HIV, HIV-specific Factors and Myocardial Disease in Women.

BACKGROUND: People with HIV (PWH) have an increased risk of cardiovascular disease (CVD). Cardiac magnetic resonance (CMR) has documented higher myocardial fibrosis, inflammation and steatosis in PWH, but studies have mostly relied on healthy volunteers as comparators and focused on men. METHODS: We investigated the associations of HIV and HIV-specific factors with CMR phenotypes in female participants enrolled in the Women's Interagency HIV Study's New York and San Francisco sites. Primary phenotypes included myocardial native (n) T1 (fibro-inflammation), extracellular volume fraction (ECV, fibrosis) and triglyceride content (steatosis). Associations were evaluated with multivariable linear regression, and results pooled or meta-analyzed across centers. RESULTS: Among 261 women with HIV (WWH, total n = 362), 76.2% had undetectable viremia at CMR. For the 82.8% receiving continuous antiretroviral therapy (ART) in the preceding 5 years, adherence was 51.7%, and 71.3% failed to achieve persistent viral suppression (42.2% with peak viral load < 200 cp/mL). Overall, WWH showed higher nT1 than women without HIV (WWOH) after full adjustment. This higher nT1 was more pronounced in those with antecedent or current viremia or nadir CD4+ count < 200 cells/µL, the latter also associated with higher ECV. WWH and current CD4+ count < 200 cells/µL had less cardiomyocyte steatosis. Cumulative exposure to specific ART showed no associations. CONCLUSIONS: Compared with sociodemographically similar WWOH, WWH on ART exhibit higher myocardial fibro-inflammation, which is more prominent with unsuppressed viremia or CD4+ lymphopenia. These findings support the importance of improved ART adherence strategies, along with better understanding of latent infection, to mitigate cardiac end-organ damage in this population.

High-Density Lipoprotein and Long-Term Incidence and Progression of Aortic Valve Calcification: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Aortic valve calcification (AVC) shares pathological features with atherosclerosis. Lipoprotein components have been detected in aortic valve tissue, including HDL (high-density lipoprotein). HDL measures have inverse associations with cardiovascular disease, but relationships with long-term AVC progression are unclear. We investigated associations of HDL cholesterol, HDL-particle number and size, apoC3-defined HDL subtypes, and, secondarily, CETP (cholesteryl ester transfer protein) mass and activity, with long-term incidence and progression of AVC. METHODS: We used linear mixed-effects models to evaluate the associations of baseline HDL indices with AVC. AVC was quantified by Agatston scoring of up to 3 serial computed tomography scans over a median of 8.9 (maximum 11.2) years of follow-up in the Multi-Ethnic Study of Atherosclerosis (n=6784). RESULTS: After adjustment, higher concentrations of HDL-C (high-density lipoprotein cholesterol), HDL-P (HDL particles), large HDL-P, and apoC3-lacking HDL-C were significantly associated with lower incidence/progression of AVC. Neither small or medium HDL-P nor apoC3-containing HDL-C was significantly associated with AVC incidence/progression. When included together, a significant association was observed only for HDL-C, but not for HDL-P. Secondary analyses showed an inverse relationship between CETP mass, but not activity, and AVC incidence/progression. In exploratory assessments, inverse associations for HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL with AVC incidence/progression were more pronounced for older, male, and White participants. ApoC3-containing HDL-C only showed a positive association with AVC in these subgroups. CONCLUSIONS: In a multiethnic population, HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL-C were inversely associated with long-term incidence and progression of AVC. Further investigation of HDL composition and mechanisms could be useful in understanding pathways that slow AVC.

HIV Testing by Gender Identity Among Sexually Active Transgender-, Intersex-, and Hijra Individuals Reached Online in India.

Online outreach may be an important strategy to reach Indian gender minority (GM) populations for HIV testing. However, little is known about Indian GM populations reached online who are sexually active and their HIV testing behaviors. We conducted a secondary analysis of an India wide online cross-sectional survey to assess HIV testing and identify associated factors. The 467 GM respondents identified their gender as transgender women (29.6%), Hijra (5.1%), intersex (37%), or gender non-binary (28.3%). Overall, almost half (47.5%) had never been tested for HIV; among respondents having condomless anal sex, half (50%) reported never testing for HIV. A decreased odds of ever HIV testing was associated with being unsure how to access free testing (compared to being easy; AOR = 0.36, 95%CI 0.20, 0.63) and unaware of comfortable testing sites (AOR = 0.32, 95% CI 0.20, 0.63). Increased odds of testing were associated with identifying as Hijra (compared to transgender women; AOR = 4.07, 95%CI 1.18-16.92) and disclosing sexual behaviors to a doctor (AOR = 3.20, 95% CI 1.91, 5.46). In this GM sample recruited online, HIV testing rates were low. Online interventions are needed to engage individuals with diverse GM identities in India for linkage to accessible and acceptable HIV testing options.

People with HIV who smoke cigarettes non-daily.

Cigarette smoking is a leading cause of mortality in people with HIV (PWH) in the United States (US). A rising proportion of US tobacco users smoke non-daily, a phenomenon that is common among PWH. PWH who smoke non-daily may be attractive targets for cessation efforts, and, thus, a fuller understanding of non-daily smoking in PWH is important. We merged datasets from two randomized controlled tobacco treatment trials for PWH conducted in three cities from 2014-2020. The final dataset included 872 PWH. We analyzed sociodemographic characteristics and behavioral measures, such as nicotine dependence, motivation to quit, anxiety, and other substance use for associations with non-daily smoking, and we assessed non-daily smoking as a predictor of cessation. 13.4% of the sample smoked non-daily. In multivariable analyses, non-White race, higher anxiety, and higher motivation to quit were associated with non-daily smoking. PWH who smoked non-daily had 2.14 times the odds of those who smoked daily of quitting at six-months (95% C.I.:1.30-3.51, P=0.002). PWH who smoke non-daily differ in some demographic and behavioral characteristics from those who smoke daily. PWH reporting non-daily smoking were more likely to quit in our trials and targeting them should be a priority of future cessation efforts.

Receiving hemodialysis in Hispanic ethnic dense communities is associated with better adherence and outcomes among young patients: a retrospective analysis of the Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Hispanic ethnic density (HED) is a marker of better health outcomes among Hispanic patients with chronic disease. It is unclear whether community HED is associated with mortality risk among ethnically diverse patients receiving maintenance hemodialysis. METHODS: A retrospective analysis of patients in the United States cohort of the Dialysis Outcomes and Practice Patterns Study (DOPPS) database (2011-2015) was conducted (n = 4226). DOPPS data was linked to the American Community Survey database by dialysis facility zip code to obtain % Hispanic residents (HED). One way ANOVA and Kruskal Wallis tests were used to estimate the association between tertiles of HED with individual demographic, clinical and adherence characteristics, and facility and community attributes. Multivariable Cox proportional hazards models were used to estimate the mortality hazard ratio (HR) and 95% CIs by tertile of HED, stratified by age; a sandwich estimator was used to account for facility clustering. RESULTS: Patients dialyzing in facilities located in the highest HED tertile communities were younger (61.4 vs. 64.4 years), more commonly non-White (62.4% vs. 22.1%), had fewer comorbidities, longer dialysis vintage, and were more adherent to dialysis treatment, but had fewer minutes of dialysis prescribed than those in the lowest tertile. Dialyzing in the highest HED tertile was associated with lower hazard of mortality (HR, 0.86; 95% CI, 0.72-1.00), but this association attenuated with the addition of individual race/ethnicity (HR, 0.92; 95% CI, 0.78-1.09). In multivariable age-stratified analyses, those younger than 64 showed a lower hazard for mortality in the highest (vs. lowest) HED tertile (HR, 0.66; 95% CI, 0.49-0.90). Null associations were observed among patients ≥ 64 years. CONCLUSIONS: Treating in communities with greater HED and racial/ethnic integration was associated with lower mortality among younger patients which points to neighborhood context and social cohesion as potential drivers of improved survival outcomes for patients receiving hemodialysis.

Factors Influencing the Referral of Patients with Prediabetes to a Diabetes Prevention Program in the Bronx, New York.

INTRODUCTION: Disparate engagement in the Diabetes Prevention Program (DPP) may occur as early as the point of referral for certain subgroups, including Black and Hispanic men. We aimed to determine patient demographic and provider characteristics associated with referrals to a health system DPP in the Bronx, New York. METHODS: Patient and health system characteristics for DPP-eligible patients seen in primary care between July 1, 2015, and December 31, 2017, were obtained through the electronic health record. Generalized mixed-effects modeling was used to test the association between referral rate and clinical and sociodemographic variables. RESULTS: Of 26,727 eligible patients, 66% were female, 46% were Hispanic, and 39% were non-Hispanic Black. Only 10% (n = 2,785) of eligible patients were referred to DPP. In the adjusted analyses, lower odds of referral were observed for men versus women (OR = 0.60; 95% CI, 0.52-0.66), for non-Hispanic White versus Hispanic patients (OR = 0.53; 95% CI, 0.40-0.71), and for uninsured patients versus Medicaid patients (OR = 0.66; 95% CI, 0.54-0.80). The odds were higher for patients in the highest versus lowest hemoglobin A1c (OR = 2.49; 95% CI, 2.27-2.72) category; for those in the highest versus lowest body mass index categories (OR = 1.61; 95% CI, 1.45-1.79); for middle-aged patients (aged 45-64 y) versus those aged 18-26 y (OR =1.63; 95% CI, 1.33-2.00); and for patients being seen by a family versus an internal medicine physician (OR = 1.65; 95% CI, 1.22-2.22). CONCLUSION: We identified under-referral for men and highlighted other patient and health system factors associated with referral rates. Interventions to address bias in referrals and increase referrals for men at high risk for diabetes, not typically represented in DPP, are recommended.

Peer mentorship to improve outcomes in patients on hemodialysis (PEER-HD): a randomized controlled trial protocol.

BACKGROUND: Patients receiving in-center hemodialysis experience disproportionate morbidity and incur high healthcare-related costs. Much of this cost stems from potentially avoidable hospitalizations. Peer mentorship has been used effectively to improve outcomes for patients with complex chronic diseases. We propose testing the efficacy of peer mentorship on hospitalization rates among patients receiving hemodialysis. METHODS: This is a multicenter parallel group randomized controlled pragmatic trial of patients treated at hemodialysis facilities in Bronx, NY and Nashville, TN. The study has two phases. Phase 1 will enroll and train 16 hemodialysis patients (10 in Bronx, NY and 6 in Nashville TN) to be mentors using a program focused on enhancing self-efficacy, dialysis self-management and autonomy-supportive communication skills. Phase 2 will enroll 200 high risk adults receiving hemodialysis (140 in Bronx, NY and 60 in Nashville, TN), half of whom will be randomized to intervention and half to usual care. Intervention participants are assigned to weekly telephone calls with trained mentors (see Phase 1) for a 3-month period. The primary outcome of Phase 1 will be engagement of mentors with training and change in knowledge scores and autonomy skills from pre- to post-training. The primary outcome of Phase 2 will be the composite count of ED visits and hospitalizations at the end of study follow-up in patient participants assigned to intervention as compared to those assigned to usual care. Secondary outcomes for Phase 2 include the change over the trial period in validated survey scores measuring perception of social support and self-efficacy, and dialysis adherence metrics, among intervention participants as compared to usual care participants. DISCUSSION: The PEER-HD study will test the feasibility and efficacy of a pragmatic peer-mentorship program designed for patients receiving hemodialysis on ED visit and hospitalization rates. If effective, peer-mentorship holds promise as a scalable patient-centered intervention to decrease hospital resource utilization, and by extension morbidity and cost, for patients receiving maintenance in-center hemodialysis. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03595748 ; 7/23/2018. TRIAL SPONSOR: National Institutes of Diabetes, Digestive and Kidney Disease (NIDDK) 5R18DK118471. FUNDING: Funding for this study was provided by the National Institutes of Diabetes, Digestive and Kidney Disease: R18DK118471. STUDY STATUS: This is an ongoing study and not complete. We are still collecting data for observational follow-up on participants. RELATED ARTICLES: No related articles for this study have been submitted to any journal. The study sponsor and funders had no role in the design, analysis or interpretation of this data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Gestational Diabetes, Subsequent Type 2 Diabetes, and Food Security Status: National Health and Nutrition Examination Survey, 2007-2018.

INTRODUCTION: Despite many studies linking various risk factors to the association between gestational diabetes and subsequent type 2 diabetes, little is known about how food insecurity affects their association. We aimed to assess how the association between gestational diabetes and subsequent type 2 diabetes varies by food security status among women in the US. METHODS: This study is a secondary data analysis of 9,505 US women aged 20 years or older who had at least 1 live birth; we used cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) from 2007 through 2018. The main outcome was a diagnosis of type 2 diabetes in the subsequent years after the first live birth. We used multivariable survey-weighted negative binomial regressions to examine whether the association between gestational diabetes and subsequent type 2 diabetes differed by food security status, with and without adjusting for health behavior factors. RESULTS: Gestational diabetes was significantly associated with subsequent type 2 diabetes (incidence rate ratio [IRR], 2.57; 95% CI, 2.45-2.69). The association between gestational diabetes and subsequent type 2 diabetes was significantly different by food security status (IRR, 2.34; 95% CI, 2.23-2.45 among food-secure women; IRR, 2.99; 95% CI, 2.70-3.28 among food-insecure women). CONCLUSION: The association between gestational diabetes and subsequent type 2 diabetes differs significantly by food security status. Public health and health care practitioners should consider food security status when designing and implementing diabetes prevention interventions for women with a history of gestational diabetes.

Human Group IIA Phospholipase A2-Three Decades on from Its Discovery.

Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.

Impact of state scope-of-practice laws on nurse practitioner-provided home visits.

Millions of older Americans receive nurse practitioner (NP)-provided home based primary care (HBPC). Little is known about how state scope-of- practice (SOP) laws may impact use of NP-home visits. Using 2017 Centers for Medicare and Medicaid Services Provider Utilization and Payment Data Public Use File (PUF), we examined the impact of state SOP laws on the use of NP-home visits. The PUF file was merged with the 2017 American Community Survey to assess area-level median income. Over 4.4 million home visits were provided to 1.6 million Medicare beneficiaries. NPs represented the largest share of providers (47.5%). In states with restricted SOP laws, compared to NPs, physicians and physician assistants had higher odds of providing HBPC. In states with reduced SOP laws, compared to NPs, physicians and PAs had decreased odds of providing HBPC. Our study provides evidence that SOP restrictions are associated with decreased utilization of NP-provided HBPC.

Prevalence estimation by joint use of big data and health survey: a demonstration study using electronic health records in New York city.

BACKGROUND: Electronic Health Records (EHR) has been increasingly used as a tool to monitor population health. However, subject-level errors in the records can yield biased estimates of health indicators. There is an urgent need for methods to estimate the prevalence of health indicators using large and real-time EHR while correcting the potential bias. METHODS: We demonstrate joint analyses of EHR and a smaller gold-standard health survey. We first adopted Mosteller's method that pools two estimators, among which one is potentially biased. It only requires knowing the prevalence estimates from two data sources and their standard errors. Then, we adopted the method of Schenker et al., which uses multiple imputations of subject-level health outcomes that are missing for the subjects in EHR. This procedure requires information to link some subjects between two sources and modeling the mechanism of misclassification in EHR as well as modeling inclusion probabilities to both sources. RESULTS: In a simulation study, both estimators yielded negligible bias even when EHR was biased. They performed as well as health survey estimator when EHR bias was large and better than health survey estimator when EHR bias was moderate. It may be challenging to model the misclassification mechanism in real data for the subject-level imputation estimator. We illustrated the methods analyzing six health indicators from 2013 to 14 NYC HANES and the 2013 NYC Macroscope, and a study that linked some subjects in both data sources. CONCLUSIONS: When a small gold-standard health survey exists, it can serve as a safeguard against potential bias in EHR through the joint analysis of the two sources.

Feasibility of a Smartphone-Based Tobacco Treatment for HIV-Infected Smokers.

BACKGROUND: Cigarette smoking is common among persons living with HIV (PLWH) in the United States. It is the leading cause of mortality in this group, and efforts to promote cessation have been largely unsuccessful. METHODS: From 2015 to 2017, we performed a randomized controlled trial of Positively Smoke Free-Mobile (PSF-M) versus standard care. PSF-M is a mobile Web site that offers a 42-day text message-based quit-smoking program with smartphone features including quit-day selection/calendar, educational/motivational videos, and HELP button for cravings. RESULTS: One hundred individuals enrolled, 48 were randomized to PSF-M (mean age = 45 years, 54% male, 81% black, 31% Latino) and 52 to the standard care condition. All participants were offered a 3-month supply of nicotine patches. Participants randomized to the mobile intervention visited the PSF-M home page a mean of 83 times, viewed 5.6/8 videos, logged in on 13 of 42 possible days, and received 131 texts. Among them, 77% tapped HELP for cravings, and craving response options were used by the following proportions: phone-a-friend, 58%; play-a-game, 29%; play-a-song, 4%. Older age and nonblack race were both associated with higher levels of engagement with the site. Of participants, 61% rated PSF-M very or extremely helpful, and 98% would recommend PSF-M to PLWH family or friends. Abstinence at 3 months, quit attempts, and daily cigarette intake all favored PSF-M over standard care but did not achieve statistical significance in our pilot sample. CONCLUSIONS: Smartphone-based tobacco treatment for PLWH was feasible and achieved moderate-high rates of engagement and satisfaction in a middle-aged, ethnic or racial minority group in the poorest urban community in the United States. IMPLICATIONS: Cigarette smoking has emerged as the leading killer of PLWH. Behavioral interventions have achieved only limited success in promoting cessation in this population. In this study, we explore the feasibility and preliminary efficacy of a multimodal, Web-based, quit-smoking intervention delivered to PLWH smokers via their smartphones.

A single centre experience of treatment outcomes for Helicobacter pylori infection among inner-city children and adolescents.

AIM: This study assessed treatment outcomes of Helicobacter pylori (H pylori) infection among inner-city children. METHODS: This was a retrospective study of patients aged 1-21 years who underwent initial treatment for H pylori infection from 2011 to 2015. We included patients who completed 2 weeks of treatment with documented adequate compliance after H pylori infection was diagnosed. Treatment outcomes were measured based on stool H pylori antigen and/or histology. RESULTS: Of the total 261 patients diagnosed with H pylori, 239 completed the first-line treatment. The regimens used included amoxicillin/clarithromycin/proton pump inhibitor (PPI) in 207/239 patients (86.6%), amoxicillin/metronidazole/PPI in 14/239 patients (5.8%) and other regimens in 18/239 patients (7.5%). H pylori eradication status was tested in 111/207 (53.6%) patients treated with amoxicillin/clarithromycin/PPI, and the eradication was achieved in 84/111(75.7%) patients. The treatment success rates for amoxicillin/metronidazole/PPI and other regimens were 71.4% (5/7) and 63.6% (7/11), respectively. There was no statistical significance of post-treatment stool H pylori antigen results between PPI (n = 31) and no PPI (n = 43) users. CONCLUSION: The study showed an eradication rate of 75.7% with the regimen amoxicillin/clarithromycin/PPI suggesting significant antibiotic resistance in our population. The use of PPI did not influence post-treatment stool H pylori antigen results.

Structural and Functional Aspects of Targeting the Secreted Human Group IIA Phospholipase A2.

Human group IIA secretory phospholipase A2 (hGIIA) promotes the proliferation of cancer cells, making it a compelling therapeutic target, but it is also significant in other inflammatory conditions. Consequently, suitable inhibitors of hGIIA have always been sought. The activation of phospholipases A2 and the catalysis of glycerophospholipid substrates generally leads to the release of fatty acids such as arachidonic acid (AA) and lysophospholipid, which are then converted to mediator compounds, including prostaglandins, leukotrienes, and the platelet-activating factor. However, this ability of hGIIA to provide AA is not a complete explanation of its biological role in inflammation, as it has now been shown that it also exerts proinflammatory effects by a catalysis-independent mechanism. This mechanism is likely to be highly dependent on key specific molecular interactions, and the full mechanistic descriptions of this remain elusive. The current candidates for the protein partners that may mediate this catalysis-independent mechanism are also introduced in this review. A key discovery has been that selective inhibition of the catalysis-independent activity of hGIIA is achieved with cyclised derivatives of a pentapeptide, FLSYK, derived from the primary sequence of hGIIA. The effects of hGIIA on cell function appear to vary depending on the pathology studied, and so its mechanism of action is complex and context-dependent. This review is comprehensive and covers the most recent developments in the understanding of the many facets of hGIIA function and inhibition and the insight they provide into their clinical application for disease treatment. A cyclic analogue of FLSYK, c2, the most potent analogue known, has now been taken into clinical trials targeting advanced prostate cancer.

Passenger or Patient? The Automobile: A New Frontier in Health Promotion.

Americans spend trillions of minutes in cars annually, tens of billions of minutes traveling to health care providers, and hundreds of millions of minutes ridesharing (e.g., with Uber or Lyft). From July to October 2017, we recruited rideshare users (e.g., Uber or Lyft) to participate in a survey about health messaging during rides. Responses were collected anonymously on tablet devices. We interviewed 170 ridesharers and assessed their interest in health messaging delivered during rides. Participants ranged from 19 to 79 years of age, and most (87%) reported using their smartphones to search for health information. More than 70% expressed interest in health messaging during rides, and 55% of current smokers expressed interest in quit-smoking messaging. The most popular of suggested health topics included healthy eating (61.8%), exercise (60.6%), and weight loss (40.0%), and the preferred message formats were video (33.5%), smartphone apps (33.5%), and online social network (25.3%). Free time spent riding in cars represents an enormous untapped resource, and our findings suggest that riders are receptive to the idea of health messaging delivered during rideshare trips.

Apolipoprotein E Promotes Invasion in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) patients generally have a poor prognosis, because of the invasive nature of these tumors. In comparing transcription profiles between OSCC tumors with a more invasive (worst pattern of tumor invasion 5) versus a less invasive (worst pattern of tumor invasion 3) pattern of invasion, we identified a total of 97 genes that were overexpressed at least 1.5-fold in the more invasive tumor subtype. The most functionally relevant genes were assessed using in vitro invasion assays with an OSCC cell line (UM-SCC-1). Individual siRNA knockdown of 15 of these 45 genes resulted in significant reductions in tumor cell invasion compared to a nontargeting siRNA control. One gene whose knockdown had a strong effect on invasion corresponded to apolipoprotein E (APOE). Both matrix degradation and the number of mature invadopodia were significantly decreased with APOE knockdown. APOE knockdown also resulted in increased cellular cholesterol, consistent with APOE's role in regulating cholesterol efflux. APOE knockdown resulted in decreased levels of phospho-extracellular signal-regulated kinase 1/2, phospho-c-Jun N-terminal kinase, and phospho-cJun, as well as decreased activator protein 1 (AP-1) activity. Expression of matrix metalloproteinase 7 (MMP7), an AP-1 target, was also significantly decreased. Our findings suggest that APOE protein plays a significant role in OSCC tumor invasion because of its effects on cellular cholesterol and subsequent effects on cell signaling and AP-1 activity, leading to changes in the expression of invasion-related proteins, including MMP7.

Molecular dynamics simulations reveal structural insights into inhibitor binding modes and functionality in human Group IIA phospholipase A2.

Human Group IIA phospholipase A2 (hGIIA) promotes inflammation in immune-mediated pathologies by regulating the arachidonic acid pathway through both catalysis-dependent and -independent mechanisms. The hGIIA crystal structure, both alone and inhibitor-bound, together with structures of closely related snake-venom-derived secreted phospholipase enzymes has been well described. However, differentiation of biological and nonbiological contacts and the relevance of structures determined from snake venom enzymes to human enzymes are not clear. We employed molecular dynamics (MD) and docking approaches to understand the binding of inhibitors that selectively or nonselectively block the catalysis-independent mechanism of hGIIA. Our results indicate that hGIIA behaves as a monomer in the solution environment rather than a dimer arrangement that is in the asymmetric unit of some crystal structures. The binding mode of a nonselective inhibitor, KH064, was validated by a combination of the experimental electron density and MD simulations. The binding mode of the selective pentapeptide inhibitor FLSYK to hGIIA was stipulated to be different to that of the snake venom phospholipases A2 of Daboia russelli pulchella (svPLA2 ). Our data suggest that the application of MD approaches to crystal structure data is beneficial in evaluating the robustness of conclusions drawn based on crystal structure data alone. Proteins 2017; 85:827-842. © 2016 Wiley Periodicals, Inc.

Spiritual well-being, religious activity, and the metabolic syndrome: results from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study.

Sociocultural risk and protective factors for developing the metabolic syndrome (MetS), a risk factor for cardiovascular disease (CVD), have not been well studied in Hispanics/Latinos residing in the United States (U.S.). Religiosity and/or spirituality (R/S), important aspects of Hispanic/Latino culture, have been inversely associated with CVD and multiple CVD risk factors. Cross-sectional associations between dimensions of R/S and prevalent MetS, and its five individual components were examined using multiple logistic and linear regression, among 3278 U.S., middle-aged and older Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. Dimensions of R/S were not associated with presence of the MetS. Certain dimensions of Spiritual Well-being (Meaning, Peace, Faith), and frequency of non-organizational religious activity were weakly but significantly associated with one or more MetS components including waist circumference, diastolic blood pressure, and systolic blood pressure. R/S variables were not associated with triglycerides, fasting glucose or HDL cholesterol levels. Prospective, longitudinal studies are needed to gain a deeper understanding of the nature of the relationship between R/S and health risk factors in U.S. Hispanics/Latinos.

Association of Human Antibodies to Arabinomannan With Enhanced Mycobacterial Opsonophagocytosis and Intracellular Growth Reduction.

BACKGROUND: The relevance of antibodies (Abs) in the defense against Mycobacterium tuberculosis infection remains uncertain. We investigated the role of Abs to the mycobacterial capsular polysaccharide arabinomannan (AM) and its oligosaccharide (OS) fragments in humans. METHODS: Sera obtained from 29 healthy adults before and after primary or secondary bacillus Calmette-Guerin (BCG) vaccination were assessed for Ab responses to AM via enzyme-linked immunosorbent assays, and to AM OS epitopes via novel glycan microarrays. Effects of prevaccination and postvaccination sera on BCG phagocytosis and intracellular survival were assessed in human macrophages. RESULTS: Immunoglobulin G (IgG) responses to AM increased significantly 4-8 weeks after vaccination (P < .01), and sera were able to opsonize BCG and M. tuberculosis grown in both the absence and the presence of detergent. Phagocytosis and intracellular growth inhibition were significantly enhanced when BCG was opsonized with postvaccination sera (P < .01), and these enhancements correlated significantly with IgG titers to AM (P < .05), particularly with reactivity to 3 AM OS epitopes (P < .05). Furthermore, increased phagolysosomal fusion was observed with postvaccination sera. CONCLUSIONS: Our results provide further evidence for a role of Ab-mediated immunity to tuberculosis and suggest that IgG to AM, especially to some of its OS epitopes, could contribute to the defense against mycobacterial infection in humans.

The Use of Electrical Impedance to Identify Intraneural Needle Placement in Human Peripheral Nerves: A Study on Amputated Human Limbs.

BACKGROUND: Even as the use of peripheral nerve blockade in the perioperative setting is increasing, neural injury secondary to accidental intraneural injection remains a significant patient safety concern. Current modalities, including electrical stimulation and ultrasound imaging, still lack consistency and absolute reliability in both the detection and prevention of this complication. The measurement of electrical impedance (EI) could be an easy and valuable additional tool to detect intraneural needle placement. Our objectives in this study were to measure the change in EI with intraneural needle advancement in recently amputated human limbs. METHODS: The study was conducted within 45 minutes of amputation. The nerves that were studied were the sciatic nerve in the popliteal fossa in above-knee amputations or the tibial nerve below the calf in below-knee amputations. The amputated limb was placed on a tray and under ultrasound imaging guidance, an insulated peripheral block needle connected to a nerve stimulator was placed extraneurally and subsequently advanced intraneurally. The experiment was repeated on the same nerve after exposure by surgical dissection. The differences in impedance measurements between intraneural and extraneural needle placement were compared. RESULTS: In the below-knee amputated extremity (tibial nerve, n = 6) specimens based on the ultrasound methods, mean ± SD for ultrasound-guided intraneural impedance was 10 ± 2 kΩ compared with an extraneural impedance of 6 ± 1.6 kΩ (P = 0.005). The difference between intraneural and extraneural impedance after open dissection was also significant when we repeated the analysis based on the same specimens (P = 0.005). Similarly, in the above-the-knee amputated extremity (sciatic nerve, n = 5) specimens, mean intraneural impedance was 35.2 ± 7.9 kΩ compared with an extraneural impedance of 25.2 ± 5.3 kΩ (P = 0.037). The difference between intraneural and extraneural impedance obtained after open dissection was also significant when we repeated the analysis based on the same specimens (P = 0.0002). The impedance values were consistent and similar to those obtained after open dissection. CONCLUSIONS: There is no reliable "gold standard" to predict or prevent intraneural needle placement during peripheral nerve blockade. This small sample-sized study demonstrated that there is a change in EI with intraneural needle advancement. In clinical practice, measurement of the EI in conjunction with nerve stimulation may serve as another tool to use for identifying intraneural needle placement during peripheral nerve blockade.