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Extended window of relapse recovery in RRMS: an analysis of the DECIDE dataset.
No full textBACKGROUND: The main goal of treatment in relapsing-remitting multiple sclerosis (RRMS) is to reduce the occurrence of relapses. However, little is known about the natural history of relapse recovery.
METHODS: We accessed data from DECIDE (n=1841), a phase 3 trial. We investigated factors associated with time to relapse recovery (defined as a return of the Expanded Disability Status Scale (EDSS) score to the pre-relapse level or lower), relapse severity (0.5, 1.0, or \u3e1.0 EDSS score change) and the new concept of \u27acute clinical events with stable MRI\u27 (ACES). Variables used were age, sex, disease duration, treatment arm, pre-relapse EDSS, corticosteroid use, number of relapses prior to study enrolment, MRI activity, relapse severity and affected functional system (FS).
RESULTS: We included 430 first relapses, of which 405 (94.2%) recovered during follow-up, 400 (93%) by 1 year (median time to recovery of 71 days, 95% CI 66 to 75 days). More severe relapses and relapses involving the bowel and bladder FS took a longer time to recover. Corticosteroids hastened the recovery of relapses but did not influence eventual relapse recovery. ACES occurred in 38% of relapses and was more frequent in older people and participants treated with daclizumab.
CONCLUSIONS: Most relapses (94.2%) recover, but the process of recovery can take up to 1 year and depends mostly on relapse severity. Our findings challenge the concept of 3-month and 6-month confirmed disability progression as reliable markers of permanent disability in RRMS trials. ACES occurs frequently and is associated with age
The neuronal chromatin landscape in brains from individuals with schizophrenia is linked to early fetal development.
No full textNoncoding variants increase neuropsychiatric disease risk, but our understanding of their cell-type-specific role remains incomplete. We conducted large-scale chromatin accessibility profiling of neurons and non-neurons from 2 neocortical regions in 1,393 libraries. We observed substantial differences in neuronal chromatin accessibility between schizophrenia (SCZ) cases and controls, with upregulated open chromatin regions (OCRs) in neurons associated with SCZ risk loci. A comparison of SCZ-associated OCRs with fetal brain-specific OCRs revealed a strong correlation between upregulated changes in SCZ chromatin and openness in fetal cortical brains, linking disease-related chromatin alterations to neurodevelopment. Here we show that a prominent neuronal trans-regulatory domain containing upregulated OCRs consolidates key neurodevelopmental chromatin signatures and is enriched for immature glutamatergic neurons. These findings link altered adult cortical chromatin states to early developmental mechanisms in SCZ. This study provides a comprehensive cell-type-resolved chromatin accessibility resource for the human cortex and offers insights into the regulatory architecture underlying SCZ risk
Modifying Electronic Medical Record Workflows to Improve Protein Provision to Enterally Fed ICU Patients.
No full textA Framework for Minimally Invasive Remote Robotic-Assisted Surgery: Bridging Innovation and Patient Safety.
No full textThe TRaditional versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trial: design and baseline characteristics of participants.
No full textBACKGROUND: Whether early use of higher-efficacy disease-modifying therapy (DMT) reduces later risk of disability in multiple sclerosis (MS) has not been studied as a prospective treatment strategy. Herein, we describe the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial design and provide the baseline characteristics of the enrolled population.
METHODS: TREAT-MS is a pragmatic, randomized, rater-blinded trial of DMT strategies in treatment-naive people aged 18-60 years with relapsing-remitting MS (RRMS). Participants were randomized (1:1, stratified by site and long-term disability risk classification) to one of two treatment strategies: higher-efficacy or traditional DMT; the specific DMT within the assigned strategy was chosen by the clinician/patient pair. Participants could switch DMT for breakthrough disease occurring after 6 months on DMT. The primary outcome is sustained worsening of the Expanded Disability Status Scale (EDSS)-plus, a composite endpoint that includes the EDSS and the timed 25-ft walk and 9-hole peg tests.
RESULTS: TREAT-MS includes 900 people with the following baseline characteristics: mean age 36 ± 10 years; 629 (70 %) female gender; 648 (72 %) white, 168 (19 %) Black/African American race, and 105 (12 %) Hispanic or Latino. Mean time since MS symptom onset was 2.6 (± 4.5) years, and mean EDSS score was 2.5 (± 1.3).
CONCLUSION: TREAT-MS seeks to address how early DMT strategy influences MS disability and related outcomes. The results will be generalizable to future individuals newly diagnosed with RRMS who, with their clinicians, will be able to use them to make data-driven DMT decisions about how to maximize their intermediate-term function
Post-stent balloon dilation is associated with postoperative hypotension after transcarotid artery revascularization.
No full textOBJECTIVE: Postoperative hypotension following transcarotid artery revascularization (TCAR) is associated with greater intensive care unit (ICU) utilization, longer inpatient length of hospital stay (LOS), and increased in-hospital mortality. This study\u27s aim was to identify key intraoperative and anatomic factors contributing to postoperative hypotension in the setting of TCAR for asymptomatic carotid stenosis. Identification and risk stratification of such high-risk patients is an important aspect of perioperative care to mitigate this occurrence and ensuing complications.
METHODS: This was a retrospective, single-institutional analysis of TCAR procedures performed in 94 patients with asymptomatic carotid stenosis. The primary endpoint was the development of postoperative hypotension. Secondary outcomes were rates of ICU utilization, LOS, and postoperative transient ischemic attack or stroke.
RESULTS: Ninety-four patients met inclusion criteria for this study. Baseline demographics between the two groups were comparable. Postoperative hypotension was more common in the post-stent dilation (PSD) group (75.0% vs 34.8%; P \u3c .001). Among patients with postoperative hypotension, there were greater rates of ICU utilization and incidence of prolonged inpatient LOS (\u3e1 day). However, only 19.0% of patients with postoperative hypotension following PSD required vasopressors, with a median duration of 15.9 hours. Patients that experienced postoperative hypotension had a significantly higher measured calcium volume percent (17% vs 6.5%; P = .006). Median carotid bulb dilation index was similar across groups (1.30 vs 1.30; P = .577). On multivariate logistic regression, PSD was the only factor significantly associated with postoperative hypotension (odds ratio, 4.01; 95% confidence interval, 1.36-12.78; P = .014).
CONCLUSIONS: Patients with increased vessel calcification required PSD more frequently to achieve adequate luminal gain. However, PSD was the sole intraoperative factor associated with postoperative hypotension when adjusting for covariates. This suggests that intraprocedural carotid bulb manipulation exerts increased transient distension on baroreceptors in instances of PSD, thus conferring a higher risk of this complication. The risks and benefits of post-stent balloon dilation for increased luminal gain and stent expansion should be carefully considered in these patients
Urine Extracellular Vesicle miRNA Changes Induced by Vicadrostat with/Without Empagliflozin in Patients with Chronic Kidney Disease.
No full textVicadrostat, a selective aldosterone synthase inhibitor, reduced albuminuria with concurrent renin-angiotensin system inhibition and empagliflozin, suggesting additive efficacy for chronic kidney disease (CKD) treatment. Specific urinary extracellular vesicle microRNAs (uEV miRNAs) may reflect key mechanisms of kidney injury. We investigated how vicadrostat alone or with empagliflozin affected uEV miRNA expression in study participants. Small RNA sequencing was conducted on uEV miRNAs from 435 participants with CKD who completed 14 weeks treatment in the phase II trial of vicadrostat given with or without empagliflozin. Differentially expressed uEV miRNAs in participants with ≥30% UACR (urine albumin-creatinine ratio) reduction treated with 10 or 20 mg vicadrostat were pooled and evaluated with or without empagliflozin. Changes in miRNA-142-5p correlated significantly with changes in UACR in participants treated with vicadrostat alone, whereas changes in expression of eight additional uEV miRNAs (miR-192-5p, miR-194-5p, miR-6882-5p, miR-27a-5p, miR-381-3p, miR-192-3p, miR-513a-5p, and miR-199b-3p) correlated with ≥30% UACR improvements in patients treated with vicadrostat plus empagliflozin. Cellular deconvolution revealed that these miRNAs were expressed in various kidney cell types. Vicadrostat plus empagliflozin altered uEV miRNAs involved in immunomodulatory and fibrotic pathways irrespective of participant diabetes status. Regulation of miRNAs may provide insights into synergistic mechanisms of vicadrostat and empagliflozin in CKD treatment
Evidence for improved DNA repair in the long-lived bowhead whale.
No full textAt more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth1, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto\u27s paradox2. Here, to understand the mechanisms that underlie the cancer resistance of the bowhead whale, we examined the number of oncogenic hits required for malignant transformation of whale primary fibroblasts. Unexpectedly, bowhead whale fibroblasts required fewer oncogenic hits to undergo malignant transformation than human fibroblasts. However, bowhead whale cells exhibited enhanced DNA double-strand break repair capacity and fidelity, and lower mutation rates than cells of other mammals. We found the cold-inducible RNA-binding protein CIRBP to be highly expressed in bowhead fibroblasts and tissues. Bowhead whale CIRBP enhanced both non-homologous end joining and homologous recombination repair in human cells, reduced micronuclei formation, promoted DNA end protection, and stimulated end joining in vitro. CIRBP overexpression in Drosophila extended lifespan and improved resistance to irradiation. These findings provide evidence supporting the hypothesis that, rather than relying on additional tumour suppressor genes to prevent oncogenesis3-5, the bowhead whale maintains genome integrity through enhanced DNA repair. This strategy, which does not eliminate damaged cells but faithfully repairs them, may be contributing to the exceptional longevity and low cancer incidence in the bowhead whale
Extraction site hernia and short-term outcomes following intracorporeal versus extracorporeal anastomosis for robotic and laparoscopic right colectomy: a multi-center prospective trial.
No full textBACKGROUND: Studies have shown outcomes advantages of intracorporeal compared to extracorporeal anastomosis during minimally invasive right colectomy that include less conversion to open, faster return of bowel function, and shorter hospital length of stay. The extracorporeal anastomosis and specimen extraction incision are often midline and may be associated with incisional hernias. The study aim was to determine if intracorporeal right colectomy is associated with fewer incisional hernias.
METHODS: This is the final data analysis for the ANastomotic COmparison in Right Colectomy (ANCOR) prospective multi-center study designed to compare laparoscopic- or robotic-assisted intracorporeal versus extracorporeal anastomoses in patients undergoing minimally invasive right colectomy for benign or malignant neoplasia. The primary outcome was the extraction site incisional hernia rate at 2 years. Secondary outcomes included hospital length of stay and short-term complications. Descriptive statistics [mean with standard deviation and median with interquartile range (IQR)] were applied using SAS 9.4.
RESULTS: 150 patients (30 laparoscopic and 120 robotic assisted) underwent intracorporeal anastomosis, and 150 patients (120 laparoscopic and 30 robotic assisted) underwent extracorporeal anastomosis. All extracorporeal specimen extraction sites were midline. Intracorporeal extraction sites were off-midline in 98.7%. At 2 years, extraction site hernias were significantly more common in the extracorporeal group (10.1% vs. 1.9%, p = 0.013), with only one hernia repaired in the intracorporeal group. The intracorporeal group had significantly fewer conversions to open (0% vs. 4.7%, p \u3c 0.0001), shorter extraction site incisions (4.9 cm vs. 6.0 cm, p \u3c 0.0001), shorter time to gastrointestinal recovery, shorter time to tolerating diet, shorter hospital length of stay (3.0 vs. 4.0 days, p \u3c 0.0001), and longer operative times (207.5 min vs. 173.1 min, p \u3c 0.0001). There were no significant differences between groups in postoperative complications and short-term oncologic outcomes.
CONCLUSION: Intracorporeal anastomosis during minimally invasive right colectomy is associated with a lower rate of incisional hernias and other benefits compared to the extracorporeal approach. These data support continued training in and implementation of intracorporeal anastomotic techniques.
TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03312569