Faculty Bibliography

In presynaptic nerve terminals, the endocytic apparatus rapidly restores synaptic vesicles after neurotransmitter release. Many endocytic proteins localize to the periactive zone, a loosely defined area adjacent to active zones. A prevailing model posits that recruitment of these endocytic proteins to the periactive zone is activity-dependent. We show that periactive zone targeting of endocytic proteins is largely independent of active zone machinery and synaptic activity. At mouse hippocampal synapses and Drosophila neuromuscular junctions, pharmacological or genetic silencing resulted in unchanged or increased levels of endocytic proteins including Dynamin, Amphiphysin, Nervous Wreck, Endophilin A, Dap160/Intersectin, PIPK1γ, and AP-180. Similarly, disruption of active zone assembly via genetic ablation of active zone scaffolds at each synapse did not impair the localization of endocytic proteins. Overall, our work indicates that endocytic proteins are constitutively deployed to the periactive zone and supports the existence of independent assembly pathways for active zones and periactive zones.

STUDY OBJECTIVES/OBJECTIVE:Clinical demands in the emergency department (ED) may contribute to decision and attention fatigue as clinician time-on-shift increases, impacting patient care. Emergency department pharmacists review orders and intervene to correct problems related to safety and appropriateness. This study's objective was to evaluate and characterize the rate of pharmacist interventions on ED medication orders. We hypothesized that pharmacist interventions would increase with clinician time-on-shift. METHODS:We performed a retrospective study of 2 EDs within a single health system between January 2022 and November 2023. Medication and pharmacy intervention details were extracted and linked to clinician schedules, pharmacist schedules, and ED crowding scores. Mixed-effects logistic regression modeling identified factors associated with pharmacist interventions. RESULTS:Pharmacists intervened on 9,054 (1.5%) of 622,171 medication orders placed by 308 clinicians. Pharmacy intervention rate increased with clinician time-on-shift (odds ratio 1.04 for each hour; 95% confidence interval 1.03 to 1.05), with meaningful variation in this effect between individual clinicians. Stratified by clinician type (attendings, residents, or physician assistants) and shift timing (overnight versus daytime shifts), the association between time-on-shift and pharmacy intervention rate remained positive. Stratified by site (A versus B), the association was positive at site A but not at site B. CONCLUSION/CONCLUSIONS:The likelihood of orders requiring pharmacist interventions increased as ED clinicians' time-on-shift increased. This association was consistently observed across differing clinician types and shift timing, but variable across the 2 sites of the study. Clinical staffing models and quality of care could be improved by addressing stressors and fatigue accumulation informed by this analytical model.

[This corrects the article DOI: 10.1016/j.waojou.2021.100613.].

Much has been elucidated about the neurobiological effects of early childhood trauma and its transgenerational transmission, although its integration into psychodynamic therapy has been challenging. Here we focus on a common area of interest to both areas-emotion and cognition rooted in past trauma experiences and how these experiences produce maladaptive behaviors transmitted to the next generation through parenting behaviors. We explore two mammalian research paradigms of early-life trauma explicitly within attachment, and transmission of transgenerational pathology through the caregiver to the offspring. We suggest that understanding the neurobiology through this mammalian nonhuman research can provide, in part, an understanding for the complex psychodynamic thought processes seen in adulthood, particularly as the mother begins to raise her own child. Specifically, while cognition and complex conscious and unconscious thoughts are characteristic of the human condition following early-life trauma, the mother-infant attachment system is a phylogenetically preserved system with some basic characteristics seen across species. We outline how embracing both the cognition and preserved trauma neural programing within attachment may provide some insight into cases, especially for the parent-child social interactions well documented to program the brain. Using mother-infant attachment, we suggest there is an area of convergence between clinical psychodynamic focus and basic research in brain function and mechanisms. Focusing on this convergence may provide a unique viewpoint to psychodynamics to supplement diagnosis and treatment.

Opportunistic screening leverages existing imaging examinations performed for unrelated routine clinical indications to systematically extract quantitative biomarkers. Artificial intelligence tools have made deployment at scale increasingly feasible. However, the pathway from a validated algorithm to a functioning clinical program remains poorly defined, and prospective implementation at scale is uncommon. Successful deployment requires coordinated engagement from radiologists, information technology and operational teams, and clinical care teams, each facing distinct decisions that determine whether a program functions reliably and delivers patient benefit. This article presents a practical framework for opportunistic screening implementation organized around these three stakeholder groups. We apply this framework to opportunistic CT osteoporosis screening, drawing on our experience developing such a program at a large academic medical center. The framework presented is intended to be broadly applicable across opportunistic screening applications as the field moves from algorithmic validation toward clinical translation.

BACKGROUND:Chronic kidney disease (CKD) is associated with cardiovascular disease (CVD). Exceptional parental longevity protects against CVD. We examined whether exceptional parental longevity modified the associations of kidney function and kidney aging with CVD in older adults. METHODS:We used data from LonGenity (2008-2023), a cohort of Ashkenazi Jewish adults aged 65-95, comparing the offspring of parents with exceptional longevity to the offspring of parents with usual survival. Exceptional longevity was defined as living beyond 95 years. Kidney function was estimated using glomerular filtration rate (eGFR); CKD was defined as eGFR < 60 mL/min/1.73m2. Kidney aging was assessed using kidney age gap-the difference between proteomic kidney age and chronological age. Logistic and Cox regression tested associations between eGFR and kidney aging with prevalent and incident CVD, respectively. Effect modification was tested using interaction terms and stratified analyses. RESULTS:Among 1180 participants (mean age 76 ± 7 years), 23% had CKD; median kidney age gap was -0.04 years (IQR: -0.67, 0.66); 15% had baseline CVD. eGFR and kidney aging were associated with prevalent CVD, but not incident CVD. Exceptional parental longevity did not modify the association of eGFR with prevalent or incident CVD. However, it did modify the association of kidney age gap with incident, but not prevalent, CVD. In the offspring of parents with exceptional longevity, higher kidney age gap was associated with increased incident CVD hazard (HR: 1.90; 95% CI: 1.23, 2.94), but not in the offspring of parents with usual survival (HR: 0.79 95% CI: 0.59, 1.05). CONCLUSIONS:Kidney age gap may reflect early CVD risk in biologically resilient populations, thus warranting prospective studies.

Poly(A) tails are present on most cellular and viral mRNAs, providing a platform for poly(A)-binding proteins that stimulate translation and regulate the deadenylation and stability of transcripts in the cytoplasm. Here we leverage nanopore direct RNA sequencing to analyse the distribution of poly(A) tail lengths on cellular and viral mRNAs across Herpesviridae and other DNA and RNA virus infections. We find that herpesvirus mRNA poly(A) tails are consistently longer than those on cellular and other viral transcripts, presenting a previously unrecognized yet widespread mechanism to potentially advantage herpesviral gene expression. This contrasts with the templated poly(A) tails on coronavirus RNAs and those on cytoplasmically transcribed poxviral mRNAs, which are more similar in length to those on host mRNAs. Herpesviral noncoding RNAs display differential poly(A) tailing patterns while individual herpesviral mRNAs also show variation in the extent to which their poly(A) tail lengths change during the virus lifecycle, suggestive of additional uncharacterised layers of poly(A) tail length regulation. Importantly, while we detect non-adenosine nucleotides within herpesviral poly(A) tails, which are known to oppose deadenylase activity, this "mixed tailing" is not at sufficient frequency to explain the widespread extended tails of herpesvirus mRNAs.

BACKGROUND:Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children. Long-term topical management is often limited by safety concerns, tolerability issues, and caregiver hesitancy. Topical janus kinase (JAK) inhibitors have emerged as targeted nonsteroidal therapies, with recent pediatric approval of ruxolitinib expanding treatment options. This systematic review synthesizes pediatric-only evidence on topical JAK inhibitors for AD, focusing on efficacy, safety, and treatment strategies for clinical practice. METHODS:A PRISMA-guided systematic review of PubMed, Embase, Web of Science, and ClinicalTrials.gov was conducted through November 2025. Eight studies met inclusion criteria, encompassing 541 pediatric patients treated with ruxolitinib or delgocitinib. RESULTS:Across randomized and extension studies, both agents produced rapid, clinically meaningful improvements in both disease severity and pruritus, with benefits observed within the first several weeks of treatment. Ruxolitinib showed consistent efficacy in patients with both limited and extensive disease involvement, while delgocitinib showed sustained disease control with continuous use, including in younger children and infants. Topical JAK inhibitors were generally well tolerated, with adverse event rates comparable to vehicle and few discontinuations. Application-site reactions were uncommon, and no treatment-related serious AEs were reported. CONCLUSIONS:Overall, available pediatric data supports topical JAK inhibitors as effective and well-tolerated nonsteroidal options for AD, providing rapid symptom relief and disease control that may help expand steroid-sparing treatment options for children.