Tup1 is critical for transcriptional repression in Quiescence in S. cerevisiae.

Upon glucose starvation, S. cerevisiae shows a dramatic alteration in transcription, resulting in wide-scale repression of most genes and activation of some others. This coincides with an arrest of cellular proliferation. A subset of such cells enters quiescence, a reversible non-dividing state. Here, we demonstrate that the conserved transcriptional corepressor Tup1 is critical for transcriptional repression after glucose depletion. We show that Tup1-Ssn6 binds new targets upon glucose depletion, where it remains as the cells enter the G0 phase of the cell cycle. In addition, we show that Tup1 represses a variety of glucose metabolism and transport genes. We explored how Tup1 mediated repression is accomplished and demonstrated that Tup1 coordinates with the Rpd3L complex to deacetylate H3K23. We found that Tup1 coordinates with Isw2 to affect nucleosome positions at glucose transporter HXT family genes during G0. Finally, microscopy revealed that a quarter of cells with a Tup1 deletion contain multiple DAPI puncta. Taken together, these findings demonstrate the role of Tup1 in transcriptional reprogramming in response to environmental cues leading to the quiescent state.

Genomic Analyses of Longitudinal Mycobacterium abscessus Isolates in a Multicenter Cohort Reveal Parallel Signatures of In-Host Adaptation.

BACKGROUND: Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an increasingly frequent cause of opportunistic infections. Mycobacterium abscessus complex (MABC) is one of the major NTM lung pathogens that disproportionately colonize and infect the lungs of individuals with cystic fibrosis (CF). MABC infection can persist for years, and antimicrobial treatment is frequently ineffective. METHODS: We sequenced the genomes of 175 isolates longitudinally collected from 30 patients with MABC lung infection. We contextualized our cohort amidst the broader MABC phylogeny and investigated genes undergoing parallel adaptation across patients. Finally, we tested the phenotypic consequences of parallel mutations by conducting antimicrobial resistance and mercury-resistance assays. RESULTS: We identified highly related isolate pairs across hospital centers with low likelihood of transmission. We further annotated nonrandom parallel mutations in 22 genes and demonstrated altered macrolide susceptibility co-occurring with a nonsynonymous whiB1 mutation. Finally, we highlighted a 23-kb mercury-resistance plasmid whose loss during chronic infection conferred phenotypic susceptibility to organic and nonorganic mercury compounds. CONCLUSIONS: We characterized parallel genomic processes through which MABC is adapting to promote survival within the host. The within-lineage polymorphisms we observed have phenotypic effects, potentially benefiting fitness in the host at the putative detriment of environmental survival.

Spatial Epidemiologic Analysis and Risk Factors for Nontuberculous Mycobacteria Infections, Missouri, USA, 2008-2019.

Nontuberculous mycobacteria (NTM) infections are caused by environmental exposure. We describe spatial distribution of NTM infections and associations with sociodemographic factors and flooding in Missouri, USA. Our retrospective analysis of mycobacterial cultures reported to the Missouri Department of Health and Social Services surveillance system during January 1, 2008-December 31, 2019, detected geographic clusters of infection. Multilevel Poisson regression quantified small-area geographic variations and identified characteristics associated with risk for infection. Median county-level NTM infection rate was 66.33 (interquartile range 51-91)/100,000 persons. Risk of clustering was significantly higher in rural areas (rate ratio 2.82, 95% CI 1.90-4.19) and in counties with >5 floodings per year versus no flooding (rate ratio 1.38, 95% CI 1.26-1.52). Higher risk for NTM infection was associated with older age, rurality, and more flooding. Clinicians and public health professionals should be aware of increased risk for NTM infections, especially in similar environments.

Analysis of financial challenges faced by graduate students in Canada.

Graduate students are vital to the creation of research and innovation in Canada. The National Graduate Student Finance Survey was launched in 2021 by the Ottawa Science Policy Network to investigate the financial realities of Canadian graduate students. Closing in April 2022, the survey received 1305 responses from graduate students representing various geographical locations, years of study, fields of education, and demographic backgrounds. The results capture a snapshot into graduate student finances, including an in-depth analysis of stipends, scholarships, debt, tuition, and living expenses. In its entirety, we found that the majority of graduate students are facing serious financial concerns. This is largely due to stagnant funding for students both from federal and provincial granting agencies and from within their institutions. This reality is even worse for international students, members of historically underrepresented communities, and those with dependents, all of whom experience additional challenges that impact their financial security. Based on our findings, we propose several recommendations to the Tri-Council agencies (Natural Sciences and Engineering Research Council, Social Science and Humanities Research Council, and Canadian Institute for Health Research) and academic institutions to strengthen graduate student finances and help sustain the future of research in Canada.

Body Imaging of Bacterial and Parasitic Zoonoses: Keys to Diagnosis.

Zoonotic infections, which are transmitted from animals to humans, have been a substantial source of human disease since antiquity. As the human population continues to grow and human influence on the planet expands, humans frequently encounter both domestic and wild animals. This has only increased as deforestation, urbanization, agriculture, habitat fragmentation, outdoor recreation, and international travel evolve in modern society, all of which have resulted in the emergence and reemergence of zoonotic infections. Zoonotic infections pose a diagnostic challenge because of their nonspecific clinical manifestations and the need for specialized testing procedures to confirm these diagnoses. Affected patients often undergo imaging during their evaluation, and a radiologist familiar with the specific and often subtle imaging patterns of these infections can add important clinical value. The authors review the multimodality thoracic, abdominal, and musculoskeletal imaging findings of zoonotic bacterial (eg, Bartonella henselae, Pasteurella multocida, Francisella tularensis, Coxiella burnetii, and Brucella species), spirochetal (eg, Leptospira species), and parasitic (eg, Echinococcus, Paragonimus, Toxocara, and Dirofilaria species) infections that are among the more commonly encountered zoonoses in the United States. Relevant clinical, epidemiologic, and pathophysiologic clues such as exposure history, occupational risk factors, and organism life cycles are also reviewed. Although many of the imaging findings of zoonotic infections overlap with those of nonzoonotic infections, granulomatous diseases, and malignancies, radiologists' familiarity with the imaging patterns can aid in the differential diagnosis in a patient with a suspected or unsuspected zoonotic infection. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Therapeutic efficacy of favipiravir against Bourbon virus in mice.

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV.

A Cluster of Cefepime-induced Neutropenia During Outpatient Parenteral Antimicrobial Therapy.

A cluster of cefepime-induced neutropenia (CIN) was identified from June 2017 to May 2018 in a regional outpatient parenteral antimicrobial therapy population. Our data suggest prolonged courses of cefepime (≥2 weeks), administered by rapid intravenous push, were associated with a higher risk of CIN.

Tobacco Use Prevalence and Smoking Cessation Pharmacotherapy Prescription Patterns Among Hospitalized Patients by Medical Specialty.

INTRODUCTION: Effective smoking cessation medications are readily available but may be underutilized in hospital settings. In our large, tertiary care hospital, we aimed to (1) characterize patient tobacco use prevalence across medical specialties, (2) determine smoking cessation pharmacotherapy prescription variation across specialties, and (3) identify opportunities for improvement in practice. METHODS: Using electronic health records at Barnes Jewish Hospital, we gathered demographic data, admitting service, admission route, length of stay, self-reported tobacco use, and smoking cessation prescriptions over a 6-year period, from 2010 to 2016. We then compared tobacco use prevalence and smoking cessation prescriptions across medical specialties using a cross-sectional, retrospective design. RESULTS: Past 12-month tobacco use was reported by patients in 27.9% of inpatient admissions; prescriptions for smoking cessation pharmacotherapy were provided during 21.5% of these hospitalizations. The proportion of patients reporting tobacco use was highest in psychiatry (55.3%) and lowest in orthopedic surgery (17.1%). Psychiatric patients who reported tobacco use were most likely to receive pharmacotherapy (71.8% of admissions), and plastic surgery patients were least likely (4.7% of admissions). Compared with Caucasian tobacco users, African American patients who used tobacco products were less likely to receive smoking cessation medications (adjusted odds ratio [aOR] = 0.65; 95% confidence interval [CI] = 0.62 to 0.68). CONCLUSIONS: Among hospitalized tobacco users, safe and cost-effective pharmacotherapies are under-prescribed. We identified substantial variation in prescribing practices across different medical specialties and demographic groups, suggesting the need for an electronic medical record protocol that facilitates consistent tobacco use cessation pharmacotherapy treatment. IMPLICATIONS: Tobacco use cessation pharmacotherapy is underutilized during hospitalization, and prescription rates vary greatly across medical specialties and patient characteristics. Hospitals may benefit from implementing policies and practices that standardize and automate the offer of smoking pharmacotherapy for all hospitalized patients who use tobacco.

A Randomized Trial of Palliative Care Discussions Linked to an Automated Early Warning System Alert.

OBJECTIVE: To determine whether an Early Warning System could identify patients wishing to focus on palliative care measures. DESIGN: Prospective, randomized, pilot study. SETTING: Barnes-Jewish Hospital, Saint Louis, MO (January 15, 2015, to December 12, 2015). PATIENTS: A total of 206 patients; 89 intervention (43.2%) and 117 controls (56.8%). INTERVENTIONS: Palliative care in high-risk patients targeted by an Early Warning System. MEASUREMENTS AND MAIN RESULTS: Advanced directive documentation was significantly greater prior to discharge in the intervention group (37.1% vs 15.4%; p < 0.001) as were first-time requests for advanced directive documentation (14.6% vs 0.0%; p < 0.001). Documentation of resuscitation status was also greater prior to discharge in the intervention group (36.0% vs 23.1%; p = 0.043). There was no difference in the number of patients requesting a change in resuscitation status between groups (11.2% vs 9.4%; p = 0.666). However, changes in resuscitation status occurred earlier and on the general medicine units for the intervention group compared to the control group. The number of patients transferred to an ICU was significantly lower for intervention patients (12.4% vs 27.4%; p = 0.009). The median (interquartile range) ICU length of stay was significantly less for the intervention group (0 [0-0] vs 0 [0-1] d; p = 0.014). Hospital mortality was similar (12.4% vs 10.3%; p = 0.635). CONCLUSIONS: This study suggests that automated Early Warning System alerts can identify patients potentially benefitting from directed palliative care discussions and reduce the number of ICU transfers.

The number of discharge medications predicts thirty-day hospital readmission: a cohort study.

BACKGROUND: Hospital readmission occurs often and is difficult to predict. Polypharmacy has been identified as a potential risk factor for hospital readmission. However, the overall impact of the number of discharge medications on hospital readmission is still undefined. METHODS: To determine whether the number of discharge medications is predictive of thirty-day readmission using a retrospective cohort study design performed at Barnes-Jewish Hospital from January 15, 2013 to May 9, 2013. The primary outcome assessed was thirty-day hospital readmission. We also assessed potential predictors of thirty-day readmission to include the number of discharge medications. RESULTS: The final cohort had 5507 patients of which 1147 (20.8 %) were readmitted within thirty days of their hospital discharge date. The number of discharge medications was significantly greater for patients having a thirty-day readmission compared to those without a thirty-day readmission (7.2 ± 4.1 medications [7.0 medications (4.0 medications, 10.0 medications)] versus 6.0 ± 3.9 medications [6.0 medications (3.0 medications, 9.0 medications)]; P < 0.001). There was a statistically significant association between increasing numbers of discharge medications and the prevalence of thirty-day hospital readmission (P < 0.001). Multiple logistic regression identified more than six discharge medications to be independently associated with thirty-day readmission (OR, 1.26; 95 % CI, 1.17-1.36; P = 0.003). Other independent predictors of thirty-day readmission were: more than one emergency department visit in the previous six months, a minimum hemoglobin value less than or equal to 9 g/dL, presence of congestive heart failure, peripheral vascular disease, cirrhosis, and metastatic cancer. A risk score for thirty-day readmission derived from the logistic regression model had good predictive accuracy (AUROC = 0.661 [95 % CI, 0.643-0.679]). CONCLUSIONS: The number of discharge medications is associated with the prevalence of thirty-day hospital readmission. A risk score, that includes the number of discharge medications, accurately predicts patients at risk for thirty-day readmission. Our findings suggest that relatively simple and accessible parameters can identify patients at high risk for hospital readmission potentially distinguishing such individuals for interventions to minimize readmissions.

Mycobacterium ulcerans infection imported from Australia to Missouri, USA, 2012.

Buruli ulcer, the third most common mycobacterial disease worldwide, rarely affects travelers and is uncommon in the United States. We report a travel-associated case imported from Australia and review 3 previous cases diagnosed and treated in the United States. The differential diagnoses for unusual chronic cutaneous ulcers and those nonresponsive to conventional therapy should include Mycobacterium ulcerans infection.

Cost-effectiveness of using Quantiferon Gold (QFT-G)® versus tuberculin skin test (TST) among U.S. and foreign born populations at a public health department clinic with a low prevalence of tuberculosis.

OBJECTIVE: The purpose of this study was to determine the cost benefit to routinely using QFT-G versus the standard TST for screening U.S. and foreign born populations at a public health department clinic with a low prevalence of tuberculosis. DESIGN AND SAMPLE: A comparative cost analysis of the monetization between QFT-G and TST was conducted: Data from the health department's Chest Clinic patients seen in 2007 were used to model cost predictions. MEASURES: The net costs of screening, x-rays, the standard 9 months of latent tuberculosis infection treatment, laboratory, and administration for U.S. born patients and foreign born patients were investigated. RESULTS: There are no apparent cost savings for U.S. born individuals, but due to the higher specificity of QFT-G for foreign born BCG-vaccinated individuals, there are unnecessary expenditures associated with the higher number of false positives incurred when using TST compared with QFT-G on 1,000 foreign born individuals (69%, 18%). CONCLUSION: QFT-G is cost-effective and should be used at local health department clinics that want to achieve savings in screening and treating those suspected of having TB infection, especially for high-risk populations such as foreign born individuals.

Patient needs from general practice following a traumatic injury: a qualitative study using narrative interviews with British service personnel.

OBJECTIVES: To explore the first period of sick leave in military patients following a traumatic battle injury, and the role of primary care. To identify if and where patients perceived difficulties. METHOD: Participants were recruited from The Defence Medical Rehabilitation Centre (DMRC) Headley Court on their second admission. Purposive sampling was used to access a range of different injuries and experiences. Nine patients were interviewed at DMRC where they were asked to recount their stories throughout rehabilitation. Thematic and structural analysis of the narrative accounts was applied. RESULTS: The majority of problems encountered by the participants occurred during their initial period of sick leave between Royal Centre for Defence Medicine (RCDM), Queen Elizabeth Hospital, Birmingham, and DMRC. Participants often had difficulty identifying who to contact if they had a problem on sick leave, with many ringing secondary care directly. Time spent travelling to medical reviews was identified as affecting the quality of leave. CONCLUSIONS: There is a need for greater patient understanding regarding whom to contact should they develop problems while on sick leave. A patient passport containing all discharge documentation and simplified contact details may help reduce patient confusion regarding whom to contact. GPs require greater awareness and understanding of the complexity of these patients' injuries and the need for early secondary care review to prevent delayed or inappropriate admissions. Most problems that patients face will occur on their first period of sick leave. Reducing the time spent on sick leave before admission to DMRC would limit the likelihood of problems occurring at this high-risk time.

Leveraging Bluetooth low-energy technology to improve contact tracing among healthcare personnel in hospital setting during the coronavirus disease 2019 (COVID-19) pandemic.

To improve contact tracing for healthcare workers, we built and configured a Bluetooth low-energy system. We predicted close contacts with great accuracy and provided an additional contact yield of 14.8%. This system would decrease the effective reproduction number by 56% and would unnecessarily quarantine 0.74% of employees weekly.

Body temperature patterns as a predictor of hospital-acquired sepsis in afebrile adult intensive care unit patients: a case-control study.

INTRODUCTION: Early treatment of sepsis improves survival, but early diagnosis of hospital-acquired sepsis, especially in critically ill patients, is challenging. Evidence suggests that subtle changes in body temperature patterns may be an early indicator of sepsis, but data is limited. The aim of this study was to examine whether abnormal body temperature patterns, as identified by visual examination, could predict the subsequent diagnosis of sepsis in afebrile critically ill patients. METHODS: Retrospective case-control study of 32 septic and 29 non-septic patients in an adult medical and surgical ICU. Temperature curves for the period starting 72 hours and ending 8 hours prior to the clinical suspicion of sepsis (for septic patients) and for the 72-hour period prior to discharge from the ICU (for non-septic patients) were rated as normal or abnormal by seven blinded physicians. Multivariable logistic regression was used to compare groups in regard to maximum temperature, minimum temperature, greatest change in temperature in any 24-hour period, and whether the majority of evaluators rated the curve to be abnormal. RESULTS: Baseline characteristics of the groups were similar except the septic group had more trauma patients (31.3% vs. 6.9%, p = .02) and more patients requiring mechanical ventilation (75.0% vs. 41.4%, p = .008). Multivariable logistic regression to control for baseline differences demonstrated that septic patients had significantly larger temperature deviations in any 24-hour period compared to control patients (1.5°C vs. 1.1°C, p = .02). An abnormal temperature pattern was noted by a majority of the evaluators in 22 (68.8%) septic patients and 7 (24.1%) control patients (adjusted OR 4.43, p = .017). This resulted in a sensitivity of 0.69 (95% CI [confidence interval] 0.50, 0.83) and specificity of 0.76 (95% CI 0.56, 0.89) of abnormal temperature curves to predict sepsis. The median time from the temperature plot to the first culture was 9.40 hours (IQR [inter-quartile range] 8.00, 18.20) and to the first dose of antibiotics was 16.90 hours (IQR 8.35, 34.20). CONCLUSIONS: Abnormal body temperature curves were predictive of the diagnosis of sepsis in afebrile critically ill patients. Analysis of temperature patterns, rather than absolute values, may facilitate decreased time to antimicrobial therapy.

The energy demands of portable gas analysis system carriage during walking and running.

The aim of this study was to evaluate the carriage of a portable gas analyser during prolonged treadmill exercise at a variety of speeds. Ten male participants completed six trials at different speeds (4, 8 and 12 km h(- 1)) for 40 min whilst wearing the analyser (P) or where the analyser was externally supported (L). Throughout each trial, respiratory gases, heart rate (HR), perceptions of effort and energy expenditure (EE) were measured. Significantly higher EE occurred during P12 (p = 0.01) than during L12 (855.3 ± 104.3; CI = 780.7-930.0 and 801.5 ± 82.2 kcal; CI = 742.7-860.3 kcal, respectively), but not at the other speeds; despite this, perceptions of effort and HR responses were unaffected. This additional EE is likely caused by alterations to posture which increase oxygen demand. The use of such systems is unlikely to affect low-intensity tasks, but researchers should use caution when interpreting data, particularly when exercise duration exceeds 30 min and laboratory-based analysers should be used where possible.

Missed Opportunities in the Diagnosis of Tuberculosis Meningitis.

Background: Tuberculosis meningitis (TBM) has high mortality and morbidity. Diagnostic delays can impact TBM outcomes. We aimed to estimate the number of potentially missed opportunities (MOs) to diagnose TBM and determine its impact on 90-day mortality. Methods: This is a retrospective cohort of adult patients with a central nervous system (CNS) TB International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) diagnosis code (013*, A17*) identified in the Healthcare Cost and Utilization Project, State Inpatient and State Emergency Department (ED) Databases from 8 states. Missed opportunity was defined as composite of ICD-9/10 diagnosis/procedure codes that included CNS signs/symptoms, systemic illness, or non-CNS TB diagnosis during a hospital/ED visit 180 days before the index TBM admission. Demographics, comorbidities, admission characteristics, mortality, and admission costs were compared between those with and without a MO, and 90-day in-hospital mortality, using univariate and multivariable analyses. Results: Of 893 patients with TBM, median age at diagnosis was 50 years (interquartile range, 37-64), 61.3% were male, and 35.2% had Medicaid as primary payer. Overall, 407 (45.6%) had a prior hospital or ED visit with an MO code. In-hospital 90-day mortality was not different between those with and without an MO, regardless of the MO coded during an ED visit (13.7% vs 15.2%, P = .73) or a hospitalization (28.2% vs 30.9%, P = .74). Independent risk of 90-day in-hospital mortality was associated with older age, hyponatremia (relative risk [RR], 1.62; 95% confidence interval [CI], 1.1-2.4; P = .01), septicemia (RR, 1.6; 95% CI, 1.03-2.45; P = .03), and mechanical ventilation (RR, 3.4; 95% CI, 2.25-5.3; P < .001) during the index admission. Conclusions: Approximately half the patients coded for TBM had a hospital or ED visit in the previous 6 months meeting the MO definition. We found no association between having an MO for TBM and 90-day in-hospital mortality.