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Abstract Background Healthy eating is vital to well-being and during the COVID-19 pandemic, it was especially important for boosting immunity and protecting against viral infections. Yet, by many accounts, keeping a nutritious diet was a casualty of the pandemic rather than a means to fight it. Young adults experienced disproportionate pandemic-related disruptions during a formative stage of development while little is still known about dietary outcomes. Methods We employed a cross-sectional design to examine dietary disparities targeting young adults (ages 18–28) during the COVID-19 lockdown period. Participants (N = 254) responded to a 15–20-min online survey with questions related to food composition and sources of food, perceptions of healthy eating, weight change, physical activity, and food insecurity. Comparisons were made by household income and gender. Multiple regression analyses were conducted to investigate factors that predicted perceptions of healthy eating behaviors while controlling for other sociodemographic factors. Results A clear overall trend toward unhealthy behaviors was found while positive changes were also identified. Consumption of junk food significantly increased (+ 3%), 40% gained weight, a third were less active, and 5–8% were food insecure on a regular basis. Meanwhile, eating food from restaurants declined and, for some, home-based cooking increased. Lower income participants were overly represented in unhealthy changes and higher income participants were disproportionately represented in healthy changes. Males reported more changes in dietary composition while females reported more fluctuation in weight. Reduced activity, weight gain, and food insecurity predicted unhealthy eating behaviors. Living with friend(s)/roommate(s) predicted healthier eating, but only among lower income participants. Conclusions It is recommended that pandemic minded public health interventions account for negative dietary trends with particular attention to low-income young adults. Solutions should be geared toward reshaping fiscal, social and physical environments, rather than relying solely on behavioral interventions.

Abstract Purpose Osteoarthritis (OA) causes pain and disability, with onset often during working age. Joint pain is associated with functional difficulties and may lead to work instability. The aims of this systematic review are to identify: the impact of OA on work participation; and biopsychosocial and work-related factors associated with absenteeism, presenteeism, work transitions, work impairment, work accommodations, and premature work loss. Methods Four databases were searched, including Medline. The Joanna Briggs Institute Critical Appraisal tools were used for quality assessment, with narrative synthesis to pool findings due to heterogeneity of study designs and work outcomes. Results Nineteen studies met quality criteria (eight cohort; 11 cross-sectional): nine included OA of any joint(s), five knee-only, four knee and/or hip, and one knee, hip, and hand OA. All were conducted in high income countries. Absenteeism due to OA was low. Presenteeism rates were four times greater than absenteeism. Performing physically intensive work was associated with absenteeism, presenteeism, and premature work loss due to OA. Moderate-to-severe joint pain and pain interference were associated with presenteeism, work transition, and premature work loss. A smaller number of studies found that comorbidities were associated with absenteeism and work transitions. Two studies reported low co-worker support was associated with work transitions and premature work loss. Conclusions Physically intensive work, moderate-to-severe joint pain, co-morbidities, and low co-worker support potentially affects work participation in OA. Further research, using longitudinal study designs and examining the links between OA and biopsychosocial factors e.g., workplace accommodations, is needed to identify targets for interventions. Systematic review registration PROSPERO 2019 CRD42019133343 .

Abstract Background Black Americans have disproportionately higher rates and earlier onset of Alzheimer’s disease and related dementias (ADRD) relative to White Americans. We currently lack a comprehensive understanding of how the lived experience and broader societal factors, including cumulative exposure to structural racism and the mechanisms underlying the risks, may contribute to elevated ADRD risk in Black Americans. Methods The Think PHRESH study builds on existing, community-based research infrastructure, from the ongoing Pittsburgh Hill/Homewood Research on Neighborhood Change and Health (PHRESH) studies, to examine the contributions of dynamic neighborhood socioeconomic conditions across the lifecourse to cognitive outcomes in mid- and late-life adults living in two historically disinvested, predominantly Black communities (anticipated n = 1133). This longitudinal, mixed-methods study rests on the premise that neighborhood racial segregation and subsequent disinvestment contributes to poor cognitive outcomes via factors including (a) low access to educational opportunities and (b) high exposure to race- and socioeconomically-relevant stressors, such as discrimination, trauma, and adverse childhood events. In turn, these cumulative exposures foster psychological vigilance in residents, leading to cardiometabolic dysregulation and sleep disruption, which may mediate associations between neighborhood disadvantage and ADRD risk. This premise recognizes the importance of potential protective factors that may promote cognitive health, including neighborhood social cohesion, safety, and satisfaction. The proposed study will leverage our existing longitudinal data on risk/protective factors and biobehavioral mediators and will include: (1) up to three waves of cognitive assessments in participants ages 50 years + and one assessment in participants ages 35–49 years; clinical adjudication of ADRD will be completed in participants who are 50+, (2) extensive surveys of risk and protective factors, (3) two assessments of blood pressure and objectively measured sleep, (4) a comprehensive assessment of life and residential history; and (5) two rounds of in-depth qualitative interviews to reveal lifecourse opportunities and barriers experienced by Black Americans in achieving optimal cognitive health in late life. Discussion Understanding how structural racism has influenced the lived experience of Black Americans, including dynamic changes in neighborhood conditions over time, is critical to inform multi-level intervention and policy efforts to reduce pervasive racial and socioeconomic disparities in ADRD.

Abstract There are high levels of work disability, absenteeism (sick leave) and presenteeism (reduced productivity) amongst people with inflammatory arthritis. WORKWELL is a multi-centre, randomised controlled trial of job retention vocational rehabilitation for employed people with inflammatory arthritis. The trial tested the effectiveness and cost-effectiveness of the WORKWELL programme compared to the receipt of written self-help information only. Both arms continued to receive usual care. In March 2020, due to the COVID-19 pandemic, the WORKWELL trial paused to recruitment and intervention delivery. To successfully re-start, protocol amendments were rapidly submitted and changes to existing trial procedures were made. The WORKWELL protocol was adapted in response to both the practical issues likely faced by many clinical research studies active across NHS sites during the pandemic and additional trial-specific challenges. A key eligibility criterion for the trial required participants to be in paid work for at least 15 h per week. However, UK national lockdowns led to a substantial proportion of the workforce suddenly being furloughed or unable to work, and many people with arthritis taking immunosuppressive medications were asked to shield themselves. Thus, the number of eligible participants was reduced. Those continuing to work were harder to identify, as hospital clinics moved to remote delivery, and also to then screen, consent and treat, as the hospital research staff and clinical therapists were re-deployed. New recruitment and consent strategies were applied, and where sites had reduced capacity, responsibilities were absorbed by the trial management team. Remote intervention delivery and electronic data capture were also implemented. By rapidly adapting the WORKWELL protocol and procedures, the trial successfully reopened to recruitment in July 2020, only 4 months after the trial pause. We were able to achieve recruitment figures above the pre-COVID target and maintain a high retention rate. In addition, we found many of the protocol changes beneficial, as these streamlined trial procedures, thus improving efficiency. It is likely that many strategies implemented in response to the pandemic may become standard practice in future research within trials of a similar design and methodology. Trial registration: ClinicalTrials.gov NCT03942783 . Retrospectively registered on 08 May 2019. ISRCTN Registry ISRCTN61762297 . Retrospectively registered on 13 May 2019.

Abstract Background The Workwell trial is a multi-centre randomised controlled trial with the aims of evaluating the effectiveness and cost-effectiveness of job retention vocational rehabilitation for employed people with inflammatory arthritis, who are experiencing work difficulties due to their arthritis. Vocational rehabilitation is delivered by health service occupational therapists, who have received additional training in providing this Workwell intervention. A process evaluation will be undertaken alongside the main trial to investigate implementation fidelity; understand key stakeholders’ perspectives of the intervention and the social and structural context in which the intervention is provided; and explore issues related to future implementation in clinical practice. This protocol describes the aims, objectives, and methodology of the Workwell trial process evaluation. Methods This mixed methods process evaluation will follow the Medical Research Council’s Guidance on process evaluations for complex interventions. It will be underpinned by the conceptual framework for implementation fidelity (CFIF) and normalisation process theory (NPT). We will analyse treatment records, work assessments, and treatment notes to ascertain implementation fidelity. Semi-structured interviews with trial participants, their employer/line managers, treating therapists, and their therapy service managers will be undertaken to explore perceptions of the intervention, contextual factors, and potential for future implementation in practice. Interview topic guides will be informed by NPT. Therapists’ views about Workwell training will be explored via questionnaires following training, and interviews and focus groups following treatment delivery to inform future implementation. Quantitative data will be analysed descriptively. Qualitative data will be analysed using thematic analysis. NPT will guide data analysis and interpretation. Findings from the different elements of this embedded design process evaluation will be reported separately and then the elements integrated. The process evaluation data will be analysed independently of the Workwell trial outcome evaluation. The process evaluation data will then be reviewed in the light of the trial findings. Discussion Few trials of job retention vocational rehabilitation in arthritis have included process evaluations. This process evaluation will assist in understanding factors influencing trial outcomes and identifying potential contextual barriers and facilitators for the potential implementation of Workwell vocational rehabilitation into clinical services. Trial registration ClinicalTrials.gov NCT03942783 . Registered on 08 May 2019. ISRCTN Registry ISRCTN61762297 . Registered on 13 May 2019. Retrospectively registered.

Abstract Background A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. Results We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients—those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. Conclusions Our ‘omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.

Close monitoring after diagnosis of patients with stage I-III non-small cell lung cancer (NSCLC) may result in fitter patients with lower disease burden at the time of metastatic recurrence or progression compared to patients diagnosed initially as stage IV (de novo). We compared the presentation, treatments, and outcomes of patients with KRASG12C-mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRASG12C-mutated NSCLC who developed stage IV disease at recurrence (n = 38), de novo stage IV patients (n = 71) had worse ECOG performance status (p = 0.007), greater numbers of extra-thoracic metastatic sites (p = 0.001), and were less likely to receive 2nd/3rd line systemic therapy (p = 0.05, p = 0.002) or targeted therapy (p = 0.001). De novo metastatic patients had shorter overall survival than metastatic patients at recurrence (9.1 versus 24.2 months; adjusted-hazard-ratio=1.94 (95% CI: 1.14–3.28; p = 0.01)). There is a critical need for well-tolerated targeted therapies in the first-line setting for metastatic patients with de novo, high-burden, stage IV KRASG12C-mutated NSCLCs.

Abstract Background Nonmedical use of prescription opioids (defined as taking opioid medications for hedonic effects or in a manner other than prescribed) and the use of heroin have emerged in recent years as major public health concerns in the United States. Of particular concern is the prevalence of opioid use among emerging adults (ages 18–25), as this is a developmental period of heightened vulnerability and critical social, neurological, and psychological development. Data from 2015 show that American Indian/Alaska Native (AI/AN) people have the highest rates of diagnosis for opioid use disorders (OUDs). One recent study found that the overdose death rate among urban-dwelling AI/AN individuals was 1.4 times higher compared to those living in rural areas. To date, there are no evidence-based prevention programs addressing opioid use among urban AI/AN emerging adults that integrate culturally-appropriate strategies with evidence-based treatment. Traditions and Connections for Urban Native Americans (TACUNA) builds on our prior work with AI/AN communities across California to develop and evaluate culturally appropriate programming to address opioid, alcohol, and cannabis use among urban AI/AN emerging adults. Methods/design In a randomized controlled trial, 18–25 year old urban AI/AN emerging adults will receive either TACUNA (n = 185), which comprises three virtual workshops utilizing motivational interviewing, social network visualization, and integrating traditional practices and a wellness circle, or one virtual culturally sensitive opioid education workshop (n = 185). We will evaluate intervention effects on primary outcomes of frequency of opioid, alcohol, and cannabis use, as well as secondary outcomes of social network characteristics and cultural connectedness, over a 12-month period. Discussion This project has the potential to expand the range and effectiveness of opioid, alcohol, and cannabis services for urban AI/AN emerging adults by addressing the opioid epidemic and use of other substances at both the community and individual level. In addition, it provides important culturally grounded conceptual and practical information to advance the field of substance use interventions and enhance resiliency among this population. Trial registration: ClinicalTrials.gov Identifier: NCT04617938. Registered October 26, 2020 https://clinicaltrials.gov/ct2/show/record/NCT04617938 .

Abstract Background Work problems are common in people with inflammatory arthritis. Up to 50% stop work within 10 years due to their condition and up to 67% report presenteeism (i.e. reduced work productivity), even amongst those with low disease activity. Job retention vocational rehabilitation (JRVR) may help prevent or postpone job loss and reduce presenteeism through work assessment, work-related rehabilitation and enabling job accommodations. This aims to create a better match between the person’s abilities and their job demands. The objectives of the Workwell trial are to test the overall effectiveness and cost-effectiveness of JRVR (WORKWELL) provided by additionally trained National Health Service (NHS) occupational therapists compared to a control group who receive self-help information both in addition to usual care. Methods Based on the learning from a feasibility trial (the WORK-IA trial: ISRCTN76777720 ), the WORKWELL trial is a multi-centre, pragmatic, individually-randomised parallel group superiority trial, including economic evaluation, contextual factors analysis and process evaluation. Two hundred forty employed adults with rheumatoid arthritis, undifferentiated inflammatory arthritis or psoriatic arthritis (in secondary care), aged 18 years or older with work instability will be randomised to one of two groups: a self-help written work advice pack plus usual care (control intervention); or WORKWELL JRVR plus a self-help written work advice pack and usual care. WORKWELL will be delivered by occupational therapists provided with additional JRVR training from the research team. The primary outcome is presenteeism as measured using the Work Limitations Questionnaire-25. A comprehensive range of secondary outcomes of work, health, contextual factors and health resource use are included. Outcomes are measured at 6- and 12- months (with 12-months as the primary end-point). A multi-perspective within-trial cost-effectiveness analyses will also be conducted. Discussion This trial will contribute to the evidence base for provision of JRVR to people with inflammatory arthritis. If JRVR is found to be effective in enabling people to keep working, the findings will support decision-making about provision of JRVR by rheumatology teams, therapy services and healthcare commissioners, and providing evidence of the effectiveness of JRVR and the economic impact of its implementation. Trial registration Clinical Trials.Gov: NCT03942783 . Registered 08/05/2019 ( https://clinicaltrials.gov/ct2/show/NCT03942783 ); ISRCTN Registry: ISRCTN61762297 . Registered:13/05/2019 ( http://www.isrctn.com/ISRCTN61762297 ). Retrospectively registered.

BackgroundLimitations in laboratory diagnostic capacity impact population surveillance of COVID-19. It is currently unknown whether participatory surveillance tools for COVID-19 correspond to government-reported case trends longitudinally and if it can be used as an adjunct to laboratory testing. The primary objective of this study was to determine whether self-reported COVID-19-like illness reflected laboratory-confirmed COVID-19 case trends in Ontario Canada.MethodsWe retrospectively analyzed longitudinal self-reported symptoms data collected using an online tool-Outbreaks Near Me (ONM)-from April 20th, 2020, to March 7th, 2021 in Ontario, Canada. We measured the correlation between COVID-like illness among respondents and the weekly number of PCR-confirmed COVID-19 cases and provincial test positivity. We explored contemporaneous changes in other respiratory viruses, as well as the demographic characteristics of respondents to provide context for our findings.ResultsBetween 3,849-11,185 individuals responded to the symptom survey each week. No correlations were seen been self-reported CLI and either cases or test positivity. Strong positive correlations were seen between CLI and both cases and test positivity before a previously documented rise in rhinovirus/enterovirus in fall 2020. Compared to participatory surveillance respondents, a higher proportion of COVID-19 cases in Ontario consistently came from low-income, racialized and immigrant areas of the province- these groups were less well represented among survey respondents.InterpretationAlthough digital surveillance systems are low-cost tools that have been useful to signal the onset of viral outbreaks, in this longitudinal comparison of self-reported COVID-like illness to Ontario COVID-19 case data we did not find this to be the case. Seasonal respiratory virus transmission and population coverage may explain this discrepancy.

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein.

Background: The current GP workforce is insufficient to manage rising demand in patient care within out-of-hours (OOH) primary care services. To meet this challenge, non-medical practitioners (NMPs) are employed to fulfil tasks traditionally carried out by GPs. It is important to learn from experiences of task-shifting in this setting to inform optimal delivery of care. Aim: To synthesise qualitative evidence of experiences of task-shifting in the OOH primary care setting. Design & setting: Systematic review of qualitative studies and thematic synthesis. Method: Electronic searches were conducted across CINAHL (Cumulative Index of Nursing and Allied Health Literature), PsychINFO, Cochrane, MEDLINE, Embase, and OpenGrey for qualitative studies of urgent or OOH primary care services, utilising task-shifting or role delegation. Included articles were quality appraised and key findings collated through thematic synthesis. Results: A total of 2497 studies were screened, of which six met the inclusion criteria. These included interviews with 15 advanced nurse practitioners (ANPs), three physician assistants (PAs), two paramedics, and a focus group of 22 GPs, and focus groups with 33 nurses. Key findings highlight the importance of clearly defining and communicating the scope of practice of NMPs, and of building their confidence by appropriate training, support, and mentoring. Conclusion: While NMPs may have the potential to make a substantial contribution to OOH primary care services, there has been very little research on experiences of task-shifting. Evidence to date highlights the need for further training specific to OOH services. Mentorship and support to manage the sometimes challenging cases presenting to OOH could enable more effective OOH services and better patient care.

Abstract Background Fungi are constantly exposed to nitrogen limiting environments, and thus the efficient regulation of nitrogen metabolism is essential for their survival, growth, development and pathogenicity. To understand how the rice blast pathogen Magnaporthe oryzae copes with limited nitrogen availability, a global proteome analysis under nitrogen supplemented and nitrogen starved conditions was completed. Methods M. oryzae strain 70–15 was cultivated in liquid minimal media and transferred to media with nitrate or without a nitrogen source. Proteins were isolated and subjected to unfractionated gel-free based liquid chromatography-tandem mass spectrometry (LC-MS/MS). The subcellular localization and function of the identified proteins were predicted using bioinformatics tools. Results A total of 5498 M. oryzae proteins were identified. Comparative analysis of protein expression showed 363 proteins and 266 proteins significantly induced or uniquely expressed under nitrogen starved or nitrogen supplemented conditions, respectively. A functional analysis of differentially expressed proteins revealed that during nitrogen starvation nitrogen catabolite repression, melanin biosynthesis, protein degradation and protein translation pathways underwent extensive alterations. In addition, nitrogen starvation induced accumulation of various extracellular proteins including small extracellular proteins consistent with observations of a link between nitrogen starvation and the development of pathogenicity in M. oryzae. Conclusion The results from this study provide a comprehensive understanding of fungal responses to nitrogen availability.

Abstract Background Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. Methods We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. Results Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosph atase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. Conclusions These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.

This article draws from inquiry-based research that explored the efficacy of practitioners' efforts to create an asset-oriented field experience with preservice teachers and middle school students, responding to the challenge of building a virtual learning community during the pandemic. Through thematic analysis (Braun & Clarke, 2006), we investigated the pedagogical practices of one preservice English teacher who engaged three emergent bilingual middle school students in composing multimodal identity artifacts during a nine-week project. The findings of this study point to the value placed on acompañamiento--that is, learning "alongside" and "with" students (Sepúlveda, 2011). This aspect of the instructional design was found to be especially important in building a sense of community in the virtual classroom space.

Background The insulin/insulin‐like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin‐2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin‐like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss‐of‐function and protein delivery methods. Methods and Results Insl6‐deficient and wild‐type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6‐knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6‐knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis‐associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol‐challenged hearts treated with INSL6 protein. Conclusions Endogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II– and isoproterenol‐induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.

The marine sponge Haliclona simulans collected from the Irish Sea yielded two new steroids: 24-vinyl-cholest-9-ene-3β,24-diol and 20-methyl-pregn-6-en-3β-ol,5a,8a-epidioxy, along with the widely distributed 24-methylenecholesterol. One of the steroids possesses an unusually short hydrocarbon side chain. The structures were elucidated using nuclear magnetic resonance spectroscopy and confirmed using electron impact- and high resolution electrospray-mass spectrometry. All three steroids possess antitrypanosomal and anti-mycobacterial activity. All the steroids were found to possess low cytotoxicity against Hs27 which was above their detected antitrypanosomal potent concentrations.

Background: Antivenom is the definitive treatment for venomous snakebites, but is expensive and not available in many rural and poorly developed regions. Timely transportation to facilities that stock and administer antivenom may not be available in rural areas with poorly developed emergency medical services. These factors have led to consideration of measures to delay onset of toxicity or alternatives to antivenom therapy. Methods: PubMed searches were conducted for articles on snakebite treatment, or that contained first aid, emergency medical services, tourniquets, pressure immobilization bandages, suction devices, and lymphatic flow inhibitors. Results: The reviewed articles describe how venoms spread after a venomous snakebite on an extremity, list the proposed first aid measures for delaying the spread of venoms, and evaluate the scientific studies that support or refute methods of snakebite first aid. The recommendations for field treatment of venomous snakebites will be discussed. Conclusions: The evidence suggests that pressure immobilization bandages and related strategies are the best interventions to delay onset of systemic toxicity from venomous snakebites but may increase local toxicity for venoms that destroy tissue at the site of the bite, so their use should be individualized to the circumstances and nature of the venom.

Epidemiological investigation of the impact of climate change on human health, particularly chronic diseases, is hindered by the lack of exposure metrics that can be used as a marker of climate change that are compatible with health data. Here, we present a surrogate exposure metric created using a 30-year baseline (1960-1989) that allows users to quantify long-term changes in exposure to frequency of extreme heat events with near unabridged spatial coverage in a scale that is compatible with national/state health outcome data. We evaluate the exposure metric by decade, seasonality, area of the country, and its ability to capture long-term changes in weather (climate), including natural climate modes. Our findings show that this generic exposure metric is potentially useful to monitor trends in the frequency of extreme heat events across varying regions because it captures long-term changes; is sensitive to the natural climate modes (ENSO events); responds well to spatial variability, and; is amenable to spatial/temporal aggregation, making it useful for epidemiological studies.