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Importance SARS-CoV-2 infection has been linked to neurotoxic effects and cognitive deficits. Objective To determine whether decreases in cognitive function were accelerated after SARS-CoV-2 infection compared with individuals not infected. Design, Setting, and Participants Multicenter, prospective cohort study from 2016 to 2022 among 3525 participants alive on March 1, 2020, and enrolled in The Atherosclerosis Risk in Communities (ARIC) study and the Collaborative Cohort of Cohorts for COVID-19 Research study who completed a prepandemic cognitive assessment and a pandemic-era assessment of SARS-CoV-2 infection. Final analyses performed in November 2024. Exposure SARS-CoV-2 infection determined via self-report of a positive SARS-CoV-2 test or health care professional diagnosis of COVID-19, a positive SARS-CoV-2 antinucleocapsid antibody response, or presence of an administrative code for COVID-19 on medical records. Main outcomes and measures A neuropsychological battery assessed multiple cognitive domains, and a cocalibrated confirmatory factor analysis generated factor scores for global cognitive function. The primary outcome was the rate of excess change in cognitive function. Results The 3525 eligible participants had a mean (SD) age of 80.8 (4.7) years, 2085 (59.1%) were female, 752 (21.4%) were Black, and 2773 (78.6%) were White. SARS-CoV-2 infection was detected among 307 participants (8.7%), 103 of whom (33.6%) were hospitalized. Among uninfected participants, the mean annualized change in cognitive function was −0.09 (95% CI, −0.13 to −0.04). Compared with this rate, change was faster (β = −0.06; 95% CI, −0.09 to −0.02) among participants hospitalized for infection, but not different from participants who were infected but not hospitalized (β = 0.00; 95% CI, −0.02 to 0.03). The association among participants hospitalized for infection was evident in the cognitive domains of memory and executive function, but not language. Conclusions and relevance This cohort study of older participants found accelerated decreases in cognition among individuals hospitalized for SARS-CoV-2 infection, but not nonhospitalized infection, in comparison with individuals not yet infected.

Importance Monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased risk of cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have demonstrated cardiorenal benefits in patients with type 2 diabetes, but their effectiveness in patients with MGUS remains unexplored. Objective To assess the effectiveness of GLP-1 RAs for primary prevention of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with MGUS and diabetes. Design, Setting, and Participants This retrospective cohort study used a propensity score–matched analysis of data from the TriNetX Global Database, encompassing patients diagnosed with diabetes and MGUS between January 1, 2018, and January 13, 2023. Patients with prior heart failure (HF), ischemic heart disease, coronary revascularization, or stroke or transient ischemic attack before MGUS diagnosis were excluded. The cohort was divided into 2 groups: GLP-1 RA users and nonusers at baseline. After 1:1 propensity score matching, GLP-1 RA users and nonusers were compared up to 5 years from the MGUS diagnosis date. Data analyses were completed January 19, 2025. Exposure GLP-1 RA use within 1 year before MGUS diagnosis. Main Outcomes and Measures The primary end point was MACCE, defined as a composite of all-cause mortality, new-onset HF, acute coronary syndrome, and stroke or transient ischemic attack. Secondary end points included individual MACCE components, decompensated HF, and acute kidney injury or end-stage kidney disease. Results A total of 4871 patients with MGUS (mean [SD] age, 68.9 [10.1] years; 2366 [48.5%] male) were included (473 GLP-1 RA users and 4398 non-users). A total of 460 users were matched to 460 nonusers, with balanced characteristics (mean [SD] age, 65.0 [10.6] vs 65.1 [11.0] years; 229 [49.7%] male vs 234 [50.8%] male), including 14 patients (3.0%) vs 13 patients (2.8%) identifying as Asian, 8 (21.3%) vs 92 (20.0%) as Black or African American, 25 patients (5.4%) vs 20 patients (4.3%) as Hispanic or Latino, and 243 patients (52.8%) vs 250 patients (54.3%) as White. GLP-1 RA use was associated with a significantly lower risk of MACCE (hazard ratio [HR], 0.75; 95% CI, 0.60-0.93). Significant reductions were also observed in all-cause mortality (HR, 0.57; 95% CI, 0.37-0.87), new-onset HF (HR, 0.69; 95% CI, 0.54-0.90), decompensated HF (HR, 0.60; 95% CI, 0.43-0.84), and acute kidney injury or end-stage kidney disease (HR, 0.73; 95% CI, 0.57-0.92). Conclusions and Relevance The findings of this cohort study of GLP-1 RA use vs no use in patients with MGUS and diabetes suggest the potential of GLP-1 RA for primary prevention of MACCE. These findings warrant further investigation in prospective randomized trials.

ABSTRACT The purpose of this study was to establish tentative Clinical and Laboratory Standards Institute (CLSI) M45 MIC and disk diffusion (DD) breakpoints (BPs) for Pseudomonas other than Pseudomonas aeruginosa (POPA). Mechanisms of antimicrobial resistance (AMR) and the modified carbapenem inactivation method (mCIM) to detect carbapenemase production were also evaluated. MIC data from P. aeruginosa and POPA from 2013 to 2022 were evaluated to compare the MIC distributions and modal MICs relative to the CLSI M100 P. aeruginosa BPs. A disk-to-MIC correlation study with 83 isolates was completed by testing reference broth microdilution and DD from the same inoculum, and the error-rate bounded method was used to establish DD BPs. For most antimicrobials, the modal MICs between P. aeruginosa and POPA were within 1-doubling dilution and lower than the M100 P. aeruginosa- susceptible BP. For amikacin, the modal MIC for POPA was 2-doubling dilutions lower than P. aeruginosa and was evaluated relative to the Enterobacterales BP. For aztreonam and trimethoprim-sulfamethoxazole, the modal MICs were elevated, and no BPs were set. New DD correlates were established for most antimicrobial agents, except for fluoroquinolones, where the P. aeruginosa correlates were suitable. AMR genes conferring resistance to multiple antimicrobial classes were identified by WGS. Beta-lactamase genes were identified in 30 (36.1%) isolates, with metallo-beta-lactamases (90.6%) predominating. The mCIM had a sensitivity and specificity of 100%. Upon review, the CLSI M45 committee proposed tentative MIC and DD BPs for expanded-spectrum cephalosporins (ceftazidime and cefepime), carbapenems (meropenem and imipenem), fluoroquinolones (ciprofloxacin and levofloxacin), and the aminoglycosides (amikacin and tobramycin). IMPORTANCE Pseudomonas species other than Pseudomonas aeruginosa (POPA) can cause opportunistic infections which may be difficult to treat due to a variety of antimicrobial resistance mechanisms. Antimicrobial susceptibility testing is a critical component of patient management for these infections. Currently, the Clinical and Laboratory Standards Institute (CLSI) M100 non-Enterobacterales breakpoints and methodology are utilized for POPA by US clinical laboratories and likely do not accurately predict susceptibility results. The purpose of this study was to establish tentative CLSI M45 MIC and disk diffusion breakpoints for POPA. Mechanisms of antimicrobial resistance and the modified carbapenem inactivation method to detect carbapenemase production were also evaluated. We present the data used by the volunteers tasked by CLSI to develop POPA breakpoints in the M45 guidelines.

Background: In the emergency setting, many diagnostic pathways incorporate change in high-sensitivity cardiac troponin (hs-cTn) concentrations (i.e., the delta) to classify patients as low-risk (rule-out) or high-risk (rule-in) for possible myocardial infarction (MI). However, the impact of analytical variation on the delta for correct classification is unknown, especially at concentrations below and around the 99th percentile. Our objective was to assess the impact of delta variation for correct risk classification across the European Society of Cardiology (ESC 0/1 h and 0/2 h), the High-STEACS, and the common change criteria (3C) pathways. Methods: A yearlong accuracy study for hs-cTnT was performed where laboratories across Canada tested three patient-based samples (level 1 target value = 6 ng/L, level 2 target value = 9 ng/L, level 3 target value = 12 ng/L) monthly across 41 different analyzers. The assigned low-delta between levels 1 and 2 was 3 ng/L (i.e., 9 − 6 = 3 ng/L) and the assigned high-delta between levels 1 and 3 was 6 ng/L (i.e., 12 − 6 = 6 ng/L). The low- and high-deltas for each analyzer were determined monthly from the measured values, with the difference calculated from the assigned deltas. The obtained deltas were then assessed via the different pathways on correct classification (i.e., percent correct with 95% confidence intervals, CI) and using non-parametric analyses. Results: The median (interquartile range) difference between the measured versus assigned low-delta (n = 436) and high-delta (n = 439) was −1 ng/L (−1 to 0). The correct classification differed among the pathways. The ESC 0/1 h pathway yielded the lowest percentage of correct classification at 35.3% (95% CI: 30.8 to 40.0) for the low-delta and 90.0% (95% CI: 86.8 to 92.6) for the high-delta. The 3C and ESC 0/2 h pathways yielded higher and equivalent estimates on correct classification: 95.2% (95% CI: 92.7 to 97.0) for the low-delta and 98.2% (95% CI: 96.4 to 99.2) for the high-delta. The High-STEACS pathway yielded 99.5% (95% CI: 98.4 to 99.9) of correct classifications for the high-delta but only 36.2% (95% CI: 31.7 to 40.9) for the low-delta. Conclusions: Analytical variation will impact risk classification for MI when using hs-cTn deltas alone per the pathways. The 3C and ESC 0/2 h pathways have <5% misclassification when using deltas for hs-cTnT in this dataset. Additional studies with different hs-cTnI assays at concentrations below and near the 99th percentile are warranted to confirm these findings.

Introduction: Workplace violence (WPV) in healthcare is detrimental to staff and institutions. The prevalence of events continues to increase despite efforts to mitigate events. WPV is associated with psychological and physical consequences and has been attributed to healthcare workers leaving the field, further contributing to the shortage of frontline healthcare staff. Healthcare workers often underreport WPV events due to cultures of acceptance, lack of knowledge of resources, and feeling unsupported during or after an event. Aim: This quality improvement project aimed to implement a WPV bundle and evaluate the effectiveness of staff utilization of WPV resources, perceived confidence, knowledge, and support during and after WPV events in a general surgery unit. Method: A hybrid education bundle, named the Violet Education Bundle, includes education for nurses on de-escalation techniques, incident reporting, standardization of shift-change huddle reporting, and resources for psychological support. A single-group, pre- and post-test design was utilized, and a paired t -test was employed to test for statistical significance. Results: With 23.2% of staff ( N = 20) completing both the pre-/post-survey (support, confidence, knowledge, and resource utilization sections) at both time points, no pre- to post-implementation outcome increases were statistically significant. Conclusion: Though the 60-day follow-up might have contributed to the null findings, nurses anecdotally expressed that they found the resources valuable and appreciated having them in one place. Future research should include an assessment of effectiveness for improving staff confidence, knowledge, perceived support, and reduced incidence and complications of WPV events over a sustained period of time.

Abstract Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8 + T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8 + T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

INTRODUCTION: Many patients with chronic pouchitis and Crohn's-like disease of the pouch (CLDP) are treated with biologics; however, the comparative effectiveness of advanced therapies in this population has not been systematically evaluated. We sought to compare the effectiveness of antitumor necrosis factor α (anti-TNF) therapies and ustekinumab in patients with chronic inflammatory conditions of the pouch. METHODS: We conducted a prospective, multicenter, cohort study. We included patients with chronic pouchitis and CLDP initiating treatment with anti-TNF therapies or ustekinumab. The primary outcome was clinical remission at 6 months after induction. We also evaluated clinical remission at 6 months among patients with chronic pouchitis and CLDP separately. RESULTS: Among 132 patients, 106 (80%) had a diagnosis of CLDP and 82 (62%) initiated therapy with ustekinumab. A significantly higher proportion of patients with CLDP treated with ustekinumab were in clinical remission at 6 months as compared with patients treated with anti-TNF therapy (62% vs 40%, P = 0.027); however, there was no significant difference among patients with chronic pouchitis ( P = 0.946). There was no independent statistical significance in the odds of remission at 6 months among patients with CLDP among patients receiving ustekinumab compared with anti-TNF therapy (adjusted odds ratio 1.91, 95% confidence interval 0.69–5.30) after adjusting for presence of a fistula, number of preoperative advanced therapies, and number of advanced therapies after IPAA. DISCUSSION: These data suggest the potential benefit of ustekinumab in patients with CLDP and should prompt future novel effectiveness evaluations in this population.

Objectives: Esophageal cancer (EC) often presents with dysphagia due to tumor obstruction. Esophageal stenting has the potential of palliating dysphagia, improving nutrition, preventing aspiration, and improving quality of life (QoL) but may be associated with risks. The present systematic review and guidelines are intended to assist treatment decision-making when considering stent placement in patients with EC based on the available evidence. Methods: Using the population, intervention, comparator, outcome, timing and study design framework, the evidence was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included prospective phase II-III trials and retrospective analyses published between January 1, 2010 and December 3, 2024 in the Ovid Medline database. These references were assessed by American Radium Society (ARS) Appropriate Use Criteria (AUC) methodology. RAND-UCLA consensus methodology was used to rate the appropriateness of the use of stents. Results: ARS AUC recommendations include (1) esophageal stenting is usually not appropriate in patients with early-stage EC in whom upfront surgery is planned; (2) esophageal stenting is usually not appropriate in patients with locally-advanced EC in whom neoadjuvant/perioperative therapy and esophagectomy or definitive chemoradiation is planned; (3) esophageal stenting may be appropriate in the setting of metastatic EC, especially in patients with short life expectancy with limited treatment options; (4) esophageal stenting is usually not appropriate for benign stricture following curative-intent therapy; (5) esophageal stenting is usually not appropriate for locally recurrent tumor in the setting of prior radiation; and (6) esophageal stenting is usually appropriate for management of tracheoesophageal fistula before curative-intent treatment. Conclusions: This ARS AUC summary provides guidelines for the use of esophageal stents in patients with EC provides based on available evidence.

ABSTRACT Background and Purpose Diffusion tensor imaging (DTI) is commonly used to assess the integrity of gray and white matter (WM) structures in progressive supranuclear palsy (PSP). Beyond DTI, nontraditional diffusion techniques such as diffusion kurtosis imaging (DKI) have been shown to characterize brain tissue further. In this work, we aim to determine the utility of DKI in the differential diagnosis of PSP—Richardson syndrome (PSP‐RS) and PSP with predominant parkinsonism (PSP‐P) from Parkinson's disease (PD) and controls. Methods A multishell diffusion‐weighted sequence was acquired at 3 Tesla on a Siemens system in 22 patients with PSP‐RS, 23 with PSP‐P, 19 with PD, and 19 controls. Fractional anisotropy, mean diffusivity, kurtosis fractional anisotropy (KFA), and mean kurtosis (Kmean) were calculated for nine deep gray matter regions and six different WM tracts. Results DKI identified differences (not found by DTI) between control and PSP groups in the globus pallidum externus, subthalamic region, and putamen, with Kmean in the putamen able to differentiate PSP‐RS and PD. DKI WM measurements in the body of the corpus callosum and dentatorubrothalamic tract differentiated PSP‐RS from PD, and the corticostriatal tract differentiated PSP‐P from PD. KFA in the body of the corpus callosum identified worse microstructural anomalies in PSP‐RS compared to PSP‐P. DKI metrics correlated with the severity of ocular motor impairment and parkinsonism scores. Conclusions DKI measurements could differentiate PSP‐RS, PSP‐P, and PD and, hence, may be a promising imaging tool for studying structural neuropathological changes in PSP.