Citations

Abstract Background Uncertainty exists regarding the effectiveness of COVID-19 vaccine to prevent postacute sequelae of COVID-19 (PASC) following a breakthrough infection. While most studies based on symptom surveys found an association between preinfection vaccination status and PASC symptoms, studies of medically attended PASC are less common and have reported conflicting findings. Methods In this retrospective cohort of patients with an initial SARS-CoV-2 infection who were continually empaneled for primary care in a large US health system, the electronic health record was queried for preinfection vaccination status, demographics, comorbidity index, and diagnosed conditions. Multivariable logistic regression was used to model the outcome of a medically attended PASC diagnosis within 6 months of SARS-CoV-2 infection. Likelihood ratio tests were used to assess the interaction between vaccination status and prevalent variant at the time of infection and between vaccination status and hospitalization for SARS-CoV-2 infection. Results During the observation period, 6.9% of patients experienced medically attended and diagnosed PASC. A diagnosis of PASC was associated with older age, female sex, hospitalization for the initial infection, and an increased severity-weighted comorbidity index and was inversely associated with infection during the Omicron period. No difference in the development of diagnosed PASC was observed between unvaccinated patients and those vaccinated with either 2 doses of an mRNA vaccine or >2 doses. Conclusions We found no association between vaccination status at the time of infection and development of medically diagnosed PASC. Vaccine remains an important measure to prevent SARS-CoV-2 infection and severity. Further research is needed to identify effective measures to prevent and treat PASC.

Abstract Purpose Research suggests that burnout can begin early in medical school, yet burnout among preclerkship students remains underexplored. This study aimed to characterize burnout signs, sources, coping strategies, and potential interventions among preclerkship students at one U.S. medical school. Method The authors conducted a qualitative study of preclerkship students at Mayo Clinic Alix School of Medicine (MCASOM) in June 2019. Participants completed 2 Maslach Burnout Inventory (MBI) items (measuring frequency of emotional exhaustion and depersonalization) and 2 free-text questions on burnout before participating in 1 of 3 semistructured focus groups. Focus group questions were derived from a literature review on medical student burnout with input from the MCASOM Student Life and Wellness Committee. Group discussions were recorded, transcribed, coded inductively, and analyzed iteratively (along with free-text comments) using a general inductive approach from a constructivist perspective. Results Eighteen of 111 eligible students (16%) participated, with 5/18 (28%) reporting weekly emotional exhaustion and/or depersonalization on MBI items. Analysis of focus group transcripts showed that most students had experienced burnout symptoms during their first or second year, corresponding with school-related stressors and manifesting in cognitive-emotional, physical, and verbal-behavioral ways. Students identified systemic, institutional, and individual burnout drivers and discussed how these drivers interacted (e.g., high standards of excellence at the system level interacted with anxiety and maladaptive thinking at the individual level, creating pressure to always do more). Students used various coping strategies (e.g., self-care, peer support, reframing, and compartmentalization) but emphasized limitations of these strategies and recommended interventions directed toward systemic and institutional burnout drivers. Conclusions This study offers insights into burnout signs and sources among preclerkship medical students that can inform future large-scale studies. Results suggest that burnout emerges from dynamic interactions among systemic, institutional, and individual factors and may benefit from multipronged interventions.

ABSTRACT Some negative-sense RNA viruses, including measles virus (MeV), share the characteristic that during their infection cycle, cytoplasmic inclusion bodies (IBs) are formed where components of the viral replication machinery are concentrated. As a foci of viral replication, how IBs act to enhance the efficiency of infection by affecting virus-host interactions remains an important topic of investigation. We previously established that upon MeV infection, the epigenetic host protein, WD repeat-containing protein 5 (WDR5), translocates to cytoplasmic viral IBs and facilitates MeV replication. We now show that WDR5 is recruited to IBs by forming a complex with IB-associated MeV phosphoprotein via a conserved binding motif located on the surface of WDR5. Furthermore, we provide evidence that WDR5 promotes viral replication by suppressing a major innate immune response pathway, the double-stranded RNA-mediated activation of protein kinase R and integrated stress response. IMPORTANCE MeV is a pathogen that remains a global concern, with an estimated 9 million measles cases and 128,000 measles deaths in 2022 according to the World Health Organization. A large population of the world still has inadequate access to the effective vaccine against the exceptionally transmissible MeV. Measles disease is characterized by a high morbidity in children and in immunocompromised individuals. An important area of research for negative-sense RNA viruses, including MeV, is the characterization of the complex interactome between virus and host occurring at cytoplasmic IBs where viral replication occurs. Despite the progress made in understanding IB structures, little is known regarding the virus-host interactions within IBs and the role of these interactions in promoting viral replication and antagonizing host innate immunity. Herein we provide evidence suggesting a model by which MeV IBs utilize the host protein WDR5 to suppress the protein kinase R-integrated stress response pathway.

ABSTRACT Errors in antibiotic prescriptions are frequent, often resulting from the inadequate coverage of the infection-causative microorganism. The efficacy of iAST, a machine-learning-based software offering empirical and organism-targeted antibiotic recommendations, was assessed. The study was conducted in a 12-hospital Spanish institution. After model fine-tuning with 27,531 historical antibiograms, 325 consecutive patients with acute infections were selected for retrospective validation. The primary endpoint was comparing each of the top three of iAST’s antibiotic recommendations’ success rates (confirmed by antibiogram results) with the antibiotic prescribed by the physicians. Secondary endpoints included examining the same hypothesis within specific study population subgroups and assessing antibiotic stewardship by comparing the percentage of antibiotics recommended that belonged to different World Health Organization AWaRe groups within each arm of the study. All of iAST first three recommendations were non-inferior to doctor prescription in the primary endpoint analysis population as well as the secondary endpoint. The overall success rate of doctors’ empirical treatment was 68.93%, while that of the first three iAST options was 91.06% ( P < 0.001), 90.63% ( P < 0.001), and 91.06% ( P < 001), respectively. For organism-targeted therapy, the doctor’s overall success rate was 84.16%, and that of the first three ranked iAST options was 97.83% ( P < 0.001), 94.09% ( P < 0.001), and 91.30% ( P < 0.001), respectively. In empirical therapy, compared to physician prescriptions, iAST demonstrated a greater propensity to recommend access antibiotics, fewer watch antibiotics, and higher reserve antibiotics. In organism-targeted therapy, iAST advised a higher utilization of access antibiotics. The present study demonstrates iAST accuracy in predicting antibiotic susceptibility, showcasing its potential to promote effective antibiotic stewardship. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT06174519 .

Dysregulated actin cytoskeleton gives rise to aberrant cell motility and metastatic spread of tumor cells. This study evaluates the effect of overexpression of wild-type versus functional mutants of MRTF-A on migration and invasion of breast cancer (BC) cells. Our studies indicate that SRF's interaction is critical for MRTF-A-induced promotion of both two-dimensional and three-dimensional cell migration, while the SAP-domain function is important selectively for three-dimensional cell migration. Increased MRTF-A activity is associated with more effective membrane protrusion, a phenotype that is attributed predominantly to SRF's interaction with MRTF. We demonstrate formin-family protein mDia2 as an important mediator of MRTF-stimulated actin polymerization at the leading edge and cell migration. Multiplexed quantitative immunohistochemistry and transcriptome analyses of clinical BC specimens further demonstrate a positive correlation between nuclear localization of MRTF with malignant traits of cancer cells and enrichment of MRTF–SRF gene signature in pair-matched distant metastases versus primary tumors. In conclusion, this study establishes a novel mechanism of MRTF-dependent regulation of cell migration and provides evidence for the association between MRTF activity and increased malignancy in human BC, justifying future development of specific small molecule inhibitors of the MRTF-SRF transcriptional complex as potential therapeutic agents in BC.

AbstractDue to the anatomic complexity of the head and neck and variable proximity between laboratory and operating room (OR), effective communication during frozen section analysis (FSA) between surgeons and pathologists is challenging. This proof‐of‐concept study investigates an augmented reality (AR) protocol that allows pathologists to virtually join the OR from the laboratory. Head and neck cancer specimens were scanned ex vivo using a 3‐dimensional scanner and uploaded into an AR platform. Eight head and neck specimens were discussed by surgeons and pathologists in an AR environment. AR‐guided intraoperative consultation was used for specimen orientation and discussion of FSA margin sampling sites. One patient had positive initial margins on FSA and was re‐resected to negative final margins. AR‐guided FSA is possible and allows pathologists to join the operating from any location for intraoperative discussion.

Background Professional opinion polling has become a popular means of seeking advice for complex nephrology questions in the #AskRenal community on X. ChatGPT is a large language model with remarkable problem-solving capabilities, but its ability to provide solutions for real-world clinical scenarios remains unproven. This study seeks to evaluate how closely ChatGPT's responses align with current prevailing medical opinions in nephrology. Methods Nephrology polls from X were submitted to ChatGPT-4, which generated answers without prior knowledge of the poll outcomes. Its responses were compared to the poll results (inter-rater) and a second set of responses given after a one-week interval (intra-rater) using Cohen's kappa statistic (κ). Subgroup analysis was performed based on question subject matter. Results Our analysis comprised two rounds of testing ChatGPT on 271 nephrology-related questions. In the first round, ChatGPT's responses agreed with poll results for 163 of the 271 questions (60.2%; κ = 0.42, 95% CI: 0.38–0.46). In the second round, conducted to assess reproducibility, agreement improved slightly to 171 out of 271 questions (63.1%; κ = 0.46, 95% CI: 0.42–0.50). Comparison of ChatGPT's responses between the two rounds demonstrated high internal consistency, with agreement in 245 out of 271 responses (90.4%; κ = 0.86, 95% CI: 0.82–0.90). Subgroup analysis revealed stronger performance in the combined areas of homeostasis, nephrolithiasis, and pharmacology (κ = 0.53, 95% CI: 0.47–0.59 in both rounds), compared to other nephrology subfields. Conclusion ChatGPT-4 demonstrates modest capability in replicating prevailing professional opinion in nephrology polls overall, with varying performance levels between question topics and excellent internal consistency. This study provides insights into the potential and limitations of using ChatGPT in medical decision making.

BACKGROUND: Associations between magnetic resonance imaging markers of cerebral small vessel disease (CSVD) and dementia risk in older adults have been established, but it remains unclear how lifestyle factors, including psychosocial health, may modify this association. METHODS: Social support and social isolation were assessed among participants of the community-based ARIC (Atherosclerosis Risk in Communities) Study, via self-reported questionnaires (1990–1992). Following categorization of both factors, participants were classified as having strong or poor mid-life social relationships. At visit 5 (2011–2013), participants underwent 3T brain magnetic resonance imaging quantifying CSVD measures: white matter hyperintensity volume, microbleeds (subcortical), infarcts (lacunar), and white matter integrity (diffusion tensor imaging). Incident dementia cases were identified from the time of imaging through December 31, 2020 with ongoing surveillance. Associations between CSVD magnetic resonance imaging markers and incident dementia were evaluated using Cox proportional-hazard regressions adjusted for demographic and additional risk factors (from visit 2). Effect modification by mid-life social relationships was evaluated. RESULTS: Of the 1977 participants with magnetic resonance imaging, 1617 participants (60.7% women; 26.5% Black participants; mean age at visit 2, 55.4 years) were examined. In this sample, mid-life social relationships significantly modified the association between white matter hyperintensity volume and dementia risk ( P interaction=0.001). Greater white matter hyperintensity volume was significantly associated with risk of dementia in all participants, yet, more substantially in those with poor (hazard ratio, 1.84 [95% CI, 1.49–2.27]) versus strong (hazard ratio, 1.26 [95% CI, 1.08–1.47]) mid-life social relationships. Although not statistically significant, subcortical microbleeds in participants with poor mid-life social relationships were associated with a greater risk of dementia, relative to those with strong social relationships, in whom subcortical microbleeds were no longer associated with elevated dementia risk. CONCLUSIONS: The elevated risk of dementia associated with CSVD may be reduced in participants with strong mid-life social relationships. Future studies evaluating psychosocial health through the life course and the mechanisms by which they modify the relationship between CSVD and dementia are needed.

Abstract Background Slower speaking rates and higher pause rates are found in individuals with migraine or post‐traumatic headache during headache compared to when headache‐free. We aimed to determine whether headache intensity influences the speaking rate and pause rate of participants with migraine or acute post‐traumatic headache (aPTH) following mild traumatic brain injury (mTBI). Methods Using a speech elicitation tool, participants with migraine, aPTH, and healthy controls (HC) submitted speech samples over a period of 3 months. Speaking and pause rates were calculated when participants were headache‐free and when they had mild or moderate headache. In this observational study, speaking and pause rates in participants with migraine and aPTH were compared to HC, controlling for age, sex, and days since mTBI (participants with aPTH only). Results A total of 2902 longitudinal speech samples from 13 individuals with migraine (mean age = 33.5, SD = 6.6; 12 females/1 male), 43 individuals with aPTH (mean age = 44.4, SD = 13.5; 28 females/15 males), and 56 HC (mean age = 40.8, SD = 13.0; 36 females/20 males) were collected. There was no difference in speaking rate between HC and the combined headache cohort of participants (migraine and aPTH) when they had headache freedom or a mild headache. When participants had moderate intensity headache, their speaking rate was significantly slower compared to that of HC and compared to their speaking rate during mild headache intensity or headache freedom. For the combined headache cohort of participants, pause rates were significantly higher when they had headache freedom or had a headache of mild or moderate intensity relative to HC. Compared to participants' pause rate during headache freedom, their pause rate was significantly higher during mild and moderate headache intensity. Participants with aPTH had significantly slower speaking rates compared to participants with migraine during headache freedom, mild headache intensity, and moderate headache intensity. Participants with aPTH had significantly higher pause rates compared to participants with migraine when experiencing moderate headache intensity. Discussion For both aPTH and migraine, more severe headache pain was associated with higher pause rates and slower speaking rates, suggesting that speaking rate and pause rate could serve as objective biomarkers for headache‐related pain. Slower speaking rate in participants with aPTH could reflect additional consequences of TBI‐related effects on motor control and speech production.