Citations

Abstract Purpose To evaluate the association of long-term, continuous tirzepatide use with cardiometabolic risk parameters and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk in real-world practice. Methods This multicenter retrospective observational study included 1,028 adults with overweight or obesity who received weekly subcutaneous tirzepatide for at least 12 months within the Mayo Clinic Health System from June 2022 through May 2024. ASCVD risk analyses included 275 individuals with complete baseline and 12-month follow-up data. Outcomes were changes in cardiometabolic parameters, estimated 10-year ASCVD risk, and ASCVD risk category. Results At 12 months, median total body weight loss (TBWL) was 12.6%. Fasting glucose, HbA1c, triglycerides, and alanine aminotransferase decreased by 19.5%, 16.0%, 8.5%, and 10.6%, respectively, whereas HDL cholesterol increased by 11.3% (all P < .001). Mean 10-year ASCVD risk did not change significantly overall (mean relative change, −3.7%; P = .18), but changes differed by TBWL category (ANOVA, P < .001). ASCVD risk decreased among individuals achieving 10%–20% TBWL (−9.6%; P = .009) and >20% TBWL (−14.2%; P = .005), but not among those achieving <10% TBWL (+7.7%; P = .22). Low-risk prevalence increased from 38.3% to 46.4% (P < .001), with 11.7% transitioning from higher-risk categories to low risk. Main findings Continuous tirzepatide use for at least 12 months was associated with clinically meaningful improvements in cardiometabolic parameters. Reductions in estimated 10-year ASCVD risk were observed among individuals achieving at least 10% TBWL, supporting greater weight loss as an important marker of cardiovascular risk improvement.

Abstract The nuclear pore complex (NPC) and its building-block proteins, nucleoporins (NUP), play fundamental roles in maintaining cellular fitness by regulating nucleocytoplasmic transport, chromatin and transcriptional activity, and genome stability. These core biological processes are critical for cancer cells, and thus, tumor-driven co-option of NUP-regulated functions has emerged as an important mechanism contributing to the pathogenesis of multiple malignancies. This review discusses how NUP dysregulation mechanistically contributes to tumor initiation and progression and how these insights open opportunities for innovative anticancer therapies, including using clinical-grade molecular glues that induce selective NUP degradation and pharmacologically inhibiting NPC-regulated epigenomic/transcriptomic signaling and nucleocytoplasmic transport. Significance: Recent studies demonstrate that NUPs play fundamental roles in cancer pathogenesis by dysregulating key NPC functions and driving tumorigenesis and disease progression. NUPs and NPC-regulated mechanisms can be pharmacologically targeted, providing a strong rationale for developing much-needed innovative therapeutic strategies to combat cancer.

Background Staphylococcus aureus causes a multiplicity of human diseases acquired in community and healthcare settings alike around the globe. While most studies focus on coding changes to assess genome evolution and study genetic adaptation, interrogation of silent mutations in the form of synonymous codon usage bias is less well-studied. As such, understanding of patterns in codon bias at the gene and genome levels, and how codon bias impacts protein expression in S. aureus remains incomplete. Methods The codon bias of 2,565 protein encoding genes from NCTC 8325 was queried against all publicly available closed S. aureus genomes. Using public BioSample data, genomes were sorted by disease state, submitting institution, and collection site. Codon bias was assessed at the level of gene and genome using the codon adaptation index (CAI), calculated using 30S and 50S ribosomal genes. Gene set enrichment analysis was applied to determine associations between physiological functions, CAI gene scores, and interquartile ranges. CAI scores were also compared to an in vitro S. aureus proteomics database to correlate codon bias and protein expression. Results CAI scores varied within and between isolates at the gene and genome levels. Genes with ribosome-associated functions were most enriched among high CAI genes, and had low CAI interquartile ranges (IQR), suggesting selective pressure to maintain high expression of these genes across all S. aureus isolates. Genome sequences submitted by Aga Khan University Hospital, Nairobi, Kenya were most different from others. For the LAC USA 300 strain, CAI and protein expression were moderately positively correlated (cor = 0.534, p < 2.2e-16). Conclusions Codon bias in S. aureus was shown to vary between gene, and to be a source of genetic variation between isolates; CAI and in vitro protein expression were positively correlated.

Background Studies suggest that hypoperfusion from heart failure (HF) may contribute to cognitive decline. However, the relationship between the HF subtypes and cognition remains poorly described in real‐world populations. Methods We conducted a cross‐sectional study of patients aged ≥18 years seen at the Mayo Clinic in 2022 who underwent echocardiogram and cognitive assessment within 1 year. HF was classified per the 2022 American Heart Association as no HF, HF with preserved ejection fraction (EF), HF with mildly reduced EF, and HF with reduced EF. Cognitive impairment was categorized using the Montreal Cognitive Assessment score as normal (≥26), mild (18–25), and moderate to severe (<18). Linear regression assessed EF–Montreal Cognitive Assessment correlation and logistic regression the association between HF subtypes and cognitive dysfunction, adjusting for age, sex, race, and vascular risk factors. Results A total of 1592 patients met inclusion criteria (mean age, 75.7±13.8 years; 48.5% women). Lower EF was associated with worse cognitive performance (postadjustment β=0.033, P =0.013). Patients with HF with reduced EF and patients with HF with preserved EF had significantly lower Montreal Cognitive Assessment scores than those without HF (17.6±6.2 and 18.9±5.8 versus 19.9±6.0, P <0.001). The prevalence of moderate to severe cognitive impairment was highest in HF with reduced EF (43.3%), followed by HF with preserved EF (34.4%), no heart failure (28.6%), and HF with mildly reduced EF (23.4%) (adjusted trend P =0.032). Conclusions HF, independent of ejection fraction alone, is associated with cognitive impairment. Further studies should confirm these findings and evaluate the impact of interventions targeting EF and HF subtypes on cognitive outcomes.

Background Competition for urgent and emergent operating-room access is a significant challenge in many hospitals. Evidence-based benchmarks for early intervention are well established for emergencies like acute appendicitis or hip fracture. In contrast, laparoscopic cholecystectomy for acute cholecystitis or symptomatic cholelithiasis is often delayed. The purpose of this study was to evaluate the clinical and economic impact of delays in laparoscopic cholecystectomy across the US. Methods The Nationwide Readmissions Database was queried for patients aged ≥18 years admitted between 2021 and 2022 undergoing urgent or emergent laparoscopic cholecystectomy. Patients were stratified based on operative timing (<3 vs ≥ 3 days). The primary outcome was 30-day readmission. Secondary outcomes included VTE, SSI, and total cost. Propensity score matching (1:1) was performed using 46 covariates. Linear regression assessed the cost associated with each additional hospital day prior to surgery, with a subgroup analysis of safety-net hospitals. Results Among 136,893 patients, 24,496 (17.9%) experienced delayed laparoscopic cholecystectomy. After matching (n = 48,992), delays were associated with increased odds of readmission (9.5%; OR 1.22 [1.15-1.29], P < 0.001) and VTE (1.5%; OR 1.51 [1.30-1.77], P < 0.001). SSI (0.2%) was not significantly different. The mean total cost was $25,957 ± $21,609 for delayed patients vs $20,784 ± $20,027 for early surgery. Linear regression revealed an incremental cost of $1,695 per additional hospital day prior to surgery, rising to $2071 per day in safety-net hospitals ( P < 0.001). Discussion Delays in laparoscopic cholecystectomy have significant clinical and economic impacts, underscoring the urgent need for national benchmarks to standardize operative timing and reduce disparities for patients in safety-net hospitals.

Extracorporeal membrane oxygenation (ECMO) provides life support for severe respiratory and cardiac failure, including failure from severe infection such as sepsis and acute respiratory distress syndrome. Additionally, ECMO-acquired infections are frequent and associated with prolonged hospitalization, increased healthcare utilization, and higher mortality. This review summarizes current evidence regarding the epidemiology, pathophysiology, diagnosis, prevention, and management of infectious adverse events during ECMO. Future work should aim to refine ECMO-related infectious adverse event definitions, improve harmonized multicenter data collection, and to invest in high-quality, well-designed studies.

ABSTRACT BACKGROUND War refugees are prone to psychiatric ailments due to multiple psychosocial stressors. Afghan refugees remain underrepresented in psychiatric studies. Therefore, a study exploring factors contributing to their mental health disorders is essential to guide rehabilitation efforts worldwide. METHODS This descriptive cross-sectional study evaluates the demographics, psychosocial stressors, psychiatric illnesses, and psychotropic drug use among Afghan refugees visiting the Psychiatry Outpatient Department (OPD) in Islamabad, Pakistan. Convenience sampling was employed on a sample population (n) of 75 participants. Data was collected via a structured questionnaire and analyzed using SPSS v21.0. Qualitative and quantitative variables were analyzed statistically. RESULTS Nearly 64%(n=48) of the participants were female. About 46.7%(n=35) of participants were uneducated, and 53.3%(n=40) were unemployed. 86.7%(n=65) of participants were married, while 2.7%(n=2) were divorced. 91%(n=61) of the married and divorced participants had an arranged marriage, 46.3%(n=31) had 5-8 children, and 67.2%(n=45) had experienced physical and/or emotional abuse. 74.7%(n=56) of the total participants reported a loss in the family, while 77.3%(n=58) had experienced trauma. 62.7%(n=47) had depression and associated psychotropic use, e.g., SSRIs (42.7%), TCAs (16%), and Benzodiazepines (13.3%). Alarmingly, 37.3%(n=28) reported a previous suicide attempt. CONCLUSION This study explores the psychosocial stressors faced by Afghan refugees in Pakistan, including displacement, abuse, trauma, and family/income loss. It emphasizes the importance of evidence-based psychiatric care, rehabilitative interventions, and culturally sensitive care to counter psychiatric morbidities and underscores the need for future research to improve the mental health of refugees globally.