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Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n = 183), Chinese (n = 71), European (n = 416), and Hispanic/Latino (n = 301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises ∼50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods at https://doi.org/10.5281/zenodo.4837327.

BackgroundUnaddressed age-related hearing loss is highly prevalent among older adults, typified by negative consequences for speech-in-noise perception and psychosocial wellbeing. There is promising evidence that group singing may enhance speech-in-noise perception and psychosocial wellbeing. However, there is a lack of robust evidence, primarily due to the literature being based on small sample sizes, single site studies, and a lack of randomized controlled trials. Hence, to address these concerns, this SingWell Project study utilizes an appropriately powered sample size, multisite, randomized controlled trial approach, with a robust preplanned statistical analysis.ObjectiveTo explore if group singing may improve speech-in-noise perception and psychosocial wellbeing for older adults with unaddressed hearing loss.MethodsWe designed an international, multisite, randomized controlled trial to explore the benefits of group singing for adults aged 60 years and older with unaddressed hearing loss (registered at clinicaltrials.gov, ID: NCT06580847). After undergoing an eligibility screening process and completing an information and consent form, we intend to recruit 210 participants that will be randomly assigned to either group singing or an audiobook club (control group) intervention for a training period of 12-weeks. The study has multiple timepoints for testing, that are broadly categorized as macro (i.e., pre- and post-measures across the 12-weeks), or micro timepoints (i.e., pre- and post-measures across a weekly training session). Macro measures include behavioural measures of speech and music perception, and psychosocial questionnaires. Micro measures include psychosocial questionnaires and heart-rate variability.HypothesesWe hypothesize that group singing may be effective at improving speech perception and psychosocial outcomes for adults aged 60 years and older with unaddressed hearing loss-more so than participants in the control group.

Transrectal ultrasonography is known as the gold standard for pregnancy detection, but requires costly equipment and technical skills; therefore, access to an inexpensive and more user-friendly method with similar accuracy could benefit cattle producers. Detection of pregnancy-associated glycoproteins can accurately determine pregnancy in ruminants; however, usually requires specialized equipment for the assay. Thus, the objectives of these studies were to 1) validate the IDEXX Alertys OnFarm Pregnancy Test (lateral flow) and compare the accuracy of all three commercial PAG assays to transrectal ultrasonography and 2) to determine the postpartum interval necessary for clearance of pregnancy-associated glycoproteins from the previous pregnancy to avoid false positives. In study 1, blood samples from previously identified pregnant Bos taurus females from six different herds (nulliparous n = 1,205 and multiparous n = 1,539; samples collected between d 27 to 285 of gestation over a three-year period) were utilized. In study 2, postpartum females (primiparous n = 48 and multiparous n = 66) from one herd were utilized: (n = 1,066; samples collected weekly for up to 12 weeks postpartum). In study 1, level of agreement between different methods of pregnancy detection was determined by Pearson's correlation and Kappa scores. In study 2, data were analyzed as a repeated measure using the MIXED procedure of SAS with main effects of parity, days postpartum (dpp), and parity by days postpartum, then data were analyzed further using the REG procedure of SAS. In study 1, transrectal ultrasonography and lateral flow were positively correlated (r = 0.77; P

BackgroundA common complaint in older adults is trouble with their memory, especially for new information. Current knowledge about normal aging and changes in memory identify a divide between memory tasks that are unaffected by aging and those that are. Among the unaffected are recognition tasks. These memory tasks rely on accessing well-known information, often include environmental support, and tend to be automatic. Negative age effects on memory are often observed at both encoding and during recall. Older adults often have difficulty with recall tasks, particularly those that require effortful self-initiated processing, episodic memory, and retention of information about contextual cues. Research in memory for music in healthy aging suggests a skill-invariance hypothesis: that age effects dominate when general-purpose cognitive mechanisms are needed to perform the musical task at hand, while experience effects dominate when music-specific knowledge is needed to perform the task [1].AimsThe goals of this pair of studies were to investigate the effects of age and familiarity on musical memory in the context of real pieces of music, and to compare a live concert experimental setting with a lab-based experimental setting.MethodParticipants' task was to click a button (or press the spacebar) when they heard the target theme in three pieces of music. One was Mozart's Eine Kleine Nachtmusik and the others were original pieces commissioned for this study, one tonal and one atonal. Participants heard the relevant theme three times before listening to a piece of music. The music was performed by the Newfoundland Symphony Orchestra; participants either attended the concert, or watched a recording of the concert in the lab. Participants also completed two short cognitive tests and filled out a questionnaire collecting demographic information and a hearing abilities self-assessment.ResultsWe find a significant effect of familiarity and setting but not of age or musical training on recognition performance as measured by d'. More specifically, performance is best for the familiar, tonal piece, moderate for the unfamiliar tonal piece and worst for the unfamiliar atonal piece. Performance was better in the live setting than the lab setting.ConclusionsThe absence of an age effect provides encouraging evidence that music's diverse cues may encourage cognitive scaffolding, in turn improving encoding and subsequent recognition. Better performance in an ecological versus lab setting supports the expansion of ecological studies in the field.

Background and objectivesTransgender and gender diverse (trans) health research has grown rapidly, highlighting the need to characterize the scientific evidence base. We conducted a systematic review of peer-reviewed research on disease burden and correlates in trans adolescents and adults over a 20-month period to identify knowledge gaps and assess methodological characteristics including measurement of gender identity, community engagement, and study quality.Data sources, eligibility criteria, and synthesis methodsWe searched seven databases using terms related to (a) transgender populations and (b) health or disease. Eligible studies were in English, French, or Spanish and reported original quantitative data on mental health or substance use conditions, infectious diseases, or non-communicable conditions in at least 25 trans individuals aged 15+. Quality assessment was performed in duplicate on a 10% sample of articles and findings were summarized using narrative synthesis.ResultsThe 328 included studies were conducted in 45 countries, with most from North America (54%) and limited research from South Asia (3%), Sub-Saharan Africa (3%), and the Middle East and North Africa (2%). Most studies used cross-sectional designs (73%) and convenience sampling (65%). Only 30% of studies reported any form of community engagement. Mental health and substance use disorders were the most studied area (77% of studies) and non-communicable conditions the least (16%). Available data indicated that trans populations experience high disease burden with considerable heterogeneity within and across settings. Of 39 articles assessed for quality, 80% were rated as fair, 18% as poor, and 3% as good quality.Conclusions and implicationsGeographic, gender-specific, and topical gaps remain in trans health, but we found more research from African countries, with transmasculine people, and on non-communicable conditions than previous syntheses. Areas for growth in trans health research include community engagement, non-binary health, chronic and age-related conditions, and health determinants.RegistrationPROSPERO CRD42021234043.

Mechanisms controlling CO2 and CH4 production in wetlands are central to understanding carbon cycling and greenhouse gas exchange. However, the volatility of these respiration products complicates quantifying their rates of production in the field. Attempts to circumvent the challenges through closed system incubations, from which gases cannot escape, have been used to investigate bulk in situ geochemistry. Efforts towards mapping mechanistic linkages between geochemistry and microbiology have raised concern regarding sampling and incubation-induced perturbations. Microorganisms are impacted by oxygen exposure, increased temperatures and accumulation of metabolic products during handling, storage, and incubation. We probed the extent of these perturbations, and their influence on incubation results, using high-resolution geochemical and microbial gene-based community profiling of anaerobically incubated material from three wetland habitats across a permafrost peatland. We compared the original field samples to the material anaerobically incubated over 50 days. Bulk geochemistry and phylum-level microbiota in incubations largely reflected field observations, but divergence between field and incubations occurred in both geochemistry and lineage-level microbial composition when examined at closer resolution. Despite the changes in representative lineages over time, inferred metabolic function with regards to carbon cycling largely reproduced field results suggesting functional consistency. Habitat differences among the source materials remained the largest driver of variation in geochemical and microbial differences among the samples in both incubations and field results. While incubations may have limited usefulness for identifying specific mechanisms, they remain a viable tool for probing bulk-scale questions related to anaerobic C cycling, including CO2 and CH4 dynamics.

BackgroundGenome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.Methods and resultsUsing samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.ConclusionThis study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

BackgroundTransgender women (TW) are disproportionately affected by both HIV and cardiovascular disease (CVD).ObjectivesWe aim to quantify prevalence of elevated predicted CVD risk for TW compared to cisgender women (CW) and cisgender men (CM) in HIV care and describe the impact of multiple operationalizations of CVD risk score calculations for TW.DesignWe conducted a cross-sectional analysis of patients engaged in HIV care between October 2014 and February 2018.SettingThe Centers for AIDS Research Network of Integrated Clinical Systems, a collaboration of 8 HIV clinical sites in the United States contributed data for this analysis.Patients221 TW, 2983 CW, and 13467 CM.MeasurementsThe measure of interest is prevalence of elevated 10-year cardiovascular disease risk based on ACC/AHA Pooled Cohort Risk Assessment equations (PCE) and the Framingham Risk Score (FRS), calculated for TW by: birth-assigned sex (male); history of exogenous sex hormone use (female/male); and current gender (female).ResultsUsing birth-assigned sex, the adjusted prevalence ratio (aPR) was 2.52 (95% CI: 1.08,5.86) and 2.58 (95% CI: 1.71,3.89) comparing TW to CW, by PCE and FRS, respectively. It was 1.25 (95% CI: 0.54,2.87) and 1.25 (95% CI: 0.84,1.86) comparing TW to CM, by PCE and FRS, respectively. If TW were classified according to current gender versus birth-assigned sex, their predicted CVD risk scores were lower.LimitationsPCE and FRS have not been validated in TW with HIV. Few adjudicated CVD events in the data set precluded analyses based on clinical outcomes.ConclusionsAfter adjustment for demographics and history of HIV care, prevalence of elevated CVD risk in TW was similar to CM and equal to or higher than in CW, depending operationalization of the sex variable. Future studies with CVD outcomes are needed to help clinicians accurately estimate CVD risk among TW with HIV.

The fossil record for Cretaceous birds in Australia has been limited to rare skeletal material, feathers, and two tracks, a paucity shared with other Gondwanan landmasses. Hence the recent discovery of 27 avian footprints and other traces in the Early Cretaceous (Barremian-Aptian, 128-120 Ma) Wonthaggi Formation of Victoria, Australia amends their previous rarity there, while also confirming the earliest known presence of birds in Australia and the rest of Gondwana. The avian identity of these tracks is verified by their tridactyl forms, thin digits relative to track lengths, wide divarication angles, and sharp claws; three tracks also have hallux imprints. Track forms and sizes indicate a variety of birds as tracemakers, with some among the largest reported from the Early Cretaceous. Although continuous trackways are absent, close spacing and similar alignments of tracks on some bedding planes suggest gregariousness. The occurrence of this avian trace-fossil assemblage in circumpolar fluvial-floodplain facies further implies seasonal behavior, with trackmakers likely leaving their traces on floodplain surfaces during post-thaw summers.

The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 (GSTM1) gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol. Subjects were exposed for 3 h in random order to 0 parts per billion (ppb) (filtered air), 70 ppb, and 120 ppb ozone, alternating 15 min of moderate exercise and rest. Blood was obtained the day before, approximately 4 h after, and approximately 22 h after each exposure. Linear mixed effect and logistic regression models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. The definition of statistical significance was p

Background: Unaddressed age-related hearing loss is highly prevalent among older adults, typified by negative consequences for speech-in-noise perception and psychosocial wellbeing. There is promising evidence that group singing may enhance speech-in-noise perception and psychosocial wellbeing. However, there is a lack of robust evidence, primarily due to the literature being based on small sample sizes, single site studies, and a lack of randomized controlled trials. Hence, to address these concerns, this SingWell Project study utilizes an appropriately powered sample size, multisite, randomized controlled trial approach, with a robust preplanned statistical analysis. Objective: To explore if group singing may improve speech-in-noise perception and psychosocial wellbeing for older adults with unaddressed hearing loss. Methods: We designed an international, multisite, randomized controlled trial to explore the benefits of group singing for adults aged 60 years and older with unaddressed hearing loss (registered at clinicaltrials.gov, ID: NCT06580847). After undergoing an eligibility screening process and completing an information and consent form, we intend to recruit 210 participants that will be randomly assigned to either group singing or an audiobook club (control group) intervention for a training period of 12-weeks. The study has multiple timepoints for testing, that are broadly categorized as macro (i.e., pre- and post-measures across the 12-weeks), or micro timepoints (i.e., pre- and post-measures across a weekly training session). Macro measures include behavioural measures of speech and music perception, and psychosocial questionnaires. Micro measures include psychosocial questionnaires and heart-rate variability. Hypotheses: We hypothesize that group singing may be effective at improving speech perception and psychosocial outcomes for adults aged 60 years and older with unaddressed hearing loss—more so than participants in the control group. [ABSTRACT FROM AUTHOR]

BackgroundMultimorbidity is one of the greatest challenges facing health and social care systems globally. It is associated with high rates of health service use, adverse healthcare events, and premature death. Despite its importance, little is known about the effects of contextual determinants such as household and area characteristics on health and care outcomes for people with multimorbidity. This study protocol presents a plan for the examination of associations between individual, household, and area characteristics with important health and social care outcomes.MethodsThe study will use a cross-section of data from the SAIL Databank on 01 January 2019 and include all people alive and registered with a Welsh GP. The cohort will be stratified according to the presence or absence of multimorbidity, defined as two or more long-term conditions. Multilevel models will be used to examine covariates measured for individuals, households, and areas to account for social processes operating at different levels. The intra-class correlation coefficient will be calculated to determine the strength of association at each level of the hierarchy. Model outcomes will be any emergency department attendance, emergency hospital or care home admission, or mortality, within the study follow-up period.DiscussionHousehold and area characteristics might act as protective or risk factors for health and care outcomes for people with multimorbidity, in which case results of the analyses can be used to guide clinical and policy responses for effective targeting of limited resources.

PurposeUnpaid family caregivers provide extensive support for community-dwelling persons living with dementia, impacting family caregivers' health and wellbeing. Further, unpaid family caregiving in rural settings has additional challenges because of lower access to services. This systematic review examines qualitative evidence to summarize the experiences and needs of rural unpaid family caregivers of persons living with dementia.MethodsCINAHL, SCOPUS, EMBASE, Web of Science, PsychINFO, ProQuest, and Medline were searched for articles investigating the experience and needs of rural family caregivers of persons living with dementia. Eligibility criteria were: 1) original qualitative research; 2) written in the English language; 3) focused on the perspectives of caregivers of community-dwelling persons with dementia; 4) focused on rural settings. Study findings were extracted from each article and a meta-aggregate process was used to synthesize the findings.FindingsOf the 510 articles screened, 36 studies were included in this review. Studies were of moderate to high quality and produced 245 findings that were analyzed to produce three synthesized findings: 1) the challenge of dementia care; 2) rural limitations; 3) rural opportunities.ConclusionsRurality is perceived as a limitation for family caregivers in relation to the scope of services provided but can be perceived as a benefit when caregivers experience trustworthy and helpful social networks in rural settings. Implications for practice include establishing and empowering community groups to partner in the provision of care. Further research must be conducted to better understand the strengths and limitations of rurality on caregiving.

Physiological function is regulated through cellular communication that is facilitated by multiple signaling molecules such as second messengers. Analysis of signal dynamics obtained from cell and tissue imaging is difficult because of intricate spatially and temporally distinct signals. Signal analysis tools based on static region of interest analysis may under- or overestimate signals in relation to region of interest size and location. Therefore, we developed an algorithm for biological signal detection and analysis based on dynamic regions of interest, where time-dependent polygonal regions of interest are automatically assigned to the changing perimeter of detected and segmented signals. This approach allows signal profiles to be rigorously and precisely tracked over time, eliminating the signal distortion observed with static methods. Integration of our approach with state-of-the-art image processing and particle tracking pipelines enabled the isolation of dynamic cellular signaling events and characterization of biological signaling patterns with distinct combinations of parameters including amplitude, duration, and spatial spread. Our algorithm was validated using synthetically generated datasets and compared with other available methods. Application of the algorithm to volumetric time-lapse hyperspectral images of cyclic adenosine monophosphate measurements in rat microvascular endothelial cells revealed distinct signal heterogeneity with respect to cell depth, confirming the utility of our approach for analysis of 5-dimensional data. In human tibial arteries, our approach allowed the identification of distinct calcium signal patterns associated with atherosclerosis. Our algorithm for automated detection and analysis of second messenger signals enables the decoding of signaling patterns in diverse tissues and identification of pathologic cellular responses.

ObjectiveInvestigate the association between adverse childhood experiences and pre-pregnancy body mass index (BMI) in a population-based cohort in Trøndelag county, Norway.Materials and methodsWe linked data from the third (2006-2008) or fourth (2017-2019) survey of the Trøndelag Health Study (HUNT) and the Medical Birth Registry of Norway for 6679 women. Multiple logistic regression models were used to examine the association between adverse childhood experiences and pre-pregnancy BMI. Adverse childhood experiences were self-reported in adulthood and included perceiving childhood as difficult, parental divorce, parental death, dysfunctional family environment, bad childhood memories and lack of support from a trusted adult. Pre-pregnancy BMI was derived from the Medical Birth Registry of Norway or BMI measurement from the HUNT survey conducted within 2 years prior to the woman's pregnancy.ResultsPerceiving childhood as difficult was associated with higher odds of pre-pregnancy underweight (OR 1.78, 95%CI 0.99-3.22) and obesity (OR 1.58, 95%CI 1.14-2.2). A difficult childhood was positively associated with obesity with an adjusted OR of 1.19, 95%CI 0.79-1.81 (class I obesity), 2.32, 95%CI 1.35-4.01 (class II obesity) and 4.62, 95%CI 2.0-10.65 (class III obesity). Parental divorce was positively associated obesity (OR 1.34, 95%CI 1.10-1.63). Bad childhood memories were associated with both overweight (OR 1.34, 95%CI 1.01-1.79) and obesity (OR 1.63, 95%CI 1.13-2.34). Parental death was not associated with pre-pregnancy BMI.ConclusionsChildhood adversities were associated with pre-pregnancy BMI. Our results suggest that the positive associations between childhood adversities and pre-pregnancy obesity increased with increasing obesity level.

Rising temperatures and heatwaves increase mortality. Many of the subpopulations most vulnerable to heat-related mortality are in prisons, facilities that may exacerbate temperature exposures. Yet, there is scare literature on the impacts of heat among incarcerated populations. We analyzed data on mortality in U.S. state and private prisons from 2001–2019 linked to daily maximum temperature data for the months of June, July, and August. Using a case-crossover approach and distributed lag models, we estimated the association of increasing temperatures with total mortality, heart disease-related mortality, and suicides. We also examined the association with extreme heat and heatwaves (days above the 90th percentile for the prison location) and assessed effect modification by personal, facility, and regional characteristics. There were 12,836 deaths during summer months. The majority were male (96%) and housed in a state-operated prison (97%). A 10°F increase was associated with a 5.2% (95% CI: 1.5%, 9.0%) increase in total mortality and a 6.7% (95% CI: -0.6%, 14.0%) increase in heart disease mortality. The association between temperature and suicides was delayed, peaking around lag 3 (exposure at three days prior death). Two- and three-day heatwaves were associated with increased total mortality of 5.5% (95% CI: 0.3%, 10.9%) and 7.4% (95% CI: 1.6%, 13.5%), respectively. The cumulative effect (lags 1–3) of an extreme heat day was associated with a 22.8% (95% CI: 3.3%, 46.0%) increase in suicides. We found the greatest increase in mortality among people ≥ 65 years old, incarcerated less than one year, held in the Northeast region, and in urban or rural counties. These findings suggest that warm temperatures are associated with increased mortality in prisons, yet this vulnerable population’s risk has largely been overlooked.

Transrectal ultrasonography is known as the gold standard for pregnancy detection, but requires costly equipment and technical skills; therefore, access to an inexpensive and more user-friendly method with similar accuracy could benefit cattle producers. Detection of pregnancy-associated glycoproteins can accurately determine pregnancy in ruminants; however, usually requires specialized equipment for the assay. Thus, the objectives of these studies were to 1) validate the IDEXX Alertys OnFarm Pregnancy Test (lateral flow) and compare the accuracy of all three commercial PAG assays to transrectal ultrasonography and 2) to determine the postpartum interval necessary for clearance of pregnancy-associated glycoproteins from the previous pregnancy to avoid false positives. In study 1, blood samples from previously identified pregnant Bos taurus females from six different herds (nulliparous n = 1,205 and multiparous n = 1,539; samples collected between d 27 to 285 of gestation over a three-year period) were utilized. In study 2, postpartum females (primiparous n = 48 and multiparous n = 66) from one herd were utilized: (n = 1,066; samples collected weekly for up to 12 weeks postpartum). In study 1, level of agreement between different methods of pregnancy detection was determined by Pearson's correlation and Kappa scores. In study 2, data were analyzed as a repeated measure using the MIXED procedure of SAS with main effects of parity, days postpartum (dpp), and parity by days postpartum, then data were analyzed further using the REG procedure of SAS. In study 1, transrectal ultrasonography and lateral flow were positively correlated (r = 0.77; P <0.01), with 92.4% agreement. In study 2, the abundance of absorbance of PAGs rapidly decreased from 0 to 50 days postpartum, then continued to gradually decrease (P <0.01; r = 0.90). Prior to 42 days postpartum, PAG concentrations were sufficiently elevated resulting in false positive readings in all assays. In conclusion, there is very good agreement between transrectal ultrasonography and PAG assays, but likelihood of false positive results are highif assays are performed fewer than 42 days postpartum. [ABSTRACT FROM AUTHOR]

Background: A common complaint in older adults is trouble with their memory, especially for new information. Current knowledge about normal aging and changes in memory identify a divide between memory tasks that are unaffected by aging and those that are. Among the unaffected are recognition tasks. These memory tasks rely on accessing well-known information, often include environmental support, and tend to be automatic. Negative age effects on memory are often observed at both encoding and during recall. Older adults often have difficulty with recall tasks, particularly those that require effortful self-initiated processing, episodic memory, and retention of information about contextual cues. Research in memory for music in healthy aging suggests a skill-invariance hypothesis: that age effects dominate when general-purpose cognitive mechanisms are needed to perform the musical task at hand, while experience effects dominate when music-specific knowledge is needed to perform the task [1]. Aims: The goals of this pair of studies were to investigate the effects of age and familiarity on musical memory in the context of real pieces of music, and to compare a live concert experimental setting with a lab-based experimental setting. Method: Participants' task was to click a button (or press the spacebar) when they heard the target theme in three pieces of music. One was Mozart's Eine Kleine Nachtmusik and the others were original pieces commissioned for this study, one tonal and one atonal. Participants heard the relevant theme three times before listening to a piece of music. The music was performed by the Newfoundland Symphony Orchestra; participants either attended the concert, or watched a recording of the concert in the lab. Participants also completed two short cognitive tests and filled out a questionnaire collecting demographic information and a hearing abilities self-assessment. Results: We find a significant effect of familiarity and setting but not of age or musical training on recognition performance as measured by d'. More specifically, performance is best for the familiar, tonal piece, moderate for the unfamiliar tonal piece and worst for the unfamiliar atonal piece. Performance was better in the live setting than the lab setting. Conclusions: The absence of an age effect provides encouraging evidence that music's diverse cues may encourage cognitive scaffolding, in turn improving encoding and subsequent recognition. Better performance in an ecological versus lab setting supports the expansion of ecological studies in the field. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, healthcare workers faced grave responsibilities amidst rapidly changing policies and material and staffing shortages. Moral injury, psychological distress following events where actions transgress moral beliefs/ expectations, increased among healthcare workers. We used a sequential mixed methods approach to examine workplace and contextual factors related to moral injury early in the pandemic. Using a Total Worker Health® framework, we 1) examined factors associated with moral injury among active healthcare professionals (N = 14,145) surveyed between May-August 2020 and 2) qualitatively analyzed open-ended responses from 95 randomly selected participants who endorsed moral injury on the survey. Compared to inpatient hospital, outpatient (OR = 0.74 [0.65, 0.85]) or school clinic settings (OR = 0.37 [0.18, 0.75]) were associated with lower odds of moral injury; while group care settings increased odds (OR = 1.36 [1.07, 1.74]). Working with COVID+ patients (confirmed+ OR = 1.27 [1.03, 1.55]), PPE inadequacy (OR = 1.54 [1.27, 1.87]), and greater role conflict (OR = 1.57 [1.53, 1.62]) were associated with greater odds of moral injury. Qualitative findings illustrate how outside factors as well as organizational policies and working conditions influenced moral injury. Moral injury experiences affected staff turnover and patient care, potentially producing additional morally injurious effects. Worker- and patient-centered organizational policies are needed to prevent moral injury among healthcare workers. The generalizability of these findings may be limited by our predominantly white and female sample. Further research is indicated to replicate these findings in minoritized samples. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction

Opsins are photosensitive proteins catalyzing light-dependent processes across the tree of life. For both microbial (type 1) and metazoan (type 2) opsins, photosensing depends upon covalent interaction between a retinal chromophore and a conserved lysine residue. Despite recent discoveries of potential opsin homologs lacking this residue, phylogenetic dispersal and functional significance of these abnormal sequences have not yet been investigated. We report discovery of a large group of putatively non-retinal binding opsins, present in a number of fungal and microbial genomes and comprising nearly 30% of opsins in the Halobacteriacea, a model clade for opsin photobiology. We report phylogenetic analyses, structural modeling, genomic context analysis and biochemistry, to describe the evolutionary relationship of these recently described proteins with other opsins, show that they are expressed and do not bind retinal in a canonical manner. Given these data, we propose a hypothesis that these abnormal opsin homologs may represent a novel family of sensory opsins which may be involved in taxis response to one or more non-light stimuli. If true, this finding would challenge our current understanding of microbial opsins as a light-specific sensory family, and provides a potential analogy with the highly diverse signaling capabilities of the eukaryotic G-protein coupled receptors (GPCRs), of which metazoan type 2 opsins are a light-specific sub-clade.

Repellents serve an important role in bite protection. Tick repellents largely rely on biomechanisms that induce responses with direct contact, but synthetic pyrethroids used as spatial repellents against insects have received recent attention for potential use in tick protection systems. An in vitro vertical climb assay was designed to assess spatial repellency against Dermacentor variabilis, Amblyomma americanum, and Ixodes scapularis adult, female ticks. Climbing behavior was assessed with and without the presence of two spatial repellents, transfluthrin and metofluthrin. Repellency parameters were defined to simulate the natural questing behavior of ambushing ticks, including measures of detachment, pseudo-questing duration, climbing deterrence, and activity. Significant effects were observed within each parameter. D. variabilis showed the greatest general susceptibility to each repellent, followed by A. americanum, and I. scapularis. The most important and integrative measure of repellency was climbing deterrence-a measure of the spatial repellent's ability to disrupt a tick's natural propensity to climb. Transfluthrin deterred 75% of D. variabilis, 67% of A. americanum, and 50% of I. scapularis. Metofluthrin was slightly more effective, deterring 81% of D. variabilis, 73% of A. americanum, and 72% of I. scapularis. The present study poses a novel paradigm for repellency and reports a preliminary assessment of spatial repellent effect on tick behavior. Further research will assess spatial repellency in a more natural setting, scale exposure conditions, and incorporate host cues.

Peatlands account for 15 to 30% of the world's soil carbon (C) stock and are important controls over global nitrogen (N) cycles. However, C and N concentrations are known to vary among peatlands contributing to the uncertainty of global C inventories, but there are few global studies that relate peatland classification to peat chemistry. We analyzed 436 peat cores sampled in 24 countries across six continents and measured C, N, and organic matter (OM) content at three depths down to 70 cm. Sites were distinguished between northern (387) and tropical (49) peatlands and assigned to one of six distinct broadly recognized peatland categories that vary primarily along a pH gradient. Peat C and N concentrations, OM content, and C:N ratios differed significantly among peatland categories, but few differences in chemistry with depth were found within each category. Across all peatlands C and N concentrations in the 10-20 cm layer, were 440 ± 85.1 g kg-1 and 13.9 ± 7.4 g kg-1, with an average C:N ratio of 30.1 ± 20.8. Among peatland categories, median C concentrations were highest in bogs, poor fens and tropical swamps (446-532 g kg-1) and lowest in intermediate and extremely rich fens (375-414 g kg-1). The C:OM ratio in peat was similar across most peatland categories, except in deeper samples from ombrotrophic tropical peat swamps that were higher than other peatlands categories. Peat N concentrations and C:N ratios varied approximately two-fold among peatland categories and N concentrations tended to be higher (and C:N lower) in intermediate fens compared with other peatland types. This study reports on a unique data set and demonstrates that differences in peat C and OM concentrations among broadly classified peatland categories are predictable, which can aid future studies that use land cover assessments to refine global peatland C and N stocks.

Borrelia burgdorferi is an important tickborne human pathogen comprising several strains based on nucleotide sequence of the outer surface protein C (ospC) gene. Detection and characterization of different ospC genotypes is vital for research on B. burgdorferi and the risk it poses to humans. Here we present a novel, multiplex assay based on Luminex xMAP technology for the detection of B. burgdorferi ospC genotypes. The assay has five major steps: amplification of the ospC gene, hydrolyzation of surplus primers and nucleotides, incorporation of biotinylated nucleotides into the template DNA, hybridization to Luminex microspheres, and detection of fluorescent signals corresponding to each ospC genotype. We validated the protocol by comparing results obtained from our method against results from an established ospC genotyping method. This protocol can be used for the characterization of ospC genotypes in B. burgdorferi infected ticks, reservoir hosts, and/or clinical samples.

BackgroundHIV-related self-stigma is a significant barrier to HIV management. However, very little research has explored this phenomenon, particularly in sub-Saharan Africa. This study explored the beliefs, experiences, and impacts of HIV self-stigma amongst adolescents and young adults (AYALHIV) in Harare, Zimbabwe to inform future interventions. It aimed to capture the lived experience of self-stigmatization among AYALHIV and its impact on their social context using Corrigan et al (2009) self-stigma framework of 'awareness', 'agreement', and 'application'.MethodsVirtual semi-structured key informant interviews were conducted between June and July 2020 with adolescents and young adults (Female = 8; Male = 8) living with HIV (18-24 years) in Harare, Zimbabwe. We conducted the interviews with a purposive sample of AYALHIV enrolled in Africaid's 'Zvandiri' program which provides HIV support services. Interviews were mainly conducted in English and with three in Shona, the main indigenous language. Audio-recorded qualitative data were transcribed, translated into English (where necessary) and deductively coded using Corrigan et al.'s self-stigma framework. The outbreak of SARS-CoV-2 coincided with the commencement of data collection activities, which impacted on both the sample size and a shift from in-person to virtual interviewing methods.ResultsSixteen respondents (50% male) took part in the interviews. The mean age of respondents was 22 years. All respondents reported HIV-related self-stigma either occasionally or frequently. Three main themes of self-stigmatizing experiences emerged: disclosure, relationships, and isolation. These themes were then analyzed within the self-stigma development framework by Corrigan et al. (2009) known as 'the three As': awareness, agreement, and application of self-stigmatizing thoughts. Respondents' experiences of self-stigma reportedly led to poor well-being and decreased mental and physical health. Gendered experiences and coping mechanisms of self-stigma were reported. Data suggested that context is key in the way that HIV is understood and how it then impacts the way people living with HIV (PLHIV) live with, and experience, HIV.ConclusionsHIV-related negative self-perceptions were described by all respondents in this study, associated with self-stigmatizing beliefs that adversely affected respondents' quality of life. Study findings supported Corrigan et al.'s framework on how to identify self-stigma and was a useful lens through which to understand HIV-related self-stigma among young people in Harare. Study findings highlight the need for interventions targeting PLHIV and AYALHIV to be context relevant if they are to build individual resilience, while working concurrently with socio-political and systemic approaches that challenge attitudes to HIV at the wider societal levels. Finally, the gendered experiences of self-stigma point to the intersecting layers of self-stigma that are likely to be felt by particularly marginalized populations living with HIV and should be further explored.

Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n = 183), Chinese (n = 71), European (n = 416), and Hispanic/Latino (n = 301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises ∼50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods at https://doi.org/10.5281/zenodo.4837327.

The mechanisms controlling the extraordinarily slow carbon (C) mineralization rates characteristic of Sphagnum-rich peatlands ("bogs") are not fully understood, despite decades of research on this topic. Soluble phenolic compounds have been invoked as potentially significant contributors to bog peat recalcitrance due to their affinity to slow microbial metabolism and cell growth. Despite this potentially significant role, the effects of soluble phenolic compounds on bog peat C mineralization remain unclear. We analyzed this effect by manipulating the concentration of free soluble phenolics in anaerobic bog and fen peat incubations using water-soluble polyvinylpyrrolidone ("PVP"), a compound that binds with and inactivates phenolics, preventing phenolic-enzyme interactions. CO2 and CH4 production rates (end-products of anaerobic C mineralization) generally correlated positively with PVP concentration following Michaelis-Menten (M.M.) saturation functions. Using M.M. parameters, we estimated that the extent to which phenolics inhibit anaerobic CO2 production was significantly higher in the bog-62 ± 16%-than the fen-14 ± 4%. This difference was found to be more substantial with regards to methane production-wherein phenolic inhibition for the bog was estimated at 54 ± 19%, while the fen demonstrated no apparent inhibition. Consistent with this habitat difference, we observed significantly higher soluble phenolic content in bog vs. fen pore-water. Together, these findings suggest that soluble phenolics could contribute to bogs' extraordinary recalcitrance and high (relative to other peatland habitats) CO2:CH4 production ratios.

PurposeWe aimed to discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). We conducted a genome-wide association study (GWAS) in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels.MethodsWe stratified the cohort based on T2D status and conducted association analyses of TG levels for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochran's Q-test and we validated the significantly associated variants in the Mass General Brigham Biobank (MGBB).ResultsAmong 21,176 T2D and 402,944 non-T2D samples from UKB, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2 = 98.4%; pheterogeneity = 2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: -0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene, between HLA-DQB1 and HLA-DQA2 genes. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity = 9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications.ConclusionIn conclusion, we identified an intergenic variant near HLA-DQB1/DQA2 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.

Auditory stream segregation, or separating sounds into their respective sources and tracking them over time, is a fundamental auditory ability. Previous research has separately explored the impacts of aging and musicianship on the ability to separate and follow auditory streams. The current study evaluated the simultaneous effects of age and musicianship on auditory streaming induced by three physical features: intensity, spectral envelope and temporal envelope. In the first study, older and younger musicians and non-musicians with normal hearing identified deviants in a four-note melody interleaved with distractors that were more or less similar to the melody in terms of intensity, spectral envelope and temporal envelope. In the second study, older and younger musicians and non-musicians participated in a dissimilarity rating paradigm with pairs of melodies that differed along the same three features. Results suggested that auditory streaming skills are maintained in older adults but that older adults rely on intensity more than younger adults while musicianship is associated with increased sensitivity to spectral and temporal envelope, acoustic features that are typically less effective for stream segregation, particularly in older adults.

Participation in valued interpersonal and community activities is a key component of rehabilitation for Veterans with amputation. The purpose of this study was to identify specific factors that promote or inhibit participation to inform development of interventions that may facilitate participation in desired life activities. A convenience sample of 408 Veterans with at least one lower limb amputation and who had received outpatient care from the Regional Amputation Center (RAC) completed a mailed survey. Participation was measured using the Community Participation Indicators (CPI) Importance, Control, and Frequency scales and the Patient Reported Outcome Measurement Information System (PROMIS) Ability to Participate in Social Roles and Satisfaction with Social Participation scales. Multiple imputation procedures were used to address missing data. Correlates of participation were examined through multiple linear regression. A total of 235 participants completed the survey, a response rate of 58%. Levels of participation, measured with the PROMIS instruments, were 43.2 (SD = 8.1) for Ability and 46.4 (SD = 8.6) for Satisfaction. Regression analyses found robust amputation-specific correlates for participation, including body image and balance confidence. Generic (non-amputation specific) correlates for participation included depression and pain interference. Development of treatment approaches and devices that can address body image, balance confidence, pain, and mental health concerns such as depression have the potential to enhance the participation and rehabilitation of Veterans with lower limb amputation.

IntroductionThe association between childhood sexual abuse and HIV risk among men who have sex with men (MSM) is well established. However, no studies have examined the potential impact of other forms of childhood maltreatment on HIV incidence in this population.MethodsWe explored the impact of child physical abuse (CPA) on HIV seroconversion in a cohort of gay/bisexual men aged 15 to 30 in Vancouver, Canada. Cox proportional hazard models were used, controlling for confounders.ResultsAmong 287 participants, 211 (73.5%) reported experiencing CPA before the age of 17, and 42 (14.6%) reporting URAI in the past year. After a median of 6.6 years follow-up, 16 (5.8%) participants HIV-seroconverted. In multivariate analysis, CPA was significantly associated with HIV seroconversion (adjusted hazard ratio [AHR] = 4.89, 95% confidence interval (CI): 1.65-14.48), after controlling for potential confounders.ConclusionOur study uncovered a link between childhood physical violence and HIV incidence. Results highlight an urgent need for screening of young gay and bisexual men for histories of violence, and social and structural supports to prevent HIV transmission in this population.

Behavioral thermoregulation is an important defense against the negative impacts of climate change for ectotherms. In this study we examined the use of burrows by a common intertidal crab, Minuca pugnax, to control body temperature. To understand how body temperatures respond to changes in the surface temperature and explore how efficiently crabs exploit the cooling potential of burrows to thermoregulate, we measured body, surface, and burrow temperatures during low tide on Sapelo Island, GA in March, May, August, and September of 2019. We found that an increase in 1°C in the surface temperature led to a 0.70-0.71°C increase in body temperature for females and an increase in 0.75-0.77°C in body temperature for males. Body temperatures of small females were 0.3°C warmer than large females for the same surface temperature. Female crabs used burrows more efficiently for thermoregulation compared to the males. Specifically, an increase of 1°C in the cooling capacity (the difference between the burrow temperature and the surface temperature) led to an increase of 0.42-0.50°C for females and 0.34-0.35°C for males in the thermoregulation capacity (the difference between body temperature and surface temperature). The body temperature that crabs began to use burrows to thermoregulate was estimated to be around 24°C, which is far below the critical body temperatures that could lead to death. Many crabs experience body temperatures of 24°C early in the reproductive season, several months before the hottest days of the year. Because the use of burrows involves fitness trade-offs, these results suggest that warming temperatures could begin to impact crabs far earlier in the year than expected.

Mechanisms controlling CO2 and CH4 production in wetlands are central to understanding carbon cycling and greenhouse gas exchange. However, the volatility of these respiration products complicates quantifying their rates of production in the field. Attempts to circumvent the challenges through closed system incubations, from which gases cannot escape, have been used to investigate bulk in situ geochemistry. Efforts towards mapping mechanistic linkages between geochemistry and microbiology have raised concern regarding sampling and incubation-induced perturbations. Microorganisms are impacted by oxygen exposure, increased temperatures and accumulation of metabolic products during handling, storage, and incubation. We probed the extent of these perturbations, and their influence on incubation results, using high-resolution geochemical and microbial gene-based community profiling of anaerobically incubated material from three wetland habitats across a permafrost peatland. We compared the original field samples to the material anaerobically incubated over 50 days. Bulk geochemistry and phylum-level microbiota in incubations largely reflected field observations, but divergence between field and incubations occurred in both geochemistry and lineage-level microbial composition when examined at closer resolution. Despite the changes in representative lineages over time, inferred metabolic function with regards to carbon cycling largely reproduced field results suggesting functional consistency. Habitat differences among the source materials remained the largest driver of variation in geochemical and microbial differences among the samples in both incubations and field results. While incubations may have limited usefulness for identifying specific mechanisms, they remain a viable tool for probing bulk-scale questions related to anaerobic C cycling, including CO2 and CH4 dynamics.

Large-scale atmospheric conditions in the Northeast Pacific Ocean affect both the freshwater environment in the Columbia River Basin and marine conditions along the coasts of Oregon, Washington, and British Columbia, resulting in correlated conditions in the two environments. For migrating species, such as salmonids that move through multiple habitats, these correlations can amplify the impact of good or poor physical conditions on growth and survival, as movements among habitats may not alleviate effects of anomalous conditions. Unfortunately, identifying the mechanistic drivers of salmon survival in space and time is hindered by these cross-habitat correlations. To address this issue, we modeled the marine survival of Snake River spring/summer Chinook salmon with multiple indices of the marine environment and an explicit treatment of the effect of arrival timing from freshwater to the ocean, and found that both habitats contribute to marine survival rates. We show how this particular carryover effect of freshwater conditions on marine survival varies by year and rearing type (hatchery or wild), with a larger effect for wild fish. As environmental conditions change, incorporating effects from both freshwater and marine habitats into salmon survival models will become more important, and has the additional benefit of highlighting how management actions that affect arrival timing may improve marine survival.

Blood pressure regulation following spinal cord injury (SCI) is often compromised due to impaired vascular sympathetic control, leading to increased reliance on cardiovagal baroreflex sensitivity to maintain pressure. Whole-body exercise improves cardiovagal baroreflex sensitivity in uninjured individuals, though has not been explored in those with SCI. Our objective was to determine changes in cardiovagal baroreflex sensitivity following 6 months of high-intensity, whole-body exercise in individuals with SCI compared to lower-intensity, arms only exercise, or waitlist. This randomized controlled trial recruited individuals with SCI aged 18-40 years old. Sixty-one individuals were randomized, with 38 completing at least one cardiovagal baroreflex sensitivity assessment. Whole-body exercise was performed with hybrid functional electrical stimulation rowing prescribed as two to three times per week, for 30-60 minutes with a target heart rate of >75% of maximum. The arms only exercise group performed upper body rowing exercise with the same prescription as whole-body exercise. Waitlist controls were not enrolled in any explicit training regimen. After 6 months, those in arms only exercise or waitlist crossed over to whole-body exercise. Cardiovagal baroreflex sensitivity was assessed via the neck suction technique at baseline and at three-month intervals thereafter. Intention to treat analysis with a structured equation model demonstrated no significant effect of waitlist control or arms only exercise on cardiovagal baroreflex sensitivity. Whole-body exercise significantly improved cardiovagal baroreflex sensitivity at 6 months for those initially randomized (p = 0.03), as well as those who crossed over from arms only exercise or waitlist control (p = 0.03 for each). However, amount of exercise performed and aerobic gains (VO2max) each poorly correlated with increases in cardiovagal baroreflex sensitivity (R2

Rigorous healthcare design research is critical to inform design decisions that improve human experience. Current limitations in the field include a lack of consistent and valid measures that provide feedback about the role of the built environment in producing desirable outcomes. Research findings about nurses’ efficiency, quality of care, and satisfaction related to inpatient unit designs have been mixed, and there was previously no validated instrument available to quantitatively measure nurses’ ability to work efficiently and effectively in their environment. The objective of this study was to develop, refine, and validate a survey instrument to measure affordance of the care environment to nurse practice, based on various aspects of their work in inpatient units. The HDR Clinical Activities Related to the Environment (CARE) Scale Inpatient Version was developed using item design, refinement, and reliability and validity testing. Psychometric methods from classical test theory and item response theory, along with statistical analyses involving correlations and factor analysis, and thematic summaries of qualitative data were conducted. The four-phase process included (1) an initial pilot study, (2) a content validation survey, (3) cognitive interviews, and (4) a final pilot study. Results from the first three phases of analysis were combined to inform survey scale revisions before the second pilot survey, such as a reduction in the number and rewording of response options, and refinement of scale items. The updated 9-item scale showed excellent internal consistency and improved response distribution and discrimination. The factor analysis revealed a unidimensional measure of nurse practice, as well as potential subscales related to integration, efficiency, and patient care. Within the healthcare design industry, this scale is much needed to generate quantitative and standardized data and will facilitate greater understanding about the aspects of an inpatient healthcare facility that best support nurses’ ability to provide quality patient care.

Technologies and practices that reduce the environmental impacts of US agriculture are well documented. Less is known about how best to encourage their adoption. We report on the results of a large randomized controlled trial conducted with nearly 10,000 agricultural producers in the United States. The experiment was embedded in US Department of Agriculture outreach efforts to improve soil conservation practices. USDA varied the content of mailings to test two sets of competing theories about outreach to agricultural producers. Contrary to conventional wisdom, we find no evidence that acknowledging the link between climate change and agricultural production discourages conservation action. Furthermore, we find that producers who were invited to a webinar were less likely to take any action to learn more about conservation practices than producers who were not told about the webinar, a result that runs counter to the popular wisdom that offering more options leads to more action.

Treatment of hematologic malignancies is a formidable challenge for hematologists and there is an urgent need to identify safe and efficacious agents either via synthesis in the laboratory or isolation from natural products. Here, we report the cytotoxicity of extracts from mushroom Gymnopilus purpureosquamulosus Høil (G. pps) and describe its molecular mechanisms. Using leukemia, lymphoma and multiple myeloma cell lines, 28-35 ppm G. pps extract inhibited cell proliferation by ~46-79%, which correlates with activation of apoptosis as indicated by increase in annexin V-positive cells (~5-8-fold), production of reactive oxygen species (~2-3-fold), cells in sub G0/G1 phase (~3-13-fold), caspase 3 enzymatic activity (~1.6-2.9-fold), DNA fragmentation, PARP1 cleavage and down-regulation of prosurvival proteins. Mitochondrial membrane potential decreased and leakage of pro-apoptotic factors to cytoplasm was observed, consistent with the activation of intrinsic apoptosis. Western blot analysis showed activation of the ASK1-MEK-SAPK/JNK and ASK1-P38 MAPK pathways possibly due to changes in the cellular redox status as suggested by decreased protein levels of peroxiredoxin, thioredoxin and thioredoxin reductase. Moreover, antioxidant N-acetylcysteine alleviated the cytotoxicity of G. pps. Pharmacological inhibition of SAPK/JNK and P38 alleviated the G. pps-mediated cytotoxicity. The extract activated apoptosis in leukemia and lymphoma patient cell samples but not in mononuclear cells from healthy donors further supporting the therapeutic values of G. pps for hematologic malignancies.

AimHow reduced femoral neck anteversion alters the distribution of pressure and contact area in Hip Resurfacing Arthroplasty (HRA) remains unclear. The purpose of this study was to quantitatively describe the biomechanical implication of different femoral neck version angles on HRA using a finite element analysis.Materials and methodsA total of sixty models were constructed to assess the effect of different femoral neck version angles on three different functional loads: 0°of hip flexion, 45°of hip flexion, and 90° of hip flexion. Femoral version was varied between 30° of anteversion to 30° of retroversion. All models were tested with the acetabular cup in four different positions: (1) 40°/15° (inclination/version), (2) 40°/25°, (3) 50°/15°, and (4) 50°/25°. Differences in range of motion due to presence of impingement, joint contact pressure, and joint contact area with different femoral versions and acetabular cup positions were calculated.ResultsImpingement was found to be most significant with the femur in 30° of retroversion, regardless of acetabular cup position. Anterior hip impingement occurred earlier during hip flexion as the femur was progressively retroverted. Impingement was reduced in all models by increasing acetabular cup inclination and anteversion, yet this consequentially led to higher contact pressures. At 90° of hip flexion, contact pressures and contact areas were inversely related and showed most notable change with 30° of femoral retroversion. In this model, the contact area migrated towards the anterior implant-bone interface along the femoral neck.ConclusionFemoral retroversion in HRA influences impingement and increases joint contact pressure most when the hip is loaded in flexion. Increasing acetabular inclination decreases the area of impingement but doing so causes a reciprocal increase in joint contact pressure. It may be advisable to study femoral neck version pre-operatively to better choose hip resurfacing arthroplasty candidates.

IntroductionThe Eastern Europe and Central Asian (EECA) region has the highest increase in HIV incidence and mortality globally, with suboptimal HIV treatment and prevention. All EECA countries (except Russia) are low and middle-income (LMIC). While LMIC are home to 80% of all older people living with HIV (OPWH), defined as ≥50 years, extant literature observed that newly diagnosed OPWH represent the lowest proportion in EECA relative to all other global regions. We examined HIV diagnoses in OPWH in Ukraine, a country emblematic of the EECA region.MethodsWe analysed incident HIV diagnoses from 2015-2018 and mortality trends from 2016-2018 for three age groups: 1) 15-24 years; 2) 25-49 years; and 3) ≥50 years. AIDS was defined as CD4ResultsFrom 2015-2018, the proportion of OPWH annually diagnosed with HIV increased from 11.2% to 14.9% (pConclusionsThese findings suggest a reassessment of HIV testing, prevention and treatment strategies in Ukraine is needed to bring OPWH into focus. OPWH are more likely to present with late-stage HIV and have higher mortality rates. Re-designing testing practices is especially crucial since OPWH are absent from targeted testing programs and are increasingly diagnosed as they present with AIDS-defining symptoms. New strategies for linkage and treatment programs should reflect the distinct needs of this target population.

BackgroundType III interferon, or interferon lambda (IFNλ) is a crucial antiviral cytokine induced by influenza infection. While IFNλ is important for anti-viral host defense, published data demonstrate that IFNλ is pathogenic during influenza/bacterial super-infection. It is known that polymorphisms in specific IFNλ genes affect influenza responses, but the effect of IFNλ subtypes on bacterial super-infection is unknown.MethodsUsing an established model of influenza, Staphylococcus aureus super-infection, we studied IFNλ3-/- and control mice to model a physiologically relevant reduction in IFNλ and to address its role in super-infection.ResultsSurprisingly, IFNλ3-/- mice did not have significantly lower total IFNλ than co-housed controls, and displayed no change in viral or bacterial clearance. Importantly, both control and IFNλ3-/- mice displayed a positive correlation between viral burden and total IFNλ in the bronchoalveolar lavage during influenza/bacterial super-infection, suggesting that higher influenza viral burden drives a similar total IFNλ response regardless of IFNλ3 gene integrity. Interestingly, total IFNλ levels positively correlated with bacterial burden, while viral burden and bronchoalveolar lavage cellularity did not.ConclusionsThese data suggest IFNλ2 can compensate for IFNλ3 to mount an effective antiviral and defense, revealing a functional redundancy in these highly similar IFNλ subtypes. Further, the IFNλ response to influenza, as opposed to changes in cellular inflammation or viral load, significantly correlates with susceptibility to bacterial super-infection. Moreover, the IFNλ response is regulated and involves redundant subtypes, suggesting it is of high importance to pulmonary pathogen defense.

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.

BACKGROUND:Increased maternal health care (MHC) service utilisation in Bangladesh over the past decades has contributed to improvements in maternal health outcomes nationally, yet there is little understanding of Indigenous women's experiences of accessing MHC services in Bangladesh. METHODS:Face-to-face semi-structured qualitative interviews with 21 Indigenous women (aged 15-49 years) within 36 months of delivery from three ethnic groups (Chakma, Marma and Tripura) were conducted between September 2017 and February 2018 in Khagrachhari district. Purposive sampling was used to recruit women representative of the population distribution in terms of age, ethnic community and service use experience. All interviews were conducted in Bangla language and audio-recorded with consent. Interviews were transcribed directly into English before being coded. Data were analysed thematically using a qualitative descriptive approach aided by NVivo12 software. RESULTS:Of the 21 women interviewed, 14 had accessed at least one MHC service during their last pregnancy or childbirth and were categorised as the User group. The remaining seven participants were categorised as 'Non-users' as they had not access antenatal care, facility delivery or postnatal care services. Women reported that they wanted culturally relevant, respectful, home-based and affordable care, and generally perceived formal MHC services as being only for complications and emergencies. Barriers to accessing MHC services included low levels of understanding about the importance of MHC services, concerns about service costs, limited transport and fears of intrusive practices. Experiences within health services that deterred women from accessing future MHC services included demands for unofficial payments and abusive treatment by public facility staff. CONCLUSION:Improving access to MHC services for the CHT Indigenous women requires improved understandings of cultural values, priorities and concerns. Multifaceted reform is needed at individual, community and health systems levels to offer culturally appropriate health education and flexible service delivery options.

Studies of viral suppression on first-line antiretroviral therapy (ART) in persons living with human immunodeficiency virus (PLHIV) in Haiti are limited, particularly among PLHIV outside of the Ouest department, where the capital Port-au-Prince is located. This study described the prevalence and risk factors for delayed viral suppression among PLHIV in all geographic departments of Haiti between 2013 and 2017. Individuals who received viral load testing 3 to 12 months after ART initiation were included. Data on demographics and clinical care were obtained from the Haitian Active Longitudinal Tracking of HIV database. Multivariable logistic regression was performed to predict delayed viral suppression, defined as a viral load ≥1000 HIV-1 RNA copies/mL after at least 3 months on ART. Viral load test results were available for 3,368 PLHIV newly-initiated on ART. Prevalence of delayed viral suppression was 40%, which is slightly higher than previous estimates in Haiti. In the multivariable analysis, delayed viral suppression was significantly associated with younger age, receiving of care in the Ouest department, treatment with lamivudine (3TC), zidovudine (AZT), and nevirapine (NVP) combined ART regimen, and CD4 counts below 200 cells/mm3. In conclusion, this study was the first to describe and compare differences in delayed viral suppression among PLHIV by geographic department in Haiti. We identified populations to whom public health interventions, such as more frequent viral load testing, drug resistance testing, and ART adherence counseling should be targeted.

Evidence from neuroimaging and brain stimulation studies suggest that visual information about objects in the periphery is fed back to foveal retinotopic cortex in a separate representation that is essential for peripheral perception. The characteristics of this phenomenon have important theoretical implications for the role fovea-specific feedback might play in perception. In this work, we employed a recently developed behavioral paradigm to explore whether late disruption to central visual space impaired perception of color. In the first experiment, participants performed a shape discrimination task on colored novel objects in the periphery while fixating centrally. Consistent with the results from previous work, a visual distractor presented at fixation ~100ms after presentation of the peripheral stimuli impaired sensitivity to differences in peripheral shapes more than a visual distractor presented at other stimulus onset asynchronies. In a second experiment, participants performed a color discrimination task on the same colored objects. In a third experiment, we further tested for this foveal distractor effect with stimuli restricted to a low-level feature by using homogenous color patches. These two latter experiments resulted in a similar pattern of behavior: a central distractor presented at the critical stimulus onset asynchrony impaired sensitivity to peripheral color differences, but, importantly, the magnitude of the effect was stronger when peripheral objects contained complex shape information. These results show a behavioral effect consistent with disrupting feedback to the fovea, in line with the foveal feedback suggested by previous neuroimaging studies.