Citations

ABSTRACT Background Valganciclovir is the preferred antiviral agent for cytomegalovirus (CMV) prophylaxis in solid organ transplant (SOT) recipients; however, limited data exist to guide optimal dosing in patients requiring intermittent hemodialysis (iHD). This study evaluated the safety and efficacy of our institution's current dosing strategy of valganciclovir 450 mg three times weekly. Methods In this single‐center, retrospective study, adult liver, heart, lung, and kidney transplant recipients from January 2014 to November 2024 were included. Patients requiring ≥ 3 iHD sessions posttransplant and receiving valganciclovir 450 mg three times weekly were compared with recipients with normal renal function receiving 900 mg once daily. The primary outcomes were the risk of neutropenia, leukopenia, and thrombocytopenia within 3.5 months posttransplant. Results A total of 116 patients were included in the iHD cohort and were matched 1:2 to 232 patients in the normal renal function cohort. Rates of leukopenia and neutropenia were comparable between cohorts. However, thrombocytopenia occurred significantly more frequently in the iHD cohort (45.2% vs. 26.7%; p = 0.002). No significant differences were observed in rates of CMV infection between groups. Conclusion Valganciclovir 450 mg three times weekly appears safe and effective for CMV prophylaxis in SOT recipients requiring iHD, though it may be associated with an increased risk of thrombocytopenia. image

Abstract Background At hospice enrollment, patients are asked preferences regarding antibiotic use. Limited evidence on how these medications impact survival makes it difficult for clinicians to offer clear guidance. To support decision-making and antimicrobial stewardship, we assessed the association between antibiotic use and survival in outpatient hospice patients. Methods The association between antibiotic use and survival was evaluated using a time-dependent Cox proportional hazards model, adjusted for age, sex, Charlson Comorbidity Index, and hospice-qualifying conditions (HQCs). The cohort included patients enrolled in a large health system’s outpatient hospice program between June 20, 2017, and January 1, 2023. Results Among 6169 patients with an HQC, 1233 received at least one antimicrobial prescription during the study period. The median time from hospice enrollment to first prescription was 16 days (IQR 3-83). Antimicrobial prescribing patterns varied by HQC category. In time-dependent Cox models, antibiotic use was associated with increased hazard of death (aHR 1.47; 95% confidence interval [CI], 1.37–1.57).Stratified analyses showed the strongest association with increased mortality in patients with cancer HQCs (aHR 1.67; 95% CI, 1.50–1.87) and a survival benefit in those with infectious HQCs (aHR 0.60; 95% CI, 0.40–0.89). Discussion Physicians, patients, and families often overestimate the benefits of antibiotics near the end of life. The observed increase in mortality shortly after antibiotic initiation suggests that symptoms prompting antibiotic use may reflect the dying process rather than treatable infection. Knowledge of the limited role of antibiotics in prolonging life in hospice settings may improve decision-making and enhance the quality of end-of-life care.

Robotic surgery offers advantages over traditional open, laparoscopic, and endoscopic approaches, including faster patient recovery and reduced surgeon fatigue. The da Vinci 5 (DV5), is the newest system in the most widely used family of surgical robots. This pilot study examined the usability of the DV5 compared with the da Vinci Xi (DV Xi) from the perspective of the surgical team. A consulting surgeon, trainees, Certified Surgical Assistants (CSAs), and Certified Surgical Technicians (CSTs) were recruited during colorectal surgery cases using the DV5 or DV Xi. Team members completed pre- and postoperative surveys assessing discomfort, workload, and usability. Objective postural data were collected from the consulting surgeon and trainee. Nine cases were evaluated (DV5 = 5). The DV5 improved neck posture for surgeons and trainees, with no workload differences for other team members. The DV5 significantly improved physical ergonomic usability for the surgeon at the console.

Ear, nose, and throat (ENT) surgeons often perform multiple daily procedures requiring sustained postures while wearing headlights or loupes, increasing the risk of work-related musculoskeletal disorders (WMSDs). This in situ case study aimed to (1) evaluate ENT surgeon workload and (2) introduce ergonomic interventions through workflow changes, education, and personal protective equipment. Three trained ergonomists observed the intraoperative workflow of three ENT surgeons at a tertiary academic hospital, identifying awkward postures. Surgeons received education on surgical microbreaks and OR-Stretch before trialing passive exoskeletons. Exoskeleton effectiveness was evaluated using interviews and surveys. Workflow interventions improved neck posture. One surgeon reported reduced body-part discomfort but increased subjective workload when using the exoskeleton, while interviews identified aesthetic concerns. This exploratory case study identified workflow issues and introduced ergonomic interventions. Although one surgeon reported reduced discomfort with an exoskeleton, larger studies are needed to establish quantitative trends.

Abstract BRCA1 -deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1–FANCM synthetic lethality in human BRCA1 -deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome-wide structural variation in BRCA1 -deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 -associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II-occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in BRCA1 -mutant breast cancer cells, linking FANCM-mediated genome protection to transcription–replication encounters. BRCA1 -altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome–transcriptome integration links newly emerged SVs to configuration-dependent local transcriptional changes. Together, these findings establish FANCM as a replication-stress safeguard coupling survival to restraint of structural genome evolution.

Background Studies have demonstrated neighborhood structural inequities are associated with cardiovascular outcomes among breast cancer survivors. We investigated the associations between bias in mortgage lending practices (contemporary redlining and racial lending bias) and cardiovascular outcomes in women with breast cancer. Methods Using the SEER (Surveillance, Epidemiology, and End Results)–Medicare database, we identified 51 007 Black and White women diagnosed with breast cancer between 2010 and 2014 with follow‐up through 2020. We used Home Mortgage Disclosure Act data to calculate census‐tract contemporary redlining index and racial lending bias index, and assessed indices continuously and categorically (low, moderate, or high). We used Cox proportional hazards regression to estimate multivariable‐adjusted, cause‐specific hazard ratios (HRs) for major adverse cardiovascular events, ischemic heart disease, heart failure, stroke, and cardiovascular death. Results In the overall population, a 10%‐unit increase in redlining was associated with increased risk of major adverse cardiovascular events (HR, 1.04 [95% CI, 1.02–1.06]). Among Black women, those in high redlining neighborhoods had an increased heart failure risk compared with those in low redlining neighborhoods (HR, 1.22 [95% CI, 1.05–1.41]). Similarly, White women in high redlining neighborhoods had an increased risk of ischemic heart disease (HR, 1.23 [95% CI, 1.15–1.30]) and stroke (HR, 1.09 [95% CI, 1.03–1.16]). Black women in high racial lending bias neighborhoods had reduced cardiovascular mortality risk compared with those in low racial lending bias neighborhoods (HR, 0.69 [95% CI, 0.54–0.90]). Conclusions We identified associations between contemporary redlining and cardiovascular outcomes among breast cancer survivors. High racial lending bias was associated with reduced cardiovascular mortality risk among Black women. Bias in mortgage lending practices may serve as a structural driver of cardiovascular disparities.

Abstract The 6th Edition of the World Health Organization Classification of Digestive System Tumours has introduced two new categories of gastric neuroendocrine tumors, reflecting recent data on subtypes that do not conform to the three established subtypes: type 1 (associated with autoimmune gastritis), type 2 (associated with Zollinger-Ellison Syndrome) and type 3 (sporadic). The new type 4 category is exceptionally rare and is caused by endogenous dysfunction of parietal cell proton pumps, potentially secondary to mutation of ATP4A. Type 5 gastric NETs are caused by chronic pharmacologic inhibition of the parietal cell proton pump, typically due to proton pump inhibitor use, and are increasingly common. Given the relatively low malignant potential of the new subtypes compared to sporadic (type 3) gastric NETs, it is important that clinicians and pathologists recognize these entities, limiting radical surgical resections when unnecessary.

ABSTRACT Commercial antimicrobial susceptibility testing (AST) systems for gram-negative bacteria provide operational advantages over reference broth microdilution (BMD) testing, but the results produced by commercial AST systems might not be as accurate as the reference method. Assessing and comparing the performance of AST systems can be informative for clinical microbiology practice. In total, 280 clinical isolates and 100 isolates from the U.S. Centers for Disease Control and Prevention Antimicrobial Resistance Isolate Bank, including Enterobacterales and Pseudomonas aeruginosa, were intended to be tested using disk diffusion (DD) and automated commercial AST systems, such as Selux AST System (Selux Diagnostics), MicroScan (Beckman Coulter), Phoenix (Becton, Dickinson and Company), and Vitek 2 (bioMérieux). These results were compared to BMD as the reference standard. In total, 372 isolates were assessed. For Enterobacterales, the greatest frequency of very major errors was identified with cefepime by Vitek 2 (29.0%) and ertapenem by DD (9.1%); essential agreement less than 90% was identified with the following combinations: aztreonam by MicroScan (86.4%), aztreonam by Vitek 2 (88.9%), cefepime by Selux (86.3%), cefepime by Vitek 2 (76.8%), ceftazidime by Vitek 2 (89.9%), and levofloxacin by MicroScan (83.4%). For P. aeruginosa , essential agreement less than 90% was identified with the following combinations: gentamicin by Selux (87.2%), tobramycin by Selux (86.6%), and ciprofloxacin by Phoenix (88.4%). Overall, antimicrobials that had low demonstrable bias across all automated commercial AST systems included ampicillin, amoxicillin-clavulanate, ceftazidime-avibactam, ertapenem, and trimethoprim-sulfamethoxazole. Comparing commercial testing systems head-to-head against a reference standard provides insight into the strengths and weaknesses of the performance of these test systems, and these insights can subsequently inform local decisions regarding further investigations and potential operational mitigation strategies. IMPORTANCE This study assessed and compared the performance of multiple commercial antimicrobial susceptibility testing (AST) systems and disk diffusion methods. The accuracy of determining minimum inhibitory concentrations or zone diameters of antimicrobials and the associated interpretive categories were studied for 372 isolates of Enterobacterales and Pseudomonas aeruginosa . Performance of the evaluated systems revealed that multiple antimicrobial-organism combinations were below the standards typically required by regulatory agencies and clinical laboratories. These deficiencies varied across the commercial platforms and disk diffusion methods, highlighting the importance of benchmarking studies that compare the performance using identical isolates. These identified performance weaknesses may warrant further study and/or the implementation of mitigation strategies in clinical laboratory operations to prevent the reporting of errant results.

Abstract Objective The validity of progression-free survival (PFS) as a surrogate for overall survival (OS) in the antibody-drug conjugate (ADCs) era remains uncertain. We evaluated the association between treatment effects on PFS and OS in randomized trials of ADCs for metastatic breast cancer (mBC) and explored the surrogate threshold effect (STE). Methods PubMed, Embase, Cochrane, and ClinicalTrials.gov were searched for published randomized controlled phase II–IV trials evaluating ADCs in mBC and reporting hazard ratios (HRs) for both PFS and OS. A meta-epidemiological approach was used. The primary metric was the ratio of hazard ratios (rHR = HR_PFS/ HR_OS), with rHR < 1 indicating a larger effect on PFS. Trial-level associations were assessed using weighted linear regression (R²) and Spearman’s correlation. Results Twenty-one trials (n = 21; 18 phase III) evaluating nine ADCs were included. The pooled rHR was 0.79 (95% CI, 0.73–0.86), indicating a larger relative effect on PFS than OS. Numerically, the largest discrepancies were observed in triple-negative disease (rHR 0.72) and trials allowing crossover (rHR 0.71). Concordant statistical significance between endpoints occurred in 76% of the trials, whereas 24% showed a significant PFS benefit without OS improvement. The trial-level association between PFS and OS was moderate (R² = 0.62; ρ = 0.67). Conclusion Treatment effects on PFS consistently exceeded those on OS, although effect directions were highly concordant between endpoints. These findings provide an exploratory framework to contextualize the relationship between PFS and OS in ADC trials, requiring further validation in diverse clinical settings.