Harbor–UCLA Medical Center

Abstract Background Non-ischemic cardiomyopathy (NICM) represents a major cause of heart failure with limited tools for early risk stratification. Atrial fibrillation (AF) is a well-established contributor to cardiomyopathy but is often clinically silent in its early stages. The atrial fibrillation polygenic risk score (AF-PRS) reflects genetic susceptibility to AF and may identify individuals at risk for AF-related cardiomyopathy. We hypothesized that higher AF-PRS is associated with greater risk of NICM. Methods This was a retrospective cohort study of 16,801 individuals of European ancestry from the Sanford Biobank and Imagenetics program with genetic sequencing and longitudinal electronic health record data. AF-PRS was calculated using 315 genome-wide significant single-nucleotide polymorphisms with standard quality control. NICM was defined by International Classification of Diseases, 10th Revision, Clinical Modification codes, excluding ischemic etiologies. Cox regression models evaluated the association between AF-PRS and incident NICM, adjusting for age, sex, smoking status, body mass index (BMI), hypertension, and diabetes. AF-PRS was analyzed both as a quasi-continuous variable (15% quartile increments) and dichotomized at the 85th percentile. Sensitivity analyses assessed associations with all-cause cardiomyopathy and ischemic cardiomyopathy. Survival analysis was used to model time-to-event outcomes. Results Among all participants, 418 (2.5%) had NICM. 99% were Caucasian. NICM cases were older and more often male (both p<0.001) than those without a diagnosis. After multivariable adjustment for sex, smoking status, BMI, and hypertension, a linear AF-PRS (15% increments) was specifically predictive of increased hazard risk of NICM (HR = 1.09 [1.03, 1.15], p < 0.001). Conclusion These findings complement recent evidence of bidirectional genetic relationships between cardiomyopathy and AF, supporting comprehensive genetic risk assessment in cardiovascular disease prevention. Clinical implementation requires validation in diverse populations and prospective evaluation. Future research should investigate the mechanistic pathways linking AF-associated genetic variants to cardiomyopathy development and evaluate whether AF-PRS-guided screening improves clinical outcomes. Visual abstract: Summary of study design, exposure, outcome, key findings, and clinical implications. This graphical abstract provides a comprehensive overview of the study investigating the association between atrial fibrillation polygenic risk score (AF-PRS) and non-ischemic cardiomyopathy (NICM). Abbreviations: AF, atrial fibrillation; AF-PRS, atrial fibrillation polygenic risk score; CI, confidence interval; HR, hazard ratio; ICD-10, International Classification of Diseases, 10th Revision; ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; PPV, positive predictive value; PRS, polygenic risk score; SNP, single nucleotide polymorphism. Created in BioRender. https://BioRender.com/ k3t1w68

Introduction: Withdrawal of life-sustaining treatment (WLST) is the most common mode of death in pediatric intensive care units (PICUs), yet data on how WLST is operationalized remain limited. Prior studies have not adequately examined variability in WLST medical management practices for children across institutions or over time. We hypothesized that substantial institutional and temporal variation exists in WLST practices related to analgesic and sedative use, vasoactive medication discontinuation, neuromuscular blockade, and post-extubation respiratory support. Methods: We performed a secondary analysis of the multicenter DONATE study (2009-2021), which included 905 pediatric patients who died following WLST defined as terminal extubation. Data were abstracted from 9 U.S. tertiary-care PICUs and included medications and interventions administered before and after extubation. Site-level differences were assessed using chi-square or Fisher’s exact tests. Logistic regression was used to assess temporal trends. Results: Of 905 patients, 75.1% died within 1 hour of WLST. Opioids were administered in 79.7% (site range 68-89%, p< 0.001; no significant temporal trend); benzodiazepines in 56.0% (site range 41-66%, p< 0.001; decrease over time OR 0.95 per year, 95% CI 0.90-0.99, p=0.04); dexmedetomidine in 15.5% (site range 4-21%, p=0.002; increase over time OR 1.16 per year, 95% CI 1.05-1.27, p=0.004). Vasoactive infusions were discontinued in 88.1% of cases (site range 59-100%, p< 0.001; increase over time OR 1.15 per year, 95% CI 1.04-1.26, p=0.007). Neuromuscular blockade was used in 5.1% of patients (site range 0-13%, p< 0.001; increase over time OR 1.23 per year, 95% CI 1.08-1.40, p=0.002). Use of any post-extubation respiratory support was rare (5.5%) with no significant site or temporal variation. Conclusions: There is substantial institutional and temporal variability in WLST practices across US PICUs. These findings highlight a need for clearer guidance to reduce variability and support consistent, high-quality end-of-life care for critically ill children.

Candida albicans is a major human fungal pathogen that reproduces by mitotic growth of diploid cells but can also undergo a parasexual cycle. The latter involves an uncoordinated process of ploidy reduction via aberrant mitotic divisions following the fusion of opposite- or same-sex cells. The ability of parasex to recapitulate the genome plasticity of meiosis remains largely unclear. Here we induced parasexual crosses between genetically distinct strains and analysed the genotypic make-up of parasexual progeny following whole-genome sequencing or selective genotyping to determine the genomic landscape generated by the parasexual cycle. Our results show that C. albicans parasex leads to high levels of recombination and chromosome shuffling as observed in a conventional meiosis. Parasexual progeny also showed diversity in the pathogenesis-related phenotypes of filamentation, drug response and in vivo fitness that was associated with variation in inherited, recombinant genotypes. We propose that the parasexual cycle in non-meiotic eukaryotes can enable escape from a purely asexual mode of reproduction and confer the ability to rapidly adapt to new or changing host niches among commensal and pathogenic species.

This study aimed to evaluate the current literature on its use and derivation of clinically meaningful changes (CMC) in patient-reported outcome measures (PROMs) for evaluation of post-treatment outcomes after anterior cruciate ligament (ACL) reconstruction. A systematic search following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines was conducted using PubMed, Scopus and Web of Science databases from 2008 to 2024. Inclusion criteria included full-text articles in the English language regarding ACL reconstruction that used and described the derivation of CMC metrics in PROMs with a minimum 1-year follow-up. Studies were excluded if they were non-human research, narrative or systematic reviews, case studies, editorials, commentaries, or if CMCs were derived from previous studies. CMC terms included: Minimal Clinically Important Difference (MCID), Patient Acceptable Symptom State (PASS), Minimal Detectable Change (MDC), Substantial Clinical Benefit (SCB), Minimal Important Difference (MID) and Minimal Important Change (MIC). Twenty-two studies met the inclusion criteria with 4852 total patients with a mean age of 24.2 years. The MCID was calculated in 14 studies (63.6%). MCID was calculated using distribution-based methods in 11 studies (50.0%), anchor-based methods in one study (4.5%) and both methods in one study (4.5%). MDC was derived in three studies (13.6%), using distribution-based methods. PASS was derived in six studies (7.3%), SCB was derived in two studies (9.1%), MID was derived in one study (4.5%), and MIC was derived in one study (4.5%), all using anchor-based methods. There is inconsistency in the ACL literature regarding the use and derivation of CMC metrics for the assessment of PROMs. With increased use of PROMs in literature to develop Clinical Practice Guidelines and guide Medicare/Medicaid decisions, standardization of PROM interpretation is necessary. Clear definitions and consistency in the derivation of CMC metrics will help increase standardization in patient outcome assessments. Level IV.

This article provides a focused update to the clinical practice guideline on the treatment and management of patients with coronavirus disease 2019 (COVID-19), developed by the Infectious Diseases Society of America. The guideline panel presents a recommendation on the use of abatacept in hospitalized adults with severe or critical COVID-19. The recommendation is based on evidence derived from a systematic literature review and adheres to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

Multicancer detection (MCD) tests are an emerging innovation in cancer screening that use blood samples to detect multiple cancer types at once, potentially identifying malignancies earlier and with greater accessibility than traditional, site-specific screening methods. Several tests have demonstrated the ability to detect cancer signals and suggest tissue of origin, which may enhance screening for cancers with existing screening tests and fill critical gaps for cancers lacking effective screening modalities. However, MCD testing raises concerns about the potential for substantial harm, including false-positive test results leading to short-term emotional distress and wasteful and potentially risky testing, unwarranted reassurance when results are falsely negative, the identification of indolent cancers (overdiagnosis), and increased strain on health care resources. Unclear follow-up protocols and limited harms reporting further complicate their use. Equity issues persist, as clinical trials may lack diverse representation and potentially miss population-specific risks. To ensure that MCD tests provide a net benefit to patients and to minimize the burden on health systems, rigorous evaluation, transparent harms reporting, and the implementation of robust practices for follow-up and shared decision-making are essential. As these tests evolve and their use becomes more widespread, careful integration into existing screening practices will be key to maximizing benefit while minimizing unintended consequences.

BackgroundThe SHIELD Regional Collaborative (JAMA 2024, PMID: 38557703) was a quasi-experimental decolonization initiative that found a 27% reduction in infection-related hospitalizations among the 16 nursing homes that adopted universal decolonization— chlorhexidine bathing and nasal iodophor. We evaluated whether this intervention also reduced antibiotic use.MethodsThis SHIELD secondary analysis compared 16 participating nursing homes vs 45 non-participants in Orange County, CA to evaluate the effect of universal decolonization on antibiotic use in residents, defined as the number of days of antibiotic administration during the 7 days reported for each Minimum Data Set (MDS) assessment (admission, quarterly, discharge). We conducted a difference-in-differences analysis using generalized linear mixed logistic regression models to account for clustering within facility, and to assess the relative change in the odds of antibiotic use using an interaction term between participation status and time period.ResultsCompared with the baseline period, decolonization nursing homes had a 48.1% reduction (OR=0.519, 95% CI: 0.512-0.527) in antibiotic use in the intervention period compared to a 41.2% reduction in routine care nursing homes (OR=0.588, 95% CI: 0.577-0.599), resulting in an 11.7% greater reduction in the odds of antibiotic use (relative OR=0.883; 95% CI 0.854-0.912; p< 0.0001) in decolonization nursing homes after the intervention, adjusting for age, gender, race, ethnicity, insurance, and coexisting conditions. Predicted probabilities showed antibiotic use decreased from 6.9% to 3.7% in the decolonization group compared to a decline from 7.0% to 4.2% in the routine care group.ConclusionThese findings support universal decolonization as an effective strategy to reduce antibiotic use in nursing homes. In addition to improved health outcomes, this reduction in antibiotic use plus the previously shown reduction in infection-related hospitalizations supports universal decolonization as a cost-saving strategy for nursing homes.DisclosuresLoren G. Miller, MD MPH, Armata: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Paratek: Grant/Research Support Susan Huang, MD, MPH, Xttrium: Conducting studies in which participating nursing homes and hospitalized patients receive contributed antiseptic products|Xttrium Laboratories: Conducting studies in which participating nursing homes and hospitalized patients receive contributed antiseptic product