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HIV incidence among African American (AA) young men who have sex with men (YMSM) has remained stable even though they made up the largest number of new HIV diagnoses among men who have sex with men (MSM) in 2017. HIV spreads at increased rates in dense sexual networks. Identifying the location of risk behaviors "activity spaces" could inform geographically circumscribed HIV prevention interventions. Utilizing the modified social ecological model we completed five semi-structured focus groups incorporating a modified social mapping technique, based on Singer et al.'s approach. Participants included 27 AA YMSM. Focus groups explored how and where HIV transmission happens in Jackson, Mississippi. Result themes included: 1) location of sexual behaviors, 2) knowledge of geographic hotspots of HIV infection in Jackson, and 3) traveling to meet partners: at home and away. HIV transmission or "activity spaces" may be occurring outside identified HIV hot spots. Mixed geospatial and qualitative methods offered a comprehensive assessment of where HIV transmission occurs, and suggests that geographically circumscribed interventions may need to focus on where individuals living with HIV reside and in specific geographic locations where they engage in behaviors that raise their HIV acquisition risks.

More than 2 million people are incarcerated in the United States with many millions more processed through correctional facilities annually. Communities impacted by incarceration are also disproportionately impacted by the HIV and sexually transmitted infection (STI) epidemics. However, relatively little is known about the behaviors that place individuals with a history of incarceration at risk for HIV/STI acquisition. We utilized clinical data from patients presenting to an STI clinic located in Providence, Rhode Island. A latent class analysis was conducted on reported HIV acquisition risk behavior and STI testing results on a total of 1129 encounters where a history of incarceration was reported. A total of three classes were identified. Class 1 (

Latino sexual minority men (LSMM) experience sexual and behavioral health disparities. Yet, LSMM are underrepresented in sexual and behavioral health research, creating scientific inequity. There is, therefore, a need to identify the barriers and facilitators to LSMM's participation in sexual and behavioral health research, which is the gap that the current study sought to fill. We interviewed LSMM (n = 28; age 18-40, 57% US born) and key informants (n = 10) regarding LSMM's barriers and facilitators to participating in sexual and behavioral health research and suggestions for increasing participation. The research team coded the data via thematic analysis. We found that relational factors are central to understanding LSMM's participation in sexual and behavioral health research. Some relational experiences (e.g., interpersonal stigma) interfered with participation, whereas others (e.g., altruistic desires to contribute to community well-being) facilitated participation. The findings are consolidated within a new relational framework for understanding LSMM's participation in sexual and behavioral health research. Study findings highlight the centrality of relational factors in influencing LSMM's participation in sexual and behavioral health research. Relational factors can be used to inform the development of culturally relevant recruitment strategies to improve representation of LSMM in sexual and behavioral health research. Implementing these recommendations may address scientific inequity, whereby LSMM are disproportionately impacted by sexual and behavioral health concerns yet underrepresented in related research.

Maternal stress in pregnancy exerts powerful programming effects into the next generation. Yet it remains unclear whether and how adversity from other times in the woman's life influences her prenatal stress and her offspring's stress functioning. In a sample of 217 Black American mother-infant dyads, we examined whether different types of maternal stress were differentially related to her infant's stress functioning within the first few months after birth. We prospectively assessed maternal distress (perceived stress, depression, and anxiety) early and late in pregnancy, infant behavioral adaption in the context of a mild stressor at 2 weeks of age, and infant diurnal cortisol at 3-6 months of age. We additionally collected retrospective reports of maternal experiences of lifetime discrimination and childhood adversity. Maternal distress experienced late, but not early, in pregnancy predicted lower infant attention in the context of a stressor. Moreover, lifetime experiences of discrimination indirectly impacted infant attention by increasing maternal distress late in pregnancy. These effects were specific to infant behavioral adaptation and were not related to infant diurnal cortisol levels. However, infant diurnal cortisol levels were associated with maternal experiences of discrimination from prior to pregnancy and adversity from the mother's childhood even after controlling for prenatal distress. Our results underscore the cascading nature of stress across the mother's life span and across generations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The purpose of this study was to evaluate the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on sexual behavior, mental health, and substance use among men who have sex with men (MSM) engaged in pre-exposure prophylaxis (PrEP) care. Generalized linear mixed models and logistic mixed-effect models examined change over time for number of sexual partners, mood, and alcohol consumption. From February 29, 2020 to July 31, 2020, 177 MSM actively engaged in PrEP care were evaluated. The median age was 37 [interquartile range (IQR 30, 51]. Patients in the sample were largely representative of the clinic population and identified as White (73.0%), Black/African American (9.2%), and other race (17.2%), and 11.8% identified as Hispanic/Latino ethnicity. Men reported an average of 2.60 fewer sexual partners (95% CI -4.04, -1.40) during the pandemic compared to pre-COVID-19. Rates of depressive symptoms and alcohol use remained stable and few patients reported substance use. The reduced number of sexual partners may be explained by patients' efforts to reduce risk of exposure to COVID-19 and low rates of psychosocial symptoms may be indicative of only the highest functioning patients continuing to engage in care. Reductions in sexual partners may offset reduced engagement in care and help mitigate risk of HIV and other sexually transmitted infections (STIs).El propósito de este estudio fue evaluar el impacto que tuvo la pandemia causada por la enfermedad del coronavirus 2019 (COVID-19) en el comportamiento sexual, la salud mental y el uso de sustancias en hombres que tienen sexo con hombres (HSH) que reciben profilaxis previa a la exposición (PrEP). Los modelos lineales mixtos generalizados y los modelos logísticos de efectos mixtos examinaron el cambio a través del tiempo en el número de parejas sexuales, el estado de ánimo y el consumo de alcohol. Desde el 29 de febrero de 2020 hasta el 31 de julio de 2020, se evaluaron 177 HSH que recibían los servicios de la PrEP. La mediana de edad fue de 37 (rango intercuartílico (IQR: 30, 51). Los pacientes de la muestra eran en gran parte representativos de la población de la clínica y se identificaban como Blancos (73.0%), Negros/Afroamericanos (9.2%) y de Otra raza (17.2%) y el 11.8% se identificó de origen Hispano/Latino. Los hombres reportaron un promedio de 2.60 parejas sexuales menos (IC del 95%: -4.04, -1.40) durante la pandemia en comparación con antes de COVID-19. Las tasas de síntomas depresivos y el uso de alcohol se mantuvieron estables y pocos pacientes reportaron uso de sustancias. El número reducido de parejas sexuales puede explicarse por los esfuerzos de los pacientes para reducir su riesgo de exposición al COVID-19 y las bajas tasas de síntomas psicosociales pueden ser indicativos de que solo los pacientes con mayor funcionamiento continúan participando. La reducción en el número de parejas sexuales puede contrarrestar la baja participación en la atención medica de la PrEP y ayudar a mitigar el riesgo de contraer el VIH y otras infecciones de transmisión sexual (ITS).

COVID-19 is a public health crisis that has fundamentally altered health care provision. The purpose of this study was to examine the impact of COVID-19 on pre-exposure prophylaxis (PrEP) care. We reviewed all patient records for those who presented for PrEP care at a PrEP program in Providence, Rhode Island from September 1st, 2019 to May 29th, 2020. The number of PrEP encounters decreased but was not significantly different over time (ps .05). Patients were still able to access PrEP clinical services during the COVID-19 pandemic. Implementing flexible and timely PrEP delivery approaches in this setting likely minimized the disruption of PrEP care during COVID-19.COVID-19 es una crisis de salud pública que ha alterado fundamentalmente la prestación de servicios de salud. El propósito de este estudio fue examinar el impacto de COVID-19 en los servicios de la profilaxis preexposición (PrEP). Revisamos todos los registros de pacientes que se presentaron para recibir atención de PrEP en un programa de PrEP en Providence, Rhode Island desde el 1 de septiembre de 2019 hasta el 29 de mayo de 2020. El número de encuentros de PrEP disminuyó pero no fue significativamente diferente con el paso del tiempo (ps .05). Los pacientes aún pudieron acceder a los servicios clínicos de PrEP durante la pandemia de COVID-19. La implementación de enfoques de entrega de PrEP que eran flexibles y oportunos en este entorno probablemente minimizó la interrupción de la atención médica de la PrEP durante COVID-19.

COVID-19 has disproportionately affected vulnerable populations across the U.S. Street-based sex workers are one vulnerable population whose health and impact of COVID-19 have been understudied to date. The goal of this study was to evaluate findings from a community needs assessment with street-based sex workers on impact of COVID-19 on health behaviors and social circumstances. A brief survey was developed at a community-based harm reduction and recovery services organization. Surveys were administered by peer specialists to street-based sex workers during street outreach in April and May 2020. A total of 46 surveys were analyzed. Many individuals reported continuing to do sex work and use substances during the COVID pandemic. Slightly more than a quarter of individuals (n = 13; 28.3%) indicated using personal protective equipment while doing sex work and described challenges to using precautions when working with clients. Individuals had used marijuana (n = 32, 71.1%), cocaine (n = 17, 39.5%), prescription stimulants (n = 9, 21.4%), methamphetamines (n = 5, 11.9%), prescription opioids (n = 12, 27.3%), street opioids (n = 12, 27.3%), sedatives (n = 11, 25.0%), hallucinogens (n = 3, 6.8%), inhalants (n = 3, 7.0%), or some other substance (n = 4, 8.7%) in the past 30 days. About half (48.8%) reported that COVID-19 had a major impact on their lives. This study is among the first to characterize the impact of COVID-19 on street-based sex workers. From a public health standpoint, this group also represents a high-priority population given their vulnerability and close contact with others, which increases the potential for community spread.

Despite many successful clinical trials to test HIV-prevention interventions for sexual minority men (SMM), not all SMM are reached by these trials. Identifying factors associated with non-participation in these trials could help to ensure the benefits of research extend to all SMM. Prospective participants in New York City and Miami were screened to determine eligibility for a baseline assessment for a mental health/HIV-prevention trial (N = 633 eligible on screen). Logistic regression and classification and regression tree (CART) analysis identified predictors of non-participation in the baseline, among those who were screened as eligible and invited to participate. Individuals who reported unknown HIV status were more likely to be non-participators than those who reported being HIV-negative (OR = 2.39; 95% CI 1.41, 4.04). In New York City, Latinx SMM were more likely to be non-participators than non-Latinx white SMM (OR = 1.81; 95% CI, 1.09, 2.98). A CART model pruned two predictors of non-participation: knowledge of HIV status and age, such that SMM with unknown HIV status and SMM ages 18-19 were less likely to participate. Young SMM who did not know their HIV status, and thus are more likely to acquire and transmit HIV, were less likely to participate. Additionally, younger SMM (18-19 years) and Latinx SMM in New York City were less likely to participate. The findings suggest the importance of tailored recruitment to ensure HIV-prevention/mental health trials reach all SMM.A pesar de muchos ensayos clínicos exitosos para probar intervenciones de prevención del VIH para hombres de minorías sexuales (HMS), no todos los HMS son alcanzados por estos ensayos. La identificación de factores asociados con la no participación en estos ensayos podría ayudar a asegurar que los beneficios de la investigación se extiendan a todos los HMS. Se realizaron evaluaciones de teléfono para determinar la elegibilidad para la visita inicial para un ensayo de salud mental/prevención del VIH (N = 633 elegibles en las evaluaciones). La regresión logística y el análisis de arboles de regresión y clasificación (ARC) identificaron predictores de no participación en la visita inicial, entre aquellos que fueron evaluados como elegibles e invitados a participar. Los individuos que reportaron estado desconocido de VIH fueron más probables a ser no participantes que aquellos que reportaron ser VIH negativos (RP = 2.39; IC 95% 1.41, 4.04). En la ciudad de Nueva York, HMS latinx eran más probable a no participar que los HMS blancos no latinx (RP = 1.81; IC 95%, 1.09, 2.98). Un modelo de ARC podó dos predictores de no participación: el conocimiento del estado de VIH y la edad, tal que los HMS con estado desconocido del VIH y las HMS de 18–19 años eran menos probables a participar. Los HMS jóvenes que no conocían su estado de VIH, y por lo tanto eran más probables a adquirir y transmitir el VIH, tenían menos probabilidades de participar. Además, las HMS más jóvenes (18–19 años) y los HMS latinx en la ciudad de Nueva York eran menos probables a participar. Los resultados sugieren la importancia de un reclutamiento personalizado para garantizar que los ensayos de prevención del VIH y salud mental lleguen a todos los SMM.

Syndemics, or comorbid and mutually reinforcing psychosocial problems, are associated with increased HIV risk among men who have sex with men (MSM). Although the dynamic interplay among syndemic indicators is theorized to be crucial for increasing risk of HIV acquisition, novel approaches are needed to understand how these syndemic problems interrelate. This study examined the associations between nine self-reported syndemic indicators in 194 MSM at high risk of HIV acquisition. We compared exploratory factor analyses (EFA) to a network analysis. In the present study, network analysis consisted of edges representing bidirectional partial polychoric correlations between nodes, which represent psychosocial syndemic indicators. EFA yielded a 1-factor solution including suicidal ideation (SI), injection drug use (IDU), depression, social anxiety, intimate partner violence, substance use, and sexual compulsivity, and excluded heavy drinking and childhood sexual abuse. Network analysis yielded a pattern of interconnectedness with the most central nodes being SI, IDU, substance use, and depression. Statistically significant relationships (absolute edge weights) were found between SI and depression, social anxiety, and IDU, and IDU and substance use. These results suggest that depression and substance use, especially more severe presentations of these conditions such as SI and IDU, are prominent interconnected components of the HIV syndemic among MSM at high risk for HIV acquisition. SI, IDU, substance use, and depression may indeed be prudent targets of intervention. Future research on the inclusion of these syndemic indicators in analytical models involving interaction terms may be warranted.

Background Pre-exposure prophylaxis (PrEP) can significantly reduce HIV acquisition especially among communities with high HIV prevalence, including men who have sex with men (MSM). Much research has been finding suboptimal PrEP persistence; however, few studies examine factors that enhance PrEP persistence in real-world settings. Methods We interviewed 33 patients who identified as MSM at three different PrEP clinics in three regions of the U.S. (Northeast, South, Midwest). Participants were eligible if they took PrEP and had been retained in care for a minimum of 6 months. Interviews explored social, structural, clinic-level and behavioral factors that influencing PrEP persistence. Results Through thematic analysis we identified the following factors as promoting PrEP persistence: (1) navigation to reduce out-of-pocket costs of PrEP (structural), (2) social norms that support PrEP use (social), (3) access to LGBTQ + affirming medical providers (clinical), (4) medication as part of a daily routine (behavioral), and (5) facilitation of sexual health agency (belief). Discussion In this sample, persistence in PrEP care was associated with structural and social supports as well as a high level of perceived internal control over protecting their health by taking PrEP. Patients might benefit from increased access, LGBTQ + affirming medical providers, and communications that emphasize PrEP can promote sexual health.

The coronavirus disease 2019 (COVID-19) pandemic continues to put strain on health systems in the United States, leading to significant shifts in the delivery of routine clinical services, including those offering HIV pre-exposure prophylaxis (PrEP). We aimed to assess whether individuals discontinued PrEP use at higher rates during the COVID-19 pandemic and the extent to which disruptions to usual clinical care were mitigated through telehealth.Using data from an ongoing prospective cohort of men who have sex with men (MSM) newly initiating PrEP in 3 mid-sized cities (n = 195), we calculated the rate of first-time discontinuation of PrEP use in the period before the COVID-19 pandemic and during the COVID-19 pandemic and compared these rates using incidence rate ratios (IRRs). Furthermore, we compared the characteristics of patients who discontinued PrEP use during these periods with those who continued to use PrEP during both periods.Rates of PrEP discontinuation before the COVID pandemic and during the COVID-19 pandemic were comparable [4.29 vs. 5.20 discontinuations per 100 person-months; IRR: 1.95; 95% confidence interval (CI): 0.83 to 1.77]. Although no significant differences in the PrEP discontinuation rate were observed in the overall population, the rate of PrEP discontinuation increased by almost 3-fold among participants aged 18-24 year old (IRR: 2.78; 95% CI: 1.48 to 5.23) and by 29% among participants covered by public insurance plans at enrollment (IRR: 1.29; 95% CI: 1.03 to 5.09). Those who continued to use PrEP were more likely to have had a follow-up clinical visit by telehealth in the early months of the pandemic (45% vs. 17%).In this study, rates of PrEP discontinuation were largely unchanged with the onset of the COVID-19 pandemic. The use of telehealth likely helped retain patients in PrEP care and should continue to be offered in the future.

Objective Race-related lifetime stress exposure (LSE) including racial discrimination, trauma, and stressful life events have been shown to contribute to racial health disparities. However, little is known about associations between race-related stressors and premature biological aging that confer the risk of adverse health outcomes. Even less is known about the mechanisms through which race-related stressors may be associated with accelerated aging. Early evidence suggests psychological processes such as anger, and particularly the internalization of anger, may play a role. Methods In a community sample of predominantly low-income Black adults (n = 219; age = 45.91 [12.33] years; 64% female), the present study examined the association of race-related LSE (as defined by exposure to racial discrimination, trauma, and stressful life events) and epigenetic age acceleration through anger expression. Results Internalized and externalized anger expression were each significantly associated with LSE and age acceleration. Although LSE was not directly associated with age acceleration (ΔR2 = 0.001, p = .64), we found that greater LSE was indirectly associated with age acceleration through increases in internalized, but not externalized, anger (indirect effect: β = 0.03, standard error = 0.02, 95% confidence interval = 0.003 to 0.08; total effect: β = 0.02, 95% confidence interval = -0.25 to 0.31). Conclusions These results suggest race-related LSE may elicit the internalization of anger, which, along with the externalization of anger, may initiate detrimental epigenetic alterations that confer the risk of adverse health outcomes. These findings lay the groundwork for longitudinal studies of the association between race-related stress and racial health disparities.

SARS-CoV-2 is a novel coronavirus and the cause of COVID-19 (https://www.who.int/). There are currently 45 million individuals diagnosed with COVID-19 and over 1.2 million who have died worldwide.1 Of these, nine million cases and over 228 000 deaths have occurred in the USA.1 COVID-19 has disproportionately impacted individuals with comorbidities and of older age. Other social risk factors predicting vulnerability to COVID-19 include low socioeconomic status, race/ethnicity and occupational setting. There has been a higher number of COVID-19 cases and deaths among marginalised groups. Populations in the USA with a greater COVID-19 burden include African American/black and Hispanic/Latino communities. There are limited data on SARS-CoV-2 and sexual orientation and gender diversity. However, based on existing health disparities, the lesbian, gay, bisexual, transgender and queer (LGBTQ+) community is also likely to be disproportionately impacted by COVID-19. A key component of addressing COVID-19 is diagnostic testing for SARS-CoV-2. However, approaches and models to implementing accessible SARS-CoV-2 testing, especially for vulnerable communities, have not been well described. STIs also disproportionately affect underserved and marginalised communities, with 376 million new infections of curable STIs worldwide in 2016.2 In the USA, African American/black, Hispanic/Latino and LGBTQ+ individuals are at a greater risk for STIs due to proximal and distal social determinants of health, including economic stability, physical environments, social and community context, education, and healthcare access.3 Similarly, the impact of social determinants has worsened STI health outcomes among vulnerable populations across the world.3 Given the overlap in communities affected by COVID-19 and STIs, there are significant lessons to be learned from experiences with STI testing. We examine challenges related to COVID-19 testing and offer potential solutions derived from STI testing that may increase access for those most at risk and mitigate health disparities (figure 1). Figure 1 Improving access to COVID-19 testing. The ability to …

Retention in HIV pre-exposure prophylaxis (PrEP) care is critical for effective PrEP implementation. Few studies have reported long-term lost to follow-up (LTFU) and re-engagement in PrEP care in the United States. Medical record data for all cisgender patients presenting to the major Rhode Island PrEP clinic from 2013 to 2019 were included. LTFU was defined as no PrEP follow-up appointment within 98 days. Re-engagement in care was defined as individuals who were ever LTFU and later attended a follow-up appointment. Recurrent event survival analysis was performed to explore factors associated with PrEP retention over time. Of 654 PrEP patients, the median age was 31 years old [interquartile range (IQR): 25, 43]. The majority were male (96%), White (64%), non-Hispanic (82%), and insured (97%). Overall, 72% patients were ever LTFU and 27% of those ever LTFU re-engaged in care. Female patients were 1.37 times [crude hazard ratio (cHR): 1.37; 95% confidence interval (CI): 0.86–2.18] more likely to be LTFU than male patients, and a 1-year increase in age was associated with a 1% lower hazard of being LTFU (cHR: 0.99; CI: 0.98–0.99). Being either heterosexual (aHR: 2.25, 95% (CI): 1.70–2.99] or bisexual (aHR: 2.35, 95% CI: 1.15–4.82) was associated with a higher hazard of loss to follow-up compared with having same-sex partners only. The majority of PrEP users were LTFU, especially at the first 6 months of PrEP initiation. Although a significant number were re-engaged in care, targeted interventions are needed to improve retention in PrEP care. This study characterized the natural projection of loss to follow-up and re-engagement in HIV PrEP care using a longitudinal clinic cohort data and explored associated factors for guiding future interventions to improve retention in PrEP care.

Background Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. Methods Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. Results We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all $$p p < 0.05 ), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ($$\rho =0.19$$ ρ = 0.19 , $$p=0.004$$ p = 0.004 ; $$\rho =0.2$$ ρ = 0.2 , $$p=0.004$$ p = 0.004 , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ($$t=4.0$$ t = 4.0 , $$p=8.8\times 10^{-5}$$ p = 8.8 × 10 - 5 ), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ($$t=-3.3$$ t = - 3.3 , $$p=0.001$$ p = 0.001 ). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ($$t=-2.3$$ t = - 2.3 , $$p=0.02$$ p = 0.02 , and $$t=4.2$$ t = 4.2 , $$p={3.2\times 10^{-5}}$$ p = 3.2 × 10 - 5 for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: $$-0.22\pm 0.05$$ - 0.22 ± 0.05 ; testosterone: $$-0.35\pm 0.15$$ - 0.35 ± 0.15 from 0.1%-ile to 99.9%-ile; SHBG: $$0.64\pm 0.15$$ 0.64 ± 0.15 from 0.1%-ile to 99.9%-ile). Limitations In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. Conclusions These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.

Psychosocial syndemic conditions have received more attention regarding their deleterious effects on HIV acquisition risk than for their potential impact on HIV treatment and viral suppression. To examine syndemic conditions' impact on the HIV care continuum, we analyzed data collected from people living with HIV (N = 14,261) receiving care through The Centers for AIDS Research Network of Integrated Clinical Systems at seven sites from 2007 to 2017 who provided patient-reported outcomes ∼4-6 months apart. Syndemic condition count (depression, anxiety, substance use, and hazardous drinking), sexual risk group, and time in care were modeled to predict antiretroviral therapy (ART) adherence and viral suppression (HIV RNA

Latino sexual minority men (LSMM) are disproportionately affected by HIV in the United States. Concurrently, behavioral health disparities, including mental health and substance use concerns, worsen HIV disparities affecting LSMM. Yet, evidence-based HIV prevention and behavioral health services are insufficiently scaled up and out to this population, perpetuating health disparities, thwarting efforts to control the HIV epidemic, and highlighting the need for culturally relevant evidence-based implementation strategies that address these disparities. Participants included 28 LSMM with varying degrees of engagement in HIV prevention and behavioral health services, and 10 stakeholders with experience delivering HIV prevention and behavioral health services to LSMM in South Florida, an HIV epicenter in general and in particular for LSMM. Participants completed semistructured interviews (English/Spanish) regarding LSMM's barriers and facilitators to engaging in HIV prevention and behavioral health services. Interviews were audio recorded and analyzed using thematic analysis. The 16 themes that emerged from the qualitative analysis were consistent with the consolidated framework for implementation research, an implementation research framework that articulates barriers and facilitators to implementing clinical interventions. Findings suggested the need for implementation strategies that simplify and reduce costs of HIV prevention and behavioral health services, address syndemic challenges impacting service use among LSMM, reduce stigma about service utilization, leverage peer networks, increase provider and community knowledge about services, and build LSMM's readiness and motivation to engage in services. Such strategies may ultimately address HIV and behavioral health disparities among LSMM and facilitate achievement of ending the HIV epidemic goals in this disproportionally affected population.

Maternal stress during pregnancy can cause alterations to the fetal hypothalamus–pituitary–adrenal (HPA) axis, a phenomenon known as fetal programming that may have lasting effects on offspring outcomes, including depression. Evidence suggests that these effects may vary with respect to the offspring's genetic risk. Nonetheless, few studies have examined these effects into adulthood, when risk for depression onset is highest. The present study builds upon the extant literature by examining the interaction of maternal prenatal perceived stress (MPPS) and offspring HPA-axis polygenic risk to predict offspring depression in early adulthood. A total of 381 mother–child dyads participated in a prospective, longitudinal study that spanned from pregnancy until offspring were 20 years of age. Polygenic risk was defined by a multilocus genetic profile score (MGPS) that reflected the additive risk of three HPA-axis candidate genes. The results indicated that the interaction of MPPS and HPA-axis MGPS confers risk for offspring depression at age 20, in line with the differential susceptibility model. This interaction may be specific to prenatal stress, as maternal stress during early childhood did not interact with genetic risk to predict depression. These findings provide the first evidence that genetic variants that are associated with the HPA axis may act in a polygenic, additive fashion to moderate the association between fetal programming and adult depression.

Author(s): Satyanarayana, Satyanand; Safren, Steven A; Rogers, Brooke G; Bainter, Sierra A; Christopoulos, Katerina A; Fredericksen, Rob J; Mathews, William C; Moore, Richard D; Mugavero, Michael J; Napravnik, Sonia; Carrico, Adam W; Mimiaga, Matthew J; Mayer, Kenneth H; Crane, Heidi M | Abstract: IntroductionLittle is known about onward HIV transmissions from people living with HIV (PLWH) in care. Antiretroviral therapy (ART) has increased in potency, and treatment as prevention (TasP) is an important component of ending the epidemic. Syndemic theory has informed modelling of HIV risk but has yet to inform modelling of HIV transmissions.MethodsData were from 61,198 primary HIV care visits for 14,261 PLWH receiving care through the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) at seven United States (U.S.) sites from 2007 to 2017. Patient-reported outcomes and measures (PROs) of syndemic conditions - depressive symptoms, anxiety symptoms, drug use (opiates, amphetamines, crack/cocaine) and alcohol use - were collected approximately four to six months apart along with sexual behaviours (meann=n4.3 observations). Counts of syndemic conditions, HIV sexual risk group and time in care were modelled to predict estimated HIV transmissions resulting from sexual behaviour and viral suppression status (HIV RNAnln400/mL) using hierarchical linear modelling.ResultsPatients averaged 0.38 estimated HIV transmissions/100 patients/year for all visits with syndemic conditions measured (down from 0.83, first visit). The final multivariate model showed that per 100 patients, each care visit predicted 0.05 fewer estimated transmissions annually (95% confidence interval (CI): 0.03 to 0.06; pnln0.0005). Cisgender women, cisgender heterosexual men and cisgender men of undisclosed sexual orientation had, respectively, 0.47 (95% CI: 0.35 to 0.59; pnln0.0005), 0.34 (95% CI: 0.20 to 0.49; pnln0.0005) and 0.22 (95% CI: 0.09 to 0.35; pnln0.005) fewer estimated HIV transmissions/100 patients/year than cisgender men who have sex with men (MSM). Each within-patient syndemic condition predicted 0.18 estimated transmissions/100 patients/year (95% CI: 0.12 to 0.24; pnln0.0005). Each between-syndemic condition predicted 0.23 estimated HIV transmissions/100 patients/year (95% CI: 0.17 to 0.28; pnln0.0005).ConclusionsEstimated HIV transmissions among PLWH receiving care in well-resourced U.S. clinical settings varied by HIV sexual risk group and decreased with time in care, highlighting the importance of TasP efforts. Syndemic conditions remained a significant predictor of estimated HIV transmissions notwithstanding the effects of HIV sexual risk group and time in care.

Poor sleep leads to poor health outcomes. Inpatient sleep disturbance has been studied primarily in the ICU. Minimal research exists on sleep in surgical populations.We recruited patients undergoing elective, inpatient general surgery procedures. Participants wore Fitbit trackers while inpatient to measure total sleep time (CDC recommendation is 7 or more hours per night). At discharge, patients completed the Richards-Campbell Sleep Questionnaire (RCSQ) to measure inpatient sleep quality. The RCSQ combines 5 domains into a cumulative score (0 to 100); a higher score means better sleep quality. Patients also completed the outpatient Pittsburgh Sleep Quality Index preoperatively and postoperatively. The primary end point was percentage of patients with total sleep score ≥ 50. Secondary outcomes included mean RCSQ domain scores, Fitbit total sleep time, and percentage with Pittsburgh Sleep Quality Index Score indicating poor sleep.We included 64 patients (mean ± SD age 55.0 ± 14.1 years). Mean ± SD RCSQ total sleep score was 49 ± 20.5 and 53.1% with total sleep score50. Mean ± SD RCSQ domain scores were Awakenings: 40.4 ± 22.8, Sleep Quality: 49.1 ± 27.9, Sleep Latency: 49.2 ± 25.3, Sleep Depth: 50.2 ± 26.5, Returning to Sleep: 55.9 ± 28.1, and Noise Disturbance: 59.1 ± 27.9. On night one, 25 devices (40%) had recorded sleep data due to enough sleep. Mean ± SD total sleep time on night 1 was 4.7 ± 2.8 hours. Mean total sleep time for nights 2, 3, and 4 remained fewer than 7 hours. Percentages for each night that achieved the CDC goal of 7 or more hours were as follows: night one 10.9%, night two 32.8%, night three 35.3%, and night four 27.6%. Per the Pittsburgh Sleep Quality Index, 88.1% of patients were poor sleepers preoperatively and 84.5% were poor sleepers at follow-up (p = 0.6).Elective general surgery patients experience a severe inpatient sleep disturbance, worse than in similarly studied ICU cohorts. This disturbance is driven primarily by nighttime awakenings.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

OBJECTIVE/BACKGROUND: Insomnia is a prevalent and interfering comorbidity of HIV infection. Nearly 70% of people living with HIV/AIDS (PLWHA) experience symptoms of insomnia and associated distress. The current study examined the mechanisms of insomnia in HIV health status and health-related quality of life and explored behavioral pathways to explain relationships. PARTICIPANTS: Participants (N = 103) were active patients in an HIV clinic located within a nonprofit, tertiary care hospital in a large, urban city in the Southeast United States. METHODS: Participants completed a clinical sleep interview and self-report assessments for adherence to antiretroviral medication, depression (PHQ-9), quality of life (ACTG-QOL), and relevant covariates. Viral load and CD4 were obtained via medical chart review. RESULTS: Insomnia affected 67% of the clinic sample. Insomnia symptoms were directly associated with poorer health-related quality of life (p

Previous studies suggest epigenetic alterations may contribute to the association between maternal prenatal depression and adverse offspring outcomes. Developmental researchers have recently begun to examine these associations in relation to epigenetic age acceleration/deceleration, a biomarker of developmental risk that reflects the deviation between epigenetic age and chronological age. In the perinatal period, preliminary studies indicate that maternal prenatal depression may lead to epigenetic age deceleration in newborns, which may predict adverse developmental outcomes. The present study examined the relationship between maternal prenatal exposures (i.e., depression, stress, and SSRI use) and offspring epigenetic age deceleration in 303 mother-offspring dyads. Women were recruited in the first trimester of pregnancy and followed longitudinally until delivery. Maternal depression, perceived stress, and SSRI use were assessed at each prenatal visit. Newborn epigenetic age was determined via cord blood samples. Results indicated maternal prenatal stress was not associated with newborn epigenetic age deceleration (ΔR(2) = 0.002; p = 0.37). Maternal prenatal depression was associated with decelerated epigenetic age (ΔR(2) = 0.01, p = 0.04), but this relationship did not hold when accounting for maternal use of SSRIs (ΔR(2) = 0.002, p = 0.43). Conversely, maternal SSRI use significantly predicted newborn epigenetic age deceleration over and above the influence of maternal depression (ΔR(2) = 0.03, p = 0.001). These findings suggest maternal prenatal SSRI use may significantly contribute to the previously documented association between maternal prenatal depression and epigenetic age deceleration. Further studies are needed to examine how these epigenetic differences at birth may contribute to adverse outcomes in later development.

Interventions addressing syndemics and ART adherence are needed for individuals with uncontrolled HIV and psychosocial problems. Twenty-seven participants with detectable HIV plasma viral load (PVL) or recent STI participated in an open trial of transdiagnostic adherence counseling and cognitive behavioral therapy. Outcomes were collected at baseline, 4-, and 8-months. Log PVL improved from baseline to 4-month (γ = − 1.13, 95% CI − 1.72, − 0.55, p

OBJECTIVE: People living with HIV/AIDS (PLWHA) are disproportionally exposed to a host of structural, community, and individual-level physical and psychosocial stressors also termed ‘syndemic conditions.’ The current study aimed to examine the association between experiencing syndemic conditions and physiological stress response and be associated with bodily inflammation, including Interlekin-6 (IL-6) and C-reactive protein (CRP) in PLWHA. DESIGN: Participants (N = 103) were recruited from a public HIV clinic. They provided saliva samples of IL-6 and CRP and completed psychosocial measures. MAIN OUTCOME MEASURES: Levels of circulating salivary IL-6 and CRP. RESULTS: When predictors (birth country, recent housing instability, and incarceration history) were simultaneously entered into a regression model, only incarceration history was negatively associated with IL-6 [b = −.27, t(98) = −3.11, p = .002]. For CRP, the resulting regression model was not significant, [F(3, 98) = 2.23, p = .090]. CONCLUSION: Although we had expected higher levels of syndemics to be associated with higher levels of circulating inflammation, in our sample, length of incarceration was associated with lower levels of circulating IL-6. Findings are therefore suggestive of a stress response disruption resulting in a negative feedback loop as the long-term impact of chronic stress on inflammation.

Background Vaccines are effective in preventing Coronavirus Disease 2019 (COVID-19). Vaccine hesitancy defined as delay of acceptance or refusal of the vaccine is a major barrier to effective implementation. Methods Participants were recruited statewide through an English and Spanish social media marketing campaign conducted by a local news station during a one-month period as vaccines were becoming available in Rhode Island (from December 21, 2020 to January 22, 2021). Participants completed an online survey about COVID-19 vaccines and vaccine hesitancy with constructs and items adopted from the Health Belief Model. Results A total of 2,007 individuals completed the survey. Eight percent (n = 161) reported vaccine hesitancy. The sample had a median age of 58 years (interquartile range [IQR]: 45, 67), were majority female (78%), White (96%), Non-Hispanic (94%), employed (58%), and reported an annual individual income of $50,000 (59%). COVID-19 vaccine hesitancy was associated with attitudes and behaviors related to COVID-19. A one unit increase in concern about COVID-19 was associated with a 69% (Adjusted Odds Ratio: 0.31, 95% CI: 0.26–0.37) decrease in vaccine hesitancy. A one-level increase in the likelihood of getting influenza vaccine was associated with a 55% (AOR: 0.45 95% CI: 0.41–0.50) decrease in vaccine hesitancy. Conclusions COVID-19 vaccine hesitancy was relatively low in a state-wide survey in Rhode Island. Future research is needed to better understand and tailor messaging related to vaccine hesitancy.

PURPOSE: There have been significant biomedical improvements in the treatment and prevention of HIV over the past few decades. However, new transmissions continue to occur. Alcohol use is a known barrier to medication adherence and consistent condom use and therefore may affect treatment as prevention (TasP) efforts. The purpose of this study was to further explore how alcohol is associated with condom use and sexual transmission behavior in three international cities. METHOD: HIV Prevention Trials Network 063 was an observational mixed-methods study of HIV-infected patients currently in care in Rio de Janeiro, Brazil; Chiang Mai, Thailand; and Lusaka, Zambia. Across these three global cities, 80 qualitative interviews were conducted from 2010 to 2012. From these interviews, quotes related to substance use, almost all of which were alcohol, were analyzed using thematic analysis to identify how the use was related to sexual transmission behaviors. RESULTS: Overall, the theme that alcohol impairs cognitive abilities emerged from the data and included the following subthemes: expectancies, impaired decision-making, loss of control, and less concern for others. Themes specific to international settings and risk subgroups were also identified. CONCLUSION: Our analysis identified how alcohol influences sexual transmission behavior in HIV patients in three international settings. These findings may provide direction for content development for future secondary prevention interventions to effectively implement TasP internationally.

Sleep problems are prevalent in people living with HIV/AIDS; however, few studies examine how poor sleep affects mental health and quality of life longitudinally. A sample of people living with HIV/AIDS from a randomized trial ( N = 240; mean age = 47.18; standard deviation = 8.3; 71.4% male; 61.2% White) completed measures of depression (Montgomery–Åsberg Depression Rating Scale), health-related quality of life (AIDS Clinical Trial Group Quality of Life Measure), and life satisfaction (Quality of Life Inventory) at baseline and 4, 8, and 12 months. Controlling for time, condition, and relevant interactions, sleep problems significantly predicted worse outcomes over time ( ps

The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD.

People with HIV experience elevated levels of co-occurring psychosocial concerns, which can interfere with HIV-related self-care behaviors, such as medication adherence. We recently developed transdiagnostic, integrated cognitive-behavioral therapy and motivational interviewing psychotherapy to address interrelated psychosocial problems (syndemics) that can interfere with medication adherence and self-care among people with uncontrolled HIV (i.e., a detectable viral load). Through completion of a field trial that included development, clinical supervision, treatment, and administrative coordination of this project, we identified recommendations for engaging, retaining, and delivering transdiagnostic cognitive-behavioral therapy/motivational interviewing to individuals with HIV and experiencing psychosocial and structural barriers to mental and physical health. We describe these recommendations, which include (a) building the relationship; (b) addressing HIV in the context of syndemics; (c) attending to the impact of stigma on health; (d) being flexible in delivering the treatment; (e) managing emergent crises with relevant skill material; (f) tailoring the treatment to education, language, and sociocultural context; (g) implementing problem-solving skills for structural barriers; (h) scheduling flexibly and following up; (i) colocating mental health services and coordinating among providers; and (j) providing a comfortable and affirming physical space. In addition to describing these recommendations, we provide clinical examples and highlight empirical research to illustrate and support using these recommendations. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Approximately 1.1 million individuals in the United States are living with HIV/AIDS. HIV disproportionately affects young, black men who have sex with men (YBMSM). Recent biomedical advances, including the use of antiretroviral therapy as pre-exposure prophylaxis (PrEP), hold promise for preventing HIV infections. However, PrEP uptake remains slow among those most at-risk. To develop and test an intervention to address HIV disparities in YBMSM, we conducted qualitative interviews with 29 YBMSM from Jackson, Mississippi, to learn more about their views of PrEP. Twenty-nine PrEP-eligible YBMSM were enrolled and participated in either semistructured interviews or focus groups. They were asked about PrEP use, messaging, and promotion. Data were coded based on an iteratively developed coding scheme and entered into NVivo to facilitate thematic analysis. Our analysis identified the following three main themes: (1) the role of setting, context, and stigma in health care, (2) targeted PrEP messaging is further stigmatizing, and (3) recommendations for PrEP messaging and care. YBMSM in our sample felt highly stigmatized in their current environment and felt that PrEP messaging targeting YBMSM only enhanced their sense of marginalization. They concluded that broad and inclusive messaging would be just as relevant and cause less stigma. Our findings were somewhat surprising, as several prior studies benefited from using targeted materials to engage YBMSM in HIV prevention and PrEP uptake. The study's location may explain this difference in findings, which suggests the importance of considering local conditions and opinions when developing interventions for HIV prevention among minority populations.

Biological sex is an important factor in mental health, and a non-binary view of how variation in sex and gender influence mental health represents a new research frontier that may yield new insights. The recent acceleration of research into sexual orientation, gender identity, and mental health has generally been conducted without sufficient understanding of the opinions of sexual and gender minorities (SGM) toward this research. We surveyed 768 individuals, with an enrichment of LGBTQ+ stakeholders, for their opinions regarding genetic research of SGM and mental health. We found that the key predictors of attitudes toward genetic research specifically on SGM are 1) general attitudes toward genetic and mental health research 2) tolerance of SGM and associated behaviors 3) non-cisgender stakeholder status and 4) age of the respondent. Non-heterosexual stakeholder status was significantly associated with increased willingness to participate in genetic research if a biological basis for gender identity were discovered. We also found that non-stakeholders with a low tolerance for SGM indicated their SGM views would be positively updated if science showed a biological basis for their behaviors and identities. These findings represent an important first step in understanding and engaging the LGBTQ+ stakeholder community in the context of genetic research.

Sulfur and nitrogen mustards are internationally banned vesicants listed as Schedule 1 chemical agents in the Chemical Weapons Convention. These compounds are highly reactive electrophiles that form stable adducts to a variety of available amino acid residues on proteins upon exposure. We present a quantitative exposure assay that simultaneously measures agent specific protein adducts to cysteine for sulfur mustard (HD) and three nitrogen mustards (HN1, HN2, and HN3). Proteinase K was added to a serum or plasma sample to digest protein adducts and form the target analyte, the blister agent bound to the tripeptide cysteine-proline-phenylalanine (CPF). The mustard adducted-tripeptide was purified by solid phase extraction and analyzed using isotope dilution LC-MS/MS. Product ion structures were identified using high-resolution product ion scan data for HD-CPF, HN1-CPF, HN2-CPF, and HN3-CPF. Thorough matrix comparison, analyte recovery, ruggedness, and stability studies were incorporated during method validation to produce a robust method. The method demonstrated long term-stability, precision (RSD < 15%), and intra- and inter-day accuracies > 85% across the reportable range of 3.00–200 ng/mL for each analyte. Compared to previously published assays, this method quantitates both sulfur and nitrogen mustard exposure biomarkers, requires only 10 μL of sample volume, and can use either a liquid sample or dried sample spot.

Biomedical samples may be used to determine human exposure to nerve agents through the analysis of specific biomarkers. Samples received may include serum, plasma, whole blood, lysed blood and, due to the toxicity of these compounds, postmortem blood. To quantitate metabolites resulting from exposure to sarin (GB), soman (GD), cyclosarin (GF), VX and VR, these blood matrices were evaluated individually for precision, accuracy, sensitivity and specificity. Accuracies for these metabolites ranged from 100 to 113% with coefficients of variation ranging from 2.31 to 13.5% across a reportable range of 1-100 ng/mL meeting FDA recommended guidelines for bioanalytical methods in all five matrices. Limits of detection were calculated to be 0.09-0.043 ng/mL, and no interferences were detected in unexposed matrix samples. The use of serum calibrators was also determined to be a suitable alternative to matrix-matched calibrators. Finally, to provide a comparative value between whole blood and plasma, the ratio of the five nerve agent metabolites measured in whole blood versus plasma was determined. Analysis of individual whole blood samples (n = 40), fortified with nerve agent metabolites across the reportable range, resulted in average nerve agent metabolite blood to plasma ratios ranging from 0.53 to 0.56. This study demonstrates the accurate and precise quantitation of nerve agent metabolites in serum, plasma, whole blood, lysed blood and postmortem blood. It also provides a comparative value between whole blood and plasma samples, which can assist epidemiologists and physicians with interpretation of test results from blood specimens obtained under variable conditions.

Over the past decade, a focus on de novo mutations has rapidly accelerated gene discovery in autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental disorders (NDDs). However, recent studies suggest that only a minority of cases are attributable to de novo mutations, and instead these disorders often result from an accumulation of various forms of genetic risk. Consequently, we adopted an inclusive approach to investigate the genetic risk contributing to a case of male monozygotic twins with ASD and ID. At the time of the study, the probands were 7 yr old and largely nonverbal. Medical records indicated a history of motor delays, sleep difficulties, and significant cognitive deficits. Through whole-genome sequencing of the probands and their parents, we uncovered elevated common polygenic risk, a coding de novo point mutation in CENPE, an ultra-rare homozygous regulatory variant in ANK3, inherited rare variants in NRXN3, and a maternally inherited X-linked deletion situated in a noncoding regulatory region between ZNF81 and ZNF182. Although each of these genes has been directly or indirectly associated with NDDs, evidence suggests that no single variant adequately explains the probands’ phenotype. Instead, we propose that the probands’ condition is due to the confluence of multiple rare variants in the context of a high-risk genetic background. This case emphasizes the multifactorial nature of genetic risk underlying most instances of NDDs and aligns with the “female protective model” of ASD.

Organophosphorus nerve agent (OPNA) adducts to butyrylcholinesterase (BChE) can be used to confirm exposure in humans. A highly accurate method to detect G-series and V-series OPNA adducts to BChE in 75 μL of filtered blood, serum, or plasma has been developed using immunomagnetic separation (IMS) coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS). The reported IMS method captures > 88% of the BChE in a specimen and corrects for matrix effects on peptide calibrators. The optimized method has been used to quantify baseline BChE levels (unadducted and OPNA-adducted) in a matched set of serum, plasma and whole blood (later processed in-house for plasma content) from 192 unexposed individuals to determine the interchangeability of the tested matrices. The results of these measurements demonstrate the ability to accurately measure BChE regardless of the format of the blood specimen received. Criteria for accepting or denying specimens were established through a series of sample stability and processing experiments. The results of these efforts are an optimized and rugged method that is transferrable to other laboratories and an increased understanding of the BChE biomarker in matrix.

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

Here, we report an enhanced throughput method for the diagnosis of human exposure to sulfur mustard. A hydroxyethylthioethyl (HETE) ester-adducted tripeptide, produced by pronase digestion of human serum albumin, was selected as the quantitative exposure biomarker. Cibacron Blue enrichment was developed from an established cartridge method into a 96-well plate format, increasing throughput and ruggedness. This new method decreased sample volume 2.5-fold. Addition of a precipitation and solid-phase extraction concentration step increased the sensitivity of the method. With the conversion to a 96-well plate and optimization of chromatography, the method resulted in a 3-fold decrease in analysis time. Inclusion of a confirmation ion has increased specificity. The method was found to be linear between 0.050 and 50 mM sulfur mustard exposure with a precision for both quality control samples of ≤6.5% relative standard deviation and an accuracy of >96%. The limit of detection (3So) was calculated to be ~0.0048 mM, an exposure value similar to that of the HETE-albumin adduct method first described by Noort and coworkers (Noort et al., 1999; Noort el al., 2004) which used protein precipitation to isolate albumin. A convenience set of 124 plasma samples from healthy unexposed individuals was analyzed using this method to assess background levels of exposure to sulfur mustard; no positive results were detected. © The Author [2013]. Published by Oxford University Press. All rights reserved.

Sirtuin 2 (SIRT2) is a sirtuin family deacetylase that directs acetylome signaling, protects genome integrity, and is a murine tumor suppressor. We show that SIRT2 directs replication stress responses by regulating the activity of cyclin-dependent kinase 9 (CDK9), a protein required for recovery from replication arrest. SIRT2 deficiency results in replication stress sensitivity, impairment in recovery from replication arrest, spontaneous accumulation of replication protein A to foci and chromatin, and a G2/M checkpoint deficit. SIRT2 interacts with and deacetylates CDK9 at lysine 48 in response to replication stress in a manner that is partially dependent on ataxia telangiectasia and Rad3 related (ATR) but not cyclin T or K, thereby stimulating CDK9 kinase activity and promoting recovery from replication arrest. Moreover, wild-type, but not acetylated CDK9, alleviates the replication stress response impairment of SIRT2 deficiency. Collectively, our results define a function for SIRT2 in regulating checkpoint pathways that respond to replication stress through deacetylation of CDK9, providing insight into how SIRT2 maintains genome integrity and a unique mechanism by which SIRT2 may function, at least in part, as a tumor suppressor protein.

Chlorine is a public health concern and potential threat due to its high reactivity, ease and scale of production, widespread industrial use, bulk transportation, massive stockpiles, and history as a chemical weapon. This work describes a new, sensitive, and rapid stable isotope dilution method for the retrospective detection and quantitation of two chlorine adducts. The biomarkers 3-chlorotyrosine (Cl-Tyr) and 3,5-dichlorotyrosine (Cl2-Tyr) were isolated from the pronase digest of chlorine exposed whole blood, serum, or plasma by solid phase extraction (SPE), separated by reversed-phase HPLC, and detected by tandem mass spectrometry (MS/MS). The calibration range is 2.50–1000 ng/ml (R2 ≥ 0.998) with a lowest reportable limit (LRL) of 2.50 ng/mL for both analytes, an accuracy of ≥ 93%, and an LOD of 0.443 ng/mL for Cl-Tyr and 0.396 ng/mL for Cl2-Tyr. Inter- and intra-day precision of quality control samples had coefficients of variation of ≤ 10% and ≤ 7.0%, respectively. Blood and serum samples from 200 healthy individuals and 175 individuals with chronic inflammatory disease were analyzed using this method to assess background levels of chlorinated tyrosine adducts. Results from patients with no known inflammatory disease history (healthy) showed baseline levels of

Dried matrix spots are safer to handle and easier to store than wet blood products, but factors such as intraspot variability and unknown sample volumes have limited their appeal as a sampling format for quantitative analyses. In this work, we introduce a dried spot activity assay for quantifying butyrylcholinesterase (BChE) specific activity which is BChE activity normalized to the total protein content in a sample spot. The method was demonstrated with blood, serum, and plasma spotted on specimen collection devices (cards) which were extracted to measure total protein and BChE activity using a modified Ellman assay. Activity recovered from dried spots was ∼80% of the initial spotted activity for blood and90% for plasma and serum. Measuring total protein in the sample and calculating specific activity substantially improved quantification and reduced intraspot variability. Analyte stability of nerve agent adducts was also evaluated, and the results obtained via BChE-specific activity measurements were confirmed by quantification of BChE adducts using a previously established LC-MS/MS method. The spotted samples were up to 10 times more resistant to degradation compared to unspotted control samples when measuring BChE inhibition by the nerve agents sarin and VX. Using this method, both BChE activity and adducts can be accurately measured from a dried sample spot. This use of a dried sample spot with normalization to total protein is robust, demonstrates decreased intraspot variability without the need to control for initial sample volume, and enhances analyte stability.

Tri-ortho-cresyl phosphate (ToCP) is an anti-wear, flame retardant additive used in industrial lubricants, hydraulic fluids and gasoline. The neurotoxic effects of ToCP arise from the liver-activated metabolite 2-(o-cresyl)-4H-1,3,2-benzodioxaphosphoran-2-one (cresyl saligenin phosphate or CBDP), which inhibits esterase enzymes including butyrylcholinesterase (BChE). Following BChE adduction, CBDP undergoes hydrolysis to form the aged adduct ortho-cresyl phosphoserine (oCP-BChE), thus providing a biomarker of CBDP exposure. Previous studies have identified ToCP in aircraft cabin and cockpit air, but assessing human exposure has been hampered by the lack of a laboratory assay to confirm exposure. This work presents the development of an immunomagnetic-UHPLC-MS/MS method for the quantitation of unadducted BChE and the long-term CBDP biomarker, oCP-BChE, in human serum. The method has a reportable range from 2.0 ng/ml to 150 ng/ml, which is consistent with the sensitivity of methods used to detect organophosphorus nerve agent protein adducts. The assay demonstrated high intraday and interday accuracy (≥85%) and precision (RSD ≤ 15%) across the calibration range. The method was developed for future analyses of potential human exposure to CBDP. Analysis of human serum inhibited in vitro with CBDP demonstrated that the oCP-BChE adduct was stable for at least 72 h at 4, 22 and 37 °C. Compared to a previously reported assay, this method requires 75% less sample volume, reduces analysis time by a factor of 20 and demonstrates a threefold improvement in sensitivity. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Sulfur mustard binds to reactive cysteine residues, forming a stable sulfur-hydroxyethylthioethyl [S-HETE] adduct that can be used as a long-term biomarker of sulfur mustard exposure in humans. The digestion of sulfur mustard-exposed blood samples with proteinase K following total protein precipitation with acetone produces the tripeptide biomarker [S-HETE]-Cys-Pro-Phe. The adducted tripeptide is purified by solid phase extraction, separated by ultra-high pressure liquid chromatography, and detected by isotope dilution tandem mass spectrometry. This approach was thoroughly validated and characterized in our laboratory. The average interday relative standard deviation was ≤ 9.49%, and the range of accuracy was between 96.1-109% over a concentration range of 3.00 to 250. ng/mL with a calculated limit of detection of 1.74 ng/mL. A full 96-well plate can be processed and analyzed in 8 h which is five times faster than our previous 96-well plate method and only requires 50 µL of serum, plasma, or whole blood. Extensive ruggedness and stability studies and matrix comparisons were conducted to create a robust, easily transferrable method. As a result, a simple and high-throughput method has been developed and validated for the quantitation of sulfur mustard blood protein adducts in low volume blood specimens which should be readily adaptable for quantifying human exposures to other alkylating agents.

Objectives: Electronic cigarette (e-cigarette) use is increasing in the U.S. Although marketed as a safer alternative for cigarettes, initial evidence suggests that e-cigarettes may pose a secondhand exposure risk. The current study explored the prevalence and correlates of support for e-cigarette bans. Methods: A sample of 265 current/former smokers completed a cross-sectional telephone survey from June–September 2014, 45% Black, 31% White, 21% Hispanic. Items assessed support for home and workplace bans for cigarettes and e-cigarettes and associated risk perceptions. Results: Most participants were aware of e-cigarettes (99%). Results demonstrated less support for complete e-cigarette bans in homes and workplaces compared to cigarettes. Support for complete e-cigarette bans was strongest among older, higher income, married respondents, and former smokers. Complete e-cigarette bans were most strongly endorsed when perceptions of addictiveness and health risks were high. While both e-cigarette lifetime and never-users strongly supported cigarette smoking bans, endorsement for e-cigarette bans varied by lifetime use and intentions to use e-cigarettes. Conclusions: Support for indoor e-cigarette bans is relatively low among individuals with a smoking history. Support for e-cigarette bans may change as evidence regarding their use emerges. These findings have implications for public health policy.

This work describes a new specific, sensitive, and rapid stable isotope dilution method for the simultaneous detection of the organophosphorus nerve agents (OPNAs) tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), VR, VX, and VM adducts to tyrosine (Tyr). Serum, plasma, and lysed whole blood samples (50 μL) were prepared by protein precipitation followed by digestion with Pronase. Specific Tyr adducts were isolated from the digest by a single solid phase extraction (SPE) step, and the analytes were separated by reversed-phase ultra high performance liquid chromatography (UHPLC) gradient elution in less than 2 min. Detection was performed on a triple quadrupole tandem mass spectrometer using time-triggered selected reaction monitoring (SRM) in positive electrospray ionization (ESI) mode. The calibration range was characterized from 0.100-50.0 ng/mL for GB- and VR-Tyr and 0.250-50.0 ng/mL for GA-, GD-, GF-, and VX/VM-Tyr (R(2) ≥ 0.995). Inter- and intra-assay precision had coefficients of variation of ≤17 and ≤10%, respectively, and the measured concentration accuracies of spiked samples were within 15% of the targeted value for multiple spiking levels. The limit of detection was calculated to be 0.097, 0.027, 0.018, 0.074, 0.023, and 0.083 ng/mL for GA-, GB-, GD-, GF-, VR-, and VX/VM-Tyr, respectively. A convenience set of 96 serum samples with no known nerve agent exposure was screened and revealed no baseline values or potential interferences. This method provides a simple and highly specific diagnostic tool that may extend the time postevent that a confirmation of nerve agent exposure can be made with confidence.