that probiotics, for example, could reduce the abundance of antibiotic-resistance genes and merit further investigation.

    Antimicrobial resistance (AMR) is a global health emergency. Drug-resistant infections kill more than 1.27 million people a year worldwide. If no action is taken, antimicrobial resistance could overtake cancer as the leading cause of death worldwide by 2050, and is projected to kill 10 million people globally.

    Infants are highly susceptible to infections due to their immature immune system. At the same time, their gut microbiota is full of diverse bacteria, many of which harbor resistance against a broad range of antibiotics, even in the absence of antibiotic exposure. The gut resistome-;the collection of antibiotic-resistant genes (ARGs) harbored in the genomes of infant gut microbes-;develops when microbes flood the gut immediately after birth, and is an important piece of the AMR puzzle.

    The gut mobilome-;the collection of diverse mobile genetic elements (MGEs) within the gut, plays a key role in the spread of ARGs. Bacteria swap genetic material, like ARGs, through horizontal gene transfer. With so many bacteria in close proximity, the gut provides ideal conditions for this exchange of ARGs.

    While many intestinal bacteria harbouring ARGs do not pose a health threat, some ARGs are acquired by microbes with pathogenic potential. When these genes are transmitted to a pathogen, this has dire consequences for both the individual patient and society.

    Understanding the factors influencing the development of the infant gut resistome and mobilome is therefore crucial for developing strategies to mitigate AMR prevalence.

    Several previous clinical studies have provided important but fragmented insights into the gut resistome, but their small sample sizes and inherent biases (e.g., selection bias and confounding) limit the generalisability of the findings.

    To overcome these limitations, researchers conducted a meta-analysis of infant cohorts based on metagenomics data from 14 studies spanning 10 countries and three continents.

    They investigated the extent to which antibiotic use, birth mode, prematurity, feeding practices, and geography influenced the abundance and diversity of ARGs and MGEs in 3,981 gut metagenome faecal samples from 1,275 infants. To track the infants’ microbiomes, infants’ stools were sampled longitudinally up to 14 months of age.

    Researchers used published shotgun metagenomes (untargeted genetic sequencing of all bacteria living in the gut) to examine the associations between the diversity and load of ARGs and MGEs and antibiotic use, birth mode, prematurity, feeding practices, and geography, as well as to identify which bacterial species are major hosts of ARGs within infants’ gut.

    Overall, the analyses found that use of antibiotics, Caesarean delivery, and prematurity was significantly associated with reduced beneficial gut microbe diversity compared to full-term, vaginally-born infants not exposed to antibiotics.

    On the other hand, vaginal birth was linked to lower abundance but more diverse ARGs compared to C-section delivery.

    Vaginally born infants are exposed to more vaginal and gut bacteria compared to C-section born babies, who are primarily exposed to skin bacteria. Since bacteria correlate with the collection of antibiotic-resistant genes in the gut, higher antibiotic-resistant gene diversity in vaginally born infants is expected. However, the presence of higher levels of certain commensal bacteria-;which supply their host with essential nutrients and help defend the host against opportunistic pathogens-;in vaginally born infants may suppress pathogenic bacteria (which are likely to carry a higher abundance of antibiotic-resistant genes), thereby reducing the overall abundance.”


    Ahmed Bargheet, lead author from UiT The Artic University of Norway

    As expected, the analyses found that antibiotic use was linked to higher ARG and MGE abundance. However, antibiotic use had no significant impact on the ARGs’ diversity.

    Surprisingly, exclusively breastfed infants showed no significant effects on ARG diversity or abundance.

    Importantly, the researchers detected 199 clinically relevant ARGs (that confer resistance to clinically relevant antibiotics), whose diversity increased with age during the first two years of life. “The diversity of the ARGs increased over time, mirroring the diversity of the bacteria. However, the abundance of ARGs decreased over time, possibly due to a reduction in the abundance of pathogenic bacteria such as Escherichia coli“, says Bargheet.

    Interestingly, two African cohorts (from Zimbabwe and South Africa) had a statistically significant and higher ARG and MGE abundance compared to the European cohorts. “It’s possible that Zimbabwe and South Africa used more antibiotics in their infant cohorts than the Europeans”, says Bargheet. “In Zimbabwe, the regulation and control of antibiotics is not as strict as in some regions of Europe, leading to a situation where antibiotics can often be purchased over the counter without a prescription, potentially exacerbating antimicrobial resistance.”

    The authors further confirmed E. Coli as the main host of ARGs in the guts of infants, and concerningly, nearly half of the ARGs co-localized with plasmids, allowing efficient transfer between bacteria. Furthermore, E. coli strain diversity was found to be reduced during breastfeeding, but increased with age. Interestingly, antibiotic use had no significant impact on the E. coli strain diversity.

    “Our meta-analysis of the available evidence clearly shows that C-section delivery, antibiotic use, and prematurity play an underappreciated role in antibiotic resistance in infants by altering early life resistome and mobilome, leading to an increased gut carriage of antibiotic resistance genes and mobile genetic elements”, says Bargheet.

    “This has important implications for the antibiotic resistance crisis. By gaining insight into these factors, we aim to develop targeted interventions like probiotics, that could significantly reduce the number of deaths caused by antimicrobial resistance. This research not only addresses a pressing global health challenge but also sets the stage for breakthroughs in medical treatment and infection control. As we move forward, our focus remains on turning these findings into actionable strategies that can save lives and curb the spread of resistant infections.”

    Despite the important findings, the authors note several limitations, including that the impact of hospitalization and other clinical variables could not be examined in this analysis due to a lack of data.

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  • New system personalizes chemotherapy doses for cancer patients

    New system personalizes chemotherapy doses for cancer patients

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    When cancer patients undergo chemotherapy, the dose of most drugs is calculated based on the patient’s body surface area. This is estimated by plugging the patient’s height and weight into an equation, dating to 1916, that was formulated from data on just nine patients.

    This simplistic dosing doesn’t take into account other factors and can lead to patients receiving either too much or too little of a drug. As a result, some patients likely experience avoidable toxicity or insufficient benefit from the chemotherapy they receive.

    To make chemotherapy dosing more accurate, MIT engineers have come up with an alternative approach that can enable the dose to be personalized to the patient. Their system measures how much drug is in the patient’s system, and these measurements are fed into a controller that can adjust the infusion rate accordingly.

    This approach could help to compensate for differences in drug pharmacokinetics caused by body composition, genetic makeup, chemotherapy-induced toxicity of the organs that metabolize the drugs, interactions with other medications being taken and foods consumed, and circadian fluctuations in the enzymes responsible for breaking down chemotherapy drugs, the researchers say.

    Recognizing the advances in our understanding of how drugs are metabolized, and applying engineering tools to facilitate personalized dosing, we believe, can help transform the safety and efficacy of many drugs.”


    Giovanni Traverso, associate professor of mechanical engineering at MIT, gastroenterologist at Brigham and Women’s Hospital, and  senior author of the study

    Louis DeRidder, an MIT graduate student, is the lead author of the paper, which appears today in the journal Med.

    Continuous monitoring

    In this study, the researchers focused on a drug called 5-fluorouracil, which is used to treat colorectal cancers, among others. The drug is typically infused over a 46-hour period, and the dosage is determined using a formula based on the patient’s height and weight, which gives the estimated body surface area.

    However, that approach doesn’t account for differences in body composition that can affect how the drug spreads through the body, or genetic variations that influence how it is metabolized. Those differences can lead to harmful side effects, if too much drug is present. If not enough drug is circulating, it may not kill the tumor as expected.

    “People with the same body surface area could have very different heights and weights, could have very different muscle masses or genetics, but as long as the height and the weight plugged into this equation give the same body surface area, their dose is identical,” says DeRidder, a PhD candidate in the Medical Engineering and Medical Physics program within the Harvard-MIT Program in Health Sciences and Technology.

    Another factor that can alter the amount of drug in the bloodstream at any given time is circadian fluctuations of an enzyme called dihydropyrimidine dehydrogenase (DPD), which breaks down 5-fluorouracil. DPD’s expression, like many other enzymes in the body, is regulated on a circadian rhythm. Thus, the degradation of 5-FU by DPD is not constant but changes according to the time of the day. These circadian rhythms can lead to tenfold fluctuations in the amount of 5-fluorouracil in a patient’s bloodstream over the course of an infusion.

    “Using body surface area to calculate a chemotherapy dose, we know that two people can have profoundly different toxicity from 5-fluorouracil chemotherapy. Looking at one patient, they can have cycles of treatment with minimal toxicity and then have a cycle with miserable toxicity. Something changed in how that patient metabolized chemo from one cycle to the next. Our antiquated dosing fails to capture that change, and patients suffer as a result,” says Douglas Rubinson, a clinical oncologist at Dana-Farber Cancer Institute and an author of the paper.

    One way to try to counteract the variability in chemotherapy pharmacokinetics is a strategy called therapeutic drug monitoring, in which the patient gives a blood sample at the end of one treatment cycle. After this sample is analyzed for the drug concentration, the dosage can be adjusted, if needed, at the beginning of the next cycle (usually two weeks later for 5-fluorouracil). This approach has been shown to result in better outcomes for patients, but it is not widely used for chemotherapies such as 5-fluorouracil.

    The MIT researchers wanted to develop a similar type of monitoring, but in a manner that is automated and enables real-time drug personalization, which could result in better outcomes for patients. In their “closed-loop” system, drug concentrations can be continually monitored, and that information is used to automatically adjust the infusion rate of the chemotherapy drug and keep the dose within the target range. Such a closed-loop system enables personalization of the drug dose in a manner that considers circadian rhythm changes in the levels of drug-metabolizing enzymes, as well as any changes in the patient’s pharmacokinetics since their last treatment, such as chemotherapy-induced toxicity of the organs that metabolize the drugs.

    The new system they designed, known as CLAUDIA (Closed-Loop AUtomated Drug Infusion regulAtor), makes use of commercially available equipment for each step. Blood samples are taken every five minutes and rapidly prepared for analysis. The concentration of 5-fluorouracil in the blood is measured and compared to the target range. The difference between the target and measured concentration is input to a control algorithm, which then adjusts the infusion rate if necessary, to keep the dose within the range of concentrations between which the drug is effective and nontoxic.

    “What we’ve developed is a system where you can constantly measure the concentration of drug and adjust the infusion rate accordingly, to keep the drug concentration within the therapeutic window,” DeRidder says.

    Rapid adjustment

    In tests in animals, the researchers found that using CLAUDIA, they could keep the amount of drug circulating in the body within the target range around 45 percent of the time. Drug levels in animals that received chemotherapy without CLAUDIA remained in the target range only 13 percent of the time, on average. In this study, the researchers did not do any tests of the effectiveness of the drug levels, but keeping the concentration within the target window is believed to lead to better outcomes and less toxicity.

    CLAUDIA was also able to keep the dose of 5-fluorouracil within the target range even when the researchers administered a drug that inhibits the DPD enzyme. In animals that received this inhibitor without continuous monitoring and adjustment, levels of 5-fluorouracil increased by up to eightfold.

    For this demonstration, the researchers manually performed each step of the process, using off-the-shelf equipment, but they now plan to work on automating each step so that the monitoring and dose adjustment can be done without any human intervention.

    To measure drug concentrations, the researchers used high-performance liquid chromatography mass spectroscopy (HPLC-MS), a technique that could be adapted to detect nearly any type of drug.

    “We foresee a future where we’re able to use CLAUDIA for any drug that has the right pharmacokinetic properties and is detectable with HPLC-MS, thereby enabling the personalization of dosing for many different drugs,” DeRidder says.

    The research was funded by the National Science Foundation Graduate Research Fellowship Program, a MathWorks Fellowship, MIT’s Karl van Tassel Career Development Professorship, the MIT Department of Mechanical Engineering, and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

    Other authors of the paper include Kyle A. Hare, Aaron Lopes, Josh Jenkins, Nina Fitzgerald, Emmeline MacPherson, Niora Fabian, Josh Morimoto, Jacqueline N. Chu, Ameya R. Kirtane, Wiam Madani, Keiko Ishida, Johannes L. P. Kuosmanen, Naomi Zecharias, Christopher M. Colangelo, Hen-Wei Huang, Makaya Chilekwa, Nikhil B. Lal, Shriya S. Srinivasan, Alison M Hayward, Brian M. Wolpin, David Trumper, Troy Quast, and Robert Langer.

    Source:

    Massachusetts Institute of Technology

    Journal reference:

    DeRidder, L. B., et al. (2024) Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing. Med. doi.org/10.1016/j.medj.2024.03.020.

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  • Study links acid-reducing drugs to increased risk of migraine

    Study links acid-reducing drugs to increased risk of migraine

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    People who take acid-reducing drugs may have a higher risk of migraine and other severe headache than people who do not take these medications, according to a study published in the April 24, 2024, online issue of Neurology® Clinical Practice, an official journal of the American Academy of Neurology. The acid-reducing drugs include proton pump inhibitors such as omeprazole and esomeprazole, histamine H2-receptor antagonists, or H2 blockers, such as cimetidine and famotidine, and antacid supplements.

    The study does not prove that acid-reducing drugs cause migraine; it only shows an association.

    Acid reflux is when stomach acid flows into the esophagus, usually after a meal or when lying down. People with acid reflux may experience heartburn and ulcers. People with frequent acid reflux may develop gastroesophageal reflux disease, or GERD, which can lead to cancer of the esophagus.

    Given the wide usage of acid-reducing drugs and these potential implications with migraine, these results warrant further investigation. These drugs are often considered to be overprescribed, and new research has shown other risks tied to long-term use of proton pump inhibitors, such as an increased risk of dementia.”

    Margaret Slavin, PhD, RDN, study author of the University of Maryland in College Park

    For the study, researchers looked at data on 11,818 people who provided information on use of acid-reducing drugs and whether they had migraine or severe headache in the past three months.

    A total of 25% of participants taking proton pump inhibitors had migraine or severe headache, compared to 19% of those who were not taking the drugs. A total of 25% of those taking H2 blockers had severe headache, compared to 20% of those who were not taking those drugs. And 22% of those taking antacid supplements had severe headache, compared to 20% of those not taking antacids.

    When researchers adjusted for other factors that could affect the risk of migraine, such as age, sex and use of caffeine and alcohol, they found that people taking proton pump inhibitors were 70% more likely to have migraine than people not taking proton pump inhibitors. Those taking H2 blockers were 40% more likely and those taking antacid supplements were 30% more likely.

    “It’s important to note that many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue,” Slavin said.

    Slavin noted that the study looked only at prescription drugs. Some of the drugs became available for over-the-counter use at non-prescription strength during the study period, but use of these over-the-counter drugs was not included in this study.

    Other studies have shown that people with gastrointestinal conditions may be more likely to have migraine, but Slavin said that relationship is not likely to fully explain the tie between acid-reducing drugs and migraine found in the study.

    A limitation of the study is that a small number of people were taking the drugs, especially the H2 blockers.

    Source:

    American Academy of Neurology

    Journal reference:

    Slavin, M., et al. (2024) Use of Acid-Suppression Therapy and Odds of Migraine and Severe Headache in the National Health and Nutrition Examination Survey. Neurology® Clinical Practice. doi.org/10.1212/CPJ.0000000000200302.

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  • Breast cancer survivors at higher risk of developing second cancers

    Breast cancer survivors at higher risk of developing second cancers

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    Survivors of breast cancer are at significantly higher risk of developing second cancers, including endometrial and ovarian cancer for women and prostate cancer for men, according to new research studying data from almost 600,000 patients in England.

    For the first time, the research has shown that this risk is higher in people living in areas of greater socioeconomic deprivation.

    Breast cancer is the most commonly diagnosed cancer in the UK. Around 56,000 people in the UK are diagnosed each year, the vast majority (over 99%) of whom are women. Improvements in earlier diagnosis and in treatments mean that five year survival rates have been increasing over time, reaching 87% by 2017 in England.

    People who survive breast cancer are at risk of second primary cancer, but until now the exact risk has been unclear. Previously published research suggested that women and men who survive breast cancer are at a 24% and 27% greater risk of a non-breast second primary cancer than the wider population respectively. There have been also suggestions that second primary cancer risks differ by the age at breast cancer diagnosis.

    To provide more accurate estimates, a team led by researchers at the University of Cambridge analysed data from over 580,000 female and over 3,500 male breast cancer survivors diagnosed between 1995 and 2019 using the National Cancer Registration Dataset. The results of their analysis are published today in Lancet Regional Health – Europe.

    It’s important for us to understand to what extent having one type of cancer puts you at risk of a second cancer at a different site. The female and male breast cancer survivors whose data we studied were at increased risk of a number of second cancers. Knowing this can help inform conversations with their care teams to look out for signs of potential new cancers.”


    Isaac Allen, First Author, Department of Public Health and Primary Care, University of Cambridge

    The researchers found significantly increased risks of cancer in the contralateral (that is, unaffected) breast and for endometrium and prostate cancer in females and males, respectively. Females who survived breast cancer were at double the risk of contralateral breast cancer compared to the general population and at 87% greater risk of endometrial cancer, 58% greater risk of myeloid leukemia and 25% greater risk of ovarian cancer.

    Age of diagnosis was important, too – females diagnosed with breast cancer under the age of 50 were 86% more likely to develop a second primary cancer compared to the general population of the same age, whereas women diagnosed after age 50 were at a 17% increased risk. One potential explanation is that a larger number of younger breast cancer survivors may have inherited genetic alterations that increase risk for multiple cancers. For example, women with inherited changes to the BRCA1 and BRCA2 genes are at increased risk of contralateral breast cancer, ovarian and pancreatic cancer.

    Females from the most socioeconomically deprived backgrounds were at 35% greater risk of a second primary cancer compared to females from the least deprived backgrounds. These differences were primarily driven by non-breast cancer risks, particularly for lung, kidney, head and neck, bladder, esophageal and stomach cancers. This may be because smoking, obesity, and alcohol consumption – established risk factors for these cancers – are more common among more deprived groups.

    Allen, a PhD student at Clare Hall, added: “This is further evidence of the health inequalities that people from more deprived backgrounds experience. We need to fully understand why they are at greater risk of second cancers so that we can intervene and reduce this risk.”

    Male breast cancer survivors were 55 times more likely than the general male population to develop contralateral breast cancer – though the researchers stress that an individual’s risk was still very low. For example, for every 100 men diagnosed with breast cancer at age 50 or over, about three developed contralateral breast cancer during a 25 year period. Male breast cancer survivors were also 58% more likely than the general male population to develop prostate cancer.

    Professor Antonis Antoniou from the Department of Public Health and Primary Care at the University of Cambridge, the study’s senior author, said: “This is the largest study to date to look at the risk in breast cancer survivors of developing a second cancer. We were able to carry this out and calculate more accurate estimates because of the outstanding data sets available to researchers through the NHS.”

    The research was funded by Cancer Research UK with support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

    Cancer Research UK’s senior cancer intelligence manager, Katrina Brown, said: “This study shows us that the risk of second primary cancers is higher in people who have had breast cancer, and this can differ depending on someone’s socioeconomic background. But more research is needed to understand what is driving this difference and how to tackle these health inequalities.”

    People who are concerned about their cancer risk should contact their GP for advice. If you or someone close to you have been affected by cancer and you’ve got questions, you can call Cancer Research UK nurses on freephone 0808 800 4040, Monday to Friday.

    Source:

    Journal reference:

    Allen, I., et al. (2024) Risks of second primary cancers among 584,965 female and male breast cancer survivors in England: a 25-year retrospective cohort study. The Lancet Regional Health – Europe. doi.org/10.1016/j.lanepe.2024.100903.

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  • USAMRAA grant supports COPD biosensor project at The Lundquist Institute

    USAMRAA grant supports COPD biosensor project at The Lundquist Institute

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    The U.S. Army Medical Research Acquisition Activity (USAMRAA) has awarded The Lundquist Institute (TLI) a four-year grant totaling $2,623,234. The research project is led by Dr. Harry Rossiter, an investigator at TLI and Professor at the David Geffen School of Medicine at UCLA. The project aims to develop wearable multiplex biosensors to monitor exacerbation risk in chronic obstructive pulmonary disease (COPD).

    COPD affects approximately 16 million Americans and is the third leading cause of death globally. Acute exacerbations of COPD (AECOPD), typically caused by a lung infection, are associated with accelerated progression of COPD and represent the greatest burden of COPD to patients and healthcare. Patients with AECOPD have increased breathlessness, typically reported several days after the initial infection, and may require treatment with antibiotics and/or hospitalization.

    The prediction of AECOPD is complex. Evidence of the early response to infection, before the onset of symptoms, is present in blood in the form of inflammatory signaling molecules. The collaborative team from the Lundquist Institute (led by Harry Rossiter, PhD) and Caltech (led by Wei Gao, PhD) have already developed a wearable nanoengineered biosensor that allows real-time, non-invasive analysis of the inflammatory signaling molecule C-reactive protein (CRP) in sweat, that is associated with the blood-borne response. Building on this development, their new research will identify molecules in sweat that predict future AECOPD, paving the way for real-time, on body, monitoring without the need for repeated blood samples.

    Our ultimate goal is to develop a wearable system to preempt AECOPD, providing an early warning system to move treatment earlier in the exacerbation process and thereby reduce patient morbidity, mortality, hospitalization, and healthcare utilization. The proposed sensor has the potential to not only revolutionize COPD management but also to impact healthcare by incorporating wearable electronics into chronic disease management.”


    Dr. Harry Rossiter

    “In partnership with Dr. Harry Rossiter and The Lundquist Institute, our team at Caltech is advancing medical technology with wearable biosensors. Our aim with this project is to transform chronic disease management and push healthcare towards continuous, non-invasive monitoring for better health,” said Dr. Wei Gao.

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  • Prenatal opioid exposure not associated with risk of neuropsychiatric disorders in children

    Prenatal opioid exposure not associated with risk of neuropsychiatric disorders in children

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    Opioid use during pregnancy is not associated with a substantial increase in the risk of neuropsychiatric disorders such as ADHD in children, finds a large study from South Korea published by The BMJ today.

    A slightly increased risk of neuropsychiatric disorders was found, but the researchers say this should not be considered clinically meaningful because it was limited to mothers exposed to more than one opioid prescription, high doses, and over longer time periods during pregnancy.

    According to 2019 data from the Centers for Disease Control and Prevention, around 7% of women in the United States were prescribed opioids during pregnancy.

    Previous studies have shown mixed findings on the association between opioid use in pregnancy and various health outcomes in offspring due to small sample sizes and short follow-up periods.

    To address this knowledge gap, an international team of researchers set out to investigate the potential association between opioid exposure during pregnancy and risk of neuropsychiatric disorders in offspring.

    Their findings are based on data from the National Health Insurance Service (NHIS) of South Korea for 3,128,571 infants born between 2010 and 2017 and 2,299,664 mothers (average age 32).

    Mothers were grouped according to dose, duration, and frequency of opioid prescriptions during pregnancy and infants were followed up for an average of six years.

    Factors including mother’s age at delivery, household income and pre-existing health conditions, and infant sex, birth weight and breastfeeding history were taken into account. A sibling comparison analysis was also carried out to account for genetics, lifestyle, and environmental influences.

    Overall, 216,012 (7%) of the 3,128,571 infants were exposed to opioids during pregnancy (prenatal exposure). 

    A small increased risk of neuropsychiatric disorders was found among children exposed to prescription opioids during pregnancy compared with those not exposed, but the researchers interpret this as clinically insignificant.

    And no significant association was noted in the sibling comparison group.

    However, exposure to prescription opioids during the first trimester of pregnancy, at higher doses, and for 60 days or more were associated with a slightly increased risk of mood disorders, ADHD, and intellectual disability.

    This is an observational study so no firm conclusions can be drawn about cause and effect, and although the researchers adjusted for a range of factors, they can’t rule out the possibility that others may have influenced their results, or that some misclassification of opioid use may have occurred. 

    Nevertheless, this was a large study based on high quality data and several statistical analyses were carried out to test the strength of the results, providing greater confidence in the conclusions.

    As such, they conclude: “These results support cautious opioid prescribing for relief of pain during pregnancy, highlighting the importance of further research for more definitive guidelines.”

    In a linked editorial, researchers agree that while short term use of lower dose prescription opioids after the first trimester appears relatively safe, caution is warranted when prescribing opioids for longer durations or at higher dosages.

    This study “provides additional evidence to inform clinical decision making for women requiring pain management during pregnancy,” they write.

    “Given the unique clinical value of opioids for managing severe pain, additional research is needed to fully characterize the degree of risk and thoroughly disentangle the association among pain, pain management, and various pregnancy outcomes,” they conclude.

    Source:

    Journal reference:

    Kang, J., et al. (2024). Prenatal opioid exposure and subsequent risk of neuropsychiatric disorders in children: nationwide birth cohort study in South Korea. BMJ. doi.org/10.1136/bmj-2023-077664.

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