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Nature exposure has been linked to a plethora of health benefits, but the mechanism for this effect is not well understood. We conducted two studies to test a new model linking the health benefits of nature exposure to reduced impulsivity in decision-making (as measured by delay discounting) via psychologically expanding space perception. In study 1 we collected a nationwide U.S. sample (n = 609) to determine whether nature exposure was predictive of health outcomes and whether impulsive decision-making mediated the effect. Results indicated that Nature Accessibility and Nature Exposure From Home significantly predicted reduced scores on the Depression, Anxiety, Stress Scales (DASS) (p < .001, p = .03, respectively) and improved general health and wellbeing (p < .001, p < .01, respectively). Nature Accessibility also predicted reduced impulsive decision-making (p < .01), and Nature Accessibility showed significant indirect effects through impulsive decision-making on both the DASS (p = .02) and general health and wellbeing (p = .04). In Study 2, a lab-based paradigm found that nature exposure expanded space perception (p < .001), and while the indirect effect of nature exposure through space perception on impulsive decision-making did not meet conventional standards of significance (p < .10), the pattern was consistent with hypotheses. This combination of ecologically-valid and experimental methods offers promising support for an impulsivity-focused model explaining the nature-health relationship. [ABSTRACT FROM AUTHOR]

Objective: Pakistan has a high pediatric burden of tuberculosis, but few studies describe the treatment experience of children with tuberculosis in Pakistan. We sought to identify risk factors for unsuccessful treatment outcomes in children with drug-susceptible tuberculosis identified in eight hospitals in Karachi, Pakistan. Design: We conducted a retrospective cohort study among children (<15 years old) treated with first-line anti-tuberculosis drugs for presumed or confirmed drug-susceptible tuberculosis between 2016 and 2017. We assessed risk factors for experiencing an unsuccessful treatment outcome through multivariable logistic regression analysis. Results: In total, 1,665 children initiated tuberculosis treatment, including 916 (55.0%) identified through intensified case finding. Unsuccessful treatment outcomes were experienced by 197 (11.8%) children, comprising 27 (1.6%) deaths, 16 (1.0%) treatment failures, and 154 (9.3%) lost to follow-up. An additional 47 (2.8%) children had outcomes not evaluable. In multivariable analysis, children 0–4 years old (OR: 1.80, 95% CI: 1.07–3.04), males (OR: 1.48, 95% CI: 1.04, 2.11), and those with bacteriologic confirmation of disease (OR: 3.39, 95% CI: 1.98, 5.80) had increased odds of experiencing an unsuccessful treatment outcome. Conclusion: Our findings suggest a need to deploy strategies to identify children earlier in the disease process and point to the need for interventions tailored for young children once treatment is initiated. [ABSTRACT FROM AUTHOR]

Objective: To compare the diagnostic performance of the GenoType MRBDRplus assay with the gold standard phenotypic drug susceptibility testing in the detection of drug resistance among culture isolates obtained from patients in Karachi, Pakistan. Design: Mycobacterium tuberculosis isolates were obtained from 96 consecutive tuberculosis patients found to have resistance to isoniazid from two health centers in Karachi (January-November 2017). Isolates were tested for drug resistance against rifampin and isoniazid using the MTBDRplus assay. Results were compared with conventional drug-susceptibility testing and the frequency of specific mutations were reported. Results: The MTBDRplus assay had a sensitivity for rifampin resistance of 98.8% (95% CI: 93.4–100) and for isoniazid resistance of 90.6% (95% CI: 83.0–95.6). The MTBDRplus assay showed mutations in rpoB in 81 of the 96 (84.4%) isolates. Of the 87 isolates showing resistance to isoniazid via the MTBDRplus assay, 71 (74.0%) isolates had mutations in the katG gene only, 15 (15.6%) isolates had mutations in the inhA promoter region, and 1 (1.0%) showed mutations in both genes. Conclusion: The GenoType MTBDRplus assay in Pakistan can identify subgroups at high-risk of having isolates with mutations in the katG and/or inhA genes. Understanding the local burden of these mutations have implications for local diagnostic and treatment guidelines. [ABSTRACT FROM AUTHOR]

Trichomonas vaginalis is the most common curable sexually transmitted infection (STI) worldwide. Although predominately asymptomatic, the disease spectrum of trichomoniasis in women is characterized primarily by signs and symptoms of vaginitis, including purulent discharge and localized vulvar pruritus and erythema. Several FDA-cleared nucleic acid amplification tests (NAATs) are available for the diagnosis of T. vaginalis infections, but laboratory developed tests (LDTs) are widely utilized and cost-effective solutions in both the research and clinical diagnostic settings. LDT diagnosis of T. vaginalis is particularly appealing since it can be performed using remnant specimens collected for other STI testing. Using a LDT implemented as part of this study, T. vaginalis was detected in 7% of participating Louisiana women (14/199). The mean T. vaginalis organism burden was 1.0x106 ± 4.5x105 organisms per mL of ThinPrep PreservCyt. Using DNA eluates obtained after HPV testing on the cobas 4800 system, the T. vaginalis LDT was characterized by excellent intra- and interassay reproducibility (coefficient of variation values all <3.5%). Compared with two commercially available NAATs from TIB MOLBIOL, the sensitivity and specificity of the LDT was 92.9 and 99.5%, respectively. Collectively, this study details the diagnostic and quantitative utility of a LDT for T. vaginalis. When applied in the clinical research setting, we confirmed the high prevalence of T. vaginalis, but also observed extraordinarily high organism burdens in the cervix. These findings highlight the unique host-pathogen relationship of T. vaginalis with lower reproductive tract tissues, and substantiate the need for continued investigation of this highly prevalent STI. [ABSTRACT FROM AUTHOR]

Miscarriage occurs in up to one in four pregnancies and can be a devastating event affecting both men and women. Unfortunately, the male partner’s experience of miscarriage is seldom researched, particularly within Australia. This qualitative study involved semi-structured telephone interviews with 10 Australian men, whose partners miscarried between three months and ten years ago. Participants were recruited through professional networks and support organisations. Interviews explored men’s general miscarriage experience and the support received or lacking from both healthcare providers and social networks. Online health seeking behaviour and opinions on online support were also discussed. Data was transcribed verbatim and analysed thematically. Most men described feeling significant grief following miscarriage and felt that there was little acknowledgment of their loss, both from healthcare providers and within their social networks. Feelings of sadness, devastation, powerlessness, fear, shock and a loss of identity were common. All men felt their primary role at the time of miscarriage was to support their partner. Most men did not want to burden their partner with their emotions or grief, and struggled to find people within their social networks to talk to about their loss, leading to feelings of isolation. Overall participants felt there was inadequate support offered to men affected by miscarriage. Men wanted information, informed professionals to talk to and male-orientated support networks. A website was one mechanism suggested by men which could adequately contribute to information and support needs during this time. Men are often greatly affected by miscarriage and yet there is all too often little acknowledgement or support available to them at this time. Men affected by miscarriage want and need further support, including reputable, Australian based information and resources tailored their needs. [ABSTRACT FROM AUTHOR]

Suburbanization is happening rapidly on a global scale, resulting in changes to the species assemblages present in previously undeveloped areas of land. Community-level changes after anthropogenic land-use change have been studied in a variety of organisms, but the effects on arthropods of medical and veterinary importance remain poorly characterized. Shifts in diversity, abundance, and community composition of such arthropods, like mosquitoes, can significantly impact vector-borne disease dynamics due to varying vectorial capacity between different species. In light of these potential implications for vector-borne diseases, we investigated changes in mosquito species assemblage after suburbanization by sampling mosquitoes in neighborhoods of different ages in Wake County, North Carolina, US. We found that independent of housing density and socioeconomic status, mosquito diversity measures decreased as suburban neighborhoods aged. In the oldest neighborhoods, the mosquito assemblage reached a distinct suburban climax community dominated by the invasive, peridomestic container-breeding Aedes albopictus, the Asian tiger mosquito. Aedes albopictus is a competent vector of many pathogens of human concern, and its dominance in suburban areas places it in close proximity with humans, allowing for heightened potential of host-vector interactions. While further research is necessary to explicitly characterize the effects of mosquito community simplification on vector-borne disease transmission in highly suburbanized areas, the current study demonstrates that suburbanization is disrupting mosquito communities so severely that they do not recover their diversity even 100 years after the initial disturbance. Our understanding of the community-level effects of anthropogenic land-use change on arthropod vectors will become increasingly important as we look to mitigate disease spread in a global landscape that is continually developed and altered by humans. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease is common in patients with systemic lupus erythematosis (SLE) and lupus nephritis (LN). Up to 80% of children with SLE develop kidney disease, which is also associated with increased risk for cardiovascular disease and death compared to those without renal involvement. Hepcidin is an iron-regulatory protein which may contribute to atherosclerosis and is elevated in autoimmune disease. Pulse wave velocity (PWV) is a validated indicator of arterial stiffness, an early marker of cardiovascular risk, and is increased in children with SLE versus healthy controls. Our objective was to quantify hepcidin and PWV in children with SLE and investigate if those with biopsy-proven LN have higher hepcidin levels and higher PWV compared to those without kidney disease. Methods: Cross-sectional analysis with hepcidin was measured via ELISA assay in 16 children aged 10–21 years with SLE recruited from a single center. Subjects were classified as having LN if histologic evidence of the disease was documented on a clinical renal biopsy. Serum hepcidin was quantified using a validated competitive enzyme-linked immunoassay. Carotid-femoral PWV was measured using applanation tonometry. Wilcoxon rank sum testing was used to compare median levels of hepcidin, PWV, and other continuous variables by nephritis status. Results: The cohort (n = 16) was 93.8% female and 68.8% African-American with mean (SD) 16 (3.6) years. 37.5% (n = 6) had LN. Overall median (IQR) hepcidin was 34.4 (18.9, 91.9) ng/ml, and PWV 4.4 (4, 4.6) meters/second. Although significance was limited by small sample size, both hepcidin and PWV were higher in the subjects with LN. Median (IQR) hepcidin in subjects with LN was 71.5 (26.4, 116.4) ng/ml compared to 27.9 (18.7, 59.7) ng/ml in those with SLE(p = 0.19). Similarly, median (IQR) PWV in those with LN was 4.4 (4.4, 4.9) meters/second compared to 3 (3.75, 4.55) meters/second in those with without kidney involvement (p = 0.10). Conclusion: PWV and serum hepcidin were higher in subjects with LN compared to those with SLE alone, suggesting that elevated hepcidin levels may be associated with morbid CV changes in children with LN. This association, along with identification of additional predictors of arterial stiffness in patients with LN, warrants further investigation. [ABSTRACT FROM AUTHOR]

Interferon-induced transmembrane protein 3 (IFITM3) is a potent antiviral protein that enhances cellular resistance to a variety of pathogens, including influenza virus. Classically defined as an interferon-stimulated gene, expression of IFITM3 on cells is rapidly up-regulated in response to type I and II interferon. Here we found that IFITM3 is rapidly up-regulated by T cells following their activation and this occurred independently of type I and II interferon and the interferon regulatory factors 3 and 7. Up-regulation of IFITM3 on effector T cells protected these cells from virus infection and imparted a survival advantage at sites of virus infection. Our results show that IFITM3 expression on effector T cells is crucial for these cells to mediate their effector function and highlights an interferon independent pathway for the induction of IFITM3 which, if targeted, could be an effective approach to harness the activity of IFITM3 for infection prevention. [ABSTRACT FROM AUTHOR]

Parenting styles vary in levels of both warmth and control, with evidence that type of parenting behavior is linked with social-emotional and other developmental outcomes for children. There are well-established associations between adult attachment and parenting styles. Given emerging evidence that people with different attachment patterns vary in how they receive and modulate sensory information, there are potential implications for parenting which have rarely received research attention. This cross-sectional study investigates the links between parenting style and parental sensory sensitivity, and the possible mediating role of parental sensory sensitivity in the relationship between adult attachment and parenting styles. A convenience sample of 155 parents of children aged 4–12 years old completed an online survey measuring: adult attachment (Experiences in Close Relationships-Modified 16-item Scale), sensory sensitivity (Highly Sensitive Persons Scale-Shortened Version), and parenting styles (Parenting Styles and Dimensions Questionnaire). Correlation, regression and mediation analyses were conducted. Analyses revealed that parents who reported more attachment insecurity also reported higher levels of parental sensory sensitivity, and more authoritarian and/or permissive (non-optimal) parenting styles. Parental sensory sensitivity was found to fully mediate the relationship between attachment avoidance and permissive parenting, and to partially mediate the relationship between attachment anxiety and both authoritarian and permissive parenting. This study represents the first quantitative evidence for associations between parental sensory sensitivity and parenting styles, and the mediating effect of parental sensory sensitivity on the known relationship between attachment insecurity and parenting. Awareness of a parent’s level of sensory sensitivity, in addition to his/her attachment style, may assist in developing effective strategies to meet both the parent’s and child’s needs and support the parent-child relationship. [ABSTRACT FROM AUTHOR]

Objective: People living with HIV (PLWH) are living longer and developing comorbidities and aging-related syndromes. New care models are needed to address the combined burden and complexity of HIV and its comorbidities in this group. The goal of this study is to describe qualitative data from patients and providers that informed the development of a comprehensive care model for older PLWH. Methods: Patient and provider perspectives on the clinical care and service needs of patients living and aging with HIV were explored via surveys and focus groups at a safety net HIV clinic in San Francisco. We surveyed 77 patients and 26 providers and conducted separate focus groups of older patients living with HIV (n = 31) and staff (n = 20). Transcripts were analyzed using thematic analysis. Themes for a care program were additionally explored using findings from the literature on HIV and aging. Findings: Themes from surveys and focus groups emphasized (a) the need for knowledge expertise in HIV and aging, (b) focus on medical conditions and determinants of health of particular import (e.g. marginal housing) among older PLWH, (c) co-locating specialty services (e.g. cardiology, geriatrics) with primary care, and (d) addressing social isolation. Findings informed the design of a comprehensive, multidisciplinary care model for PLWH called the Golden Compass program composed of four “points”: Heart and Mind (North), Bones and Strength (East), Network and Navigation (South), and Dental, Hearing, and Vision (West). Conclusion: Based on patient and clinic staff perspectives from surveys and focus groups, we designed a multidisciplinary program of integrated primary and specialty care, as well as housing and social support, to address the needs of older PLWH within a safety-net infrastructure. Golden Compass launched in 2017 for PLWH older than 50 years. Future research to evaluate the effectiveness of this care program in improving patient outcomes and satisfaction is ongoing. [ABSTRACT FROM AUTHOR]

Background: Large and giant dog breeds have a high risk for gastric dilatation-volvulus (GDV) which is an acute, life-threatening condition. Previous work by our group identified a strong risk of GDV linked to specific alleles in innate and adaptive immune genes. We hypothesize that variation in the genes of the immune system act through modulation of the gut microbiome, or through autoimmune mechanisms, or both, to predispose dogs to this condition. Here, we investigate whether differences in the canine fecal microbiome are associated with GDV and are linked to previously identified risk alleles. Methodology/Principle findings: Fecal samples from healthy Great Danes (n = 38), and dogs with at least one occurrence of GDV (n = 37) were collected and analyzed by paired-end sequencing of the 16S rRNA gene. Dietary intake and temperament were estimated from a study-specific dietary and temperament questionnaire. Dogs with GDV had significantly more diverse fecal microbiomes than healthy control dogs. Alpha diversity was significantly increased in dogs with GDV, as well as dogs with at least one risk allele for DRB1 and TRL5. We found no significant association of dietary intake and GDV. Dogs with GDV showed a significant expansion of the rare lineage Actinobacteria (p = 0.004), as well as a significantly greater abundance of Firmicutes (p = 0.004) and a significantly lower abundance of Bacteroidetes (p<0.004). There was a significant difference in the abundance of 10 genera but after correction for multiple comparisons, none were significant. Bacterial phyla were significantly different between controls and dogs with GDV and at least one risk allele for DRB1 and TRL5. Actinobacteria were significantly higher in dogs with GDV and with one risk allele for DRB1 and TLR5 but not DLA88 genes. Furthermore, Collinsella was significantly increased in dogs with at least one risk allele for DRB1 and TLR5. Logistic regression showed that a model which included Actinobacteria, at least one risk allele,and temperament, explained 29% of the variation in risk of GDV in Great Danes. Conclusions: The microbiome in GDV was altered by an expansion of a minor lineage and was associated with specific alleles of both innate and adaptive immunity genes. These associations are consistent with our hypothesis that immune genes may play a role in predisposition to GDV by altering the gut microbiome. Further research will be required to directly test the causal relationships of immune genes, the gut microbiome and GDV. [ABSTRACT FROM AUTHOR]

A mixed-methods approach was used to evaluate and improve the “late-night dining” options in a university dining hall. Surveys assessed student desires for late-night offerings, and evaluated students’ habits and motivations during late-night dining. Two interventions were implemented to see if students could be “nudged” into different choice patterns. In the first, a “veggie-heavy” entrée was added at the beginning of the entrée line, so that students would substitute an entrée containing vegetables for the alternatives. In the second, a snack-food bar was set up to cater to students who didn’t want to stand in the long entrée line, and preferred a snack. Data on food choice was collected during the interventions. Survey responses showed significant differences in the reasons females and males utilized late-night dining (p<0.001). We also found that students at late-night dining had a lower emphasis on health than the general student population. Even students at late-night who reported being health-conscious showed no difference in food selections from students who said health was not important (p = 0.883). Veggie-heavy entrées had mild success in increasing vegetable selection. However, veggie-heavy entrées were largely ignored when the other option was chicken nuggets. The snack bar was very popular. Entrée placement and convenience lines may have mild impacts on food selection in a late-night dining environment. [ABSTRACT FROM AUTHOR]

Improving diet quality while simultaneously reducing environmental impact is a critical focus globally. Metrics linking diet quality and sustainability have typically focused on a limited suite of indicators, and have not included food waste. To address this important research gap, we examine the relationship between food waste, diet quality, nutrient waste, and multiple measures of sustainability: use of cropland, irrigation water, pesticides, and fertilizers. Data on food intake, food waste, and application rates of agricultural amendments were collected from diverse US government sources. Diet quality was assessed using the Healthy Eating Index-2015. A biophysical simulation model was used to estimate the amount of cropland associated with wasted food. This analysis finds that US consumers wasted 422g of food per person daily, with 30 million acres of cropland used to produce this food every year. This accounts for 30% of daily calories available for consumption, one-quarter of daily food (by weight) available for consumption, and 7% of annual cropland acreage. Higher quality diets were associated with greater amounts of food waste and greater amounts of wasted irrigation water and pesticides, but less cropland waste. This is largely due to fruits and vegetables, which are health-promoting and require small amounts of cropland, but require substantial amounts of agricultural inputs. These results suggest that simultaneous efforts to improve diet quality and reduce food waste are necessary. Increasing consumers’ knowledge about how to prepare and store fruits and vegetables will be one of the practical solutions to reducing food waste. [ABSTRACT FROM AUTHOR]

Environmental DNA (eDNA) is revolutionizing biodiversity monitoring, occupancy estimates, and real-time detections of invasive species. In the Great Lakes, the round goby (Neogobius melanostomus), an invasive benthic fish from the Black Sea, has spread to encompass all five lakes and many tributaries, outcompeting or consuming native species; however, estimates of round goby abundance are confounded by behavior and habitat preference, which impact reliable methods for estimating their population. By integrating eDNA into round goby monitoring, improved estimates of biomass may be obtainable. We conducted mesocosm experiments to estimate rates of goby DNA shedding and decay. Further, we compared eDNA with several methods of traditional field sampling to compare its use as an alternative/complementary monitoring method. Environmental DNA decay was comparable to other fish species, and first-order decay was lower at 12°C (k = 0.043) than at 19°C (k = 0.058). Round goby eDNA was routinely detected in known invaded sites of Lake Michigan and its tributaries (range log10 4.8–6.2 CN/L), but not upstream of an artificial fish barrier. Traditional techniques (mark-recapture, seining, trapping) in Lakes Michigan and Huron resulted in fewer, more variable detections than eDNA, but trapping and eDNA were correlated (Pearson R = 0.87). Additional field testing will help correlate round goby abundance with eDNA, providing insight on its role as a prey fish and its impact on food webs. [ABSTRACT FROM AUTHOR]

Background: Recent influenza surveillance data from Africa suggest an important burden of influenza-associated morbidity and mortality. In tropical countries where influenza virus transmission may not be confined to a single season alternative strategies for vaccine distribution via antenatal care (ANC) or semiannual campaigns should be considered. Methods: Using data on monthly influenza disease burden in women of child-bearing age and infants aged 0–5 months in Kenya from 2010–2014, we estimated the number of outcomes (illnesses, medical visits, hospitalizations, and deaths) that occurred and that may have been averted through influenza vaccination of pregnant women using: 1) a year-round immunization strategy through ANC, 2) annual vaccination campaigns, and 3) semiannual vaccination campaigns. Results: During 2010–2014, influenza resulted in an estimated 279,047 illnesses, 36,276 medical visits, 1612 hospitalizations and 243 deaths in pregnant women and 157,053 illnesses, 65,177 medical visits, 4197 hospitalizations, and 755 deaths in infants aged 0–5 months in Kenya. Depending on the mode of distribution and the vaccine coverage achieved, 12.8–31.4% of influenza-associated disease in pregnant women and 11.6–22.1% in infants aged 0–5 months might have been prevented through maternal influenza immunization. In this model, point estimates for influenza-associated disease averted through maternal vaccination delivered year-round in ANC or semiannually in campaigns were higher than vaccination delivered in a single annual campaign, but confidence intervals overlapped. Conclusions: Vaccinating pregnant women against influenza can reduce the burden of influenza-associated illness, hospitalization and death in both pregnant women and their young infants. Alternative immunization strategies may avert more influenza-associated disease in countries where influenza virus transmission occurs throughout the year. [ABSTRACT FROM AUTHOR]

Breast density is associated with reduced imaging resolution in the detection of breast cancer. A biochemical approach that is not affected by density would provide an important tool to healthcare professionals who are managing women with dense breasts and suspicious imaging findings. Videssa® Breast is a combinatorial proteomic biomarker assay (CPBA), comprised of Serum Protein Biomarkers (SPB) and Tumor Associated Autoantibodies (TAAb) integrated with patient-specific clinical data to produce a diagnostic score that reliably detects breast cancer (BC) as an adjunctive tool to imaging. The performance of Videssa® Breast was evaluated in the dense (a and b) and non-dense (c and d) groups in a population of n = 545 women under age 50. The sensitivity and specificity in the dense breast group were calculated to be 88.9% and 81.2%, respectively, and 92.3% and 86.6%, respectively, for the non-dense group. No significant differences were observed in the sensitivity (p = 1.0) or specificity (p = 0.18) between these groups. The NPV was 99.3% and 99.1% in non-dense and dense groups, respectively. Unlike imaging, Videssa® Breast does not appear to be impacted by breast density; it can effectively detect breast cancer in women with dense and non-dense breasts alike. Thus, Videssa® Breast provides a powerful tool for healthcare providers when women with dense breasts present with challenging imaging findings. In addition, Videssa® Breast provides assurance to women with dense breasts that they do not have breast cancer, reducing further anxiety in this higher risk patient population. [ABSTRACT FROM AUTHOR]

Introduction: Management of persistently non-adherent youth living with HIV (YLHIV) with virologic failure (VF) on combination antiretroviral therapy (cART) remains challenging. One strategy has been using 3TC/ FTC monotherapy (3TC/FTC), which in the presence of the M184V resistance mutation, does not suppress viral replication nor select for additional drug resistance mutations, and reduces viral fitness with limited side effects. P1094 compared the immunologic outcome of continuing failing cART vs. switching to 3TC/FTC as a “bridging strategy” to subsequent suppressive cART for non-adherent YLHIV with pre-existing M184V resistance. Materials & methods: Participants with documented nonadherence, M184V mutation, CD4+ T cell count ≥100 cells/mm3 and VF (HIV-1 plasma RNA ≥400 copies/mL (2.6 log10 HIV-1 RNA) were enrolled and randomized to continue failing cART vs. switch to 3TC/FTC. The primary endpoint (time to ≥30% CD4+ T cell decline or development of CDC class C events) at 28-weeks were assessed by Kaplan-Meier (K-M) curves in an intent-to-treat analysis. Results: Thirty-three perinatally acquired YLHIV participants (16 continuing cART and 17 3TC/FTC) enrolled in the study. The median age, entry CD4+ T cell count, and viral load were 15 years (Inter-quartile range (IQR) 14–20), 472 cells/mm3 (IQR 384–651), and 4.0 log10HIV-1 RNA copies/ml (IQR 3.2–4.5), respectively. Five participants, all in the 3TC/FTC arm, reached the primary endpoint for absolute CD4+ T cell decline (p = 0.02, exact log-rank test comparing monotherapy to cART). The Kaplan-Meier estimate of probability of primary endpoint on 3TC/FTC at 28 weeks was 0.41 (standard error 0.14). There were no CDC class C events or deaths and no statistically significant difference in frequencies of adverse events between the arms. Conclusions: Non-adherent participants randomized to 3TC/FTC were more likely than those maintained on failing cART to experience a confirmed decline in CD4+ count of ≥30%. Although this study suffers from limitations of small sample size and premature discontinuation, the randomized comparison to continuing failing cART indicates that 3TC/FTC provides inferior protection from immunologic deterioration for non-adherent youth with M184V resistance. Better alternatives to 3TC/FTC such as ART with higher barriers to resistance and novel adherence and treatment strategies for nonadherent youth are urgently needed. Trial registration: Clinical Trials.gov [ABSTRACT FROM AUTHOR]

Background: Age-disparate partnerships are hypothesized to increase HIV-risk for young women. However, the evidence base remains mixed. Most studies have focused only on unprotected sex among women in the partnership. Consequently, little is known about other risky behaviours, such as transactional sex, alcohol use, and concurrency, as well as the behaviours of the men who partner with young women. We therefore examined differences in various sexual behaviours of both young women and their male partners by partnership age difference. Methods: We used nationally representative data from South Africa (2012) on partnerships reported by 16–24 year old black African women (n = 818) and by black African men in partnerships with 16–24 year old women (n = 985). We compared sexual behaviours in age-disparate partnerships and age-similar partnerships, using multiple logistic regression to control for potential confounders and to assess rural/urban differences. Results: Young women in age-disparate partnerships were more likely to report unprotected sex than young women in similar-aged partnerships (aOR:1.51; p = 0.014; 95%CI:1.09–2.11). Men in partnerships with young women were more likely to report unprotected sex (aOR:1.92; p<0.01; 95%CI:1.31–2.81), transactional sex (aOR:2.73; p<0.01; 95%CI:1.64–4.56), drinking alcohol before sex (aOR:1.60; p = 0.062; 95%CI:0.98–2.61), and concurrency (aOR:1.39; p = 0.097; 95%CI:0.94–2.07) when their partners were five or more years younger. The association between age-disparate partnerships and transactional sex (aOR:4.14; p<0.01; 95%CI: 2.03–8.46) and alcohol use (aOR:2.24; p<0.013; 95%CI:1.20–4.19) was only found in urban areas. Conclusions: Results provide evidence that young women’s age-disparate partnerships involve greater sexual risk, particularly through the risky behaviours of their male partners, with the risk amplified for young women in urban areas. [ABSTRACT FROM AUTHOR]

Despite significant advances in breast imaging, the ability to accurately detect Breast Cancer (BC) remains a challenge. With the discovery of key biomarkers and protein signatures for BC, proteomic technologies are currently poised to serve as an ideal diagnostic adjunct to imaging. Research studies have shown that breast tumors are associated with systemic changes in levels of both serum protein biomarkers (SPB) and tumor associated autoantibodies (TAAb). However, the independent contribution of SPB and TAAb expression data for identifying BC relative to a combinatorial SPB and TAAb approach has not been fully investigated. This study evaluates these contributions using a retrospective cohort of pre-biopsy serum samples with known clinical outcomes collected from a single site, thus minimizing potential site-to-site variation and enabling direct assessment of SPB and TAAb contributions to identify BC. All serum samples (n = 210) were collected prior to biopsy. These specimens were obtained from 18 participants with no evidence of breast disease (ND), 92 participants diagnosed with Benign Breast Disease (BBD) and 100 participants diagnosed with BC, including DCIS. All BBD and BC diagnoses were based on pathology results from biopsy. Statistical models were developed to differentiate BC from non-BC (i.e., BBD and ND) using expression data from SPB alone, TAAb alone, and a combination of SPB and TAAb. When SPB data was independently used for modeling, clinical sensitivity and specificity for detection of BC were 74.7% and 77.0%, respectively. When TAAb data was independently used, clinical sensitivity and specificity for detection of BC were 72.2% and 70.8%, respectively. When modeling integrated data from both SPB and TAAb, the clinical sensitivity and specificity for detection of BC improved to 81.0% and 78.8%, respectively. These data demonstrate the benefit of the integration of SPB and TAAb data and strongly support the further development of combinatorial proteomic approaches for detecting BC. [ABSTRACT FROM AUTHOR]

Research across groups and methods consistently finds a gender difference in patterns of specificity of genital response; however, empirically supported mechanisms to explain this difference are lacking. The information-processing model of sexual arousal posits that automatic and controlled cognitive processes are requisite for the generation of sexual responses. Androphilic women’s gender-nonspecific response patterns may be the result of sexually-relevant cues that are common to both preferred and nonpreferred genders capturing attention and initiating an automatic sexual response, whereas men’s attentional system may be biased towards the detection and response to sexually-preferred cues only. In the present study, we used eye tracking to assess visual attention to sexually-preferred and nonpreferred cues in a sample of androphilic women and gynephilic men. Results support predictions from the information-processing model regarding gendered processing of sexual stimuli in men and women. Men’s initial attention patterns were gender-specific, whereas women’s were nonspecific. In contrast, both men and women exhibited gender-specific patterns of controlled attention, although this effect was stronger among men. Finally, measures of attention and self-reported attraction were positively related in both men and women. These findings are discussed in the context of the information-processing model and evolutionary mechanisms that may have evolved to promote gendered attentional systems. [ABSTRACT FROM AUTHOR]

Dyskeratosis Congenita (DC) is an inherited multisystem premature aging disorder with characteristic skin and mucosal findings as well as a predisposition to cancer and bone marrow failure. DC arises due to gene mutations associated with the telomerase complex or telomere maintenance, resulting in critically shortened telomeres. The pathogenesis of DC, as well as several congenital bone marrow failure (BMF) syndromes, converges on the DNA damage response (DDR) pathway and subsequent elevation of reactive oxygen species (ROS). Historically, DC patients have had poor outcomes following bone marrow transplantation (BMT), perhaps as a consequence of an underlying DNA hypersensitivity to cytotoxic agents. Previously, we demonstrated an activated DDR and increased ROS, augmented by chemotherapy and radiation, in somatic cells isolated from DC patients with a mutation in the RNA component of telomerase, TERC. The current study was undertaken to determine whether previous findings related to ROS and DDR in TERC patients’ cells could be extended to other DC mutations. Of particular interest was whether an antioxidant approach could counter increased ROS and decrease DC pathologies. To test this, we examined lymphocytes from DC patients from different DC mutations (TERT, TINF2, and TERC) for the presence of an active DDR and increased ROS. All DC mutations led to increased steady-state p53 (2-fold to 10-fold) and ROS (1.5-fold to 2-fold). Upon exposure to ionizing radiation (XRT), DC cells increased in both DDR and ROS to a significant degree. Exposing DC cells to hydrogen peroxide also revealed that DC cells maintain a significant oxidant burden compared to controls (1.5-fold to 3-fold). DC cell culture supplemented with N-acetylcysteine, or alternatively grown in low oxygen, afforded significant proliferative benefits (proliferation: maximum 2-fold increase; NAC: 5-fold p53 decrease; low oxygen: maximum 3.5-fold p53 decrease). Together, our data supports a mechanism whereby telomerase deficiency and subsequent shortened telomeres initiate a DDR and create a pro-oxidant environment, especially in cells carrying the TINF2 mutations. Finally, the ameliorative effects of antioxidants in vitro suggest this could translate to therapeutic benefits in DC patients. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is an extremely aggressive disease, commonly displaying therapy-resistant relapse. We have previously identified neuroendocrine and epithelial phenotypes in SCLC tumours and the neuroendocrine marker, pro-opiomelanocortin (POMC), correlated with worse overall survival in patients. However, the effect of treatment on these phenotypes is not understood. The current study aimed to determine the effect of repeated irradiation treatment on SCLC cell phenotype, focussing on the neuroendocrine marker, POMC. Results: Human SCLC cells (DMS 79) were established as subcutaneous xenograft tumours in CBA nude mice and then exposed to repeated 2Gy irradiation. In untreated animals, POMC in the blood closely mirrored tumour growth; an ideal characteristic for a circulating biomarker. Following repeated localised irradiation in vivo, circulating POMC decreased (p< 0.01), in parallel with a decrease in tumour size, but remained low even when the tumours re-established. The excised tumours displayed reduced and distinctly heterogeneous expression of POMC compared to untreated tumours. There was no difference in the epithelial marker, cytokeratin. However, there were significantly more N-cadherin positive cells in the irradiated tumours. To investigate the tumour response to irradiation, DMS79 cells were repeatedly irradiated in vitro and the surviving cells selected. POMC expression was reduced, while mesenchymal markers N-cadherin, β1-integrin, fibroblast-specific protein 1, β-catenin and Zeb1 expression were amplified in the more irradiation-primed cells. There were no consistent changes in epithelial marker expression. Cell morphology changed dramatically with repeatedly irradiated cells displaying a more elongated shape, suggesting a switch to a more mesenchymal phenotype. Conclusions: In summary, POMC biomarker expression and secretion were reduced in SCLC tumours which regrew after irradiation and in repeatedly irradiation (irradiation-primed) cells. Therefore, POMC was no longer predictive of tumour burden. This highlights the importance of fully evaluating biomarkers during and after therapy to assess clinical utility. Furthermore, the gain in mesenchymal characteristics in irradiated cells could be indicative of a more invasive phenotype. [ABSTRACT FROM AUTHOR]

The public plays an important role in controlling the emergence and spread of antibiotic resistance. A large British survey showed that there is still public misunderstanding about microbes and antibiotics. e-Bug, a European DG Sanco sponsored project, aims to disseminate a school antibiotic and hygiene educational pack and website across Europe. Interactive science shows based on the e-Bug educational packs were developed to take the key health and hygiene messages from the e-Bug school resources to families. The science show was evaluated to assess public knowledge and understanding of antibiotics and antibiotic resistance pre and post intervention. An interactive stall comprised of a 3×2 m backing stand with background information, an interactive activity and discussions with a trained demonstrator was on display at a family holiday resort. Pre-piloted knowledge questionnaires were completed by parents and children pre and post intervention. Adult (≥19 years) baseline knowledge regarding antibiotics and antibiotic resistance was high although significant knowledge improvement was observed where baseline knowledge was low. Children's (5–11 years) knowledge around antibiotics and antibiotic resistance was significantly improved for all questions. The science show can be viewed as a success in improving parents' and children's knowledge of antibiotic use thereby highlighting the importance of educating the public through interaction. [ABSTRACT FROM AUTHOR]

The benefits of visual exposure to natural environments for human well-being in areas of stress reduction, mood improvement, and attention restoration are well documented, but the effects of natural environments on impulsive decision-making remain unknown. Impulsive decision-making in delay discounting offers generality, predictive validity, and insight into decision-making related to unhealthy behaviors. The present experiment evaluated differences in such decision-making in humans experiencing visual exposure to one of the following conditions: natural (e.g., mountains), built (e.g., buildings), or control (e.g., triangles) using a delay discounting task that required participants to choose between immediate and delayed hypothetical monetary outcomes. Participants viewed the images before and during the delay discounting task. Participants were less impulsive in the condition providing visual exposure to natural scenes compared to built and geometric scenes. Results suggest that exposure to natural environments results in decreased impulsive decision-making relative to built environments. [ABSTRACT FROM AUTHOR]

Background: Pediatric respiratory disease is a major cause of morbidity and mortality in the developing world. We evaluated a modified respiratory index of severity in children (mRISC) scoring system as a standard tool to identify children at greater risk of death from respiratory illness in Kenya. Materials and Methods: We analyzed data from children <5 years old who were hospitalized with respiratory illness at Siaya District Hospital from 2009–2012. We used a multivariable logistic regression model to identify patient characteristics predictive for in-hospital mortality. Model discrimination was evaluated using the concordance statistic. Using bootstrap samples, we re-estimated the coefficients and the optimism of the model. The mRISC score for each child was developed by adding up the points assigned to each factor associated with mortality based on the coefficients in the multivariable model. Results: We analyzed data from 3,581 children hospitalized with respiratory illness; including 218 (6%) who died. Low weight-for-age [adjusted odds ratio (aOR) = 2.1; 95% CI 1.3–3.2], very low weight-for-age (aOR = 3.8; 95% CI 2.7–5.4), caretaker-reported history of unconsciousness (aOR = 2.3; 95% CI 1.6–3.4), inability to drink or breastfeed (aOR = 1.8; 95% CI 1.2–2.8), chest wall in-drawing (aOR = 2.2; 95% CI 1.5–3.1), and being not fully conscious on physical exam (aOR = 8.0; 95% CI 5.1–12.6) were independently associated with mortality. The positive predictive value for mortality increased with increasing mRISC scores. Conclusions: A modified RISC scoring system based on a set of easily measurable clinical features at admission was able to identify children at greater risk of death from respiratory illness in Kenya. [ABSTRACT FROM AUTHOR]

Effective speech communication is critical to everyday quality of life and social well-being. In addition to the well-studied deficits in cognitive and motor function, depression also impacts communication. Here, we examined speech perception in individuals who were clinically diagnosed with major depressive disorder (MDD) relative to neurotypical controls. Forty-two normal-hearing (NH) individuals with MDD and 41 NH neurotypical controls performed sentence recognition tasks across three conditions with maskers varying in the extent of linguistic content (high, low, and none): 1-talker masker (1T), reversed 1-talker masker (1T_tr), and speech-shaped noise (SSN). Individuals with MDD, relative to neurotypical controls, demonstrated lower recognition accuracy in the 1T condition but not in the 1T_tr or SSN condition. To examine the nature of the listening condition-specific speech perception deficit, we analyzed speech recognition errors. Errors as a result of interference from masker sentences were higher for individuals with MDD (vs. neurotypical controls) in the 1T condition. This depression-related listening condition-specific pattern in recognition errors was not observed for other error types. We posit that this depression-related listening condition-specific deficit in speech perception may be related to heightened distractibility due to linguistic interference from background talkers. [ABSTRACT FROM AUTHOR]

Aim: To determine if there is an association between sarcopenia, physical function and self-reported fatigue in osteoarthritis (OA) and rheumatoid arthritis (RA). Methods: A cross-sectional analysis of measurements from a cohort of 157 participants with OA or RA was performed. The relationship between muscle mass (appendicular muscle index (AMI)), physical function (timed up and go, 30-seconds sit-to-stand test, 40-meter fast-paced walk test and grip-strength) and two fatigue measures (Multidimensional Assessment of Fatigue (MAF) and a fatigue Visual Analogue Scale (VAS)) was explored using hierarchical linear regression or logistic regression with established AMI cut-offs for sarcopenia. Results: There were no significant differences for perceived fatigue-related variables between OA or RA sarcopenic or non-sarcopenic participants. Participants with OA had worse physical function (TUG; P = 0.029, STS; P = 0.004, WS; P = 0.003), but participants with RA had lower grip strength (P<0.001). The RA group had higher CRP (P = 0.006), were more likely to receive glucocorticoids (P<0.001), and experienced worse fatigue (P = 0.050). The hierarchical multiple regression showed that self-reported fatigue (VAS/MAF-distress) had a significant but weak association with AMI in RA. Participants with higher percentage body fat had a significantly stronger association with sarcopenia in both OA and RA. Conclusion: Sarcopenia, when assessed by AMI, does not appear to be strongly associated with self-reported fatigue or physical function in participants with either OA or RA. Higher body fat had a moderately strong association with sarcopenia in this cross-sectional study, suggesting that body composition may be an important factor in the health of patients with longstanding OA or RA. [ABSTRACT FROM AUTHOR]

Background: Stress is a known factor related to alcohol use. However, how the relationship between alcohol craving and stress varies across the day is not fully understood. As craving is a consistent predictor of alcohol use disorder (AUD), understanding stress and craving patterns across the day in routine, non-dependent, moderate-heavy alcohol consumers may help in understanding those who may be vulnerable to transitioning into AUD. Method: Moderate-heavy drinkers were recruited from the local community (n = 32) and assessed for fluctuations in craving and stress intensity across the day via Ecological Momentary Assessment (EMA) during 3 consecutive days of imposed alcohol abstinence (abstained trial) and their normal drinking routine (normal trial). A multilevel modeling statistical approach assessed differences in diurnal craving and stress patterns with the Alcohol Craving Experience Questionnaire (ACE) examined as a moderator. Results: Immediately following alcohol consumption on normal trials, EMA craving levels were significantly reduced compared to pre-drinking levels. Moreover, the post-drinking craving levels were lower than on abstained trials. Higher ACE scores were associated with significantly higher EMA craving across the day and higher peaks at midday. Higher ACE scores were also associated with greater EMA stress across the day. Drinking relieved stress relative to abstained trials, but not in individuals with higher ACE scores. Higher stress was associated with greater EMA craving, which was stronger among those with higher ACE scores. Conclusion: These findings suggest that ACE scores are important to understanding patterns of stress and craving experienced across the day in routine, non-dependent, moderate-heavy drinkers and may provide new insights for vulnerability to transitioning into AUD. [ABSTRACT FROM AUTHOR]

Background: The Global Burden of Disease (GBD) project systematically assesses mortality, healthy life expectancy, and disability across 195 countries and territories, using the disability-adjusted life year (DALY). Disability weights in the DALY are based upon surveys that ask users to rate health states based on lay descriptions. We conducted an experimental study to examine whether the inclusion or removal of psychological, social, or familial implications from a health state description might affect individual judgments about disease severity, and thus relative disability weights. Methods: We designed a survey consisting of 36 paired descriptions in which information about plausible psychological, social, or familial implications of a health condition was either present or absent. Using a Web-based platform, we recruited 1,592 participants, who were assigned to one of two experimental groups, each of which were asked to assign a value to the health state description from 0 to 100 using a slider, with 0 as the “worst possible health” and 100 as the “best possible health.” We tested five hypotheses: (1) the inclusion of psychological, social, or familial consequences in health state descriptions will reduce the average rating of a health state; (2) the effect will be stronger for diseases with lower disability weights (i.e., less severe diseases); (3) the effect will vary across the type of additional information added to the health state description; (4) the impact of adding information on familial consequences will be stronger for female than male; (5) the effect of additional consequences on ratings of health state descriptions will not differ by levels of completed education and age. Results: On average, adding social, psychological, or familial consequences to the health state description lowered individual ratings of that description by 0.78 points. The impact of adding information had a stronger impact on ratings of the least severe conditions, reducing average ratings in this category by 1.67 points. Addition of information about child-rearing had the strongest impact, reducing average ratings by 2.09 points. We found little evidence that the effect of adding information on ratings of health descriptions varied by gender, education, or age. Conclusions: Including information about health states not directly related to major functional consequences or symptoms, particularly with respect to child-rearing and specifically for descriptions of less severe conditions, can lead to lower ratings of health. However, this impact was not consistent across all conditions or types of information, and was most pronounced for inclusion of information about child-rearing, and among the least severe conditions. [ABSTRACT FROM AUTHOR]

Background: Bacterial vaginosis (BV) affects a third of women of reproductive age in the US and there is increasing evidence to suggest it may be sexually transmitted. This study aimed to extend and validate the findings of our earlier smaller qualitative study by exploring in detail women’s views and experiences of the triggering factors associated with BV onset and recurrence. Methods: Women aged 20–49, who had experienced one or more symptomatic episode of BV within 6 months, were opportunistically recruited to complete a 38-item questionnaire on their experience of BV. Results: 103 women completed the questionnaire. Women were significantly more likely to report sexual than lifestyle factors triggered BV onset and recurrence (p<0.001). The top 3 factors women attributed to both BV onset and recurrence were identical–and all sexual. They included, in order: 1) unprotected sex; 2) sex with a new male partner; and 3) sex in general. The main lifestyle factors nominated included stress, diet, menstruation and the use of feminine hygiene products. While many women felt their BV had been transmitted through sexual contact (54%) and developed as a result of sexual activity (59%), few considered BV a sexually transmitted infection (STI) (10%). Despite this 57% felt partners should also be treated for BV. Conclusion: These data concur with our earlier qualitative findings that women believe BV is triggered by sexual activity. While many women felt BV was sexually transmitted and supported partner treatment, they did not consider BV an STI. This contradiction is likely due to information conveyed to women based on current guidelines. In the absence of highly effective BV treatments, this study highlights the need for guidelines to indicate there is scientific uncertainty around the pathogenesis of BV and to contain clear health messages regarding the evidence for practices shown to be associated with a reduced risk of BV (i.e. consistent condom use. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the effect of a 40% high-fat diet (HFD) supplemented with a dietary attainable level of quercetin (0.02%) on body composition, adipose tissue (AT) inflammation, Non-Alcoholic Fatty-Liver Disease (NAFLD), and metabolic outcomes. Diets were administered for 16 weeks to C57BL/6J mice (n = 10/group) beginning at 4 weeks of age. Body composition and fasting blood glucose, insulin, and total cholesterol concentrations were examined intermittently. AT and liver mRNA expression (RT-PCR) of inflammatory mediators (F4/80, CD206 (AT only), CD11c (AT only) TLR-2 (AT only), TLR-4 (AT only), MCP-1, TNF-α, IL-6 (AT only), and IL-10 (AT only)) were measured along with activation of NFκB-p65, and JNK (western blot). Hepatic lipid accumulation, gene expression (RT-PCR) of hepatic metabolic markers (ACAC1, SREBP-1, PPAR-γ), protein content of Endoplasmic Reticulum (ER) Stress markers (BiP, phosphorylated and total EIF2α, phosphorylated and total IRE1α, CHOP), and hepatic oxidative capacity were assessed (western blot). Quercetin administration had no effect at mitigating increases in visceral AT, AT inflammation, hepatic steatosis, ER Stress, decrements in hepatic oxidative capacity, or the development of insulin resistance and hypercholesterolemia. In conclusion, 0.02% quercetin supplementation is not an effective therapy for attenuating HFD-induced obesity development. It is likely that a higher dose of quercetin supplementation is needed to elicit favorable outcomes in obesity. [ABSTRACT FROM AUTHOR]

Ras guanine nucleotide-releasing protein-4 (RasGRP4) is an evolutionarily conserved calcium-regulated, guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor. While an important intracellular signaling protein for CD117+ mast cells (MCs), its roles in other immune cells is less clear. In this study, we identified a subset of in vivo-differentiated splenic CD117+ dendritic cells (DCs) in wild-type (WT) C57BL/6 mice that unexpectedly contained RasGRP4 mRNA and protein. In regard to the biologic significance of these data to innate immunity, LPS-treated splenic CD117+ DCs from WT mice induced natural killer (NK) cells to produce much more interferon-γ (IFN-γ) than comparable DCs from RasGRP4-null mice. The ability of LPS-responsive MCs to cause NK cells to increase their expression of IFN-γ was also dependent on this intracellular signaling protein. The discovery that RasGRP4 is required for CD117+ MCs and DCs to optimally induce acute NK cell-dependent immune responses to LPS helps explain why this signaling protein has been conserved in evolution. [ABSTRACT FROM AUTHOR]

Background: In Kenya, detailed data on the age-specific burden of influenza and RSV are essential to inform use of limited vaccination and treatment resources. Methods: We analyzed surveillance data from August 2009 to July 2012 for hospitalized severe acute respiratory illness (SARI) and outpatient influenza-like illness (ILI) at two health facilities in western Kenya to estimate the burden of influenza and respiratory syncytial virus (RSV). Incidence rates were estimated by dividing the number of cases with laboratory-confirmed virus infections by the mid-year population. Rates were adjusted for healthcare-seeking behavior, and to account for patients who met the SARI/ILI case definitions but were not tested. Results: The average annual incidence of influenza-associated SARI hospitalization per 1,000 persons was 2.7 (95% CI 1.8–3.9) among children <5 years and 0.3 (95% CI 0.2–0.4) among persons ≥5 years; for RSV-associated SARI hospitalization, it was 5.2 (95% CI 4.0–6.8) among children <5 years and 0.1 (95% CI 0.0–0.2) among persons ≥5 years. The incidence of influenza-associated medically-attended ILI per 1,000 was 24.0 (95% CI 16.6–34.7) among children <5 years and 3.8 (95% CI 2.6–5.7) among persons ≥5 years. The incidence of RSV-associated medically-attended ILI was 24.6 (95% CI 17.0–35.4) among children <5 years and 0.8 (95% CI 0.3–1.9) among persons ≥5 years. Conclusions: Influenza and RSV both exact an important burden in children. This highlights the possible value of influenza vaccines, and future RSV vaccines, for Kenyan children. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband’s fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication. [ABSTRACT FROM AUTHOR]

The ability to selectively respond to one’s own name is important for social and language development, and is disrupted in atypically developing populations (e.g., autism spectrum disorder). Research with typically developing samples using event-related potentials (ERPs) has demonstrated that the subject’s own name (SON) is differentiated from other stimuli at both early sensory and later cognitive stages of auditory processing. While neural indices of response to name have been researched extensively in adults, no such studies have been conducted with typically developing preschool children or children with autism spectrum disorder (ASD). The present study investigated ERP response to name in a sample of typically developing (TD) preschoolers (n = 19; mean age = 4.3 years) as well as a small, exploratory comparison group of preschoolers with ASD (n = 13; mean age = 4.4 years). TD preschoolers exhibited significantly greater negativity to SON over frontal regions than to an unfamiliar nonsense name, consistent with the adult SON negativity component. This component was present whether the name was spoken by a parent or an unfamiliar adult, suggesting that it reflects SON-specific processing rather than broad self-relevant information processing. Comparing preschoolers with ASD to the TD children revealed a significant SON negativity component across both groups. The amplitude of the SON negativity response was significantly correlated with social variables in the ASD group, though these correlations did not survive correction for multiple comparisons. This study is the first to demonstrate the presence of the SON component in preschool children with and without ASD. [ABSTRACT FROM AUTHOR]

Background: Individuals with neurological disorders often have difficulty negotiating stairs that can lead to injurious falls. Clinicians lack a clinical tool to identify impairments in stair negotiation and to assist their decision making regarding treatment plans to improve stair performance and safety. We developed a new tool called the Step Test Evaluation of Performance on Stairs (STEPS) that is designed to assess stair performance and safety in neurological populations. Objectives: This study aimed to determine interrater and intrarater reliability of STEPS and its concurrent content validity to various clinical balance and mobility measures using individuals with Huntington's disease (HD) as the first test population. Methods: Forty individuals with HD (mean age 50.35) participated. Three observers rated live performances of the STEPS (interrater reliability) and seven observers rated videotaped performances twice (intrarater reliability). STEPS scores correlated with clinical mobility and balance test scores. Results: Excellent inter- and intrarater reliability (ICCs = 0.91 and 0.89 respectively) and good internal consistency (α = 0.83) were found. Better STEPS performance correlated with better performance on co-administered motor and mobility measures and Stair Self-Efficacy scores. Per multivariable regression analysis, the Unified Huntington's Disease Rating Scale modified motor score and descent time were significant predictors of STEPS performance. Conclusions: The STEPS tool is easy to administer, requires no special devices and can be completed in less than five minutes. In the HD test population, it shows high reliability and validity making it a potentially useful tool for assessing maneuverability and safety on stairs in HD. The results suggest that the STEPS tool warrants further study to determine STEPS cut-off values for fall prediction in HD and may prove useful as an assessment tool for other neurological disorders. [ABSTRACT FROM AUTHOR]

Objectives: Ocular hypertension is a primary risk factor for glaucoma and results in retinal ganglion cell (RGC) degeneration. Current animal models of glaucoma lack severe RGC cell death as seen in glaucoma, making assessment of physiological mediators of cell death difficult. We developed a modified mouse model of ocular hypertension whereby long-lasting elevation of intraocular pressure (IOP) is achieved, resulting in significant reproducible damage to RGCs. Results: In this model, microbeads are mixed with hyaluronic acid and injected into the anterior chamber of C57BL/6J mice. The hyaluronic acid allows for a gradual release of microbeads, resulting in sustained blockage of Schlemm’s canal. IOP elevation was bimodal during the course of the model’s progression. The first peak occurred 1 hours after beads injection, with an IOP value of 44.69 ± 6.00 mmHg, and the second peak occurred 6–12 days post-induction, with an IOP value of 34.91 ± 5.21 mmHg. RGC damage was most severe in the peripheral retina, with a loss of 64.1% compared to that of untreated eyes, while the midperiphery exhibited a 32.4% loss, 4 weeks following disease induction. Conclusions: These results suggest that sustained IOP elevation causes more RGC damage in the periphery than in the midperiphery of the retina. This model yields significant and reproducible RGC degeneration. [ABSTRACT FROM AUTHOR]

Exogenous vascular endothelial growth factor (VEGF) accelerates compensatory lung growth (CLG) in mice after unilateral pneumonectomy. In this study, we unexpectedly discovered a method to enhance CLG with a VEGF inhibitor, soluble VEGFR1. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily intraperitoneal (ip) injection of either saline (control) or 20 μg/kg of VEGFR1-Fc. On post-operative day (POD) 4, mice underwent pulmonary function tests (PFT) and lungs were harvested for volume measurement and analyses of the VEGF signaling pathway. To investigate the role of hypoxia in mediating the effects of VEGFR1, experiments were repeated with concurrent administration of PT-2385, an inhibitor of hypoxia-induced factor (HIF)2α, via orogastric gavage at 10 mg/kg every 12 hours for 4 days. We found that VEGFR1-treated mice had increased total lung capacity (P = 0.006), pulmonary compliance (P = 0.03), and post-euthanasia lung volume (P = 0.049) compared to control mice. VEGFR1 treatment increased pulmonary levels of VEGF (P = 0.008) and VEGFR2 (P = 0.01). It also stimulated endothelial proliferation (P < 0.0001) and enhanced pulmonary surfactant production (P = 0.03). The addition of PT-2385 abolished the increase in lung volume and endothelial proliferation in response to VEGFR1. By paradoxically stimulating angiogenesis and enhancing lung growth, VEGFR1 could represent a new treatment strategy for neonatal lung diseases characterized by dysfunction of the HIF-VEGF pathway. [ABSTRACT FROM AUTHOR]

Background: Community engagement on research design is widely highlighted as an important approach for ethical research. This article reports the experience of consulting with communities on the logo used for an influenza study in Malawi. The logo was designed for use on badges worn by study researchers, participant information sheets and other project documents, and could affect perceptions of the study and consequent engagement in the research. Methods: Four focus group discussions were conducted with populations targeted by the influenza study: pregnant women, people with HIV, mothers and community members. The focus groups incorporated a participatory matrix exercise focusing on key themes emerging from the discussions such as: attractiveness, comprehension, acceptability and suggestions for improvement. Findings from the focus groups were analyzed according to these key themes. Results: The consultation highlighted important benefits of discussion with communities on research design, including providing new perspectives and helping to avoid harm. For example, people living with HIV felt that one of the possible logos could increase stigma within communities. The experience also indicated potential challenges of consultation. In particular, there were contrasting perspectives among the groups, such that the consultation did not provide a clear answer about which logo should be selected. Conclusions: Our experience adds to current evidence on community engagement by reporting on an area where there is less discussion of community consultation for design of a study logo. The consultation exercise reaffirmed the value of community engagement, but also the difficulty of relying on a brief consultation for decision-making in research design. Further ethical guidance is required on how to negotiate contradictory views during consultations. [ABSTRACT FROM AUTHOR]

The production of envelope glycoproteins (Envs) for use as HIV vaccines is challenging. The yield of Envs expressed in stable Chinese Hamster Ovary (CHO) cell lines is typically 10–100 fold lower than other glycoproteins of pharmaceutical interest. Moreover, Envs produced in CHO cells are typically enriched for sialic acid containing glycans compared to virus associated Envs that possess mainly high-mannose carbohydrates. This difference alters the net charge and biophysical properties of Envs and impacts their antigenic structure. Here we employ a novel robotic cell line selection strategy to address the problems of low expression. Additionally, we employed a novel gene-edited CHO cell line (MGAT1- CHO) to address the problems of high sialic acid content, and poor antigenic structure. We demonstrate that stable cell lines expressing high levels of gp120, potentially suitable for biopharmaceutical production can be created using the MGAT1- CHO cell line. Finally, we describe a MGAT1- CHO cell line expressing A244-rgp120 that exhibits improved binding of three major families of bN-mAbs compared to Envs produced in normal CHO cells. The new strategy described has the potential to eliminate the bottleneck in HIV vaccine development that has limited the field for more than 25 years. [ABSTRACT FROM AUTHOR]

To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94–100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing. Trial registration ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) has previously been demonstrated to accelerate compensatory lung growth (CLG) in mice and may be a useful therapy for pulmonary hypoplasia. Systemic administration of VEGF can result in side effects such as hypotension and edema. The aim of this study was to explore nasal delivery as a route for intrapulmonary VEGF administration. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily nasal instillation of VEGF at 0.5 mg/kg or isovolumetric saline. Lung volume measurement, morphometric analysis, and protein expression studies were performed on lung tissues harvested on postoperative day (POD) 4. To understand the mechanism by which VEGF accelerates lung growth, proliferation of human bronchial epithelial cells (HBEC) was assessed in a co-culture model with lung microvascular endothelial cells (HMVEC-L) treated with and without VEGF (10 ng/mL). The assay was then repeated with a heparin-binding EGF-like growth factor (HB-EGF) neutralizing antibody ranging from 0.5–50 μg/mL. Compared to control mice, the VEGF-treated group displayed significantly higher lung volume (P = 0.001) and alveolar count (P = 0.005) on POD 4. VEGF treatment resulted in increased pulmonary expression of HB-EGF (P = 0.02). VEGF-treated HMVEC-L increased HBEC proliferation (P = 0.002) while the addition of an HB-EGF neutralizing antibody at 5 and 50 μg/mL abolished this effect (P = 0.01 and 0.002, respectively). These findings demonstrate that nasal delivery of VEGF enhanced CLG. These effects could be mediated by a paracrine mechanism through upregulation of HB-EGF, an epithelial cell mitogen. [ABSTRACT FROM AUTHOR]

The purpose of this descriptive study was to assess serum levels of 25(OH) vitamin D3 (25(OH)D) in participants who voluntarily participated in a fitness assessment and correlate this with muscular strength, weekly exercise, overall body composition, and dietary intake of vitamin D and calcium. Thirty-six participants were recruited. Anthropometric measurements and handgrip strength were taken with blood analyses completed utilizing 25-hydroxyvitamin D assay. A dietary screening survey was used to assess calcium and vitamin D intake. All data collection was completed at time of assessment appointment. Statistical analyses completed utilized Pearson’s and Kendall’s Tau correlation, with level of significance set at p < 0.05. Twenty-two percent of our sample were 25(OH)D deficient and 33% 25(OH)D insufficient, with 16% consuming adequate vitamin D and 5% consuming adequate calcium. Eight of the females and one male had below average DXA assessments for bone health. Vitamin D intake was significantly correlated with serum 25(OH)D levels (τ = 0.29, p<0.01). In females there was an inverse relationship between 25(OH)D and weight (r = -0.45, p<0.05). Thirty-one percent of participants had higher than desirable waist circumference and were 25(OH)D insufficient or deficient. This sample had a high rate of 25(OH)D insufficiency and deficiency, with most not consuming adequate amounts of calcium and vitamin D. Normalizing serum 25(OH)D through food and supplements has the potential to positively impact several parameters of an individual’s health including weight status, visceral adiposity and waist circumference, and bone health. [ABSTRACT FROM AUTHOR]

Background: The topical HIV prevention (microbicides) field is in acute need of a method to rapidly and objectively measure adherence to product use in clinical trials. Infrared (IR) spectroscopy has been used in many pharmaceutical and forensic applications but has yet to be applied to adherence monitoring. In this study, we report on efforts to test the feasibility of using IR spectroscopy as a means to measure residual active or placebo vaginal product, semen exposure and vaginal insertion from a single swab. Methods: A portable IR spectrometer equipped with diamond attenuated total reflectance (ATR) was used to capture spectra of unused vs. vaginally-used swabs, vaginal swabs containing semen, and vaginal swabs to which either tenofovir-containing or matching placebo products (vaginal gel or insert) were added. Spectral data obtained from swabs placed directly on the spectrometer were divided into calibration and testing sets for developing and validating discriminant models set up to provide yes/no predictions of: vaginal vs. non-vaginal use, presence vs. no presence of each test product, and presence vs. no presence of semen. Further validation of models was performed using vaginal swabs collected from a clinical study evaluating vaginally administered placebo insert formulations. Results: For each discriminant model developed to predict vaginal vs. non-vaginal use, presence vs. no presence of each test product, and presence vs. no presence of semen, classified validation samples not included in the model development were correctly identified into their respective classes with minimal prediction error. Clinically obtained vaginal swabs collected 15–60 minutes after placebo insert use were also correctly identified, further validating the models. Conclusion: Our findings demonstrate the proof of concept that IR spectroscopy can be a method for rapid detection and characterization of microbicide products and biological fluids present in vaginal swabs. This novel method has potential to support real-time, on-site adherence monitoring in clinical or field settings. [ABSTRACT FROM AUTHOR]

Limited information is available on influenza virus sequence drift between transmission events. In countries with high HIV burdens, like South Africa, the direct and indirect effect of HIV on influenza sequence drift between transmission events may be of public health concern. To this end, we measured hemagglutinin sequence diversity between influenza transmission events using data and specimens from a study investigating household transmission dynamics of seasonal influenza viruses in 2 peri-urban communities in South Africa during the 2013 influenza season. Thirty index cases and 107 of 110 eligible household contacts were enrolled into the study, 47% (14/30) demonstrating intra-household laboratory-confirmed influenza transmission. In this study 35 partial hemagglutinin gene sequences were obtained by Sanger sequencing from 11 index cases (sampled at enrolment only) and 16 secondary cases (8 cases sampled at 1 and 8 cases sampled at 2 time-points). Viral sequence identities confirmed matched influenza transmission pairs within the 11 households with corresponding sequenced index and secondary cases. Phylogenetic analysis revealed 10 different influenza viral lineages in the 14 households. Influenza A(H1N1)pdm09 strains were shown to be genetically distinct between the 2 communities (from distinct geographic regions), which was not observed for the influenza A(H3N2) strains. Intra-host/intra-household influenza A(H3N2) sequence drift was identified in 2 households. The first was a synonymous mutation between the index case and a household contact, and the second a non-synonymous mutation between 2 serial samples taken at days 0 and 4 post enrolment from an HIV-infected secondary case. Limited inter-household sequence diversity was observed as highlighted by sharing of the same influenza strain between different households within each community. The limited intra-household sequence drift is in line with previous studies also using Sanger sequencing, corroborating the presence of strict selective bottlenecks that limit sequence variance. We were not able to directly ascertain the effect of HIV on influenza sequence drift between transmission events. [ABSTRACT FROM AUTHOR]

Background: The level of body-mass index (BMI) associated with the lowest risk of death remains unclear. Although differences in muscle mass limit the utility of BMI as a measure of adiposity, no study has directly examined the effect of muscle mass on the BMI-mortality relationship. Methods: Body composition was measured by dual-energy x-ray absorptiometry in 11,687 participants of the National Health and Nutrition Examination Survey 1999–2004. Low muscle mass was defined using sex-specific thresholds of the appendicular skeletal muscle mass index (ASMI). Proportional hazards models were created to model associations with all-cause mortality. Results: At any level of BMI ≥22, participants with low muscle mass had higher body fat percentage (%TBF), an increased likelihood of diabetes, and higher adjusted mortality than other participants. Increases in %TBF manifested as 30–40% smaller changes in BMI than were observed in participants with preserved muscle mass. Excluding participants with low muscle mass or adjustment for ASMI attenuated the risk associated with low BMI, magnified the risk associated with high BMI, and shifted downward the level of BMI associated with the lowest risk of death. Higher ASMI was independently associated with lower mortality. Effects were similar in never-smokers and ever-smokers. Additional adjustment for waist circumference eliminated the risk associated with higher BMI. Results were unchanged after excluding unintentional weight loss, chronic illness, early mortality, and participants performing muscle-strengthening exercises or recommended levels of physical activity. Conclusions: Muscle mass mediates associations of BMI with adiposity and mortality and is inversely associated with the risk of death. After accounting for muscle mass, the BMI associated with the greatest survival shifts downward toward the normal range. These results provide a concrete explanation for the obesity paradox. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that early-life exposure to particulate air pollutants pose threats to children’s cognitive development, but studies about the neurotoxic effects associated with exposures during adolescence remain unclear. We examined whether exposure to ambient fine particles (PM2.5) at residential locations affects intelligence quotient (IQ) during pre-/early- adolescence (ages 9–11) and emerging adulthood (ages 18–20) in a demographically-diverse population (N = 1,360) residing in Southern California. Increased ambient PM2.5 levels were associated with decreased IQ scores. This association was more evident for Performance IQ (PIQ), but less for Verbal IQ, assessed by the Wechsler Abbreviated Scale of Intelligence. For each inter-quartile (7.73 μg/m3) increase in one-year PM2.5 preceding each assessment, the average PIQ score decreased by 3.08 points (95% confidence interval = [-6.04, -0.12]) accounting for within-family/within-individual correlations, demographic characteristics, family socioeconomic status (SES), parents’ cognitive abilities, neighborhood characteristics, and other spatial confounders. The adverse effect was 150% greater in low SES families and 89% stronger in males, compared to their counterparts. Better understanding of the social disparities and sexual dimorphism in the adverse PM2.5–IQ effects may help elucidate the underlying mechanisms and shed light on prevention strategies. [ABSTRACT FROM AUTHOR]

Thiazide derivatives including Hydrochlorothiazide (HCTZ) represent the most common treatment of mild to moderate hypertension. Thiazides initially enhance diuresis via inhibition of the kidney Na+-Cl- Cotransporter (NCC). However, chronic volume depletion and diuresis are minimal while lowered blood pressure (BP) is maintained on thiazides. Thus, a vasodilator action of thiazides is proposed, likely via Ca2+-activated K+ (BK) channels in vascular smooth muscles. This study ascertains the role of volume depletion induced by salt restriction or salt wasting in NCC KO mice on the non-diuretic hypotensive action of HCTZ. HCTZ (20mg/kg s.c.) lowered BP in 1) NCC KO on a salt restricted diet but not with normal diet; 2) in volume depleted but not in volume resuscitated pendrin/NCC dKO mice; the BP reduction occurs without any enhancement in salt excretion or reduction in cardiac output. HCTZ still lowered BP following treatment of NCC KO on salt restricted diet with paxilline (8 mg/kg, i.p.), a BK channel blocker, and in BK KO and BK/NCC dKO mice on salt restricted diet. In aortic rings from NCC KO mice on normal and low salt diet, HCTZ did not alter and minimally decreased maximal phenylephrine contraction, respectively, while contractile sensitivity remained unchanged. These results demonstrate 1) the non-diuretic hypotensive effects of thiazides are augmented with volume depletion and 2) that the BP reduction is likely the result of HCTZ inhibition of vasoconstriction through a pathway dependent on factors present in vivo, is unrelated to BK channel activation, and involves processes associated with intravascular volume depletion. [ABSTRACT FROM AUTHOR]

Rationale: Evidence from observational studies and to a lesser extent clinical trials suggest that a healthy diet may improve symptoms and lung function in patients with asthma. We conducted a pilot study to determine the feasibility of conducting a larger scale dietary trial and to provide preliminary evidence on the impact of a healthy diet on asthma outcomes. Methods: In a randomized, two period cross-over trial, participants with asthma received a 4-week dietary intervention followed by a usual diet (or vice versa), separated by a 4-week washout. The dietary intervention was a healthy diet rich in unsaturated fat. During the dietary intervention, participants ate three meals per week on site at the Johns Hopkins ProHealth Research Center. All remaining meals and snacks were provided for participants to consume off-site. During the control diet, participants were instructed to continue their usual dietary intake. Relevant biomarkers and asthma clinical outcomes were assessed at 0, 2, and 4 weeks after starting each arm of the study. Results: Eleven participants were randomized, and seven completed the full study protocol. Among these seven participants, average age was 42 years, six were female, and six were African American. Participant self-report of dietary intake revealed significant increases in fruit, vegetable, and omega-3 fatty acid intake with the dietary intervention compared to usual diet. Serum carotenoids (eg. lutein and beta-cryptoxanthin) increased in the intervention versus control. Total cholesterol decreased in the intervention versus control diet. There was no consistent effect on asthma outcomes. Conclusions: The findings suggest that a feeding trial in participants with asthma is feasible. Larger trials are needed to definitively assess the potential benefits of dietary interventions on pulmonary symptoms and function in patients with asthma. [ABSTRACT FROM AUTHOR]

Background: Humoral immunity plays an important role against Pneumocystis jirovecii infection, yet clinical and environmental factors that impact bronchoalveolar antibody responses to P. jirovecii remain uncertain. Methods: From October 2008—December 2011 we enrolled consecutive HIV-infected adults admitted to San Francisco General Hospital (SFGH) who underwent bronchoscopy for suspected Pneumocystis pneumonia (PCP). We used local air quality monitoring data to assign ozone, nitrogen dioxide, and fine particulate matter exposures within 14 days prior to hospital admission. We quantified serum and bronchoalveolar lavage fluid (BALF) antibody responses to P. jirovecii major surface glycoprotein (Msg) recombinant constructs using ELISA. We then fit linear regression models to determine whether PCP and ambient air pollutants were associated with bronchoalveolar antibody responses to Msg. Results: Of 81 HIV-infected patients enrolled, 47 (58%) were diagnosed with current PCP and 9 (11%) had a prior history of PCP. The median CD4+ count was 51 cells/μl (IQR 15–129) and 44% were current smokers. Serum antibody responses to Msg were statistically significantly predictive of BALF antibody responses, with the exception of IgG responses to MsgC8 and MsgC9. Prior PCP was associated with increased BALF IgA responses to Msg and current PCP was associated with decreased IgA responses. For instance, among patients without current PCP, those with prior PCP had a median 73.2 U (IQR 19.2–169) IgA response to MsgC1 compared to a 5.00 U (3.52–12.6) response among those without prior PCP. Additionally, current PCP predicted a 22.5 U (95%CI -39.2, -5.82) lower IgA response to MsgC1. Ambient ozone within the two weeks prior to hospital admission was associated with decreased BALF IgA responses to Msg while nitrogen dioxide was associated with increased IgA responses. Conclusions: PCP and ambient air pollutants were associated with BALF IgA responses to P. jirovecii in HIV-infected patients evaluated for suspected PCP. [ABSTRACT FROM AUTHOR]