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Airqtl dissects cell state-specific causal gene regulatory networks with efficient single-cell eQTL mapping
No full textSingle-cell expression quantitative trait loci (sceQTL) mapping offers a powerful approach for understanding gene regulation and its heterogeneity across cell types and states. It has profound applications in genetics and genomics, particularly causal gene regulatory network (cGRN) inference to unravel the molecular circuits governing cell identity and function. However, computational scalability remains a critical bottleneck for sceQTL mapping, prohibiting thorough benchmarking and optimization of statistical accuracy. We present airqtl, an efficient method to overcome these challenges through algorithmic advances and efficient implementations of linear mixed models. Airqtl achieves superior time complexity and over 10 times of acceleration, enabling objective method benchmarking and optimization. Airqtl offers de novo inference of robust, experimentally validated cell state-specific cGRNs that reflect perturbation outcomes. Our results dissect the drivers of cGRN heterogeneity and underscore the value of natural genetic variations in primary human cell types for biologically relevant single-cell cGRN inference.No embarg
Elucidating the Mechanisms Driving Adverse Outcomes in Racialized Perinatal Populations
No full textAdverse obstetric outcomes, such as hypertensive disorders, preterm birth, and depression, disproportionately affect marginalized populations in the US and contribute to long-term health risks like cardiovascular disease (CVD). Racism and chronic stress are drivers of these inequities, yet the biological pathways linking them to perinatal health are underexplored. Allostatic load (AL), a cumulative measure of biological wear and tear from chronic stress, offers a potential tool for exploring these relationships and informing clinical care.
We synthesized existing studies that measured AL in pregnancy, explored the feasibility of identifying AL biomarkers in clinical data, and examined the association between a biomarker-based index, modeled after AL, and adverse obstetric outcomes that impact CVD risk. We also incorporated iterative feedback from a working group of perinatal professionals. The scoping review identified 22 biomarkers and a refined index was developed using a subset. The most common combination for an index included six biomarkers, which included blood pressure and albumin. While the refined index was not significantly associated with adverse obstetric outcomes, the results highlighted stable partnerships as a protective factor.
Exploring the relationship between AL and health inequities in perinatal populations is complex, especially using retrospective clinical data. Challenges include missing data and the inconsistency in how data is documented for clinical care compared to research. Despite these limitations, there is a need to refine AL indices further and explore systematic inequities and the biological pathways that may impact perinatal outcomes. These findings may inform the development of helpful interventions.Population Health SciencesNo embarg
Characterization of the genomic landscape of canine oral osteosarcoma reveals similarities with appendicular osteosarcoma
Get PDFOsteosarcoma (OS) is the most common bone tumor in both dogs and humans. It predominantly occurs in the appendicular skeleton, with about 25% of cases occurring within the axial skeleton. Progression of local disease is often the life-limiting factor for patients with axial OS, in contrast to appendicular OS, where local disease is addressed surgically, and metastatic disease remains the primary obstacle. While OS is a rare human cancer, limiting the availability of samples, its higher incidence in dogs provides a valuable comparative model for study. Both canines and humans share commonalities in clinical presentation, but dogs have an accelerated progression. Similarly, complex structural genetic changes define appendicular OS in both dogs and people, but it is unclear whether the genomic landscape of axial OS exhibits different alterations that may separate it from appendicular OS. We performed pilot whole genome sequencing of canine primary oral (maxillary or mandibular) OS tumors (n = 8) and matched normal tissue. We found that the genetics of canine oral OS largely parallel the genetics of canine appendicular OS, including an overall low number of recurrent point mutations affecting the same gene (TP53 and SETD2, 3/8 samples). Structural variants dominated the landscape of mutational changes, with recurrent variants in DMD (4/8) and DLG2 (3/8) found at a similar incidence to appendicular OS. This pilot suggests genomic similarities between oral and appendicular OS.No embarg
Clinician profiles of suicide prevention attitudes and confidence and their association with reported suicide prevention practices
No full textMany who die by suicide seek care in general health care settings within a year before death, but only recently has suicide prevention become a core responsibility in these settings. Implementing suicide prevention practices is challenging, and common barriers to adoption include clinician attitudes and self-efficacy. Identifying clinician profiles can further illuminate patterns of suicide prevention practice attitudes and self-efficacy within clinician subgroups to inform implementation strategy selection and development. This study identified distinct clinician profiles of suicide prevention attitudes and confidence and examines their associations with suicide prevention practice delivery to patients. This study also investigated variables that help explain an individual's likelihood of belonging to latent profiles. Clinicians ( = 1,570) from one health care system completed a survey assessing attitudes, confidence in using suicide prevention practices, and current practice use. Latent profile analysis was conducted, followed by outcome and predictor analyses. Four unique profiles characterized by varying levels of attitudes and self-efficacy were identified. The profile characterized by poor attitudes toward the universal screening practice but high self-efficacy to utilize suicide prevention practices reported higher practice use with patients. Clinician characteristics (e.g., role) and contextual factors (e.g., leadership support) predicted profile membership. Results highlight meaningful variations in clinicians' suicide prevention attitudes and self-efficacy, identifying four distinct profiles. These findings highlight the need for further tailoring suicide prevention training and implementation strategy selection. Profiles characterized by neutral or low self-efficacy may benefit from implementation strategies that provide interactive assistance, while high confidence profiles may benefit from strategies targeting sustainment. Specific approaches to leverage these profiles for improved practice adoption are discussed. (PsycInfo Database Record (c) 2025 APA, all rights reserved).No embarg
Secondary accumulation of lyso-platelet activating factors in lysosomal storage diseases
Get PDFLysosomal storage diseases (LSDs) are a group of inherited disorders caused by defects in genes that encode lysosomal enzymes, transmembrane proteins, or transport proteins. These defects typically lead to the accumulation of undegraded substrates or obstructed substances in lysosomes, serving as primary storage materials. However, in certain LSDs, secondary storage products-such as glycosphingolipids, phospholipids, and cholesterol-can also accumulate in tissues, independent of the primary enzyme or protein defect. In our recent studies, we identified lyso-platelet activating factors (lyso-PAFs) as secondary storage compounds in multiple LSDs, including Niemann-Pick disease type C1 (NPC1), GM2 activator deficiency, and GM1 gangliosidosis (GM1). Our ongoing work suggests that lyso-PAFs are also prevalent secondary storage products in Niemann-Pick disease type A (NPA), Sandhoff disease (SD), Tay-Sachs disease (TSD), and Krabbe disease (KD). We observed that elevated lyso-PAF levels were significantly correlated with the accumulation of primary storage substances in these disorders, indicating their potential as biomarkers for disease progression in these LSDs. Moreover, treatment with adeno-associated virus (AAV)-based gene therapies led to a reduction in lyso-PAF levels in the central nervous systems of TSD sheep and GM1 cats, further supporting their potential as biomarkers for therapeutic efficacy. While it remains unclear whether changes in lyso-PAFs contribute directly to disease pathology or simply reflect disease progression, further research into the enzymes involved in their synthesis and degradation is essential for uncovering their functional role in the cellular physiology and pathology of LSDs. Thus, further exploration of lyso-PAF in biofluids as prognostic and pharmacodynamic biomarkers is warranted.No embarg
Pre- and postsynaptic upregulation of FasII synergistically underlies neuropathological and behavioral phenotypes in a Drosophila model of myotonic dystrophy
Get PDFMyotonic dystrophy type 1 is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. Building on an established Drosophila model, we study the neuropathological features of the disease by expressing untranslated expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, we show that both pre- and postsynaptic expressions of CUG repeats participate in inducing phenotypes in synaptic boutons, arbors, transmission and larval locomotor activity. Furthermore, expression of CUG repeats in either motorneurons or body wall muscles induces upregulation of the cell adhesion molecule FasII (NCAM1 in mammals), and the knockdown of fasII is sufficient to rescue the phenotypes. Overexpression of FasII-C, a FasII isoform with no cytoplasmic domain, mimics the phenotypes of expanded CUG expression at the neuromuscular junction. In contrary, overexpression of FasII-A-PEST+ rescues the synaptic and behavioral defects. Our study provides insights into the fundamental mechanisms underlying synapse dysregulation in myotonic dystrophy type 1.No embarg
Thoughts About the Economics of Health Policies
No full textGiven nursing's interest in health policies, the authors present a discussion of costs associated with health policies. Three examples of these costs are adolescent use of vaping and e-cigarettes, international guidelines for hypertension diagnosis and treatment, and medical aid in dying.No embarg
Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults
No full textBACKGROUND: For critically ill adults undergoing tracheal intubation, observational studies suggest that the use of etomidate to induce anesthesia may increase the risk of death. Whether the use of ketamine rather than etomidate decreases the risk of death is uncertain.
METHODS: In a randomized trial conducted in 14 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults who were undergoing tracheal intubation to receive ketamine or etomidate for the induction of anesthesia. The primary outcome was in-hospital death from any cause by day 28. The secondary outcome was cardiovascular collapse during intubation, defined by the occurrence of a systolic blood pressure below 65 mm Hg, receipt of a new or increased dose of vasopressors, or cardiac arrest.
RESULTS: A total of 2365 patients underwent randomization and were included in the trial population; 1176 were assigned to the ketamine group and 1189 to the etomidate group. In-hospital death by day 28 occurred in 330 of 1173 patients (28.1%) in the ketamine group and in 345 of 1186 patients (29.1%) in the etomidate group (risk difference adjusted for trial site, -0.8 percentage points; 95% confidence interval [CI], -4.5 to 2.9; P = 0.65). Cardiovascular collapse during intubation occurred in 260 of 1176 patients (22.1%) in the ketamine group and in 202 of 1189 patients (17.0%) in the etomidate group (risk difference, 5.1 percentage points; 95% CI, 1.9 to 8.3). Prespecified safety outcomes were similar in the two groups.
CONCLUSIONS: Among critically ill adults undergoing tracheal intubation, the use of ketamine to induce anesthesia did not result in a significantly lower incidence of in-hospital death by day 28 than etomidate. (Funded by the Patient-Centered Outcomes Research Institute and others; RSI ClinicalTrials.gov number, NCT05277896.).The CAPES Center, P50 MH129701, provided funding for this study.No embarg
MOCHA Moving Forward: findings and lessons learned from implementing a community-based chronic disease prevention study with middle-aged black men
No full textObjectives: Black men in the U.S. experience disproportionately high rates of diabetes, cardiovascular disease, and prostate cancer - conditions closely linked to chronic stressors such as racial discrimination, economic precarity, and gender role strain. In response, the Men of Color Health Awareness (MOCHA) program was developed to promote the physical, mental, social, and spiritual well-being of men of color through culturally grounded discussions on structural violence, coping, and masculinity. This paper presents findings and key implementation lessons from the MOCHA Moving Forward study, which tested two intervention models: the original MOCHA program (MO) and MOCHA+, an enhanced version incorporating culturally adapted narrative dialogue.
Design: This community-academic feasibility trial randomized 210 men aged 35-70 into MO or MOCHA+ groups. Both participated in a 10-week program focused on stress and chronic disease prevention.
Results: Among participants who completed the program, statistically significant reductions were found in self-reported stress, BMI, anxiety, and depression in the MO group. When combining MO and MOCHA+ participants, reductions in stress and BMI remained significant. However, high attrition and loss to follow-up (final sample: 38) posed challenges to feasibility and scalability.
Conclusion: Despite retention challenges, findings suggest MOCHA is a promising intervention for stress and chronic disease risk reduction among men of color. The significant outcomes observed among completers highlight the program's potential and provide critical insights for improving the feasibility of future community-based interventions. Future research should explore scalable adaptations and further refine MOCHA's culturally tailored content to better support structurally marginalized populations.No embarg
Methods of Piloting an Abstraction Tool to Describe Family Engagement in the Hospital Setting: Retrospective Chart Review
Get PDFBackground: Family engagement in hospitals is crucial for improving outcomes and ensuring holistic, patient-centered care. However, there is limited understanding of how providers document family engagement in electronic medical records (EMR) and how factors such as race and health disparities influence engagement practices. The absence of standardized EMR templates complicates tracking engagement and assessing its impact on patient outcomes. Retrospective chart review (RCR) is an effective method for investigating clinical practice and how family engagement is documented, using both structured and unstructured data from patient records. Despite its potential, gaps remain in the literature regarding distinctions between the prepilot and pilot phases in RCR studies.
Objective: This article describes the prepiloting and piloting stages in the development of an abstraction tool for an RCR study, highlighting how these phases refined the tool for extracting family engagement data from the EMRs.
Methods: A cohort of 2032 medical records was selected using the Research Patient Database Registry and EMRs. Initially, a draft tool was tested during the prepilot phase to assess its stability. To optimize diversity, the sample was then stratified by race. The modified tool was subsequently piloted on a subset of the sample.
Results: The prepilot phase tested the tool on 9 records. In the pilot phase, the tool was applied to 39 records, representing approximately 10% of the sample. After the prepiloting and piloting phases, 293 of the 405 patient records were deemed eligible for inclusion. More than three-quarters of patients had documentation of presence and communication; whereas, only about one-third had documentation of shared decision-making involving families.
Conclusions: The prepilot phase helped standardize the abstraction tool, align it with the EMRs, and address potential biases. The pilot phase provided insights into data availability and highlighted areas for refinement before finalizing the tool for the remaining records. Together, these phases ensured the tool's effectiveness for use in large-scale RCR studies.No embarg