tbuckley/cabot-search huggingface dataset:
Discrepancy Between Genetically Predicted and Observed BMI Predicts Incident Type 2 Diabetes
Authors: Tae-Min Rhee, Jaewon Choi, Hyunsuk Lee, Jordi Merino, Jun-Bean Park, Soo Heon Kwak
Journal: Diabetes Care (2024)

OBJECTIVE Obesity is a key predictor of type 2 diabetes (T2D). However, metabolic complications are not solely due to increased BMI. We hypothesized that differences between genetically predicted BMI and observed BMI (BMI-diff) could reflect deviation from individual set point and may predict incident T2D. RESEARCH DESIGN AND METHODS From the UK Biobank cohort, we selected participants of European ancestry without T2D (n = 332,154). The polygenic risk score for BMI was calculated via Bayesian regression and continuous shrinkage priors (PRS-CS). According to the BMI-diff, the 10-year risk of T2D was assessed using multivariable Cox proportional hazards model. Independent data from the Korean Genome and Epidemiology Study (KoGES) cohort from South Korea (n = 7,430) were used for replication. RESULTS Participants from the UK Biobank were divided into train (n = 268,041) and test set (n = 115,119) to establish genetically predicted BMI. In the test set, the genetically predicted BMI explained 7.1% of the variance of BMI, and there were 3,599 T2D cases (3.1%) during a 10-year follow-up. Participants in the higher quintiles of BMI-diff (more obese than genetically predicted) had significantly higher risk of T2D than those in the lowest quintile after adjusting for observed BMI: the adjusted hazard ratio of the 1st quintile (vs. 5th quintile) was 1.61 (95% CI 1.26–2.05, P &amp;lt; 0.001). Results were consistent among individuals in the KoGES study. Moreover, higher BMI than predicted was associated with impaired insulin sensitivity. CONCLUSIONS Having a higher BMI than genetically predicted is associated with an increased risk of T2D. These findings underscore the potential to reassess T2D risk based on individual levels of obesity using genetic thresholds for BMI.
The effect of transient, constricted migration on neutrophil intracellular bacteria-killing capability
Authors: Peng Wu, Alan Y Hsu, Ting Peng, Wenxue Zhao, Fei Liu, Zhaoran Zhang, Laxman Ghimire, Arumugam Balasubramanian, Xuemei Xie, Jiajia Li, Shin-Young Park, Fengxia Ma, Cheng Li, Hongbo R Luo
Journal: Immunity (2024)
Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia
Authors: Maarja Soomann, Viktor Bily, Magdeldin Elgizouli, Dennis Kraemer, Gülfirde Akgül, Horst von Bernuth, Markéta Bloomfield, Nicholas Brodszki, Fabio Candotti, Elisabeth Förster-Waldl, Tomas Freiberger, Maria Giżewska, Adam Klocperk, Uwe Kölsch, Kim E. Nichols, Renate Krüger, Ninad Oak, Małgorzata Pac, Seraina Prader, Kjeld Schmiegelow, Anna Šedivá, Georgios Sogkas, Anna Stittrich, Ulrik Kristoffer Stoltze, Katerina Theodoropoulou, Karin Wadt, Melanie Wong, Maximillian Zeyda, Jana Pachlopnik Schmid, Johannes Trück
Journal: Journal of Allergy and Clinical Immunology (2024)

Graphical abstractAbstractBackgroundAgammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1.ObjectiveWe comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1.MethodsNBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts, and no alternative diagnosis were included.ResultsThe study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19+ B cells (< 0.1 × 109/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia.ConclusionB-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.
Comprehensive Multiple Risk Factor Control in Type 2 Diabetes to Mitigate Heart Failure Risk: Insights From a Prospective Cohort Study
Authors: Ze-Gui Huang, Jing-Wei Gao, Zhi-Teng Chen, Hai-Feng Zhang, Si You, Zhuo-Chao Xiong, Yu-Biao Wu, Qing-Yuan Gao, Jing-Feng Wang, Yang-Xin Chen, Shao-Ling Zhang, Pin-Ming Liu
Journal: Diabetes Care (2024)

OBJECTIVE The impact of comprehensive risk factor control on heart failure (HF) risk and HF-free survival time in individuals with type 2 diabetes (T2D) was evaluated in this study. RESEARCH DESIGN AND METHODS This prospective study included 11,949 individuals diagnosed with T2D, matched with 47,796 non-T2D control study participants from the UK Biobank cohort. The degree of comprehensive risk factor control was assessed on the basis of the major cardiovascular risk factors, including blood pressure, BMI, LDL cholesterol, hemoglobin A1c, renal function, smoking, diet, and physical activity. Cox proportional hazards models were used to measure the associations between the degree of risk factor control and HF risk. Irwin’s restricted mean was used to evaluate HF-free survival time. RESULTS During a median follow-up of 12.3 years, 702 individuals (5.87%) with T2D and 1,402 matched control participants (2.93%) developed HF. Each additional risk factor controlled was associated with an average 19% lower risk of HF. Optimal control of at least six risk factors was associated with a 67% lower HF risk (hazard ratio [HR] 0.33; 95% CI 0.20, 0.54). BMI was the primary attributable risk factor for HF. Notably, the excess risk of HF associated with T2D could be attenuated to levels comparable to those of non-T2D control participants when individuals had a high degree of risk factor control (HR 0.66; 95% CI 0.40, 1.07), and they exhibited a longer HF-free survival time. CONCLUSIONS Comprehensive management of risk factors is inversely associated with HF risk, and optimal risk factor control may prolong HF-free survival time among individuals with T2D.
Posttraumatic Stress Disorder and Type 2 Diabetes Outcomes in Veterans
Authors: Jeffrey F. Scherrer, Joanne Salas, Wenjin Wang, Kenneth E. Freedland, Patrick J. Lustman, Paula P. Schnurr, Beth E. Cohen, Allan S. Jaffe, Matthew J. Friedman
Journal: JAMA Network Open (2024)

Importance Posttraumatic stress disorder (PTSD) symptom reduction is linked with lower risk of incident type 2 diabetes (T2D), but little is known about the association between PTSD and comorbid T2D outcomes. Whether PTSD is a modifiable risk factor for adverse T2D outcomes is unknown. Objective To determine whether patients with PTSD who improved and no longer met diagnostic criteria for PTSD had a lower risk of adverse T2D outcomes compared with patients with persistent PTSD. Design, Setting, and Participants This retrospective cohort study used deidentified data from US Veterans Health Administration (VHA) historical medical records (from October 1, 2011, to September 30, 2022) to create a cohort of patients aged 18 to 80 years with comorbid PTSD and T2D. Data analysis was performed from March 1 to June 1, 2024. Exposures Diagnoses of PTSD and T2D. Main Outcomes and Measures The main outcomes were insulin initiation, poor glycemic control, any microvascular complication, and all-cause mortality. Improvement of PTSD was defined as no longer meeting PTSD diagnostic criteria, per a PTSD Checklist score of less than 33. Entropy balancing controlled for confounding. Survival and competing risk models estimated the association between meeting PTSD criteria and T2D outcomes. Subgroup analyses examined variation by age, sex, race, PTSD severity, and comorbid depression status. Results The study cohort included 10 002 veterans. More than half of patients (65.3%) were aged older than 50 years and most (87.2%) were men. Patients identified as Black (31.6%), White (62.7%), or other race (5.7%). Before controlling for confounding with entropy balancing, patients who no longer met PTSD diagnostic criteria had similar incidence rates for starting insulin (22.4 vs 24.4 per 1000 person-years), poor glycemic control (137.1 vs 133.7 per 1000 person-years), any microvascular complication (108.4 vs 104.8 per 1000 person-years), and all-cause mortality (11.2 vs 11.0 per 1000 person-years) compared with patients with persistent PTSD. After controlling for confounding, no longer meeting PTSD criteria was associated with a lower risk of microvascular complications (hazard ratio [HR], 0.92 [95% CI, 0.85-0.99]). Among veterans aged 18 to 49 years, no longer meeting PTSD criteria was associated with a lower risk of insulin initiation (HR, 0.69 [95% CI, 0.53-0.88]) and all-cause mortality (HR, 0.39 [95% CI, 0.19-0.83]). Among patients without depression, no longer meeting PTSD criteria was associated with a lower risk of insulin initiation (HR, 0.73 [95% CI, 0.55-0.97]). Conclusions and Relevance The findings of this cohort study of patients with comorbid PTSD and T2D suggest that PTSD is a modifiable risk factor associated with a modest reduction in microvascular complications. Further research is needed to determine whether findings are similar in non-VHA health care settings.
Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF-Fusion pilocytic astrocytoma
Authors: Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P. Chandler, Roger Stupp, Adam M. Sonabend, Craig M. Horbinski, Rimas V. Lukas, Joanne Xiu, Giselle Lopez, Theodore P. Nicolaides, Valerie Brown, Nitin R. Wadhwani, Sandi K. Lam, Charles David James, Ganesh Rao, Maria G. Castro, Amy B. Heimberger, Michael DeCuypere
Journal: Journal of Clinical Investigation (2024)

Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapy strategy evaluated in multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher interferon signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia population designated MG-Act in BRAF-fused MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. TIM3 is expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain. TIM3 expression becomes upregulated on immune cells in the PA microenvironment and anti-TIM3 reprograms ex vivo immune cells from human PAs to a pro-inflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven low-grade gliomas, anti-TIM3 treatment increased median survival over IgG and anti-PD1 treated mice. ScRNA sequencing data during the therapeutic window of anti-TIM3 demonstrates enrichment of the MG-Act population. The therapeutic activity of anti-TIM3 is abrogated in the CX3CR1 microglia knockout background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade MAPK-driven gliomas.
Teplizumab induces persistent changes in the antigen‐speciﬁc repertoire in individuals at‐risk for type 1 diabetes
Authors: Ana Lledó-Delgado, Paula Preston-Hurlburt, Sophia Currie, Pamela Clark, Peter S. Linsley, S. Alice Long, Can Liu, Galina Koroleva, Andrew J. Martins, John S. Tsang, Kevan C. Herold
Journal: Journal of Clinical Investigation (2024)

BACKGROUNDTeplizumab, a non-FcR-binding anti-CD3 mAb, is approved to delay progression of type 1 diabetes (T1D) in at-risk patients. Previous investigations described the immediate effects of the 14-day treatment, but longer-term effects of the drug remain unknown.METHODSWith an extended analysis of study participants, we found that 36% were undiagnosed or remained free of clinical diabetes after 5 years, suggesting operational tolerance. Using single-cell RNA sequencing, we compared the phenotypes, transcriptome, and repertoire of peripheral blood CD8+ T cells including autoreactive T cells from study participants before and after teplizumab and features of responders and non-responders.RESULTSAt 3 months, there were transcriptional signatures of cell activation in CD4+ and CD8+ T cells including signaling that was reversed at 18 months. At that time, there was reduced expression of genes in T cell receptor and activation pathways in clinical responders. In CD8+ T cells, we found increased expression of genes associated with exhaustion and immune regulation with teplizumab treatment. These transcriptional features were further confirmed in an independent cohort. Pseudotime analysis showed differentiation of CD8+ exhausted and memory cells with teplizumab treatment. IL7R expression was reduced, and patients with lower expression of CD127 had longer diabetes-free intervals. In addition, the frequency of autoantigen-reactive CD8+ T cells, which expanded in the placebo group over 18 months, did not increase in the teplizumab group.CONCLUSIONThese findings indicate that teplizumab promotes operational tolerance in T1D, involving activation followed by exhaustion and regulation, and prevents expansion of autoreactive T cells.TRIAL REGISTRATIONClinicalTrials.gov NCT01030861.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases/NIH, Juvenile Diabetes Research Foundation.
Continuous Positive Airway Pressure Treatment and Hypertensive Adverse Outcomes in Pregnancy
Authors: Yi-Chieh Lee, Yun-Chen Chang, Liang-Wei Tseng, Wan-Ni Lin, Chun-Ting Lu, Li-Ang Lee, Tuan-Jen Fang, Wen-Nuan Cheng, Hsueh-Yu Li
Journal: JAMA Network Open (2024)

Importance Pregnancy may contribute to the development or exacerbation of obstructive sleep apnea (OSA) and increase the risk of gestational complications. Continuous positive airway pressure (CPAP) is the first-line and criterion standard treatment for OSA and is regarded as the most feasible choice during pregnancy. However, the association between CPAP therapy in pregnant women with OSA and reduced gestational complications remains inconclusive. Objective To investigate the association between CPAP therapy in pregnant women with OSA and the reduction of adverse hypertensive outcomes during gestation. Data Sources Keyword searches of PubMed, Embase, and the Cochrane Database of Systematic Reviews and Clinical Trials were conducted from inception to November 5, 2023. Study Selection Original studies reporting the treatment effect of CPAP use on lowering hypertension and preeclampsia risks in pregnant women with OSA were selected. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed in the reporting of reviews. Data were independently extracted by 2 authors. Random-effects model meta-analyses were performed and risk ratios (RRs) reported. Subgroup analysis, meta-regression based on age and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and publication bias assessment were also conducted. Main Outcome and Measures The primary outcome was the RR of gestational hypertension and preeclampsia between pregnant women with OSA receiving CPAP treatment and those who did not receive CPAP treatment. Results Six original studies in 809 participants (mean age, 31.4 years; mean BMI, 34.0) were identified and systematically reviewed for meta-analysis. The pooled results showed significant differences between the intervention (CPAP use) and the control (non-CPAP use) groups in reducing the risk of gestational hypertension (RR, 0.65; 95% CI, 0.47-0.89; P = .008) and preeclampsia (RR, 0.70; 95% CI, 0.50-0.98; P = .04). Meta-regression revealed that patients’ age (coefficient, −0.0190; P = .83) and BMI (coefficient, −0.0042; P = .87) were not correlated with reduction of risk of hypertension and preeclampsia. Conclusions and Relevance These findings suggest that implementing CPAP treatment in pregnant women with OSA may reduce the risk of gestational hypertension and preeclampsia.
Device associated complications in the intensive care unit
Authors: Roxana Hixson, Kristin Schwab Jensen, Kathryn H Melamed, Nida Qadir
Journal: BMJ (2024)

Abstract Invasive devices are routinely used in the care of critically ill patients. Although they are often essential components of patient care, devices such as intravascular catheters, endotracheal tubes, and ventilators are a common source of complications in the intensive care unit. Critical care practitioners who use these devices need to use strategies for risk reduction and understand approaches to management when adverse events occur. This review discusses the identification, prevention, and management of complications of vascular, airway, and mechanical support devices commonly used in the intensive care unit.
Patient-Reported Outcome Measures in Cancer Care
Authors: Amaris K. Balitsky, Daniel Rayner, Joanne Britto, Anath C. Lionel, Lydia Ginsberg, Wanjae Cho, Ann Mary Wilfred, Huda Sardar, Nathan Cantor, Hira Mian, Mark N. Levine, Gordon H. Guyatt
Journal: JAMA Network Open (2024)

Importance Patient-reported outcome measures (PROMs) come directly from the patient, without clinician interpretation, to provide a patient-centered perspective. Objective To understand the association of PROM integration into cancer care with patient-related, therapy-related, and health care utilization outcomes. Data Sources Searches included MEDLINE and MEDLINE Epub ahead of print, in-process, and other nonindexed citations; Embase databases (OvidSP); PsychINFO; CENTRAL; and CINAHL from January 1, 2012 to September 26, 2022. Study Selection Randomized clinical trials (RCTs) that enrolled adult patients (ages 18 years and older) with active cancer receiving anticancer therapy using a PROM as an intervention. Data Extraction and Synthesis Pairs of review authors, using prepiloted forms, independently extracted trial characteristics, disease characteristics, and intervention details. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline was followed. Random-effects analyses were conducted. Main Outcomes and Measures Overall mortality, health-related quality of life (HRQoL) measures, and hospital utilization outcomes. Results From 1996 to 2022, 45 RCTs including 13 661 participants addressed the association of PROMs with outcomes considered important to patients. The addition of a PROM likely reduced the risk of overall mortality (HR, 0.84; 95% CI, 0.72-0.98; moderate certainty), improved HRQoL (range 0-100) at 12 weeks (mean difference [MD], 2.45; 95% CI, 0.42-4.48; moderate certainty). Improvements of HRQoL at 24 weeks were not significant (MD, 1.87; 95% CI, −1.21 to 4.96; low certainty). There was no association between the addition of a PROM and HRQoL at 48 weeks. The addition of a PROM was not associated with reduced ED visits (OR, 0.74; 95% CI, 0.54-1.02; low certainty) or hospital admissions (OR, 0.86; 95% CI, 0.73-1.02; low certainty). Conclusion and Relevance The findings of this study suggest that the integration of PROMs into cancer care may improve overall survival and quality of life.
Use of Generative AI to Identify Helmet Status Among Patients With Micromobility-Related Injuries From Unstructured Clinical Notes
Authors: Kathryn G. Burford, Nicole G. Itzkowitz, Ashley G. Ortega, Julien O. Teitler, Andrew G. Rundle
Journal: JAMA Network Open (2024)

Importance Large language models (LLMs) have potential to increase the efficiency of information extraction from unstructured clinical notes in electronic medical records. Objective To assess the utility and reliability of an LLM, ChatGPT-4 (OpenAI), to analyze clinical narratives and identify helmet use status of patients injured in micromobility-related accidents. Design, Setting, and Participants This cross-sectional study used publicly available, deidentified 2019 to 2022 data from the US Consumer Product Safety Commission’s National Electronic Injury Surveillance System, a nationally representative stratified probability sample of 96 hospitals in the US. Unweighted estimates of e-bike, bicycle, hoverboard, and powered scooter–related injuries that resulted in an emergency department visit were used. Statistical analysis was performed from November 2023 to April 2024. Main Outcomes and Measures Patient helmet status (wearing vs not wearing vs unknown) was extracted from clinical narratives using (1) a text string search using researcher-generated text strings and (2) the LLM by prompting the system with low-, intermediate-, and high-detail prompts. The level of agreement between the 2 approaches across all 3 prompts was analyzed using Cohen κ test statistics. Fleiss κ was calculated to measure the test-retest reliability of the high-detail prompt across 5 new chat sessions and days. Performance statistics were calculated by comparing results from the high-detail prompt to classifications of helmet status generated by researchers reading the clinical notes (ie, a criterion standard review). Results Among 54 569 clinical notes, moderate (Cohen κ = 0.74 [95% CI, 0.73-0.75) and weak (Cohen κ = 0.53 [95% CI, 0.52-0.54]) agreement were found between the text string–search approach and the LLM for the low- and intermediate-detail prompts, respectively. The high-detail prompt had almost perfect agreement (κ = 1.00 [95% CI, 1.00-1.00]) but required the greatest amount of time to complete. The LLM did not perfectly replicate its analyses across new sessions and days (Fleiss κ = 0.91 across 5 trials; P &amp;amp;lt; .001). The LLM often hallucinated and was consistent in replicating its hallucinations. It also showed high validity compared with the criterion standard (n = 400; κ = 0.98 [95% CI, 0.96-1.00]). Conclusions and Relevance This study’s findings suggest that although there are efficiency gains for using the LLM to extract information from clinical notes, the inadequate reliability compared with a text string–search approach, hallucinations, and inconsistent performance significantly hinder the potential of the currently available LLM.