Faculty Bibliography

Neurons undergo extensive metabolic reprogramming during differentiation; this reprogramming leads to specific changes in the kinetics and concentrations of metabolites. We developed an in-cell NMR-based method that monitors this metabolic transformation with subminute time resolution. Undifferentiated SH-SY5Y human neuronal precursor cells were encapsulated into alginate gel beads and differentiated inside the gel. Real time pulse chase (RTPC) in-cell NMR was used to measure relative steady state concentrations of glycolysis and TCA cycle metabolites and the kinetics of metabolite production and clearance in differentiated and undifferentiated cells. Neuronal differentiation slowed glycolysis, increased TCA cycle activity and glutamate production. Fructose 1,6 bisphosphate and glutathione were identified as major biomarkers of undifferentiated and differentiated cells, respectively. The results demonstrate that RTPC-NMR analysis of neuronal cells is an effective method for studying changes in metabolite profiles induced by stress and drug-induced stimuli.

BACKGROUND:Data on the differential impact of interventions on subsequent myocardial infarction (MI) type are limited. OBJECTIVES/OBJECTIVE:This post-hoc analysis was done to evaluate the 30-day rate of subsequent MI by type (ie, type 1 and 2) among patients enrolled in the MINT (Myocardial Ischemia and Transfusion; NCT02981407) trial. METHODS:Subdistribution HRs and cumulative incidences of subsequent MI types were computed using Fine-Gray subdistribution models that accounted for the competing risk of death and other MI types, if applicable. Effect modification of treatment strategy by index MI type was tested using log-binomial regression models. RESULTS:Among 3,504 MINT trial patients, 275 (7.8%) had a 30-day subsequent MI, of which 118 (43%) were type 2 MI, 79 (28%) were uncertain MI type, 40 (15%) were type 4 MI, and 38 (14%) were type 1 MI. The rate of subsequent type 2 MI in patients randomized to the restrictive vs liberal transfusion was 3.5% (n = 61) vs 3.2% (n = 57) (HR: 1.07; 95% CI: 0.74-1.53) as compared with a subsequent type 1 MI rate of 1.3% (n = 23) vs 0.9% (n = 15) (HR: 1.53; 95% CI: 0.80-2.94). CONCLUSIONS:Among patients with MI and anemia, subsequent MI occurred within 30 days in 7.8% of patients, with type 2 MI occurring 3 times more often than type 1 MI. A differential effect of the restrictive vs liberal transfusion strategy on the type of subsequent MI (eg, type 1 vs type 2) was not observed.

PURPOSE/OBJECTIVE:This study evaluates radiographic outcomes and reoperations in patients undergoing anterior vertebral body tethering (VBT) of the lumbar spine. METHODS:A retrospective review of an EOS database identified pediatric patients who underwent lumbar VBT. Demographic and surgical data were collected, as well as radiographic and clinical outcomes including complications, reoperations, and conversion to posterior spinal fusion (PSIF). Analyses included paired t-tests, Wilcoxon signed-rank tests and chi-square. RESULTS:Thirty-two patients with idiopathic scoliosis who underwent thoracolumbar VBT with 2-year follow-up were included. Mean age at surgery was 13.7 ± 1.8 years (mean follow-up 2.0 ± 0.2 years); median Sanders score was 3 (50% ≤ 3). Lumbar Cobb decreased from 48° ± 12 to 20° ± 10 postoperatively (p < 0.001) with correction loss to 29° ± 12 at 2 years (p < 0.001). Tethered Cobb decreased from 46° ± 8 to 13° ± 9 postoperatively (p < 0.001), with correction loss to 17° ± 12 at 2 years (p = 0.284). At 2 years, 31% had > 5° of correction loss and 84% had a tethered Cobb < 30°. Correction loss did not differ by Sanders stage (p = 0.92). Seven patients (23.3%) demonstrated > 5° of additional curve correction postoperatively. Four patients (12.5%) had unplanned reoperation and five others (15.6%) required PSIF: 28.1% total reoperation rate. CONCLUSIONS:Lumbar VBT provided substantial initial correction with maintenance of correction across the tethered levels at 2-year follow-up. While most patients maintained a tethered Cobb angle < 30° at 2 years, 28.1% of patients underwent reoperation (12.5% UPROR; 15.6% PSIF conversion). Longer follow-up in larger multicenter cohorts is required to more accurately define lumbar VBT durability and conversion-to-fusion risk. LEVEL OF EVIDENCE/METHODS:IV.

This multinational cone-beam computed tomography (CBCT) study evaluated the root canal morphology of mandibular first premolars (M1Ps) from 21 countries and compared how well the Ahmed and Vertucci classification systems represented these patterns. A total of bilateral mandibular first premolars from eligible CBCT scans were assessed using both systems, and the data were analyzed with a hierarchical probabilistic approach to account for population and imaging-related variation. Across the overall dataset, a simple single-canal configuration was the dominant pattern, and this remained the most common finding in all populations despite limited but structured variation in less frequent subclasses. The Ahmed system classified all observed configurations, whereas the Vertucci system left approximately 10.2% of cases without an equivalent category. In addition, Ahmed preserved more anatomical detail, while Vertucci compressed several distinct configurations into broader groups. Demographic and imaging-related factors had modest effects, with voxel size showing the clearest technical influence on the detection of more complex patterns. Overall, M1P morphology showed a stable global pattern with secondary heterogeneity, and the Ahmed system provided a more complete and informative representation for CBCT-based morphology assessment across diverse populations.

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:Apical aneurysms in hypertrophic cardiomyopathy (HCM) have been linked to sudden cardiac death (SCD) and a nidus for thromboembolism. Uncertainty remains regarding the level of risk and significance of aneurysm size. OBJECTIVES/OBJECTIVE:The objective of the study was to determine the rate of SCD events and prevalence of apical thrombus or embolic events by size (maximum transverse dimension). METHODS:Apical aneurysms were identified in 510 patients from 10 centers, followed a median of 4.1 years for SCD events (SCD, appropriate implantable cardioverter defibrillator therapy, and resuscitated SCD) or development of apical thrombus/thromboembolism. Relationship between size and SCD events was analyzed using multivariable Cox proportional hazard models. RESULTS:In 510 HCM patients: 19% had small aneurysms (<10 mm), 39% medium (10-19 mm), 39% large (20-39 mm), and 3% very large (≥40 mm). SCD event rate was 2.1%/year, with risk increasing with increasing aneurysm size: 0.2%/year in small, 2.3%/year in medium, 3.0%/year in large and 8.2%/year in very large (P < 0.001). On multivariable analysis, greater size was associated with SCD events, independent of other risk markers or European Society of Cardiology-SCD score. Either an embolic event (3.6% of patients) or apical thrombus (10% of patients) occurred in 13% of patients and was independently associated with greater aneurysm size, 3% in small to 25% in very large aneurysms (P < 0.001). CONCLUSIONS:In a large cohort of HCM patients with apical aneurysms, rates of SCD events were high, with continuous relationship between size and risk. Small aneurysms (<10 mm) were associated with low risk for SCD events (0.2%/year), whereas aneurysms ≥10 mm with high risk (>2%/year). Although embolic events were uncommon, increasing aneurysm size was associated with the prevalence of apical thrombi.

Alopecia areata (AA) is a common T-cell mediated autoimmune disorder, which leads to sudden, non-scarring hair loss. An association between hair pigmentation and AA pathogenesis has long been postulated. Recent epidemiological evidence supports this link, indicating that individuals with darker hair colours have a higher risk of AA, while those with lighter hair colours exhibit a lower risk. This study aimed to investigate whether a shared genetic basis between hair colour determination and AA risk underlies this observation. To explore this, we analysed data from our AA genome-wide association study (GWAS) of 16 310 Caucasians from the US and Central Europe and a recently published GWAS of hair colour that involved 343 234 UK Biobank participants. Genetic correlations between the two traits were investigated using both polygenic risk score and linkage disequilibrium score regression (LDSC) analyses. No evidence was found for a strong, broadly shared genetic component for hair colour and AA. However, a suggestive weak inverse association with genetically predicted blond hair and AA risk was observed. Given the modest sample size of the AA-GWAS (~4100 cases), these findings are likely underpowered and should be interpreted as exploratory and hypothesis-generating, warranting replication in larger, independent cohorts.

BACKGROUND:Cardiac dysfunction is more common in people with HIV (PWH) than those without HIV (PWoH), with mitochondrial dysfunction implicated in pathogenesis. We investigated whether variations in mitochondrial DNA (mtDNA) and certain dideoxynucleoside analogs (D-drugs) relate to left ventricular diastolic dysfunction (LVDD) in PWH. METHODS:We included individuals with echocardiograms from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. LVDD was defined using characterizing heart function on antiretroviral therapy criteria. mtDNA haplogroups were inferred using HaploGrep. Separate exploratory multivariable logistic regressions examined associations between LVDD and African (L0L1, L2, L3, or "other") or European haplogroups (UK, H, JT, or "other"), D-drugs, and their interactions. No adjustments were made for multiple comparisons. RESULTS:Among 842 men (455 PWH and 387 PWoH) and 898 women (620 PWH and 278 PWoH), LVDD prevalence was 29% in women and 24% in men. Among non-Hispanic White men with HIV, European haplogroup H was associated with lower odds of LVDD (odds ratio [OR], 0.50; 95% CI, 0.26-0.93), while haplogroup clade JT was associated with increased odds (OR, 2.09; 95% CI, 1.00-4.36). In men with HIV, D-drug exposure was associated with increased odds of LVDD (OR, 1.94; 95% CI, 1.21-3.13). No significant associations were observed between haplogroups and LVDD in women. HIV serostatus modified the association of haplogroup L2 (pinteraction = 0.036) and L3 (pinteraction = 0.045) with LVDD in women. CONCLUSIONS:Mitochondrial genetic variation and D-drug use were associated with altered LVDD risk in men with HIV, highlighting potential biological mechanisms that may be targeted for surveillance or therapeutic strategies.