Pathogenic hypothalamic extracellular matrix promotes metabolic disease.

Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3-8, but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases.

The Use of Telepsychiatry Services in Emergency Settings: Scoping Review.

BACKGROUND: Telepsychiatry (TP), a live video meeting, has been implemented in many contexts and settings. It has a distinct advantage in the psychiatric emergency department (ED) setting, as it expedites expert assessments for psychiatric patients. However, limited knowledge exits for TP's effectiveness in the ED setting, as well as the process of implementing TP in this setting. OBJECTIVE: This scoping review aimed to review the existing evidence for the administrative and clinical outcomes for TP in the ED setting and to identify the barriers and facilitators to implementing TP in this setting. METHODS: The scoping review was conducted according to the guidelines for the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). Three electronic databases were examined: PubMed, Embase, and Web of Science. The databases were searched from January 2013 to April 2023 for papers and their bibliography. A total of 2816 potentially relevant papers were retrieved from the initial search. Studies were screened and selected independently by 2 authors. RESULTS: A total of 11 articles were included. Ten papers reported on administrative and clinical outcomes of TP use in the ED setting and 1 on the barriers and facilitators of its implementation. TP is used in urban and rural areas and for settings with and with no on-site psychiatric services. Evidence shows that TP reduced waiting time for psychiatric evaluation, but in some studies, it was associated with prolonged total length of stay in the ED compared with in-person evaluation. Findings indicate lower admission rates in patients assessed with TP in the ED. Limited data were reported for TP costs, its use for involuntary commitment evaluations, and its use for particular subgroups of patients (eg, those with a particular diagnosis). A single paper examined TP implementation process in the ED, which explored the barriers and facilitators for implementation among patients and staff in a rural setting. CONCLUSIONS: Based on the extant studies, TP seems to be generally feasible and acceptable to key stakeholders. However, this review detected a gap in the literature regarding TP's effectiveness and implementation process in the ED setting. Specific attention should be paid to the examination of this service for specific groups of patients, as well as its use to enable assessments for possible involuntary commitment.

Nationwide Evaluation of Quality of Care Indicators for Individuals with Severe Mental Illness and Diabetes Mellitus, Following Israel's Mental Health Reform.

Diabetes Mellitus (DM) is more common among individuals with severe mental illness (SMI). We aimed to assess quality-of-care-indicators in individuals with SMI following the 2015 Israel's Mental-Health-reform. We analyzed yearly changes in 2015-2019 of quality-of-care-measures and intermediate-DM-outcomes, with adjustment for gender, age-group, and socioeconomic status (SES) and compared individuals with SMI to the general adult population. Adults with SMI had higher prevalences of DM (odds ratio (OR) = 1.64; 95% confidence intervals (CI): 1.61-1.67) and obesity (OR = 2.11; 95% CI: 2.08-2.13), compared to the general population. DM prevalence, DM control, and obesity rates increased over the years in this population. In 2019, HbA1c testing was marginally lower (OR = 0.88; 95% CI: 0.83-0.94) and uncontrolled DM (HbA1c > 9%) slightly more common among patients with SMI (OR = 1.22; 95% CI: 1.14-1.30), control worsened by decreasing SES. After adjustment, uncontrolled DM (adj. OR = 1.02; 95% CI: 0.96-1.09) was not associated with SMI. Cardio-metabolic morbidity among patients with SMI may be related to high prevalences of obesity and DM rather than poor DM control. Effective screening for metabolic diseases in this population and social reforms are required.

Post-nursing early life macronutrient balance promotes persistent and malleable biometric and metabolic traits in mice.

It is known that dietary factors within the gestational and nursing period affect early life and stably affect later life traits in animals. However, there is very little understanding of whether dietary factors within the early life period from post-nursing to adulthood affect traits in adulthood. To address this, we conducted studies on male C57Bl/6J mice fed from 3 weeks (immediately post-nursing) until 12 weeks (full maturity) using nine different diets varying in all three major macronutrients to parse out the effects of individual macronutrients. Early life macronutrient balance affected body composition and glucose homeostasis in early adulthood, with dietary protein and fat showing major effects. Despite this, mice showed rapid reversal of the effects on body composition and glucose homeostasis of early life diet feeding, upon standard diet feeding in adulthood. However, some traits were persistent, with early life low dietary protein levels stably affecting lean and muscle mass, and early life dietary fat levels stably affecting serum and liver triglyceride levels. In summary, macronutrient balance in the post-nursing early life period does not stably affect adiposity or glucose homeostasis but does impact muscle mass and lipid homeostasis in adulthood, with prominent effects of both protein and fat levels. KEY POINTS: Early life dietary low protein and high fat levels lowered and heightened body mass, respectively. These effects did not substantially persist into adulthood with rapid catch-up growth on a normal diet. Early life protein (negative) and fat (positive) levels affected fat mass. Early life low protein levels negatively affected lean mass. Low protein effects on lower lean and muscle mass persisted into adulthood. Early life macronutrient balance effects did not affect later life glucose homeostasis but early life high fat level affected later life dyslipidaemia. Effects of dietary carbohydrate levels in early and later life were minor.

Gaps in evidence on treatment of male osteoporosis: a Research Agenda.

OBJECTIVE: To identify key research gaps regarding medication therapy to prevent osteoporotic fractures in men. DATA SOURCES: Articles from the peer-reviewed literature containing empirical studies of the use of medication therapy for fracture prevention in men, either in clinical trials or observational studies. STUDY SELECTION AND DATA EXTRACTION: We searched PubMed with search terms including "osteoporosis AND medication therapy management". We read all articles to ensure that they were indeed empirical studies of our topic. For each included study, we searched for all articles in the bibliography, all articles that cited the article, and all related articles, using these functions in PubMed. DATA SYNTHESIS: We have identified six research gaps that could inform the more rational, evidence-based treatment of male osteoporosis. Specifically, among men, we lack key information about: (1) whether treatment can prevent clinical fractures, (2) rates of side effects and complications of therapy, (3) the role of testosterone in treatment, (4) the comparative effectiveness of different therapeutic regimens, (5) role of drug holidays for those receiving bisphosphonates and sequential therapies, and (6) effectiveness of therapy for secondary prevention. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Addressing these six topics should be key goal for the next decade of research on male osteoporosis.

Vaccine hesitancy among health-care professionals in the era of COVID-19.

Health-care professionals (HCPs) are key trusted figures in addressing coronavirus disease 2019 (COVID-19) challenges. They are thought to influence others' health decisions by personal example. However, during the COVID-19 crisis, some HCPs hesitated to be vaccinated. We examined factors contributing to that decision. We performed 12 semi-structured interviews, between February and May 2021, with Israeli HCPs who had declined or delayed COVID-19 vaccination. Three coders conducted a combined top-down and bottom-up analysis. We identified four main themes shaping vaccine decision-making: (i) sources of information, (ii) perceptions of necessity and risks of the vaccine, (iii) individual versus collective responsibility and (iv) political climate and media influence. Participants were worried about long-term effectiveness and safety, and while many agreed that high-risk populations should be vaccinated, all considered themselves to be at low risk for serious disease. Some felt they should avoid taking a perceived risk (accepting a new vaccine) to protect society, although they felt pressured to do so. Vaccination campaign politization and the way the media approached the subject also contributed to mistrust and hesitancy to be vaccinated. These findings help us understand HCP beliefs and uncertainties about COVID-19 vaccinations. This study can help inform future campaigns targeted at HCPs to promote the acceptance of vaccines.

Greater temporal regularity of primary care visits was associated with reduced hospitalizations and mortality, even after controlling for continuity of care.

BACKGROUND: Previous studies have shown that more temporally regular primary care visits are associated with improved patient outcomes. OBJECTIVE: To examine the association of temporal regularity (TR) of primary care with hospitalizations and mortality in patients with chronic illnesses. Also, to identify threshold values for TR for predicting outcomes. DESIGN: Retrospective cohort study. PARTICIPANTS: We used data from the electronic health record of a health maintenance organization in Israel to study primary care visits of 70,095 patients age 40 + with one of three chronic conditions (diabetes mellitus, heart failure, chronic obstructive pulmonary disease). MAIN MEASURES: We calculated TR for each patient during a two-year period (2016-2017), and divided patients into quintiles based on TR. Outcomes (hospitalization, death) were observed in 2018-2019. Covariates included the Bice-Boxerman continuity of care score, demographics, and comorbidities. We used multivariable logistic regression to examine TR's association with hospitalization and death, controlling for covariates. KEY RESULTS: Compared to patients receiving the most regular care, patients receiving less regular care had increased odds of hospitalization and mortality, with a dose-response curve observed across quintiles (p for linear trend < 0.001). For example, patients with the least regular care had an adjusted odds ratio of 1.40 for all-cause mortality, compared to patients with the most regular care. Analyses stratified by age, sex, ethnic group, area-level SES, and certain comorbid conditions did not show strong differential associations of TR across groups. CONCLUSIONS: We found an association between more temporally regular care in antecedent years and reduced hospitalization and mortality of patients with chronic illness in subsequent years, after controlling for covariates. There was no clear threshold value for temporal regularity; rather, more regular primary care appeared to be better across the entire range of the variable.

Patient-level predictors of temporal regularity of primary care visits.

BACKGROUND: Patients with chronic diseases should meet with their primary care doctor regularly to facilitate proactive care. Little is known about what factors are associated with more regular follow-up. METHODS: We studied 70,095 patients age 40 + with one of three chronic conditions (diabetes mellitus, heart failure, chronic obstructive pulmonary disease), cared for by Leumit Health Services, an Israeli health maintenance organization. Patients were divided into the quintile with the least temporally regular care (i.e., the most irregular intervals between visits) vs. the other four quintiles. We examined patient-level predictors of being in the least-temporally-regular quintile. We calculated the risk-adjusted regularity of care at 239 LHS clinics with at least 30 patients. For each clinic, compared the number of patients with the least temporally regular care with the number predicted to be in this group based on patient characteristics. RESULTS: Compared to older patients, younger patients (age 40-49), were more likely to be in the least-temporally-regular group. For example, age 70-79 had an adjusted odds ratio (AOR) of 0.82 compared to age 40-49 (p < 0.001 for all findings discussed here). Males were more likely to be in the least-regular group (AOR 1.18). Patients with previous myocardial infarction (AOR 1.07), atrial fibrillation (AOR 1.08), and current smokers (AOR 1.12) were more likely to have an irregular pattern of care. In contrast, patients with diabetes (AOR 0.79) or osteoporosis (AOR 0.86) were less likely to have an irregular pattern of care. Clinic-level number of patients with irregular care, compared with the predicted number, ranged from 0.36 (fewer patients with temporally irregular care) to 1.71 (more patients). CONCLUSIONS: Some patient characteristics are associated with more or less temporally regular patterns of primary care visits. Clinics vary widely on the number of patients with a temporally irregular pattern of care, after adjusting for patient characteristics. Health systems can use the patient-level model to identify patients at high risk for temporally irregular patterns of primary care. The next step is to examine which strategies are employed by clinics that achieve the most temporally regular care, since these strategies may be possible to emulate elsewhere.

Prevalence of Frailty and Associations with Oral Anticoagulant Prescribing in Atrial Fibrillation.

BACKGROUND: Frailty is often cited as a factor influencing oral anticoagulation (OAC) prescription in patients with non-valvular atrial fibrillation (NVAF). We sought to determine the prevalence of frailty and its association with OAC prescription in older veterans with NVAF. METHODS: We used ICD-9 codes in Veterans Affairs (VA) records and Medicare claims data to identify patients with NVAF and CHA2DS2VASC ≥2 receiving care between February 2010 and September 2015. We examined rates of OAC prescription, further stratified by direct oral anticoagulant (DOAC) or vitamin K antagonist (VKA). Participants were characterized into 3 categories: non-frail, pre-frail, and frail based on a validated 30-item EHR-derived frailty index. We examined relations between frailty and OAC receipt; and frailty and type of OAC prescribed in regression models adjusted for factors related to OAC prescription. RESULTS: Of 308,664 veterans with NVAF and a CHA2DS2VASC score ≥2, 121,839 (39%) were prescribed OAC (73% VKA). The mean age was 77.7 (9.6) years; CHA2DS2VASC and ATRIA scores were 4.6 (1.6) and 5.0 (2.9) respectively. Approximately a third (38%) were frail, another third (32%) were pre-frail, and the remainder were not frail. Veterans prescribed OAC were younger, had higher bleeding risk, and were less likely to be frail than participants not receiving OAC (all p's<0.001). After adjustment for factors associated with OAC use, pre-frail (OR: 0.89, 95% CI: 0.87-0.91) and frail (OR: 0.66, 95% CI: 0.64-0.68) veterans were significantly less likely to be prescribed OAC than non-frail veterans. Of those prescribed OAC, pre-frail (OR:1.27, 95% CI: 1.22-1.31) and frail (OR: 1.75, 95% CI: 1.67-1.83) veterans were significantly more likely than non-frail veterans to be prescribed a DOAC than a VKA. CONCLUSIONS: There are high rates of frailty among older veterans with NVAF. Frailty using an EHR-derived index is associated with decreased OAC prescription.

Israeli COVID lockdowns mildly reduced overall use of preventive health services, but exacerbated some disparities.

BACKGROUND: During 2020, Israel experienced two COVID-19-related lockdowns that impacted the provision of primary and secondary preventive care. METHODS: We examined the month-by-month performance of selected preventive care services using data from Israel's national Quality Indicators in Community Healthcare program. Process of care measures included hemoglobin A1c (HbA1c) testing, cholesterol testing, colon cancer screening and mammography. Intermediate outcome measures included low-density lipoprotein control and HbA1c control. Measures were stratified by sex and by area-level socioeconomic position (SEP). Diabetes and mammography are presented in this abstract due to space limitations. RESULTS: Annual HbA1c testing among persons with diabetes decreased from 90.9% in 2019 to 88.0% in 2020. Performance of HbA1c tests during lockdown months was as low as half the usual amount. There were compensatory increases in testing during post-lockdown months that did not quite make up for the missed tests. In 2019, 9.0% of Israelis with diabetes had poor glycemic control (HbA1c ≥ 9.0); in 2020, it was 8.8%. In total, 4.5% fewer mammograms were performed in 2020 compared with 2019. Women in the lowest SEP level performed 10.4% fewer mammograms in 2020 than in 2019, while women in the highest SEP level performed 3.1% more mammograms. CONCLUSIONS: Prolonged COVID lockdowns in 2020 were associated with marked decreases in the performance of preventive health services during those months. Compensatory spikes following the end of lockdowns partly, but did not completely, make up for the missed care. COVID lockdowns may have exacerbated socioeconomic disparities in some preventive health services.

Homelessness and Veteran Status in Relation to Nonfatal and Fatal Opioid Overdose in Massachusetts.

BACKGROUND: Compared with non-Veterans, Veterans are at higher risk of experiencing homelessness, which is associated with opioid overdose. OBJECTIVE: To understand how homelessness and Veteran status are related to risks of nonfatal and fatal opioid overdose in Massachusetts. DESIGN: A cross-sectional study. PARTICIPANTS: All residents aged 18 years and older during 2011-2015 in the Massachusetts Department of Public Health's Data Warehouse (Veterans: n=144,263; non-Veterans: n=6,112,340). A total of 40,036 individuals had a record of homelessness, including 1307 Veterans and 38,729 non-Veterans. MAIN MEASURES: The main independent variables were homelessness and Veteran status. Outcomes included nonfatal and fatal opioid overdose. RESULTS: A higher proportion of Veterans with a record of homelessness were older than 45 years (77% vs. 48%), male (80% vs. 62%), or receiving high-dose opioid therapy (23% vs. 15%) compared with non-Veterans. The rates of nonfatal and fatal opioid overdose in Massachusetts were 85 and 16 per 100,000 residents, respectively. Among individuals with a record of homelessness, these rates increased 31-fold to 2609 and 19-fold to 300 per 100,000 residents. Homelessness and Veteran status were independently associated with higher odds of nonfatal and fatal opioid overdose. There was a significant interaction between homelessness and Veteran status in their effects on risk of fatal overdose. CONCLUSIONS: Both homelessness and Veteran status were associated with a higher risk of fatal opioid overdoses. An understanding of health care utilization patterns can help identify treatment access points to improve patient safety among vulnerable individuals both in the Veteran population and among those experiencing homelessness.

The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis.

Aberrant activity of the glucocorticoid (GC)/glucocorticoid receptor (GR) endocrine system has been linked to obesity-related metabolic dysfunction. Traditionally, the GC/GR axis has been believed to play a crucial role in adipose tissue formation and function in both, white (WAT) and brown adipose tissue (BAT). While recent studies have challenged this notion for WAT, the contribution of GC/GR signaling to BAT-dependent energy homeostasis remained unknown. Here, we have generated and characterized a BAT-specific GR-knockout mouse (GRBATKO ), for the first time allowing to genetically interrogate the metabolic impact of BAT-GR. The HPA axis in GRBATKO mice was intact, as was the ability of mice to adapt to cold. BAT-GR was dispensable for the adaptation to fasting-feeding cycles and the development of diet-induced obesity. In obesity, glucose and lipid metabolism, insulin sensitivity, and food intake remained unchanged, aligning with the absence of changes in thermogenic gene expression. Together, we demonstrate that the GR in UCP1-positive BAT adipocytes plays a negligible role in systemic metabolism and BAT function, thereby opposing a long-standing paradigm in the field.

Guideline-discordant dosing of direct-acting oral anticoagulants in the veterans health administration.

BACKGROUND: Clear guidelines exist to guide the dosing of direct-acting oral anticoagulants (DOACs). It is not known how consistently these guidelines are followed in practice. METHODS: We studied patients from the Veterans Health Administration (VA) with non-valvular atrial fibrillation who received DOACs (dabigatran, rivaroxaban, apixaban) between 2010 and 2016. We used patient characteristics (age, creatinine, body mass) to identify which patients met guideline recommendations for low-dose therapy and which for full-dose therapy. We examined how often patient dosing was concordant with these recommendations. We examined variation in guideline-concordant dosing by site of care and over time. We examined patient-level predictors of guideline-concordant dosing using multivariable logistic models. RESULTS: A total of 73,672 patients who were prescribed DOACS were included. Of 5837 patients who were recommended to receive low-dose therapy, 1331 (23%) received full-dose therapy instead. Of 67,935 patients recommended to receive full-dose therapy, 4079 (6%) received low-dose therapy instead. Sites varied widely on guideline discordant dosing; on inappropriate low-dose therapy, sites varied from 0 to 15%, while on inappropriate high-dose therapy, from 0 to 41%. Guideline discordant therapy decreased by about 20% in a relative sense over time, but its absolute numbers grew as DOAC therapy became more common. The most important patient-level predictors of receiving guideline-discordant therapy were older age and creatinine function being near the cutoff value. CONCLUSIONS: A substantial portion of DOAC prescriptions in the VA system are dosed contrary to clinical guidelines. This phenomenon varies widely across sites of care and has persisted over time.

Conceptual approach to developing quality measures for transgender patients.

BACKGROUND: Valid and reliable quality measures can help catalyze improvements in health care. The care of transgender patients is ripe for quality measurement, as there is increasing awareness of the increasing prevalence of this population and the urgency of improving the health care they receive. While best practices may not exist for some aspects of transgender health care, other aspects are characterized by well-developed and highly evidence-based recommendations. Our objective was to create a list of potential quality measures for transgender care. METHODS AND RESULTS: In consultation with our advisory panel, which consisted of clinical and academic experts in transgender medicine, we selected eight prominent clinical practice guidelines of transgender health care for review. Our four team investigators carefully reviewed all eight clinical practice guidelines. Through the course of multiple consensus-building meetings, we iteratively refined items until we had agreed upon a list of forty potential quality measures, all of which met the criteria for quality measures set forth in the Center for Medicare and Medicaid Services Blueprint for developing quality measures. CONCLUSIONS: This manuscript explains the origin of the quality measures we developed, and also provides a useful roadmap to any group hoping to develop quality measures for a field that has not previously had any.

Beyond Gender Identity Disorder Diagnoses Codes: An Examination of Additional Methods to Identify Transgender Individuals in Administrative Databases.

BACKGROUND: Large administrative databases often do not capture gender identity data, limiting researchers' ability to identify transgender people and complicating the study of this population. OBJECTIVE: The objective of this study was to develop methods for identifying transgender people in a large, national dataset for insured adults. RESEARCH DESIGN: This was a retrospective analysis of administrative claims data. After using gender identity disorder (GID) diagnoses codes, the current method for identifying transgender people in administrative data, we used the following 2 strategies to improve the accuracy of identifying transgender people that involved: (1) Endocrine Disorder Not Otherwise Specified (Endo NOS) codes and a transgender-related procedure code; or (2) Receipt of sex hormones not associated with the sex recorded in the patient's chart (sex-discordant hormone therapy) and an Endo NOS code or transgender-related procedure code. SUBJECTS: Seventy-four million adults 18 years and above enrolled at some point in commercial or Medicare Advantage plans from 2006 through 2017. RESULTS: We identified 27,227 unique transgender people overall; 18,785 (69%) were identified using GID codes alone. Using Endo NOS with a transgender-related procedure code, and sex-discordant hormone therapy with either Endo NOS or transgender-related procedure code, we added 4391 (16%) and 4051 (15%) transgender people, respectively. Of the 27,227 transgender people in our cohort, 8694 (32%) were transmasculine, 3959 (15%) were transfeminine, and 14,574 (54%) could not be classified. CONCLUSION: In the absence of gender identity data, additional data elements beyond GID codes improves the identification of transgender people in large, administrative claims databases.

Assessing and Expanding the Evidence Base for Project ECHO and ECHO-Like Models: Findings of a Technical Expert Panel.

BACKGROUND: In 2003, Project ECHO (Extension for Community Healthcare Outcomes) began using technology-enabled collaborative models of care to help general practitioners in rural settings manage hepatitis C. Today, ECHO and ECHO-like models (EELM) have been applied to a variety of settings and health conditions, but the evidence base underlying EELM is thin, despite widespread enthusiasm for the model. METHODS: In April 2018, a technical expert panel (TEP) meeting was convened to assess the current evidence base for EELM and identify ways to strengthen it. RESULTS: TEP members identified four strategies for future implementors and evaluators of EELM to address key challenges to conducting rigorous evaluations: (1) develop a clear understanding of EELM and what they are intended to accomplish; (2) emphasize rigorous reporting of EELM program characteristics; (3) use a wider variety of study designs to fill key knowledge gaps about EELM; (4) address structural barriers through capacity building and stakeholder engagement. CONCLUSIONS: Building a strong evidence base will help leverage the innovative aspects of EELM by better understanding how, why, and in what contexts EELM improve care access, quality, and delivery, while also improving provider satisfaction and capacity.

Temporal trends in pharmacologic prophylaxis for venous thromboembolism after hip and knee replacement in older adults.

Trends in prescription for venous thromboembolism (VTE) prophylaxis following total hip (THR) and knee replacement (TKR) since the approval of direct oral anticoagulants (DOACs) and the 2012 guideline endorsement of aspirin are unknown, as are the risks of adverse events. We examined practice patterns in the prescription of prophylaxis agents and the risk of adverse events during the in-hospital period (the 'in-hospital sample') and 90 days following discharge (the 'discharge sample') among adults aged ⩾ 65 undergoing THR and TKR in community hospitals in the Institute for Health Metrics database over a 30-month period during 2011 to 2013. Eligible medications included fondaparinux, DOACs, low molecular weight heparin (LMWH), other heparin products, warfarin, and aspirin. Outcomes were validated by physician review of source documents: VTE, major hemorrhage, cardiovascular events, and death. The in-hospital and the discharge samples included 10,503 and 5722 adults from 65 hospitals nationwide, respectively (mean age 73, 74 years; 61%, 63% women). Pharmacologic prophylaxis was near universal during the in-hospital period (93%) and at discharge (99%). DOAC use increased substantially and was the prophylaxis of choice for nearly a quarter (in-hospital) and a third (discharge) of the patients. Aspirin was the sole discharge prophylactic agent for 17% and 19% of patients undergoing THR and TKR, respectively. Warfarin remained the prophylaxis agent of choice for patients aged 80 years and older. The overall risk of adverse events was low, at less than 1% for both the in-hospital and discharge outcomes. The low number of adverse events precluded statistical comparison of prophylaxis regimens.

Learning Latent Space Representations to Predict Patient Outcomes: Model Development and Validation.

BACKGROUND: Scalable and accurate health outcome prediction using electronic health record (EHR) data has gained much attention in research recently. Previous machine learning models mostly ignore relations between different types of clinical data (ie, laboratory components, International Classification of Diseases codes, and medications). OBJECTIVE: This study aimed to model such relations and build predictive models using the EHR data from intensive care units. We developed innovative neural network models and compared them with the widely used logistic regression model and other state-of-the-art neural network models to predict the patient's mortality using their longitudinal EHR data. METHODS: We built a set of neural network models that we collectively called as long short-term memory (LSTM) outcome prediction using comprehensive feature relations or in short, CLOUT. Our CLOUT models use a correlational neural network model to identify a latent space representation between different types of discrete clinical features during a patient's encounter and integrate the latent representation into an LSTM-based predictive model framework. In addition, we designed an ablation experiment to identify risk factors from our CLOUT models. Using physicians' input as the gold standard, we compared the risk factors identified by both CLOUT and logistic regression models. RESULTS: Experiments on the Medical Information Mart for Intensive Care-III dataset (selected patient population: 7537) show that CLOUT (area under the receiver operating characteristic curve=0.89) has surpassed logistic regression (0.82) and other baseline NN models (<0.86). In addition, physicians' agreement with the CLOUT-derived risk factor rankings was statistically significantly higher than the agreement with the logistic regression model. CONCLUSIONS: Our results support the applicability of CLOUT for real-world clinical use in identifying patients at high risk of mortality.

Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart.

BACKGROUND: Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. METHODS: Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice. RESULTS: Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ-mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ-deficient mice. CONCLUSIONS: This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.

microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis.

In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte-specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR-379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR-controlled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction.