tbuckley/cabot-search huggingface dataset:
A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease
Authors: Hamilton Se-Hwee Oh, Deniz Yagmur Urey, Linda Karlsson, Zeyu Zhu, Yuanyuan Shen, Amelia Farinas, Jigyasha Timsina, Michael R Duggan, Jingsha Chen, Ian H Guldner, Nader Morshed, Chengran Yang, Daniel Western, Muhammad Ali, Yann Le Guen, Alexandra Trelle, Sanna-Kaisa Herukka, Tuomas Rauramaa, Mikko Hiltunen, Anssi Lipponen, Antti J Luikku, Kathleen L Poston, Elizabeth Mormino, Anthony D Wagner, Edward N Wilson, Divya Channappa, Ville Leinonen, Beth Stevens, Alexander J Ehrenberg, Rebecca F Gottesman, Josef Coresh, Keenan A Walker, Henrik Zetterberg, David A Bennett, Nicolai Franzmeier, Oskar Hansson, Carlos Cruchaga, Tony Wyss-Coray
Journal: Nature Medicine (2025)

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10-4) and A+T1+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10-16) over a 15-year follow-up, adjusting for CSF pTau181:Aβ42, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.
Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death
Authors: Marc Humbert, Vallerie V. McLaughlin, David B. Badesch, H. Ardeschir Ghofrani, J. Simon R. Gibbs, Mardi Gomberg-Maitland, Ioana R. Preston, Rogerio Souza, Aaron B. Waxman, Victor M. Moles, Laurent Savale, Carmine Dario Vizza, Stephan Rosenkranz, Yaru Shi, Barry Miller, Harald S. Mackenzie, Samuel S. Kim, Maria José Loureiro, Mahesh J. Patel, Joerg Koglin, Alexandra G. Cornell, Marius M. Hoeper
Journal: New England Journal of Medicine (2025)

Sotatercept improves exercise capacity and delays the time to clinical worsening in patients with World Health Organization (WHO) functional class II or III pulmonary arterial hypertension. The effects of add-on sotatercept in patients with advanced pulmonary arterial hypertension and a high risk of death are unclear. In this phase 3 trial, we randomly assigned patients with pulmonary arterial hypertension (WHO functional class III or IV) and a high 1-year risk of death (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management Lite 2 risk score, ≥9) who were receiving the maximum tolerated dose of background therapy to receive add-on sotatercept (starting dose, 0.3 mg per kilogram of body weight; escalated to target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was a composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension, assessed in a time-to-first-event analysis. A total of 172 patients were included (86 each in the sotatercept and placebo groups). The trial was stopped early on the basis of the efficacy results of a prespecified interim analysis. At least one primary end-point event occurred in 15 patients (17.4%) in the sotatercept group and in 47 patients (54.7%) in the placebo group (hazard ratio, 0.24; 95% confidence interval, 0.13 to 0.43; P<0.001). Death from any cause occurred in 7 patients (8.1%) in the sotatercept group and in 13 patients (15.1%) in the placebo group; lung transplantation in 1 patient (1.2%) and 6 patients (7.0%), respectively; and hospitalization for worsening pulmonary arterial hypertension in 8 patients (9.3%) and 43 patients (50.0%). The most common adverse events with sotatercept were epistaxis and telangiectasia. Among high-risk adults with pulmonary arterial hypertension who were receiving the maximum tolerated dose of background therapy, treatment with sotatercept resulted in a lower risk of a composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension than placebo. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; ZENITH ClinicalTrials.gov number, NCT04896008.).
An Oral PCSK9 Inhibitor for Treatment of Hypercholesterolemia
Authors: Michael J Koren, Rick B Vega, Nikhil Agrawal, Yuejia Xu, April M Barbour, Hongtao Yu, Emelie Wallerstedt, Debra Carter, Jessica Middlemiss, Lee Twaddle, Michael C McCarthy, Jaya B Rosenmeier
Journal: Journal of the American College of Cardiology (2025)
Lighting up Resistance: Rapid Antimicrobial Susceptibility Testing of Gram‐Negative Bacteria in Bloodstream Infections Using an Aggregation‐Induced Emission Bioprobe
Authors: Xiaoxue Ge, Meng Gao, Nannan Cao, Meiwei Mou, Shujuan Guan, Bairong He, Xiumei Hu, Bo Situ, Lei Zheng
Journal: Advanced Healthcare Materials (2025)

Rapid and accurate antimicrobial susceptibility testing (AST) is crucial for guiding treatment and combating resistance. However, conventional ASTs are time-consuming and require pure colonies, delaying the initiation of targeted antimicrobial therapy. Herein, a novel AST based on an aggregation-induced emission luminogen (AIEgen), DATVP, which can directly assess the antimicrobial susceptibility of Gram-negative bacteria in positive blood cultures, is reported. DATVP specifically lights up Gram-negative bacteria with damaged cell membranes while showing no fluorescence in intact bacteria. The antimicrobial-induced fluorescence turn-on of DATVP is found to be fast (within 6 h) and sensitive, allowing for reliable determination of antimicrobial susceptibility. Using DATVP, a wash-free AST is developed and its performance was validated on clinical isolates. The DATVP-based AST showed high categorical agreement (84-95%) with the standard method while shortening the time-to-result from days to hours. This method represents a new paradigm in phenotypic AST, offering speed, simplicity, and direct applicability to patient samples, with the potential to enable timely and targeted antimicrobial treatment.
Prognostic Validation of the International Consensus (<scp>ICC</scp>) Re‐Classification of Acute Myeloid Leukemia With Myelodysplasia‐Related Changes (<scp>AML</scp>‐<scp>MRC</scp>) Into Genetic Subcategories
Authors: Ayalew Tefferi, Daniel A. Arber
Journal: American Journal of Hematology (2025)
British Society of Gastroenterology guidelines for diagnosis and management of autoimmune hepatitis
Authors: Dermot Gleeson, Rosemary Bornand, Ann Brownlee, Harpreet Dhaliwal, Jessica K Dyson, Janeane Hails, Paul Henderson, Deirdre Kelly, George F Mells, Rosa Miquel, Ye H Oo, Anthea Sutton, Andrew Yeoman, Michael A Heneghan
Journal: Gut (2025)

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.
Non-ICANS neurological complications after CAR T-cell therapies: recommendations from the EBMT Practice Harmonisation and Guidelines Committee
Authors: Charlotte E Graham, Roser Velasco, Ana Alarcon Tomas, Orla P Stewart, Guillaume Dachy, Francesca Del Bufalo, Matteo Doglio, Jan-Inge Henter, Guillermo Ortí, Zinaida Peric, Claire Roddie, Niels W C J van de Donk, Matthew J Frigault, Annalisa Ruggeri, Francesco Onida, Isabel Sánchez-Ortega, Ibrahim Yakoub-Agha, Olaf Penack
Journal: The Lancet Oncology (2025)
Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation
Authors: Eva M Pålsson-McDermott, Luke A J O'Neill
Journal: Cell Metabolism (2025)

The reprogramming of metabolic pathways and processes in immune cells has emerged as an important aspect of the immune response. Metabolic intermediates accumulate as a result of metabolic adaptations and mediate functions outside of metabolism in the regulation of immunity and inflammation. In macrophages, there has been a major focus on 3 metabolites linked to the Krebs cycle, itaconate, succinate, and fumarate, which have been shown to regulate multiple processes. Here, we discuss recent progress on these 3 metabolites with regard to their effect on macrophages in host defense and inflammatory diseases. We also consider the therapeutic opportunities presented from the mimicry of these metabolites or by targeting the enzymes that make or metabolize them in order to leverage the body's own anti-inflammatory response.
Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria
Authors: Camila Marques-da-Silva, Clyde Schmidt-Silva, Carson Bowers, Nana Appiah Essel Charles-Chess, Cristina Samuel, Justine C Shiau, Eui-Soon Park, Zhongyu Yuan, Bae-Hoon Kim, Dennis E Kyle, John T Harty, John D MacMicking, Samarchith P Kurup
Journal: Cell Host & Microbe (2025)
Reference-free variant calling with local graph construction with ska lo (SKA)
Authors: Romain Derelle, Kieran Madon, Joel Hellewell, Víctor Rodríguez-Bouza, Nimalan Arinaminpathy, Ajit Lalvani, Nicholas J Croucher, Simon R Harris, John A Lees, Leonid Chindelevitch
Journal: Molecular Biology and Evolution (2025)

Abstract The study of genomic variants is increasingly important for public health surveillance of pathogens. Traditional variant calling methods from whole-genome sequencing data rely on reference-based alignment, which can introduce biases and require significant computational resources. Alignment-free and reference-free approaches offer an alternative by leveraging k-mer-based methods, but existing implementations often suffer from sensitivity limitations, particularly in high mutation density genomic regions. Here, we present ska lo, a graph-based algorithm that aims to identify within-strain variants in pathogen whole-genome sequencing data by traversing a coloured De Bruijn graph and building variant groups (ie, sets of variant combinations). Through in-silico benchmarking and real-world dataset analyses, we demonstrate that ska lo achieves high sensitivity in SNP calls while also enabling the detection of insertions and deletions, as well as SNP positioning on a reference genome for recombination analyses. These findings highlight ska lo as a simple, fast and effective tool for pathogen genomic epidemiology, extending the range of reference-free variant calling approaches. ska lo is freely available as part of the SKA program (https://github.com/bacpop/ska.rust).
Characteristics of patients seeking skin-related minor ailment pharmacy services in Ontario, Canada: A population-based cross-sectional study
Authors: Rita J Iskandar, Mina Tadrous, Paul Nguyen, Lisa Dolovich, Michael Green, Eliot Frymire, Aaron M Drucker
Journal: British Journal of Dermatology (2025)

As healthcare systems are increasingly strained, policymakers in various jurisdictions have turned to pharmacies to offload services to treat minor ailments. These services were recently implemented in Ontario, Canada's largest province, with 7 of 19 eligible minor ailments being skin conditions. In this letter, we provide the first description of the initial uptake of this new service for skin conditions, describing its users and how they compare to the general population of Ontario. Our findings show high utilization, highlighting the growing role of pharmacy-based skin services. Users tend to be already strongly connected to the healthcare system, suggesting potential disparities in access. These insights offer valuable guidance for policymakers as they refine and expand such programs.
Gene-by-environment interactions and adaptive body size variation in mice from the Americas
Authors: Katya L Mack, Nico P Landino, Mariia Tertyshnaia, Tiffany C Longo, Sebastian A Vera, Lilia A Crew, Kristi McDonald, Megan Phifer-Rixey
Journal: Molecular Biology and Evolution (2025)

Abstract The relationship between genotype and phenotype is often mediated by the environment. Moreover, gene-by-environment (GxE) interactions can contribute to variation in phenotypes and fitness. In the last 500 years, house mice have invaded the Americas. Despite their short residence time, there is evidence of rapid climate adaptation, including shifts in body size and aspects of metabolism with latitude. Previous selection scans have identified candidate genes for metabolic adaptation. However, environmental variation in diet as well as GxE interactions likely impact body mass variation in wild populations. Here, we investigated the role of the environment and GxE interactions in shaping adaptive phenotypic variation. Using new locally adapted inbred strains from North and South America, we evaluated response to a high fat diet, finding that sex, strain, diet, and the interaction between strain and diet contributed significantly to variation in body size. We also found that the transcriptional response to diet is largely strain-specific, indicating that GxE interactions affecting gene expression are pervasive. Next, we used crosses between strains from contrasting climates to characterize gene expression regulatory divergence on a standard diet and on a high fat diet. We found that gene regulatory divergence is often condition-specific, particularly for trans-acting changes. Finally, we found evidence for lineage-specific selection on cis-regulatory variation involved in diverse processes, including lipid metabolism. Overlap with scans for selection identified candidate genes for environmental adaptation with diet-specific effects. Together, our results underscore the importance of environmental variation and GxE interactions in shaping adaptive variation in complex traits.
Genetic Confounding in the Association Between Traumatic Brain Injury and Mental Disorder or Suicide
Authors: Søren Dinesen Østergaard, Jessica Mundy, Alisha Silvia Mercedes Hall, Katherine L. Musliner
Journal: JAMA Psychiatry (2025)

Importance Traumatic brain injury is common and occurs across all ages. Observational studies have shown that traumatic brain injury is associated with a wide range of mental disorders and suicide. Whether these associations represent a causal effect is, however, difficult to establish, and confounding by genetic liability for mental disorder may play a substantial role. Objective To investigate whether observational associations between traumatic brain injury and mental disorder or suicide could be confounded by genetic liability for mental disorder. Design, Setting, and Participants This cohort study was conducted from October 2023 to January 2025. The study population consisted of the general population subcohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) sample, which is a representative sample of the Danish population born between 1981 and 2008 that has been genotyped. Exposures Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, and attention-deficit/hyperactivity disorder (ADHD) calculated from the genotypes and genome-wide association summary statistics. Main Outcomes and Measures The primary outcome was traumatic brain injury, operationalized via hospital diagnoses. The associations between PRSs for schizophrenia, bipolar disorder, depression, and ADHD, respectively, and traumatic brain injury were examined via Cox proportional hazards regression, yielding hazard rate ratios (HRRs) with 95% confidence intervals. Results The final cohort consisted of a total of 40 274 individuals, of whom 19 802 (49.2%) were female. A total of 3341 (8.3%) of the cohort members (of whom 1464 [43.8%] were female and 1877 [56.2%] were male) experienced traumatic brain injury during follow-up. All 4 PRSs showed statistically significant positive associations with traumatic brain injury (PRS-schizophrenia: HRR, 1.06; 95% CI, 1.02-1.10; P = .002; PRS-bipolar disorder: HRR, 1.04; 95% CI, 1.00-1.08; P = .04; PRS-depression: HRR, 1.10; 95% CI, 1.06-1.14; P &amp;amp;lt; .001; and PRS-ADHD: HRR, 1.12; 95% CI, 1.08-1.16; P &amp;amp;lt; .001). Conclusions and Relevance The results of this cohort study suggest that confounding by genetic liability for mental disorder could explain some of the association between traumatic brain injury and mental disorder or suicide. Consequently, genetic liability for mental disorder should be factored into future studies of these associations to avoid overestimation of causality.
Care of Patients With Chronic Venous Disease of the Legs
Authors: Emily A. Goodman, Jason T. Alexander, Trissa A. Babrowski
Journal: JAMA (2025)

This JAMA Clinical Guidelines Synopsis summarizes the 2022-2023 recommendations on evaluation and management of chronic venous disease of the lower extremities from the Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society.
Spending on Glucagon-Like Peptide-1 Receptor Agonists Among US Adults
Authors: Stavros Tsipas, Tamkeen Khan, Fleetwood Loustalot, Klodiana Myftari, Gregory Wozniak
Journal: JAMA Network Open (2025)

This economic evaluation estimates annual total US spending on glucagon-like peptide-1 receptor agonists from 2018 to 2023.
Preferred Advanced Airway Device Use Among Adults With Out-of-Hospital Cardiac Arrest
Authors: Christopher B. Gage, Henry E. Wang, Jacob C. Kamholz, Jonathan R. Powell, Ashish R. Panchal
Journal: JAMA Network Open (2025)

This cross-sectional study assesses the temporal trends in advanced airway strategies for US adults with out-of-hospital cardiac arrest from 2018 to 2023.
Preventive Health Care Use Among Adults Eligible for Lung Cancer Screening in the US
Authors: Alexandra L. Potter, Soneesh Kothagundla, Chinmay Haridas, Allison E. B. Chang, Lecia V. Sequist, Chi-Fu Jeffrey Yang
Journal: JAMA (2025)

This study examines the use of preventive lung, breast, and colorectal cancer screening among eligible and ineligible US adults.
Should Inflammation Be a Specifier for Major Depression in the <i>DSM-6</i>?
Authors: Manish K. Jha, Marion Leboyer, Carmine M. Pariante, Andrew H. Miller
Journal: JAMA Psychiatry (2025)

This Viewpoint discusses the opportunity to include inflammatory biomarkers as specifiers for major depression in the upcoming Sixth Edition of the Diagnostic and Statistical Manual of Mental Disorders ( DSM-6 ).
Pembrolizumab in Relapsed or Refractory Mycosis Fungoides or Sézary Syndrome
Authors: Omar Elghawy, Jonathan H. Sussman, Austin G. Yang, Colin J. Thomas, Jordan S. Carter, Daniel J. Landsburg, Jakub Svoboda, Ellen Kim, Alain H. Rook, Jina Chung, John P. Plastaras, Michael LaRiviere, Harper Hubbeling, Monica Chelius, Sunita D. Nasta, Elise A. Chong, Stephen J. Schuster, Stefan K. Barta
Journal: JAMA Dermatology (2025)

This case series reported survival, response, and safety outcomes for patients with mycosis fungoides or Sézary syndrome who received pembrolizumab at a single institution.
SGLT2 Inhibitors Blunt Kidney Magnesium Wasting in Acute Cisplatin-Induced Hypomagnesemia with Effects on the TAL and DCT
Authors: Erika F. Jesus, Weverton M. Luchi, Paulo C. Castro, Flavia L. Martins, Marcos V. Caetano, Vanderlene L. Kung, Antonio C. Seguro, James A. McCormick, Adriana C.C. Girardi
Journal: Journal of the American Society of Nephrology (2025)

Background: Cisplatin, a chemotherapeutic agent, induces kidney magnesium wasting and hypomagnesemia. Recent studies suggest that SGLT2 inhibitors elevate serum magnesium concentration in patients with or without diabetes. We hypothesized that the SGLT2 inhibitor empagliflozin attenuates acute cisplatin-induced hypomagnesemia by acting on the thick ascending limb (TAL) and distal convoluted tubule (DCT), key sites of magnesium reabsorption. Methods: Adult male Wistar rats received weekly treatments of cisplatin (2.5 mg/kg) or saline (vehicle) for five weeks. After three weeks, rats were randomized to receive empagliflozin (10 mg/kg/day) or water (vehicle) for the next fifteen days. Results: Cisplatin-treated rats developed significant hypomagnesemia with increased fractional excretion of magnesium (FEMg 2+ ). Empagliflozin treatment reduced FEMg 2+ and restored serum magnesium levels. In the TAL, cisplatin-treated rats had higher NKCC2 abundance but lower phosphorylated NKCC2 and claudin-16 levels than empagliflozin-treated cisplatin rats, whose protein levels were similar to controls. In contrast, claudin-19 abundance in the TAL was higher in cisplatin-treated rats than in controls and unaffected by empagliflozin treatment. In the DCT, cisplatin-treated rats displayed reduced abundance of the NaCl cotransporter (NCC), the magnesium channel TRPM6, and NCC phosphorylation, all of which were rescued by empagliflozin. Unexpectedly, cisplatin-treated rats exhibited higher mRNA expression and protein abundance of TRPM7 compared to empagliflozin-treated cisplatin rats, whose levels were similar to controls. Diuretic challenge tests with furosemide or hydrochlorothiazide confirmed reduced NKCC2 and NCC activity in cisplatin-treated rats. However, the natriuretic response to furosemide or hydrochlorothiazide did not differ between control and empagliflozin-treated cisplatin rats. Immunohistochemistry suggested that empagliflozin reversed cisplatin-induced DCT remodeling. Conclusions: Empagliflozin reduces kidney magnesium wasting and restores serum magnesium in cisplatin-treated rats, likely through reversing NKCC2 inhibition and claudin-16 downregulation in the TAL while normalizing NCC function and restoring TRPM6 expression in the DCT.
Association of Social Risk Factors with Kidney Function Recovery among Patients with Acute Kidney Injury Receiving Outpatient Dialysis
Authors: Seda Babroudi, Hocine Tighiouart, Daniel E. Weiner, Javier A. Neyra, Ronald Sanders, Harold J. Manley, Eduardo K. Lacson, David A. Drew
Journal: Journal of the American Society of Nephrology (2025)
<scp>NLRC4</scp> Regulates Th2 Differentiation in Mice With Allergic Airway Inflammation Induced by House Dust Mite
Authors: So‐Won Pak, Woong‐Il Kim, Se‐Jin Lee, Junhyeong Lee, Min‐Jung Park, Jong‐Hwan Park, Jong‐Choon Kim, Taesoo Kim, Joong‐Sun Kim, Yun Hee Kim, In‐Sik Shin
Journal: Allergy (2025)