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Purpose This study aimed to examine the association between confidence in accessing HIV services, primary sources of HIV information, and primary care provider status for African American and Latinx individuals in Indiana. Methods An online survey was disseminated to African American and Latinx individuals using snowball and social media recruitment methods, resulting in a final sample size of n = 308. A multivariable linear regression analysis was performed to examine the relationships between confidence accessing HIV services, primary care provider status, sexual identification, and sources of HIV information. Results Of the total respondents, 62.5% (n = 193) identified as male and 36.9% (n = 114) identified as female. Most identified as African American (72.5%, n = 224), followed by 27.2% (n = 84) who identified as Latinx. Participants who used their primary care providers as a primary source of obtaining HIV information had a significantly higher level of comfort with accessing HIV services. Those who identified family members as a primary source of HIV information and those who identified as bisexual demonstrated a lower level of confidence in accessing HIV services. Discussion This study's results enhance our understanding of marginalization within minority groups regarding sexual identification and accessing HIV services. These results also offer insight into the importance of healthcare access because having a primary care provider was a strong predictor of increased confidence in accessing HIV services.

Lung cancer is the leading cause of cancer-related deaths. While the recent use of immune checkpoint inhibitors significantly improves patient outcomes, responsiveness remains restricted to a small proportion of patients. Conventional dendritic cells (DCs) play a major role in anticancer immunity. In mice, two subpopulations of DCs are found in the lung: DC2s (CD11b+Sirpα+) and DC1s (CD103+XCR1+), the latest specializing in the promotion of anticancer immune responses. However, the impact of lung cancer on DC populations and the consequent influence on the anticancer immune response remain poorly understood. To address this, DC populations were studied in murine models of Lewis Lung Carcinoma (LLC) and melanoma-induced lung metastasis (B16F10). We report that direct exposure to live or dead cancer cells impacts the capacity of DCs to differentiate into CD103+ DC1s, leading to profound alterations in CD103+ DC1 proportions in the lung. In addition, we observed the accumulation of CD103loCD11b+ DCs, which express DC2 markers IRF4 and Sirpα, high levels of T-cell inhibitory molecules PD-L1/2 and the regulatory molecule CD200. Finally, DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to the anti-PD-1 immune checkpoint therapy; the co-injection restored sensitivity to immunotherapy. Thus, we demonstrate that lung tumor development leads to the accumulation of CD103loCD11b+ DCs with a regulatory potential combined with a reduced proportion of highly-specialized antitumor CD103+ DC1s, which could promote cancer growth. Additionally, promoting an anticancer DC signature could be an interesting therapeutic avenue to increase the efficacy of existing immune checkpoint inhibitors.

Health assessments have potential to improve health of older people. This study compares long-term health care utilisation, physical functioning, and mortality for women aged 75 years or over who have had a health assessment and those who have not. Prospective data on health service use, physical functioning, and deaths among a large cohort of women born 1921–26 were analysed. Propensity score matching was used to produce comparable groups of women according to whether they had a health assessment or not. The study population included 6128 (67.3%) women who had an assessment, and 2971 (32.7%) women who had no assessment. Propensity matching produced 2101 pairs. Women who had an assessment had more use of other health services, longer survival, and were more likely to survive with high physical functioning compared to women with no assessment. Among women who had good baseline physcial functioning scores, women who had an assessment had significantly lower odds of poor outcomes at 1000 days follow-up compared to women who had no assessment (OR: 0.67, 95%CI: 0.52, 0.85). This large observational study shows the real-world potential for assessments to improve health outcomes for older women. However, they also increased health service use. This increased healthcare is likely to be an important mechanism in improving the women’s health outcomes.

Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling and that its loss/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, MEK1/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions.

Qualitative health data are rarely shared in the United States (U.S.). This is unfortunate because gathering qualitative data is labor and time-intensive, and data sharing enables secondary research, training, and transparency. A new U.S. federal policy mandates data sharing by 2023, and is agnostic to data type. We surveyed U.S. qualitative researchers (N = 425) on the barriers and facilitators of sharing qualitative health or sensitive research data. Most researchers (96%) have never shared qualitative data in a repository. Primary concerns were lack of participant permission to share data, data sensitivity, and breaching trust. Researcher willingness to share would increase if participants agreed and if sharing increased the societal impact of their research. Key resources to increase willingness to share were funding, guidance, and de-identification assistance. Public health and biomedical researchers were most willing to share. Qualitative researchers need to prepare for this new reality as sharing qualitative data requires unique considerations.

The reasons for Thoroughbred (TB) horses not entering training or exiting the racing industry, are of interest to regulators, welfare groups and the broader community. Speculation about the outcomes of these horses threatens the community acceptance, or social license, of the TB breeding and racing industries. A representative survey of the 2010 Victorian born TB foal crop was used to determine the outcomes and reasons for exit for horses that had not entered training, or had exited training and racing by eight years of age. Horses exported for racing or breeding (4%), or that were still actively racing (7%) at the start of the follow up period were excluded from the study. An online questionnaire was sent to breeders or trainers of 3,176 TB horses eligible for enrolment in the study. Of the 2,005 (63%) responses received, the two most frequent outcomes were that the horse had either been retired or rehomed (65%), or deceased (16%). For the 1,637 TB horses that had entered training, the majority of retirements were voluntary (59%), followed by involuntary retirements due to health disorders (28%). For TBs that did not have an industry record of entering training (n = 368), death (34%), or retirement or being rehomed (27%), were the most frequent barriers to entering training. The median age of retirement for TBs that raced was five (Q1 4; Q3 6) years regardless of sex, or whether their first race start was at two, three or four years of age. Relatively large numbers of horses voluntarily retiring at five-years of age suggests that industry-level, rather than individual horse-level factors are the predominant influences on racing career duration.

Objective To develop and validate a prediction model for excess pregnancy weight gain using early pregnancy factors. Design Prospective cohort study Setting We recruited from 12 obstetrical, family medicine, and midwifery centers in Ontario, Canada Participants We recruited English-speaking women with singleton pregnancies between 8+0–20+6 weeks. Of 1296 women approached, 1050 were recruited (81%). Of those, 970 women had complete data (970/1050, 92%) and were recruited at a mean of 14.8 weeks. Primary outcome measure We collected data on psychological, physical, and social factors and used stepwise logistic regression analysis to develop a multivariable model predicting our primary outcome of excess pregnancy weight gain, with random selection of 2/3 of women for training data and 1/3 for testing data. Results Nine variables were included in the final model to predict excess pregnancy weight gain. These included nulliparity, being overweight, planning excessive gain, eating in front of a screen, low self-efficacy regarding pregnancy weight gain, thinking family or friends believe pregnant women should eat twice as much as before pregnancy, being agreeable, and having emotion control difficulties. Training and testing data yielded areas under the receiver operating characteristic curve of 0.76 (95% confidence interval, 0.72 to 0.80) and 0.62 (95% confidence interval 0.56 to 0.68), respectively. Conclusions In this first validated prediction model in early pregnancy, we found that nine psychological, physical, and social factors moderately predicted excess pregnancy weight gain in the final model. This research highlights the importance of several predictors, including relatively easily modifiable ones such as appropriate weight gain plans and mindfulness during eating, and lays an important methodological foundation for other future prediction models.

Background Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy. Methods We performed a secondary analysis of a multicenter phase 2/3, randomized, open-label trial in Europe, North and South America from 2002 to 2009. Children aged 31 days to Results The modified intention-to-treat analysis included 263 participants. Seventy-two percent (n = 190) of participants experienced at least one treatment disruption during study. At 4 years, treatment disruption probabilities were 70% (protease inhibitor) vs. 63% (non-nucleoside reverse transcriptase inhibitor). The unadjusted hazard ratio (HR) for treatment disruptions comparing protease inhibitor vs. non-nucleoside reverse transcriptase inhibitor-based regimens was 1.19, 95% confidence interval [CI] 0.88–1.61 (adjusted HR 1.24, 95% CI 0.91–1.68). By study end, treatment disruption probabilities converged (protease inhibitor 81%, non-nucleoside reverse transcriptase inhibitor 84%) with unadjusted HR 1.11, 95% CI 0.84–1.48 (adjusted HR 1.13, 95% CI 0.84–1.50). Reported reasons for treatment disruptions suggested that participants on protease inhibitors experienced greater tolerability problems. Conclusions Children had similar time to treatment disruption for initial protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, despite greater reported tolerability problems with protease inhibitor regimens. Initial pediatric antiretroviral therapy with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor may be acceptable for maintaining optimal, continuous therapy.

Currently, there is a paucity of data on the barriers for Australian Thoroughbred horses transitioning from stud farm to racetrack. This paper reports the reasons why horses failed to enter race training and documents their exit destinations. Biographical records of Australian Thoroughbred horses born in 2014 were investigated to determine the number of horses that had not officially entered race training by the start of the 4-year old racing season (1 August 2018). Of the 13,677 foals born in 2014, 66% had commenced training and 51% had raced before the beginning of their 4-year-old season in Australia. A sampling frame based on the post code of the premises where foals were born and records from Racing Australia were used to select a geographically representative sample of the 2014 Australian Thoroughbred foal crop (n = 4,124). From the population eligible for sampling 1,275 horses that had not entered training were enrolled in the survey and their breeders were sent an online questionnaire with follow-up phone calls for those who had not responded. Of the 633 responses (50% of 1275) the most frequent outcomes for horses were: death (38%, n = 239), participation in the racing industry in their 4-year old racing season (24%, n = 154) and retirement (16%, n = 100) either as Australian Stud Book (ASB) bloodstock (n = 17), or as horses rehomed outside the Thoroughbred industry (n = 83). Illness or injury was the most frequent reason for horses not entering race training that were ASB bloodstock, rehomed or deceased. There was a loss of traceability at the point of sale with most horses sold at 1 year of age. This study provides important information on the reasons, alternative outcomes and gaps in traceability for horses not entering training prior to the 4-year-old racing season.

IntroductionNasopharyngeal (NP) colonization with antimicrobial-resistant bacteria is a global public health concern. Antimicrobial-resistance (AMR) genes carried by the resident NP microbiota may serve as a reservoir for transfer of resistance elements to opportunistic pathogens. Little is known about the NP antibiotic resistome. This study longitudinally investigated the composition of the NP antibiotic resistome in Streptococcus-enriched samples in a South African birth cohort.MethodsAs a proof of concept study, 196 longitudinal NP samples were retrieved from a subset of 23 infants enrolled as part of broader birth cohort study. These were selected on the basis of changes in serotype and antibiogram over time. NP samples underwent short-term enrichment for streptococci prior to total nucleic acid extraction and whole metagenome shotgun sequencing (WMGS). Reads were assembled and aligned to pneumococcal reference genomes for the extraction of streptococcal and non-streptococcal bacterial reads. Contigs were aligned to the Antibiotic Resistance Gene-ANNOTation database of acquired AMR genes.ResultsAMR genes were detected in 64% (125/196) of the samples. A total of 329 AMR genes were detected, including 36 non-redundant genes, ranging from 1 to 14 genes per sample. The predominant AMR genes detected encoded resistance mechanisms to beta-lactam (52%, 172/329), macrolide-lincosamide-streptogramin (17%, 56/329), and tetracycline antibiotics (12%, 38/329). MsrD, ermB, and mefA genes were only detected from streptococcal reads. The predominant genes detected from non- streptococcal reads included blaOXA-60, blaOXA-22, and blaBRO-1. Different patterns of carriage of AMR genes were observed, with only one infant having a stable carriage of mefA, msrD and tetM over a long period.ConclusionThis study demonstrates that WMGS can provide a broad snapshot of the NP resistome and has the potential to provide a comprehensive assessment of resistance elements present in this niche.

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.

ObjectiveObservational tuberculosis cohort studies are often limited by a lack of long-term data characterizing survival beyond the initial treatment outcome. Though Cox proportional hazards models are often applied to these data, differential risk of long-term survival, dependent on the initial treatment outcome, can lead to violations of model assumptions. We evaluate the performance of two alternate censoring approaches on reducing bias in treatment effect estimates.DesignWe simulate a typical multidrug-resistant tuberculosis cohort study and use Cox proportional hazards models to assess the relationship of an aggressive treatment regimen with hazard of death. We compare three assumptions regarding censored observations to determine which produces least biased treatment effect estimates: conventional non-informative censoring, an extension of short-term survival informed by literature, and incorporation of predicted long-term vital status.ResultsThe treatment regimen's protective effect on death is consistently underestimated by the conventional censoring method, up to 7.6%. Models using the two alternative censoring techniques produce treatment effect estimates consistently stronger and less biased than the conventional method, underestimating the treatment effect by less than 2.4% across all scenarios.ConclusionsWhen model assumptions are violated, alternative censoring techniques can more accurately estimate associations between treatment and long-term survival. In multidrug-resistant tuberculosis cohort analyses, this bias reduction may yield more accurate and, larger effect estimates. This bias reduction can be achieved through use of standard statistical procedures with a simple re-coding of the censoring indicator.

The destinations of Thoroughbred (TB) racehorses exiting the racing industry is a high-profile issue with ethical and welfare implications of interest to both animal welfare groups and racing regulators. This cross-sectional study investigated the reasons that TBs temporarily or permanently exited racing and training in Australia in the 2017–2018 racing season and the outcomes for these horses post-racing. An online questionnaire was sent to the last registered trainers of a representative sample of 2,509 ‘inactive’ TBs. Inactive horses were defined as those horses that were recorded as ‘active’ but had not trialled or raced in the last 6 months of the racing season or had an inactive status recorded in the Racing Australia database. Of the 1,750 responses received, the largest group of inactive TBs had permanently exited the racing industry (45% retired, 5.3% deceased). A relatively large group exited racing temporarily (43%) but participated in the racing industry in the following season. The reasons for retirement were predominantly voluntary, such as poor performance or owner’s request. Almost one third of retirements were due to injuries with tendon or ligament problems the most frequently conditions listed. The median age at retirement was five (Q1 4; Q3 7) years. Extrapolation of the survey results to the population of horses racing or training in Australia in 2017–2018 (n = 37,750) show that that 17% of the population retire each year and 2.1% die. These estimates provide benchmarks for industry and animal welfare organisations to resource and measure the effectiveness of interventions.

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.

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.

Comprehensive assessment of food insecurity across all college community members is lacking. This research surveyed a random sample of an entire campus population at a Northeast University in two surveys (spring 2017, n = 1,037 and fall 2017, n = 1,123). Analysis of variance, t-tests, and multivariable logit models were used to understand food insecurity outcomes and comparisons among groups. The overall rate of food insecurity on campus was 19.6% (spring) and 15.0% (fall). Food insecurity rates were highest among undergraduates, graduate and medical students, and staff as compared to faculty. First generation students and off-campus students were also more likely to be food insecure in both surveys, while people of color were more likely to be food insecure in the spring survey. Findings suggest university members beyond undergraduates also face high rates of food insecurity, which has important implications for efforts to reduce food insecurity on college campuses.

Acute viral wheeze in children is a major cause of hospitalisation and a major risk factor for the development of asthma. However, the role of the respiratory tract microbiome in the development of acute wheeze is unclear. To investigate whether severe wheezing episodes in children are associated with bacterial dysbiosis in the respiratory tract, oropharyngeal swabs were collected from 109 children with acute wheezing attending the only tertiary paediatric hospital in Perth, Australia. The bacterial community from these samples was explored using next generation sequencing and compared to samples from 75 non-wheezing controls. No significant difference in bacterial diversity was observed between samples from those with wheeze and healthy controls. Within the wheezing group, attendance at kindergarten or preschool was however, associated with increased bacterial diversity. Rhinovirus (RV) infection did not have a significant effect on bacterial community composition. A significant difference in bacterial richness was observed between children with RV-A and RV-C infection, however this is likely due to the differences in age group between the patient cohorts. The bacterial community within the oropharynx was found to be diverse and heterogeneous. Age and attendance at day care or kindergarten were important factors in driving bacterial diversity. However, wheeze and viral infection were not found to significantly relate to the bacterial community. Bacterial airway microbiome is highly variable in early life and its role in wheeze remains less clear than viral influences.

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” entree was added at the beginning of the entree line, so that students would substitute an entree 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 entree 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

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.

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.

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.

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.

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.

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.

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.

Background The study objectives were to describe the incidence and the nature of patient safety incidents (PSIs) in primary care general practice settings, and to explore the association between these incidents and practice or organizational characteristics. Methods GPs, randomly selected from a national influenza surveillance network (n = 800) across France, prospectively reported any incidents observed each day over a one-week period between May and July 2013. An incident was an event or circumstance that could have resulted, or did result, in harm to a patient, which the GP would not wish to recur. Primary outcome was the incidence of PSIs which was determined by counting reports per total number of patient encounters. Reports were categorized using existing taxonomies. The association with practice and organizational characteristics was calculated using a negative binomial regression model. Results 127 GPs (participation rate 79%) reported 317 incidents of which 270 were deemed to be a posteriori judged preventable, among 12,348 encounters. 77% had no consequences for the patient. The incidence of reported PSIs was 26 per 1000 patient encounters per week (95% CI [23‰ -28‰]). Incidents were three times more frequently related to the organization of healthcare than to knowledge and skills of health professionals, and especially to the workflow in the GPs’ offices and to the communication between providers and with patients. Among GP characteristics, three were related with an increased incidence in the final multivariable model: length of consultation higher than 15 minutes, method of receiving radiological results (by fax compared to paper or email), and being in a multidisciplinary clinic compared with sole practitioners. Conclusions Patient safety incidents (PSIs) occurred in mean once every two days in the sampled GPs and 2% of them were associated with a definite possibility for harm. Studying the association between organizational features of general practices and PSIs remains a major challenge and one of the most important issues for safety in primary care.

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

BackgroundIndividuals 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.ObjectivesThis 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.MethodsForty 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.ResultsExcellent 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.ConclusionsThe 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.

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.

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.

BACKGROUND The South African Department of Health (DOH) publishes annual guidelines identifying priority groups, including immunosuppressed individuals and healthcare workers (HCW), for influenza vaccination and treatment. How these guidelines have impacted HCW and their patients, particularly those infected with HIV, remains unknown. METHODS We aimed to describe the knowledge, attitudes and practices regarding influenza and the vaccine among South African HCW. Surveys were distributed by two local non-governmental organizations in public health clinics and hospitals in 21 districts/municipalities (5 of 9 provinces). RESULTS There were 1164 respondents; median age 41 years; 978/1126 (87%) female; 801/1122 (71%) nurses. One-third (34%) of HCW reported getting influenza vaccine 2013/2014 and most (94%) recommended influenza vaccine to patients infected with HIV. Ability to get vaccine free of charge (aOR 1.69; 95% CI 1.21-2.37) and having received influenza government training (aOR 1.50; 95% CI 1.04-2.15) were significantly associated with self-reported vaccination in 2013/2014. Self-reported 2013/2014 vaccination (aOR 3.76; 95% CI 1.28-11.03) and availability of influenza vaccine during the healthcare visit (aOR 2.56; 95% CI 1.18-5.57) were significantly associated with recommending influenza vaccine to patients infected with HIV/AIDS. CONCLUSION Only one-third of participants were vaccinated in 2013-2014 but those who were vaccinated were more likely to recommend vaccination to their patients. Free and close access to influenza vaccine were associated with a higher likelihood of getting vaccinated in 2013/2014. HCW who reported getting the influenza vaccine themselves, had vaccine to offer during the patient consult and were familiar with DOH guidelines/trainings were more likely to recommend vaccine to HIV-infected patients.

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.

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.

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.

A number of HIV-1 subtypes are identified in Pakistan by characterization of partial viral gene sequences. Little is known whether new recombinants are generated and how they disseminate since whole genome sequences for these viruses have not been characterized. Near full-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes or next generation sequencing from 34 HIV-1-infected individuals in Pakistan. Phylogenetic tree analysis showed that the newly characterized sequences were 16 subtype As, one subtype C, and 17 A/G recombinants. Further analysis showed that all 16 subtype A1 sequences (47%), together with the vast majority of sequences from Pakistan from other studies, formed a tight subcluster (A1a) within the subtype A1 clade, suggesting that they were derived from a single introduction. More in-depth analysis of 17 A/G NFLG sequences showed that five shared similar recombination breakpoints as in CRF02 (15%) but were phylogenetically distinct from the prototype CRF02 by forming a tight subcluster (CRF02a) while 12 (38%) were new recombinants between CRF02a and A1a or a divergent A1b viruses. Unique recombination patterns among the majority of the newly characterized recombinants indicated ongoing recombination. Interestingly, recombination breakpoints in these CRF02/A1 recombinants were similar to those in prototype CRF02 viruses, indicating that recombination at these sites more likely generate variable recombinant viruses. The dominance and fast dissemination of new CRF02a/A1 recombinants over prototype CRF02 suggest that these recombinant have more adapted and may become major epidemic strains in Pakistan.

Obesity is one of the dramatic health issues affecting developed and developing nations, and exercise is a well-established intervention strategy. While exercise-by-genotype interactions have been shown in humans, overall little is known. Using the natural negative geotaxis of Drosophila melanogaster, an important model organism for the study of genetic interactions, a novel exercise machine, the TreadWheel, can be used to shed light on this interaction. The mechanism for inducing exercise with the TreadWheel is inherently gentle, thus minimizing possible confounding effects of other stressors. Using this machine, we were able to assess large cohorts of adult flies from eight genetic lines for their response to exercise after one week of training. We measured their triglyceride, glycerol, protein, glycogen, glucose content, and body weight, as well as their climbing ability and feeding behavior in response to exercise. Exercised flies showed decreased stored triglycerides, glycogen, and body weight, and increased stored protein and climbing ability. In addition to demonstrating an overall effect of TreadWheel exercise on flies, we found significant interactions of exercise with genotype, sex, or genotype-by-sex effects for most of the measured phenotypes. We also observed interaction effects between exercise, genotype, and tissue (abdomen or thorax) for metabolite profiles, and those differences can be partially linked to innate differences in the flies' persistence in maintaining activity during exercise bouts. In addition, we assessed gene expression levels for a panel of 13 genes known to be associated with respiratory fitness and found that many responded to exercise. With this study, we have established the TreadWheel as a useful tool to study the effect of exercise in flies, shown significant genotype-specific and sex-specific impacts of exercise, and have laid the ground work for more extensive studies of how genetics, sex, environment, and aging interact with exercise to influence metabolic fitness in Drosophila.

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.

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.

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 PM2.5levels 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 PM2.5preceding 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.

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.

FKBP5 is a critical component of the Hypothalamic-Pituitary-Adrenal (HPA) axis, a system which regulates our response to stress. It forms part of a complex of chaperones, which inhibits binding of cortisol and glucocorticoid receptor translocation to the nucleus. Variations in both the HPA axis and FKBP5 have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near FKBP5 in 476 bipolar disorder suicide attempters and 473 bipolar disorder non-attempters. Following stringent quality control checks, we performed single-variant, gene-level and haplotype tests on the resulting 481 variants. Secondary analyses investigated whether sex-specific variations in FKBP5 increased the risk of attempted suicide. One variant, rs141713011, showed an excess of minor alleles in suicide attempters that was statistically significant following correction for multiple testing (Odds Ratio = 6.65, P-value = 7.5 x 10−4, Permuted P-value = 0.038). However, this result could not be replicated in an independent cohort (Odds Ratio = 0.90, P-value = 0.78). Three female-specific and four male-specific variants of nominal significance were also identified (P-value < 0.05). The gene-level and haplotype association tests did not produce any significant results. This comprehensive study of common and rare variants in FKBP5 focused on both regulatory and coding regions in relation to attempted suicide. One rare variant remained significant following correction for multiple testing but could not be replicated. Further investigation is required in larger sample sets to fully elucidate the association of this variant with suicidal behavior.