Acute severe ulcerative colitis (ASUC) is a medical emergency affecting up to 25% of patients with ulcerative colitis (UC), with colectomy required in approximately 25–30% of cases during the initial admission. Intravenous corticosteroids remain the first-line therapy, though one-third of patients do not respond, necessitating rescue with infliximab or calcineurin inhibitors, which are both supported by randomized trials and guideline recommendations. Comparative studies and meta-analyses have shown similar efficacy between these agents, while sequential use is associated with higher adverse event rates and should be restricted to specialized centers. Recent data have refined infliximab use, with the PREDICT-UC trial showing no superiority of intensified dosing over standard regimens. Emerging therapies are under investigation: vedolizumab has been used as maintenance following calcineurin induction; ustekinumab has shown benefits in retrospective UC cohorts, particularly after cyclosporine; and Janus kinase (JAK) inhibitors represent the most recent addition. The randomized TACOS trial and the prospective TRIUMPH study demonstrated an improved short-term response with tofacitinib in steroid-refractory ASUC, and real-world reports suggest promising outcomes with upadacitinib. While infliximab and cyclosporine remain as standard rescue therapies, ongoing trials with novel agents are likely to broaden treatment options. This review summarizes the clinical features, initial management, and the role of advanced therapies in ASUC.

Our aims were to investigate the trends in observed vs expected all-cause mortality and the effects of serostatus and sex on all-cause and cause-specific mortality in individuals with rheumatoid arthritis (RA) in a large community-based longitudinal cohort study. This retrospective cohort study evaluated all-cause and cause-specific mortality in RA using a community population-based inception cohort of adult residents of Olmsted County, Minnesota, with incident RA from 1980 to 2019 meeting American College of Rheumatology 1987 criteria, and non-RA residents matched 3:1 to patients with RA by age and sex. Underlying cause of death was obtained from death certificates. Competing risks/cumulative incidence methods were used to compare cause-specific mortality incidence between individuals with and without RA. Cox models estimated the effect of RA on risk of cause-specific mortality, adjusting for sex, age, and calendar year of index. Interactions for RA with sex, age, seropositivity, and calendar year were examined. The study included 1337 patients with RA and 4011 non-RA comparators. All-cause mortality was significantly increased in both female and male individuals with RA, specifically in seropositive RA, and declined after the 1980s. The increased risk of death due to respiratory causes in patients with RA was significantly different depending on seropositive vs seronegative status (adjusted hazard ratio 2.26 [95% CI 1.56-3.26] vs 0.52 [95% CI 0.24-1.13], interaction P < 0.001). There were no significant differences in cause-specific mortality based on sex. Seropositivity in persons with RA associates with a significantly increased risk of death, particularly due to respiratory causes, whereas no increased risk was found in seronegative patients.

To compare postoperative complications between staged versus unstaged tympanoplasty and subtotal petrosectomy (STP) in adults undergoing cochlear implants with noncholesteatoma chronic otitis media (NCCOM) and tympanic membrane perforation. PubMed/MEDLINE, Cochrane CENTRAL, Embase, CINAHL, Web of Science, WHO Global Index Medicus, ClinicalTrials.gov, and WHO ICTRP. A systematic search of databases was conducted by a research librarian from inception through November 18, 2024. Eligible studies for inclusion must have reported on adult cochlear implant recipients undergoing surgical management of NCCOM with perforation. Using a random effects model, complication rates were pooled and compared between staged and unstaged surgeries using relative risk (RR) with 95% CI. Of 1265 studies identified, 19 met inclusion criteria (n = 84). Fifty three (63.1%) patients underwent unstaged surgery. Amongst all patients, STP was performed more than tympanoplasty (72.6%, 61/84 vs 27.4%, 23/84), and the overall complication rate was 11.9% (10/84). There was no significant difference in complication rates between combined staged and unstaged surgeries [RR: 1.13 (95% CI, 0.18-7.04)] as well staged and unstaged tympanoplasty [RR: 0.34 (95% CI, 0.11-0.1.01)]. However, complication rates were lower for staged than unstaged STP [RR: 0 (95% CI, 0.0-0.07)]. Staged and unstaged surgery for NCCOM and cochlear implant may result in comparable complication rates, however the wide CIs for RR statistics in comparisons between combined staged and unstaged procedures as well as staged and unstaged tympanoplasty indicate a need for similar studies of larger populations.

The purpose of this 1-year study was to assess the effect of osteogenic loading combined with melatonin on musculoskeletal health and well-being in a population with osteopenia. Participants were randomized into one of four groups and received mock loading plus plant fiber as placebo (ML/Placebo), mock loading plus 5 mg melatonin (ML/Melatonin), osteogenic loading plus placebo (OL/Placebo), and osteogenic loading plus 5 mg melatonin (OL/Melatonin). The loading protocol was designed to deliver multiples of body weight (MOB; 1-2 MOB for mock loading and 1.5-4.2 MOB for osteogenic loading) to the upper body (targeting the arm, chest, and shoulders), core (targeting the spine and core stability), lower body (targeting the legs and hip) and postural (targeting the spine and posture). Following these interventions, musculoskeletal health was measured by DXA and functional testing using timed-up-and-go (TUG) and sit-to-stand (STS) assessments. Markers of bone health (e.g., P1NP, CTX, CRP, cortisol, and melatonin) were assessed in urine collected during the night (10 pm-6 am). Mental health assessments were conducted using PSS, CES-D, STAI and QualiOst. Time-dependent increases in the amount of force exerted (in lbs) were observed in the OL groups for all musculoskeletal systems targeted, compared to those participants receiving ML. Over 12mos, compared to baseline, participants in the OL/Melatonin group had statistically significant increases in lumbar spine T-scores (mean difference [MD] = 0.13, standard deviation [SD] = 0.05, p = 0.015) and BMD (MD = 0.013, SD = 0.006, p = 0.021). No other statistically significant effects were noted for T-scores, BMD, or FRAX scores. Additionally, no significant differences were observed when T-scores were compared between groups. Functional assessments at 12mos revealed increases in TUG times (MD = -1.7, SD = 0.3, p = 0.002) from baseline and deterioration for STS (MD = 2.8, SD = 0.59, p = 0.004) from month 03 for ML/placebo group, which did not occur for the other interventions. Correlation analysis revealed negative associations between TUG performance and CTX levels starting at 3mos in the OL/Melatonin group (r = -0.960, p = 0.04). The change in STS repetitions over a 12-month period (12mo-0mo) was negatively associated with the P1NP:CTX ratio (r = -0.978, p = 0.02) and positively associated with melatonin levels in the OL/Melatonin group (r = 0.958, p = 0.04). No changes in nocturnal output of CRP or cortisol and subject-reported outcomes were observed for any of the interventions within and between groups. The results from this study reveal that osteogenic loading combined with melatonin may be an alternative therapeutic intervention for those with osteopenia.

BackgroundThe COVID-19 pandemic magnified longstanding racial and ethnic disparities in pediatric health, but it is unclear which populations experienced the largest disparities. Our objective was to determine whether disparities in COVID-19 severity differed with respect to patient factors analyzed as effect modifiers.MethodsUsing data from the Premier Healthcare Database, this retrospective cohort study included encounters among inpatients < 19 years old from April 2020 through September 2022 in the USA with a COVID-19 diagnosis. Outcomes of COVID-19 severity were intensive care unit (ICU) admission and ventilator use. Comparisons between Black and White patients and Hispanic and White patients were adjusted for confounders using propensity score weights, reported as risk differences (RDs) in percentage points, and tested for heterogeneity (interaction P) across subgroups of effect modifiers such as complex chronic conditions (CCCs) and insurance status.ResultsOf 8947 pediatric inpatients with primary COVID-19 diagnosis, 3858 were White, 2153 were Black, and 2936 were Hispanic. Among children with a CCC, 14.3% of Black inpatients required a ventilator compared to 9.8% of White inpatients; among children without a CCC, 3.2% of both Black and White inpatients required a ventilator (RDs 4.5 vs 0.0; interaction P = .013). Comparisons of Hispanic and White inpatients showed a similar trend in ventilator use, with larger disparities among inpatients with CCCs and no difference among those without CCCs (RDs 2.7 vs −0.7; interaction P=.031). Among children with government insurance, 25.9% of Black inpatients were admitted to the ICU compared to 20.8% of White inpatients; among children with private insurance, Black and White inpatients had comparable ICU admission rates of 20.0% and 21.4%, respectively (RDs 5.1 vs −1.4; interaction P = .025).ConclusionsAmong hospitalized children, racial and ethnic disparities in COVID-19 severity were largest for those with CCCs or government insurance. These results can help identify target populations for interventions to reduce inequity.

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell-derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated ASCC3 variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the Fmr1 KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal Fmr1 KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive-like behavior, and social interaction deficits after 1 month in 2-month-old Fmr1 KO mice compared with untreated Fmr1 KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.