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ABSTRACT The objective of this study is to describe outcomes of rapid exome (rES) and rapid genome sequencing (rGS) in an inpatient setting. This is a retrospective cohort of inpatients with rES or rGS during their hospitalization between April 2016 and November 2023. Medical records were reviewed to measure primary outcomes: diagnostic yield, medical management changes, and anticipatory guidance updates. Descriptive analysis and formal comparisons (Welch's t ‐test with post hoc power analysis, Fischer's exact test) were performed, with rES and rGS comparisons limited to 2023 due to test distribution. Of 95 patients, most (74.7% [71/95]) were < 12 months old and admitted in neonatal (44.2% [42/95]) or pediatric (29.5% [28/95]) intensive care units. Common indications for rapid sequencing included multiple congenital anomalies (24.2% [23/95]), neurological concerns (23.3% [22/95]), and acute illness (16.8% [16/95]). Mean turnaround time of testing significantly shortened for rES from 2021 (13.2 [SD = 5.9] days) to 2023 (8.1 [SD = 4.1] days) ( p ‐value = 0.018; power = 0.74). Diagnostic yield was 29.5% (28/95) and did not significantly differ between rES (13.6% [3/22]) and rGS (35.0% [7/20]) ( p ‐value = 0.15). Sequencing led to medical management changes (86.0% [74/86]) and anticipatory guidance updates (41.4% [39/95]) with similar rates observed in diagnostic and non‐diagnostic tests. Our findings suggest rES or rGS implementation may influence diagnosis and care strategies in critically ill patients.

Background REM sleep behaviour disorder (RBD) is a prodrome of α -synucleinopathy, yet mechanistic pathways are unresolved. Narcolepsy type 1 with RBD (NT1-RBD) provides a human model of orexin deficiency. We tested whether REM motor semiology differs categorically between isolated RBD (iRBD) and NT1-RBD. Methods We retrospectively analyzed blinded video-polysomnographic scorings from 57 patients (iRBD n = 34; NT1-RBD n = 23). Across 857 REM events (iRBD 717; NT1-RBD 140), we classified topography (head/neck, trunk, upper, lower limbs), complexity (elementary vs. complex), content (scenic, violent, self-referential), vocal/orofacial features, spatial distribution and laterality using a pre-specified codebook. The patient was the primary unit of inference. Binary features used Fisher’s exact tests with Cohen’s h ; the per-patient complex-event proportion used Mann–Whitney and Cliff’s δ (bootstrap 95% CI). Robustness checks comprised Beta-Binomial posteriors (Beta [1,1]) and patient-label permutation tests (10,000 permutations). Results REM motor phenotypes diverged categorically. Lower-limb dominance occurred in 18/23 (78.3%) NT1-RBD vs. 7/34 (20.6%) iRBD (Fisher p &lt; 0.0001; Cohen’s h ≈ +1.23), whereas upper-limb dominance occurred in 24/34 (70.6%) iRBD vs. 2/23 (8.7%) NT1-RBD ( p &lt; 0.0001; h ≈ −1.40). Any complex event was present in 27/34 (79.4%) iRBD vs. 3/23 (13.0%) NT1-RBD ( p &lt; 0.0001; h ≈ −1.46); violent enactments in 16/34 (47.1%) vs. 0/23 (0%) ( p &lt; 0.0001; h ≈ −1.51). The per-patient complex-event proportion was higher in iRBD [median 0.21 (0.05–0.33)] than NT1-RBD [0.00 (0.00–0.00)] (Mann–Whitney p &lt; 0.0001; Cliff’s δ = −0.665; 95% CI −0.853 to −0.441). Event-level summaries were concordant; permutation p -values were 0.0001 for upper-limb involvement and 0.0083 for complex behaviour. Conclusion iRBD and NT1-RBD exhibit qualitatively distinct REM motor phenotypes: upper-body-dominant, complex/scenic behaviours in iRBD versus elementary, predominantly bilateral lower-limb behaviours with notable trunk recruitment in NT1-RBD, supported by large effect sizes and convergent robustness checks. These findings motivate mechanistic studies of hypothalamic-brainstem-cortical integration in REM and suggest that semiological profiling may aid stratification in prodromal neurodegeneration.

Abstract Background and Aims Upadacitinib (UPA)—an oral, reversible selective Janus kinase inhibitor—has a favorable benefit–risk profile for patients with Crohn’s disease (CD) and ulcerative colitis (UC). We evaluated the benefit–risk of UPA in select subgroups with CD or UC. Methods Patients were randomized to UPA 45 mg (UPA45) once daily (QD) or placebo (PBO) induction for 12 (CD: U-EXCEED, U-EXCEL) or 8 weeks (UC: U-ACHIEVE, U-ACCOMPLISH). Clinical responders were re-randomized to QD UPA 15 mg (UPA15), UPA 30 mg (UPA30), or PBO for 52-week maintenance (CD: U-ENDURE; UC: U-ACHIEVE). This exploratory post hoc analysis assessed efficacy and safety outcomes (adverse events of special interest [AESIs]: serious infections, major adverse cardiovascular [CV] events, malignancies, and venous thromboembolic events) by CV risk, prior treatment failure, and age. Results This analysis included 1021 patients with CD and 1097 with UC during induction, and 673 with CD and 746 with UC during maintenance. Improved efficacy outcomes comparable to the overall study populations were observed with UPA versus PBO across subgroups. Patients receiving UPA30 generally showed numerically higher rates of improvements versus UPA15. AESI rates were generally comparable between UPA and PBO across subgroups except for numerically higher rates of herpes zoster and serious infections in CD with UPA. Conclusions UPA resulted in consistent benefit versus placebo across CV risk, prior treatment failure, and age subgroups. No treatment differences were seen in AESIs across subgroups except herpes zoster and serious infections, reinforcing the favorable benefit–risk profile for UPA in CD and UC seen in the overall study populations. Clinical trial numbers NCT02819635, NCT03653026, NCT03345836, NCT03345849, NCT03345823

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

The integration of mobile health (mHealth) technologies is transforming neurosurgery. Despite its potential, many uses remain unrealized due to the unique challenges and complexity of developing mHealth technology. While neurosurgeons bring invaluable clinical expertise and an understanding of patient needs, the technical intricacies of application development often require collaboration with developers and computer scientists, a process that can feel unfamiliar and difficult to navigate. The aim of this article was to demystify mHealth development by providing a guide for neurosurgeons seeking to develop disease-specific mHealth applications. We outline this process using the development of SynapTrack, an mHealth tool designed to provide objective assessments of degenerative cervical myelopathy, a chronic condition caused by symptomatic compression of the cervical spinal cord. This article offers neurosurgeons concrete guidance on navigating key considerations such as design decisions, algorithm integration, database architecture, and data security. By grounding these insights with SynapTrack, this guide offers a transparent view into the development process and provides a practical framework that can be adapted to the development of other mHealth tools. The aim of this work was to foster interdisciplinary collaboration and enable neurosurgeons to develop mHealth applications tailored to the specific needs of their specialty.

Background: The U.S. Food and Drug Administration has approved a bupivacaine and meloxicam extended-release (ER) intra-articular injection for pain during total knee arthroplasty (TKA). However, the real-world evidence with regard to analgesic efficacy of that medication has been limited. This randomized clinical trial investigated the efficacy of this new medication compared with our standard periarticular injection for postoperative analgesia after primary TKA. Methods: Eligible patients undergoing primary, unilateral TKA for osteoarthritis at our academic center were enrolled. Patients were blinded and were randomized 1:1 to the bupivacaine-meloxicam ER (ZYNRELEF) injection group or the standard injection (ropivacaine, ketorolac, epinephrine) control group. A standardized, multimodal analgesic pathway was implemented. Numeric Rating Scale (NRS) pain scores and tallies of opioid consumption were collected. The primary outcome was the area under the curve (AUC) for NRS pain, adjusted for opioid consumption, over 72 hours. The minimal clinically important difference was considered to be 30%. Power analysis determined a minimum of 44 patients per group. The final groups included 53 patients in the experimental group and 48 patients in the control group. Results: Similar postoperative analgesia was observed, with an AUC for the adjusted NRS pain score up to 72 hours of 331 in the experimental group and 373 in the control group (p = 0.09). The mean maximum NRS pain scores were similar and reflected good, but not complete, analgesia. Scores were 3 to 5 on the day of the surgery, 4 to 6 on postoperative day (POD) 1, 5 to 6 on POD 2, and 4 to 5 on POD 3 (p > 0.05). One patient in the experimental group and 2 patients in the control group had early postoperative complications, none of which was deemed to be related to the analgesic choice. Conclusions: This randomized clinical trial demonstrated similar analgesia with a bupivacaine-meloxicam ER solution and a standard periarticular injection up to 72 hours after primary TKA. Cost, reimbursement, and convenience may ultimately prove to be more important than analgesic differences when choosing between these 2 effective options for managing postoperative pain. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background and Aims The long-term efficacy and safety of upadacitinib in patients with moderate to severe Crohn’s disease (CD) were evaluated in the U-ENDURE Long-Term Extension (LTE) study. Here we report the results after 2 years of total maintenance treatment. Methods U-ENDURE is an ongoing 240-week LTE study conducted at 243 sites across 43 countries (first patient enrolled in LTE 21 March 2019). Patients who completed the 52-week maintenance study continued their previously assigned treatment, once-daily upadacitinib 15 mg or upadacitinib 30 mg. Efficacy was analyzed at week 48 of the LTE; safety was analyzed in the cumulative study population (combined 52 week maintenance and 48 week LTE) and the LTE study population only (cutoff date: 19 December 2023). Results From LTE week 0 to week 48, as-observed efficacy rates for clinical remission (per stool frequency/abdominal pain score, upadacitinib 15 mg: 78.3% to 82.9%; upadacitinib 30 mg: 84.7% to 76.6%; per CD Activity Index, upadacitinib 15 mg: 81.3% to 83.1%; upadacitinib 30 mg: 86.1% to 86.8%), endoscopic response (upadacitinib 15 mg: 59.6% to 67.1%; upadacitinib 30 mg: 71.2% to 69.6%), inflammatory biomarkers, and quality-of-life outcomes remained stable. The safety profile of the cumulative maintenance population observed through LTE week 48 was consistent with previous trials in the upadacitinib CD program. Treatment-emergent adverse event rates for the cumulative maintenance population were 283.1 and 273.4 events/100 patient-years for upadacitinib 15 mg and upadacitinib 30 mg, respectively. Event rates of serious treatment-­emergent adverse events were 16.0 events/100 patient-years for upadacitinib 15 mg and 14.6 events/100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest (≥ 5.0 events/100 patient-years) were hepatic disorder, lymphopenia, creatine phosphokinase elevation, herpes zoster, and anemia. There was 1 treatment-emergent adverse event of suicide leading to death. Conclusion Sustained clinical, endoscopic, quality-of-life, and biomarker outcomes were observed in patients who were initial responders to upadacitinib and completed 2 years of maintenance therapy, with no new safety signals identified. Clinical trial identifier U-ENDURE; ClinicalTrials.gov number, NCT03345823.