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Importance High-quality evidence guiding opioid prescribing decisions for acute pain across common diagnoses is lacking. Objective To describe pain trajectories and patterns of opioid and nonopioid treatment use among individuals who were offered opioids for the treatment of acute pain. Design, Setting, and Participants This was a prospective cohort study of patients recruited from 5 US health systems between September 2020 and March 2023 in emergency departments (EDs), primary care clinics, dental practices, or after cesarean delivery or knee replacement. Eligible patients were opioid-naive adults aged 18 years or older at all study sites, as well as adolescents aged 15 to17 years undergoing impacted molar extraction at 1 site, who were offered an opioid prescription for acute pain. Analysis was conducted April 2023 through February 2026. Exposure Offer of a prescription for an opioid analgesic. Main Outcomes and Measures Time to pain resolution (3 consecutive reports of no pain), patterns of opioid and nonopioid treatment use, and opioid-related adverse effects, ascertained from digital questionnaires. Results Among 1708 enrolled patients (median age, 38 years [IQR, 28-52 years]; 615 [36.0%] reporting race or ethnicity underrepresented in studies of acute pain management) followed up for 180 days, 915 (53.6%) were recruited in EDs, 307 (18.0%) in primary or urgent care, 263 (15.4%) in dental settings, and 223 (13.1%) in inpatient settings. Pain sources included dental (302 patients [17.7%]), trauma or injury (302 [17.7%]), obstetric (176 [10.3%]), musculoskeletal (131 [7.7%]), and low back (100 [5.9%]). Among 1502 patients reporting pain level at least once, median time to pain resolution irrespective of the treatment approach was 20 days (IQR, 8-88 days), with longer durations for surgical pain (74 days [IQR, 30 days to not reached]) and low back pain (69 days [IQR, 18 days to not reached]). The median time to opioid discontinuation among 1189 patients (69.6%) who reported any opioid use was 7 days (IQR, 2-31 days); an estimated 10.0% (95% CI, 7.7%-12.7%) of patients used opioids for at least 90 days, with higher rates in people reporting frequent pain before enrollment. Of 1482 patients (86.8%) completing at least 1 survey during the first 2 weeks of follow-up, 1153 (77.8%) reported using any opioids and 1287 (86.8%) reported using acetaminophen or ibuprofen. Among 619 (52.1%) patients with any opioid use who reported the dose of opioids taken in the first 15 days, daily doses were low (median, 10 [IQR, 5-15] morphine milligram equivalents). Most respondents reported leftover opioids (657 of 982 responding [66.9%]). Conclusions and Relevance In this cohort study of opioid-naive patients with acute pain, opioid use was generally low dose and of short duration, although some patients reported prolonged opioid use; most reported achieving pain resolution within 3 weeks, with longer times for surgical and low back pain. The findings suggest current guidelines for multimodal treatment and for short-duration opioid prescriptions if needed will serve many but not all patients, and treatment should be tailored to address individual patients’ needs.

Importance Risk-reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high-risk individuals, but adverse effects from premature menopause are a barrier to uptake. Interval salpingectomy with delayed oophorectomy (ISDO) may be an effective alternative. Objective To evaluate the association of ISDO vs RRSO and sexual function and menopausal symptoms. Design, Setting, and Participants This prospective, multicenter, nonrandomized (patient preference) clinical trial was performed among Women Choosing Surgical Prevention participants with a pathogenic or likely pathogenic germline variant conferring an increased risk for ovarian cancer. Patients from 9 US centers were enrolled from June 2, 2016, to October 28, 2020; chose ISDO or RRSO; and were followed up for 24 months. The analysis was performed on November 13, 2024. Interventions Participant-selected RRSO or ISDO. Main Outcomes and Measures Changes in sexual function and menopausal symptoms from baseline to 6, 12, and 24 months. Inverse probability weighting was applied to achieve covariate balance across groups. Results The analytic sample included 334 female participants (mean [95% CI] age at consent, 39.2 [38.7-.9.7] years) who underwent RRSO (n = 165) or ISDO (n = 169) and completed 6-month questionnaires. Significantly more participants experienced clinically meaningful worsening of sexual function at 6 months compared with baseline after RRSO vs ISDO (33.1% [39 of 118] vs 16.8% [17 of 101], respectively; odds ratio, 2.00 [95% CI, 1.20-3.35]) and at 12 months (39.2% [38 of 97] vs 18.3% [17 of 93], respectively; odds ratio, 1.69 [95% CI, 1.09-2.63]). This finding was no longer significant at 24 months. When restricted to the RRSO group who took hormone replacement therapy, there was no significant worsening of total sexual function scores or menopausal symptoms compared with baseline. No interval ovarian cancers were reported. Conclusions and Relevance This nonrandomized clinical trial comparing RRSO with ISDO found that ISDO was less likely to impair sexual function, which addresses an important barrier to surgical prevention in high-risk patients in premenopause. After RRSO, use of hormone replacement therapy mitigated menopausal symptoms and prevented decline in sexual function. More information is needed about the safety of ISDO. Trial Registration ClinicalTrials.gov Identifier: NCT02760849

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Abstract Background Alzheimer’s disease (AD) is clinicopathologically heterogeneous. A proportion of patients living with AD present clinically at a younger onset of cognitive symptoms before 65 years old and/or non-amnestic clinical syndromes. Neuropathologically, corticolimbic distribution of neurofibrillary tangle pathology occurs on a continuum with some cases having greater cortical tau pathology relative to limbic regions and others with relatively restricted accumulation in limbic structures. These patterns of corticolimbic tangle distribution are associated with clinical presentation and age at onset. This study sought to examine protein expression differences across the spectrum of clinicopathologic heterogeneity using the NULISA targeted proteomics platform. Methods A series of thirteen neuropathologically diagnosed AD cases from Mayo Clinic prospectively followed research studies were selected to reflect heterogeneity of clinical syndromes and corticolimbic distribution of tangle pathology. Frozen postmortem brain tissue samples were isolated from inferior parietal cortex and homogenized in RIPA buffer for analysis using Alamar Biosciences’ NULISA CNS disease 120 panel. Applying a conservative detection threshold of 75% level of detection for the novel application of NULISA in human brain, we evaluated levels of 69 of 129 protein targets across samples. We examined associations between age at onset cognitive symptoms and corticolimbic distribution of tangles (CLix) separately with individual protein targets using linear regression analysis. Results AD cases with a younger age at onset had higher measured levels of ubiquitin, while older age was associated with higher levels of total tau, CRH, and NPTX2. Investigations of corticolimbic heterogeneity revealed AD cases with lower CLix score (i.e., cortical predominant distribution of tau) had higher measured p-tau181, p-tau231, ubiquitin, and p62. AD cases with higher CLix (i.e., relative cortical sparing) had higher levels of total tau, CRH, NPTX2, MDH1, and HBA1. Brain-derived total tau consistently showed a stronger association in both models. Conclusion This work demonstrates the utility of postmortem proteomics for investigating biomarkers associated with AD clinicopathologic heterogeneity. We observed proteomic differences in synapse integrity, tau post-translational modification, and ubiquitination associated with age at symptomatic onset and corticolimbic distribution of tangle pathology.

Background/Purpose Although intravenous (IV) regular insulin has been the main treatment option for management of acute hyperkalemia, our institution utilizes IV insulin lispro as the preferred rapid-acting insulin. Little data currently exists on the safety or efficacy of insulin lispro for this indication. This study aims to evaluate the safety and efficacy of this alternative. Methods This study is a retrospective chart review of adult patients who received IV insulin lispro in an academic medical center Emergency Department (ED) for the treatment of hyperkalemia. The main efficacy and safety outcomes evaluated within 6 hours post-insulin administration were: change in serum potassium concentration and the incidence of hypoglycemia. Results One hundred and thirteen IV insulin lispro administrations were included. For evaluation of efficacy, the mean serum potassium before insulin administration was 6.6 mmol/L. The mean first serum potassium concentration after insulin administration was 5.5 mmol/L, with a serum potassium decrease of 1.1 mmol/L. As for safety, the mean blood glucose before insulin administration was 147.8 mg/dL. The mean first blood glucose after insulin administration was 149.9 mg/dL. Dextrose was co-administered 90.2% of the time. There were a total of 18 hypoglycemic events (15.9%), including 3 events that met the criteria for severe hypoglycemia (2.7%). Conclusion For treatment of hyperkalemia in ED patients, IV insulin lispro appears to be an efficacious alternative to IV insulin regular. However, a further review of its safety profile is warranted.

Context.— The diagnosis and characterization of well-differentiated neuroendocrine tumors (WDNETs) on cytology is challenging, with recognized pitfalls that may have therapeutic and prognostic implications. Objective.— To analyze data curated by the College of American Pathologists educational slide program for accuracy in the cytologic diagnosis of WDNET. The current state of cytologic diagnosis of WDNET is also reviewed for educational purposes. Design.— The study cohort included non-gynecologic cytology slides reviewed by participants in the College of American Pathologists Non-Gynecologic Cytopathology Education program. Individual responses for cytotechnologists or cytologists (CT) and pathologists were collated for WDNET. The data were analyzed for concordance with the correct general diagnosis and concordance with the correct reference diagnosis. The exact reference diagnosis available for each site was “pancreatic neuroendocrine tumor,” “liver, well/moderately differentiated neuroendocrine tumor,” and “lung, well/moderately differentiated neuroendocrine tumor.” Performance measures were assessed. Results.— The WDNET analysis includes 8941 responses from 1382 laboratories. The selection of the general diagnosis of “malignant” or “suspicious for malignancy” was greater than 90% in all body sites. Pathologists correctly identifying WDNET was highest in the pancreas (2501/2738, 91.3%) compared with the lung (805/1019, 79.0%) and liver (1444/1966, 73.4%). Pathologists had better concordance with the diagnosis of WDNET in all sites than CTs ( P < .001). Conclusions.— This large study, encompassing pathologists and CTs, confirms that although participants can identify WDNET on cytology, opportunities for greater accuracy and education persist. The most common incorrect response in the pancreas was adenocarcinoma, while the most common misdiagnosis was small cell carcinoma in the lung and liver.

Background: The dysregulation of the CDK1/Cyclin B1 complex drives tumor progression in breast cancer (BC). The natural flavonoid luteolin (LT) shows anti-cancer potential, but its mechanism targeting CDK1/CCNB1 remains unclear. Methods: CDK1, CCNB1, and CCNB2 expression were profiled in normal and BC cell lines. An engineered HEK293T GST-CDK1/CCNB1 cell model was used to evaluate LT’s effects on proliferation, ROS levels, and target gene transcription. Computational approaches (molecular docking, dynamics simulations, pharmacophore modeling, MM/GBSA, ADMET, and network pharmacology) assessed LT and its analogues. Results: CDK1/CCNB1 expression was lower in MCF7 BC cells than in normal cells, suggesting the loss of a growth barrier. In engineered HEK293T cells, LT suppressed CCNB1 transcription with minimal effect on CDK1 levels, correlating with anti-proliferative and ROS-modulating effects. Computational analyses confirmed stable LT binding to the CDK1/CCNB1 complex. Designed LT analogues showed improved binding and favorable ADMET profiles. Network pharmacology identified cell cycle regulation, particularly in BC stem cells, as the primary pathway targeted. Conclusions: LT and its analogues inhibit the CDK1/Cyclin B1 complex, revealing a dual mechanism that suppresses both tumor growth and BC stemness.

Ehlers-Danlos syndrome (EDS) is a heritable collagen disorder characterized by joint hypermobility and tissue fragility, with hypermobile Ehlers-Danlos syndrome (hEDS) as the most common subtype. Rates of gastroesophageal reflux disease (GERD) symptoms are reportedly higher in the hEDS population than the general population. This could be caused by increased esophageal hypersensitivity and/or connective tissue laxity leading to hiatal hernias or increased relaxations of the lower esophageal sphincter. Despite this, Barrett’s esophagus rates in hEDS do not appear to be higher than in the general population. This review examines the epidemiology, pathophysiology, and unique considerations for management of GERD in hEDS.