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In most people living with HIV (PLWH) on effective antiretroviral therapy (ART), cell-associated viral transcripts are readily detectable in CD4+ T cells despite the absence of viremia. Quantification of HIV RNA species provides insights into the transcriptional activity of proviruses that persist in cells and tissues throughout the body during ART (‘HIV reservoir’). One such technique for HIV RNA quantitation, ‘HIV transcription profiling’, developed in the Yukl laboratory, measures a series of HIV RNA species using droplet digital PCR. To take advantage of advances in digital (d)PCR, we adapted the ‘HIV transcription profiling’ technique to Qiagen’s dPCR platform (QIAcuity) and compared its performance to droplet digital (dd)PCR (Bio-Rad QX200 system). Using RNA standards, the two technologies were tested in parallel and assessed for multiple parameters including sensitivity, specificity, linearity, and intra- and inter-assay variability. The newly validated dPCR assays were then applied to samples from PLWH to determine HIV transcriptional activity relative to HIV reservoir size. We report that HIV transcriptional profiling was readily adapted to dPCR and assays performed similarly to ddPCR, with no differences in assay characteristics. We applied these assays in a cohort of 23 PLWH and found that HIV reservoir size, based on genetically intact proviral DNA, does not predict HIV transcriptional activity. In contrast, levels of total DNA correlated with levels of most HIV transcripts (initiated, proximally and distally elongated, unspliced, and completed, but not multiply spliced), suggesting that a considerable proportion of HIV transcripts likely originate from defective proviruses. These findings may have implications for measuring and assessing curative strategies and clinical trial outcomes.

Functional and oxygenated stream beds provide crucial habitat for multiple endangered stream taxa, including endangered freshwater mussels, fishes, and insect larvae. Stream bed restoration measures such as substrate raking are often applied to mitigate excess fine sediment introductions and stream bed colmation, yet such measures are controversial. In this study, we conducted a systematic experiment in which sites with stream bed raking and removal of macrophytes were monitored over two years and compared with before-treatment conditions and untreated reference sites in the Swedish Brånsån stream, which still contains a population of the endangered freshwater pearl mussel Margaritifera margaritifera. The stream bed restoration resulted in improved habitat quality, as evident from decreased substrate compaction, increased redox potential, and oxygen supply into the stream bed. In contrast to previous studies in Central European catchments with more intensive agricultural catchment uses, the effects of the restoration measure were much longer, extending over two years. Consequently, stream bed raking and macrophyte removal can be considered a useful and more long-lasting restoration measure than currently assumed, especially in streams where excess input of fine sediment has already been mitigated, where catchment land use is rather extensive, and where near-natural flow regimes still prevail.

Abstract Qualitative comparative analysis (QCA) is a relatively new method that examines causal complexity. Its use in mental health research is nascent. In low-income and fragile settings, with weak mental health service provision, identifying pathways of recovery from psychological distress can inform the appropriate deployment of scarce community and public resources. This paper examines the use of QCA to identify predictors of recovery in Sierra Leone. Our study explored lay perceptions of the signs of recovery from psychological distress caused by such events as the loss of a family member, severe sickness, and loss of a relationship. The data drew upon 75 interviews with women and men, across four districts of Sierra Leone, who described the signs of recovery from psychological distress they have observed in one person known to them. The truth table generated through QCA software indicated two signs of recovery— work/study and healthy relations—to be the most prevalent across different combinations of predictive factors. Further analysis of the truth table and sub-set relations suggested that work/study and healthy relations frequently served as sufficient conditions for reported recovery from distress to occur. QCA provided a means to identify sufficient predictive factors for recovery from psychological distress to occur. The findings suggest that to enable recovery from psychological distress, support needs to be broad and bring together services that will enable individuals to improve their social and relational wellbeing. Responses to distress need to involve a wide range of community-based stakeholders who will help individuals to engage in constructive activity and strengthen relations with their family members, friends, and the broader community. QCA is potentially well-positioned to unpack complexity in mental health research.

Abstract Background Studies of psychological distress in Sierra Leone have typically used measures which were developed for use in other contexts, and which often have not been adapted or validated for use in Sierra Leone. This has resulted in a lack of reliable information about the patterns of psychological distress within the population, which is a barrier to the development of effective and appropriate mental health services. The aim of the study was to develop a locally-appropriate measure of psychological distress for Sierra Leone. Methods The new measure consists of two instruments: the Sierra Leone Psychological Distress Scale (SLPDS) and a gendered measure of ability to carry out daily tasks—a Function scale—as an indication of the severity of distress. A three-phase mixed methods exploratory sequential study was conducted. Phase 1 was item generation and testing, leading to the development of a set of potential items for both instruments. Phase 2 was a small pilot study (N = 202) leading to the selection of the final set of items for both measures. Phase 3 was a validation phase where the SLPDS and the Function scale were administered with a larger sample of 904 respondents. Item analysis was used to assess the internal consistency of the scales, and Exploratory Factor Analysis to explore the properties of the SLPDS. Results Exploratory factor analysis using the principal axis factoring with an oblique rotation identified a three-factor structure for the 18-item SLPDS. Internal consistency for the SLPDS (Cronbach’s alpha = 0.89) and three subscales was good (Cronbach’s alpha > 0.73). The internal reliability of the male and female versions of the Function scale was also found to be acceptable (Cronbach’s alpha = 0.90 for the female scale and 0.79 for the male scale). Conclusions Together the SLPD and Function scales provide a locally-validated tool which will enable government bodies and local and international non-governmental organisations in Sierra Leone to assess mental health and psychosocial needs. This will support both effective service provision and the evaluation of initiatives designed to improve mental health and psychosocial wellbeing.

Abstract Politically oriented “fake news”—false stories or headlines created to support or attack a political position or person—is increasingly being shared and believed on social media. Many online platforms have taken steps to address this by adding a warning label to articles identified as false, but past research has shown mixed evidence for the effectiveness of such labels, and many prior studies have looked only at either short-term impacts or non-political information. This study tested three versions of fake news labels with 541 online participants in a two-wave study. A warning that came before a false headline was initially very effective in both discouraging belief in false headlines generally and eliminating a partisan congruency effect (the tendency to believe politically congenial information more readily than politically uncongenial information). In the follow-up survey two weeks later, however, we found both high levels of belief in the articles and the re-emergence of a partisan congruency effect in all warning conditions, even though participants had known just two weeks ago the items were false. The new pre-warning before the headline showed some small improvements over other types, but did not stop people from believing the article once seen again without a warning. This finding suggests that warnings do have an important immediate impact and may work well in the short term, though the durability of that protection is limited.

Abstract Background There is increasing global evidence that mental health is strongly determined by social, economic and environmental factors, and that strategic action in these areas has considerable potential for improving mental health and preventing and alleviating mental disorders. Prevention and promotion activities in mental health must address the needs prioritised by local actors. The aim of this study was to identify stressors with the potential to influence emotional wellbeing and distress within the general population of Sierra Leone, in order to contribute to an inter-sectoral public mental health approach to improving mental health within the country. Methodology Respondents were a convenience sample of 153 respondents (60 women, 93 men) from five districts of Sierra Leone. Using freelisting methodology, respondents were asked to respond to the open question ‘What kind of problems do women/men have in your community?’. Data analysis involved consolidation of elicited problems into a single list. These were then organised thematically using an adaptation of the socio-ecological model, facilitating exploration of the interactions between problems at individual, family, community and societal levels Results Overall, respondents located problems predominantly at community and societal levels. Although few respondents identified individual-level issues, they frequently described how problems at other levels contributed to physical health difficulties and emotional distress. Women identified significantly more problems at the family level than men, particularly related to relationships with an intimate partner. Men identified significantly more problems at the societal level than women, primarily related to lack of infrastructure. Men and women were equally focused on problems related to poverty and lack of income generating opportunities. Conclusion Poverty and inability to earn an income underpinned many of the problems described at individual, family and community level. Actions to address livelihoods, together with improving infrastructure and addressing gender norms which are harmful to both men and women, are likely key to improving the wellbeing of the Sierra Leone population.

Objective: To evaluate the impact of an electronic witnessing system (EWS) on witnessing standard operating procedures and to assess embryologist perceptions of the EWS. Design: Prospective cohort study. Setting: Private in vitro fertilization laboratory network. Patient(s): None. Intervention(s): None Main Outcome Measure(s): The time difference between manual and electronic double-witnessing procedures, and embryologist perceptions of the EWS. Result(s): From 342 witnessing times analyzed (114 EWS, 114 manual, and 114 interruptions to witnesses), the EWS reduced mean (SD) total witnessing time (in seconds) by 91.5 (23.6) for intracytoplasmic sperm injection, 62.0 (17.9) for Day 3 embryo assessment, 58.3 (18.9) for fresh embryo transfer, and 59.4 (13.3) for frozen embryo transfer. This time reduction significantly decreased the overall time required for double-witnessing by 3.1- to 5.2-fold. A survey with 50 embryologists within the laboratory network indicated that most embryologists considered the EWS to improve sample traceability (78.3%), reduce errors in labeling issues (80.4%), and reduce the risk of sample mismatch errors by minimizing disruptions (60.9%). Furthermore, 82.6% thought that visual completion of the EWS dashboard provided peace of mind when leaving work and 84.8% were more confident knowing that all procedures were completed according to the EWS. Conclusion(s): An EWS can improve laboratory efficiency by significantly decreasing the time required for witnessing procedures and by minimizing interruptions. The EWS was well perceived by embryologists and laboratory managers and enhanced their confidence and peace of mind with regard to witnessing compliance and safety/accuracy.

BackgroundGiven the increased use of technology in health care, both in extent and application, the importance of understanding the ethical implications of new health technologies increases. Profound insight into the possible ethical implications of new health technologies enhances the research and development of such technologies and the likelihood of eventual successful implementation in clinical practice. ObjectiveThis study aimed to gain an understanding of how and if researchers focused on health technologies describe the actual or possible ethical aspects of their research findings. MethodsAn established framework for scoping reviews was used to guide the methodology. Studies published in PubMed over the last 10 years were included if they study or refer to ethics in relation to health technology as defined by established frameworks. In total, 14,532 articles were screened, 692 were retained for full-text evaluation, and 227 were included for data extraction. ResultsIn total, 250 (80.9%, N=309) studies were conducted in North America and Europe; literature review studies were dominant. Most studies (52.9%, 120/227) had no direct reference to any of the 4 basic ethical principles: beneficence, nonmaleficence, autonomy, and justice. In cases where studies referenced ethical theory, consequentialism dominated. ConclusionsWhen research about technology and ethics is published, the predominant focus is on its intent rather than its actual effect on patients. This lack of insight is problematic considering the vast advancement of technology in which ethics cannot keep up with understanding and offer insights on addressing ethical issues. This finding has implications for practice, research, and education.

The United Nations (UN) Sustainable Development Goals (SDGs) and the UN Decade of Ocean Science for Sustainable Development (Ocean Decade) bring increased attention to various aspects of ocean governance, including equity. One of the Ocean Decade's identified challenges is to develop a sustainable and equitable ocean economy, but questions arise about how to conceptualize the multiple dimensions of equity in an ocean context. These questions become more complex as activities move away from coastal ecosystems and communities into off-shore Areas Beyond National Jurisdiction (ABNJ), where ocean resources are recognized simultaneously as unowned/open access and as common heritage. In this paper, we mobilize the Earth System Governance analytics of ‘architecture’ and ‘agency’, to reflect on the possibilities for equity in ABNJ. Motivated by the general attention to equity in UN initiatives like the SDGs and the Ocean Decade, we describe current UN architecture for ocean governance, including principles that might support equity. Existing UN architecture focuses on distributional equity among nation states, with less attention to recognitional or procedural equity. State actors have most agency, while non-state actors can exercise some via broad UN declarations and through mechanisms like ‘major groups.’ We use on-going negotiations in the International Seabed Authority on rules for mineral exploitation and in the Intergovernmental Conference on an international legally binding instrument under UNCLOS on the conservation and sustainable use of marine biological diversity of Areas Beyond National Jurisdiction to illustrate how existing architecture shapes possibilities for equity in ABNJ. As new governance possibilities are imagined, attending to existing architecture and agency can help avoid further entrenching existing power imbalances and unwittingly reproducing or exacerbating inequities.

Varicella zoster virus (VZV) induces orofacial pain and female rats show greater pain than male rats. During the proestrus phase of the estrous cycle the VZV induce pain response is attenuated in female rats. A screen of gene expression changes in diestrus and proestrus female rats indicated neurexin 3α (Nrxn3α) was elevated in the central amygdala of proestrus rats vs. diestrus rats. GABAergic neurons descend from the central amygdala to the lateral parabrachial region and Nrxn3α is important for presynaptic γ-Aminobutyric acid (GABA) release. Thus, we hypothesized that the reduced orofacial pain in male rats and proestrus female rats is the result of increased Nrxn3α within the central amygdala that increases GABA release from axon terminals within the parabrachial and inhibits ascending pain signals. To test this hypothesis Nrxn3 α expression was knocked-down by infusing shRNA constructs in the central amygdala. Then GABA release in the parabrachial was quantitated concomitant with measuring the pain response. Results revealed that knockdown of Nrxn3α expression significantly increases the pain response in both male rats and proestrus female rats vs. diestrus rats. GABA release was significantly reduced in the parabrachial of male and proestrus female rats after Nrxn3α knockdown. Neuronal activity of excitatory neurons was significantly inhibited in the parabrachial after Nrxn3α knockdown. These results are consistent with the idea that Nrxn3 within the central amygdala controls VZV associated pain by regulating GABA release in the lateral parabrachial that then modulates ascending orofacial pain signals.

Abstract The spread of invasive insect species causes enormous ecological damage and economic losses worldwide. A reliable method that tracks back an invaded insect's origin would be of great use to entomologists, phytopathologists, and pest managers. The spongy moth (Lymantria dispar, Linnaeus 1758) is a persistent invasive pest in the Northeastern United States and periodically causes major defoliations in temperate forests. We analyzed field‐captured (Europe, Asia, United States) and laboratory‐reared L. dispar specimens for their natal isotopic hydrogen and nitrogen signatures imprinted in their biological tissues (δ2H and δ15N) and compared these values to the long‐term mean δ2H of regional precipitation (Global Network of Isotopes in Precipitation) and δ15N of regional plants at the capture site. We established the percentage of hydrogen–deuterium exchange for L. dispar tissue (Pex = 8.2%) using the comparative equilibration method and two‐source mixing models, which allowed the extraction of the moth's natal δ2H value. We confirmed that the natal δ2H and δ15N values of our specimens are related to the environmental signatures at their geographic origins. With our regression models, we were able to isolate potentially invasive individuals and give estimations of their geographic origin. To enable the application of these methods on eggs, we established an egg‐to‐adult fraction factor for L. dispar (Δegg‐adult = 16.3 ± 4.3‰). Our models suggested that around 25% of the field‐captured spongy moths worldwide were not native in the investigated capture sites. East Asia was the most frequently identified location of probable origin. Furthermore, our data suggested that eggs found on cargo ships in the United States harbors in Alaska, California, and Louisiana most probably originated from Asian L. dispar in East Russia. These findings show that stable isotope biomarkers give a unique insight into invasive insect species pathways, and thus, can be an effective tool to monitor the spread of insect pest epidemics.

Retro-odontoid pseudotumor formation consists of an abnormal growth of granulation tissue typically posterior to the odontoid process, resulting as a manifestation of atlantoaxial instability. This instability can occur as a result of conditions ranging from severe mechanical trauma to metabolic disease or autoimmune conditions such as rheumatoid arthritis. A pseudotumor may impinge on the spinal nerves or even the spinal cord and brainstem, manifesting symptoms from severe neck pain to cervicomedullary compression or myelopathy, and in some cases even sudden death. The objective of this review is to consolidate the findings in published case reports and relevant prior literature reviews regarding the formation of retro-odontoid pseudotumor. We address the pathophysiology involved in acquired and congenital pseudotumor formation, including those associated with rheumatoid arthritis (panni). Additionally, we discuss past and current operative techniques designed to curtail and ultimately regress a retro-odontoid pseudotumor and pannus. Surgical techniques that are addressed include ventral decompression (both transoral and transnasal), dorsal decompression, and indications for posterior instrumentation in pannus formation, particularly in cases that may be sufficiently treated in lieu of an anterior approach. Finally, we will examine the role of external orthoses as both a method of conservative treatment as well as a potential adjunct to the aforementioned surgical procedures.

Abstract Telomere length is predictive of adult health and survival across vertebrate species. However, we currently do not know whether such associations result from among-individual differences in telomere length determined genetically or by early-life environmental conditions, or from differences in the rate of telomere attrition over the course of life that might be affected by environmental conditions. Here, we measured relative leukocyte telomere length (RLTL) multiple times across the entire lifespan of dairy cattle in a research population that is closely monitored for health and milk production and where individuals are predominantly culled in response to health issues. Animals varied in their change in RLTL between subsequent measurements and RLTL shortened more during early life and following hotter summers which are known to cause heat stress in dairy cows. The average amount of telomere attrition calculated over multiple repeat samples of individuals predicted a shorter productive lifespan, suggesting a link between telomere loss and health. TL attrition was a better predictor of when an animal was culled than their average TL or the previously for this population reported significant TL at the age of 1 year. Our present results support the hypothesis that TL is a flexible trait that is affected by environmental factors and that telomere attrition is linked to animal health and survival traits. Change in telomere length may represent a useful biomarker in animal welfare studies.

The low nitrogen content of Bangka Island’s post-tin-mining soil may limit its suitability for agricultural production. In this study, we investigated the effect of locally available organic soil amendments on nitrogen fixation (N2–fixation) and crop nitrogen (N) uptake in a cassava–legume intercrop system. Cassava was intercropped with centrosema in post-tin-mining soils with six treatments, including a control and different soil amendments, such as dolomite, compost, charcoal, a combined treatment of charcoal and compost, and a combined treatment of compost and sawdust. The percentages of N derived from N2-fixation (%Ndfa) with the different seasons and treatments were comparable. Nonetheless, due to the higher shoot biomass accumulation, the mass of N2–fixation in soil amended with compost and when combined with charcoal was significantly higher than the control (50 to 73 kg ha−1). Treatments with compost and its combination with charcoal exhibited higher N uptake from the cassava–centrosema intercropped system (82 and 137 kg ha−1) and higher inorganic ammonium (NH4+) concentrations in the soil at harvest time (5.5 and 6.7 µg g−1). When combined with organic soil amendments, N2–fixation from centrosema produces not only higher biomass, but also higher N contribution to the system. Overall, locally available organic amendments, particularly the combined application of charcoal and compost, showed promise for improving N2–fixation of intercrop centrosema as well as for increasing N availability in the soil, which is of critical importance for crop growth in post-mining soils that have lost fertility.

A multiplexed enzyme-linked immunosorbent assay (ELISA) that simultaneously measures antibody binding to multiple antigens can extend the impact of serosurveillance studies, particularly if the assay approaches the simplicity, robustness, and accuracy of a conventional single-antigen ELISA. Here, we report on the development of multiSero, an open-source multiplex ELISA platform for measuring antibody responses to viral infection. Our assay consists of three parts: (1) an ELISA against an array of proteins in a 96-well format; (2) automated imaging of each well of the ELISA array using an open-source plate reader; and (3) automated measurement of optical densities for each protein within the array using an open-source analysis pipeline. We validated the platform by comparing antibody binding to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antigens in 217 human sera samples, showing high sensitivity (0.978), specificity (0.977), positive predictive value (0.978), and negative predictive value (0.977) for classifying seropositivity, a high correlation of multiSero determined antibody titers with commercially available SARS-CoV-2 antibody tests, and antigen-specific changes in antibody titer dynamics upon vaccination. The open-source format and accessibility of our multiSero platform can contribute to the adoption of multiplexed ELISA arrays for serosurveillance studies, for SARS-CoV-2 and other pathogens of significance.

Shortness of breath, chest pain, and palpitations occur as postacute sequelae of COVID-19, but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults more than 8 weeks after confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. We enrolled 102 participants at a median of 7.2 months following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years, and 41% of participants were women. Female sex, hospitalization, IgG antibody against SARS-CoV-2 receptor binding domain, and C-reactive protein were associated with symptoms. Regarding echocardiographic findings, 4 of 47 participants (9%) with symptoms had pericardial effusions compared with 0 of 55 participants without symptoms; those with effusions had a median of 4 symptoms compared with a median of 1 symptom in those without effusions. There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters or other biomarkers. Among adults more than 8 weeks after SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation, and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying postacute sequelae of COVID-19 is warranted.

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4+ T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory CD4+ T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory CD4+ T cells when compared with naive, central, and transitional memory CD4+ T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target.

The COVID-19 pandemic has impacted breastfeeding and lactation globally, with clinical practices implemented early in the pandemic being mostly anti-breastfeeding, e.g., separation of mothers from their infants, and not evidence based. As the pandemic has progressed, evidence has emerged reconfirming the value of human milk and the importance of protecting and supporting breastfeeding, especially the initiation of lactation. However, it is clear that COVID-19 has changed the clinical care paradigm around breastfeeding and lactation support and, as such, it is imperative that practices adapt and evolve to maintain the emphasis on lactation support. We participated in a round table conference aiming to rescue and develop protocols and practices that support breastfeeding during the COVID-19 pandemic. One key area to target will be to maximize the use of the antenatal period. The early identification of lactation risk factors together with the development of person-centered methods to deliver breastfeeding information and education to parents-to-be will be critical. In addition, the establishment of a hospital culture that values breastfeeding and prioritizes the use of human milk will be integral for the motivation of health care professionals. That culture will also support active management of the initiation of lactation and the development of a 'back-up plan' toolkit to support the mother experiencing lactation difficulties. Post-discharge support will also be crucial with the development of both in-person and virtual lactation support programs, in particular for the immediate post-discharge period to benefit mothers who experience an early discharge process. These measures will allow for a new, adapted framework of practice that acknowledges the current COVID-19 paradigm and maintains the emphasis on the need to protect and support breastfeeding and the use of human milk.

Vegetative filter strips (VFS) are best management practices with the primary aim of protecting surface waters from eutrophication resulting from excess nutrient inputs from agricultural sources. However, we argue that there is a substantial time and knowledge lag from the science underpinning VFS to policy and implementation. Focussing on phosphorus (P), we strive to introduce a holistic view on VFS that accounts for the whole functional soil volume, temporal and seasonal effects, the geospatial context, the climatic and physico-chemical basic conditions, and the intricate bio-geochemical processes that govern nutrient retention, transformation, and transport. Specifically, we suggest a step-wise approach to custom VFS designs that links and matches the incoming P from event to multi-annual timescales from the short- and mid-term processes of P retention in the effective soil volume and to the longer-term P retention and offtake coupled to the soil-vegetation system. An a priori assessment of the P export potential should be followed by bespoke VFS designs, in line with local conditions and socio-economic and ecological constraints. To cope with increasingly nutrient saturated or functionally insufficient VFS installed over the last decades, concepts and management strategies need to encompass the transition in understanding of VFS as simple nutrient containers to multifunctional buffer zones that have a complex inner life. We need to address these associated emerging challenges and integrate their implications more thoroughly into VFS research, monitoring, policy, and implementation than ever before. Only then we may get VFS that are effective, sustainable, and persistent.

IntroductionMore older adults die from lung cancer worldwide than breast, prostate, and colorectal cancers combined. Current lung cancer treatments may prolong life, but can also cause considerable treatment-related toxicity.ObjectiveThis study is a secondary analysis of a cluster-randomized clinical trial which evaluated whether providing a geriatric assessment (GA) summary and GA-guided management recommendations can improve grade 3-5 toxicity among older adults with advanced lung cancer.MethodsWe analyzed participants aged ≥70 years(y) with stage III & IV (advanced) lung cancer and ≥1 GA domain impairment starting a new cancer treatment with high-risk of toxicity within the National Cancer Institute’s Community Oncology Research Program. Community practices were randomized to the intervention arm (oncologists received GA summary & recommendations) versus usual care (UC: no summary or recommendations given). The primary outcome was grade 3-5 toxicity through 3 months post-treatment initiation. Secondary outcomes included 6-month (mo) and 1-year overall survival (OS), treatment modifications, and unplanned hospitalizations. Outcomes were analyzed using generalized linear mixed and Cox proportional hazards models with practice site as a random effect. Trial Registration: NCT02054741.Results & ConclusionAmong 180 participants with advanced lung cancer, the mean age was 76.3y (SD 5.1), 39.4% were female and 82.2% had stage IV disease. The proportion of patients who experienced grade 3-5 toxicity was significantly lower in the intervention arm vs UC (53.1% vs 71.6%, P=0.01). More participants in the intervention arm received lower intensity treatment at cycle 1 (56.3% vs 35.3%; P

Abstract Background Rwandan adolescents have limited access to high-quality family planning and reproductive health (FP/RH) information and care to prevent unplanned pregnancy and HIV/STIs. In addition to the immediate implications for health and well-being, teenage pregnancy is a significant cause of school drop-out, limiting girls’ future potential and employment opportunities. This study introduces a direct-to-consumer digital education program that uses storytelling to deliver age-appropriate FP/RH information and economic empowerment training to adolescents. It also facilitates access to high-quality, youth-friendly FP/RH care and products. We evaluate two different school-based models of its implementation to understand how to optimize the uptake of contraception and HIV testing among adolescents. Methods The study consists of two distinct phases. The first formative intervention design phase, conducted from 2016 to 2019, used a human-centered design methodology to develop the intervention alongside over 600 Rwandan adolescents, their parents, teachers, and healthcare providers. Through this methodology, we sought to maximize the fit between evidence-based practices (uptake of modern contraception and HIV testing) and the implementation context of adolescents in Rwanda. The second phase is an impact evaluation, in which we will use a Hybrid Trial Type 2 Effectiveness-Implementation study design to determine the overall effectiveness of this digital intervention as well as the relative effectiveness of the two different school-based implementation models. This takes the form of a 3-arm cluster-randomized non-inferiority trial, with a sample of 6000 youth aged 12–19 in 60 schools across 8 districts in Rwanda. Primary outcome measures include use of modern contraception, delayed initiation of childbearing, and uptake of HIV testing. Discussion This study will yield insights into not only whether this digital intervention is successful in achieving the intended sexual and reproductive health outcomes, but also which mechanisms are likely to drive this effectiveness. The methodologies used are broadly applicable to the design, implementation, and evaluation of other behavior-based health programs in low and middle-income countries. Trial registration ClinicalTrials.gov Identifier: NCT04198272 . Prospectively registered 13 December 2019.

Abstract Background Conflict and displacement impact the social fabric of communities through the disruption of social connections and the erosion of trust. Effective humanitarian assistance requires understanding the social capital that shapes patterns of help-seeking in these circumstances - especially with stigmatised issues such as violence against women (VAW) and intimate partner violence (IPV). Methods A novel social mapping methodology was adopted amongst a Yezidi population displaced by ISIS (ISIS: Islamic State of Iraq and Syria, locally known as Da’esh) occupation and a neighbouring settled Yezidi population in the Kurdistan region of northern Iraq in late 2016. Six participatory workshops were conducted to identify available resources with respect to: meeting basic needs, dispute resolution and VAW. Subsequently, 51 individual interviews were conducted (segmented by gender and settlement status) to identify connectedness to, and trust in, the resources identified, with a focus on IPV against women. Results 90% of participants reported God as a key source of help in the previous 6 months, representing the most widely cited resource. Following God, the most accessed and trusted resources were family and community, with NGO (non-governmental organisation) provision being the least. Women drew more strongly upon familial resources than men (Χ 2 = 5.73, df = 1, p = 0.017). There was reduced trust in resources in relation to seeking help with IPV. A distinction between trust to provide emotional support and trust to resolve issues was identified. Settled women were 1.6 times more likely to trust community members and government services and 3.7 times more likely to trust NGOs than displaced women. Conclusions Mapping social connections and trust provides valuable insight into the social capital available to support help-seeking in populations of humanitarian concern. For these Yezidi populations, family, religious and community resources were the most widely utilised and trusted. Trust was mostly reserved for family and their main religious leader regarding IPV against women. Lack of trust appeared to be a major barrier to stronger engagement with available NGO provision, particularly amongst displaced women. The role of faith and religious resources for this population is clearly significant, and warrants an explicitly faith-sensitive approach to humanitarian assistance.

Abstract Background Opioids, such as heroin, kill more people worldwide by overdose than any other type of drug, and death rates associated with opioid poisoning in the UK are at record levels (World Drug Report 2018 [Internet]. [cited 2019 Nov 19]. Available from: http://www.unodc.org/wdr2018/ ; Deaths related to drug poisoning in England and Wales - Office for National Statistics [Internet]. [cited 2019 Nov 19]. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2018registrations ). Naloxone is an opioid antagonist which can be distributed in ‘kits’ for administration by witnesses in an overdose emergency. This intervention is known as take-home naloxone (THN). We know that THN can save lives on an individual level, but there is currently limited evidence about the effectiveness of THN distribution on an aggregate level, in specialist drug service settings or in emergency service settings. Notably, we do not know whether THN kits reduce deaths from opioid overdose in at-risk populations, if there are unforeseen harms associated with THN distribution or if THN is cost-effective. In order to address this research gap, we aim to determine the feasibility of a fully powered cluster randomised controlled trial (RCT) of THN distribution in emergency settings. Methods We will carry out a feasibility study for a RCT of THN distributed in emergency settings at four sites, clustered by Emergency Department (ED) and catchment area within its associated ambulance service. THN is a peer-administered intervention. At two intervention sites, emergency ambulance paramedics and ED clinical staff will distribute THN to adult patients who are at risk of opioid overdose. At two control sites, practice will carry on as usual. We will develop a method of identifying a population to include in an evaluation, comprising people at risk of fatal opioid overdose, who may potentially receive naloxone included in a THN kit. We will gather anonymised outcomes up to 1 year following a 12-month ‘live’ trial period for patients at risk of death from opioid poisoning. We expect approximately 100 patients at risk of opioid overdose to be in contact with each service during the 1-year recruitment period. Our outcomes will include deaths, emergency admissions, intensive care admissions, and ED attendances. We will collect numbers of eligible patients attended by participating in emergency ambulance paramedics and attending ED, THN kits issued, and NHS resource usage. We will determine whether to progress to a fully powered trial based on pre-specified progression criteria: sign-up of sites (n = 4), staff trained (≥ 50%), eligible participants identified (≥ 50%), THN provided to eligible participants (≥ 50%), people at risk of death from opioid overdose identified for inclusion in follow-up (≥ 75% of overdose deaths), outcomes retrieved for high-risk individuals (≥ 75%), and adverse event rate (< 10% difference between study arms). Discussion This feasibility study is the first randomised, methodologically robust investigation of THN distribution in emergency settings. The study addresses an evidence gap related to the effectiveness of THN distribution in emergency settings. As this study is being carried out in emergency settings, obtaining informed consent on behalf of participants is not feasible. We therefore employ novel methods for identifying participants and capturing follow-up data, with effectiveness dependent on the quality of the available routine data. Trial registration ISRCTN13232859 (Registered 16/02/2018)

Abstract Sputum induction is a non-invasive method to evaluate the airway environment, particularly for asthma. RNA sequencing (RNA-seq) of sputum samples can be challenging to interpret due to the complex and heterogeneous mixtures of human cells and exogenous (microbial) material. In this study, we develop a pipeline that integrates dimensionality reduction and statistical modeling to grapple with the heterogeneity. LDA(Latent Dirichlet allocation)-link connects microbes to genes using reduced-dimensionality LDA topics. We validate our method with single-cell RNA-seq and microscopy and then apply it to the sputum of asthmatic patients to find known and novel relationships between microbes and genes.

Abstract Background The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs. Methods We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities. Results Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers. Conclusions The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.

Abstract Background Clinical practice guidelines and policies direct community mental health services to provide preventive care to address chronic disease risks, however, such care is infrequently provided in routine consultations. An alternative model of care is to appoint a clinician to the dedicated role of offering and providing preventive care in an additional consultation: the ‘specialist clinician’ model. Economic evaluations of models of care are needed to determine the cost of adhering to guidelines and policies, and to inform pragmatic service delivery decisions. This study is an economic evaluation of the specialist clinician model; designed to achieve policy concordant preventive care delivery. Methods A retrospective analysis of the incremental costs, cost-effectiveness, and budget impact of a ‘specialist preventive care clinician’ (an occupational therapist) was conducted in a randomised controlled trial, where participants were randomised to receive usual care; or usual care plus the offer of an additional preventive care consultation with the specialist clinician. The study outcome was client acceptance of referrals to two free telephone-based chronic disease prevention services. This is a key care delivery outcome mandated by the local health district policy of the service. The base case analysis assumed the mental health service cost perspective. A budget impact analysis determined the annual budget required to implement the model of care for all clients of the community mental health service over 5 years. Results There was a significantly greater increase from baseline to follow-up in the proportion of intervention participants accepting referrals to both telephone services, compared to usual care. The incremental cost-effectiveness ratio was $347 per additional acceptance of a referral (CI: $263–$494). The annual budget required to implement the model of care for all prospective clients was projected to be $711,446 over 5-years; resulting in 2616 accepted referrals. Conclusions The evaluation provides key information regarding the costs for the mental health service to adhere to policy targets, indicating the model of care involved a low per client cost whilst increasing key preventive care delivery outcomes. Additional modelling is required to further explore its economic benefits. Trial registration ACTRN12616001519448. Registered 3 November 2016, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371709 .

Abstract Background Conditions affecting the elbow joint are a common cause of lameness in dogs. Primary-care veterinary clinical data are now recognised as a valuable research resource. Using data from the VetCompass Programme, this study aimed to report the frequency and risk factors for elbow joint disease in dogs under primary veterinary care in the UK and describe clinical management. Results From 455,069 dogs under veterinary care, the one-year period prevalence for elbow joint disease diagnosis was 0.56% (95% CI: 0.53–0.60). Of 616 incident cases, the most common specific variants of elbow joint disease were osteoarthritis (n = 468, 75.97%), elbow dysplasia (190, 30.84%) and traumatic (41, 6.66%). The most common signs described by the owners were lameness (n = 466, 75.65%), difficulty exercising (123, 19.97%) and pain (86, 13.96%). The most common findings recorded on veterinary examination were pain (n = 283, 45.94%), lameness (278, 45.13%) and reduced range of movement (243, 39.45%). Common medications used included non-steroidal anti-inflammatory drugs (n = 544, 88.31%), tramadol (121, 19.64%) and disease modifying agents (118, 19.16%). Of 109 deaths involving euthanasia with information available from the 616 incident cases, elbow joint disease contributed to the decision to euthanase in 45 (41.28%) dogs. Five breeds showed increased odds of elbow joint disease compared with crossbred dogs: Rottweiler (OR: 6.16, 95% CI 3.89–9.75), Labrador Retriever (OR: 5.94, 95% CI 4.65–7.60), German Shepherd Dog (OR: 4.13, 95% CI 2.88–5.93), Golden Retriever (OR: 3.11, 95% CI 1.93–5.00) and English Springer Spaniel (OR: 2.00, 95% CI 1.26–3.18). Additional risk factors included having an adult bodyweight that was equal or higher than their breed/sex mean, advancing age, being male, being neutered, being insured and larger bodyweight. Conclusions Elbow joint disease is a relatively common diagnosis in dogs and has a high welfare impact as evidenced by the high proportion of cases recorded with pain, lameness and analgesic therapy. There are strong breed predispositions, in particular for large breed dogs. These findings present a clear case for improved breeding programmes to reduce the burden of elbow joint disease.

Abstract Hybridization is a natural process at species range boundaries, but increasing numbers of species are hybridizing due to direct or indirect human activities. In such cases of anthropogenic hybridization, subsequent introgression can threaten the survival of native species. To date, many such systems have been studied with too few genetic markers to assess the level of threat resulting from advanced backcrossing. Here, we use 44,999 single nucleotide polymorphisms (SNPs) and the ADMIXTURE program to study two areas of Scotland where a panel of 22 diagnostic microsatellites previously identified introgression between native red deer (Cervus elaphus) and introduced Japanese sika (Cervus nippon). In Kintyre, we reclassify 26% of deer from the pure species categories to the hybrid category whereas in the NW Highlands we only reclassify 2%. As expected, the reclassified individuals are mostly advanced backcrosses. We also investigate the ability of marker panels selected on different posterior allele frequency criteria to find hybrids assigned by the full marker set and show that in our data, ancestry informative markers (i.e. those that are highly differentiated between the species, but not fixed) are better than diagnostic markers (those markers that are fixed between the species) because they are more evenly distributed in the genome. Diagnostic loci are concentrated on the X chromosome to the detriment of autosomal coverage.