Assessing ascertainment bias in atrial fibrillation across US minority groups.

The aim of this study is to define atrial fibrillation (AF) prevalence and incidence rates across minority groups in the United States (US), to aid in diversity enrollment target setting for randomized controlled trials. In AF, US minority groups have lower clinically detected prevalence compared to the non-Hispanic or Latino White (NHW) population. We assess the impact of ascertainment bias on AF prevalence estimates. We analyzed data from adults in Optum's de-identified Clinformatics® Data Mart Database from 2017-2020 in a cohort study. Presence of AF at baseline was identified from inpatient and/or outpatient encounters claims using validated ICD-10-CM diagnosis algorithms. AF incidence and prevalence rates were determined both in the overall population, as well as in a population with a recent stroke event, where monitoring for AF is assumed. Differences in prevalence across cohorts were assessed to determine if ascertainment bias contributes to the variation in AF prevalence across US minority groups. The period prevalence was respectively 4.9%, 3.2%, 2.1% and 5.9% in the Black or African American, Asian, Hispanic or Latino, and NHW population. In patients with recent ischemic stroke, the proportion with AF was 32.2%, 24.3%, 25%, and 24.5%, respectively. The prevalence of AF among the stroke population was approximately 7 to 10 times higher than the prevalence among the overall population for the Asian and Hispanic or Latino population, compared to approximately 5 times higher for NHW patients. The relative AF prevalence difference of the Asian and Hispanic or Latino population with the NHW population narrowed from respectively, -46% and -65%, to -22% and -24%. The study findings align with previous observational studies, revealing lower incidence and prevalence rates of AF in US minority groups. Prevalence estimates of the adult population, when routine clinical practice is assumed, exhibit higher prevalence differences compared to settings in which monitoring for AF is assumed, particularly among Asian and Hispanic or Latino subgroups.

Trailblazing New Paths to e-Learning Engagement.

E-learning modules are a common component of orientation and other education initiatives, but their usefulness can be limited by poor engagement. This article presents the results of an experimental cohort study testing interventions designed to improve learner engagement with e-learning modules.

Association of Remdesivir Treatment With Mortality Among Hospitalized Adults With COVID-19 in the United States.

Importance: SARS-CoV-2, which causes COVID-19, poses considerable morbidity and mortality risks. Studies using data collected during routine clinical practice can supplement randomized clinical trials to provide needed evidence, especially during a global pandemic, and can yield markedly larger sample sizes to assess outcomes for important patient subgroups. Objective: To evaluate the association of remdesivir treatment with inpatient mortality among patients with COVID-19 outside of the clinical trial setting. Design, Setting, and Participants: A retrospective cohort study in US hospitals using health insurance claims data linked to hospital chargemaster data from December 1, 2018, to May 3, 2021, was conducted among 24 856 adults hospitalized between May 1, 2020, and May 3, 2021, with newly diagnosed COVID-19 who received remdesivir and 24 856 propensity score-matched control patients. Exposure: Remdesivir treatment. Main Outcomes and Measures: All-cause inpatient mortality within 28 days of the start of remdesivir treatment for the remdesivir-exposed group or the matched index date for the control group. Results: A total of 24 856 remdesivir-exposed patients (12 596 men [50.7%]; mean [SD] age, 66.8 [15.4] years) and 24 856 propensity score-matched control patients (12 621 men [50.8%]; mean [SD] age, 66.8 [15.4] years) were included in the study. Median follow-up was 6 days (IQR, 4-11 days) in the remdesivir group and 5 days (IQR, 2-10 days) in the control group. There were 3557 mortality events (14.3%) in the remdesivir group and 3775 mortality events (15.2%) in the control group. The 28-day mortality rate was 0.5 per person-month in the remdesivir group and 0.6 per person-month in the control group. Remdesivir treatment was associated with a statistically significant 17% reduction in inpatient mortality among patients hospitalized with COVID-19 compared with propensity score-matched control patients (hazard ratio, 0.83 [95% CI, 0.79-0.87]). Conclusions and Relevance: In this retrospective cohort study using health insurance claims and hospital chargemaster data, remdesivir treatment was associated with a significantly reduced inpatient mortality overall among patients hospitalized with COVID-19. Results of this analysis using data collected during routine clinical practice and state-of-the-art methods complement results from randomized clinical trials. Future areas of research include assessing the association of remdesivir treatment with inpatient mortality during the circulation of different variants and relative to time from symptom onset.

Durability of Protection Post-Primary COVID-19 Vaccination in the United States.

The durability of immune responses after COVID-19 vaccination will drive long-term vaccine effectiveness across settings and may differ by vaccine type. To determine durability of protection of COVID-19 vaccines (BNT162b2, mRNA-1273, and Ad26.COV2.S) following primary vaccination in the United States, a matched case-control study was conducted in three cohorts between 1 January and 7 September 2021 using de-identified data from a database covering 168 million lives. Odds ratios (ORs) for developing outcomes of interest (breakthrough SARS-CoV-2 infection, hospitalization, or intensive care unit admission) were determined for each vaccine (no direct comparisons). In total, 17,017,435 individuals were identified. Relative to the baseline, stable protection was observed for Ad26.COV2.S against infections (OR [95% confidence interval (CI)], 1.31 [1.18-1.47]) and hospitalizations (OR [95% CI], 1.25 [0.86-1.80]). Relative to the baseline, protection waned over time against infections for BNT162b2 (OR [95% CI], 2.20 [2.01-2.40]) and mRNA-1273 (OR [95% CI], 2.07 [1.87-2.29]) and against hospitalizations for BNT162b2 (OR [95% CI], 2.38 [1.79-3.17]). Baseline protection remained stable for intensive care unit admissions for all three vaccines. Calculated baseline VE was consistent with published literature. This study suggests that the three vaccines in three separate populations may have different durability profiles.

Diagnostic accuracy of the repeatable battery of the assessment of neuropsychological status update, Spanish version, in predicting Alzheimer's disease among Hispanic older adults in the United States reporting memory problems.

OBJECTIVES: There are few standardized, Spanish-language diagnostic tools to help identify Hispanic persons at early stages of Alzheimer's disease (AD). This study evaluated the accuracy of the Spanish version of the Repeatable Battery for the Assessment of Neuropsychological Status-Update (RBANS) in predicting AD in older Hispanic adults in the United States reporting memory problems. METHODS: We analyzed data from age, sex, and education level propensity score-matched Hispanic memory clinic patients with (n = 38) and without (n = 38) a clinical diagnosis of AD. Estimates of diagnostic accuracy included sensitivity, specificity, predictive value, and receiver operating characteristic analysis. RESULTS: After controlling for sex and matched pairs, the Total Scale score [area under curve (AUC) = 0.7417] and the Immediate (AUC = 0.7258) and Delayed (AUC = 0.7735) Memory index scores provided better estimates of diagnostic accuracy than Language, Attention, and Visuospatial/Constructional index scores. A minus 2-standard deviation (SD) cut point enhanced the predictive probability of the Delayed Memory index score. A cut point of -1.5 SD optimized the predictive probability of the Total Scale score. CONCLUSIONS: These results suggest that optimal cutoff values for the RBANS Delayed Memory index and Total Scale scores that may help identify Hispanic patients with AD as part of a comprehensive diagnostic AD assessment.

Cardiovascular risk prediction model and stratification in patients with type 2 diabetes enrolled in a Medicare Advantage plan.

BACKGROUND: Cardiovascular (CV) risk tools have been developed both nationally and internationally to identify patients at risk for developing CV disease or experiencing a CV event. However, these tools vary widely in the definitions of endpoints, the time at which the endpoints are measured, patient populations, and their validity. The primary limitation of some of the most commonly utilized tools is the lack of specificity for a type 2 diabetes (T2D) population and/or among older patients. OBJECTIVE: To develop a predictive model within an older population of patients with T2D to identify patients at risk for CV events. METHODS: This retrospective cohort study used claims, laboratory, and enrollment data during the 2011-2018 study period. Patients with T2D were identified based on diagnoses and/or medications from 2012-2013. The patient cohort was split into 3 different datasets. The holdout dataset included only those patients residing in the northeastern United States. The rest of the sample was then randomly split: 70% for the training dataset, which were used to fit the predictive model, and 30% for the test dataset to assess internal validity. The primary outcome was the first composite CV event defined as at least 1 of the following: inpatient hospitalization for myocardial infarction, ischemic stroke, unstable angina, or heart failure; or any evidence of revascularization. A survival model for the composite outcome was fitted with baseline demographic and clinical characteristics prognostic for the dependent variable utilizing augmented backwards elimination. For assessing model performance, accuracy, sensitivity, specificity, and the c-statistic were used. Patients were ranked as having a low, moderate, or high probability of a future CV event. RESULTS: A total of 362,791 patients were identified. The holdout dataset included only those patients residing in the northeastern United States (n = 8,303). There were 248,142 patients included in the training dataset and 106,346 patients in the test dataset. The proportion with at least 1 observed composite CV event was 20.9%. The final model included 42 variables. The c-statistic was 0.68, and the accuracy, sensitivity, and specificity were approximately 63%. Results were consistent across the training, test, and holdout samples. The optimal cut points minimizing the difference in sensitivity and specificity for low-, moderate-, and high-risk future CV events were determined to be less than 0.18, 0.18-0.63, and greater than 0.63, respectively, in the training dataset at 5 years. The 5-year observed event risk was 11%, 27%, and 51% for patients classified as low, moderate, and high risk of a future CV event, respectively. CONCLUSIONS: A model predicting CV events among older patients with T2D using administrative claims to identify those at risk may be used for focusing interventions to prevent future events. DISCLOSURES: This study was funded by Boehringer Ingelheim (BI) and conducted as part of the BI-Humana Research Collaboration. Caplan is employed by Humana Healthcare Research, Inc., a wholly owned subsidiary of Humana Inc., which received fees to conduct the study from the sponsor BI. At the time of the study, Hayden and Harvey were employees of Humana Healthcare Research, Inc. Additionally, Prewitt, who owns stock in Humana Inc, and Chiguluri are employees of Humana Inc. Kattan, associated with the Cleveland Clinic in Ohio, served as a consultant to BI, and Pimple and Goss are employees of BI. Luthra was employed by BI for the duration of the study. Portions of this work were accepted as an abstract and presented as a poster at the American Diabetes Association 2020 virtual meeting, June 12-16, 2020.

Type 2 Autoimmune Hepatitis and Nonadherence to Medication Correlate With Premature Birth and Risk of Postpartum Flare.

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that affects all ages, including women of childbearing age. Optimal management during pregnancy is poorly defined. We aimed to explore the clinical and biochemical course of AIH in the antenatal and postpartum periods, and assess factors associated with premature birth and postpartum flares. Pregnant women with AIH reviewed in the autoimmune liver disease clinic at the Queen Elizabeth Hospital Birmingham between 2009 and 2020 were identified retrospectively, and clinical, biochemical, and immunological data 1 year before conception to 1 year postpartum were collected. Analysis was performed to identify trends in blood markers over the antenatal period, with an interrupted time series approach used to assess postpartum trends. Data were available for n = 27 pregnancies (n = 20 women), with median gestation of 38 weeks (30% premature) and most having type 1 AIH (78%) and delivering via caesarean section (63%). Levels of alanine transaminase, aspartate transaminase, and immunoglobulin G all declined significantly during gestation, followed by significant step-change increases after delivery. Postpartum flare developed in 58% of pregnancies. AIH type 2 was associated with a higher rate of premature births (67% vs. 19%, P = 0.044), and a trend toward a higher rate of postpartum flare (100% vs. 48%, P = 0.053). Although not significant, medication nonadherence was associated with almost double the risk of prematurity (40% vs. 24%, P = 0.415) and postpartum flare (80% vs. 44%, P = 0.109). Conclusion: Biochemical and immunological remission of AIH occurs during pregnancy, although subsequent postpartum flare is common. Type 2 AIH is associated with a higher risk of premature birth and postpartum flare, although further research is required to validate and explain this finding.

Home-based exercise in patients with refractory fatigue associated with primary biliary cholangitis: a protocol for the EXerCise Intervention in cholesTatic LivEr Disease (EXCITED) feasibility trial.

INTRODUCTION: Fatigue is the most commonly reported symptom of the liver disease primary biliary cholangitis (PBC). It affects 40%-80% of patients, has no effective treatment and is associated with heightened mortality risk. The pathogenesis is unknown, but muscle bioenergetic abnormalities have been proposed to contribute. Directly observed exercise has been shown to attenuate symptoms in small groups; however, due to the rare nature of the disease, home-based interventions need to be evaluated for feasibility, safety and efficacy. METHODS AND ANALYSIS: This is a phase 1/pilot, single-arm, open-label clinical trial evaluating a novel home-based exercise programme in patients with PBC with severe fatigue. Forty patients with moderate-severe fatigue (PBC40 fatigue domain score >33; other causes of fatigue excluded) will be selected using a convenience sampling method. A 12-week home-based exercise programme, consisting of individualised resistance, aerobic exercises and telephone health calls (first 6 weeks only), will be delivered. Measures of fatigue (PBC40 fatigue domain; fatigue impact scale), quality of life, sleep (Epworth Sleep Score), physical activity, anxiety and depression, aerobic exercise capacity (incremental shuttle walk test; Duke Activity Status Index) and functional capacity (short physical performance battery) will be assessed at baseline and at 6 and 12 weeks following the intervention. ETHICS AND DISSEMINATION: The protocol is approved by the National Research Ethics Service Committee London (IRAS 253115). Recruitment commenced in April 2019 and ended in March 2020. Participant follow-up is due to finish by December 2020. Findings will be disseminated through peer-reviewed publication, conference presentation and social media. TRIAL REGISTRATION NUMBER: NCT04265235.

Phenotypic clustering of heart failure with preserved ejection fraction reveals different rates of hospitalization.

AIMS: Approximately 50% of patients with heart failure have preserved (≥50%) ejection fraction (HFpEF). Improved understanding of the phenotypic heterogeneity of HFpEF might facilitate development of targeted therapies and interventions. METHODS: This retrospective study characterized a cohort of patients with HFpEF based on similar clinical profiles and evaluated 1-year heart failure related hospitalization. Enrolment, medical and pharmacy data were used to identify patients newly diagnosed with heart failure enrolled in a Medicare Advantage Prescription Drug or commercial healthcare plan. To identify only those patients with HFpEF, we used natural language processing techniques of ejection fraction values abstracted from a linked free-text clinical notes data source. The study population comprised 1515 patients newly identified with HFpEF between 1 January 2011 and 31 December 2015. RESULTS: Using unsupervised machine learning, we identified three distinguishable patient clusters representing different phenotypes: cluster-1 patients had the lowest prevalence of heart failure comorbidities and highest mean age; cluster-2 patients had higher prevalence of metabolic syndrome and pulmonary disease, despite younger mean age; and cluster-3 patients had higher prevalence of cardiac arrhythmia and renal disease. Cluster-3 had the highest 1-year heart failure related hospitalization rates. Within-cluster analysis, prior use of diuretics (cluster-1 and cluster-2) and age (cluster-2 and cluster-3) was associated with 1-year heart failure related hospitalization. Combination therapy was associated with decreased 1-year heart failure related hospitalization in cluster-1. CONCLUSION: This study demonstrated that clustering can be used to characterize subgroups of patients with newly identified HFpEF, assess differences in heart failure related hospitalization rates at 1 year and suggest patient subtypes may respond differently to treatments or interventions.

Metabolic Monitoring Rates of Youth Treated with Second-Generation Antipsychotics in Usual Care: Results of a Large US National Commercial Health Plan.

Objectives: To examine metabolic monitoring rates in commercially insured children and adolescents treated with a second-generation antipsychotic (SGA) during calendar years (CYs) 2016 and 2017. Methods: In this retrospective study, data were collected from a large national commercial health plan for the period covering January 1, 2016 to December 31, 2017. Commercially insured children and adolescents, aged 8-19 years with ≥2 SGA prescription claims during the CY, were identified for the CY2016 and CY2017 cohorts. The primary outcome of interest was the percentage of subjects with any glucose or lipid metabolism parameter monitoring. Other calculated metabolic testing rates included glucose, hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), other cholesterol (including triglycerides), and combined glucose and lipid metabolism testing (≥1 test for blood glucose or HbA1c and ≥1 test for LDL-C or other cholesterol). Results: In CY2016 and CY2017, 1502 and 1239 subjects, respectively, were identified for this study. The most common psychiatric diagnoses in CY2016 and CY2017 were major depressive disorder (57.1%, 56.5%, respectively), anxiety disorders (42.9%, 47.5%), attention-deficit/hyperactivity disorder (41.6%, 45.8%), and bipolar disorder (24.1%, 25.9%). The rate of any metabolic testing was 53.5% in CY2016 and 51.3% in CY2017. Glucose testing (50.3%, 46.9%, respectively) was most common in both CYs, followed by LDL-C testing (31.2%, 28.5%). Rates of combined glucose and lipid metabolism testing were 30.7% in CY2016 and 26.9% in CY2017. Conclusions: Given the known potential for adverse cardiometabolic effects, rates of metabolic monitoring associated with SGA use in children and adolescents urgently need to be improved. There is a critical need for understanding barriers to routine monitoring, particularly of lipids, and developing interventions to enhance metabolic monitoring.

The Relationship Between Anticholinergic Exposure and Falls, Fractures, and Mortality in Patients with Overactive Bladder.

BACKGROUND: Understanding risk factors associated with falls is important for optimizing care and quality of life for older patients. OBJECTIVE: Our objective was to determine the relationship between anticholinergic exposure and falls, fractures, and all-cause mortality. METHODS: An observational retrospective cohort study was conducted using administrative claims data from 1 January 2007 to 30 September 2015. Individuals aged 65-89 years newly diagnosed or treated for overactive bladder (OAB) were identified. Index date was the first OAB diagnosis or OAB medication prescription claim. Follow-up began on the index date and continued until death, disenrollment, or end of study period. The Anticholinergic Cognitive Burden (ACB) scale was used to define and quantify daily anticholinergic exposure and intensity. The primary study outcome was a combined endpoint of falls or fractures. All-cause mortality was a secondary endpoint. RESULTS: There were 113,311 patients with mean age of 74.8 ± standard deviation (SD) 6.2 years included. Current anticholinergic exposure was associated with a 1.28-fold increased hazard of a fall/fracture (95% confidence interval [CI] 1.23-1.32) compared with unexposed person-time, and past exposure was associated with a 1.14-fold increased hazard of a fall/fracture (95% CI 1.12-1.17). Compared with unexposed person-time, low-, moderate-, and high-intensity anticholinergic exposure was associated with a 1.04-fold (95% CI 1.00-1.07), 1.13-fold (95% CI 1.09-1.17), and 1.31-fold (95% CI 1.26-1.36) increased hazard of falls/fractures, respectively. A similar pattern was observed for all-cause mortality. CONCLUSIONS: Anticholinergic exposure is associated with an increased risk of falls or fractures in older patients and is an important consideration when evaluating treatment options for such patients with OAB.

Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis.

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends.

Association of obesity with healthcare resource utilization and costs in a commercial population.

OBJECTIVE: To examine the association of obesity with healthcare resource utilization (HRU) and costs among commercially insured individuals. METHODS: This retrospective observational cohort study used administrative claims from 1 January 2007 to 1 December 2013. The ICD-9-CM status codes (V85 hierarchy) from 2008 to 2012 classified body mass index (BMI) into the World Health Organizations' BMI categories. The date of first observed BMI code was defined as the index date and continuous eligibility for one year pre- and post- index date was ensured. Post-index claims determined individuals' HRU and costs. Sampling weights developed using the entropy balance method and National Health and Nutrition Examination Survey data ensured representation of the US adult commercially insured population. Baseline characteristics were described across BMI classes and associations between BMI categories, and outcomes were examined using multivariable regression. RESULTS: The cohort included 9651 individuals with BMI V85 codes. After weighting, the BMI distribution was: normal (31.1%), overweight (33.4%), obese class I (22.0%), obese class II (8.1%) and obese class III (5.4%). Increasing BMI was associated with greater prevalence of cardiometabolic conditions, including hypertension, type 2 diabetes and metabolic syndrome. The use of antihypertensives, antihyperlipidemics, antidiabetics, analgesics and antidepressants rose with increasing BMI. Greater BMI level was associated with increased inpatient, emergency department and outpatient utilization, and higher total healthcare, medical and pharmacy costs. CONCLUSIONS: Increasing BMI was associated with higher prevalence of cardiometabolic conditions and higher HRU and costs. There is an urgent need to address the epidemic of obesity and its clinical and economic impacts.

A comparison of entropy balance and probability weighting methods to generalize observational cohorts to a population: a simulation and empirical example.

PURPOSE: We compared methods to control bias and confounding in observational studies including inverse probability weighting (IPW) and stabilized IPW (sIPW). These methods often require iteration and post-calibration to achieve covariate balance. In comparison, entropy balance (EB) optimizes covariate balance a priori by calibrating weights using the target's moments as constraints. METHODS: We measured covariate balance empirically and by simulation by using absolute standardized mean difference (ASMD), absolute bias (AB), and root mean square error (RMSE), investigating two scenarios: the size of the observed (exposed) cohort exceeds the target (unexposed) cohort and vice versa. The empirical application weighted a commercial health plan cohort to a nationally representative National Health and Nutrition Examination Survey target on the same covariates and compared average total health care cost estimates across methods. RESULTS: Entropy balance alone achieved balance (ASMD ≤ 0.10) on all covariates in simulation and empirically. In simulation scenario I, EB achieved the lowest AB and RMSE (13.64, 31.19) compared with IPW (263.05, 263.99) and sIPW (319.91, 320.71). In scenario II, EB outperformed IPW and sIPW with smaller AB and RMSE. In scenarios I and II, EB achieved the lowest mean estimate difference from the simulated population outcome ($490.05, $487.62) compared with IPW and sIPW, respectively. Empirically, only EB differed from the unweighted mean cost indicating IPW, and sIPW weighting was ineffective. CONCLUSION: Entropy balance demonstrated the bias-variance tradeoff achieving higher estimate accuracy, yet lower estimate precision, compared with IPW methods. EB weighting required no post-processing and effectively mitigated observed bias and confounding. Copyright © 2016 John Wiley & Sons, Ltd.

An orphaned Mce-associated membrane protein of Mycobacterium tuberculosis is a virulence factor that stabilizes Mce transporters.

Mycobacterium tuberculosis proteins that are exported out of the bacterial cytoplasm are ideally positioned to be virulence factors; however, the functions of individual exported proteins remain largely unknown. Previous studies identified Rv0199 as an exported membrane protein of unknown function. Here, we characterized the role of Rv0199 in M. tuberculosis virulence using an aerosol model of murine infection. Rv0199 appears to be a member of a Mce-associated membrane (Mam) protein family leading us to rename it OmamA, for orphaned Mam protein A. Consistent with a role in Mce transport, we showed OmamA is required for cholesterol import, which is a Mce4-dependent process. We further demonstrated a function for OmamA in stabilizing protein components of the Mce1 transporter complex. These results indicate a function of OmamA in multiple Mce transporters and one that may be analogous to the role of VirB8 in stabilizing Type IV secretion systems, as structural similarities between Mam proteins and VirB8 proteins are predicted by the Phyre 2 program. In this study, we provide functional information about OmamA and shed light on the function of Mam family proteins in Mce transporters.

Reliability and validity testing of the Creighton Competency Evaluation Instrument for use in the NCSBN National Simulation Study.

AIM: The Creighton Competency Evaluation Instrument (CCEI) was modified from an existing instrument, the Creighton Simulation Evaluation Instrument, for use in the National Council of States Boards of Nursing National Simulation Study (NCSBN NSS). BACKGROUND: The CCEI was developed for the NCSBN NSS for use as the evaluation instrument for both simulation and traditional clinical experiences in associate and baccalaureate nursing programs. METHOD: Five nursing programs assisted with reliability and validity testing of the CCEI. Using a standardized validation questionnaire, faculty rated the CCEI on its ability to accurately measure student performance and clinical competency. Videos scripted at three levels of performance were used to test reliability. RESULTS: Content validity ranged from 3.78 to 3.89 on a four-point Likert-like scale. Cronbach's alpha was > .90 when used to score three different levels of simulation performance. CONCLUSION: The CCEI is useful for evaluating both the simulation and traditional clinical environments.

Filtration improves the performance of a high-throughput screen for anti-mycobacterial compounds.

The tendency for mycobacteria to aggregate poses a challenge for their use in microplate based assays. Good dispersions have been difficult to achieve in high-throughput screening (HTS) assays used in the search for novel antibacterial drugs to treat tuberculosis and other related diseases. Here we describe a method using filtration to overcome the problem of variability resulting from aggregation of mycobacteria. This method consistently yielded higher reproducibility and lower variability than conventional methods, such as settling under gravity and vortexing.

Reversible acetylation regulates acetate and propionate metabolism in Mycobacterium smegmatis.

Carbon metabolic pathways are important to the pathogenesis of Mycobacterium tuberculosis, the causative agent of tuberculosis. However, extremely little is known about metabolic regulation in mycobacteria. There is growing evidence for lysine acetylation being a mechanism of regulating bacterial metabolism. Lysine acetylation is a post-translational modification in which an acetyl group is covalently attached to the side chain of a lysine residue. This modification is mediated by acetyltransferases, which add acetyl groups, and deacetylases, which remove the acetyl groups. Here we set out to test whether lysine acetylation and deacetylation impact acetate metabolism in the model mycobacteria Mycobacterium smegmatis, which possesses 25 candidate acetyltransferases and 3 putative lysine deacetylases. Using mutants lacking predicted acetyltransferases and deacetylases we showed that acetate metabolism in M. smegmatis is regulated by reversible acetylation of acetyl-CoA synthetase (Ms-Acs) through the action of a single pair of enzymes: the acetyltransferase Ms-PatA and the sirtuin deacetylase Ms-SrtN. We also confirmed that the role of Ms-PatA in regulating Ms-Acs regulation depends on cAMP binding. We additionally demonstrated a role for Ms-Acs, Ms-PatA and Ms-SrtN in regulating the metabolism of propionate in M. smegmatis. Finally, along with Ms-Acs, we identified a candidate propionyl-CoA synthetase, Ms5404, as acetylated in whole-cell lysates. This work lays the foundation for studying the regulatory circuit of acetylation and deacetylation in the cellular context of mycobacteria.

A hermetically sealed, fluid-filled surgical enclosure for microgravity.

INTRODUCTION: Expeditionary spaceflight is fraught with significant risks to human health, including trauma and other emergency medical events. To address several of the basic challenges of surgical care in reduced gravity, we are developing the Aqueous Immersion Surgical System (AISS), an optically clear enclosure pressurized by a fluid medium. The AISS is designed to prevent contamination of the spacecraft with blood and tissue debris, reduce intraoperative blood loss, and maintain visualization of the operative field. METHODS: An early prototype of the AISS was tested in reduced gravity during parabolic flight. A clear, aqueous field was created in a watertight chamber containing a mock vascular network. Hemorrhage was simulated by severing several of the analogue vessels. Experiments were performed to evaluate the benefits of surrounding a surgical cavity with fluid medium, as compared to an air environment, with respect to maintaining a clear view and achieving hemostasis. RESULTS: Qualitative evaluation of audio and video recorded during parabolic flight confirm AISS capacity to maintain visualization of the surgical field during a hemorrhage situation and staunch bleeding by raising interchamber pressure. DISCUSSION: Evaluation of the AISS in reduced gravity corroborates observations in the literature regarding the difficulty in maintaining visualization of the surgical field when performing procedures in an air environment. By immersing the surgical field in fluid we were able to apply suction directly to the hemorrhage and also achieve hemostasis.

The ins and outs of Mycobacterium tuberculosis protein export.

Mycobacterium tuberculosis is an important pathogen that infects approximately one-third of the world's population and kills almost two million people annually. An important aspect of M. tuberculosis physiology and pathogenesis is its ability to export proteins into and across the thick mycobacterial cell envelope, where they are ideally positioned to interact with the host. In addition to the specific proteins that are exported by M. tuberculosis, the systems through which these proteins are exported represent potential targets for future drug development. M. tuberculosis possesses two well-known and conserved export systems: the housekeeping Sec pathway and the Tat pathway. In addition, M. tuberculosis possesses specialized export systems including the accessory SecA2 pathway and five ESX pathways. Here we review the current understanding of each of these export systems, with a focus on M. tuberculosis, and discuss the contribution of each system to disease and physiology.