Faculty Bibliography

BACKGROUND:Almost 75% of patients with relapsing multiple sclerosis (pwRMS) with suboptimal response to other disease-modifying therapies (DMTs) showed no evidence of disease activity (NEDA-3) when treated with ocrelizumab in a large single-arm multicentre trial over 2 years. We aimed to assess the 4-year effectiveness and safety of ocrelizumab in pwRMS who entered a 2-year extension trial. METHODS:PwRMS completing CASTING were eligible to rollover into LIBERTO if available in the country of residence. PwRMS received ocrelizumab every 24 weeks; the same frequency was used for clinical assessments. Primary endpoint was the proportion of patients who had NEDA-3 over 4 years. Safety was assessed by rate and nature of adverse events (AEs). RESULTS:A total of 439 pwRMS rolled over to LIBERTO, of which 68.1% completed the study; most patients discontinued from LIBERTO due to country-specific changes in reimbursement but most remained on ocrelizumab outside the trial. Over 4 years, 79.5% of patients showed no 24-week confirmed disability progression, 87.5% no relapses, and 90.0% no radiological activity. A total of 65.6% of patients (n = 290) showed NEDA-3, with the proportion of patients achieving NEDA-3 yearly remaining above 84.8%. Over 4 years, infections (72.9% of patients) and infusion-related reactions (44.2%) were the most reported AEs. Serious AEs were reported in 9.3% of patients. Five (1.1%) patients discontinued due to AEs. CONCLUSIONS:Findings suggest that switching to ocrelizumab is safe for patients with early RRMS and suboptimal response to previous DMTs, resulting in significant and durable control of disease activity. TRIAL REGISTRATION/BACKGROUND:LIBERTO (NCT03599245), extension study to CASTING (NCT02861014); first patient enrolled 12.07.2018; https://clinicaltrials.gov/study/NCT03599245. CHORDS (NCT02637856), ENSEMBLE (NCT03085810).

Therapeutic options for chronic kidney disease (CKD) have expanded substantially in recent years, creating new opportunities to reduce residual kidney and cardiovascular risk through combination therapy. Evidence from large, randomized trials and meta-analyses demonstrates that sodium-glucose co-transporter 2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and glucagon-like peptide-1 (GLP-1) receptor agonists provide independent and additive benefits, with emerging data showing that select combinations may also improve safety. A risk-based approach, anchored in albuminuria and supported by validated risk equations, can guide treatment intensity, support more timely initiation of multidrug regimens, and improve health system efficiency. Addressing implementation barriers, advancing single-pill combinations, and leveraging adaptive and combination therapy trials will be essential to translate these therapeutic advances into improved long-term outcomes for people with CKD.

Replica exchange (REX) is one of the most widely used enhanced sampling methodologies. However, its efficiency is often limited by the requirement for a large number of intermediate temperature replicas. Here, we present Generative Replica Exchange (GREX), an enhanced sampling approach that integrates deep generative models into the REX framework to eliminate the need for this temperature ladder. Drawing inspiration from reservoir replica exchange (res-REX), GREX utilizes trained normalizing flows to generate high-temperature configurations on demand and map them directly to the target distribution. To achieve this, we implement the potential energy as a constraint in GREX, eliminating the need for training data at the target temperature. This approach reduces production simulations to a single replica run at the target temperature while maintaining a Metropolis-filtered acceptance step for generated proposals. We validated GREX on benchmark systems of increasing complexity, highlighting its superior efficiency and practical applicability for molecular simulations. To further demonstrate its applicability to larger biomolecular systems, we applied GREX to bovine pancreatic trypsin inhibitor (BPTI), a 58-residue protein with slow conformational dynamics for which conventional REX and related methods face computational challenges.

Atrial fibrillation (AF) is the most common sustained arrhythmia, with a prevalence and incidence significantly higher in adults with chronic kidney disease (CKD) compared to the general population. This risk increases with reduced kidney function, affecting up to 25% of all CKD patients and 30% of those on receiving chronic dialysis. AF is associated with increased morbidity and mortality, including higher risks of stroke, heart failure, myocardial dysfunction and progression to kidney failure. The bidirectional relationship between AF and CKD is driven by a convergence of traditional risk factors-such as hypertension and diabetes-and CKD-specific abnormalities. Key pathophysiologic mechanisms include systemic inflammation, oxidative stress, autonomic dysfunction, and disordered mineral metabolism. These factors promote structural remodeling, atrial fibrosis, and electrical instability, creating a highly arrhythmogenic substrate. Treatment options for AF include anticoagulation, rate and rhythm control medications, other cardiovascular therapies (e.g. sodium glucose cotransporter 2 inhibitors[SGLT2i]) and procedures aimed at normalizing rhythm and reducing stroke risk. Patients with CKD are often undertreated with AF medications and procedures, in part due to lack of robust randomized clinical trial data on efficacy and safety, particularly with advanced CKD. This narrative review summarizes key literature on the epidemiology, risk factors, mechanisms and treatment of AF in adults with CKD, and highlights critical areas for future research.

BACKGROUND:Despite prevalent gender discrimination in medical education, its influence on personal and professional development, foundational competencies in medical training per the Association of American Medical Colleges (AAMC), remains unclear. This retrospective cross-sectional study assesses how experiences of gender discrimination in medical school influence personal and professional identity formation (PPIF) among males and females. METHODS:Deidentified student-level data were procured from the AAMC data warehouse for 37,610 MD students who matriculated in 2014-2015 and took the Graduation Questionnaire (GQ) between 2016-2020. Gender discrimination frequency was categorized as 'Never', 'Isolated', and 'Recurrent' from GQ responses to questions about denial of opportunities, offensive remarks, and lower evaluations due to gender. Students self-reported their sex as male, female or declined to answer. PPIF was assessed using two separate GQ metrics assessing student agreement on a 5-point Likert scale that their medical school fostered and nurtured their development as a person and a future physician, respectively, and dichotomized. RESULTS:Female students experienced higher rates of isolated (12.6%) and recurrent (20.1%) gender discrimination than males (4.3% isolated, 6.2% recurrent). Females reported slightly lower personal (71.2%) but similar professional development (92.2%) rates compared to males (73.4% personal, 91.2% professional). Both sexes experiencing gender discrimination had lower likelihoods of PPIF than their counterparts without these experiences. If recurrent discrimination occurred, the aRR (95%CI) of professional development was 0.89 (0.87-0.90) for females and 0.78 (0.74-0.81) for males, while for personal development, it was 0.69 (0.67-0.71) for females and 0.61 (0.58-0.66) for males. Compared to females, males showed sharper declines in professional development as discrimination frequency increased from never to isolated (aRR = 0.93, 95% CI [0.92-0.94], p < 0.001) and isolated to recurrent (aRR = 0.95, 95% CI [0.93-0.97], p < 0.001). CONCLUSIONS:Gender discrimination negatively influences PPIF for both female and male medical students. Efforts to combat discrimination in medical training and promote holistic student development should be considered. Future work is needed to understand the influence of gender discrimination on the comprehensive development of gender-diverse medical students.

National efforts promoting high-quality cleft care rely on accreditation by the American Cleft Palate-Craniofacial Association (ACPA), though accreditation does not account for regional disease burden. Using U.S. natality and global health datasets (2014-2021), cleft incidence, prevalence, and disability-adjusted life years (DALYs) were compared with trends in ACPA accreditation. While births and cleft incidence declined nationally, accreditation expanded substantially. Conversely, prevalence and DALYs rose regionally without corresponding increases in accredited centers. Several states demonstrated discordant trends between burden and access. These findings suggest misalignment between accredited cleft care availability and evolving geographic disease burden, underscoring the need for data-driven resource planning.

BACKGROUND/UNASSIGNED:The practice of living donor kidney transplantation has evolved through innovations in logistics, technology, and clinical practice. In the United States, Good Samaritan donation, a historical label exclusive to nondirected donors, now incorporates voucher-based models. METHODS/UNASSIGNED:To determine how voucher-based nondirected living kidney donation has influenced the volume and practice of Good Samaritan living kidney donation in the United States, we analyzed living donor kidney transplants from 2000 to 2024 using data from the National Kidney Registry (103 transplant centers) and the Scientific Registry of Transplant Recipients. Temporal trends were derived by linear regression. RESULTS/UNASSIGNED:We identified 4662 Good Samaritan living donor kidney transplants, defined as historical nondirected and novel voucher-based nondirected donations. Of 2131 Good Samaritan living donor kidney transplants facilitated by the National Kidney Registry, donors had a median age of 43 y, were predominantly of White race (93%), and were women (60%). Recipients had a median age of 52 y and were racially and ethnically diverse (63% White, 14% Black, and 10% Hispanic). Annual Good Samaritan donation counts in the United States increased from 17 in 2000 to 439 in 2024, corresponding to a growth rate of 14.5%. Voucher-based nondirected donations increased from 2 in 2015 to 314 in 2024, comprising 72% of all Good Samaritan donations in that year. CONCLUSIONS/UNASSIGNED:The advent of voucher-based nondirected donation correlated with growth in Good Samaritan donation volume. Given the prevalence of voucher-based donations, connecting local kidney paired donation practices to voucher-based nondirected donation may improve access to and participation in living kidney donation.

KEY POINTS/CONCLUSIONS:In this cohort study of 720,348 adults referred for kidney transplantation from 2014 to 2025, only 48% were evaluated and 19% were waitlisted. Progression from referral to evaluation, waitlisting and kidney transplantation was limited by individual, center-level, and geographic factors. Some centers evaluated and waitlisted patients at rates far below the national average, and low-volume centers had lower rates of transplantation. BACKGROUND:Kidney transplantation is a cost-effective, lifesaving treatment of kidney failure, compared with dialysis. Unfortunately, most patients with kidney failure never undergo transplantation. METHODS:Using Epic Cosmos electronic health record data on all patients referred for kidney transplantation from 2014 to 2025, we assessed the stage-specific progression and attrition in the process of evaluation, waitlisting, and kidney transplantation. Center-level and individual (socioeconomic, geographic, and insurance status) factors associated with access to evaluation, waitlisting, and kidney transplantation were characterized using modified Poisson regression. RESULTS:Among 720,348 referred candidates, the median age was 55 years (interquartile range [IQR], 42-64); 47% of patients were White, 52% were male, and 87% were English speaking. Eighty-five percent of patients lived in urban areas. Of the referred candidates, 48% initiated evaluation, 19% were waitlisted, and 10% ultimately underwent transplantation. Among the referred patients who initiated evaluation, the median (IQR) time to evaluation initiation was two (1-4) months after referral; among the patients who were waitlisted, the median (IQR) time to waitlisting was four (2-9) months after evaluation initiation. Patients who were never married (0.94; 95% confidence interval [CI], 0.93 to 0.94), had severe obesity (0.70; 95% CI, 0.69 to 0.72), or were from rural zip codes (relative risk, 0.98; 95% CI, 0.97 to 1.00) were less likely to initiate evaluation. Low-volume centers had lower relative rates of transplantation (0.92; 95% CI, 0.88 to 0.96). In centers with documentation for nonprogression to evaluation, reasons for removal included not meeting criteria/not a candidate (18%), patient decision (13%), unable to contact (12%), death (4%), and financial/insurance complications (7%). CONCLUSIONS:Our study shows substantial attrition before kidney transplant waitlisting.