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INTRODUCTION: Depression is one of the most common yet underdiagnosed perinatal complications and our understanding of its pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants (e.g., biological, behavioral, environmental, social) and interactions among determinants of perinatal depression and the quality of methods applied. METHODS: Four databases (i.e., PubMed, CINAHL, APA PsycInfo, Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, depression was examined in a specific subpopulation evidenced to have psychological consequences due to situational stressors (e.g., fetal/infant loss, neonatal intensive care unit admission), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias. RESULTS: Of the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 32% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias. CONCLUSIONS: Future research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.

BackgroundParkinson disease (PD) psychosis (PDP) is a disabling non-motor symptom. Pharmacologic treatment is limited to pimavanserin, quetiapine, and clozapine, which do not worsen parkinsonism. A Food and Drug Administration black box warning exists for antipsychotics, suggesting increased mortality in elderly patients with dementia. However, the reasons for higher mortality are unknown.AimExpanding on prior work exploring mortality in treated PDP patients, we conducted a retrospective comparison to understand the links between treatment regimen, clinical characteristics, and negative outcomes.MethodsElectronic medical record data extraction included clinically diagnosed PD patients between 4/29/16-4/29/19 and excluded patients with primary psychiatric diagnoses or atypical parkinsonism. Mortality and clinical characteristics during the study period were compared between untreated patients and those receiving pimavanserin, quetiapine, or both agents (combination). Mortality analyses were adjusted for age, sex, levodopa equivalent daily dose (LEDD), and dementia.ResultsThe pimavanserin group (n = 34) had lower mortality than the untreated group (n = 66) (odds ratio = 0.171, 95% confidence interval: 0.025-0.676, p = 0.026). The untreated group had similar mortality compared to the quetiapine (n = 147) and combination (n = 68) groups. All treated groups had a higher LEDD compared to the untreated group, but no other differences in demographics, hospitalizations, medical comorbidities, medications, or laboratory values were found between the untreated and treated groups.ConclusionsPDP patients receiving pimavanserin had lower mortality than untreated patients. We found no other clear differences in clinical characteristics to explain the mortality risk. Prospective randomized trials are needed to definitively identify the optimal PDP treatment regimen and associated risks.

[This corrects the article DOI: 10.1371/journal.pone.0245064.].

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate's degree, vocational or technical training [reference category]; bachelor's degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor's degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor's degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

A common way of illustrating phylogeographic results is through the use of haplotype networks. While these networks help to visualize relationships between individuals, populations, and species, evolutionary studies often only quantitatively analyze genetic diversity among haplotypes and ignore other network properties. Here, we present a new metric, haplotype network branch diversity (HBd), as an easy way to quantifiably compare haplotype network complexity. Our metric builds off the logic of combining genetic and topological diversity to estimate complexity previously used by the published metric haplotype network diversity (HNd). However, unlike HNd which uses a combination of network features to produce complexity values that cannot be defined in probabilistic terms, thereby obscuring the values' implication for a sampled population, HBd uses frequencies of haplotype classes to incorporate topological information of networks, keeping the focus on the population and providing easy-to-interpret probabilistic values for randomly sampled individuals. The goal of this study is to introduce this more intuitive metric and provide an R script that allows researchers to calculate diversity and complexity indices from haplotype networks. A group of datasets, generated manually (model dataset) and based on published data (empirical dataset), were used to illustrate the behavior of HBd and both of its terms, haplotype diversity, and a new index called branch diversity. Results followed a predicted trend in both model and empirical datasets, from low metric values in simple networks to high values in complex networks. In short, the new combined metric joins genetic and topological diversity of haplotype networks, into a single complexity value. Based on our analysis, we recommend the use of HBd, as it makes direct comparisons of network complexity straightforward and provides probabilistic values that can readily discriminate situations that are difficult to resolve with available metrics.

IntroductionContemporary phase 2 TB disease treatment clinical trials have found that microbiologic treatment responses differ between African versus non-African regions, the reasons for which remain unclear. Understanding host and disease phenotypes that may vary by region is important for optimizing curative treatments.MethodsWe characterized clinical features and the serum proteome of phase 2 TB clinical trial participants undergoing treatment for smear positive, culture-confirmed TB, comparing host serum protein expression in clinical trial participants enrolled in African and Non-African regions. Serum samples were collected from 289 participants enrolled in the Centers for Disease Control and Prevention TBTC Study 29 (NCT00694629) at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment).ResultsAfter a peptide level proteome analysis utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS) and subsequent statistical analysis, a total of 183 core proteins demonstrated significant differences at both baseline and at week 8 timepoints between participants enrolled from African and non-African regions. The majority of the differentially expressed proteins were upregulated in participants from the African region, and included acute phase proteins, mediators of inflammation, as well as coagulation and complement pathways. Downregulated proteins in the African population were primarily linked to nutritional status and lipid metabolism pathways.ConclusionsWe have identified differentially expressed nutrition and lipid pathway proteins by geographic region in TB patients undergoing treatment for pulmonary tuberculosis, which appear to be associated with differential treatment responses. Future TB clinical trials should collect expanded measures of nutritional status and further evaluate the relationship between nutrition and microbiologic treatment response.

Several candidate HIV subunit vaccines based on recombinant envelope (Env) glycoproteins have been advanced into human clinical trials. To facilitate biopharmaceutical production, it is necessary to produce these in CHO (Chinese Hamster Ovary) cells, the cellular substrate used for the manufacturing of most recombinant protein therapeutics. However, previous studies have shown that when recombinant Env proteins from clade B viruses, the major subtype represented in North America, Europe, and other parts of the world, are expressed in CHO cells, they are proteolyzed and lack important glycan-dependent epitopes present on virions. Previously, we identified C1s, a serine protease in the complement pathway, as the endogenous CHO protease responsible for the cleavage of clade B laboratory isolates of -recombinant gp120s (rgp120s) expressed in stable CHO-S cell lines. In this paper, we describe the development of two novel CHOK1 cell lines with the C1s gene inactivated by gene editing, that are suitable for the production of any protein susceptible to C1s proteolysis. One cell line, C1s-/- CHOK1 2.E7, contains a deletion in the C1s gene. The other cell line, C1s-/- MGAT1- CHOK1 1.A1, contains a deletion in both the C1s gene and the MGAT1 gene, which limits glycosylation to mannose-5 or earlier intermediates in the N-linked glycosylation pathway. In addition, we compare the substrate specificity of C1s with thrombin on the cleavage of both rgp120 and human Factor VIII, two recombinant proteins known to undergo unintended proteolysis (clipping) when expressed in CHO cells. Finally, we demonstrate the utility and practicality of the C1s-/- MGAT1- CHOK1 1.A1 cell line for the expression of clinical isolates of clade B Envs from rare individuals that possess broadly neutralizing antibodies and are able to control virus replication without anti-retroviral drugs (elite neutralizer/controller phenotypes). The Envs represent unique HIV vaccine immunogens suitable for further immunogenicity and efficacy studies.

It has been established in recent years that the gut microbiome plays a role in health and disease, potentially via alterations in metabolites that influence host physiology. Although sleep disruption and gut dysbiosis have been associated with many of the same diseases, studies investigating the gut microbiome in the context of sleep disruption have yielded inconsistent results, and have not assessed the fecal metabolome. We exposed mice to five days of sleep disruption followed by four days of ad libitum recovery sleep, and assessed the fecal microbiome and fecal metabolome at multiple timepoints using 16S rRNA gene amplicons and untargeted LC-MS/MS mass spectrometry. We found global shifts in both the microbiome and metabolome in the sleep-disrupted group on the second day of recovery sleep, when most sleep parameters had recovered to baseline levels. We observed an increase in the Firmicutes:Bacteroidetes ratio, along with decreases in the genus Lactobacillus, phylum Actinobacteria, and genus Bifidobacterium in sleep-disrupted mice compared to control mice. The latter two taxa remained low at the fourth day post-sleep disruption. We also identified multiple classes of fecal metabolites that were differentially abundant in sleep-disrupted mice, some of which are physiologically relevant and commonly influenced by the microbiome. This included bile acids, and inference of microbial functional gene content suggested reduced levels of the microbial bile salt hydrolase gene in sleep-disrupted mice. Overall, this study adds to the evidence base linking disrupted sleep to the gut microbiome and expands it to the fecal metabolome, identifying sleep disruption-sensitive bacterial taxa and classes of metabolites that may serve as therapeutic targets to improve health after poor sleep.

Growing conditions for crops such as coffee and wine grapes are shifting to track climate change. Research on these crop responses has focused principally on impacts to food production impacts, but evidence is emerging that they may have serious environmental consequences as well. Recent research has documented potential environmental impacts of shifting cropping patterns, including impacts on water, wildlife, pollinator interaction, carbon storage and nature conservation, on national to global scales. Multiple crops will be moving in response to shifting climatic suitability, and the cumulative environmental effects of these multi-crop shifts at global scales is not known. Here we model for the first time multiple major global commodity crop suitability changes due to climate change, to estimate the impacts of new crop suitability on water, biodiversity and carbon storage. Areas that become newly suitable for one or more crops are Climate-driven Agricultural Frontiers. These frontiers cover an area equivalent to over 30% of the current agricultural land on the planet and have major potential impacts on biodiversity in tropical mountains, on water resources downstream and on carbon storage in high latitude lands. Frontier soils contain up to 177 Gt of C, which might be subject to release, which is the equivalent of over a century of current United States CO2 emissions. Watersheds serving over 1.8 billion people would be impacted by the cultivation of the climate-driven frontiers. Frontiers intersect 19 global biodiversity hotspots and the habitat of 20% of all global restricted range birds. Sound planning and management of climate-driven agricultural frontiers can therefore help reduce globally significant impacts on people, ecosystems and the climate system.

BackgroundSkin and soft tissue infections (SSTI) are a common but preventable cause of morbidity and mortality among people who inject drugs (PWID). They can be severe, and hospitalisations of PWID with SSTI are rising. The most common SSTI presentations are abscesses and cellulitis.MethodsWe used data from Care & Prevent, a cross-sectional community survey of PWID in London. We reported the lifetime prevalence of SSTI, severity of infections, key risk factors, and associated sequelae. Pictorial questions were used to assess SSTI severity.ResultsWe recruited 455 PWID. SSTI lifetime prevalence was high: 64% reported an abscess and/or cellulitis. Over one-third (37%) reported a severe infection, 137 (47%) reported hospitalisation. SSTIrisk factors were: aged 35+ years, injecting once or more times a day, subcutaneous or intra-muscular injections, and making four or more attempts to achieve an injection. Those who reported having other health conditions were at higher odds of having an abscess or cellulitis, with risk tending to increase with number of reported conditions. Half (46%) employed self-care for their worst SSTI, and 43% waited for ten or more days before seeking medical care or not seeking medical care at all.ConclusionsAbscess and cellulitis are very common among PWID in London. We corroborate findings indicating SSTIs are associated with risks, e.g. venous access problems, as well as other co-morbid conditions: septicaemia, endocarditis, DVT, and kidney disease. These co-morbidities may impact SSTIs severity and outcomes. Delayed healthcare seeking potentially exacerbates infection severity, which in turn increases poorer health outcomes and complications.

Background: Vaccination during pregnancy is an important healthcare intervention for safeguarding the health of the mother and their infants. Ethnic disparities in recruitment to vaccine research studies during pregnancy potentially contribute to health inequalities. The aim of the current study was to explore the barriers and enablers influencing the willingness of pregnant women from ethnic minority backgrounds to participate in vaccine research studies. Methods and findings: Semi-structured qualitative online interviews were conducted with 23 pregnant women from diverse ethnic backgrounds in the UK. Interviews were transcribed verbatim, and thematically analysed. Our findings suggest that participants perceived vaccines and vaccine research, in principle, to be beneficial to the individual and to society, and understood the value of vaccination in mitigating severity of disease and protecting the health of mothers and their infants. Apprehension over the safety of vaccination in pregnancy was common and reduced willingness to participate. For those that decided to participate in vaccine trials in pregnancy, this was seen as an act of solidarity, a way to contribute to a collective responsibility for the public health of the community. Personal and community connections and representation—seeing people from their own communities represented in in the recruitment process shapped decisions about vaccine trial participating. Trust and mistrust in health systems, shaped by past experiences of interacting with healthcare professionals were likely to inform whether they would consider participating. Practical considerations such as excessive time commitments related to study procedures, travel and organising childcare were barrier to participation. The level of invasiveness of trial procedures were also a concern, although increased monitoring during the trial was seen as a potential benefit, mitigating some safety concerns. Conclusions: Our study reinforcing previously identified barriers to vaccine participation among pregnant women from diverse ethnic communities. This study underlines the need to develop tailored interventions that focus on fostering trust with the aid of community engagement to understand cultural contexts, establishing authentic representation, and address practical considerations, to contribute to enhancing vaccine trial participation in pregnancy in those from diverse ethnic communities. [ABSTRACT FROM AUTHOR]

Background: HIV self-testing (HIVST) may facilitate marginalised populations' uptake of HIV testing, but whether the extent of marginalisation challenges individual uptake of HIVST remains under-researched. We aim to explore the perspectives of multiply marginalised cis-gender gay, bisexual and other men who have sex with men (GBMSM) and trans women on whether HIVST might increase their uptake of HIV testing. Methods: We reanalysed qualitative interview data from SELPHI (the UK's largest HIVST randomised trial) collected between 2017 and 2020 from marginalised populations, defined as people self-identifying as non-heterosexual, transgender, non-White ethnicity and/or with low educational attainment. Thirty-eight interviews with multiply marginalised individuals were thematically examined using the framework method. We specifically focussed on kit usability (a function of the interaction between blood-based HIVST kits and users), perspectives on how HIVST can improve access to HIV testing and suggestions on need-based scale-up of HIVST. Results: HIVST kits were considered usable and acceptable by multiply marginalised GBMSM and trans women. The majority of interviewees highlighted multi-levelled barriers to accessing HIV testing services due to structural and social marginalisation. Their multiply marginalised identities did not impede HIVST uptake but often form motivation to self-test. Three potential roles of HIVST in the HIV testing landscape were identified: (1) alternation of HIVST and facility-based testing, (2) integration of HIVST into sexual health services and (3) substituting facility-based testing with HIVST in the future. Perceived beneficiaries of HIVST included trans communities, individuals with undisclosed sexuality and people with physical disabilities. Discussion: HIVST can facilitate marginalised populations' access and uptake of HIV testing by alternating with, integrating into and substituting for facility-based services in the UK. Marginalised identities did not present challenges but rather opportunities for person-centred scale-up of HIVST. Future implementation programmes should ensure equitable access to HIVST among trans people, men unable to disclose their sexuality, and perhaps people with physical disabilities. [ABSTRACT FROM AUTHOR]

Introduction: A key goal for working age stroke survivors is to return to work, yet only around 50% achieve this at 12 months. Currently, there is limited evidence of effectiveness of early stroke-specialist vocational rehabilitation (ESSVR) interventions from randomised controlled trials. This study examined fidelity to ESSVR and explored social and structural factors which may have influenced implementation in the RETurn to work After stroKE (RETAKE) randomised controlled trial. Methods: Mixed-methods process evaluation assessing intervention fidelity and incorporating longitudinal case-studies exploring stroke survivors' experiences of support to return to work. Normalisation Process Theory, and the Conceptual Model for Implementation Fidelity, informed data collection and analysis. Results: Sixteen sites across England and Wales participated in RETAKE. Forty-eight occupational therapists (OTs), supported by 6 mentors experienced in vocational rehabilitation (VR), delivered the intervention (duration 12 months) between February 2018 and April 2022. Twenty-six participants (15 ESSVR, 11 usual care (UC)) were included in longitudinal case-studies. An additional 18 participants (8 ESSVR and 10 UC) were interviewed once. Nineteen OTs, 6 mentors and 19 service managers were interviewed. Fidelity was measured for 39 ESSVR participants; mean fidelity score was 78.8% (SD:19.2%, range 31–100%). Comparison of the experiences of ESSVR and UC participants indicated duration and type of support to return to work were perceived to be better for ESSVR participants. They received early, co-ordinated support including employer liaison and workplace adjustments where appropriate. In contrast, UC participants reported limited or no VR or return to work support from health professionals. Typically, UC support lasted 2–8 weeks, with poor communication and co-ordination between rehabilitation providers. Mentor support for OTs appeared to increase fidelity. Service managers indicated ESSVR would enhance post-stroke services. Conclusions: ESSVR was valued by participants and was delivered with fidelity; implementation appeared to be facilitated by mentor support for OTs. [ABSTRACT FROM AUTHOR]

Uncomplicated urinary tract infections (uUTI) are generally treated empirically with antibiotics. However, antibiotic allergies limit the available oral treatment options for some patients. We assessed the proportion of self-reported antibiotic allergies among US women with uUTI. We performed a cross-sectional survey of US women (≥18 years) with a self-reported uUTI in the previous 60 days and an oral antibiotic prescription. Participants completed an online questionnaire about their most recent uUTI episode. Descriptive self-reported allergy data were stratified into subgroups by whether the participant had recurrent UTI (≥2 uUTIs in the past 6 months or ≥3 uUTIs in past 12 months, including the index episode), the number of different antibiotics given for the index episode (1, 2, ≥3), and whether the treatment was clinically aligned according to Infectious Diseases Society of America uUTI guidelines. Overall, 375 participants completed the questionnaire. The most commonly prescribed antibiotics were trimethoprim-sulfamethoxazole (SXT; 38.7%), ciprofloxacin (22.7%), and nitrofurantoin (18.9%). Most participants (62.7%) received only 1 antibiotic for their uUTI, and most (56.5%) were classified as having a non-recurrent uUTI. No antibiotic allergies were reported for most participants (69.3%), with 24.0% reporting 1 antibiotic allergy and 6.7% reporting ≥2 antibiotic allergies. Allergies to ≥2 antibiotic types were more common among participants classified as having recurrent uUTI, or who used multiple antibiotics to treat their uUTI. The most common allergy was to SXT (15.7%), followed by amoxicillin-clavulanate (8.3%) and ciprofloxacin (5.3%). Similar allergy trends were seen across subgroups, except higher rates of ciprofloxacin allergy were seen in participants given multiple antibiotics. Antibiotic allergies were relatively frequent in this uUTI cohort and the most common allergy was to SXT, which was the most prescribed antibiotic. Allergies to antibiotics reduce the available treatment options for uUTI in some patients. [ABSTRACT FROM AUTHOR]

Introduction: Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. Methods and analysis: Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2–0.4 mg/kg of CBD per day and escalating monthly up to 0.8–1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. Discussion: This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. Trial registration: CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033. [ABSTRACT FROM AUTHOR]

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

Marine reserves are implemented to achieve a variety of objectives, but are seldom rigorously evaluated to determine whether those objectives are met. In the rare cases when evaluations do take place, they typically focus on ecological indicators and ignore other relevant objectives such as socioeconomics and governance. And regardless of the objectives, the diversity of locations, monitoring protocols, and analysis approaches hinder the ability to compare results across case studies. Moreover, analysis and evaluation of reserves is generally conducted by outside researchers, not the reserve managers or users, plausibly thereby hindering effective local management and rapid response to change. We present a framework and tool, called MAREA, to overcome these challenges. Its purpose is to evaluate the extent to which any given reserve has achieved its stated objectives. MAREA provides specific guidance on data collection and formatting, and then conducts rigorous causal inference analysis based on data input by the user, providing real-time outputs about the effectiveness of the reserve. MAREAs ease of use, standardization of state-of-the-art inference methods, and ability to analyze marine reserve effectiveness across ecological, socioeconomic, and governance objectives could dramatically further our understanding and support of effective marine reserve management.

Effective symptom management is a critical component of cancer treatment. Computational tools that predict the course and severity of these symptoms have the potential to assist oncology clinicians to personalize the patient's treatment regimen more efficiently and provide more aggressive and timely interventions. Three common and inter-related symptoms in cancer patients are depression, anxiety, and sleep disturbance. In this paper, we elaborate on the efficiency of Support Vector Regression (SVR) and Non-linear Canonical Correlation Analysis by Neural Networks (n-CCA) to predict the severity of the aforementioned symptoms between two different time points during a cycle of chemotherapy (CTX). Our results demonstrate that these two methods produced equivalent results for all three symptoms. These types of predictive models can be used to identify high risk patients, educate patients about their symptom experience, and improve the timing of pre-emptive and personalized symptom management interventions.

Contemporary climate change has been widely documented as the apparent cause of range contraction at the edge of many species distributions but documentation of climate change as a cause of extirpation and fragmentation of the interior of a species' core habitat has been lacking. Here, we report the extirpation of the American pika (Ochotona princeps), a temperature-sensitive small mammal, from a 165-km2 area located within its core habitat in California's Sierra Nevada mountains. While sites surrounding the area still maintain pikas, radiocarbon analyses of pika fecal pellets recovered within this area indicate that former patch occupancy ranges from before 1955, the beginning of the atmospheric spike in radiocarbon associated with above ground atomic bomb testing, to c. 1991. Despite an abundance of suitable rocky habitat climate warming appears to have precipitated their demise. Weather station data reveal a 1.9°C rise in local temperature and a significant decline in snowpack over the period of record, 1910-2015, pushing pika habitat into increasingly tenuous climate conditions during the period of extirpation. This is among the first accounts of an apparently climate-mediated, modern extirpation of a species from an interior portion of its geographic distribution, resulting in habitat fragmentation, and is the largest area yet reported for a modern-era pika extirpation. Our finding provides empirical support to model projections, indicating that even core areas of species habitat are vulnerable to climate change within a timeframe of decades.

Introduction: The incidence of varicella in Canada has decreased by almost 99% since vaccination was introduced. However, variation in the timing and eligibility of vaccination programs across the country has resulted in some cohorts being under-vaccinated and therefore potentially susceptible to infection. Methods: We used nationally representative specimens from the Biobank of Statistics Canada's Canadian Health Measures Survey (CHMS) as well as residual specimens from Ontario collected between 2009–2014 to estimate population immunity across age-groups and geography, and identify any groups at increased risk of varicella infection. Results: The weighted proportion of specimens with antibody levels above the threshold of protection was 93.6% (95% CI: 92.4, 95.0). Protection was lowest among those aged 3–5 years (54.3%; 95% CI: 47.3, 61.4), but increased with age. Individuals born outside Canada had more than twice the odds of varicella susceptibility than those born in Canada (aOR: 2.7; 95% CI: 1.4, 5.0; p = 0.004). There were no differences by sex or geography within Canada, and there were no statistically significant differences when Ontario CHMS sera were compared to Ontario residual sera, apart from in participants aged 12–19 year age-group, for whom the CHMS estimate (91.2%; 95% CI: 86.7, 95.7) was significantly higher (p = 0.03) than that from residual specimens (85.9%, 95% CI: 81.1, 90.8). Discussion: Varicella immunity in Canada is changing. Children appear to have low population immunity, placing them at greater risk of infection and at increased risk of severe disease as they age. Our results underscore the importance of performing periodic serosurveys to monitor further population immunity changes as the proportion of vaccine-eligible birth-cohorts increases, and to continually assess the risk of outbreaks. [ABSTRACT FROM AUTHOR]

We analyzed COI barcode sequences from 138 over-a-century old specimens of Calinaga including 36 name-bearing type specimens stored at the Natural History Museum London. These new data, combined with previously available RPS5 sequences, divide the Calinaga samples into four well-supported mitochondrial lineages that together with a novel wing-pattern analysis, support the recognition of six species (lhatso, buddha, brahma, aborica, formosana and davidis), with all other names subsumed either as subspecies or synonyms. One new taxon is described, Calinaga aborica naima Vane-Wright, ssp. n. [ABSTRACT FROM AUTHOR]

Hyponatremia, though common in women with preeclampsia, has not been well studied. Our primary objectives are to assess the clinical characteristics and emergency therapy applied to subjects diagnosed with preeclampsia. We hypothesize that hyponatremia present in preeclamptic patients with severe features is associated with greater use of emergency hypertensives, antenatal steroids, and cesarean delivery. This is a retrospective descriptive study utilizing an electronic health record database (TriNetX ®). We collected and evaluated the following data of subjects aged 15 to 54 years with preeclampsia with severe features diagnosis: demographics, diagnostic codes, medication codes, procedure codes, deaths, and laboratory results. A total of 2,901 subjects [215 (7.4%)] with a sodium level below 134 mEq/L and [2686 (92.6%)] with a sodium level above 135 mEq/L were included. A higher proportion of subjects in the below 134 sodium group received emergency antihypertensives [165 (76.7%) versus 1811 (67.4%), p = 0.01], antenatal steroids [103 (47.9%) versus 953 (35.5%), p = 0.001], and cesarean section [27 (12.6%) versus 97 (3.6%), p = <0.001]. We found that hyponatremia may be associated with emergency antihypertensive use, antenatal steroid use, and cesarean section in patients with preeclampsia with severe features. Future research is needed to determine if routine sodium levels assessed in preeclamptic subjects with severe features identify subjects at risk of receiving these treatments. [ABSTRACT FROM AUTHOR]

Postural instability is a common symptom of vestibular dysfunction that impacts a person's day-to-day activities. Vestibular rehabilitation is effective in decreasing dizziness, visual symptoms and improving postural control through several mechanisms including sensory reweighting of the vestibular, visual and somatosensory systems. As part of the sensory reweighting mechanisms, vestibular activation exercises with headshaking influence vestibular-ocular reflex (VOR). However, combining challenging vestibular and postural tasks to facilitate more effective rehabilitation outcomes is under-utilized. Understanding how and why this may work is unknown. The aim of the study was to assess sensory reweighting of postural control processing and VOR after concurrent vestibular activation and weight shift training (WST) in healthy young adults. Forty-two participants (18–35years) were randomly assigned into four groups: No training/control (CTL), a novel visual feedback WST coupled with a concurrent, rhythmic active horizontal or vertical headshake activity (HHS and VHS), or the same WST with no headshake (NHS). Training was performed for five days. All groups performed baseline- and post-assessments using the video head impulse test, sensory organization test, force platform rotations and electro-oculography. Significantly decreased horizontal eye movement variability in the HHS group compared to the other groups suggests improved gaze stabilization (p =.024). Significantly decreased horizontal VOR gain (p =.040) and somatosensory downweighting (p =.050) were found in the combined headshake groups (HHS and VHS) compared to the other two groups (NHS and CTL). The training also showed a significantly faster automatic postural response (p =.003) with improved flexibility (p =.010) in the headshake groups. The concurrent training influences oculomotor function and suggests improved gaze stabilization through vestibular recalibration due to adaptation and possibly habituation. The novel protocol could be modified into progressive functional activities that would incorporate gaze stabilization exercises. The findings may have implications for future development of vestibular rehabilitation protocols. [ABSTRACT FROM AUTHOR]

Background: Family caregivers often play a key role in medical decision-making for patients with cancer. Adult-children account for nearly half of caregivers, but often have less experience with serious illness care and decision-making and face unique relational challenges as the patient's child. Yet little research explores the potentially distinctive decision-making, involvement in decisions, and support needs of adult-child caregivers. Methods: Analysis of survey data of U.S. cancer caregivers conducted by CancerCare® in 2021. Chi-square tests and multivariable regression models assessed whether adult-child and spousal caregivers differed on the type of medical decisions they participated in (e.g., treatment planning, medication management), who made the decision (e.g., caregiver or joint decision), and the resources that informed decisions (e.g., friends and family, education materials). Results: Adult-children (N = 892) were less likely than spouses (N = 314) to participate in treatment planning (beta = -0.41; 95%CI = -0.81,-0.01), but more likely to be involved in decisions about whether to challenge medical authority (e.g., seeking alternative treatment, second opinion) (beta = 0.50; 95%CI = 0.22,0.78). Compared to spouses, adult-children made joint decisions with patients less often (-13.2-percentage points; 95%CI = -19.64,-6.67) and acted as primary decision-maker more frequently (5.60-percentage points; 95%CI = 0.01,10.43). More adult-children than spouses sought help and information regarding decisions from the oncology team (8.42-percentage points; 95%CI = 1.98,14.87) and friends and family (7.91-percentage points; 95%CI = 1.34,14.48). Conclusions: How cancer caregivers and patients are related to each other shapes caregivers' medical decision-making. Adult-children's and spouses' probabilities of participating in and influencing decisions differed for certain types of decisions while adult-children were more likely to seek information and social support regarding decisions. These findings highlight the importance of the patient's and caregiver's relationship type in medical decision-making, suggesting that decision support programs may be more effective if they tailor programs by relationship type. [ABSTRACT FROM AUTHOR]

Due to the highly transmissible nature of porcine reproductive and respiratory syndrome (PRRS), implementation of regional programs to control the disease may be critical. Because PRRS is not reported in the US, numerous voluntary regional control projects (RCPs) have been established. However, the effect of RCPs on PRRS control has not been assessed yet. This study aims to quantify the extent to which RCPs contribute to PRRS control by proposing a methodological framework to evaluate the progress of RCPs. Information collected between July 2012 and June 2015 from the Minnesota Voluntary Regional PRRS Elimination Project (RCP-N212) was used. Demography of premises (e.g. composition of farms with sows = SS and without sows = NSS) was assessed by a repeated analysis of variance. By using general linear mixed-effects models, active participation of farms enrolled in the RCP-N212, defined as the decision to share (or not to share) PRRS status, was evaluated and used as a predictor, along with other variables, to assess the PRRS trend over time. Additionally, spatial and temporal patterns of farmers' participation and the disease dynamics were investigated. The number of farms enrolled in RCP-N212 and its geographical coverage increased, but the proportion of SS and NSS did not vary significantly over time. A significant increasing (p

Cancer stem cells (CSCs) typically have the capacity to evade chemotherapy and may be the principal source of metastases. CSCs for human pancreatic ductal carcinoma (PDAC) have been identified, but neither the metastatic potential nor the chemoresistance of these cells has been adequately evaluated. We have addressed these issues by examining side-population (SP) cells isolated from the Panc-1 and BxPC3 lines of human PDAC cells, the oncogenotypes of which differ. SP cells could be isolated from monolayers of Panc-1, but only from spheroids of BxPC3. Using orthotopic xenografts into the severely immunocompromised NSG mouse, we found that SP cells isolated from both cell lines produced tumors that were highly metastatic, in contrast to previous experience with PDAC cell lines. SP cells derived from both cell lines expressed the ABCG2 transporter, which was demonstrably responsible for the SP phenotype. SP cells gave rise to non-SP (NSP) cells in vitro and in vivo, a transition that was apparently due to posttranslational inhibition of the ABCG2 transporter. Twenty-two other lines of PDAC cells also expressed ABCG2. The sensitivity of PDAC SP cells to the vinca alkaloid vincristine could be greatly increased by verapamil, a general inhibitor of transporters. In contrast, verapamil had no effect on the killing of PDAC cells by gemcitabine, the current first-line therapeutic for PDAC. We conclude that the isolation of SP cells can be a convenient and effective tool for the study of PDAC CSCs; that CSCs may be the principal progenitors of metastasis by human PDAC; that the ABCG2 transporter is responsible for the SP phenotype in human PDAC cells, and may be a ubiquitous source of drug-resistance in PDAC, but does not confer resistance to gemcitabine; and that inhibition of ABCG2 might offer a useful adjunct in a therapeutic attack on the CSCs of PDAC.

Hemodialysis using hollow-fiber membranes provides life-sustaining treatment for nearly 2 million patients worldwide with end stage renal disease (ESRD). However, patients on hemodialysis have worse long-term outcomes compared to kidney transplant or other chronic illnesses. Additionally, the underlying membrane technology of polymer hollow-fiber membranes has not fundamentally changed in over four decades. Therefore, we have proposed a fundamentally different approach using microelectromechanical systems (MEMS) fabrication techniques to create thin-flat sheets of silicon-based membranes for implantable or portable hemodialysis applications. The silicon nanopore membranes (SNM) have biomimetic slit-pore geometry and uniform pores size distribution that allow for exceptional permeability and selectivity. A quantitative diffusion model identified structural limits to diffusive solute transport and motivated a new microfabrication technique to create SNM with enhanced diffusive transport. We performed in vitro testing and extracorporeal testing in pigs on prototype membranes with an effective surface area of 2.52 cm2 and 2.02 cm2, respectively. The diffusive clearance was a two-fold improvement in with the new microfabrication technique and was consistent with our mathematical model. These results establish the feasibility of using SNM for hemodialysis applications with additional scale-up.

The ranges and abundances of species that depend on freshwater habitats are declining worldwide. Efforts to counteract those trends are often hampered by a lack of information about species distribution and conservation status and are often strongly biased toward a few well-studied groups. We identified the 3,906 vascular plants, macroinvertebrates, and vertebrates native to California, USA, that depend on fresh water for at least one stage of their life history. We evaluated the conservation status for these taxa using existing government and non-governmental organization assessments (e.g., endangered species act, NatureServe), created a spatial database of locality observations or distribution information from ~400 data sources, and mapped patterns of richness, endemism, and vulnerability. Although nearly half of all taxa with conservation status (n = 1,939) are vulnerable to extinction, only 114 (6%) of those vulnerable taxa have a legal mandate for protection in the form of formal inclusion on a state or federal endangered species list. Endemic taxa are at greater risk than non-endemics, with 90% of the 927 endemic taxa vulnerable to extinction. Records with spatial data were available for a total of 2,276 species (61%). The patterns of species richness differ depending on the taxonomic group analyzed, but are similar across taxonomic level. No particular taxonomic group represents an umbrella for all species, but hotspots of high richness for listed species cover 40% of the hotspots for all other species and 58% of the hotspots for vulnerable freshwater species. By mapping freshwater species hotspots we show locations that represent the top priority for conservation action in the state. This study identifies opportunities to fill gaps in the evaluation of conservation status for freshwater taxa in California, to address the lack of occurrence information for nearly 40% of freshwater taxa and nearly 40% of watersheds in the state, and to implement adequate protections for freshwater taxa where they are currently lacking.

Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that plays a key role in innate immunity. TLR3 signalling has numerous functions in liver, both in health and disease. Here we report that TLR3 is expressed by quiescent hepatic stellate cells (HSC) where it functions to induce transcription and secretion of functional interferons as well as a number of other cytokines and chemokines. Upon transdifferentiation into myofibroblasts, HSCs rapidly loose the ability to produce interferon gamma (IFNγ). Mechanistically, this gene silencing may be due to Polycomb complex mediated repression via methylation of histone H3 lysine 27. In contrast to wild type, quiescent HSC isolated from tlr3 knockout mice do not produce IFNγ in response to Poly(I∶C) treatment. Therefore, quiescent HSC may contribute to induction of the hepatic innate immune system in response to injury or infection.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

The genioglossus is a major upper airway dilator muscle thought to be important in obstructive sleep apnea pathogenesis. Aging is a risk factor for obstructive sleep apnea although the mechanisms are unclear and the effects of aging on motor unit remodeled in the genioglossus remains unknown. To assess possible changes associated with aging we compared quantitative parameters related to motor unit potential morphology derived from EMG signals in a sample of older (n = 11; >55 years) versus younger (n = 29;

Background: Hospital infection control policies protect patients and healthcare workers (HCWs) and limit the spread of pathogens, but adherence to COVID-19 guidance varies. We examined hospital HCWs' enactment of social distancing and use of personal protective equipment (PPE) during the COVID-19 pandemic, factors influencing these behaviours, and acceptability and feasibility of strategies to increase social distancing. Methods: An online, cross-sectional survey (n = 86) and semi-structured interviews (n = 22) with HCWs in two English hospitals during the first wave of the COVID-19 pandemic (May-December 2020). The Capability, Opportunity, Motivation (COM-B) model of behaviour change underpinned survey and topic guide questions. Spearman Rho correlations examined associations between COM-B domains and behaviours. Interviews were analysed using inductive and deductive thematic analysis. Potential strategies to improve social distancing were selected using the Behaviour Change Wheel and discussed in a stakeholder workshop (n = 8 participants). Results: Social distancing enactment was low, with 85% of participants reporting very frequently or always being in close contact with others in communal areas. PPE use was high (88% very frequently or always using PPE in typical working day). Social distancing was associated with Physical Opportunity (e.g., size of physical space), Psychological Capability (e.g., clarity of guidance), and Social Opportunity (e.g., support from managers). Use of PPE was associated with Psychological Capability (e.g., training), Physical Opportunity (e.g., availability), Social Opportunity (e.g., impact on interactions with patients), and Reflective Motivation (e.g., beliefs that PPE is effective). Local champions and team competition were viewed as feasible strategies to improve social distancing. Conclusions: It is valuable to understand and compare the drivers of individual protective behaviours; when faced with the same level of perceived threat, PPE use was high whereas social distancing was rarely enacted. Identified influences represent targets for intervention strategies in response to future infectious disease outbreaks. [ABSTRACT FROM AUTHOR]

The COVID-19 outbreak led governmental officials to close many businesses and schools, including colleges and universities. Thus, the ability to resume normal campus operation required adoption of safety measures to monitor and respond to COVID-19. The objective of this study was to determine the efficacy of wastewater-based epidemiology as a surveillance method in monitoring COVID-19 on a college campus. The use of wastewater monitoring as part of a surveillance program to control COVID-19 outbreaks at East Carolina University was evaluated. During the Spring and Fall 2021 semesters, wastewater samples (N = 830) were collected every Monday, Wednesday, and Friday from the sewer pipes exiting the dormitories on campus. Samples were analyzed for SARS-CoV-2 and viral quantification was determined using qRT-PCR. During the Spring 2021 semester, there was a significant difference in SARS-CoV-2 virus copies in wastewater when comparing dorms with the highest number student cases of COVID-19 and those with the lowest number of student cases, (p = 0.002). Additionally, during the Fall 2021 semester it was observed that when weekly virus concentrations exceeded 20 copies per ml, there were new confirmed COVID-19 cases 85% of the time during the following week. Increases in wastewater viral concentration spurred COVID-19 swab testing for students residing in dormitories, aiding university officials in effectively applying COVID testing policies. This study showed wastewater-based epidemiology can be a cost-effective surveillance tool to guide other surveilling methods (e.g., contact tracing, nasal/salvia testing, etc.) to identify and isolate afflicted individuals to reduce the spread of pathogens and potential outbreaks within a community. [ABSTRACT FROM AUTHOR]

Background: Following traumatic brain injury (TBI) some patients develop lingering comorbid symptoms of fatigue and cognitive impairment. The mild cognitive impairment self-reported by patients is often not detected with neurocognitive tests making it difficult to determine how common and severe these symptoms are in individuals with a history of TBI. This study was conducted to determine the relative prevalence of fatigue and cognitive impairment in individuals with a history of TBI. Methods: The Fatigue and Altered Cognition Scale (FACs) digital questionnaire was used to assess self-reported fatigue and cognitive impairment. Adults aged 18–70 were digitally recruited for the online anonymous study. Eligible participants provided online consent, demographic data, information about lifetime TBI history, and completed the 20 item FACs questionnaire. Results: A total of 519 qualifying participants completed the online digital study which included 204 participants with a history of TBI of varied cause and severity and 315 with no history of TBI. FACs Total Score was significantly higher in the TBI group (57.7 ± 22.2) compared to non-TBI (39.5 ± 23.9; p<0.0001) indicating more fatigue and cognitive impairment. When stratified by TBI severity, FACs score was significantly higher for all severity including mild (53.9 ± 21.9, p<0.0001), moderate (54.8 ± 24.4, p<0.0001), and severe (59.7 ± 20.9, p<0.0001) TBI. Correlation analysis indicated that more severe TBI was associated with greater symptom severity (p<0.0001, r = 0.3165). Ancillary analysis also suggested that FACs scores may be elevated in participants with prior COVID-19 infection but no history of TBI. Conclusions: Adults with a history of even mild TBI report significantly greater fatigue and cognitive impairment than those with no history of TBI, and symptoms are more profound with greater TBI severity. [ABSTRACT FROM AUTHOR]

Introduction: Harm arising from National Health Service (NHS) healthcare results in significant human cost for the patient, those who care for them, and the medical staff involved. Furthermore, patient harm results in substantial financial costs to the public purse. Improving how NHS providers in England respond to patient harm could reduce the number of claims for clinical negligence brought against NHS. Doing so will ensure those affected receive the justice they deserve and protect the public purse. Law and policy are key to supporting providers of NHS healthcare to respond to patient harm but are not necessarily understood and therefore can be challenging to apply to practice. Research exploring how law and policy supports this understanding is limited. The purpose of this scoping review is to address this knowledge gap and improve understanding by critically evaluating how law and policy supports providers of NHS healthcare in England to respond to patient harm. Methods and analysis: The review will use the methodological framework proposed by Arskey and O'Malley, Levac et al and the Joanna Briggs Institute. Search strategies will be developed using selected key words and index terms. MEDLINE, CINAHL, and Westlaw and reference lists of relevant publications will be searched to identify relevant grey literature. Two reviewers will independently assess the extracted data against the eligibility criteria. All studies identified will be charted and the results presented as a narrative synthesis. [ABSTRACT FROM AUTHOR]