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Understanding the role different habitats play in the life histories of fishes is important for the development of holistic aquatic ecosystem management plans. We used otolith trace element analysis to reconstruct the life history of estuarine triplefin Forsterygion nigripenne and infer its habitat use. Analysis of otoliths using laser ablation inductively coupled plasma mass spectrometry showed an elemental profile without prominent changes in elemental concentration. The otolith elemental profiles were not indicative of movement between waters with substantial Sr:Ca and Ba:Ca differences. The Sr:Ca and Ba:Ca profiles were indicative of within—and near—estuary movements encompassing short time periods. Overall, the otolith microchemical profile was likely indicative of a life history closely associated with estuaries. However, it is difficult to rule out brief excursions to the marine environment given that may not have been of sufficient duration to be recorded in the elemental composition of the otolith. This suggests that F. nigripenne is the only species in southern New Zealand known to be closely associated with estuarine habitat for its entire life cycle.

We evaluated the effects of a culturally adapted evidence-based HIV prevention intervention (Mpowerment), named “Tayf”, on condom use and HIV testing among young men who have sex with men (YMSM) in Beirut. A 2-year implementation of Tayf was carried out independently and in parallel with a research cohort of 226 YMSM who were surveyed at baseline and months 6, 12, 18 and 24 after Tayf initiation. Primary outcomes were (1) any condomless anal sex with HIV-positive or unknown status partners in the past 3 months, and (2) HIV testing in the past six months. Hierarchical logistic regression models examined the association of Tayf participation with the outcomes averaged across all assessments, and the moderating effect of Tayf participation on change in the outcomes over the follow-up period. A total of 331 YMSM attended at least one event, including 33% of the cohort. Tayf participation was associated with a higher rate of any condomless sex with HIV-positive or unknown status partners averaged across the five assessments, but there was no moderating effect of Tayf participation on change in this outcome over time. Tayf participation was associated with higher HIV testing when averaged across all assessments, but its interaction with time showed that the strength of this association diminished over time. In conclusion, Tayf proved feasible and acceptable in Beirut, but with limited effects. Further work is needed, including innovative publicity and marketing strategies, to bolster effects in high stigma settings where security and legal risks are prominent.

ObjectiveThe objective of this study was to assess the potential of combining graph learning methods with latent variable estimation methods for mining clinically useful information from observational clinical data sets.Materials and MethodsThe data set contained self-reported measures of psychopathology symptoms from a clinical sample receiving treatment for alcohol use disorder. We used the traditional graph learning methods: Graphical Least Absolute Shrinkage and Selection Operator, and Friedman's hill climbing algorithm; traditional latent variable estimation method factor analysis; recently developed graph learning method Greedy Fast Causal Inference; and recently developed latent variable estimation method Find One Factor Clusters. Methods were assessed qualitatively by the content of their findings.ResultsRecently developed graphical methods identified potential latent variables (ie, not represented in the model) influencing particular scores. Recently developed latent effect estimation methods identified plausible cross-score loadings that were not found with factor analysis. A graphical analysis of individual items identified a mistake in wording on 1 questionnaire and provided further evidence that certain scores are not reflective of indirectly measured common causes.Discussion and ConclusionOur findings suggest that a combination of Greedy Fast Causal Inference and Find One Factor Clusters can enhance the evidence-based information yield from psychopathological constructs and questionnaires. Traditional methods provided some of the same information but missed other important findings. These conclusions point the way toward more informative interrogations of existing and future data sets than are commonly employed at present.

Theoretical models of addiction suggest that alterations in addiction domains including incentive salience, negative emotionality, and executive control lead to relapse in alcohol use disorder (AUD). To determine whether the functional organization of neural networks underlying these domains predict subsequent relapse, we generated theoretically defined addiction networks. We collected resting functional magnetic resonance imaging data from 45 individuals with AUD during early abstinence (number of days abstinent M = 25.40, SD = 16.51) and calculated the degree of resting-state functional connectivity (RSFC) within these networks. Regression analyses determined whether the RSFC strength in domain-defined addiction networks measured during early abstinence predicted subsequent relapse (dichotomous or continuous relapse metrics). RSFC within each addiction network measured during early abstinence was significantly lower in those that relapsed (vs. abstained) and predicted subsequent time to relapse. Lower incentive salience RSFC during early abstinence increased the odds of relapsing. Neither RSFC in a control network nor clinical self-report measures predicted relapse. The association between low incentive salience RSFC and faster relapse highlights the need to design timely interventions that enhance RSFC in AUD individuals at risk of relapsing faster.

BACKGROUND Medical mistrust, a result of systemic racism, is prevalent among Black Americans and may play a role in COVID-19 inequities. In a convenience sample of HIV-positive Black Americans, we examined associations of COVID-19-related medical mistrust with COVID-19 vaccine and COVID-19 treatment hesitancy and negative impacts of COVID-19 on antiretroviral therapy (ART) adherence. METHODS Participants were 101 HIV-positive Black Americans (age: M = 50.3 years; SD = 11.5; 86% cisgender men; 77% sexual minority) enrolled in a randomized controlled trial of a community-based ART adherence intervention in Los Angeles County, CA. From May to July 2020, participants completed telephone interviews on negative COVID-19 impacts, general COVID-19 mistrust (eg, about the government withholding information), COVID-19 vaccine and treatment hesitancy, and trust in COVID-19 information sources. Adherence was monitored electronically with the Medication Event Monitoring System. RESULTS Nearly all participants (97%) endorsed at least one general COVID-19 mistrust belief, and more than half endorsed at least one COVID-19 vaccine or treatment hesitancy belief. Social service and health care providers were the most trusted sources. Greater COVID-19 mistrust was related to greater vaccine and treatment hesitancy [b (SE) = 0.85 (0.14), P < 0.0001 and b (SE) = 0.88 (0.14), P < 0.0001, respectively]. Participants experiencing more negative COVID-19 impacts showed lower ART adherence, assessed among a subset of 49 participants [b (SE) = -5.19 (2.08), P = 0.02]. DISCUSSION To prevent widening health inequities, health care providers should engage with communities to tailor strategies to overcome mistrust and deliver evidence-based information, to encourage COVID-19 vaccine and treatment uptake.

Guided by the minority stress model, we assessed depression and its relationship to structural and sexual minority-related stressors and social support in a sample of 226 young (age 18-29 years) men who have sex with men in Beirut, Lebanon. The sample was recruited with long-chain peer referrals and administered a survey that included the PHQ-9 measure of depression. 16% had current major depression based on our PHQ-9 criteria, and 33% reported any lifetime history of suicidal ideation (including 8% who had made an attempt); 69% had experienced any sexual minority-related discrimination in the past year. In bivariate analysis, structural (unemployment, no legal resident status) and sexual minority-related (greater number of types of discrimination experienced, greater discomfort with one's sexual orientation) stressors were associated with major depression, as was lower social support. Discomfort with one's sexual orientation was the only correlate of major depression when controlling for other stressors, social support and socio-demographics. These findings highlight a high level of depression, and the potential for community building and social solidarity for mitigating the effects of stressors based in personal security, internalized stigma and discrimination.

Neurofibromatosis Type 1 (NF1)-related Malignant Peripheral Nerve Sheath Tumors (MPNST) are highly resistant sarcomas that account for significant mortality. The mechanisms of therapy resistance are not well-understood in MPNSTs, particularly with respect to kinase inhibition strategies. In this study, we aimed to quantify the impact of both the genomic context and targeted therapy on MPNST resistance using reverse phase phosphoproteome array (RPPA) analysis. We treated tumorgrafts from three genetically engineered mouse models using MET (capmatinib) and MEK (trametinib) inhibitors and doxorubicin, and assessed phosphosignaling at 4 h, 2 days, and 21 days. Baseline kinase signaling in our mouse models recapitulated an MET-addicted state (NF1-MET), P53 mutation (NF1-P53), and HGF overexpression (NF1). Following perturbation with the drug, we observed broad and redundant kinome adaptations that extended well beyond canonical RAS/ERK or PI3K/AKT/mTOR signaling. MET and MEK inhibition were both associated with an initial inflammatory response mediated by kinases in the JAK/STAT pathway and NFkB. Growth signaling predominated at the 2-day and 21-day time points as a result of broad RTK and intracellular kinase activation. Interestingly, AXL and NFkB were strongly activated at the 2-day and 21-day time points, and tightly correlated, regardless of the treatment type or genomic context. The degree of kinome adaptation observed in innately resistant tumors was significantly less than the surviving fractions of responsive tumors that exhibited a latency period before reinitiating growth. Lastly, doxorubicin resistance was associated with kinome adaptations that strongly favored growth and survival signaling. These observations confirm that MPNSTs are capable of profound signaling plasticity in the face of kinase inhibition or DNA damaging agent administration. It is possible that by targeting AXL or NFkB, therapy resistance can be mitigated.

BACKGROUND: Anxiety and depression (“internalizing”) disorders occur in approximately 50% of patients with alcohol use disorder (AUD) and mark a two-fold increase in the rate of relapse in the months following treatment. In a previous study using network modeling, we found that perceived stress and drinking to cope (DTC) with negative affect were central to maintaining network associations between internalizing psychopathology (anxiety and depression) and drinking in comorbid individuals. Here, we extend this approach to a causal framework. METHODS: Measures of internalizing psychopathology, drinking urges/behavior, abstinence self-efficacy, and DTC were obtained from 362 adult AUD treatment patients who had a co-occurring anxiety disorder. Data were analyzed using a machine-learning algorithm (“Greedy Fast Causal Inference; GFCI) that infers paths of causal influence while identifying potential influences associated with unmeasured (“latent”) variables. RESULTS: Drinking to cope with negative affect served as a central hub for two distinct causal paths leading to drinking behavior, 1) a direct syndromic pathway originating with social anxiety and 2) an indirect stress pathway originating with perceived stress. CONCLUSIONS: Findings expand the field’s knowledge of the paths of influence that lead from internalizing disorder to drinking in AUD as shown by the first application in psychopathology of a powerful network analysis algorithm (GFCI) to model these causal relationships.

Black people living with HIV (BPLWH) are less likely to adhere to antiretroviral treatment than are members of other racial/ethnic groups. Data were combined from two studies of BPLWH (n = 239) to estimate adherence trajectories using a semiparametric, group-based modeling strategy over three time-points (spanning 6 months). Analyses identified three groups of individuals (high-stable, moderately low-stable, low-decreasing). Multinomial logistic regressions were used to predict trajectory membership with multiple levels of socio-ecological factors (structural, institutional/health system, community, interpersonal/network, individual). Older age was associated with being in the high-stable group, whereas substance use, lower perceived treatment effectiveness, and lower quality healthcare ratings were related to being in the moderately low-stable group. In sum, multiple socio-ecological factors contribute to adherence among BPLWH and thus could be targeted in future intervention efforts.

BackgroundSleepio is an automated digital program that delivers digital cognitive behavioural therapy for insomnia (dCBT-I). Sleepio has been proven effective in improving sleep difficulties; however, evidence for the possible impact of Sleepio use on healthcare costs in the UK has not, to the authors’ knowledge, previously been developed.AimTo identify the effect of a population-wide rollout of Sleepio in terms of primary care costs in the NHS in England.Design & settingThe study was conducted in the Thames Valley region of England, where access to Sleepio was made freely available to all residents between October 2018 and January 2020. The study relies on a quasi-experimental design, using an interrupted time series (ITS) to compare the trend in primary care costs before and after the rollout of Sleepio.MethodPrimary care data for people with relevant characteristics from nine general practices in Buckinghamshire was used. Primary care costs include general practice contacts and prescriptions. Segmented regression analysis was used to estimate primary and secondary outcomes.ResultsFor the 10 705 patients included in the sample, the total saving over the 65-week follow-up period was £71 027. This corresponds to £6.64 per person in the sample or around £70.44 per Sleepio user. Secondary analyses suggest that savings may be driven primarily by reductions in prescribing.ConclusionSleepio rollout reduced primary care costs. National adoption of Sleepio may reduce primary care costs by £20 million in the first year. The expected impact on primary care costs in any particular setting will depend on the uptake of Sleepio.

IMPACT: Our research has the potential to impact human health by identifying gender specific neural markers of emotion regulation in alcohol use disorder. OBJECTIVES/GOALS: Emotion dysregulation is known to be mediated by altered functional organization of the limbic system in addiction. This preliminary study sought to identify gender effects in the association between emotion regulation and resting-state functional connectivity (rsFC) of a negative affect network. METHODS/STUDY POPULATION: 55 individuals receiving treatment for alcohol use disorder (˜2 weeks of abstinence) were recruited for this study and included in this analysis (N=55; Age: M=41.78, SD=10.66; 21 females). RsFC within a network involved in the withdrawal/negative affect stage of addiction and Personality Inventory for DSM-5 (PID-5) metrics were collected from all participants. RsFC data were preprocessed using the Human Connectome Project pipelines. Correlations between (a) rsFC within the withdrawal/negative affect network and the (b) scores of the negative affect subscale of the PID-5 instrument were conducted for each gender separately. RESULTS/ANTICIPATED RESULTS: Independent samples t-test showed a statistically significant gender difference in the PID-5 negative affect scores (Males: M=1.02, SD=0.66; Females: M=1.53, SD=0.51); t(55)=-3.002, p=0.004. Only females showed a significant correlation between rsFC within the withdrawal/negative affect network and negative affect scores of the PID-5 (r=0.51, p

Young gay men in Beirut are at significantly elevated risk of HIV infection compared with the general Lebanese population. Despite nascent HIV prevention efforts in the region, there is a need for effective community-level HIV prevention interventions tailored for young gay men. This qualitative study examined internal dynamics within Beirut's gay community as a basis for developing community-level interventions. Peer ethnographers were trained to collect field notes on conversations between young gay men in public spaces in Beirut, and conducted follow-up focus groups with young gay men. Analyses revealed three major themes: (1) the need for safe spaces in which to socialise, (2) the importance of being able to locate and connect with other young gay men, and (3) ambivalence regarding a gay community that was supportive in some ways but also fragmented and often judgemental. Study findings also confirm the existence of external threats to community such as stigma, cultural and familial norms regarding heterosexuality and criminalisation of refugee status. Understanding such community dynamics and the environmental context is central to designing effective community-based HIV prevention programmes.

Black men who have sex with men (BMSM) show lower levels of adherence to antiretroviral therapy (ART) for HIV medications than other racial/ethnic groups in the U.S. Yet, little is known about age differences in factors that predict ART adherence among BMSM. We combined data from two surveys of HIV-positive BMSM, resulting in 209 participants (130 aged 18-50 years; 79 aged 50 years or older). Multivariate linear regressions examined associations between baseline characteristics and adherence to HIV medications as well as interactions of baseline characteristics with age. The associations between trust in healthcare and doctor satisfaction ratings with higher adherence were stronger for older vs younger men (p < .05); the association between problem drinking and lower adherence was stronger among younger men (p < .05). Future research should examine how interventions may address these age-specific factors to improve ART adherence among BMSM living with HIV.

IMPACT: Our research has the potential to impact human health by identifying a neural network that can be used to predict time to relapse in individuals with alcohol use disorder. OBJECTIVES/GOALS: Preoccupation towards alcohol use (e.g. craving, rumination, and poor executive control) is a maladaptive behavior associated with relapse risk. We investigated whether alterations in resting state networks known to mediate preoccupation could predict time to relapse in alcohol use disorder (AUD). METHODS/STUDY POPULATION: 50 participants with alcohol use disorder (AUD) (Age: M=41.76, SD=10.22, 19 females) were recruited from an addiction treatment program at ˜2 weeks of abstinence. fMRI data were preprocessed with the Human Connectome Project pipeline. Strength of resting state functional connectivity (RSFC) within two networks known to mediate the ‘Preoccupation go’ (PG) and ‘Preoccupation stop’ (PS) stages of addiction were calculated. T-tests were conducted to compare RSFC between subsequent abstainers and relapsers (after 4 months). Linear regressions were conducted to determine whether RSFC (of PG and PS networks) can predict time to relapse. Craving measures were included in the model. RESULTS/ANTICIPATED RESULTS: 19 AUD relapsed during the 4-month follow-up period. There were no RSFC group effects (subsequent abstainers and relapsers) in the PG or PS networks. Number of days to relapse could be predicted by PG RSFC (F(1,17)=14.90, p=0.001, r 2=0.47). Time to relapse increased by 13.19 days for each PG RSFC unit increase. Number of days to relapse could be predicted by PS RSFC (F(1,17)=9.39, p=0.002, r ²=0.36). Time to relapse increased by 12.94 days for each PS RSFC unit increase. After adding a self-report craving measure (i.e. Penn Alcohol Craving Scale) in the prediction model, both PG and PS RSFC still significantly predicted time to relapse. Craving metric did not predict time to relapse. DISCUSSION/SIGNIFICANCE OF FINDINGS: RSFC in preoccupation networks during short-term abstinence predicted time to relapse. These preliminary findings highlight promising targets for AUD neuromodulation interventions aimed to reduce relapse. Future larger scale studies that examine the effects of covariates and mediators are needed.

Contains fulltext : 174490.pdf (Publisher’s version ) (Open Access) Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response. 10 p.

Partial migration, or variation in migratory propensity within populations, has been reported across a range of taxa, including fish. Otolith microchemistry has revealed a high degree of life history plasticity in many amphidromous species, with diadromous and non-diadromous recruitment occurring. We examined this plasticity and its effect on population structure, dispersal and recruitment in Galaxias brevipinnis, an amphidromous fish widespread around New Zealand. We used otolith microchemistry analyses to examine recruitment sources and fish surveys to assess abundance and size structure in two large river systems, each containing naturally formed lakes and no obvious physical barriers to migration. Otolith analyses revealed discrete recruitment sources for stream-resident populations, with marine recruitment supporting populations downstream from lakes and exclusively lake-derived recruitment for populations upstream of lakes. Although diadromous G. brevipinnis were abundant within 10km of the sea, the abundance and relative proportion of younger fish declined as distance upstream increased, until a lake was reached, at which point abundance and the proportion of small individuals increased. The results provide a strong indication that supply is limiting recruitment for G. brevipinnis as distance from pelagic larval habitat increases, and that discrete recruitment sources and population structuring exist even within drainages.

A substantial number of people who have problems with alcohol also experience strong anxiety and mood problems. This article provides an overview of the evolving perspectives of this association in the context of three related disciplines—psychiatry, psychology, and neuroscience. Psychiatric and epidemiological studies show that having either an anxiety- or alcohol-related diagnosis elevates the prospective risk for developing the other disorder. From the psychological perspective, behavioral research demonstrates that drinking to cope with negative affect is a potent marker for current and future problems with alcohol. Neuroscientific research implicates overlapping neurobiological systems and psychological processes in promoting the rise of negative affect and alcohol misuse. The psychiatric perspective that alcohol misuse and co-occurring anxiety represent neurobiologically distinct diagnostic conditions has dominated the field for many decades. However, recent research provides increasing support for the neuroscientific perspective that these conditions share underlying, mutually exacerbating, neurobiological processes.

Contains fulltext : 209315.pdf (Publisher’s version ) (Closed access) The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/). 8 p.

We review the association of negative emotions and alcohol use disorder (AUD) through the lens of three discrete disciplines: psychology, psychiatry, and neuroscience. Taking an integrative view of these models and related findings we conclude that: (1) drinking to cope (DTC) serves as the primary final common pathway linking negative emotions to AUD; (2) the quantity rather than the quality of negative emotions modulate their association to drinking and AUD; (3) chronic alcohol use is a neurobiological insult that can dysregulate mood/stress systems leading to a cycle of escalating negative emotions and DTC; (4) preaddiction chronic/traumatic stress or psychiatric disorder constitutes a neurobiological vulnerability to develop a cycle of escalating negative emotions and DTC; (5) increased risk for relapse among those with preaddiction chronic/traumatic stress or psychiatric disorder likely marks a retarded neurobiological re-regulation of stress-mood systems during abstinence; (6) standard psychiatric treatments for anxiety and depression with comorbid AUD improves the former, but only minimally affects the latter; and (7) cognitive-behavioral treatment explicitly focused on reducing DTC and pharmacological treatment targeting neurobiological stress systems show promise in improving AUD associated with strong negative emotions.

Objective We sought to determine the prevalence, molecular epidemiology, and factors associated with Staphylococcus aureus environmental surface and pet colonization in households of children with community-associated methicillin-resistant S. aureus (CA–MRSA) infection. Methods Between 2012 and 2015, 150 children with CA–MRSA infections and their household contacts and pets were enrolled in this cross-sectional study in metropolitan Saint Louis, MO. Cultures to detect S. aureus were collected from 3 anatomic sites of household members, 2 dog/cat sites, and 21 environmental surfaces in each household. Molecular epidemiology of S. aureus isolates was determined via repetitive-sequence PCR. Generalized linear models were developed to identify factors associated with S. aureus/MRSA household contamination. Results MRSA was recovered from environmental surfaces in 69 (46%) households (median 2 surfaces [range 1–18]). The enrollment infecting strain type was the most common strain recovered from the environment in most (64%) households. In generalized linear models, factors associated with a higher proportion of MRSA-contaminated environmental surfaces were household member MRSA colonization burden, MRSA as the dominant S. aureus strain colonizing household members, more strain types per household member, index case African–American race, and renting (vs. owning) the home. Of 132 pets, 14% were colonized with MRSA. Pets whose primary caretaker was MRSA-colonized were more likely to be MRSA-colonized than pets whose primary caretaker was not MRSA-colonized (50% vs. 4%, p Conclusions Household environments and pet dogs and cats serve as reservoirs of MRSA. Household member MRSA colonization burden predicts environmental MRSA contamination. Longitudinal studies will inform the directionality of household transmission.

BackgroundGlomerular diseases of the kidney are presently differentiated, diagnosed and treated according to conventional clinical or structural features. While etiologically diverse, these diseases share common clinical features including but not limited to reduced glomerular filtration rate, increased serum creatinine and proteinuria suggesting shared pathogenic mechanisms across diseases. Renal biopsies from patients with nephrotic syndrome (NS) or ANCA-associated vasculitis (AAV) were evaluated for molecular signals cutting across conventional disease categories as candidates for therapeutic targets.MethodsRenal biopsies were obtained from patients with NS (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy) (n=187) or AAV (granulomatosis with polyangiitis or microscopic polyangiitis) (n=80) from the Nephrotic Syndrome Study Network (NEPTUNE) and the European Renal cDNA Bank. Transcriptional profiles were assessed for shared disease mechanisms.ResultsIn the discovery cohort, 10–25% transcripts were differentially regulated versus healthy controls in both NS and AAV, >500 transcripts were shared across diseases. The majority of shared transcripts (60–77%) were validated in independent samples. Therapeutically targetable networks were identified, including inflammatory JAK-STAT signaling. STAT1 eQTLs were identified and STAT1 expression associated with GFR-based outcome. A transcriptional STAT1 activity score was generated from STAT1-regulated target genes which correlated with CXCL10 (pConclusionAAV and NS caused from histopathologically distinct disease categories share common intra-renal molecular pathways cutting across conventional disease classifications. This approach provides a starting point for de novo drug development, and repurposing efforts in rare kidney diseases.

In 2012, our research with young men who have sex with men (YMSM) in Beirut showed high rates of recent condomless anal sex and low rates of recent HIV testing. In 2017, we collected data from YMSM to assess for temporal changes and sociodemographic correlates. Propensity score weighting was used to eliminate any sociodemographic differences between the 2012 (n = 164) and 2017 (n = 226) samples of YMSM (age 18–29) recruited with long-chain peer referral sampling. Regression analysis was used to examine sociodemographic correlates of recent condomless anal sex and HIV testing using the 2017 sample, and whether these behaviors differed between the samples. Compared to the 2012 sample, the 2017 sample was about half as likely to report any condomless anal sex in the past 3 months with partners whose HIV status was positive or unknown (14% vs. 23%; OR [95%CI] 0.56 [0.32, 0.98]), and nearly 2.5 times as likely to report HIV testing in the past 6 months (48% vs. 27%; OR [95%CI] 2.44 [1.46, 4.10]). In the 2017 sample, any recent condomless anal sex with partners whose HIV status was positive or unknown was associated with employment and Christian religious affiliation. Low income was the sole correlate of having recently tested for HIV. These findings suggest a temporal trend toward increased HIV protective behaviors among YMSM in Beirut over the past 5 years. Further inroads could be secured if HIV prevention programming targeted economic influences.

We examined individual-level, partnership-level, and sexual event-level factors associated with condom use during receptive anal intercourse (RAI) among 163 low-income, racially/ethnically diverse, HIV-negative men who have sex with men (MSM) in Los Angeles (2007-2010). At baseline, 3-month, and 12-month visits, computer-assisted self-interviews collected information on ≤3 recent male partners and the last sexual event with those partners. Factors associated with condom use during RAI at the last sexual event were identified using logistic generalized linear mixed models. Condom use during RAI was negatively associated with reporting ≥ high school education (adjusted odds ratio [AOR] = 0.32, 95 % confidence interval [CI] 0.11-0.96) and methamphetamine use, specifically during RAI events with non-main partners (AOR = 0.20, 95 % CI 0.07-0.53) and those that included lubricant use (AOR = 0.20, 95 % CI 0.08-0.53). Condom use during RAI varies according to individual-level, partnership-level, and sexual event-level factors that should be considered in the development of risk reduction strategies for this population.

Stigma may contribute to HIV-related disparities among HIV-positive Black Americans.We examined whether social network characteristics moderate stigma's effects.At baseline and 6 months post-baseline, 147 HIV-positive Black Americans on antiretroviral treatment completed egocentric social network assessments, from which we derived a structural social support capacity measure (i.e., ability to leverage support from the network, represented by the average interaction frequency between the participant and each alter). Stigma was operationalized with an indicator of whether any social network member had expressed stigmatizing attributions of blame or responsibility about HIV. Daily medication adherence was monitored electronically.In a multivariate regression, baseline stigma was significantly related to decreased adherence over time. The association between stigma and non-adherence was attenuated among participants who increased the frequency of their interactions with alters over time.Well-connected social networks have the potential to buffer the effects of stigma.

We examined how functional social support, HIV-related discrimination, internalized HIV stigma, and social network structure and composition were cross-sectionally associated with network members’ knowledge of respondents’ serostatus among 244 HIV-positive African Americans in Los Angeles. Results of a generalized hierarchical linear model indicated people in respondents’ networks who were highly trusted, well-known to others (high degree centrality), HIV-positive, or sex partners were more likely to know respondents’ HIV serostatus; African American network members were less likely to know respondents’ serostatus, as were drug-using partners. Greater internalized stigma among respondents living with HIV was associated with less knowledge of their seropositivity within their social network whereas greater respondent-level HIV discrimination was associated with more knowledge of seropositivity within the network. Additional research is needed to understand the causal mechanisms and mediating processes associated with serostatus disclosure as well as the long-term consequences of disclosure and network members’ knowledge of respondents’ serostatus.

In the United States, black men who have sex with men (MSM) are the group most affected by the HIV/AIDS epidemic. Pre-exposure prophylaxis (PrEP) is an important new HIV prevention strategy that may help reduce new HIV infections among black MSM. This analysis examined the association between HIV/AIDS conspiracy beliefs and intentions to adopt PrEP among 224 black MSM. The likelihood of adopting PrEP was assessed and more than half (60%) of the study population indicated a high intention to adopt PrEP. HIV/AIDS genocidal and treatment-related conspiracies were assessed using scales previously validated with black MSM. Almost two-thirds (63%) endorsed at least one of eight HIV/AIDS conspiracy beliefs presented. In multivariable analyses, black MSM who agreed with the genocidal or treatment-related conspiracy beliefs scales had a lower intention to adopt PrEP (Adjusted Odds Ratio [AOR] = 0.73, 95% CI = 0.54, 0.99 and AOR = 0.36, 95% CI = 0.23, 0.55, respectively). Our findings indicate that preexisting HIV/AIDS conspiracy beliefs may deter some black MSM from adopting PrEP. We suggest strategies PrEP implementers may want to employ to address the influence that HIV/AIDS conspiracy beliefs may have on the adoption of PrEP among black MSM, a population disproportionately affected by HIV/AIDS.

HIV disproportionately affects young Black men who have sex with men in the USA, with especially high rates in the Deep South. In this Alabama study, we interviewed 24 pairs of young Black men who have sex with men aged 19-24 and their close friends (n = 48) about sexual scripts, dating men and condom use. Three main themes emerged from the study: the power dynamics of 'top' and 'bottom' sexual positions for condom use; gender stereotyping in the iconic style of the 'I Love Lucy' show of the 1950s; and the sexual dominance of 'trade' men. Gender stereotyping was attributed to the cultural mores of Black families in the South, to the preferences of 'trade' men who exerted sexual and financial control and to internalised stigma relating to being Black, gay and marginalised. The findings suggest that HIV prevention education for young Black men who have sex with men is misguided if gendered power dynamics are ignored, and that funded access to self-protective strategies such as pre-exposure prophylaxis and post-exposure prophylaxis could reduce HIV risk for this severely affected population.

Evidence-based HIV treatment adherence interventions have typically shown medium-sized effects on adherence. Prior evidence-based HIV treatment adherence interventions have not been culturally adapted specifically for Black/African Americans, the population most affected by HIV disparities in the USA, who exhibit lower adherence than do members of other racial/ethnic groups. We conducted a randomized controlled trial of Rise, a 6-month culturally congruent adherence counseling intervention for HIV-positive Black men and women. Rise was delivered by a trained peer counselor who used a problem-solving approach to address culturally congruent adherence barriers (e.g., medical mistrust, HIV stigma) and assisted with linkage to supportive services. A total of 215 participants were randomized to the intervention group (n = 107) or a wait-list control group (n = 108). Adherence was assessed daily via electronic monitoring. In a repeated measures multivariate logistic regression model of dichotomous adherence (using a clinically significant cutoff of 85% of doses taken), adjusted for sociodemographic and medical covariates, adherence in the intervention group improved over time relative to the control group, (OR = 1.30 per month (95% CI = 1.12–1.51), p

Internalizing disorders co-occur with alcohol use disorder (AUD) at a rate that exceeds chance and compromise conventional AUD treatment. The "vicious cycle" model of comorbidity specifies drinking to cope (DTC) as a link between these disorders that, when not directly addressed, undermines the effectiveness of conventional treatments. Interventions based on this model have proven successful but there is no direct evidence for how and to what extent DTC contributes to the maintenance of comorbidity. In the present study, we used network analysis to depict associations between syndrome-specific groupings of internalizing symptoms, alcohol craving, and drinking behavior, as well as DTC and other extradiagnostic variables specified in the vicious cycle model (e.g., perceived stress and coping self-efficacy). Network analyses of 362 individuals with comorbid anxiety and AUD assessed at the beginning of residential AUD treatment indicated that while internalizing conditions and drinking elements had only weak direct associations, they were strongly connected with DTC and perceived stress. Consistent with this, centrality indices showed that DTC ranked as the most central/important element in the network in terms of its "connectedness" to all other network elements. A series of model simulations-in which individual elements were statistically controlled for-demonstrated that DTC accounted for all the relationships between the drinking-related elements and internalizing elements in the network; no other variable had this effect. Taken together, our findings suggest that DTC may serve as a "keystone" process in maintaining comorbidity between internalizing disorders and AUD. (PsycINFO Database Record

Recent studies using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) have found that some personality disorders (PDs) increase the persistence of several Axis I disorders. However, these effects are potentially confounded with the data collection wave in which PDs were assessed. Our aim was to extend published analyses to the case of anxiety disorders and to determine the robustness of the associations to analyses examining time-of-measurement effects. Persistence of anxiety disorders was defined either as follow-up diagnosis among participants diagnosed at baseline (“prediction”) or baseline diagnosis among participants diagnosed at follow-up (“post-diction”). Results revealed a robust pattern of higher odds ratios for post-diction among PDs assessed at baseline, and lower odds ratios for post-diction among PDs assessed at follow-up, suggesting a time of measurement artifact. Although only 4% of associations were robust to both predictive and post-dictive analyses, these were consistent with previous research.

The first study of the chemical constituents of Combretum inflatum has resulted in the isolation of seven new acetylated dammarane-type bisdesmosides (1-7). Their structures were determined from microgram quantities on hand using Bruker BioSpin TCI 1.7 mm MicroCryoProbe technology, ESIMS, and comparison to data found in the literature. Compounds 1-7 were screened for inhibition of an Escherichia coli strain UTI89 biofilm, MRSA inhibition, and cytotoxicity in NCI-H460 human lung cancer cells. Compounds 3-7 reduced the growth of MRSA at 16 μg/mL by 71-45%, and compound 7 had an IC₅₀ value of 3.9 μM in NCI-H460.

Paroxetine alone is not sufficient to decrease alcohol use in socially anxious alcoholics seeking anxiety treatment. We tested the hypothesis that adding a brief-alcohol-intervention (BI) to paroxetine would decrease alcohol use. All subjects (N = 83) had a diagnosis of social anxiety disorder, endorsed drinking to cope with anxiety, were NIAAA-defined at-risk drinkers, and were randomized to either paroxetine alone, or paroxetine plus BI. Both groups showed significant improvement in both social anxiety severity (F(5,83) = 61.5, p < 0.0001) and drinking to cope (e.g. F(4,79) = 23, p < 0.0001) and these two constructs correlated with each other (B = 3.39, SE = 0.696, t(71) = 4.88, p < 0.001). BI was not effective at decreasing alcohol use (e.g. no main effect of group, all p values >0.3). Paroxetine decreased social anxiety severity in the face of heavy drinking and decreasing the anxiety was related to a concurrent decrease in coping related drinking. BI was not effective at decreasing drinking or drinking to cope.

Background Statins are recommended for use in patients with peripheral arterial disease (PAD) to reduce cardiovascular events and mortality. However, much of the data regarding benefits of statins stem from the cardiovascular literature. Here, we review the literature regarding statin use specifically in patients with PAD regarding its effects on cardiovascular events and mortality, limb-related outcomes, statin use after endovascular interventions, statin dosing, and concerns about statins. Methods We performed a literature review using PubMed for literature after the year 2000. Search terms included "statins," "peripheral arterial disease," "peripheral vascular disease," "lipid-lowering medication," and "cardiovascular disease." Results There is good evidence of statins lowering cardiovascular events and cardiovascular-related mortality in patients with PAD. Though revascularization rates were reduced with statins, amputation rates and amputation-free survival did not improve. Small randomized controlled trials show that patients taking statins can slightly improve pain-free walking distance or pain-free walking time, although the extent of the effect on quality of life is unclear. Statin use for patients undergoing endovascular interventions is recommended because of the reduction of postoperative cardiovascular events. Not enough data exist to support local effects of systemic statin therapy, such as prevention of restenosis. For statin dosing, there is little increased benefit to intense therapy compared with the adverse effects, whereas moderate-dose therapy has significant benefits with very few adverse effects. Adverse effects of moderate-dose statin therapy are rare and mild and are greatly outweighed by the cardiovascular benefits. Conclusions There is strong evidence to support use of statins in patients with PAD to reduce cardiovascular events and mortality. Use in patients undergoing open and endovascular interventions is also recommended. Statin use may reduce the need for revascularization, but reductions in amputation have not been shown. Moderate-dose statin therapy is safe, and the minor risks are greatly outweighed by benefits.

A fundamental feature of community-based participatory research (CBPR) is sharing findings with community members and engaging community partners in the dissemination process. To be truly collaborative, dissemination should involve community members in a two-way dialogue about new research findings. Yet little literature describes how to engage communities in dialogue about research findings, especially with historically marginalized communities where mistrust of researchers may exist because of past or present social injustices. Through a series of interactive community presentations on findings from a longitudinal study, we developed a process for community dissemination that involved several overlapping phases: planning, outreach, content development, interactive presentations, and follow-up. Through this process, we built on existing and new community relationships. Following each interactive presentation, the research team debriefed and reviewed notes to identify lessons learned from the process. Key themes included the importance of creating a flexible dissemination plan, tailoring presentations to each community group, establishing a point person to serve as a community liaison, and continuing dialogue with community members after the presentations. Core strategies for developing trust during dissemination included engaging community members at every step, reserving ample time for discussion during presentations, building rapport by sharing personal experiences, being receptive to and learning from criticism, and implementing input from community members. This process led to a deeper understanding of research findings and ensured that results reached community members who were invested in them.

High-throughput natural products chemistry methods have facilitated the isolation of eight new and two known beilschmiedic acid derivatives from the leaves of a Gabonese species of Beilschmiedia. This class of compounds appears to be unique to two genera of the Lauraceae, and exhibits remarkable structural complexity for a fatty acid. Eight of the compounds were isolated in microgram quantities necessitating the use of a 1.7mm MicroCryoProbe to obtain NMR data, including a complete HMBC, for structure elucidation and dereplication. All of the compounds were screened for cytotoxic activity against NCI-H460 human lung cancer cells and antibacterial activity against a clinical isolate of methicillin-resistant Staphylococcus aureus. Results from enzymatic assays provided evidence that the observed activity was not the result of membrane disruption as one might expect from lipophilic compounds such as these.

The frequent co-occurrence of alcohol dependence and anxiety disorder is a long-standing clinical conundrum. An underdeveloped perspective on this issue concerns the impact of a co-occurring anxiety disorder on the sequence and developmental course of alcohol-related milestones. Extrapolating from the body of basic science indicating overlap in the neurobiological processes associated with both anxiety disorder and alcohol dependence-particularly those involving the hypothalamic-pituitary-adrenal axis and elements of the amygdala- we hypothesized that anxiety-disordered individuals are vulnerable to the rapid development of alcohol dependence. Specifically, we predicted that the time from pre-dependence alcohol milestones (e.g., age at which regular drinking began) to post-dependence alcohol milestones would be briefer ("telescoped") among those with an anxiety disorder.Seventy-eight individuals with alcohol dependence who had recently begun a chemical dependency treatment program underwent a diagnostic interview to determine the presence of current anxiety disorders and to establish the age at which several alcohol use and dependence milestones were first achieved.We found that, compared with others in the sample, anxiety-disordered individuals transitioned significantly more quickly from the time they first began drinking regularly and first began getting drunk regularly to the onset of alcohol dependence, as well as from most pre-dependence alcohol milestones to the point at which their alcohol dependence was most severe.Individuals with anxiety disorders transition from regular drinking to alcohol dependence more rapidly than do individuals without anxiety disorders. These findings contribute to an improved understanding of the etiology of comorbidity and suggest novel directions for future research.

Approximately half of those receiving treatment for an alcohol use disorder (AUD) also suffer with an anxiety or depressive (internalizing) disorder. Because all internalizing disorders mark a poor alcohol treatment outcome, it seems reasonable to supplement AUD treatment with a psychiatric intervention when these disorders co-occur with AUD. However, this conclusion may be faulty given that the various possible interrelationships between AUD and internalizing disorders do not uniformly imply a high therapeutic yield from this approach. Unfortunately, the studies conducted to date have been too few and too small to resolve this important clinical issue with confidence. Therefore, we used a meta-analytic method to synthesize the effects from published randomized controlled trials examining the impact of supplementing AUD treatment with a psychiatric treatment for co-occurring internalizing disorder (N = 15). We found a pooled effect size (d) of .32 for internalizing outcomes and .22 for a composite of alcohol outcomes; however, the alcohol outcomes effect sizes were greater than this for some specific outcome domains. Subgroups that differed in terms of internalizing outcomes included treatment type (medication vs. cognitive behavioral therapy) and treatment focus (anxiety vs. depression). There was also a trend for the studies with better internalizing disorder outcomes to have better alcohol outcomes. These results indicate that clinical outcomes (both psychiatric and alcohol-related) could be somewhat improved by supplementing AUD treatment with psychiatric treatment for co-occurring internalizing disorder.

Alcohol dependence (AD) is more likely to occur among individuals with rather than without an anxiety disorder. Self-medication theory (SMT) holds that drinking behavior is negatively reinforced when alcohol temporarily reduces anxiety and that the resulting escalation of drinking increases the risk for AD. We set out to empirically scrutinize SMT using the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) dataset. We found that only a minority (about 20%) of anxiety disordered individuals endorsed drinking to control anxiety symptoms. This minority drank more alcohol, had a higher cross-sectional rate of AD, and was at higher risk for developing new AD over four years compared to anxiety disordered non-self-medicators and individuals with no anxiety disorder. Consistent with SMT, increased prospective risk for AD among self-medicators is partially mediated by an increased level of alcohol use. Understanding the processes that promote and inhibit self-medication should be a priority for anxiety disorder researchers.

People living with HIV infection have a significantly higher rate of anal cancer as compared with that of uninfected people. It is believed that high-grade anal dysplasia secondary to human papillomavirus infection is a precursor to anal cancer. Considering this, screening and treatment of high-grade anal dysplasia is a possible means of preventing the development of anal cancer. No national or international guidelines exist to guide practice for screening and management of anal dysplasia. On the basis of a review of research and expert recommendations, a guide to practice for screening and management of anal dysplasia and anal cancer is made for clinicians.

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive, chemoresistant sarcomas that develop in patients with the genetic disorder Neurofibromatosis Type 1 (NF1). Loss of TRP53 and amplification of the receptor tyrosine kinase (RTK) MET is observed 25-50% of cases. To investigate the role of MET and p53 in MPNST progression, we developed three MPNST mouse models: an NF1 null and MET overexpression MPNST model (NF1-MET), an NF1 and TRP53 heterozygous knockout model (NF1-p53), and a NF1 null model (NF1). Using orthotopic tumorgrafts from these models, we tested the efficacy of MET (capmatinib) and MEK (trametinib) inhibition on MPNST growth. Trametinib moderately inhibited tumor growth in all of the models; however, combined inhibition of MEK and MET was highly effective in both the NF1-MET and NF1 models. NF1-p53 tumors were the least responsive to combined inhibition and upregulated AKT signaling in response to single agent therapy. These data suggest that alternate RTK signaling pathways downstream of MET may compensate for MEK inhibition, and that p53 loss promotes kinome reprogramming in response to targeted inhibition in MPNSTs. To determine the effects of MEK, MET, PI3K, and mTOR inhibition on kinome signaling, we generated MPNST cell lines from each of our MPNST models. Western blot analysis revealed that NF1-MET MPNST cells are highly sensitive to MET inhibition, NF1-p53 MPNST cells maintain ERK and AKT activity in the presence of MET inhibition, and NF1-p53 MPNST cells uniquely upregulate MEK signaling in response to PI3K/mTOR inhibition. These results suggest p53 plays a unique role in kinome reprograming and resistance to kinase inhibitors. Currently, we are determining the effects of combined kinase inhibition on proliferation of MPNST cells and utilizing reverse phase protein arrays to evaluate the effect of MET and MEK inhibition on the phospho-proteome in our MPNST models. By understanding these complex signaling networks we will identify combinations of targeted therapies that can be used to effectively treat MPNSTs. Citation Format: Jamie Grit, Matt Pridgeon, Elizabeth Tovar, Zachary Madaj, Jackie Peacock, Julia Wulfkuhle, Emanuel Petricoin, Carrie Graveel, Matt Steensma. Predicting response to kinase inhibitors based on tumor genomics in NF1-related MPNSTs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 822.

Bioassay-guided fractionation of the antibacterial ethyl acetate-ethanol (50 : 50) extract obtained from the aerial parts of Penstemon centranthifolius led to the isolation of six phenylethanoid glycosides (1–6) and eleven iridoid glycosides (7–17). Their structures were determined on the basis of spectroscopic analysis and comparison with the literature. Among them, two phenylethanoid glycosides, 4″′-O–acetylverbascoside (1) and verbascoside (2), were found to show significant inhibition of the formation of bacterial biofilms by Escherichia coli UTI89. Compound 1 showed 77% biofilm inhibition at 2.5 µg/mL, and compound 2 showed 60% inhibition at 5 µg/mL. Copyright © 2009 John Wiley & Sons, Ltd.