Citations

Abstract Context Data on cognition in patients with primary aldosteronism (PA) are scarce. Mild autonomous cortisol secretion (MACS), defined based on post-dexamethasone cortisol >1.8 mcg/dL, is diagnosed in up to 30% of patients with PA. Objectives (1) Assess cognition in patients with PA vs referent subjects with hypertension and (2) determine differences in cognition between patients with PA and those with MACS. Methods A prospective, cross-sectional study, 2019-2023. Cognition was assessed by National Institute of Health Toolbox Cognition Battery and reported as T-scores corrected for age, sex, race, and education. Only subjects with hypertension were included. Results Cognitive assessment was performed in 52 patients with PA (including 11 patients with both PA and MACS, median age of 51.0 years, 30 (57.7%) women), 47 patients with MACS (median age of 57.0 years, 31 (66.0%) women), and 52 referent subjects (median age of 66.1 years, 30 (57.7%) women). When compared to referents, and after adjusting for age, smoking, systolic blood pressure, and alcohol use, patients with PA had lower total cognition (β = −5.7, P = .023), notably fluid cognition (β = −6.8, P = .017), including attention and executive function (β = −5.6, P = .012) and cognitive flexibility and executive function (β = −8.2, P = .006). When compared to patients with MACS, patients with PA had a higher processing speed (β = 9.0, P = .003). No differences in cognition were found between patients with PA with and without MACS. Conclusion Patients with PA demonstrated lower cognition compared with referents and processing speed compared with MACS. Future studies should characterize the impact of MACS on the cognition of patients with PA.

Abstract Introduction Combat casualty care requires standardized proficiency criteria to ensure readiness in austere environments, yet gaps persist in defining performance thresholds for critical trauma skills. The Combat Medical Skills Sustainment Consortium (CMSSC), a novel military-civilian collaboration, aimed to validate competency thresholds for 21 Department of Defense-identified trauma skills. Materials and Methods A prospective cohort study (2022-2025) enrolled 1,495 military and civilian personnel across five academic centers, stratified by experience (novice, intermediate, expert). Skills, including cricothyroidotomy, whole blood transfusion, and ultrasound-guided vascular access, were assessed using validated checklists in Role 2-congruent simulations. Statistical analysis compared checklist performance against participant experience with a priori checklist scores estimated at 40% (novices) and 90% (experts). Results Competency thresholds were established, ranging from 77% (mechanical ventilation) to 100% (handoff). Experts achieved 85%-98% proficiency across most skills, with novices at 34%-97%. A ceiling effect was observed for less complex skills consistent with the power law of practice. Conclusion The Combat Medical Skills Sustainment Consortium validated standardized assessment tools, with potential to address readiness gaps through military-civilian synergy. Findings support consortium-guided curriculum development and highlight the need for longitudinal skill decay studies. Impact This study sets a benchmark for trauma care skills assessment, facilitating rapid adoption across military and civilian settings.

Abstract Despite the reported benefits of testosterone replacement therapy (TRT), prior studies have shown that TRT is correlated with increased incidence of adverse outcomes after orthopedic procedures. There is a paucity of literature assessing the outcomes of patients on preoperative TRT undergoing distal radius open reduction and internal fixation (DR-ORIF). Our purpose was to evaluate rates of surgical and medical complications in patients on TRT undergoing DR-ORIF with a matched control cohort. The PearlDiver database was queried for patients who used TRT within 3 months prior to the index procedure. Patients were matched 1:4 with nonuser controls using propensity score matching. Matching was conducted based on age, Elixhauser Comorbidity Index, hypogonadism, osteoporosis, and other comorbidities. Complications were assessed at 90 days and 2 years. Statistical analyses were conducted using chi-square tests. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for each complication. Statistical significance was determined at a p-value of < 0.05. The matched group included 657 TRT users and 2,236 controls. There were significant differences in depression (control: 40.6% vs. TRT: 45.7%, p = 0.02) and rates of hypogonadism (control: 74.1% vs. TRT: 77.9%, p = 0.05) between the groups. No other statistically significant demographic or characteristic differences were noted. TRT use was not associated with increased surgical or medical complication rates at 90 days postoperatively. At 2 years, TRT use was associated with a greater incidence of revision (OR: 2.80, 95% CI: 1.34–5.85) and nonunion (OR: 2.76, 95% CI: 1.59–4.81). There were no other associations noted at 2 years. Preoperative TRT was associated with an increased risk of revision surgery and nonunion at 2 years postoperatively. No other significant associations in the risk of major or minor complications were observed. Level III

Abstract Cockayne Syndrome is an ultra-rare premature aging condition associated with UV sensitivity, neurocognitive decline, retinopathy, metronidazole-induced lethality, and sensorineural hearing loss. In 70% of affected patients, bi-allelic pathogenic variants in ERCC6 are identified. Although the role of ERCC6 in DNA damage repair has been studied, little is known about the mechanism for defective ERCC6 function in clinical findings, particularly hearing loss. To identify the mechanism of disease caused by pathogenic variants in ERCC6, we developed a zebrafish (Danio rerio) ercc6 loss of function model. We assessed survival after UV and metronidazole exposure, measured basal respiration rates, and evaluated mechanoelectrical transduction function and counts of lateral line hair cells. We found that UV exposure significantly reduces ercc6−/− larval viability. Metronidazole treatment results in complete lethality; wildtype controls show nearly complete survival. ercc6−/− embryos have significantly increased oxygen consumption, suggesting abnormal mitochondrial function. Phalloidin staining of lateral line hair cells with and without UV treatment shows no difference in hair cell counts per neuromast between treatment groups. Mechanoelectrical transduction function after UV exposure, measured by FM1–43 uptake, is reduced. Metronidazole lethality is reduced, oxygen consumption rates are restored, and mechanoelectrical transduction function is preserved by treatment with Mn(III)tetrakis(4-benzoic acid)porphyrin Chloride (MnTBAP), a superoxide dismutase mimetic. We propose that defective mitochondrial function and increased reactive oxygen species levels provide a mechanism for hair cell dysfunction in this model of Cockayne Syndrome. These results provide a foundation for further experiments to explore disease mechanisms and treatment modalities for this premature aging condition.

Abstract Context Evidence on the evolution of cardiometabolic comorbidities following surgical remission of hypercortisolism is scarce. Objective To determine the impact of surgical remission on cardiometabolic comorbidities in patients with endogenous hypercortisolism and to identify factors associated with cardiometabolic improvement. Methods Prospective single-center cohort study (2019-2025) of adults with Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS) with surgical remission of hypercortisolism. Outcomes included (1) changes in severity of hypertension, diabetes mellitus (DM), hyperlipidemia, and obesity between baseline, 3, and 12 months postremission and (2) factors associated with improvement in comorbidities. Results Among 357 patients (49% MACS, 36% pituitary CS, 10% adrenal CS, 5% ectopic CS; median age 53 years [interquartile range 42-62]; 81% women), 336 (94%) had hypertension, 241 (68%) had obesity, and 122 (35%) had DM. At a median of 12 months postsurgery, improvement in hypertension occurred in 70% (90/128) of patients with CS and 51% (60/117) of patients with MACS, DM in 90% (46/51) patients with CS and 37% (13/35) patients with MACS, and obesity in 79% (77/97) patients with CS and 20% (14/71) patients with MACS. In a multivariable analysis, higher baseline biochemical severity scores were associated with improvement in hypertension [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1-1.5), DM (OR 2.5, 95% CI 1.7-4.1), and obesity (OR 1.5, 95% CI 1.2-1.8) at a median of 12 months postremission of hypercortisolism. Conclusion Postsurgical improvement of cardiometabolic comorbidities was observed in both patients with CS and MACS. Higher baseline biochemical severity scores were associated with higher postremission improvement in comorbidities.

Background/Objective: The COVID-19 pandemic led to a widespread transition to online learning. Yet, it is unclear how this shift in learning format impacted school attendance in adolescents with chronic pain, a group that struggles with school absenteeism. This study compared school attendance and format (e.g., in-person, online) in patients with chronic pain attending an Intensive Interdisciplinary Pain Treatment Program (IIPT) before the pandemic to an age- and gender-matched sample of youth attending the program after the pandemic. Methods: Participants were 226 school aged adolescents (13–18 years; M age = 15.89, SD = 1.46) enrolled in an IIPT before and after the COVID-19 pandemic. Patients admitted before March 2020 (pre-pandemic group; n = 113) were compared to an age- and gender-matched group of patients who were admitted to the IIPT from November 2021 to November 2023 (post-pandemic group = 113). Upon admission to the program, participants completed validated measures of internalizing symptoms and functional disability. They also completed structured questions related to pain and school history. Results: Significantly more patients in the post-pandemic group were attending school through online and home-schooling options (p < 0.01). Youth who attended the IIPT after the pandemic missed fewer school days (p < 0.05) than those who attended before the pandemic. The groups did not differ in functional disability or internalizing symptoms. However, participants in the post-pandemic group who attended online school missed more school days (p < 0.01) and experienced greater functional disability (p < 0.05) than those who attended in person. Conclusions: The findings highlight how the COVID-19 pandemic may lead to sustained changes in the way adolescents with chronic pain attend school, with implications for increased functional disability and school dropout among this vulnerable population.

Abstract Objective Evidence on the duration of post-operative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. We sought to determine the duration of post-operative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism. Methods We conducted a single-center prospective cohort study, 2019-2025, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, body mass index (BMI), clinical, and biochemical hypercortisolism severity, subtype of hypercortisolism, pre-surgical hypercortisolism duration, glucocorticoid type, and nadir cortisol in relation to duration of AI were investigated. Results The 242 patients [41% MACS, 46% pituitary CS, 12% adrenal CS, 1% ectopic CS, median age 50 years (IQR: 40-60), 85% women] who developed postsurgical AI were followed for a median duration of 13.7 months (IQR 7.2-26.3). The median time to recovery of AI was shorter in MACS vs. overt CS (3.9 months (95% CI: 3.3-6.2) vs. 13.5 months (95% CI 11.3-18.3), P value &lt; .001). On multivariable analysis adjusting for age, sex, BMI, and glucocorticoid type, moderate to severe biochemical severity score (β = 11, P value &lt; .001) and moderate to severe clinical severity score (β=8.7, P &lt; .001), were associated with a longer duration of AI. Conclusions Baseline clinical and biochemical hypercortisolism severity scores may inform individualized counseling on post-operative AI duration in patients treated for CS and MACS.

Abstract Introduction: Elranatamab (Elra) is a bispecific antibody (BsAb) targeting BCMA that is approved for patients with triple class exposed relapsed refractory myeloma (RRMM) on the basis of the MagnetisMM-3 phase 2 trial. For BCMA naïve patients, an overall response rate (ORR) of 61.0% and median progression free survival (PFS) of 17.2m was observed with a median overall survival (OS) of 24.6m. However, efficacy and safety information in the real world is lacking. Methods: This was an international retrospective study of patients with RRMM treated with Elra monotherapy outside of clinical trials. Data was collected through the International Myeloma Foundation Immunotherapy Database from 7 countries (UK, USA, Canada, Greece, Spain, Czech Republic and Singapore). High-risk cytogenetic abnormalities (HRCA) were defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (range). PFS, OS were evaluated using the Kaplan-Meier method and reported with 95% confidence intervals. Results: 79 patients were included. Median age was 67 years (range: 41-95y) with 20% ≥75 years. Racial distribution was: 75% White, 16% Black/African American, 8% Asian/Pacific. 55% were ECOG performance status (PS) 1-2. Patients received a median of 5 prior lines (range 1-11), and 35% were BCMA exposed (9% CAR-T, 5% ADC, 7% BsAb, 8% BsAb plus CAR-T, 4% ADC plus BsAb). Of those with available data, 45% had HRCA,13% had extramedullary disease (EMD) and 32% had penta-drug refractory RRMM. Overall, 48% would not have been eligible for the MagnetisMM-3 trial. Median follow-up was 6.3m (range 0.5-35.0). ORR was 53% (PR 11%, VGPR 33%, CR 8%, sCR 1%) and 67% for BCMA naïve patients. Responses were significantly lower for BCMA exposed patients (ORR 31%) but did not differ by age (51% &lt;75yrs vs 60% ≥75yrs). On univariate analysis, prior BCMA exposure, platelets &lt;50, presence of HRCA and penta-refractoriness were significantly associated with a lower response rate. PFS for the whole cohort at 6 and 12m was 64% (95%CI, 54-77%) and 52% (40-67%); for BCMA naïve patients, it was 77% (65-90%) and 67% (54-84%), respectively. Within the whole cohort, PFS was shorter for: BCMA exposed (median 4.0m vs not reached (NR)), platelets &lt;50 (2.0 vs 21.7m), HRCA (7.2m vs NR), penta-refractory (4.3m vs NR). PFS did not differ significantly by EMD, PS, age, or creatinine clearance. OS for the whole cohort at 6 and12m was 74% (64-85%) and 58% (45-74%); for BCMA-naïve patients, it was 80% (43-85%) and 70% (57-87%), respectively. Within the whole cohort, OS was shorter for: BCMA exposed (median 10.3m vs NR), platelets &lt;50 (4.3m vs NR), HRCA (10.7m vs NR) and penta-refractory (10.3m vs NR). Univariate regression analysis demonstrated that prior BCMA exposure, platelets &lt;50 and penta-refractoriness were significantly associated with a worse PFS and OS, and HRCA predicted poorer survival CRS was observed in 41% of patients (grade(G)1: 35%, G2: 5%, ≥G3: 0%) with most occurring with the first step up dose (SUD): SUD1: 29%, SUD2: 15%, full dose: 4%. Tocilizumab was used in 20% and steroids in 3%. ICANS was observed in 4 cases (5%): G1: 2, G2: 1, G4: 1. Treatment was with steroids (n=3) and tocilizumab (n=2). G3-4 thrombocytopenia was observed in 19% and 14% required platelet transfusions. G3-4 neutropenia occurred in 25% with overall 31% requiring GCSF. Infections were reported in 33 (42%) patients with median time to infection of 41 days. A total of 94 infection episodes were observed over 581 personal months. There were 2 infection-related deaths reported (1 had IVIG, 1 did not). 64% had hypogammaglobulinemia (IgG &lt; 400mg/dl) and IVIG was given in 65% of patients. Conclusions: In this first international real world analysis, Elranatamab achieved a response rate of 67% and a 12m PFS of 67% in BCMA naïve patients, similar to the MagnetisMM-3 trial despite almost half not meeting trial eligibility. However, prior BCMA exposure, platelets &lt;50, high risk cytogenetics and penta refractory status were predictors of poorer outcomes. Acknowledgements: The International Myeloma Foundation, International Myeloma Working Group (IMWG)