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Mortality in COVID-19 cases was strongly associated with progressive lung inflammation and eventual sepsis. There is mounting evidence that live attenuated vaccines commonly administered during childhood, also provide beneficial non-specific immune effects, including reduced mortality and hospitalization due to unrelated infections. It has been proposed that live attenuated vaccine-associated non-specific effects are a result of inducing trained innate immunity to function more effectively against broader infections. In support of this, our laboratory has reported that immunization with a live attenuated fungal strain induces a novel form of trained innate immunity which provides protection against various inducers of sepsis in mice via myeloid-derived suppressor cells. Accordingly, we initiated a randomized control clinical trial with the live attenuated Measles, Mumps, Rubella (MMR) vaccine in healthcare workers in the greater New Orleans area aimed at preventing/reducing severe lung inflammation/sepsis associated with COVID-19 (ClinicalTrials.gov Identifier: NCT04475081). Included was an outcome to evaluate the myeloid-derived suppressor cell populations in blood between those administered the MMR vaccine vs placebo. The unanticipated emergency approval of several COVID-19 vaccines in the midst of the MMR clinical trials eliminated the ability to examine effects of the MMR vaccine on COVID-19-related health status. Unfortunately, we were also unable to show any impact of the MMR vaccine on peripheral blood myeloid-derived suppressor cells due to several inherent limitations (low percentages of blood leukocytes, small sample size), that also included a collaboration with a similar trial (CROWN CORONATION; ClinicalTrials.gov Identifier: NCT04333732) in St. Louis, MO. In contrast, monitoring the COVID-19 vaccine response in trial participants revealed that high COVID-19 antibody titers occurred more often in those who received the MMR vaccine vs placebo. While the trial was largely inconclusive, lessons learned from addressing several trial-associated challenges may aid future studies that test the non-specific beneficial immune effects of live attenuated vaccines.

Background Remote ischemic conditioning (RIC) is a noninvasive therapeutic strategy that uses brief cycles of blood pressure cuff inflation and deflation to protect the myocardium against ischemia-reperfusion injury. We sought to compare major adverse cardiovascular events (MACE) for patients who received RIC before PCI for ST-segment–elevation myocardial infarction (STEMI) compared with standard care. Methods We conducted a pre- and postimplementation study. In the preimplementation phase, STEMI patients were taken directly to the PCI lab. After implementation, STEMI patients received 4 cycles of RIC by paramedics or emergency department staff before PCI. The primary outcome was MACE at 90 days. Secondary outcomes included MACE at 30, 60, and 180 days. Inverse probability of treatment weighting using propensity scores estimated causal effects independent from baseline covariables. Results A total of 1667 (866 preimplementation, 801 postimplementation) patients were included. In the preimplementation phase, 13.4% had MACE at 90 days compared with 11.8% in the postimplementation phase (odds ratio [OR] 0.86, 95% CI 0.62-1.21). There were no significant differences in MACE at 30, 60, and 180 days. Patients presenting with cardiogenic shock or cardiac arrest before PCI were less likely to have MACE at 90 days (42.7% pre vs 27.8% post) if they received RIC before PCI (OR 0.52, 95% CI 0.27-0.98). Conclusions A strategy of RIC before PCI for STEMI did not reduce 90-day MACE. Future research should explore the impact of RIC before PCI for longer-term clinical outcomes and for patients presenting with cardiogenic shock or cardiac arrest.

Background: Chronic kidney disease (CKD) poses substantial clinical, economic, and humanistic burden in patients with type 2 diabetes (T2D). Understanding of how to optimize patient care and slow disease progression is warranted.Objective: To compare the prevalence, clinical characteristics, treatment patterns, and healthcare utilization among patients with CKD, T2D, or CKD associated with T2D.Design: Retrospective cross-sectional analysis. Patients: Adult patients with CKD, T2D, or CKD+T2D in the Cleveland Clinic Health System.Main Measures: Clinical characteristics, laboratory measures, medication utilization, cardiometabolic management and healthcare resource utilization.Key Results: In 2019, 122,276 patients were identified as CKD, 63,643 were identified as T2D, and 35,255 were identified as having CKD associated with T2D. Patients with CKD and CKD+T2D were observed to be older than those with T2D alone, 72.6, 72.2, and 63.0 years, respectively. T2D and T2D+CKD cohorts contained a higher percentage of males vs. those with CKD alone, 49.3%, 50.8%, 43.6%, respectively. ACEi/ARB therapy was observed in 27.7%, 42.4%, and 31.5% patients with CKD, T2D+CKD, and T2D, respectively. SGLT-2i therapy was only prescribed to a minority of patients with T2D (5.8%) and T2D+CKD (4.7%). Emergency department visits and hospital admissions were more prevalent in the group with CKD (26.5%, 52.9%) or CKD+T2D (28.8%, 54.9%) vs. T2D alone (18.6%, 41.8%), respectively. The majority of patients with CKD (90.4%), CKD+T2D (60.0%) or T2D (69.1%) did not have an assessment of urine protein.Conclusions: Patients with CKD+T2D or CKD have higher healthcare resource utilization than those with T2D alone. The majority of patients with CKD, CKD+T2D or T2D do not undergo assessment of urine protein and are under prescribed ACEi/ARB therapy. SGLT-2i therapy was prescribed to only a small minority of patients with T2D or CKD+T2D. An opportunity exists to improve the care of patients with CKD, both with and without T2D.

Cardiovascular disease remains the leading cause of death in adults in the United States and constitutes a substantial portion of overall national health expenditures. Aspirin is generally recommended for primary cardiovascular event prevention based on a given patient's underlying cardiovascular event risk profile, particularly for those aged 50-69 years with a 10-year risk of coronary heart disease of ≥ 10%. Evidence-based clinical guidelines are in agreement for secondary prevention consisting of lifelong, low-dose aspirin therapy following a cardiovascular event. Despite these recommendations, research suggests suboptimal concordance between guidelines and clinical practice.To evaluate the budget impact of appropriate low-dose aspirin use for primary and secondary cardiovascular event prevention compared with current rates of low-dose aspirin use.An economic model measuring budget spend for cardiovascular events, aspirin, and aspirin-related adverse events was developed from the perspective of a U.S. payer. The model compared current rates of aspirin use to appropriate rates of aspirin use according to guideline recommendations for both primary and secondary cardiovascular event prevention.For a hypothetical plan with 1 million members, an estimated 18,026 patients were on aspirin therapy for primary cardiovascular event prevention, while guidelines recommend that 55,788 patients should have been on aspirin therapy for this indication. Optimal aspirin use in the primary cardiovascular event prevention population reduced the number of nonfatal myocardial infarctions (MIs; -367), ischemic strokes (-232), and deaths (-60), with an increase in the number of gastrointestinal bleeds (169) and hemorrhagic strokes (98). Evidence-based guideline-compliant use of aspirin for primary cardiovascular event prevention resulted in total cost savings of approximately $4.2 million over a 5-year time horizon. For secondary cardiovascular event prevention, an estimated 48,663 patients were on aspirin, while clinical guidelines recommend that 71,316 patients should have been on aspirin therapy for this indication. Optimal aspirin use in secondary cardiovascular event prevention reduced the number of nonfatal MIs (-515), ischemic strokes (-375), and deaths (-217), with an increase in the number of gastrointestinal bleeds (98) and hemorrhagic strokes (58). Evidence-based guideline-compliant use of aspirin for secondary cardiovascular event prevention resulted in total cost savings of approximately $11 million over a 5-year time horizon.Appropriate low-dose aspirin use for primary and secondary cardiovascular event prevention can result in improved patient outcomes with significant cost savings for U.S. payers. As a simple and inexpensive prophylactic measure for cardiovascular event prevention, aspirin use should be carefully considered in all appropriate at-risk adult patients.Development of this manuscript and the corresponding budget impact analysis was funded by Bayer. Coppolecchia, Williamson, and Cameron are employees of Bayer. Carlton, Lennert, and Moradi are employees of Xcenda, a consulting firm that received funding from Bayer to assist in the completion of this study. Khalaf-Gillard was an employee of Xcenda at the time of the study. The corresponding poster was presented at the Academy of Managed Care Pharmacy Nexus 2017; October 16-19, 2017; Dallas, TX.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Objective To assess differences in patient-reported treatment side effects and concerns associated with azelaic acid 15% foam (AAF) vs metronidazole cream (MC) and metronidazole gel (MG). Methods This study used matching-adjusted indirect comparison (MAIC) to compare patient-reported outcomes from survey data evaluating rosacea treatments. Outcomes of interest included percentages of patients reporting concerns and side effects and measures of importance of the concerns and tolerability of the side effects. Patients in each analysis (MG vs AAF and MC vs AAF) were matched using stabilized inverse propensity scores. Results When compared to AAF, MG-treated patients more frequently reported concerns with treatment efficacy (54% vs 4%), application (7% vs 3%), and treatment side effects. MC-treated patients more frequently reported concerns with treatment efficacy (61% vs 5%) and dryness (8% vs 5%). AAF-treated patients more frequently reported concerns with cost of treatment compared with MG (7% vs 1%) and MC (9% vs 4%). Among patients reporting concerns, level of importance associated with these concerns was similar for AAF-treated patients compared with MG- and MC-treated patients. When compared to AAF-treated patients, MG-treated patients more frequently reported side effects of dryness (26% vs 15%) and uneven skin tone (3% vs 0%), and MC-treated patients more frequently reported side effects of burning (7% vs 3%), itching (7% vs 5%), and redness (7% vs 5%). MG- and MC-treated patients indicated greater intolerance for reported side effects than AAF-treated patients. Conclusions MG- and MC-treated patients more frequently reported treatment concerns and side effects than AAF-treated patients, and tolerability of those side effects was higher for patients treated with AAF. While treatment cost is a more frequent concern in patients treated with AAF, these patients less frequently reported concerns with treatment efficacy and reported similar or greater tolerance to side effects than patients treated with either MC or MG. J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.3679.

The purpose of this project was to evaluate the use of a clinical reminder system to increase the incidence of patients born between 1945 and 1965 who are offered screening for Hepatitis C Virus (HCV). A clinical reminder form was utilized to prompt primary care providers to offer screening for HCV. Pre-implementation and postimplementation data were collected via retrospective chart review. Data was analyzed to compare patients who were offered testing for HCV pre- and post-implementation of the clinical reminder system. In the pre-implementation data that was collected, 238 patients out of the 600 randomly collected met inclusion criteria of being born between 1945 and 1965. Of these 238 patients, only four were offered screening for HCV prior to implementation of the project. In the post-implementation data, 248 out of 600 patients met the inclusion criteria of being born between the ages of 1945 and 1965. Of these 248 who met inclusion criteria, 211 were offered screening for HCV. This resulted in 85% of patients who were offered screening for HCV post-implementation versus 2% pre-implementation. The results of the study showed that the use of a clinical reminder system was effective in increasing the number of patients who were offered screening for HCV. You can submit your Manuscripts at: https://symbiosisonlinepublishing.com/submitManuscript.php

Human papillomavirus (HPV) is the main etiologic agent in 90% of anogenital and 70% of oropharyngeal cancers. Seventy percent of those cancers stem from HPV 16 or HPV 18 infection, with the remaining cases attributed to other high-risk (HR) HPV genotypes. The development and use of HPV vaccines such as Gardasil have directly affected the prevalence of HR HPVs in patient populations. The decline of dominant oncogenic strains may create an ecological vacuum, potentially allowing nondominant low-risk or unknown-risk genotypes to spread and evolve. HPV 90 was recently classified as an unknown etiologic risk and has previously demonstrated an ability to become oncogenic from a single base pair mutation within the E6 viral gene. HPV 90 has also been seen to exhibit higher prevalence than other unknown risk HPVs in patient populations similar to those populations found in New Orleans. To allow for the real-time surveillance of HPV90 during the post-vaccine era, it is our goal to establish nucleic acid-based assays that allow for sensitive and specific identification of HPV90 genes within a patient sample. The assays utilized for the surveillance of HPV90 are based on both traditional and qualitative polymerase chain reaction (PCR) technology done with HPV90 genotype specific primers for the L1 and E6 genes. The amplification of a 155bp segment of HPV90 E6 was successfully done through touchdown qPCR. The amplification of HPV L1 was done with primers and cycle methods derived from the previously published PGMY09/11 primer set. Amplicons from each PCR method were visualized via gel electrophoresis. The L1 patient amplicon will be denatured and fixed to a nylon membrane to allow for analysis by dot blot using novel HPV 90 L1 specific biotinylated probes. The patient samples utilized in this study were collected from a longitudinal study examining the genotypes found in HIV+ women in the greater New Orleans area. The cohort of HIV+ women in New Orleans (n=100) had a HPV90 prevalence of 9% when examining L1 alone and a 10% prevalence when examining E6 alone. L1 and E6 have a preliminary correlation of 90%. Testing the remaining samples from the longitudinal study will determine the persistence, prevalence and oncogenic contribution of HPV90 to patients in New Orleans. Future directions include confirming our findings utilizing our conceived dot blot assay. Once established, our L1 technique could be integrated into the clinically available Roche Linear Array genotyping assay for the additional surveillance of locally relevant HPV genotypes. Note: This abstract was not presented at the conference. Citation Format: LaKia M. Williams, Alex Berry, Jennifer Cameron. Development of genetic assays for the surveillance of HPV 90 in New Orleans [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B074.

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

GPR81, which exhibits a high degree of homology with GPR109a, has been recently identified as a lactate receptor. Similar to GPR109a, the activation of GPR81 by lactate suppresses lipolysis, suggesting that GPR81 may be a potential drug target for treating dyslipidemia. In addition, the fact that GPR81 is expressed only in adipocytes, whereas GPR109a is expressed in various tissues and cells, including Langerhans cells, which are considered responsible for flushing, indicates that targeting GPR81 could lead to the development of antidyslipidemia agents with a reduced risk of this side effect. However, the pharmacological role of GPR81 remains largely unclear, mainly because of the lack of potent and selective surrogate GPR81 agonists suitable for in vivo studies. In the present study, we showed that lactate-induced suppression of lipolysis in explants of white adipose tissue (WAT) depends on the presence of GPR81. We also performed high-throughput screening (HTS) and identified four novel chemical clusters as GPR81 agonists. Chemical optimization of aminothiazole derivatives led to the discovery of a lead compound with improved potency. The compound inhibited lipolysis in differentiated 3T3-L1 adipocytes. Finally, intraperitoneal administration of this compound suppressed lipolysis in mice at doses that did not cause cutaneous flushing. This is the first description of a 50nM GPR81 selective agonist with in vivo efficacy, without the side effect, i.e., flushing. These results suggest that GPR81 is an attractive drug target for treating dyslipidemia without the risk of flushing.

Interest in how the gut microbiome can influence the metabolic state of the host has recently heightened. One postulated link is bacterial fermentation of “indigestible” prebiotics to short-chain fatty acids (SCFAs), which in turn modulate the release of gut hormones controlling insulin release and appetite. We show here that SCFAs trigger secretion of the incretin hormone glucagon-like peptide (GLP)-1 from mixed colonic cultures in vitro. Quantitative PCR revealed enriched expression of the SCFA receptors ffar2 (grp43) and ffar3 (gpr41) in GLP-1–secreting L cells, and consistent with the reported coupling of GPR43 to Gq signaling pathways, SCFAs raised cytosolic Ca2+ in L cells in primary culture. Mice lacking ffar2 or ffar3 exhibited reduced SCFA-triggered GLP-1 secretion in vitro and in vivo and a parallel impairment of glucose tolerance. These results highlight SCFAs and their receptors as potential targets for the treatment of diabetes.

(1996). Throwing a Dishcloth into the Works: Troubling Theories of Domestic Labor. Rethinking Marxism: Vol. 9, No. 2, pp. 24-44.

Early disruption of steroids affects the development of mammalian neural circuits underlying affective processes. In humans, patients with classic congenital adrenal hyperplasia (CAH) can serve as a natural model to study early hormonal alterations on functional brain development. CAH is characterized by congenital glucocorticoid insufficiency, leading to altered hypothalamic-pituitary-adrenal (HPA) function, and hyperandrogenism. Using fMRI, we compared fourteen adolescents with CAH to 14 healthy controls on amygdala response to a face viewing task. In response to negative facial emotions, CAH females activated the amygdala significantly more than healthy females, whereas CAH males did not differ from control males. Furthermore, females with CAH showed a similar pattern of amygdala activation to control males, suggesting virilized amygdala function in females with CAH. These findings suggest a prominent effect of early hyperandrogenism on the development and function of the amygdala in females with CAH, whereas no effects were detected in males with CAH. This study provides data that can be further tested in a model of the neurobiological mechanisms underlying early androgen organizational effects on amygdala function.

Introduction A growing number of studies have found evidence that anxiety and depressive disorders are associated with atypical amygdala hyperactivation, which decreases with effective treatment. Interest has emerged in this phenomenon as a possible biological marker for individuals who are likely to benefit from tailored treatment approaches. Objective The present study was designed to examine relationships between pretreatment amygdala activity and treatment response in a sample of anxious children and adolescents. Materials and methods Participants, who were diagnosed predominantly with generalized anxiety disorder (GAD), underwent functional magnetic resonance imaging (fMRI) scanning before treatment with fluoxetine or cognitive behavioral therapy (CBT). Results Results indicated significant negative associations between degree of left amygdala activation and measures of posttreatment symptom improvement in the group, as a whole. Discussion Taken together with research on associations between adult amygdala activation and treatment response, these findings suggest that patients whose pretreatment amygdala activity is the strongest may be particularly likely to respond well to such widely used treatments as selective serotonin reuptake inhibitor (SSRI) medications and CBT.

The recent discovery of an Epstein-Barr virus (EBV)-related lymphocryptovirus (LCV) naturally infecting common marmosets demonstrated that gamma-1 herpesviruses are not limited to human and Old World nonhuman primate hosts. We developed serologic assays to detect serum antibodies against lytic- and latent-infection marmoset LCV antigens in order to perform the first seroepidemiologic study of LCV infection in New World primates. In three different domestic colonies and in animals recently captured from the wild, we found that the seroprevalence of marmoset LCV infection was not as ubiquitous as with EBV or Old World LCV. These biologic differences in LCV infection of New World versus human and Old World primate hosts correlate with the evolution of the LCV viral gene repertoire.

Contemporary politics seems to be characterised by the competing claims of identity groups, and, with opposing groups drawing upon the rhetoric of truth and justice, it has become increasingly more difficult to adjudicate these claims. Recognising the limits of a politics based on established identities, Michel Foucault articulated a political project that sought to develop new forms of experience and subjectivity. In an age when men have been popularly described as coming from Mars and women from Venus, it seems unlikely that gender identities in the private sphere might offer an example for politics in the public sphere. Despite the view that women and men comprise opposing and conflicting identity groups, I propose that gendered domestic practices and subjectivities can be seen as being constantly negotiated and transformed. Using examples from several households, I argue that supposedly fixed and exclusive feminine and masculine subject positions can be made to seem precarious and tenuous, su...