Citations

Abstract The lack of a molecular understanding of mood disorders has impeded progress in diagnosis and treatment. Glycosylation may provide insights into the complex mechanisms underlying these conditions. We conducted N-glycoproteomic analysis on dorsolateral prefrontal cortex samples from individuals with major depressive disorder (MDD) and bipolar disorder (BD), in depressive or manic states at death. Additionally, we examined depression prevalence in congenital disorders of glycosylation (CDG) through a literature review and assessment of 110 CDG patients. Glycoproteomic analysis revealed a significant increase in protein glycosylation in individuals with MDD relative to both controls and individuals with BD. Depression prevalence was lower in our pediatric and adult cohort of individuals with CDG. These results suggest brain glycosylation changes may play a role in mood disorder pathology and highlight the distinct biology of unipolar and bipolar depression. Our findings propose that impaired glycosylation may confer resilience to depression, offering potential therapeutic insights.

A 32-year-old woman with Alport syndrome and prior history of diffuse leiomyomatosis of the oesophagus and bronchial tree presented with severe constipation. MRI revealed extensive leiomyomatosis of the anorectum with obstructed defecation. Colonic manometry showed megacolon, and the patient underwent total colectomy. Surgical pathology confirmed leiomyomatosis and neuronal loss in the anorectum and reduced enteric ganglion cells in the colon. Prior literature suggests obstruction-induced enteric neuropathy as a potential mechanism for megacolon. This report shows that Alport syndrome with diffuse leiomyomatosis may have other gastrointestinal involvement including megacolon in affected patients presenting with constipation.

Pancreatogenic or type 3c diabetes, which occurs as a consequence of pancreatitis, may have several mechanisms. Mechanisms overlapping with those of type 2 diabetes have been explored, including insulin resistance and insulin deficiency. However, autoimmune mechanisms in response to unmasking β-cell antigens, similar to those of type 1 diabetes (T1D), have not been thoroughly examined. We performed cross-sectional T1D autoantibody profiling in a large prospective cohort (N = 927) of adults with acute, recurrent acute, or chronic pancreatitis. We examined correlations of prevalence of autoantibodies against GAD (GAD antibody), IA-2 (IA-2 antibody), zinc transporter 8 (ZnT8; ZnT8 antibody), and insulin (insulin autoantibody [IAA]) with clinical and demographic features, including presence of diabetes, diabetes treatment, and family history of diabetes. Diabetes was present in 11 (12%) of 94 participants with acute pancreatitis, 69 (27%) of 273 with recurrent acute pancreatitis, and 235 (43%) of 560 with chronic pancreatitis. Among these groups, islet autoantibodies were respectively found in five (5.3%) of 94, 48 (17.6%) of 273, and 127 (22.6%) of 560. The proportions of individuals with diabetes who were autoantibody positive were 45%, 70%, and 54%, respectively (most commonly IAA, which may reflect exogenous insulin use). However, across the entire cohort, 27 participants (2.9%) had two, two (0.2%) had three, and one (0.1%) had four T1D-associated autoantibodies, respectively, suggesting a potential pathogenic link that should be further explored. ARTICLE HIGHLIGHTS Type 1 diabetes–associated autoimmune mechanisms have not been thoroughly examined in pancreatitis-associated diabetes. We assessed the prevalence of four islet autoantibodies in serum from a large prospective cohort of patients with acute, recurrent acute, or chronic pancreatitis. Diabetes was present in 11 (12%) of 94 participants with acute pancreatitis, 69 (27%) of 273 with recurrent acute pancreatitis, and 235 (43%) of 560 with chronic pancreatitis. Excluding those with only insulin autoantibody positivity, which is confounded by insulin treatment, islet autoantibodies were identified in 51 (5.5%) of 927 participants, and 30 (3.2%) of 297 were positive for two or more autoantibodies. Our findings suggest pancreatitis may elicit islet autoimmunity in a subset of patients, necessitating prospective longitudinal follow-up.

PURPOSE Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (<50 years, named early-onset CRC [eoCRC]) has been increasing. PATIENTS AND METHODS Individual patient data on 13,365 patients with metastatic CRC enrolled between 2000 and 2012 in 17 first-line randomized trials in the Aide et Recherche en Cancérologie Digestive database were pooled. The distribution of demographics, clinicopathologic features, biomarkers, and outcome data were summarized and compared by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group on clinical outcomes was evaluated by testing interaction effect between treatment and age variables. RESULTS Overall, 2,045 patients with eoCRC (median age, 42.5) and 11,320 patients with average-onset CRC (aoCRC; median age, 63.8) were included in this analysis. Within the eoCRC population, treatment with bevacizumab in addition to chemotherapy improved PFS (9.9 v 6.8 months; hazard ratio [HR], 0.66 [95% CI, 0.54 to 0.80]; P < .0001), which was similar to the findings in aoCRC population (9.4 v 7.3 months; HR, 0.73 [95% CI, 0.67 to 0.80]; P < .001; interaction P = .5415). However, epithelial growth factor receptor inhibitor (EGFRi) did not improve PFS in RAS wild-type (WT) patients with eoCRC who had left-sided primary tumors (8.3 v 8.9 months; HR, 1.20 [95% CI, 0.81 to 1.77]; P = .36), whereas EGFRi significantly improved PFS in the aoCRC population (9.9 v 8.5 months; HR, 0.74 [95% CI, 0.64 to 0.86]; P < .0001; interaction P = .083). CONCLUSION Treatment-naïve patients with metastatic eoCRC appear to derive similar benefit from bevacizumab as patients with aoCRC. However, patients with eoCRC with left-sided RAS/RAF WT tumors did not appear to derive benefit from first-line EGFRi.

Background and importance Rapid sequence intubation in emergency settings may involve opioid pretreatment to blunt hemodynamic responses during laryngoscopy and intubation; however, opioids may lead to postintubation hypotension, increasing morbidity and mortality. Global clinical practice varies significantly, reflecting uncertainty about opioids’ benefits and risks. Objective Our goal was to evaluate the association between opioid pretreatment and hemodynamic instability, focusing on postintubation hypotension in adult patients undergoing emergency intubation. Design, settings, and participants We performed a systematic review of randomized controlled trials and observational studies comparing opioid administration vs. no opioids before adult emergency intubations. Searches included Cochrane, Embase, Medline, Scopus, and Web of Science databases until November 2024. Elective intubations were excluded. Eight (6708 patients) studies met criteria. Outcomes measure and analysis The primary outcome was postintubation hypotension, variably defined across studies. Secondary outcomes included hypoxemia, first-attempt success, cardiac arrest, and vasopressor use. Independent reviewers conducted data extraction, risk-of-bias assessments, and certainty evaluation. Results were qualitatively synthesized. Main results Among 6708 (2757 opioids and 3951 controls) patients, postintubation hypotension incidence varied widely (risk differences: −12.5% favoring opioids to +13.2% favoring controls). The single low-risk randomized study reported opioids increased hypotension (risk difference: 13%, odds ratio: 2.15, 95% confidence interval: 1.22–3.78). Observational studies yielded inconsistent results. Secondary outcomes showed no consistent differences. Evidence certainty was very low because of risk of bias, inconsistency, and imprecision. Conclusions Current evidence regarding opioid pretreatment effect on postintubation hypotension risk during emergency intubation is limited and conflicting.

Abstract Purpose The objective of this quality improvement process was to identify quality gaps in compliance with regulatory requirements and reduce the loss of revenue resulting from noncompliance with documentation of single-dose vial waste. Methods This quality improvement initiative employed process mapping and quality gap identification to address challenges related to compliance and revenue generation. A fishbone diagram and the 5 whys technique were used to identify and analyze the root causes of missed waste documentation and workflow inconsistencies. These root causes were categorized into key areas: missing documentation, divergent workflows, inconsistencies, insufficient surveillance, and staffing issues. Leveraging these insights, we developed comprehensive educational resources such as quick reference guides and updated on-the-job training materials for the pharmacy department. Additionally, reliable, reproducible reports were created to monitor waste documentation, facilitating timely interventions whereby technicians were contacted to complete missing documentation within the 96-hour charge capture window. Results This study evaluated a total of 5,801 orders placed from October 1, 2022, to March 31, 2023, for the preimplementation period. Of these 5,801 orders, 803 (13.8%) were missing waste documentation, resulting in a total revenue loss of $362,594 when converted to the average sales price (ASP). For the postimplementation period from April 1 to September 30, 2023, a total of 10,464 orders were inspected for missing waste documentation. Only 181 orders (1.7%) were found to have incomplete waste documentation, resulting in a total revenue loss of $44,343 when converted to ASP. The postimplementation period yielded a revenue capture of $318,250, representing significant improvement in compliance with waste documentation. Conclusion This quality improvement initiative significantly reduced revenue loss from noncompliance with waste documentation for compounded sterile products. Comprehensive education and reliable reporting increased adherence to waste documentation workflows and regulatory compliance.

Powassan virus (POWV) is an emerging tick-borne flavivirus for which no vaccine or antiviral treatment exists. The incidence of human infections of POWV in North America has been increasing because of the expanding distribution of the tick vector Ixodes scapularis that transmits POWV to humans. To mitigate the dangers of handling a risk group 3 human pathogen, a chimeric virus was constructed from the genetic backbone of a yellow fever virus vaccine strain 17D (YFV-17D) and the external structural proteins of POWV lineage II. The chimera had a comparable phenotype as POWV. The atomic resolution of yellow fever virus-Powassan virus chimera (yPOWV) structure was built without ambiguity, revealing surface glycans and lipid pocket factors. The similarity to other flavivirus structures and the phenotype similar to YFV-17D suggest that there could be future potential as a vaccine candidate.

Background and Aims: Prognosticating outcomes such as hospitalizations in outpatients with cirrhosis is challenging, especially with changing etiologies and demographics. This study aims to determine the impact of multi-omic strategies on outcome prediction. Approach and Results: NACSELD3 enrolls outpatients with cirrhosis with controlled/eradicated etiologies from 10 centers and follows them systematically. At baseline, clinical/demographic and cirrhosis details were recorded and saliva and serum samples were collected for microbiome and metabolome analysis, respectively. Multi-omic bioinformatic studies to determine the interaction of microbiota and metabolites with the clinical prediction of 6-month hospitalizations were performed. Five hundred sixty-five patients (60.2 y, 68% men, 35% alcohol, 33% metabolic dysfunction-associated steatohepatitis, 21%, eradicated HCV with MELD 3.0 12) were enrolled. One hundred sixty-three (29%) required 6-month hospitalizations; most (75%) were liver-related. Those hospitalized had worse cirrhosis severity and comorbidity indices but similar demographics and oral health variables. Salivary microbiome alpha-diversity was lower (1.96±0.48 vs. 2.09±0.45, p =0.018) with greater pathobionts ( Streptococcus , Treponema, Enterococcaceae) and lower commensal genhospitalized/noera ( Veillonella, Prevotella, Haemophilus , Lachnospiraceae spp) at baseline. Serum metabolomics showed significant separation at baseline between hospitalized/non-hospitalized patients using supervised analyses with microbial-origin (phenyllactate, secondary bile acids, indoles), choline moieties, and polyamine/GABA (3-ureidopropionate/spermidine) metabolites being most prominent. Area under the curve using random forest for clinical, microbial, and metabolomic variables was higher than that of these individually. Latent factor analysis showed clinical variables (MELD 3.0, hemoglobin, and albumin) with the greatest impact, followed by salivary microbiota and then serum microbiome for hospitalization prediction. Conclusions: In a multicenter North American outpatient cirrhosis cohort with controlled etiologies, serum metabolomics and salivary microbiome add to clinical variables to prognosticate 6-month hospitalization.