Citations

ObjectiveWe aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult‐onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus.BackgroundSince the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus.MethodsHigh‐throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed.ResultsWe collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra‐TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain‐specific misexpression due to inter‐TAD deletions or duplications. The inter‐TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology.InterpretationOur study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024;96:855–870

Abstract Cardioneuroablation has emerged as a potential alternative to cardiac pacing in selected cases with vasovagal reflex syncope, extrinsic vagally induced sinus bradycardia-arrest or atrioventricular block. The technique was first introduced decades ago, and its use has risen over the past decade. However, as with any intervention, proper patient selection and technique are a prerequisite for a safe and effective use of cardioneuroablation therapy. This document aims to review and interpret available scientific evidence and provide a summary position on the topic.

Background: Acute ischemic stroke (AIS) from primary medium vessel occlusions (MeVO) is a prevalent condition associated with substantial morbidity and mortality. Despite the common use of mechanical thrombectomy (MT) in AIS, predictors of poor outcomes in MeVO remain poorly characterized. Methods: In this prospectively collected, retrospectively reviewed, multicenter, multinational study, data from the MAD-MT (Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy) registry were analyzed. The study included 1568 patients from 37 academic centers across North America, Asia, and Europe, treated with MT, with or without intravenous tissue plasminogen activator (IVtPA), between September 2017 and July 2021. Results: Among the 1568 patients, 347 (22.2%) experienced very poor outcomes (modified Rankin score (mRS), 5–6). Key predictors of poor outcomes were advanced age (odds ratio (OR): 1.03; 95% confidence interval (CI): 1.02 to 1.04; p < 0.001), higher baseline National Institutes of Health Stroke Scale (NIHSS) scores (OR: 1.07; 95% CI: 1.05 to 1.10; p < 0.001), pre-operative glucose levels (OR: 1.01; 95% CI: 1.00 to 1.02; p < 0.001), and a baseline mRS of 4 (OR: 2.69; 95% CI: 1.25 to 5.82; p = 0.011). The multivariable model demonstrated good predictive accuracy with an area under the receiver-operating characteristic (ROC) curve of 0.76. Conclusions: This study demonstrates that advanced age, higher NIHSS scores, elevated pre-stroke mRS, and pre-operative glucose levels significantly predict very poor outcomes in AIS-MeVO patients who received MT. These findings highlight the importance of a comprehensive risk assessment in primary MeVO patients for personalized treatment strategies. However, they also suggest a need for cautious patient selection for endovascular thrombectomy. Further prospective studies are needed to confirm these findings and explore targeted therapeutic interventions.

ImportanceCutaneous squamous cell carcinoma (CSCC) is the second most common malignant disease in the US. Although it typically carries a good prognosis, a subset of CSCCs are highly aggressive, carrying regional and distant metastatic potential. Due to its high incidence, this aggressive subset is responsible for considerable mortality, with an overall annual mortality estimated to equal or even surpass melanoma. Despite this morbidity, CSCC is excluded from national cancer registries, making it difficult to study its epidemiology and outcomes. Therefore, the bulk of the CSCC literature is composed of single-center and multi-institutional retrospective cohort analyses. Given variations in reporting measures and analyses in these studies, interpretability between studies and the ability to pool results are limited.ObjectiveTo define standardized reporting measures for retrospective CSCC studies.FindingsAn expert panel was convened to determine standardized guidelines for recording and analyzing retrospective CSCC data. A total of 13 dermatologists and dermatologic surgeons with more than 5 years of posttraining experience and considerable experience with performing CSCC outcomes research were recruited to the panel. Consensus recommendations were achieved for CSCC retrospective study reporting measures, definitions, and analyses.Conclusions and RelevanceThe recommendations in this report present the potential to standardize future CSCC retrospective studies. With such standardization, future work may have greater interstudy interpretability and allow for pooled analyses.

The CD40-CD40L co-stimulatory dyad has been identified as critical player in atherosclerosis. Our previous work has shown that CD40 and CD40L have cell divergent effects on atherosclerosis. Deficiency of the CD40-CD40L dendritic cell-T cell axis decreased atherosclerosis via reducing T helper 1 responses, whereas deficiency of macrophages CD40 reduced atherosclerosis by enhancing efferocytosis and reducing necrotic core content. CD40 is highly expressed on B cells and interacts with CD40L on T cells to induce antibody production and T follicular helper cell responses. We therefore hypothesize that deletion of CD40 will reduce atherosclerosis. We aim to unravel the role of B cell CD40 in atherosclerosis. CD40 expression on B cell subsets was determined on peripheral blood mononuclear cells of patients and correlated with severity of coronary artery disease (CAD). Atherosclerosis was analyzed in CD19 Cre CD40 flfl ApoE -/- mice that were fed an atherogenic diet for 14 weeks. Patients with CAD showed a decrease in CD40 on their putative B1 cells, which was associated with increased plaque burden and decreased plaque fibrosis as detected by coronary intravascular ultrasound. Depletion of CD40 on B cells in ApoE -/- mice resulted in a decreased germinal center formation and inadequate IgM production as expected. However, in line with our patient data, absence of B cell-CD40 increased atherosclerosis. This was caused by a reduction in B1 cells and consequently a reduction in atheroprotective anti-oxidation specific epitope (OSE) IgMs. Transfer of CD40-competent B1b cells in B cell-CD40-deficient mice restored anti-OSE IgM levels and prevented the increase in atherosclerosis. CD40-deficient B1b cells have an altered mTOR signaling pathway, impaired mitochondrial function, excessive uptake of lipids, increased cellular stress and accelerated cell death. Data indicate that CD40-deficiency promotes phosphorylation of RAPTOR and protein kinase B (AKT). We have identified a novel function of CD40 on B1b cells. B1b cell-CD40 exerts an anti-atherogenic role by regulating B1b cell metabolic homeostasis via mTOR pathway. Further mechanistic insights into how CD40 mounts adequate atheroprotective anti-OSE IgM production are currently being investigated.

OBJECTIVE To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin. RESEARCH DESIGN AND METHODS A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61). RESULTS The primary outcome, the treatment group difference in area under the curve for glucose &gt;180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference −12 mg/dL, 95% CI −22 to −2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose &lt;70 mg/dL occurred in one participant in each group. CONCLUSIONS Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users.

Abstract Background The PALLAS trial investigated the addition of palbociclib to standard adjuvant endocrine therapy reduces breast cancer recurrence. This pre-specified analysis was conducted to determine whether adjuvant palbociclib benefited patients diagnosed with lower risk stage IIA disease compared to those with higher stage disease. Methods PALLAS was an international, multicenter, randomized, open-label, phase III trial, representing a public-private partnership between Pfizer, the Austrian Breast Cancer Study Group and, the U.S. ALLIANCE Foundation. Patients diagnosed with stage II-III, hormone-receptor-positive, HER2/neu negative breast cancer who were within 12 months of diagnosis, and had completed all definitive therapy aside from endocrine therapy, which was started within 6 months prior to study entry. All patients were required to submit a formalin-fixed paraffin-embedded (FFPE) tumor block. Patients were randomly assigned 1:1 to receive standard adjuvant endocrine therapy (of physicians’ choice) for at least 5 years with or without 2 years of Palbociclib, administered orally at a starting dose of 125 mg daily, given for 21 days followed by a 7-day break. Results A total of 5,796 patients with HR+/HER2- early breast cancer (including 1,010 with stage IIA) were enrolled. Median follow-up was 50 months for stage IIA patients and 43.1 months overall. In the stage IIA cohort, four-year iDFS in the palbociclib arm was 92.9% versus 92.1% for ET alone (HR 0.75, 95%CI 0.48–1.19, p = 0.23). There was no differential benefit by histologic grade, chemotherapy receipt, age, or anatomic/clinical risk. Additionally, no benefit to palbociclib was seen in this cohort in invasive breast cancer-free survival (iBCFS), locoregional relapse-free survival (LRFS), distant relapse-free survival (DRFS), or overall survival (OS). For the stage IIB/III patients, 4-year iDFS was 85.3% for palbociclib + ET versus 83.6% for ET alone (HR 0.91, 95% CI 0.77–1.07, p = 0.24). Conclusions and Relevance: While there were substantial differences in outcome for stage IIA versus IIB/III patients at 4 years of follow-up, the addition of 2 years of palbociclib did not improve outcomes for patients, regardless of stage. Trial Registration: The study was registered on Clinicaltrials.gov on July 31, 2015, and was assigned the clinical trial number (NCT02513394).

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P &amp;lt; .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P &amp;lt; .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

Background: Nurtec, a versatile migraine medication, has gained popularity. However, the awareness of migraine surgery remains uncertain. Methods: Following a descriptive approach, this cross-sectional study used Google Trends data as of December 1, 2023, to analyze internet search patterns. Approval from Vanderbilt University’s institutional review board and adherence to Strengthening the Reporting of Observational Studies in Epidemiology guidelines were confirmed. Monthly relative search volume (RSV) data for “migraine surgery,” “Nurtec,” and “Rimegepant” were collected from January 1, 2004, to November 11, 2023, within the United States. Statistical analysis involved determining mean monthly RSV values and percentage changes for critical periods. Results: For “Nurtec,” a significant surge in RSV occurred from March 2020 to April 2020 (344%). Additional peaks were observed from June 2020 to July 2020 (66%), October 2020 to December 2020 (169%), May 2021 to June 2021 (33%), and May 2023 to June 2023 (14%). “Migraine surgery” exhibited a notable 400% increase in RSV, from March 2005 to May 2005. However, post-2006, RSV for “migraine surgery” consistently remained low without noticeable peaks. Conclusions: The analysis of RSV trends for “Nurtec” and “migraine surgery” from 2004 to 2023 reveals the impact of pivotal events and marketing strategies on public interest. The distinct peaks in “Nurtec” RSV align with Food & Drug Administration approvals and marketing campaigns, highlighting the medication’s accessibility. Conversely, the consistently low RSV for “migraine surgery” indicates limited awareness, emphasizing the need for enhanced promotion and education regarding surgical interventions.