Faculty Bibliography

BACKGROUND/UNASSIGNED:Recent observational studies have suggested that early treatment (<12 hours from diagnosis) of intermediate risk pulmonary embolism (PE) with catheter-based therapies may reduce morbidity and mortality. However, the effect of early versus late mechanical thrombectomy on acute pulmonary hemodynamics and right ventricular mechanics is less well defined. METHODS/UNASSIGNED:Patients enrolled in SYMPHONY-PE were divided into one of 2 groups based on the time from baseline CT pulmonary angiography to mechanical thrombectomy: Early <12 hours versus late ≥12 hours. The primary safety end point was the rate of major adverse events within 48 hours, as adjudicated by an academic independent safety board. The primary efficacy end point was the core-lab assessed mean change in right ventricle-to-left ventricle ratio from baseline to 48 hours. RESULTS/UNASSIGNED:=0.431) between groups, and there were no mortalities. The differences in efficacy outcomes were greatest in higher-risk patients per the Composite Pulmonary Embolism Shock score. CONCLUSIONS/UNASSIGNED:Early mechanical thrombectomy was associated with larger reductions in right ventricle-to-left ventricle ratio and mean pulmonary artery pressure, with no significant differences in safety event rates compared with patients who underwent late thrombectomy. Randomized trials are needed to test these associations. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06062329.

PURPOSE/OBJECTIVE:To review history of Descemet Stripping Only (DSO) in Fuchs Endothelial Corneal Dystrophy (FECD), describe the results of a clinical trial of topical ripasudil after DSO (K-321-201 study), and discuss future directions. METHODS:A one-year, phase 2, randomized, placebo-controlled multicenter clinical trial of two doses of K-321 (ripasudil) administered for 12 weeks after DSO surgery in FECD was performed. The primary endpoint, central corneal endothelial cell density (ECD) at 12 weeks after surgery, was determined by an independent reading center that was masked to study group assignment. Duration of corneal edema, need for medical or surgical rescue therapy, corneal thickness, and central ECD throughout the entire study period were also examined. Adverse events and exploratory endpoints were collected. RESULTS:P=.0065). Corneal edema cleared in 17/21 (81.0%) of the QID group at 12 weeks, compared with 2/22 (9.1%) of the placebo group (P<.0001). Rescue was required in 2/21 (9.5%) subjects in the QID group and 6/22 (27.3%) subjects in the placebo group (P=.0092). Adverse events were mild and did not lead to discontinuation of treatment. CONCLUSIONS:Topical K-321 given QID improves DSO outcomes, as demonstrated by a higher ECD, more rapid resolution of corneal edema and reduced failure rate. The medication was well-tolerated.

BACKGROUND:CD19-directed chimeric antigen receptor T-cell (CAR T) therapy has significantly improved outcomes for patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) but is frequently complicated by immune effector cell-associated neurotoxicity syndrome (ICANS), a major cause of morbidity and mortality. Preclinical and early phase clinical studies suggest that interleukin-1 blockade with anakinra may mitigate ICANS without impairing CAR T efficacy. However, real-world data evaluating the efficacy and safety of prophylactic anakinra remain limited. OBJECTIVES/OBJECTIVE:We performed a retrospective analysis comparing CAR T toxicities and clinical outcomes among patients treated with prophylactic anakinra versus controls using inverse probability of treatment weighting (IPTW), hypothesizing that anakinra prophylaxis would be associated with decreased severe ICANS. STUDY DESIGN/METHODS:In 2023, our institution implemented a policy for anakinra prophylaxis for high-risk patients based on promising early phase data. We conducted a single-center retrospective cohort study of 176 adult patients with R/R B-NHL who received CD19 CAR T therapy between 2018 and 2025. The analysis was restricted to patients meeting institutional criteria for anakinra prophylaxis (age ≥65 years or receipt of a CD28 costimulatory domain CAR T product), excluding those with baseline ICE score <8. Patients treated with anakinra in the post-policy era were compared with patients treated prior to the implementation of the policy. Inverse probability of treatment weighting (IPTW) was used to balance baseline clinical and disease-related covariates between groups. RESULTS:After IPTW, patients receiving prophylactic anakinra had a higher incidence of any-grade ICANS compared with those who did not (40.0% vs 23.0%, p = 0.03), while rates of grade ≥3 ICANS were similar between groups (p = 0.62). In multivariate regression, anakinra prophylaxis was associated with increased odds of any-grade ICANS (aOR 3.22; 95% CI 1.39-7.46) but not grade ≥3 ICANS (aOR 1.84; 95% CI 0.61-5.5). Rates of all-grade CRS were comparable (p = 0.74); however, in multivariate regression, anakinra prophylaxis was associated with increased odds of grade ≥3 CRS (aOR 17.83; 95% CI 1.30-245.21), though the estimate was imprecise due to sparse events. Grade ≥3 infections were more common in the anakinra cohort (21.5% vs 7.3%; p = 0.01) by day 30 and by day 90 (27.1% vs 10.4%; p = 0.01). Grade ≥3 infections remained associated with use of anakinra in multivariate regression (day 30: aOR 7.08; 95% CI 1.90-26.30, p = 0.004) (day 90: (aOR 5.59; 95% CI 1.83-17.04; p = 0.003). No differences in response rates, event-free or overall survival were observed between groups. CONCLUSION/CONCLUSIONS:In this single-center historical comparison of high-risk patients receiving CD19 CAR T cells, prophylactic anakinra did not reduce severe ICANS and was associated with increased immune-mediated toxicities and infectious complications. Causal inference is limited by policy-driven treatment assignment, residual temporal confounding, and limited practical overlap. These findings suggest the need for caution in routine use of anakinra prophylaxis outside of clinical trials and underscore the importance of prospective studies to better define optimal toxicity mitigation strategies.

Cannabis policies vary from strict prohibition to commercialised legalisation and are rapidly evolving worldwide. Here, we reviewed evidence for associations between international cannabis policy changes from 2000-25 and cannabis use, cannabis use disorder, and other psychiatric disorders. Commercialised legal markets for non-medical use in Canada and the USA were associated with increased prevalence of cannabis use and cannabis use disorder in adults and increases in cannabis potency since legalisation. There was no consistent evidence for associations between policy change and the prevalence or incidence of psychotic disorders. Commercialised legalisation was associated with an increase in hospital admissions for psychosis, and for psychotic disorders comorbid with cannabis use disorder. Poorly regulated legal access to medical cannabis, in the absence of efficacy and safety data, could increase risk of harm. Policies that limit commercialisation, such as strictly regulated legalisation of medical or non-medical supply, were not as strongly associated with cannabis use or psychiatric disorders, but long-term evaluation is needed. There was little evidence that decriminalisation of non-medical cannabis in Europe, Africa, Oceania, and Asia was associated with cannabis use or psychiatric disorders.

PURPOSE/OBJECTIVE:Corneal cross-linking (CXL) induces both mechanical and geometrical changes in the cornea, which are typically overlooked in pre-operative planning. We developed and calibrated a patient-specific finite element model (FEM) to predict the topographic alterations resulting from CXL and applied it to three patients with keratoconus (KC) as a proof of concept. METHODS:To calibrate the model, we performed nanoindentation and ex vivo optical coherence elastography (OCE) inflation tests before and after CXL on five human donor corneas. Nanoindentation results tuned the visco-hyperelastic parameters, while ex vivo OCE axial strains were used for validation. Personalized corneal models were generated from the topographies of the three KC patients, with regional stiffness in the affected areas adjusted based on axial strain measured by in vivo pressure-modulated OCE. Simulated CXL outcomes were then compared to 6-month clinical results. RESULTS:CXL induces a 16-fold increase in the fiber-related mechanical parameters and reduces the viscoelasticity time constant by three. In vivo OCE measurements showed an average mechanical weakening of 57% in the KC regions. When compared to the clinical topography at the 6-month follow-up, the CXL-induced curvature changes predicted by the model were -1.5 D vs. -1.76 D, -1.65 D vs. -1.91 D, and -1.76 D vs. -1.57 D, for the three patients, respectively. CONCLUSION/CONCLUSIONS:By combining FEM with in vivo corneal mechanical characterization, patient-specific topographic changes can be predicted, which has the potential to improve the planning of CXL treatments.

Larry Young had a huge impact on the study of neuropeptides and social behavior. Here I give an autobiographical perspective on how Larry and his work influenced the field and my own career.

The Yazidi community endured an unprecedented genocide by the Islamic State (ISIS) in August 2014, resulting in mass killings, kinocide, abductions, ongoing disappearances, and sexual enslavement. The intense trauma led to high prevalence rates of posttraumatic stress disorder (PTSD), depression, anxiety, and profound sleep disturbances. This comprehensive article integrates epidemiological data, neurobiological mechanisms, and clinical case reports to elucidate sleep disorders among Yazidi survivors. We detail the historical context, transgenerational trauma, specific sleep-related pathologies (insomnia, nightmares, parasomnias, and disrupted circadian rhythms), neurobiological underpinnings, cultural factors, and evidence-based interventions (e.g., Narrative Exposure Therapy (NET); Cognitive Behavioral Therapy for Insomnia (CBT-I)). Furthermore, we discuss the establishment and role of the Institute for Psychotherapy and Psychotraumatology (IPP) at the University of Duhok, outline barriers to care, and propose future research directions and policy recommendations.

AIMS/OBJECTIVE:We aimed to develop a multistage schema to stratify diabetes risk using continuous plasma glucose (PG) values (fasting and 1 h) in combination with clinical variables. METHODS:In 962 Brazilian adults, we initially estimated the probability of developing diabetes with the Finnish Diabetes Risk Score (FINDRISC). We then stratified participants with a FINDRISC score of 9 or higher into three progressive high-risk stages based on their probability of developing diabetes. We evaluated the schemás ability to predict the incidence of diabetes using robust Poisson regression with a time offset, employing bootstrap resampling for internal validation. RESULTS:to scores produced little change. CONCLUSIONS:A staging schema based on scores derived from continuous FPG and 1 h PG values along with clinical variables, applied after a FINDRISC screening, offers a nuanced and practical approach to identifying individuals for diabetes prevention.

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.