Tag: Diagnostics

  • Evolving brain sizes from 1930 to 1970 could signal decreased dementia risk, researchers say

    Evolving brain sizes from 1930 to 1970 could signal decreased dementia risk, researchers say

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    The development and upkeep of the human brain are influenced by both genetic factors and environmental conditions, which may subsequently impact the risk of dementia later in life. Thus, a recent study published in JAMA Neurology assessed whether there were changes in skull and brain size, as well as the thickness of the cortex, across individuals born between the years 1930 and 1970.

    Study: Trends in Intracranial and Cerebral Volumes of Framingham Heart Study Participants Born 1930 to 1970. Image Credit: Gorodenkoff/Shutterstock.comStudy: Trends in Intracranial and Cerebral Volumes of Framingham Heart Study Participants Born 1930 to 1970. Image Credit: Gorodenkoff/Shutterstock.com

    Background

    The health of the American populace has improved significantly due to advancements in healthcare diagnostics and treatment strategies, resulting in an extended average lifespan. However, this increase in longevity also brings a higher likelihood of encountering Alzheimer’s disease and other forms of dementia, as well as various conditions prevalent in older age.

    Fortunately, the dementia incidence is decreasing, perhaps in part because of more education and better preventive measures for cardiovascular risk. Another important contributor may be the early environment.

    The Framingham Heart Study cohort (FHS) includes many generations of people, followed up over decades. The difference between the earliest and latest subjects to be enrolled in the cohort spans over 80 years.

    This led the researchers in the current study to draw their cohort from this study group, examining trends in cardiovascular and brain health in successive generations.

    The aim was to look for a predicted increase in brain development in the US population due to changing early life environment trends. This would reflect in larger brain volumes.

    About the study

    All participants were born between 1925 and 1968. None had been diagnosed with dementia or stroke, and all had undergone magnetic resonance imaging (MRI) between 1999 and 2019. The mean age at MRI varied with the decade of birth but with overlap between decades.

    What were the findings?

    There were over 3,200 participants, the mean age at MRI being 58 years. The images revealed that multiple brain volume measurements showed an upward trajectory with the later birth cohorts.

    The investigators measured intracranial volume (ICV), hippocampal volume (HV), cortical surface area (CSA), cortical gray matter volume (CGMV), and white matter volume (WMV). Females were observed to be 5.5 inches shorter on average, with lower HV, CGMV, and WMV.

    The difference in hippocampal volume was by -0.64 mL, while males had ~54 mL and 63 mL greater volumes for gray and white matter, respectively.

    The 1930s birth cohort had a mean height of 66 inches vs 68 inches for the 1970s birth cohort. The average ICV increased by over 6%, at 1321 mL in the 1970s vs 1234 mL in the 1930s cohort, respectively.  This was after compensating for confounding factors like age, sex, and height.

    Regional measures also varied with the birth cohort, showing a definite trend. Both HV and WMV went up with the decade of birth. So did the CSA, while the cortical thickness decreased, implying cortical atrophy.

    Comparing the 1930s to the 1970s cohort, the largest increase was for CSA, which increased by 15%. The WMV and HV increased by 8% and 6%, respectively, but CGMV by 2%. The cortical thickness declined by over a fifth, from 2.3 mm to 1.9 mm, respectively. There was no significant difference between the sexes.

    Even after limiting the analysis to only those born in the 1940s and aged 55 to 65 years, the same trends were observed, though the differences were attenuated. For instance, the increase in WMV and CGMV were only 0.2% and 0.1%, respectively.

    What are the implications?

    The study results indicate that later generations are experiencing increased brain volume, both overall and regional. The difference was greatest for ICV, WMV, and HV, when the 1930s and 1940s cohorts were compared.

    We hypothesize that larger brain volumes indicate larger brain development and potentially greater “brain reserve” that could explain the declining incidence of dementia.”

    The ICV reflects normal brain development and does not go down with aging or diseases affecting the volume. In fact, the adult ICV predicts cognitive levels in old age and provides a reliable and consistent biomarker for brain size.

    HV loss may occur early in neurodegenerative conditions, including Alzheimer’s,

    The larger cortical WMV in later cohorts might be the result of greater gyrification, leading to larger CSA. The increased WMV indicates higher neuronal connectivity while reducing the effects of brain tissue loss with aging. The increase in CSA with a reduction in cortical thickness supports this explanation.

    The presence of gyri in the brain increases the brain CSA by 1,700 times compared to the brain of a shrew but limits the increase in cortical thickness to six times. Genes regulate different brain regions differently to develop gyri to various extents.

    The increase in larger brain structures is due to changes in early life experiences, including better education, social environment, and health status. The better preventive measures for cardiovascular disease may be responsible as well. Thus, modifying these factors could also improve resistance to late-life dementia.

    At the population level, these effects may be very important, helping to optimize brain development and building cognitive resilience over the decades.

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  • As AI eye exams prove their worth, lessons for future tech emerge

    As AI eye exams prove their worth, lessons for future tech emerge

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    Christian Espinoza, director of a Southern California drug-treatment provider, recently began employing a powerful new assistant: an artificial intelligence algorithm that can perform eye exams with pictures taken by a retinal camera. It makes quick diagnoses, without a doctor present.

    His clinics, Tarzana Treatment Centers, are among the early adopters of an AI-based system that promises to dramatically expand screening for diabetic retinopathy, the leading cause of blindness among working-age adults and a threat to many of the estimated 38 million Americans with diabetes.

    “It’s been a godsend for us,” said Espinoza, the organization’s director of clinic operations, citing the benefits of a quick and easy screening that can be administered with little training and delivers immediate results.

    His patients like it, too. Joseph Smith, who has Type 2 diabetes, recalled the cumbersome task of taking the bus to an eye specialist, getting his eyes dilated, and then waiting a week for results. “It was horrible,” he said. “Now, it takes minutes.”

    Amid all the buzz around artificial intelligence in health care, the eye-exam technology is emerging as one of the first proven use cases of AI-based diagnostics in a clinical setting. While the FDA has approved hundreds of AI medical devices, adoption has been slow as vendors navigate the regulatory process, insurance coverage, technical obstacles, equity concerns, and challenges of integrating them into provider systems.

    The eye exams show that the AI’s ability to provide immediate results, as well as the cost savings and convenience of not needing to make an extra appointment, can have big benefits for both patients and providers. Of about 700 eye exams conducted during the past year at Espinoza’s clinics, nearly one-quarter detected retinopathy, and patients were referred to a specialist for further care.

    Diabetic retinopathy results when high blood sugar harms blood vessels in the retina. While managing a patient’s diabetes can often prevent the disease — and there are treatments for more advanced stages — doctors say regular screenings are crucial for catching symptoms early. An estimated 9.6 million people in the U.S. have the disease.

    The three companies with FDA-approved AI eye exams for diabetic retinopathy — Digital Diagnostics, based in Coralville, Iowa; Eyenuk of Woodland Hills, California; and Israeli software company AEYE Health — have sold systems to hundreds of practices nationwide. A few dozen companies have conducted research in the narrow field, and some have regulatory clearance in other countries, including tech giants like Google.

    Digital Diagnostics, formerly Idx, received FDA approval for its system in 2018, following decades of research and a clinical trial involving 900 patients diagnosed with diabetes. It was the first fully autonomous AI system in any field of medicine, making its approval “a landmark moment in medical history,” said Aaron Lee, a retina specialist and an associate professor at the University of Washington.

    The system, used by Tarzana Treatment Centers, can be operated by someone with a high school degree and a few hours of training, and it takes just a few minutes to produce a diagnosis, without any eye dilation most of the time, said John Bertrand, CEO of Digital Diagnostics.

    The setup can be placed in any dimly lit room, and patients place their face on the chin and forehead rests and stare into the camera while a technician takes images of each eye.

    The American Diabetes Association recommends that people with Type 2 diabetes get screened every one to two years, yet only about 60% of people living with diabetes get yearly eye exams, said Robert Gabbay, the ADA’s chief scientific and medical officer. The rates can be as low as 35% for people with diabetes age 21 or younger.

    In swaths of the U.S., a shortage of optometrists and ophthalmologists can make appointments hard to schedule, sometimes booking for months out. Plus, the barriers of traveling to an additional appointment to get their eyes dilated — which means time off work or school and securing transportation — can be particularly tricky for low-income patients, who also have a higher risk of Type 2 diabetes.

    “Ninety percent of our patients are blue-collar,” said Espinoza of his Southern California clinics, which largely serve minority populations. “They don’t eat if they don’t work.”

    One potential downside of not having a doctor do the screening is that the algorithm solely looks for diabetic retinopathy, so it could miss other concerning diseases, like choroidal melanoma, Lee said. The algorithms also generally “err on the side of caution” and over-refer patients.

    But the technology has shown another big benefit: Follow-up after a positive result is three times as likely with the AI system, according to a recent study by Stanford University.

    That’s because of the “proximity of the message,” said David Myung, an associate professor of ophthalmology at the Byers Eye Institute at Stanford. When it’s delivered immediately, rather than weeks or even months later, it’s much more likely to be heard by the patient and acted upon.

    Myung launched Stanford’s automated teleophthalmology program in 2020, originally focusing on telemedicine and then shifting to AI in its Bay Area clinics. That same year, the National Committee for Quality Assurance expanded its screening standard for diabetic retinopathy to include the AI systems.

    Myung said it took about a year to sift through the Stanford health system’s cybersecurity and IT systems to integrate the new technology. There was also a learning curve, especially for taking quality photos that the AI can decipher, Myung said.

    “Even with hitting our stride, there’s always something to improve,” he added.

    The AI test has been bolstered by a reimbursement code from the Centers for Medicare & Medicaid Services, which can be difficult and time-consuming to obtain for breakthrough devices. But health care providers need that government approval to get reimbursement.

    In 2021, CMS set the national payment rate for AI diabetic retinopathy screenings at $45.36 — quite a bit below the median privately negotiated rate of $127.81, according to a recent New England Journal of Medicine AI study. Each company has a slightly different business model, but they generally charge providers subscription or licensing fees for their software.

    The companies declined to share what they charge for their software. The cameras can cost up to $20,000 and are either purchased separately or wrapped into the software subscription as a rental.

    The greater compliance with screening recommendations that the machines make possible, along with a corresponding increase in referrals to specialists, makes it worthwhile, said Lindsie Buchholz, clinical informatics lead at Nebraska Medicine, which in mid-December began using Eyenuk’s system.

    “It kind of helps the camera pay for itself,” she said.

    Today, Digital Diagnostics’ system is in roughly 600 sites nationwide, according to the company. AEYE Health said its eye exam is used by “low hundreds” of U.S. providers. Eyenuk declined to share specifics about its reach.

    The technology continues to advance, with clinical studies for additional cameras — including a handheld imager that can screen patients in the field — and looking at other eye diseases, like glaucoma. The innovations put ophthalmology alongside radiology, cardiology, and dermatology as specialties in which AI innovation is happening fast.

    “They are going to come out in the near future — cameras that you can use in street medicine — and it’s going to help a lot of people,” said Espinoza.




    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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  • Bio-Rad launches validated antibodies for rare cell and circulating tumor cell enumeration

    Bio-Rad launches validated antibodies for rare cell and circulating tumor cell enumeration

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    Bio-Rad Laboratories, Inc. (NYSE: BIO and BIO.B), a global leader in life science research and clinical diagnostics products, today announced the launch of validated antibodies for rare cell and circulating tumor cell (CTC) enumeration. Validated for use with Bio-Rad’s Celselect Slides Enumeration Stain Kits, the antibodies are specific to CTC surface markers to enable the sensitive and specific identification of target cell populations, enhancing the study of tumor heterogeneity and disease progression at various stages. 

    Bio-Rad’s Genesis Cell Isolation System is a customizable benchtop solution that uses unbiased size-based cell selection to gently and efficiently capture a wide range of CTCs and other rare cells from liquid biopsy samples. After capture, the enriched cells can be recovered for downstream analysis, or immuno-stained on-slide for immunofluorescence applications such as enumeration and identification of various CTC types. 

    The enumeration of captured CTCs provides valuable insights into the surface markers that indicate cancer type and progression and is critical to understanding the mechanisms of cancer metastasis. For successful enumeration, the antibody reagents require careful selection to ensure not only sensitivity and specificity to the target cell surface marker, but also compatibility with the staining method. Bio-Rad’s new range of validated primary and secondary antibodies enables accurate immunostaining of captured CTCs, supporting cancer researchers working in this field. 

    CTC analysis is a promising tool for the study of tumor heterogeneity and disease progression, offering real-time data and unique insights into cancer metastasis,” said Stephen Kulisch, Vice President of Marketing for Bio-Rad’s Digital Biology Group. “The introduction of validated antibodies for target cell identification reflects Bio-Rad’s growing single-cell oncology product portfolio and is a testament to our commitment to deliver highly efficient rare cell capture, enrichment, enumeration, and recovery for cancer researchers.”  

    To learn more about the new validated antibodies, visit bio-rad-antibodies.com/val-abs

    BIO-RAD and CELSELECT SLIDES are trademarks of Bio-Rad Laboratories, Inc. in certain jurisdictions.  

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  • Experts advocate three-pronged approach to identifying missing tuberculosis cases

    Experts advocate three-pronged approach to identifying missing tuberculosis cases

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    In the journey towards a world free of Tuberculosis (TB), the crucial first step begins with identifying individuals affected by the disease.

    Globally, around 1.3 million people died from TB in 2022, making it the second leading infectious killer after COVID-19, according to the World Health Organization (WHO).

    However, many people with the disease, which is particularly prevalent in the Asia Pacific region and Africa, do not even get properly diagnosed.

    Public health experts say the task of tracing these missing cases requires a three-pronged approach, involving community engagement, scaling-up the use of available technologies, and effective program management.

    “By putting communities at the core, you ensure that they are fully involved in the process of making their villages TB-free,” said Prabodh Bhambal, executive director of the Union South East Asia (USEA) Trust, at a webinar organized by Citizen News Service (CNS) this week (19 March).

    The USEA Trust is an independent trust hosted by the International Union Against Tuberculosis and Lung Disease (The Union) in New Delhi, with a flagship project that aims to transform 1,000 villages into TB-free villages with support from the JSW Foundation, the social development arm of JSW Group, an Indian conglomerate whose businesses include steel, cement, automotive and paints.

    The WHO estimates that India grapples with the world’s most extensive tuberculosis epidemic. In 2022, the country reported an incidence rate of 199 cases per 100,000 individuals in its population.

    In Uganda, where there was a similar incidence rate of 198 cases per 100,000, the government is using mobile vans to conduct screenings in local communities as part of an awareness, testing and prevention campaign.

    At the core of the campaign is the acknowledgment that relying solely on communities to visit health facilities doesn’t ensure uptake of services or effectively control TB at the community or household level.

    The campaign emphasises the need for a collective desire for change, inspiring individuals to take action and voluntarily seek healthcare services. The aim is to enhance case-finding, address missing TB cases within communities, tackle treatment defaulting, and improve the use of prevention measures.

    Stavia Turyahabwe, assistant commissioner for TB and Leprosy at Uganda’s Ministry of Health, says this approach has been highly effective. In 2022, more than 94,000 Ugandans were diagnosed with TB through the initiative, significantly contributing to improved disease detection rates, she told a two-day summit on TB and leprosy in Kampala this week (19-20 March).

    However, she added that the ministry had yet to assess its impact on TB prevalence.

    Harnessing technology, AI

    Bhambal suggests that, by effectively harnessing current technologies for TB screening and diagnosis, a substantial portion of the undetected TB cases can be identified.

    “In the small population of 5,000 people that we have screened so far under our project, we screened based on symptoms, used portable X-rays, and utilised an AI app.”

    “Through this comprehensive approach, we have successfully detected cases of TB that would have otherwise been missed if we had relied solely on symptoms,” explained Bhambal, adding: “Technology plays a crucial role in finding these cases; we just need to find the right mix.”

    Charles Olaro, director of clinical services at Uganda’s Ministry of Health, highlighted various innovations being employed in the country’s fight against TB, including GeneXpert technology, which rapidly diagnoses TB disease and drug resistance.

    “We are not solely dependent on the microscope,” he said. “For any slides that test positive, we analyze them for drug resistance using the GeneXpert.”

    Sriram Natarajan, co-founder of Indian diagnostics company Molbio Diagnostics, highlighted the limitations of microscopy in terms of detection.

    However, he added that over the last decade, the WHO has approved molecular diagnostic tools capable of being deployed even in the doctor’s surgery.

    He said these molecular tools boast sensitivity rates of up to 98 per cent, meaning that patients can be diagnosed at an early stage. However, despite these tools being available for about a decade, only about 25 to 30 per cent of TB cases globally are being diagnosed using them, according to Natarajan.

    “We now have at least two available tools, but the uptake remains a major concern,” he told the CNS webinar.

    “Both countries and their programs need to commit to implementing these tools at the primary level to ensure that everyone receives a molecular test as a confirmatory tool.”

    Investment ‘crucial’

    Natarajan says more commitment is needed from global funding agencies to focus on making these tools affordable and accessible to all.

    “If we truly want to end TB by the target year of 2030, these interventions need to be scaled up and accelerated,” he added. “It’s crucial that these efforts are taken seriously.”

    Lucica Ditiu, executive director of the Stop TB Partnership, told the CNS webinar: “It is possible to end TB. We see high-burden countries finding and treating TB.”

    High-burden countries include India, Indonesia, Bangladesh, Nigeria, South Africa and Ethiopia.

    “I want to say that, in many countries, private sector engagement is crucial to finding and treating all TB patients,” Ditiu added.

    Guy Marks, respiratory medicine expert at the University of New South Wales and president and interim executive director of The Union, says TB must be treated as a public health problem, not merely an individual patient care issue.

    “We must be brave and recognize that the current strategy to end TB in high-burden countries is not achieving the results we hope for,” he said.

    “We need to change our approach if we are to win the fight against this infectious disease.”

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  • AI analyzes lung ultrasound images to spot COVID-19

    AI analyzes lung ultrasound images to spot COVID-19

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    Artificial intelligence can spot COVID-19 in lung ultrasound images much like facial recognition software can spot a face in a crowd, new research shows.

    The findings boost AI-driven medical diagnostics and bring health care professionals closer to being able to quickly diagnose patients with COVID-19 and other pulmonary diseases with algorithms that comb through ultrasound images to identify signs of disease.

    The findings, newly published in Communications Medicine, culminate an effort that started early in the pandemic when clinicians needed tools to rapidly assess legions of patients in overwhelmed emergency rooms.

    We developed this automated detection tool to help doctors in emergency settings with high caseloads of patients who need to be diagnosed quickly and accurately, such as in the earlier stages of the pandemic. Potentially, we want to have wireless devices that patients can use at home to monitor progression of COVID-19, too.”


    Muyinatu Bell, senior author, the John C. Malone Associate Professor of Electrical and Computer Engineering, Biomedical Engineering, and Computer Science at Johns Hopkins University

    The tool also holds potential for developing wearables that track such illnesses as congestive heart failure, which can lead to fluid overload in patients’ lungs, not unlike COVID-19, said co-author Tiffany Fong, an assistant professor of emergency medicine at Johns Hopkins Medicine.

    “What we are doing here with AI tools is the next big frontier for point of care,” Fong said. “An ideal use case would be wearable ultrasound patches that monitor fluid buildup and let patients know when they need a medication adjustment or when they need to see a doctor.”

    The AI analyzes ultrasound lung images to spot features known as B-lines, which appear as bright, vertical abnormalities and indicate inflammation in patients with pulmonary complications. It combines computer-generated images with real ultrasounds of patients -; including some who sought care at Johns Hopkins.

    “We had to model the physics of ultrasound and acoustic wave propagation well enough in order to get believable simulated images,” Bell said. “Then we had to take it a step further to train our computer models to use these simulated data to reliably interpret real scans from patients with affected lungs.”

    Early in the pandemic, scientists struggled to use artificial intelligence to assess COVID-19 indicators in lung ultrasound images because of a lack of patient data and because they were only beginning to understand how the disease manifests in the body, Bell said.

    Her team developed software that can learn from a mix of real and simulated data and then discern abnormalities in ultrasound scans that indicate a person has contracted COVID-19. The tool is a deep neural network, a type of AI designed to behave like the interconnected neurons that enable the brain to recognize patterns, understand speech, and achieve other complex tasks.

    “Early in the pandemic, we didn’t have enough ultrasound images of COVID-19 patients to develop and test our algorithms, and as a result our deep neural networks never reached peak performance,” said first author Lingyi Zhao, who developed the software while a postdoctoral fellow in Bell’s lab and is now working at Novateur Research Solutions. “Now, we are proving that with computer-generated datasets we still can achieve a high degree of accuracy in evaluating and detecting these COVID-19 features.”

    Source:

    Journal reference:

    Zhao, L., et al. (2024). Detection of COVID-19 features in lung ultrasound images using deep neural networks. Communications Medicine. doi.org/10.1038/s43856-024-00463-5

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  • Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

    Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

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    Monitoring levels of DNA shed by tumors and circulating in the bloodstream could help doctors accurately assess how gastroesophageal cancers are responding to treatment, and potentially predict future prognosis, suggests a new study led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

    The study tracked minimal residual disease (the amount of cancer left following treatment) by analyzing circulating tumor DNA (ctDNA), showing how these “liquid biopsies” can provide valuable insights into treatment outcomes over time. Absence of ctDNA was seen occurring together with specific activation of T cells that are part of the immune system’s defense to recognize and fight cancer. 

    “We found that the elimination of ctDNA was a good indicator of patients’ cancer-free survival,” says Valsamo “Elsa” Anagnostou, M.D., Ph.D., senior co-author of the study and associate professor of oncology and director of the thoracic oncology biorepository at Johns Hopkins.

    Anagnostou is also leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board and co-director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins. “We were gratified to see tumor shrinkage at a molecular level together with the immune system flaring up and clearing the tumor,” she says.

    The findings, reported in a paper published March 19 in Nature Medicine, emerged from a clinical trial examining the safety and efficacy of two immunotherapy drugs -; nivolumab and relatlimab -;as part of pre-operative treatment for patients with operable esophageal and gastroesophageal junction cancer.

    Patients with gastroesophageal cancer who have successfully completed the standard treatment of chemoradiotherapy followed by surgery unfortunately often see a resurgence of the disease. Therefore, researchers are looking for new immunotherapy approaches, as well as more accurate ways to assess tumors’ response to treatment.

    Immunotherapy has not yet been broadly effective for patients with gastroesophageal cancer. By testing new treatments in patients prior to surgery, we can make these powerful observations linking treatment-induced molecular changes with survival outcomes, thus accelerating the development of different immunotherapy approaches for our patients.”


    Vincent Lam, M.D., senior study co-author, director of the Esophageal Cancer Research Program and an assistant professor of oncology at Johns Hopkins

    The trial included 32 patients with operable esophageal or gastroesophageal junction cancer, who received nivolumab either alone or in combination with relatlimab prior to and during their standard treatment of chemotherapy and radiation. The drugs tested are both immune checkpoint inhibitors, which prevent cancer cells from dampening the body’s anti-cancer immune response. Researchers used liquid biopsies -; tests that monitor trace levels of tumor DNA shed into the bloodstream -;at different timepoints during treatment. They also measured levels of tumor-recognizing T cells and other components of tumor-specific immune responses.

    About 40% of those in the nivolumab arm and 21.4% in the combination arm had a pathological complete response, meaning there was no evidence of cancer at the time of surgery. Over half of patients in both arms had a major pathological response, meaning less than 10% of cancer cells were remaining at the time of surgery.

    “Historically, about two-thirds of patients treated with standard chemoradiation prior to surgery are alive after two years,” Lam says. “In our study, some 72.5% of participants had no signs of cancer and 82.6% were still living after two years. Notably, patients with undetectable ctDNA at different timepoints following immunotherapy had significantly longer cancer-free survival.” 

    The findings “open the door for more personalized treatment,” says lead study author Ronan Kelly, M.D., M.B.A., chief of oncology at Baylor Scott & White Health – North Texas. Kelly was at Johns Hopkins at the time of the study. “We can either de-escalate or intensify the treatment for patients who have gone through the standard protocol,” he says. “If we see ctDNA is still there, and they don’t have robust T cell response, these are the patients who may benefit most from additional treatment.”

    The study adds to a growing collection of evidence showing the value of molecular readouts like ctDNA to assess response to therapy and guide future treatment plans. For example, another recent study from Anagnostou’s lab, along with a ctDNA-adaptive clinical trial led by Johns Hopkins investigators, showed that ctDNA clearance can predict the success of immunotherapy treatment in patients with advanced lung cancer.

    “You can imagine that liquid biopsies may be used to capture and monitor cancer spread in the body and determine tumor regression across all types of cancers and therapies. There’s ever-growing evidence to support the use of ctDNA in the full range of the cancer care continuum,” says Anagnostou. “We think it’s the future.”

    Additional study co-authors were Blair Landon, Dipika Singh, Jenna Canzoniero, Archana Balan, Russell Hales, K Ranh Voong, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Kristen Marrone, Gavin Pereira, Nisha Rao, Aryan Borole, Katerina Karaindrou, Zineb Belcaid, James White, Suqi Ke, Eun Ji Shin, Elizabeth Thompson, Kellie Smith, Chen Hu and Josephine Feliciano of Johns Hopkins. Experts from the Allegheny Health Network Cancer Institute also contributed to the work.

    The study was supported by Bristol Myers Squibb. Translational work was supported in part by the National Institutes of Health (grants CA121113, R37 CA251447), the Cancer Research Institute, Torrey Coast Foundation GEMINI CLIP Award, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant, the Mark Foundation for Cancer Research, and the Conquer Cancer Foundation of ASCO Career Development Award.

    Source:

    Journal reference:

    Kelly, R. J., et al. (2024). Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nature Medicine. doi.org/10.1038/s41591-024-02877-z.

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  • Rapid, easy-to-use diagnostic test could save more lives from melioidosis

    Rapid, easy-to-use diagnostic test could save more lives from melioidosis

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    Globally, more than half of patients die after infection with the neglected tropical disease, melioidosis, often before they are diagnosed. A new rapid test could save lives by diagnosing patients in hours, rather than several days taken by current bacterial culture methods, meaning they receive the correct antibiotics faster.

    The test uses CRISPR to detect a genetic target that is specific to Burkholderia pseudomallei, the bacterium that causes melioidosis, with 93 per cent sensitivity. It was developed by researchers at the Mahidol-Oxford Tropical Medicine Research Unit (MORU), Chiang Mai University, Vidyasirimedhi Institute of Science and Technology (VISTEC) in Thailand, and the Wellcome Sanger Institute in the UK.

    The results, published today (14 March) in Lancet Microbe, mean more lives could be saved from melioidosis, with a rapid, easy-to-use diagnostic test that could be rolled out globally.

    Melioidosis is a neglected tropical disease that is estimated to affect 165,000 people worldwide each year, of whom 89,000 die from the disease. It is caused by the bacterium, Burkholderia pseudomallei, which lives in soil and water in tropical and subtropical regions, and enters human bodies via inoculation through skin abrasions, ingestion or inhalation.

    It is difficult to diagnose melioidosis as symptoms vary from localised abscess or pneumonia to acute septicaemia, or may present as a chronic infection. As a result of this, and the locations of isolated communities in rural areas that it mostly affects, the disease remains hugely underreported.

    Currently, melioidosis is diagnosed in patients after bacterial samples are cultured, which takes three to four days. In Thailand, approximately 40 per cent of patients with melioidosis die, many of whom die within the first one to two days following admission to hospital, while waiting for a diagnosis.

    There is no licensed vaccine for melioidosis, but patients can be effectively treated with intravenous antibiotics – ceftazidime or carbapenem – during the first intensive phase of treatment. However, current practices often involve initially treating patients with a range of unnecessary antibiotics to target the various symptoms the disease produces, which can waste time and resources.

    In a new study, the team set out to develop a new rapid test to reduce the time taken to correctly diagnose and treat patients with melioidosis.

    The researchers identified a genetic target specific to B. pseudomallei by analysing over 3,000 B. pseudomallei genomes, most of which were sequenced at the Sanger Institute. They searched for conserved regions of the genome and screened the targets against other pathogens and human host genomes, to ensure their chosen target was specific to B. pseudomallei.

    Their test, called CRISPR-BP34, involves rupturing bacterial cells and using a recombinase polymerase amplification reaction to amplify the bacterial target DNA for increased sensitivity. Additionally, a CRISPR reaction is used to provide specificity, and a simple lateral flow ‘dipstick’ read-out is employed to confirm cases of melioidosis.

    To assess the efficacy of the test, the team collected clinical samples from 114 patients with melioidosis and 216 patients without the disease at Sunpasitthiprasong Hospital, a hospital in northeast Thailand where melioidosis is endemic. The CRISPR-BP34 test was then applied to these samples.

    The new test showed enhanced sensitivity at 93 per cent, compared to 66.7 per cent in bacterial culture methods. It also delivered results in less than four hours for urine, pus, and sputum samples, and within one day for blood samples. This is a significant improvement over the current bacterial culture diagnostic method, which typically takes three to four days.

    This new rapid diagnostic test will enable health professionals to prescribe the correct antibiotics faster, meaning fewer patients will die while waiting for a diagnosis. While saving precious time, the new test will also save resources and money, with fewer unnecessary antibiotics prescribed and less time for patients in hospital.

    In next steps for the team, they are currently designing randomized clinical trials to show the effectiveness of these tests in hospital settings. Plus, members of the team will begin investigating the role of human genetics in susceptibility and immune response to melioidosis infection.

    Dr Claire Chewapreecha, co-lead author at the Mahidol-Oxford Tropical Medicine Research Unit (MORU), Thailand, and Wellcome Sanger Institute International Fellow, said: “Working in rural Thailand has many limitations. But we have shown that limitations breed innovation, and what succeeds here can succeed anywhere. I am so proud of the team behind this new, robust rapid diagnostic test for melioidosis, and hope that it can potentially be used anywhere in the world to get the right treatments to patients faster, ultimately saving lives.”

    Dr Somsakul Wongpalee, co-lead author at Chiang Mai University, Thailand, said: “We carefully designed the rapid diagnostic test based on CRISPR-BP34, with a robust algorithm, and tested its performance in vitro. We are thrilled that the CRISPR-BP34 test demonstrates outstanding diagnostic efficacy when tested on clinical samples, showcasing its potential to significantly impact patient outcomes and potentially save lives in the near future.”

    This research is a testament to international collaboration and how the application of genomics at scale leads to clinical intervention. Using a genetic target mined from a bank of thousands of bacterial genomes, the team was able to produce an incredibly sensitive test that is specific to the bacterium behind melioidosis. I look forward to seeing the clinical impacts of this research.”

    Professor Nick Thomson, Senior Author and Head of Parasites and Microbes at the Wellcome Sanger Institute

    Professor Nick Day, senior author and Director of the Mahidol-Oxford Tropical Medicine Research Unit (MORU), Thailand, and the Wellcome Trust Thailand Asia and Africa Programme, said: “Melioidosis has been neglected despite its high mortality rate and high incidence in many parts of Asia. Early diagnosis is essential so that the specific treatment required can be started as soon as possible. The new rapid diagnostic tool developed through this collaboration has the potential to be a game-changer.”

    Source:

    Journal reference:

    Pakdeerat, S., et al. (2024) Benchmarking CRISPR-BP34 for point-of-care melioidosis detection in low-income and middle-income countries: a molecular diagnostics study. The Lancet Microbe. doi.org/10.1016/S2666-5247(23)00378-6.

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  • A call for better diagnosis and treatment

    A call for better diagnosis and treatment

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    In a recent review published in the journal Nature Reviews Microbiology, a group of authors summarized recent advancements in understanding long coronavirus disease (COVID) ‘s mechanisms, impacts, and research needs for better diagnostics and treatments.

    Review: Long COVID: major findings, mechanisms and recommendationsReview: Long COVID: major findings, mechanisms and recommendations

    Background

    Long COVID, affecting over 65 million globally, manifests through diverse, systemic symptoms regardless of initial infection severity. This condition leads to various health issues like cardiovascular diseases and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), causing widespread disability and workforce impacts. Pathogenesis theories include persistent viral presence and immune dysregulation, but no effective treatments have been established. Research has identified risk factors such as gender and socioeconomic status, although many patients had no prior conditions. Long COVID’s resemblance to other post-viral syndromes underscores the urgent need for research into its mechanisms, risk factors, and treatments to enhance patient outcomes.

    Immunological and virological discoveries in Long COVID

    Long COVID triggers significant immune changes, particularly post-mild COVID, marked by T cell exhaustion, reduced effector memory Cluster of Differentiation (CD)4+ and CD8+ T cells, elevated Programmed Death-1 (PD1) expression, and activated innate immune responses. The scarcity of naive T and B cells, alongside sustained high type I and III interferon levels, indicates continued immune dysregulation. An altered immune cell balance, including increased non-classical monocytes, reduced dendritic cells, and low cortisol, highlights a distinct immune profile in long COVID.

    Research points to autoimmunity in long COVID, highlighted by raised autoantibodies against key receptors like Angiotensin-Converting Enzyme 2 (ACE2). Viral reactivations, notably of Epstein-Barr Virus (EBV) and Human Herpesvirus 6 (HHV-6), which impact mitochondrial function and energy metabolism, play a significant role. The condition’s development is initially linked to inadequate immune responses, including poor antibody and T-cell response. Signs of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistence across multiple body tissues suggest a potential mechanism for the enduring nature of long COVID symptoms.

    Systemic impact and organ damage

    SARS-CoV-2 causes widespread organ damage beyond the respiratory system, affecting the circulatory system through endothelial dysfunction and increased thrombosis risks. Long-term alterations in blood properties and vascular density contribute to the heightened prevalence of cardiovascular diseases post-COVID, demonstrating the virus’s systemic and lasting effects.

    Neurological impact

    Long COVID induces neurological and cognitive issues, such as memory loss and cognitive impairment, with effects comparable to significant aging. Potential underlying mechanisms like neuroinflammation and neuronal damage link these symptoms to Alzheimer’s-like pathology, highlighting severe brain impacts.

    ME/CFS and related conditions

    There is a notable overlap between long COVID and ME/CFS, with many patients meeting the criteria for the latter. This relationship underscores commonalities like immune alterations and mitochondrial dysfunction, with dysautonomia commonly co-occurring, suggesting shared pathophysiological mechanisms.

    Reproductive and respiratory concerns

    Long COVID’s reproductive effects call for focused research on sex-specific impacts, while persistent respiratory symptoms underscore lasting lung damage. These aspects illustrate the condition’s broad spectrum of effects.

    Gastrointestinal symptoms and chronicity

    Persistent gastrointestinal issues and altered gut microbiota in long COVID patients emphasize its systemic nature. The diverse onset and duration of symptoms across patients highlight the condition’s complexity and the challenge of predicting individual outcomes.

    Diagnostic advances and challenges

    Diagnostic approaches for long COVID are under development, with existing techniques like tilt table tests and Magnetic Resonance Imaging (MRI) scans often failing to detect the condition effectively. Emerging diagnostics, including microclot imaging, corneal microscopy, and novel Electrocardiogram (ECG) markers, offer hope for more precise identification. Research into biomarkers and unconventional methods, such as scent detection by dogs, highlights the innovative directions being explored to improve long COVID diagnosis.

    Treatment landscape and future directions

    Current treatment strategies for long COVID are primarily symptom-focused, with some success using methods adapted from ME/CFS management. Innovations such as low-dose naltrexone and anticoagulant therapy show promise, while experimental treatments like Paxlovid and probiotics are beginning to demonstrate potential benefits. Nonetheless, the need for rigorous clinical trials to establish effective treatments remains critical, underscoring the initial stage of long COVID care and the importance of ongoing research.

    Vaccine impact and the role of variants

    Vaccination’s impact on long COVID varies, showing both minimal and reduced risk. Variants and vaccine doses may affect long COVID chances, with early studies hinting at variant-dependent risks and vaccine efficacy. Reinfections, particularly multiple ones, could heighten long COVID risks, stressing the importance of continuous research and monitoring.

    Diagnosing Long COVID: obstacles and solutions

    The early pandemic’s diagnostic challenges, such as limited polymerase chain reaction (PCR) test availability and high false-negative rates, led to widespread underdiagnosis, affecting mainly non-hospitalized individuals. Compounded by unreliable antibody tests, particularly among specific groups like women, children, and those with mild infections, these issues have significantly hindered long COVID research and patient care. Misclassification and study exclusion have clouded our understanding of the condition. A comprehensive approach incorporating insights from ME/CFS and dysautonomia is essential to improve long COVID research. Emphasizing clinical trials, diverse participant inclusion, and engaging patient communities, alongside updated healthcare training, will enhance patient outcomes and advance our knowledge of long COVID.

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  • New AI model accurately identifies tumors and diseases in medical images

    New AI model accurately identifies tumors and diseases in medical images

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    Medical diagnostics expert, doctor’s assistant, and cartographer are all fair titles for an artificial intelligence model developed by researchers at the Beckman Institute for Advanced Science and Technology.

    Their new model accurately identifies tumors and diseases in medical images and is programmed to explain each diagnosis with a visual map. The tool’s unique transparency allows doctors to easily follow its line of reasoning, double-check for accuracy, and explain the results to patients.

    The idea is to help catch cancer and disease in its earliest stages -; like an X on a map -; and understand how the decision was made. Our model will help streamline that process and make it easier on doctors and patients alike.”


    Sourya Sengupta, study’s lead author and graduate research assistant at the Beckman Institute

    This research appeared in IEEE Transactions on Medical Imaging.

    Cats and dogs and onions and ogres

    First conceptualized in the 1950s, artificial intelligence -; the concept that computers can learn to adapt, analyze, and problem-solve like humans do -; has reached household recognition, due in part to ChatGPT and its extended family of easy-to-use tools.

    Machine learning, or ML, is one of many methods researchers use to create artificially intelligent systems. ML is to AI what driver’s education is to a 15-year-old: a controlled, supervised environment to practice decision-making, calibrating to new environments, and rerouting after a mistake or wrong turn.

    Deep learning -; machine learning’s wiser and worldlier relative -; can digest larger quantities of information to make more nuanced decisions. Deep learning models derive their decisive power from the closest computer simulations we have to the human brain: deep neural networks.

    These networks -; just like humans, onions, and ogres -; have layers, which makes them tricky to navigate. The more thickly layered, or nonlinear, a network’s intellectual thicket, the better it performs complex, human-like tasks.

    Consider a neural network trained to differentiate between pictures of cats and pictures of dogs. The model learns by reviewing images in each category and filing away their distinguishing features (like size, color, and anatomy) for future reference. Eventually, the model learns to watch out for whiskers and cry Doberman at the first sign of a floppy tongue.

    But deep neural networks are not infallible -; much like overzealous toddlers, said Sengupta, who studies biomedical imaging in the University of Illinois Urbana-Champaign Department of Electrical and Computer Engineering.

    “They get it right sometimes, maybe even most of the time, but it might not always be for the right reasons,” he said. “I’m sure everyone knows a child who saw a brown, four-legged dog once and then thought that every brown, four-legged animal was a dog.”

    Sengupta’s gripe? If you ask a toddler how they decided, they will probably tell you.

    “But you can’t ask a deep neural network how it arrived at an answer,” he said.

    The black box problem

    Sleek, skilled, and speedy as they may be, deep neural networks struggle to master the seminal skill drilled into high school calculus students: showing their work. This is referred to as the black box problem of artificial intelligence, and it has baffled scientists for years.

    On the surface, coaxing a confession from the reluctant network that mistook a Pomeranian for a cat does not seem unbelievably crucial. But the gravity of the black box sharpens as the images in question become more life-altering. For example: X-ray images from a mammogram that may indicate early signs of breast cancer.

    The process of decoding medical images looks different in different regions of the world.

    “In many developing countries, there is a scarcity of doctors and a long line of patients. AI can be helpful in these scenarios,” Sengupta said.

    When time and talents are in high demand, automated medical image screening can be deployed as an assistive tool -; in no way replacing the skill and expertise of doctors, Sengupta said. Instead, an AI model can pre-scan medical images and flag those containing something unusual -; like a tumor or early sign of disease, called a biomarker -; for a doctor’s review. This method saves time and can even improve the performance of the person tasked with reading the scan.

    These models work well, but their bedside manner leaves much to be desired when, for example, a patient asks why an AI system flagged an image as containing (or not containing) a tumor.

    Historically, researchers have answered questions like this with a slew of tools designed to decipher the black box from the outside in. Unfortunately, the researchers using them are often faced with a similar plight as the unfortunate eavesdropper, leaning against a locked door with an empty glass to their ear.

    “It would be so much easier to simply open the door, walk inside the room, and listen to the conversation firsthand,” Sengupta said.

    To further complicate the matter, many variations of these interpretation tools exist. This means that any given black box may be interpreted in “plausible but different” ways, Sengupta said.

    “And now the question is: which interpretation do you believe?” he said. “There is a chance that your choice will be influenced by your subjective bias, and therein lies the main problem with traditional methods.”

    Sengupta’s solution? An entirely new type of AI model that interprets itself every time -; that explains each decision instead of blandly reporting the binary of “tumor versus non-tumor,” Sengupta said.

    No water glass needed, in other words, because the door has disappeared.

    Mapping the model

    A yogi learning a new posture must practice it repeatedly. An AI model trained to tell cats from dogs studying countless images of both quadrupeds.

    An AI model functioning as doctor’s assistant is raised on a diet of thousands of medical images, some with abnormalities and some without. When faced with something never-before-seen, it runs a quick analysis and spits out a number between 0 and 1. If the number is less than .5, the image is not assumed to contain a tumor; a numeral greater than .5 warrants a closer look.

    Sengupta’s new AI model mimics this setup with a twist: the model produces a value plus a visual map explaining its decision.

    The map -; referred to by the researchers as an equivalency map, or E-map for short -; is essentially a transformed version of the original X-ray, mammogram, or other medical image medium. Like a paint-by-numbers canvas, each region of the E-map is assigned a number. The greater the value, the more medically interesting the region is for predicting the presence of an anomaly. The model sums up the values to arrive at its final figure, which then informs the diagnosis.

    “For example, if the total sum is 1, and you have three values represented on the map -; .5, .3, and .2 -; a doctor can see exactly which areas on the map contributed more to that conclusion and investigate those more fully,” Sengupta said.

    This way, doctors can double-check how well the deep neural network is working -; like a teacher checking the work on a student’s math problem -; and respond to patients’ questions about the process.

    “The result is a more transparent, trustable system between doctor and patient,” Sengupta said.

    X marks the spot

    The researchers trained their model on three different disease diagnosis tasks including more than 20,000 total images.

    First, the model reviewed simulated mammograms and learned to flag early signs of tumors. Second, it analyzed optical coherence tomography images of the retina, where it practiced identifying a buildup called Drusen that may be an early sign of macular degeneration. Third, the model studied chest X-rays and learned to detect cardiomegaly, a heart enlargement condition that can lead to disease.

    Once the mapmaking model had been trained, the researchers compared its performance to existing black-box AI systems -; the ones without a self-interpretation setting. The new model performed comparably to its counterparts in all three categories, with accuracy rates of 77.8% for mammograms, 99.1% for retinal OCT images, and 83% for chest x-rays compared to the existing 77.8%, 99.1%, and 83.33.%

    These high accuracy rates are a product of the deep neural network, the non-linear layers of which mimic the nuance of human neurons.

    To create such a complicated system, the researchers peeled the proverbial onion and drew inspiration from linear neural networks, which are simpler and easier to interpret.

    “The question was: How can we leverage the concepts behind linear models to make non-linear deep neural networks also interpretable like this?” said principal investigator Mark Anastasio, a Beckman Institute researcher and the Donald Biggar Willet Professor and Head of the Illinois Department of Bioengineering. “This work is a classic example of how fundamental ideas can lead to some novel solutions for state-of-the-art AI models.”

    The researchers hope that future models will be able to detect and diagnose anomalies all over the body and even differentiate between them.

    “I am excited about our tool’s direct benefit to society, not only in terms of improving disease diagnoses, but also improving trust and transparency between doctors and patients,” Anastasio said.

    Source:

    Journal reference:

    Sengupta, S., et al. (2024) A Test Statistic Estimation-based Approach for Establishing Self-interpretable CNN-based Binary Classifiers. IEEE Transactions on Medical Imaging. doi.org/10.1109/TMI.2023.3348699.

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  • New scSNV-seq technique unveils genetic drivers of diseases like cancer and Alzheimer’s

    New scSNV-seq technique unveils genetic drivers of diseases like cancer and Alzheimer’s

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    Scientists have developed a new screening tool to uncover how genetic changes affect gene activity and can lead to diseases such as cancer, autoimmunity, neurodegeneration and cardiovascular disease. This new tool enables the investigation of thousands of DNA mutations identified by genetic studies in one experiment, guiding the development of advanced diagnostics and treatments.

    The technique, called scSNV-seq, enables researchers to rapidly assess the impact of thousands of genetic changes in cells that have never been screened before, directly connecting these changes to how those same cells operate. This provides a comprehensive view from which researchers can pinpoint the mutations that contribute to disease. This will offer crucial insights for developing targeted therapies.

    In the new study, published in Genome Biology, researchers from the Wellcome Sanger Institute and their collaborators at Open Targets and EMBL’s European Bioinformatics Institute (EMBL-EBI) applied scSNV-seq to the blood cancer gene, JAK1. The technique accurately assessed the impact of JAK1 mutations, revealing for the first time that certain mutations caused a “halfway house” phenotype cycling between different states. This is not possible under previous approaches.

    The technique is designed to demonstrate versatility across cell types, including hard-to-culture primary cells like T cells and stem-cell derived neurons, as well as various editing methods such as base editing and prime editing. Applied on a large scale, scSNV-seq could transform understanding of the genetic changes driving cancer and decoding genetic risk for Alzheimer’s, arthritis, diabetes and other complex diseases.

    Advances in human genetics combined with the increasing affordability of DNA sequencing technologies have unveiled hundreds of thousands of disease-related genetic variants that are increasing at a staggering rate. Yet, tools to interpret them lag behind, sometimes relying on tedious manual processes.

    When using advanced gene-editing tools to introduce defined genetic mutations, using current screening methods, it is difficult to distinguish between cells where the editing did not work and those where it successfully introduced a harmless change without affecting the cell’s behaviour.

    Researchers from the Wellcome Sanger Institute and their collaborators set out to address this with a new screening technique, scSNV-seq, which directly couples the specific genetic information in the genotype of a cell to its gene activity. The team tested the effectiveness of scSNV-seq by altering specific DNA bases within the JAK1 gene, which is linked to inflammation and cancer, to study their effects on cell behavior.

    They demonstrated scSNV-seq could accurately categorise different types of genetic changes into three categories: benign, causing loss of function, and altering function. They showed certain mutations caused an intermediate phenotype cycling between different states – an observation not possible under existing approaches.

    Dr Sarah Cooper, first author of the study at the Wellcome Sanger Institute, said: “In an era where the rate of genetic variant discovery outpaces our ability to interpret their effects, scSNV-seq fills a major gap for studying challenging cells like T cells and neurons. We are already using it to shed light on the impact of Alzheimer’s and Parkinson’s risk variants on brain cells.”

    Our technique is able to directly connect effects of mutations to how a cell behaves, revealing downstream impacts that previous technologies alone cannot deliver. The technique speeds up the identification of causal genetic mutations, which will allow better diagnosis and deepens our molecular understanding of diseases, paving the way for more targeted and effective treatments.”

    Dr Andrew Bassett, Senior Study Author, Wellcome Sanger Institute

    Source:

    Journal reference:

    Cooper, S.E., et al. (2024) scSNV-seq: high-throughput phenotyping of single nucleotide variants by coupled single-cell genotyping and transcriptomics. Genome Biology. doi.org/10.1186/s13059-024-03169-y.

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