"You Don't Look Anorexic": Atypical anorexia patient experiences of weight stigma in medical care.

Eating disorders (ED) and weight stigma pose significant healthcare challenges. Patients at higher weights, like some with atypical anorexia (AAN), may face increased challenges due to weight stigma. This study analyzed patients' lived experiences with weight stigma in healthcare. Thirty-eight adult patients with AAN completed in-depth, semi-structured interviews regarding healthcare experiences. Guided by narrative inquiry approaches, transcripts were thematically coded. Across the illness trajectory (ED development, pre-treatment, treatment, post-treatment), patients reported that weight stigma in healthcare contributed to initiation and persistence of ED behaviors. Themes included "providers pathologizing patient weight," which patients reported triggered ED behaviors and relapse, "provider minimization and denial" of patients' EDs, which contributed to delays in screening and care, and "overt forms of weight discrimination," leading to healthcare avoidance. Participants reported that weight stigma prolonged ED behaviors, delayed care, created suboptimal treatment environments, deterred help-seeking, and lowered healthcare utilization. This suggests that many providers (pediatricians, primary care providers, ED treatment specialists, other healthcare specialists) may inadvertently reinforce patients' EDs. Increasing training, screening for EDs across the weight spectrum, and targeting health behavior promotion rather than universal weight loss, could enhance quality of care and improve healthcare engagement for patients with EDs, particularly those at higher weights.

Sex Differences in Comorbid Mental and Substance Use Disorders Among Primary Care Patients With Opioid Use Disorder.

OBJECTIVE: The authors sought to characterize the 3-year prevalence of mental disorders and nonnicotine substance use disorders among male and female primary care patients with documented opioid use disorder across large U.S. health systems. METHODS: This retrospective study used 2014-2016 data from patients ages ≥16 years in six health systems. Diagnoses were obtained from electronic health records or claims data; opioid use disorder treatment with buprenorphine or injectable extended-release naltrexone was determined through prescription and procedure data. Adjusted prevalence of comorbid conditions among patients with opioid use disorder (with or without treatment), stratified by sex, was estimated by fitting logistic regression models for each condition and applying marginal standardization. RESULTS: Females (53.2%, N=7,431) and males (46.8%, N=6,548) had a similar prevalence of opioid use disorder. Comorbid mental disorders among those with opioid use disorder were more prevalent among females (86.4% vs. 74.3%, respectively), whereas comorbid other substance use disorders (excluding nicotine) were more common among males (51.9% vs. 60.9%, respectively). These differences held for those receiving medication treatment for opioid use disorder, with mental disorders being more common among treated females (83% vs. 71%) and other substance use disorders more common among treated males (68% vs. 63%). Among patients with a single mental health condition comorbid with opioid use disorder, females were less likely than males to receive medication treatment for opioid use disorder (15% vs. 20%, respectively). CONCLUSIONS: The high rate of comorbid conditions among patients with opioid use disorder indicates a strong need to supply primary care providers with adequate resources for integrated opioid use disorder treatment.

Optimal LentiCRISPR-Based System for Sequential CRISPR/Cas9 Screens.

The advent of genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening has advanced the understanding of molecular systems within cells. Here, we demonstrate the utility of sequentially performed CRISPR knockout screens that use an existing library to explore a biological question across the human genome, and then the remaining cells are used to examine each gene candidate against one common gene of interest. We call this approach "Many vs One" CRISPR screening, made possible by a modified 7SK promoter in place of the U6 promoter to drive expression of a single guide RNA. Inserting this novel 7SK promoter into the ubiquitously used lentiCRISPRv2 backbone is crucial, because it overcomes the need for a substantial increase in CRISPR library coverage during screening, sample processing, and next generation sequencing. This new 7SK vector equals the original lentiCRISPRv2 in lentiviral titer, knockout efficiency, and ease of use.

Blockade of 20-hydroxyeicosatetraenoic acid receptor lowers blood pressure and alters vascular function in mice with smooth muscle-specific overexpression of CYP4A12-20-HETE synthase.

OBJECTIVE: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a vasoactive eicosanoid exhibiting effects on vascular smooth muscle cell (VSMC) via G-protein coupled receptor 75 (GPR75) and include stimulation of contractility, migration, and growth. We examined whether VSMC-targeted overexpression of CYP4A12, the primary 20-HETE-producing enzyme in mice, is sufficient to promote hypertension. METHODS: Mice with VSM-specific Cyp4a12 overexpression (Myh11-4a12) and their littermate controls (WT) were generated by crossbreeding Cyp4a12-floxed with Myh11-Cre mice. The 20-HETE receptor blocker, N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide (AAA), was administered in the drinking water. Experiments were carried out for 12 days. SBP was measured by tail cuff. Renal interlobar and mesenteric arteries were harvested for assessment of gene expression, 20-HETE levels, vascular contractility, vasodilation, and remodeling. RESULTS: Vascular and circulatory levels of 20-HETE were several folds higher in Myh11-4a12 mice compared with WT. The Myh11-4a12 mice compared with WT were hypertensive (145 ±â€Š2 vs. 127 ±â€Š2 mmHg; P < 0.05) and their vasculature displayed a contractile phenotype exemplified by increased contractility, reduced vasodilatory capacity, and increased media to lumen ratio. All these features were reversed by the administration of AAA. The mechanism of increased contractility includes, at least in part, Rho-kinase activation followed by increased myosin light chain phosphorylation and activation of the contractile apparatus. CONCLUSION: VSM-specific Cyp4a12 overexpression is sufficient to alter VSM cell phenotype through changes in contractile markers and enhancement in contractility that promote hypertension and vascular dysfunction in a 20-HETE-dependent manner. The 20-HETE receptor GPR75 may represent a novel target for the treatment of hypertension and associated vascular conditions.

Social and economic cost of eating disorders in the United States: Evidence to inform policy action.

OBJECTIVE: To estimate one-year costs of eating disorders in the United States (U.S.) from a societal perspective, including the costs to the U.S. health system, individual and family productivity costs, lost wellbeing, and other societal economic costs, by setting and payer. Findings will inform needed policy action to mitigate the impact of eating disorders in the U.S. METHOD: Costs of eating disorders were estimated using a bottom-up cost-of-illness methodology, based on the estimated one-year prevalence of eating disorders. Intangible costs of reduced wellbeing were also estimated using disability-adjusted life years. RESULTS: Total economic costs associated with eating disorders were estimated to be $64.7 billion (95% CI: $63.5-$66.0 billion) in fiscal year 2018-2019, equivalent to $11,808 per affected person (95% CI: $11,754-$11,863 per affected person). Otherwise Specified Feeding or Eating Disorder accounted for 35% of total economic costs, followed by Binge Eating Disorder (30%), Bulimia Nervosa (18%) and Anorexia Nervosa (17%). The substantial reduction in wellbeing associated with eating disorders was further valued at $326.5 billion (95% CI: $316.8-$336.2 billion). DISCUSSION: The impact of eating disorders in the U.S. is substantial when considering both economic costs and reduced wellbeing (nearly $400 billion in fiscal year 2018-2019). Study findings underscore the urgency of identifying effective policy actions to reduce the impact of eating disorders, such as through primary prevention and screening to identify people with emerging or early eating disorders in primary care, schools, and workplaces and ensuring access to early evidence-based treatment.

Burkitt Lymphomas Evolve to Escape Dependencies on Epstein-Barr Virus.

Epstein-Barr Virus (EBV) can transform B cells and contributes to the development of Burkitt lymphoma and other cancers. Through decades of study, we now recognize that many of the viral genes required to transform cells are not expressed in EBV-positive Burkitt lymphoma (BL) tumors, likely due to the immune pressure exerted on infected cells. This recognition has led to the hypothesis that the loss of expression of these viral genes must be compensated through some mechanisms. Recent progress in genome-wide mutational analysis of tumors provides a wealth of data about the cellular mutations found in EBV-positive BLs. Here, we review common cellular mutations found in these tumors and consider how they may compensate for the viral genes that are no longer expressed. Understanding these mutations and how they may substitute for EBV's genes and contribute to lymphomagenesis can serve as a launchpad for more mechanistic studies, which will help us navigate the sea of genomic data available today, and direct the discoveries necessary to improve the treatment of EBV-positive BLs.

The Second Wave of Public Policy Advocacy for Eating Disorders: Charting the Course to Maximize Population Impact.

Over the past decade, a first wave of US public policy advocacy for eating disorders made substantial progress, with passage of the federal 21st Century Cures Act in 2016 as its crowning achievement. However, the US response to eating disorders continues to fall short in several ways. On the cusp of a second wave of policy advocacy, efforts must be broadened to target structural determinants of illness and inequities to maximize clinical impact and diminish suffering. Mental health clinicians, patients, and their families will be essential players in public policy advocacy efforts in this regard.

Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation.

Arterial stiffness plays a causal role in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome P450 (CYP450)-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and loosely associated with obesity in humans. However, the role of 20-HETE in the regulation of large artery remodeling in metabolic syndrome has not been investigated. We hypothesized that elevated 20-HETE in metabolic syndrome increases matrix metalloproteinase 12 (MMP12) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure. 20-HETE production was increased ~7 fold in large, conduit arteries of metabolic syndrome (JCR:LA-cp, JCR) vs. normal Sprague-Dawley (SD) rats. This correlated with increased elastin degradation (~7 fold) and decreased arterial compliance (~75% JCR vs. SD). 20-HETE antagonists blocked elastin degradation in JCR rats concomitant with blocking MMP12 activation. 20-HETE antagonists normalized, and MMP12 inhibition (pharmacological and MMP12-shRNA-Lnv) significantly improved (~50% vs. untreated JCR) large artery compliance in JCR rats. 20-HETE antagonists also decreased systolic (182 ±â€¯3 mmHg JCR, 145 ±â€¯3 mmHg JCR + 20-HETE antagonists) but not diastolic blood pressure in JCR rats. Whereas diastolic pressure was fully angiotensin II (Ang II)-dependent, systolic pressure was only partially Ang II-dependent, and large artery stiffness was Ang II-independent. Thus, 20-HETE-dependent regulation of systolic blood pressure may be a unique feature of metabolic syndrome related to high 20-HETE production in large, conduit arteries, which results in increased large artery stiffness and systolic blood pressure. These findings may have implications for management of systolic hypertension in patients with metabolic syndrome.

Evaluating the Impact of the Affordable Care Act on HIV Care, Outcomes, Prevention, and Disparities: A Critical Research Agenda.

In the United States (U.S.), health care policy plays a critical role in ensuring adequate care for people living with HIV (PLWH), eliminating new HIV infections, and reducing health disparities. The 2010 Patient Protection and Affordable Care Act (ACA) was designed to make health care more accessible, of higher quality, and more affordable. Many provisions of the ACA are considered relevant to HIV care and prevention. Because PLWH have unique care needs and many groups at risk for infection are members of vulnerable populations, timely and comprehensive evaluation of the ACA in terms of HIV is critical. In this paper, we discuss components of the ACA relevant to HIV care and prevention, describe their anticipated and initial effects, and finally, outline a research agenda to inform future HIV programming and policy.