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Aims Frailty is associated with an increased risk of all-cause mortality and cardiovascular (CV) events. Limited data exist from the modern era of CV prevention on the relationship between frailty and CV mortality. We hypothesized that frailty is associated with an increased risk of CV mortality. Methods and results All US Veterans aged ≥65 years who were regular users of Veteran Affairs care from 2002 to 2017 were included. Frailty was defined using a 31-item previously validated frailty index, ranging from 0 to 1. The primary outcome was CV mortality with secondary analyses examining the relationship between frailty and CV events (myocardial infarction, stroke, revascularization). Survival analysis models were adjusted for age, sex, ethnicity, geographic region, smoking, hyperlipidaemia, statin use, and blood pressure medication use. There were 3 068 439 US Veterans included in the analysis. Mean age was 74.1 ± 5.8 years in 2002, 76.0 ± 8.3 years in 2014, 98% male, and 87.5% White. In 2002, the median (interquartile range) frailty score was 0.16 (0.10–0.23). This increased and stabilized to 0.19 (0.10–0.32) for 2006–14. The presence of frailty was associated with an increased risk of CV mortality at every stage of frailty. Frailty was associated with an increased risk of myocardial infarction and stroke, but not revascularization. Conclusion In this population, both the presence and severity of frailty are tightly correlated with CV death, independent of underlying CV disease. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished. Key Question Can an electronic frailty index identify adults aged 65 and older who are at risk of CV mortality and major CV events? Key Finding Among 3 068 439 US Veterans aged 65 and older, frailty was associated with an increased risk of CV mortality at every level of frailty. Frailty was also associated with an increased risk of myocardial infarction and stroke, but not revascularization. Take Home Message Both the presence and severity of frailty are associated with CV mortality and major CV events, independent of underlying CV disease.

Background Chronic health conditions associated with long-term drug use may pose additional risks to people who use drugs (PWUD) when coupled with COVID-19 infection. Despite this, PWUD, especially those living in rural areas, may be less likely to seek out health services. Previous research has highlighted the increased disease burden of COVID-19 among PWUD. Our manuscript supplements this literature by exploring unique attitudes of PWUD living in rural areas toward the pandemic, COVID-19 vaccination, and the role of harm reduction (HR) organizations in raising health awareness among PWUD. Methods Semi-structured interviews were conducted with 20 PWUD living in rural southern Illinois. Audio recordings were professionally transcribed. A preliminary codebook was created based on interview domains. Two trained coders conducted iterative coding of the transcripts, and new codes were added through line-by-line coding and thematic grouping. Results Twenty participants (45% female, mean age of 38) completed interviews between June and November 2021. Participants reported negative impacts of the pandemic on mental health, financial wellbeing, and drug quality. However, the health impacts of COVID-19 were often described as less concerning than its impacts on these other aspects of life. Many expressed doubt in the severity of COVID-19 infection. Among the 16 unvaccinated participants who reported receiving most of their information from the internet or word of mouth, uncertainty about vaccine contents and distrust of healthcare and government institutions engendered wariness of the vaccination. Distrust of healthcare providers was related to past stigmatization and judgement, but did not extend to the local HR organization, which was unanimously endorsed as a positive institution. Among participants who did not access services directly from the HR organization, secondary distribution of HR supplies by other PWUD was a universally cited form of health maintenance. Participants expressed interest in low-threshold healthcare, including COVID-19 vaccination, should it be offered in the local HR organization’s office and mobile units. Conclusion COVID-19 and related public health measures have affected this community in numerous ways. Integrating healthcare services into harm reduction infrastructures and mobilizing secondary distributors of supplies may promote greater engagement with vaccination programs and other healthcare services. Trial number NCT04427202.

BACKGROUND AND AIMS: Limited and inconsistent data are available on the relation between egg consumption and risk of myocardial infarction (MI) and it is unclear if adiposity or type 2 diabetes modifies egg-MI relation. We tested the primary hypothesis that egg consumption is positively associated with incidence of MI among veterans. In secondary analyses, we examined potential effect modification of egg-MI relation by adiposity and type 2 diabetes. METHODS: We analyzed data collected on 188,267 US veterans who were enrolled in the Million Veteran Program (MVP) from 2011 to 2018. Information on egg consumption was obtained via self-administered food frequency questionnaire and we used electronic health records to identify incident MI. RESULTS: The mean age was 64.4 (SD=12.0) years and 9.9% of the population were female. We ascertained 10,260 new cases of non-fatal MI during an average follow up of 3.24 years (range: 0.002 to 7.49 y). Hazard ratio (95% CI) for non-fatal MI were 1.00 (ref), 0.93 (0.85–0.1.02), 0.96 (0.87–1.05), 0.98 (0.89–1.07), 1.08 (0.98–1.19), 1.11 (1.00–1.24), and 1.13 (1.00–1.28) for egg consumption of

Objective Obesity has been identified as a risk factor for severe COVID‐19 caused by the SARS‐CoV2 virus, however a direct association with mortality has not been reported. We sought to determine whether obesity is a risk factor for mortality among COVID‐19 patients. Methods The study was a retrospective cohort, including patients with COVID‐19 between March 1 and April 18, 2020. The primary objective was to determine if obesity is a predictor of mortality. Results A total of 238 patients were included, 218 patients (91.6%) were African American, 113 (47.5%) were male, and the mean age was 58.5 years. Of the included patients, 146 (61.3%) were obese (BMI >30kg/m2), with 63 (26.5%), 29 (12.2%), and 54 (22.7%) with class 1, 2, and 3 obesity, respectively. Obesity was identified as a predictor for mortality (OR 1.7(1.1‐2.8),p=0.016), as was male gender (OR 5.2(1.6‐16.5),p=0.01) and older age (OR 3.6(2.0‐6.3),p

BACKGROUND AND AIMS: Observational and clinical trial evidence suggests an inverse association of omega-3 polyunsaturated fatty acid with coronary artery disease (CAD) mortality, although relationships with non-fatal CAD and stroke are less clear. We investigated whether omega-3 fatty acid supplement use and fish intake were associated with incident non-fatal CAD and ischemic stroke among US Veterans. METHODS: The Million Veteran Program (MVP) is an ongoing nation-wide longitudinal cohort study of US Veterans with self-reported survey, biospecimen, and electronic health record data. Regular use of omega-3 supplements (yes/no) and frequency of fish intake within the past year were assessed using a food frequency questionnaire. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of omega-3 supplement use and fish intake with incident non-fatal CAD and ischemic stroke, defined from electronic health records using validated algorithms. Multivariable models included demographics, body mass index, education, smoking status, alcohol intake, and exercise frequency. RESULTS: Among 197,761 participants with food frequency data (mean age: 66 ± 12 years, 92% men), 21% regularly took omega-3 supplements and median fish intake was 1 (3–5 ounce) serving/week. Over a median follow-up of 2.9 years for non-fatal CAD and 3.3 years for non-fatal ischemic stroke, we observed 6,265 and 4,042 incident cases of non-fatal CAD and non-fatal ischemic stroke, respectively. Omega-3 fatty acid supplement use was independently associated with a lower risk of non-fatal ischemic stroke [HR (95% CI): 0.88 (0.81, 0.95)] but not non-fatal CAD [0.99 (0.93, 1.06)]. Fish intake was not independently associated with non-fatal CAD [1.01 (0.94, 1.09) for 1–3 servings/month, 1.03 (0.98, 1.11) for 1 serving/week, 1.02 (0.93, 1.11) for 2–4 servings/week, and 1.15 (0.98, 1.35) for ≥5 servings/week, reference =

Background: Cixutumumab, a monoclonal antibody targeting insulin-like growth factor I receptor, did not improve undetectable PSA rate at 28 weeks when combined with androgen deprivation in the randomized phase II SWOG S0925 trial for patients with new metastatic hormone-sensitive prostate cancer. We now present mature survival analyses, along with pre-specified secondary and exploratory endpoints. Methods: We randomized 210 patients to androgen deprivation with or without cixutumumab, 105 per treatment arm. We used Kaplan-Meier curves to analyze overall survival, radiographic progression-free survival, and castration resistance-free survival by treatment arm, disease volume, and risk group. We explored differences in survival by treatment arm via covariate-adjusted Cox proportional hazards models adjusted for disease volume and risk. Results: No difference was seen between treatment arms in overall survival (HR 1.01 [0.70-1.45]; p=0.97), radiographic progression-free survival (HR 1.17 [0.85-1.60]; p=0.35), or castration resistance-free survival (HR 1.02 [0.75-1.41]; p=0.88). At baseline, 105/198 (53.0%) patients had high risk features and 119/210 (56.7%) had high volume disease; 16.7% of patients had discordant classifications of high or low category for risk and volume. Adjusting for risk or volume yielded no differences in overall survival between arms. Inferior survival was observed in high risk (HR 1.89 [1.29-2.80]; p=0.001) and high volume (HR 2.75 [1.84-4.10]; p0.2 to ≤4.0 ng/mL (HR 3.72 [1.99-6.95]; p4.0 ng/mL (HR 7.13 [4.24-11.9]; p

Summary Current single-cell RNA sequencing (scRNA-seq) protocols are limited by the number of cells that can be simultaneously sequenced, restricting the ability to resolve heterogeneity of rare cell types. We describe here a protocol for rapid isolation of myeloid cells from tumor-harboring mouse cerebellum without cell sorting to minimize cell damage for scRNA-seq. This protocol includes the procedures for further enrichment of myeloid cells using CD11b+ magnetic beads, followed by the generation of scRNA library and sequencing analysis. For complete details on the use and execution of this protocol, please refer to Dang et al. (2021)., Graphical abstract, Highlights • Isolation of myeloid cells from tumor-bearing mouse cerebellum • Single-cell RNA sequencing (scRNA-seq) of murine cerebellar myeloid cells • Identification of the major myeloid subsets using scRNA-seq data, Current single-cell RNA sequencing (scRNA-seq) protocols are limited by the number of cells that can be simultaneously sequenced, restricting the ability to resolve heterogeneity of rare cell types. We describe here a protocol for rapid isolation of myeloid cells from tumor-harboring mouse cerebellum without cell sorting to minimize cell damage for scRNA-Seq. This protocol includes the procedures for further enrichment of myeloid cells using CD11b+ magnetic beads, followed by the generation of scRNA library and sequencing analysis.

BACKGROUND: Although previous studies have suggested cocoa products may promote cardiovascular health in the general population, no public data are available from patients receiving care in a national integrated health care system. OBJECTIVES: We tested the hypothesis that regular chocolate consumption is associated with a lower risk of coronary artery disease (CAD) events among participants of the Million Veteran Program (MVP). Secondary analysis examined if the main hypothesis was observed among participants with type 2 diabetes. METHODS: We analyzed data from MVP participants who completed the food frequency section of the MVP Lifestyle Survey and were free of CAD at the time of survey completion. CAD events during follow-up (International Statistical Classification of Diseases Ninth Revision codes 410–411 and 413–414, and Tenth Revision codes I20–I25 except I25.2) were assessed using electronic health records. We fitted a Cox proportional hazard model to estimate the RR of CAD. RESULTS: Of 188,447 MVP enrollees with survey data, mean ± SD age was 64 ± 12.0 y and 90% were men. For regular chocolate (28.3 g/serving) consumption of

Cardiovascular disease (CVD), including stroke and coronary artery disease (CAD), is the major cause of mortality for Americans. Nuts have been shown to improve a variety of cardiovascular disease risk factors. This study aimed to test the hypothesis that nut consumption is inversely associated with risk of incidence of stroke, CAD, and CVD mortality in the prospective Million Veterans Program (MVP). A total of 179,827 MVP participants enrolled between 2011 and 2018 were free of CVD prior to assessment of nut consumption via the food frequency questionnaire. Incident stroke and CVD events were ascertained from the Veterans Affairs electronic medical health records and the National Death Index. We used the Cox regression model to compute multivariable adjusted hazard ratios. Over the 3.5-year median follow-up, 3362 new cases of ischemic stroke were identified. When compared with participants who rarely or never consumed nuts, those consuming nuts ≥ 5 times per week were 19% less likely to experience a stroke (95% CI: 8% to 28%), 22% less likely to suffer from CAD (95% CI: 16% to 28%), and 24% less likely to die from CVD (95% CI: 7% to 37%). Consumption of peanut butter was not associated with risk of stroke. Increased dietary intake of nuts, but not peanut butter, was associated with a lower risk of stroke, CAD, and CVD death.

In response to the novel Coronavirus Disease 2019 (COVID-19) pandemic, the Department of Veterans Affairs (VA) Million Veteran Program (MVP) organized efforts to better understand the impact of COVID-19 on Veterans by developing and deploying a self-reported survey.The MVP COVID-19 Survey was developed to collect COVID-19 specific elements including symptoms, diagnosis, hospitalization, behavioral and psychosocial factors and to augment existing MVP data with longitudinal collection of key domains in physical and mental health. Due to the rapidly evolving nature of the pandemic, a multipronged strategy was implemented to widely disseminate the COVID-19 Survey and capture data using both the online platform and mailings.We limited the findings of this paper to the initial phase of survey dissemination which began in May 2020. A total of 729,625 eligible MVP Veterans were invited to complete version 1 of the COVID-19 Survey. As of October 31, 2020, 58,159 surveys have been returned. The mean and standard deviation (SD) age of responders was 71 (11) years, 8.6% were female, 8.2% were Black, 5.6% were Hispanic, and 446 (0.8%) self-reported a COVID-19 diagnosis. Over 90% of responders reported wearing masks, practicing social distancing, and frequent hand washing.The MVP COVID-19 Survey provides a systematic collection of data regarding COVID-19 behaviors among Veterans and represents one of the first large-scale, national surveillance efforts of COVID-19 in the Veteran population. Continued work will examine the overall response to the survey with comparison to available VA health record data.

BACKGROUND: Prescription opioid use (POU) among young adults is increasing. This represents a major public health concern due to the increased risks of opioid use misuse and opioid-related overdose. Limited research has examined the POU among young black men who have sex with men (YBMSM), a diverse group experiencing continued increases in HIV incidence over the past decade. OBJECTIVE: The current study aims to examine the prevalence and both the individual and network characteristics of POU among YBMSM. METHODS: Data come from a longitudinal cohort study of 16–29 year old YBMSM (N =514) between 2013 and 2016 in Chicago. Bivariate and multivariable associations were estimated using general estimating equations (GEE). RESULTS: Approximately 4.2% of YBMSM reported POU in the past 12 months with a cumulative incidence rate of 4.1% over the 18-month follow-up period. YBMSM having criminal justice involvements, experiencing violence, or using any illicit drug other than marijuana in the past 12 months were more likely to report POU in the past 12 months. The presence of a mother figure, however, was associated with a decreased risk of POU in the past 12 months, while engaging in condomless anal sex with their named sexual partners was associated with an increased risk of POU in the past 12 months. CONCLUSIONS: This is one of the first studies to describe POU among a population-based sample of YBMSM. The high incidence rate of POU among YBMSM is alarming, and it underscores the need for further analysis on POU among this key population.

Opioid overprescribing is a major driver of the current opioid overdose epidemic. However, annual opioid prescribing in the USA dropped from 782 to 640 morphine milligram equivalents per capita between 2010 and 2015, while opioid overdose deaths increased by 63%. To better understand the role of prescription opioids and health care utilization prior to opioid-related overdose, we analyzed the death records of decedents who died of an opioid overdose in Illinois in 2016 and linked to any existing controlled substance monitoring program (CSMP) and emergency department (ED) or hospital discharge records. We found that of the 1893 opioid-related overdoses, 573 (30.2%) decedents had not filled an opioid analgesic prescription within the 6 years prior to death. Decedents without an opioid prescription were more likely to be black (33.3% vs 20.2%, p

Background Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. Methods An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization. Results The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality. Conclusion A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.

The exposome represents the array of dietary, lifestyle, and demographic factors to which an individual is exposed. Individual components of the exposome, or groups of components, are recognized as influencing many aspects of human physiology, including cardiometabolic health. However, the influence of the whole exposome on health outcomes is poorly understood and may differ substantially from the sum of its individual components. As such, studies of the complete exposome are more biologically representative than fragmented models based on subsets of factors. This study aimed to model the system of relationships underlying the way in which the diet, lifestyle, and demographic components of the overall exposome shapes the cardiometabolic risk profile. The current study included 36,496 US Veterans enrolled in the VA Million Veteran Program (MVP) who had complete assessments of their diet, lifestyle, demography, and markers of cardiometabolic health, including serum lipids, blood pressure, and glycemic control. The cohort was randomly divided into training and validation datasets. In the training dataset, we conducted two separate exploratory factor analyses (EFA) to identify common factors among exposures (diet, demographics, and physical activity) and laboratory measures (lipids, blood pressure, and glycemic control), respectively. In the validation dataset, we used multiple normal regression to examine the combined effects of exposure factors on the clinical factors representing cardiometabolic health. The mean ± SD age of participants was 62.4 ± 13.4 years for both the training and validation datasets. The EFA revealed 19 Exposure Common Factors and 5 Physiology Common Factors that explained the observed (measured) data. Multivariate regression in the validation dataset revealed the structure of associations between the Exposure Common Factors and the Physiology Common Factors. For example, we found that the factor for fruit consumption was inversely associated with the factor summarizing total cholesterol and low-density lipoprotein cholesterol (LDLC, p = 0.008), and the latent construct describing light levels of physical activity was inversely associated with the blood pressure latent construct (p &lt, 0.0001). We also found that a factor summarizing that participants who frequently consume whole milk are less likely to frequently consume skim milk, was positively associated with the latent constructs representing total cholesterol and LDLC as well as systolic and diastolic blood pressure (p = 0.0006 and &lt, 0.0001, respectively). Multiple multivariable-adjusted regression analyses of exposome factors allowed us to model the influence of the exposome as a whole. In this metadata-rich, prospective cohort of US Veterans, there was evidence of structural relationships between diet, lifestyle, and demographic exposures and subsequent markers of cardiometabolic health. This methodology could be applied to answer a variety of research questions about human health exposures that utilize electronic health record data and can accommodate continuous, ordinal, and binary data derived from questionnaires. Further work to explore the potential utility of including genetic risk scores and time-varying covariates is warranted.

Racial/ethnic health disparities persist among veterans despite comparable access and quality of care. We describe racial/ethnic differences in self-reported health characteristics among 437,413 men and women (mean age (SD) = 64.5 (12.6), 91% men, 79% White) within the Million Veteran Program. The Cochran–Mantel–Haenszel test and linear mixed models were used to compare age-standardized frequencies and means across race/ethnicity groups, stratified by gender. Black, Hispanic, and Other race men and women reported worse self-rated health, greater VA healthcare utilization, and more combat exposure than Whites. Compared to White men, Black and Other men reported more circulatory, musculoskeletal, mental health, and infectious disease conditions while Hispanic men reported fewer circulatory and more mental health, infectious disease, kidney, and neurological conditions. Compared to White women, Black women reported more circulatory and infectious disease conditions and Other women reported more infectious disease conditions. Smoking rates were higher among Black men, but lower for other minority groups compared to Whites. Minority groups were less likely to drink alcohol and had lower physical fitness than Whites. By identifying differences in burden of various health conditions and risk factors across different racial/ethnic groups, our findings can inform future studies and ultimately interventions addressing disparities.

DYT1 dystonia is a movement disorder mainly caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), coding for torsinA. DYT1 dystonia patients show trends of decreased striatal ligand-binding activities to dopamine receptors 1 (D1R) and 2 (D2R). Dyt1 ΔGAG knock-in (KI) mice, which have the corresponding ΔGAG deletion, similarly exhibit reduced striatal D1R and D2R-binding activities and their expression levels. While the consequences of D2R reduction have been well characterized, relatively little is known about the effect of D1R reduction. Here, locomotor responses to D1R and D2R antagonists were examined in Dyt1 KI mice. Dyt1 KI mice showed significantly less responsiveness to both D1R antagonist SCH 23390 and D2R antagonist raclopride. The electrophysiological recording indicated that Dyt1 KI mice showed a significantly increased paired-pulse ratio of the striatal D1R-expressing medium spiny neurons and altered miniature excitatory postsynaptic currents. To analyze the in vivo torsinA function in the D1R-expressing neurons further, Dyt1 conditional knockout (Dyt1 d1KO) mice in these neurons were generated. Dyt1 d1KO mice had decreased spontaneous locomotor activity and reduced numbers of slips in the beam-walking test. Dyt1 d1KO male mice showed abnormal gait. Dyt1 d1KO mice showed defective striatal D1R maturation. Moreover, the mutant striatal D1R-expressing medium spiny neurons had increased capacitance, decreased sEPSC frequency, and reduced intrinsic excitability. The results suggest that torsinA in the D1R-expressing cells plays an important role in the electrophysiological function and motor performance. Medical interventions to the direct pathway may affect the onset and symptoms of this disorder.

BackgroundAsian American Pacific Islander (AAPI) sexual and gender minorities (SGM) face unique challenges in mental health and accessing high-quality health care.ObjectiveThe objective of this study was to identify barriers and facilitators for shared decision making (SDM) between AAPI SGM and providers, especially surrounding mental health.Research designInterviews, focus groups, and surveys.SubjectsAAPI SGM interviewees in Chicago (n=20) and San Francisco (n=20). Two focus groups (n=10) in San Francisco.MeasuresParticipants were asked open-ended questions about their health care experiences and how their identities impacted these encounters. Follow-up probes explored SDM and mental health. Participants were also surveyed about attitudes towards SGM disclosure and preferences about providers. Transcripts were analyzed for themes and a conceptual model was developed.ResultsOur conceptual model elucidates the patient, provider, and encounter-centered factors that feed into SDM for AAPI SGM. Some participants shared the stigma of SGM identities and mental health in their AAPI families. Their AAPI and SGM identities were intertwined in affecting mental health. Some providers inappropriately controlled the visibility of the patient's identities, ignoring or overemphasizing them. Participants varied on whether they preferred a provider of the same race, and how prominently their AAPI and/or SGM identities affected SDM.ConclusionsProviders should understand identity-specific challenges for AAPI SGM to engage in SDM. Providers should self-educate about AAPI and SGM history and intracommunity heterogeneity before the encounter, create a safe environment conducive to patient disclosure of SGM identity, and ask questions about patient priorities for the visit, pronouns, and mental health.

Introduction Incident HIV infections persist in the United States (U.S.) among marginalized populations. Targeted and cost‐efficient testing strategies can help in reaching HIV elimination. This analysis compares the effectiveness and cost of three HIV testing strategies in a high HIV burden area in the U.S. in identifying new HIV infections. Methods We performed a cost analysis comparing three HIV testing strategies in Chicago: (1) routine screening (RS) in an inpatient and outpatient setting, (2) modified partner services (MPS) among networks of the recently HIV infected and diagnosed, and (3) a respondent drive sampling (RDS)‐based social network (SN) approach targeting young African‐American men who have sex with men. All occurred at the same academic medical centre during the following times: routine testing, 2011 to 2016; MPS, 2013 to 2016; SN: 2013 to 2014. Costs were in 2016 dollars and included personnel, HIV testing, training, materials, overhead. Outcomes included cost per test, HIV‐positive test and new diagnosis. Sensitivity analyses were performed to assess the impact of population demographics. Results The RS programme completed 57,308 HIV tests resulting in 360 (0.6%) HIV‐positive tests and 165 new HIV diagnoses (0.28%). The MPS completed 146 HIV tests, resulting in 79 (54%) HIV‐positive tests and eight new HIV diagnoses (5%). The SN strategy completed 508 HIV tests, resulting in 210 (41%) HIV‐positive tests and 37 new HIV diagnoses (7.2%). Labour accounted for the majority of costs in all strategies. The estimated cost per new HIV diagnosis was $16,773 for the RS programme, $61,418 for the MPS programme and $15,683 for the SN testing programme. These costs were reduced for the RS and MPS strategies in sensitivity analyses limiting testing efficacy to the highest prevalence patient populations ($2,841 and $33,233 respectively). Conclusions The SN strategy yielded the highest proportion of new diagnoses, followed closely by the MPS programme. Both the SN strategy and RS programme were comparable in the cost per new diagnosis. A simultaneous approach that consists of RS in combination with SN testing may be most effective for identifying new HIV infections in settings with heterogeneous epidemics with both high rates of HIV prevalence and HIV testing.

Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

Objective Compare the safety and efficacy of topical gentian violet with that of nystatin oral suspension (NYS) for the treatment of oropharyngeal candidiasis in HIV-1-infected adults in resource-limited settings. Design Multicenter, open-label, evaluator-blinded, randomized clinical trial at eight international sites, within the AIDS Clinical Trials Group. Study participants and intervention Adult HIV-infected participants with oropharyngeal candidiasis, stratified by CD4 cell counts and antiretroviral therapy status at study entry, were randomized to receive either gentian violet (0.00165%, BID) or NYS (500 000 units, QID) for 14 days. Main outcome measure(s) Cure or improvement after 14 days of treatment. Signs and symptoms of oropharyngeal candidiasis were evaluated in an evaluator-blinded manner. Results The study was closed early per Data Safety Monitoring Board after enrolling 221 participants (target = 494). Among the 182 participants eligible for efficacy analysis, 63 (68.5%) in the gentian violet arm had cure or improvement of oropharyngeal candidiasis versus 61 (67.8%) in the NYS arm, resulting in a nonsizable difference of 0.007 (95% confidence interval: -0.129, 0.143). There was no sizable difference in cure rates between the two arms (-0.0007; 95% confidence interval: -0.146, 0.131). No gentian violet-related adverse events were noted. No sizable differences were identified in tolerance, adherence, quality of life, or acceptability of study drugs. In gentian violet arm, 61 and 39% of participants reported 'no' and 'mild-to-moderate' staining, respectively. Cost for medication procurement was significantly lower for gentian violet versus NYS (median $2.51 and 19.42, respectively, P = 0.01). Conclusion Efficacy of gentian violet was not statistically different than NYS, was well tolerated, and its procurement cost was substantially less than NYS.

Although the previous lanreotide autogel/depot syringe had been well received, feedback indicated that improvements could be made to make it more user-friendly. Additionally, the view that patients should have greater involvement in the research and development process is echoed by the International Neuroendocrine Cancer Alliance. A series of studies aimed to develop and validate a new syringe that works better for patients, caregivers and healthcare professionals (HCPs) by involving these groups at key stages in the development and testing process. The multicentre, international, human factor studies, consisted of four formative studies and one validation study. The formative studies collected patient, caregiver and HCP feedback on the lanreotide autogel/depot syringe on the market at the time, and on newly designed prototypes. The validation study was conducted to evaluate the final syringe to confirm that it can be used effectively and safely in the intended environment, by the intended user, for the intended purpose. Overall, 213 individuals participated in the studies; 145 contributed to the formative studies and 68 to the validation study. The validated new-generation syringe included several important updates compared with the lanreotide autogel/depot syringe currently on the market, including the flanges, which are now larger and have a better grip; the overcap, which is white, ridged, opaque and bigger; the plunger supports and the thermoformed tray. No participant hurt themselves or others during the validation study (although several misuses were reported), and all participants succeeded in delivering a complete dose and activating the safety system. With collaboration, a new syringe was developed to meet the needs of patients, caregivers and HCPs, whilst ensuring lanreotide was delivered effectively and safely. These studies highlight the importance of involving patients, caregivers and HCPs in clinical evaluation studies to develop medical products that address their concerns and meet their needs. Ipsen. Plain language summary available for this article.

INTRODUCTION: Previous studies of the relationship between fried food consumption and coronary artery disease (CAD) have yielded conflicting results. We tested the hypothesis that frequent fried food consumption is associated with a higher risk of incident CAD events in Million Veteran Program (MVP) participants. METHODS: Veterans Health Administration electronic health record data were linked to questionnaires completed at MVP enrollment. Self-reported fried food consumption at baseline was categorized: (

Introduction Although opioid prescribing has decreased since 2010, overdose deaths involving illicit opioids have continued to rise. This study explores prescribing patterns before fatal overdose of decedents who died of prescription and illicit opioid overdoses. Methods This retrospective cohort study was conducted in 2019 and included all 1,893 Illinois residents who died of an opioid-related overdose in 2016. Each decedent was linked to any existing Prescription Monitoring Program records, calculating weekly morphine milligram equivalents for 52 weeks before overdose. Results Among the 1,893 fatal opioid overdoses, 309 involved any prescription opioid and 1,461 involved illicit opioids without the involvement of prescription opioids. The death rate because of illicit opioids was 23/100,000 among black residents versus 10.5/100,000 among whites. During the last year of life, 76% of prescription opioid decedents filled any opioid prescription totaling 10.7 prescriptions per decedent, compared with 36% of illicit opioid decedents totaling 2.6 prescriptions per decedent. During the last week of life, 33% of prescription opioid decedents filled an opioid prescription totaling 0.42 prescriptions per decedent, compared with 4% of illicit opioid decedents totaling 0.05 prescriptions per decedent. Conclusions Prescribing patterns alone may not be sufficient to identify patients who are at high risk for opioid overdose, especially for those using illicit opioids. Interventions aimed at reducing opioid overdoses should take into account different patterns of opioid prescribing associated with illicit and prescription opioid overdose deaths and be designed around the local characteristics of the opioid overdose epidemic.

Mutations of HSPB5 (also known as CRYAB or αB-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to various multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aims at investigating the pathological mechanisms involved in an early onset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells (iPSCs) derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/343delT), and BHK21 cells, a cell line lacking endogenous HSPB5 expression. 343delT/343delT and WT KI/343delT iPSC-derived skeletal myotubes (iSKMs) and cardiomyocytes (iCMs) did not express detectable levels of 343delT protein, contributable to extreme insolubility of the mutant protein. Overexpression of HSPB5 343delT resulted in insoluble mutant protein aggregates and induction of a cellular stress response. Co-expression of 343delT with WT prevented visible aggregation of 343delT and improved its solubility. Additionally, in vitro refolding of 343delT in the presence of WT rescued its solubility. We demonstrate an interaction between WT and 343delT both in vitro and within cells. These data support a loss of function model for the myopathy observed in the patient, as the insoluble mutant would be unavailable to perform normal functions of HSPB5, though additional gain-of-function effects of the mutant protein cannot be excluded. Additionally, our data highlights the solubilization of 343delT by WT, concordant with the recessive inheritance of the disease and absence of symptoms in carrier individuals.

Poor glycemic control in individuals with type 1 diabetes (T1D) is associated with both micro- and macrovascular complications, but good glycemic control does not fully prevent the risk of these complications.The objective of the study was to determine whether T1D with good glycemic control have persistent abnormalities of metabolites and pathways that exist in T1D with poor glycemic control.We compared plasma metabolites in T1D with poor (glycated hemoglobin ≥ 8.5%, T1D[-] and good (glycated hemoglobin6.5%, T1D[+]) glycemic control with nondiabetic controls (ND).The study was conducted at the clinical research unit.T1D with poor (n = 14), T1D(-) and good, T1D(+) (n = 15) glycemic control and matched (for age, sex, and body mass index) ND participants were included in the study.There were no intervention.Comparison of qualitative and quantitative profiling of metabolome was performed.In T1D(-), 347 known metabolites belonging to 38 metabolic pathways involved in cholesterol, vitamin D, tRNA, amino acids (AAs), bile acids, urea, tricarboxylic acid cycle, immune response, and eicosanoids were different from ND. In T1D(+),154 known metabolites belonging to 26 pathways including glycolysis, gluconeogenesis, bile acids, tRNA biosynthesis, AAs, branch-chain AAs, retinol, and vitamin D metabolism remained altered from ND. Targeted measurements of AA metabolites, trichloroacetic acid, and free fatty acids showed directional changes similar to the untargeted metabolomics approach.Comprehensive metabolomic profiling identified extensive metabolomic abnormalities in T1D with poor glycemic control. Chronic good glycemic control failed to normalize many of these perturbations, suggesting a potential role for these persistent abnormalities in many complications in T1D.

OBJECT The impact of transsphenoidal surgery for nonfunctional pituitary adenomas (NFAs) on preoperative hypopituitarism relative to the incidence of new postoperative endocrine deficits remains unclear. The authors investigated rates of hypopituitarism resolution and development after transsphenoidal surgery. METHODS Over a 5-year period, 305 transsphenoidal surgeries for NFAs performed at The California Center for Pituitary Disorders were retrospectively reviewed. RESULTS Patients with preoperative endocrine deficits (n = 153, 50%) were significantly older (mean age 60 vs 54 years; p = 0.004), more frequently male (65% vs 44%; p = 0.0005), and had larger adenomas (2.4 cm vs 2.1 cm; p = 0.02) than patients without preoperative deficits (n = 152, 50%). Of patients with preoperative endocrine deficits, 53% exhibited symptoms. Preoperative deficit rates were 26% for the thyroid axis; 20% and 16% for the male and female reproductive axes, respectively; 13% for the adrenocorticotropic hormone (ACTH)/cortisol axis, and 19% for the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Laboratory normalization rates 6 weeks and 6 months after surgery without hormone replacement were 26% and 36% for male and 13% and 13% for female reproductive axes, respectively; 30% and 49% for the thyroid axis; 3% and 3% for the cortisol axis; and 9% and 22% for the IGF-1 axis (p < 0.05). New postoperative endocrine deficits occurred in 42 patients (13.7%). Rates of new deficits by axes were: male reproductive 3% (n = 9), female reproductive 1% (n = 4), thyroid axis 3% (n = 10), cortisol axis 6% (n = 19), and GH/IGF-1 axis 4% (n = 12). Patients who failed to exhibit any endocrine normalization had lower preoperative gland volumes than those who did not (0.24 cm3 vs 0.43 cm3, respectively; p < 0.05). Multivariate analyses revealed that no variables predicted new postoperative deficits or normalization of the female reproductive, cortisol, and IGF-1 axes. However, increased preoperative gland volume and younger age predicted the chances of a patient with any preoperative deficit experiencing normalization of at least 1 axis. Younger age and less severe preoperative hormonal deficit predicted normalization of the thyroid and male reproductive axes (p < 0.05). CONCLUSIONS After NFA resection, endocrine normalization rates in this study varied with the hormonal axis and were greater than the incidence of new endocrine deficits. Low preoperative gland volume precluded recovery. Patient age and the severity of the deficiency influenced the recovery of the thyroid and male reproductive axes, the most commonly impaired axes and most likely to normalize postoperatively. This information can be of use in counseling patients with hypopituitarism who undergo NFA surgery.

Objective. The University of Chicago Medicine (UCM) led the Expanded Testing and Linkage to Care (X-TLC) program for disproportionately affected populations on the South Side of Chicago. The X-TLC program aimed to expand routine HIV testing to high-prevalence communities with disproportionately affected populations (i.e., minority men and women, men who have sex with men, and intravenous drug users) according to CDC guidelines at multiple clinical sites. Methods. The X-TLC program used standard blood-based laboratory testing vs. point-of-care rapid testing or rapid laboratory testing with point-of-care results notification. Site coordinators and the linkage-to-care coordinator at UCM oversaw testing, test notification, and linkage to care. Results. From February 1, 2011, through December 31, 2013, the X-TLC program completed 75,345 HIV tests on 67,153 unique patients. Of the total tests, 48,044 (63.8%) were performed on patients who self-identified as African American and 6,606 (8.8%) were performed on patients who self-identified as Hispanic. Of the 67,153 patients tested, 395 (0.6%) tested positive and 176 (0.3%) were previously unaware of their HIV-positive status. Seroprevalence was even higher for EDs, where 127 of 12,957 patients tested positive for HIV (1.0% seroprevalence), than for other patient care sites, including for new diagnoses, where 50 of 12,957 patients tested positive for HIV (0.4% seroprevalence). Of the 176 newly diagnosed patients, 166 of 173 (96.0%) patients who were still alive when testing was complete received their test results, and 148 of the 166 patients who were eligible for care (89.0%) were linked to care. Patients linked to X-TLC physicians did well with respect to the continuum of care: 77 of 123 (62.6%) patients achieved HIV viral load of Conclusion. Lead organizations such as UCM were able to assist and oversee HIV screening and linkage to care for HIV patients diagnosed at community sites. HIV screening and linkage to care can be accomplished by incorporating standard testing for HIV into routine medical care.

IMPORTANCE: Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene–drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade. OBJECTIVE: To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials. DESIGN, SETTING, AND PARTICIPANTS: Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center. EXPOSURES: IL6R SNPs (rs2228145; rs4129267). MAIN OUTCOMES AND MEASURES: Phenotypes defined by International Classification of Diseases, Ninth Revision codes. RESULTS: Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank. CONCLUSIONS AND RELEVANCE: In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

Background The Department of Veterans Affairs Million Veteran Program (MVP) is the largest ongoing cohort program of its kind, with 654,903 enrollees as of June 2018. The objectives of this study were to examine gender differences in the MVP cohort with respect to response and enrollment rates; demographic, health, and health care characteristics; and prevalence of self-reported health conditions. Methods The MVP Baseline Survey was completed by 415,694 veterans (8% women), providing self-report measures of demographic characteristics, health status, and medical history. Results Relative to men, women demonstrated a higher positive responder rate (23.0% vs. 16.0%), slightly higher enrollment rate (13.5% vs. 12.9%), and, among enrollees, a lower survey completion rate (59.7% vs. 63.8%). Women were younger, more racially diverse, had higher educational attainment, and were less likely to be married or cohabitating with a partner than men. Women were more likely to report good to excellent health status but poorer physical fitness, and less likely to report lifetime smoking and drinking than men. Compared with men, women veterans showed an increased prevalence of musculoskeletal conditions, thyroid problems, gastrointestinal conditions, migraine headaches, and mental health disorders, as well as a decreased prevalence of gout, cardiovascular diseases, high cholesterol, diabetes, and hearing problems. Conclusions These results revealed some substantial gender differences in the research participation rates, demographic profile, health characteristics, and prevalence of health conditions for veterans in the MVP cohort. Findings highlight the need for tailoring recruitment efforts to ensure representation of the increasing women veteran population receiving care through the Veterans Health Administration.

Background While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. Methods and Results We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow‐up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow‐up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person‐years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84–0.99), 0.87 (0.80–0.95), 0.86 (0.79–0.94), and 0.80 (0.73–0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use ( P linear trend, Conclusions Our data are consistent with an inverse association between Dietary Approach to Stop Hypertension diet score and incidence of CAD among US veterans.

No data exist on the prevalence of ideal cardiovascular health metrics in a national sample of U.S. veterans. We assessed the prevalence of ideal Life's Simple Seven (LSS) metrics in a cross-sectional study of 554,855 U.S. veterans enrolled in the Million Veteran Program (MVP) from 2011 to 2017. We used the American Heart Association's established criteria to categorize each LSS metric as either poor, intermediate, or ideal for a veteran at time of MVP enrollment. Information on adiposity/body mass index, smoking status, diet, and physical activity was obtained from self-reported survey data, and clinical measurements for total cholesterol, blood pressure, and plasma glucose were obtained from electronic health records. Complete data on all LSS health factors were available for 201,745 veterans. The prevalence of having 0, 1, 2, 3, 4, 5, 6, and 7 ideal cardiovascular health metrics was 29.2%, 34.6%, 22.6%, 10.0%, 3.0%, 0.6%

Objective.To evaluate the initial serological responses to pneumococcal vaccination with the 13-valent protein-conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) among patients with rheumatoid arthritis (RA) treated with biological disease-modifying antirheumatic drugs (bDMARD) according to dosing and intervals between immunizations.Methods.Investigator-initiated clinical trial. Patients with RA receiving bDMARD were randomized (1:1:1) to immunization with single dose PCV13 followed by PPV23 after 16 or 24 weeks, or double dose PCV13 followed by PPV23 after 16 weeks. A comparison group of patients with RA treated with conventional synthetic (cs)DMARD received single dose PCV13 followed by PPV23 16 weeks later. Pneumococcal antibodies were collected before and 4 weeks after each vaccination. The primary endpoint was the proportion of participants responding to ≥ 6/12 pneumococcal serotypes 4 weeks after both vaccinations.Results.Sixty-five participants receiving bDMARD and 35 participants receiving csDMARD were included. After PPV23 vaccination, 87% (95% CI 0.76–0.94) and 94% (95% CI 0.77–0.99), respectively, of participants treated with bDMARD and csDMARD had reached the primary endpoint. There was no significant difference in primary endpoint between the 3 randomization arms. The response for rituximab-treated participants was 25% compared to ≥ 89% in participants treated with bDMARD with other mode of action.Conclusion.The early serological response to prime-boost vaccination with PCV13 followed by PPV23 was very similar among participants receiving bDMARD and csDMARD. However, notable differences in response were observed according to individual bDMARD. It is important to consider the RA treatment when planning pneumococcal vaccination in patients with RA.

Recent advances in the treatment of hepatitis C virus (HCV) infection have led to the availability of both highly efficacious interferon-containing and interferon-sparing regimens. However, the use of such therapies faces restrictions due to high costs. For patients who are medically eligible to receive interferon, the choice between the two will likely be impacted by preferences surrounding interferon, severity of disease, coverage policies and out-of-pocket costs. We developed a decision model to quantify the trade-offs between immediate, interferon-containing therapy and delayed, interferon-free therapy for patients with chronic, genotype 1 HCV infection. We projected the quality-adjusted life expectancy stratified by the presence or absence of cirrhosis for four strategies: (i) no treatment; (ii) immediate, one-time treatment with an interferon-containing regimen; (iii) immediate treatment as above with the opportunity for retreatment in patients who fail to achieve sustained virologic response with interferon-free therapy in 1 year; and (iv) delayed therapy with interferon-free therapy in 1 year. When compared to one-time immediate treatment with the interferon-containing regimen, delayed treatment with the interferon-free regimen in 1 year resulted in longer life expectancy, with a 0.2 quality-adjusted life year (QALY) increase in noncirrhotic patients, and a 1.1 QALY increase in patients with cirrhosis. This superiority in health benefits was lost when wait time for interferon-free therapy was greater than 3-3.2 years. In this modelling analysis, interferon-free therapy resulted in superior health benefits compared to immediate therapy with interferon until wait time exceeded 3-3.2 years. Such data can inform decision-making regarding treatment initiation for HCV as healthcare financing evolves.

OBJECTIVETo determine the impact of recurrent Clostridium difficile infection (RCDI) on patient behaviors following illness.METHODSUsing a computer algorithm, we searched the electronic medical records of 7 Chicago-area hospitals to identify patients with RCDI (2 episodes of CDI within 15 to 56 days of each other). RCDI was validated by medical record review. Patients were asked to complete a telephone survey. The survey included questions regarding general health, social isolation, symptom severity, emotional distress, and prevention behaviors.RESULTSIn total, 119 patients completed the survey (32%). On average, respondents were 57.4 years old (standard deviation, 16.8); 57% were white, and ~50% reported hospitalization for CDI. At the time of their most recent illness, patients rated their diarrhea as high severity (58.5%) and their exhaustion as extreme (30.7%). Respondents indicated that they were very worried about getting sick again (41.5%) and about infecting others (31%). Almost 50% said that they have washed their hands more frequently (47%) and have increased their use of soap and water (45%) since their illness. Some of these patients (22%–32%) reported eating out less, avoiding certain medications and public areas, and increasing probiotic use. Most behavioral changes were unrelated to disease severity.CONCLUSIONHaving had RCDI appears to increase prevention-related behaviors in some patients. While some behaviors are appropriate (eg, handwashing), others are not supported by evidence of decreased risk and may negatively impact patient quality of life. Providers should discuss appropriate prevention behaviors with their patients and should clarify that other behaviors (eg, eating out less) will not affect their risk of future illness.Infect Control Hosp Epidemiol. 2017;38:1351–1357

Background Oral miltefosine has been shown to be non-inferior to first-line, injectable meglumine antimoniate (MA) for the treatment of cutaneous leishmaniasis (CL) in children. Miltefosine may be administered via in-home caregiver Directly Observed Therapy (cDOT), while patients must travel to clinics to receive MA. We performed a cost-effectiveness analysis comparing miltefosine by cDOT versus MA for pediatric CL in southwest Colombia. Methodology/Principle findings We developed a Monte Carlo model comparing the cost-per-cure of miltefosine by cDOT compared to MA from patient, government payer, and societal perspectives (societal = sum of patient and government payer perspective costs). Drug effectiveness and adverse events were estimated from clinical trials. Healthcare utilization and costs of travel were obtained from surveys of providers and published sources. The primary outcome was cost-per-cure reported in 2015 USD. Treatment efficacy, costs, and adherence were varied in sensitivity analysis to assess robustness of results. Treatment with miltefosine resulted in substantially lower cost-per-cure from a societal and patient perspective, and slightly higher cost-per-cure from a government payer perspective compared to MA. Mean societal cost-per-cure were $531 (SD±$239) for MA and $188 (SD±$100) for miltefosine, a mean cost-per-cure difference of +$343. Mean cost-per-cure from a patient perspective were $442 (SD ±$233) for MA and $30 (SD±$16) for miltefosine, a mean difference of +$412. Mean cost-per-cure from a government perspective were $89 (SD±$55) for MA and $158 (SD±$98) for miltefosine, with a mean difference of -$69. Results were robust across a variety of assumptions in univariate and multi-way analysis. Conclusions/Significance Treatment of pediatric cutaneous leishmaniasis with miltefosine via cDOT is cost saving from patient and societal perspectives, and moderately more costly from the government payer perspective compared to treatment with MA. Results were robust over a range of sensitivity analyses. Lower drug price for miltefosine could result in cost saving from a government perspective., Author summary Cutaneous leishmaniasis (CL) is a tropical parasitic disease transmitted by sand flies that causes chronic skin and mucosal ulcers. Current standard of care therapy requires patients to travel to a clinic for twenty consecutive days for injections of meglumine antimoniate (MA). This may represent an economic burden, particularly for patients living far from healthcare services, especially children and their caregivers. We performed mathematical modeling to compare costs of the standard of care treatment with costs of miltefosine, an equivalently efficacious oral medication that allows pediatric patients to be treated at home under trained supervision of a caregiver. In our model, miltefosine led to substantially lower costs for patients and only slightly higher costs to the healthcare system. Importantly, the cost to society (combined patient and healthcare system costs) was lower for miltefosine compared to MA. Treatment of pediatric CL with miltefosine in the patient’s home could decrease overall cost of treatment, while diminishing the barriers and cost burden on patients, their caregivers, and society.

Insulin deprivation in type 1 diabetes (T1D) individuals increases lipolysis and plasma free fatty acids (FFA) concentration, which can stimulate synthesis of intramyocellular bioactive lipids such as ceramides (Cer) and long-chain fatty acid-CoAs (LCFa-CoAs). Ceramide was shown to decrease muscle insulin sensitivity, and at mitochondrial levels it stimulates reactive oxygen species production. Here, we show that insulin deprivation in streptozotocin diabetic C57BL/6 mice increases quadriceps muscle Cer content, which was correlated with a concomitant decrease in the body fat and increased plasma FFA, glycosylated hemoglobin level (%Hb A1c), and muscular LCFa-CoA content. The alternations were accompanied by an increase in protein expression in LCFa-CoA and Cer synthesis (FATP1/ACSVL5, CerS1, CerS5), a decrease in the expression of genes implicated in muscle insulin sensitivity (GLUT4, GYS1), and inhibition of insulin signaling cascade by Aktα and GYS3β phosphorylation under acute insulin stimulation. Both the content and composition of sarcoplasmic fraction sphingolipids were most affected by insulin deprivation, whereas mitochondrial fraction sphingolipids remained stable. The observed effects of insulin deprivation were reversed, except for content and composition of LCFa-CoA, CerS protein expression, GYS1 gene expression, and phosphorylation status of Akt and GYS3β when exogenous insulin was provided by subcutaneous insulin implants. Principal component analysis and Pearson's correlation analysis revealed close relationships between the features of the diabetic phenotype, the content of LCFa-CoAs and Cers containing C18-fatty acids in sarcoplasm, but not in mitochondria. Insulin replacement did not completely rescue the phenotype, especially regarding the content of LCFa-CoA, or proteins implicated in Cer synthesis and muscle insulin sensitivity. These persistent changes might contribute to muscle insulin resistance observed in T1D individuals.

Shared decision making (SDM) is a model of patient-provider communication. Little is known about the role of SDM in health disparities among Asian American and Pacific Islander (AAPI) sexual and gender minorities (SGM). We illustrate how issues at the intersection of AAPI and SGM identities affect SDM processes and health outcomes. We discuss experiences of AAPI SGM that are affected by AAPI heterogeneity, SGM stigma, multiple minority group identities, and sources of discrimination. Recommendations for clinical practice, research, policy, community development, and education are offered.

Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31513690/ We describe the epidemiological characteristics, pattern of circulation, and geographical distribution of influenza B viruses and its lineages using data from the Global Influenza B Study. We included over 1.8 million influenza cases occurred in thirty-one countries during 2000-2018. We calculated the proportion of cases caused by influenza B and its lineages; determined the timing of influenza A and B epidemics; compared the age distribution of B/Victoria and B/Yamagata cases; and evaluated the frequency of lineage-level mismatch for the trivalent vaccine. The median proportion of influenza cases caused by influenza B virus was 23.4%, with a tendency (borderline statistical significance, p = 0.060) to be higher in tropical vs. temperate countries. Influenza B was the dominant virus type in about one every seven seasons. In temperate countries, influenza B epidemics occurred on average three weeks later than influenza A epidemics; no consistent pattern emerged in the tropics. The two B lineages caused a comparable proportion of influenza B cases globally, however the B/Yamagata was more frequent in temperate countries, and the B/Victoria in the tropics (p = 0.048). B/Yamagata patients were significantly older than B/Victoria patients in almost all countries. A lineage-level vaccine mismatch was observed in over 40% of seasons in temperate countries and in 30% of seasons in the tropics. The type B virus caused a substantial proportion of influenza infections globally in the 21st century, and its two virus lineages differed in terms of age and geographical distribution of patients. These findings will help inform health policy decisions aiming to reduce disease burden associated with seasonal influenza. info:eu-repo/semantics/publishedVersion

This cohort study analyzes a nationwide database of commercially insured US individuals to determine how often naloxone is prescribed to individuals at high risk of opioid overdose., Key Points Question How often is naloxone prescribed in a clinical setting to US patients at high risk of opioid overdose? Findings In this cohort study using administrative data including 138 108 individuals, only 1.5% of high-risk patients, including individuals with prior opioid overdose or opioid misuse or dependence, were prescribed naloxone. Meaning Naloxone prescribing in the health care setting represents an opportunity to improve access to this life-saving intervention., Importance As opioid-related mortality continues to increase, naloxone remains a critical intervention in preventing overdose death. Opportunities to expand access through the health care setting should be optimized. Objective To determine the characteristics of naloxone prescribing for US patients at high risk of opioid overdose. Design, Setting, and Participants This retrospective cohort study used Truven Health MarketScan data from October 1, 2015, through December 31, 2016, of individuals with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes related to opioid use, misuse, dependence, and overdose. The cohort included 138 108 commercially insured individuals aged 15 years or older in the United States with claims related to opioid misuse or dependence, opioid-related overdose, or both. Exposures Outpatient naloxone pharmacy claims. Main Outcomes and Measures Demographic characteristics, clinical characteristics, health care service use, and proportion prescribed naloxone were included in multivariable logistic regression analyses to test the association of opioid risk group with naloxone claim. Results Of 138 108 high-risk individuals (mean [SD] age, 43.4 [0.4] years; 72 435 [52.4%] men), 2135 (1.5%) were prescribed naloxone. Having prior diagnoses of both opioid misuse or dependence and overdose was associated with a greater likelihood of receiving naloxone (odds ratio [OR], 2.32; 95% CI, 1.98-2.72; P

Our objective was to determine tuberculosis (TB) incidence and evaluate TB risk in adults after one or more years of use of combination antiretroviral therapy (cART) through a retrospective cohort study in Jos, Nigeria. We studied a cohort of HIV-infected adults treated with ART for at least 1 year. Based on immunologic and virologic responses to ART, patients were categorized into four groups: CD4 T cell count ≥350 cells/mm3 and HIV-1 RNA level ≤400 copies/ml (group 1), CD4 T cell count ≥350 cells/mm3 and HIV-1 RNA level >400 copies/ml (group 2), CD4 T cell count 400 copies/ml (group 4). Time to incident TB for the four groups was analyzed using the Kaplan–Meier method. Cox regression models were used to evaluate predictors of incident TB. In this cohort of 5,093 HIV-infected adults, of which 68.4% were female, with a mean age 35.1 years (standard deviation 9.1 years), we observed 98 cases of incident TB during 4 years and 3 months of follow-up. The overall TB incidence rate was 8.7 cases/1,000 patient-years of follow-up. Adjusted hazards for incident TB were 2.11 (95% CI 0.97–4.61), 2.05 (95% CI 1.10–3.79), and 3.65 (95% CI 1.15–5.06) in group 2, 3, and 4 patients, respectively, compared to group 1. Tuberculosis incidence in patients on ART is driven by poor immunologic and/or virologic response. Optimization of HIV treatment should be prioritized to reduce the burden of TB in this high-risk population.

Estimates of T regulatory cell populations in the periphery of patients with Crohn's disease are confounded by disease activity and concomitant immunotherapeutic agents known to affect T cell proliferation and survival. We performed deuterium pulse/chase experiments in patients with quiescent Crohn's disease on no immunotherapy and healthy control subjects to estimate T regulatory cell kinetics. Quantification of deuterated DNA isolated from T cell subsets over 10 days was determined by mass spectrophotometry. We demonstrate enhanced proliferation within the T regulatory cell population from patients with Crohn's disease when compared to non-T regulatory cells and T regulatory cells from healthy control subjects. We speculate that T regulatory cells isolated from the periphery of patients with Crohn's disease experience persistent antigen stimulation resulting in excess proliferative rates.

Background Laparoscopic adjustable gastric banding is gaining in popularity in the United States. Our objective was to examine the outcomes of laparoscopic adjustable gastric banding and the prevalence of band revision and explantation at academic medical centers. Methods Using the "International Classification of Diseases, 9th revision," diagnosis and procedure codes, data were obtained from the University Health System Consortium Clinical Database for all laparoscopic adjustable gastric banding procedures performed from 2006 to 2009. The outcome measures included demographics, length of hospital stay, perioperative morbidity, mortality, and the prevalence of band revision and explantation. Results A total of 10,151 laparoscopic gastric banding procedures were performed from January 2007 to December 2009. The mean length of stay was 1.2 days. The perioperative morbidity rate was 3.0%, and the in-hospital mortality rate was .03%. The prevalence of band revision was .76% and of band explantation was .87%. Compared with the outcome of primary gastric banding, gastric band revision or explantation was associated with a longer length of hospital stay, greater perioperative morbidity, and greater cost. Conclusion Within the context of the 3-year period of analysis, laparoscopic gastric banding was associated with low perioperative morbidity and mortality and a low prevalence of band revision and explantation.

Insulin regulates many cellular processes, but the full impact of insulin deficiency on cellular functions remains to be defined. Applying a mass spectrometry–based nontargeted metabolomics approach, we report here alterations of 330 plasma metabolites representing 33 metabolic pathways during an 8-h insulin deprivation in type 1 diabetic individuals. These pathways included those known to be affected by insulin such as glucose, amino acid and lipid metabolism, Krebs cycle, and immune responses and those hitherto unknown to be altered including prostaglandin, arachidonic acid, leukotrienes, neurotransmitters, nucleotides, and anti-inflammatory responses. A significant concordance of metabolome and skeletal muscle transcriptome–based pathways supports an assumption that plasma metabolites are chemical fingerprints of cellular events. Although insulin treatment normalized plasma glucose and many other metabolites, there were 71 metabolites and 24 pathways that differed between nondiabetes and insulin-treated type 1 diabetes. Confirmation of many known pathways altered by insulin using a single blood test offers confidence in the current approach. Future research needs to be focused on newly discovered pathways affected by insulin deficiency and systemic insulin treatment to determine whether they contribute to the high morbidity and mortality in T1D despite insulin treatment.

DYT1 early-onset generalized torsion dystonia is an inherited movement disorder associated with mutations in DYT1 that codes for torsinA protein. The most common mutation seen in this gene is a trinucleotide deletion of GAG. We previously reported a motor control deficit on a beam-walking task in our Dyt1 ΔGAG knock-in heterozygous mice. In this report we show the reversal of this motor deficit with the anticholinergic trihexyphenidyl (THP), a drug commonly used to treat movement problems in dystonia patients. THP also restored the reduced corticostriatal long-term depression (LTD) observed in these mice. Corticostriatal LTD has long been known to be dependent on D2 receptor activation. In this mouse model, striatal D2 receptors were expressed at lower quantities in comparison to wild-type mice. Furthermore, the mice were also partially resistant to FPL64176, an agonist of L-type calcium channels that have been previously reported to cause severe dystonic-like symptoms in wild-type mice. Our findings collectively suggest that altered communication between cholinergic interneurons and medium spiny neurons is responsible for the LTD deficit and that this synaptic plasticity modification may be involved in the striatal motor control abnormalities in our mouse model of DYT1 dystonia.