Citations

Abstract Context Pharmacological options for the treatment of early severe childhood obesity are limited. Objective This retrospective case series evaluates the effect of topiramate on weight and cardiometabolic parameters in young children with severe obesity, including those with hypothalamic etiologies. Methods This is a retrospective case series including 14 children with severe obesity, who were treated with topiramate prior to age 12 years. Anthropometric and metabolic data were analyzed. Results The median age at initiation of topiramate treatment was 10.1 years (range, 7.9-11.2 years) and 64% were boys. At baseline, the median body mass index (BMI) was 149% of the 95th percentile (range, 136%-200%). The median treatment duration was 14 months (interquartile range, 9.5-24 months), with a maximum tolerated dose of 75 mg (range, 50-150 mg). There was a median decrease in BMI% of the 95th percentile of 8% (95% CI, −15 to −1.02; P = .042), and a reduction in BMI z score by 0.37 (95% CI, −0.66 to −0.05; P = .028). The most notable response was in a child with hypothalamic obesity who experienced a 35-point reduction in BMI% of the 95th percentile over 24 months. While 11 of 14 children showed reduction in BMI, 3 had no change or increase in their BMI. No significant changes were observed in cardiometabolic markers or linear growth. Conclusion Topiramate monotherapy resulted in significant BMI reductions in young children with severe obesity, including those with hypothalamic obesity. Further prospective randomized controlled trials are warranted to assess its long-term efficacy for obesity management in young children.

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2 < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.

ABSTRACT Pulmonary hypertension due to interstitial lung disease (PH‐ILD) is associated with high morbidity and mortality. Real‐world patients initiating inhaled treprostinil are not well‐characterized. This retrospective cohort study aimed to evaluate healthcare resource utilization in patients with PH‐ILD who initiated treatment with inhaled treprostinil vs patients who remained untreated. Adult patients diagnosed with PH‐ILD were indexed on initiation of inhaled treprostinil and patients who remained untreated were indexed on first observed PH diagnosis (31 March 2021–30 September 2024). Patients were excluded if they were ever treated with any pulmonary arterial hypertension therapy. Inhaled treprostinil patients were matched to up to four untreated patients. All‐cause per‐patient per‐month (PPPM) hospitalizations and ICU‐related hospitalizations were the primary outcomes of interest. 294 patients treated with inhaled treprostinil and 736 untreated patients were identified. Mean all‐cause PPPM hospitalizations remained unchanged in the pre‐index vs post‐index periods in the inhaled treprostinil cohort (0.11 vs 0.12; p = 0.42) but significantly increased in untreated patients (0.12 vs 0.23; p < 0.01). ICU utilization also remained unchanged in the pre‐index vs post‐index periods for the inhaled treprostinil cohort (0.06 vs 0.07; p = 0.11) compared to the untreated cohort (0.06 vs 0.13; p < 0.01). Untreated patients had significantly higher post‐index PPPM hospitalizations ( p < 0.01) and ICU utilization ( p < 0.01) compared to inhaled treprostinil patients. Patients who initiated inhaled treprostinil had a 30% decreased risk of hospitalization compared to untreated patients (relative risk: 0.70; 95% CI: 0.59–0.83; p < 0.01). Among real‐world patients with PH‐ILD, treatment with inhaled treprostinil is associated with fewer all‐cause hospitalizations and ICU‐related hospitalizations compared to untreated patients with PH‐ILD.

Purpose: Fenestrated stent-grafts with proximal bare-metal fixation stent (BMFS) may provide better rotational movement to facilitate vessel catheterization, but novel designs with covered fixation stents (CFSs) have been increasingly utilized with lower profile fabric. This study aimed to evaluate procedural metrics and outcomes of fenestrated endovascular repair (FEVAR) using BMFS and CFS devices. Methods: Clinical data of 502 consecutive patients enrolled in a prospective, non-randomized investigational device exemption (IDE) study were reviewed. Patients with 4-vessel fenestrated stent-grafts with BMFS or CFS for treatment of complex abdominal aortic aneurysms (CAAAs) and Extent IV thoracoabdominal aortic aneurysms (TAAAs) were included. Patients with Extent I-III TAAAs and stent-grafts designed with <4 fenestrations or scallops were excluded. Endpoints were technical success, radiation exposure, major adverse events (MAEs), patient survival, freedom from secondary interventions, and target artery instability (TAI). Results: There were 147 patients (29%; 85% male, median 75 years old) treated by FEVAR using 4-vessel fenestrated stent-grafts with BMFS in 79 patients or CFS in 68 patients. Patients treated with BMFS designs had significantly (p<0.05) higher prevalence of cigarette smoking and peripheral artery disease and less often had Extent IV TAAAs. Use of BMFS designs decreased from 88% (64/73) to 20% (15/74) after 2018 (p<0.001). Technical success was similar in patients treated with or without BMFS designs (99% vs 100%, p=0.47), but total operating time and cumulative air karma were significantly lower (p<0.05) in patients with CFS designs. Overall 30-day mortality was 1%, with no difference in mortality and MAEs among patients treated with or without BMFS (1% vs 1%, p=1.0 and 15% vs 12%, p=0.59), respectively. Patient survival at 1 and 3 years was 95%±2%, and 85%±4% for all patients with no difference between groups (p=0.51). Freedom from secondary interventions was 88%±3.6% for patients with BMFS and 86%±4.6% for those with CFS at 1 year (p=0.71), with also no difference at 3 years (p=0.55). Conclusion: FEVAR for CAAAs and Extent IV TAAAs was performed with high technical success, low mortality, and MAEs, independent of the use of BMFS. There is no difference in patient survival and freedom from secondary interventions in patients treated with or without BMFS. Clinical Impact One hundred forty-seven patients were treated with bare-metal fixation-stent (79) or covered fixation stents (68). Technical success was similar (p=.47). Overall 30-day mortality was 1%, with no difference in major adverse events (MAEs; p=.59). At 1- and 3-year, there was no difference in patient survival (p=.51), freedom from secondary intervention (p=.71). In conclusion, FEVAR for CAAAs and Extent IV TAAAs was performed with high technical success, low mortality and MAEs, independent of the use of bare-metal fixation stent.

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).