Citations

Abstract Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in cognitive delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS/NUS1 cis-prenyltransferase ( cis- PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation. We describe the first mouse model of this disease, Dhdds R37H+/- strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. Dhdds R37H+/- mice present with seizures, myoclonus and memory deficits associated with reduced density or/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used “off-label” to treat genetic movement disorders, reduces seizure susceptibility to pentylenetetrazol in Dhdds R37H+/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients. Together, our results define cis- PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel congenital disorder of glycosylation associated with aberrant levels of neuronal proteins and lipids.

Key Points BeWell360-PKD shows that integrating certified health and wellness coaches and augmenting patients' personal capacity as part of autosomal dominant polycystic kidney disease care is feasible and acceptable. Embedding BeWell360 coaches reduced care burden, improved caregiver self-efficacy, and enhanced care engagement by patients with autosomal dominant polycystic kidney disease and by their informal caregivers. This aligns with evolving care standards and guidelines promoting sustainable healthy lifestyle changes through tailored, integrative behavior-change centered interventions. Background Autosomal dominant polycystic kidney disease (ADPKD) imposes substantial care burden on patients and their informal caregivers (CGs), often contributing to nonadherence and impaired quality of life. Existing care models insufficiently address the behavioral and psychosocial dimensions of this burden. To evaluate the feasibility and effect of BeWell360-PKD , a person-centered intervention integrating Health and Wellness Coaching and capacity-workload support into ADPKD care, on care burden, adherence, self-efficacy, activation, and resilience. Methods In this 6-month, single-arm, mixed-methods pilot study, seven patient-CG dyads were enrolled from tertiary care polycystic kidney disease clinic. Board-certified Health and Wellness Coachings delivered individualized coaching within routine nephrology care, emphasizing capacity-building, goal setting, and care enactment support. Primary outcomes included changes in treatment burden (treatment burden questionnaire, ADPKD impact scale) and CG burden (burden scale for family CGs short version). Secondary outcomes included patient activation and resilience and CG self-efficacy. Semistructured interviews explored participant experiences. Results Patients experienced reduced treatment burden (treatment burden questionnaire mean change −9.3) and modest, domain-specific improvements in physical and fatigue-related ADPKD symptom burden. CG self-efficacy improved (+2.4), while CG burden increased (+14.8), and patient activation declined (−6.6). Qualitative themes reflected disease burden, emotional adaptation, and the perceived value of coaching in promoting behavior change and relational support. Conclusions BeWell360-PKD was feasible to implement and demonstrated early signals of benefit in reducing patient burden and improving CG self-efficacy. Increased CG burden and declining activation highlight the complexity of dyadic adaptation in ADPKD and the need for larger, controlled studies to refine and tailor coaching interventions.

Pancreas transplant is the standard treatment for restoring endocrine function and limiting complications from diabetes, and radiologists should understand the surgical techniques, normal imaging spectrum, and various complications associated with this surgical procedure.

Importance Obesity is associated with a higher risk of recurrence, mortality, comorbidities, treatment-related adverse effects, and poor quality of life in patients with breast cancer. Scalable interventions are needed to promote weight loss in this population. Objective To evaluate the impact of a remotely delivered weight loss intervention (WLI) on weight change at 1 year in patients with breast cancer and obesity and to explore factors associated with weight change. Design, Setting, and Participants The Breast Cancer Weight Loss trial is a phase 3, randomized clinical trial evaluating the impact of a telephone-based WLI on invasive disease–free survival and other outcomes in women with obesity and early breast cancer at 637 sites across the US and Canada. Participants were enrolled to the study between August 2016 and February 2021. Participants included women with stage II to III, ERBB2 -negative breast cancer and a body mass index (BMI) of 27 or higher. Interventions Participants were randomized to a 2-year, telephone-based WLI plus health education or health education alone control group. Main Outcome and Measures The primary end point for this prespecified secondary analysis was weight change at 1 year. Weight was measured at baseline and 1 year, and changes in weight were compared between groups. Weight change was evaluated with a linear mixed-effects model including treatment group, weight over time, a time-by-group interaction, menopausal status, race and ethnicity, and hormone receptor status. Results A total of 3180 women with breast cancer and BMI of 27 and higher were included in the study; 1591 were randomized to the WLI and 1589 to the control group. At baseline, the mean (SD) age of participants was 53.4 (10.6), and the mean (SD) BMI was 34.4 (5.6). The racial and ethnic breakdown included 406 (12.8%) Black, 231 (7.3%) Hispanic or Latino, 2906 (91.4%) non-Hispanic, and 2555 (80.3%) White participants. WLI participants lost a mean of 4.3 kg (95% CI 3.9-4.6 kg), or 4.7% (95% CI, 4.3%-5.0%) of baseline body weight at 1 year vs control participants, who gained 0.9 kg (95% CI, 0.5-1.3 kg), or 1.0% (95% CI 0.1%-1.4%) of baseline body weight ( P < .001). Participants randomized to WLI experienced significant weight loss (vs control group participants) across demographic and tumor factors. WLI effect differed significantly by menopausal status, with postmenopausal participants having greater weight loss than premenopausal participants, and by race and ethnicity, with Black and Hispanic participants having less weight loss compared to other races and ethnicities. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, a telephone-based WLI induced significant weight loss in patients with breast cancer with overweight and obesity across demographic and treatment factors. Further follow-up of the Breast Cancer Weight Loss trial will evaluate whether the WLI improves disease outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT02750826

ABSTRACT Background Secukinumab, a fully human, monoclonal antibody targeting interleukin‐17A, is approved for moderate‐to‐severe HS in adults. This study evaluated pharmacokinetics (PK), high‐sensitivity C‐reactive protein (hsCRP) changes, and safety of secukinumab over 52 weeks in SUNSHINE and SUNRISE Phase 3 trials. Methods An exploratory analysis of pooled Phase‐3 trials evaluated serum PK and safety of secukinumab 300 mg every 2 (SECQ2W) or 4 weeks (SECQ4W). A population PK model assessed the effects of body weight, disease severity, and baseline hsCRP on secukinumab serum concentration. Exposure–response analysis assessed the relationship between predicted PK and HS clinical response [HiSCR]. No confirmatory statistical testing was performed. Results Mean serum trough concentration at Weeks 16, 24, and 52 was ~2‐fold higher with SECQ2W vs. SECQ4W. At Week 16, exposure overlap was high, with an estimated numerical increase in HiSCR of ~3% for SECQ2W over SECQ4W. At Week 52, HiSCR levels plateaued. At Week 16, hsCRP decreased from 18.6 ± 26.3 mg/L to 12.8 ± 18.0 mg/L (SECQ2W), 15.9 ± 27.6 mg/L to 11.5 ± 18.4 mg/L (SECQ4W), and remained unchanged with placebo (14.4 ± 22.5 mg/L to 14.7 ± 23.8 mg/L); reductions were sustained through Week 52. Higher body weight, disease severity, and baseline hsCRP were associated with lower secukinumab serum concentrations. Secukinumab immunogenicity was low (< 1%), with no new safety signals. Conclusion Secukinumab serum concentrations in patients with HS varied with body weight, disease severity, and baseline hsCRP. SECQ2W may benefit certain patients. Secukinumab reduced hsCRP through Week 52. The safety profile of secukinumab was consistent with other approved indications, with no apparent dose–response relationship observed. Trial Registration NCT03713619 (Novartis study code CAIN457M2301). NCT03713632 (Novartis study code CAIN457M2302)

Study design: Cohort study. Objective: This study aimed to evaluate influence of facet cysts on outcomes in patients undergoing lumbar decompression, and the influence of spinal fusion in patients undergoing decompression for facet cysts. Summary of Background Data: The impact of facet cysts on outcomes following lumbar spine surgery for degenerative spine disease remains unclear. Methods: Our multicenter institutional Neurosurgery Enterprise Registry was queried for patients who underwent lumbar decompression for degenerative spine conditions. Patients were divided into 2 cohorts: those with lumbar spine facet cysts and those without. Retrospective propensity-score matching was performed using 13 baseline variables to adjust for potential confounding factors, including age, sex, race, body mass index, and comorbidities. Secondary analysis comparing outcomes in patients with facet cysts cases undergoing decompression only versus those undergoing decompression and fusion was conducted. Results: A total of 6768 patients were reviewed, of which 188 (2.8%) had facet cysts, which underwent lumbar decompression during 2019–2023. After 3:1 matching, patients with facet cysts were compared with 564 patients without it. We found no significant differences in LOS, nonroutine discharge, postoperative complications, readmissions, and reoperations. In addition, in cases with facet cysts, decompression reported no increased risk for discharge opioids, readmissions, and reoperations, whereas fusion (in a separate cohort of 127 patients with facet cysts) was associated with an increased risk for nonroutine discharge (3.7% vs. 10.2%, P=0.021), complications (2.1% vs. 7.1%, P=0.042), and longer LOS (0.89±1.69 vs. 3.74±2.03 d, P<0.001) and operative time (138.78±62.99 vs. 273.07±111.51 min, P <0.001). Conclusions: The presence of facet cysts does not significantly affect outcomes of lumbar decompression for degenerative spine disease. Decompression alone for facet cysts can have better outcomes than decompression and fusion. The need for fusion should be weighted with its higher risks of complications, longer hospital stays, and nonroutine discharges.

Abstract Background and Aims The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy vs medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. Methods The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR, and randomized 2:1 to TTVR (n = 267) or control (n = 133). In a post hoc analysis, patients were stratified into severe TR (n = 172) and massive/torrential TR (n = 220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan–Meier estimates for all-cause mortality and heart failure (HF) hospitalization assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. Results One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe {1.64 [95% confidence interval (CI): 1.11, 2.43]} and massive/torrential [2.20 (1.55, 3.14)]. At 18 months, TTVR patients had similar mortality to controls [rate difference: severe 0.2% (−11.6, 11.9), massive/torrential −5.8% (−17.6, 6.0)], whereas HF hospitalization rates favoured TTVR in the massive/torrential cohort [vs control, severe 9.8% (−3.0, 22.7), massive/torrential -15.2% (−28.9, −1.5)]. Conclusions Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.