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Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute in vivo insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway's organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasising the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits. [ABSTRACT FROM AUTHOR]

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

Recovering and maintaining large carnivore populations is a global conservation challenge that requires better knowledge of the factors affecting their populations, particularly in shared landscapes (i.e. non‐protected areas where people occupy and or utilize the land).The Mexican wolf (Canis lupus baileyi) is an endangered wolf subspecies being recovered on shared landscapes in the Southwest United States and Mexico. We used data from the U.S. program to model population growth, evaluate the impact of management removal and illegal killing relative to other demographic factors, and test hypotheses about factors influencing rates of management removal and illegal killing.From 1998 to 2019, the population growth averaged 12% per year. Rates of natural reproduction, illegal killing and other mortality remained consistent over the 22 years; while releases, translocations and management removals varied markedly between two time periods, phase 1:1998–2007 and phase 2:2008–2019.The number of wolves removed for conflict management was higher during phase 1 (average ~ 13 per year, rate = 24.8%) than phase 2 (average of ~5 per year, rate = 5.2%). This decrease in management removal resulted in the wolf population resuming growth after a period of population stagnation. Two factors influenced this decrease, a change in policy regarding removal of wolves (stronger modelling support) and a decrease in the number of captive‐reared adult wolves released into the wild (weaker modelling support).Illegal mortality was relatively constant across both phases, but after the decrease in management removal, illegal mortality became the most important factor (relative importance shifted from 28.2% to 50.1%). Illegal mortality was positively correlated with rates of reintroduction and translocation of wolves and negatively correlated with the rate of management removal.Synthesis and applications. Using management removal to reduce human–carnivore conflict can have negative population impacts if not used judiciously. Recovering and maintaining carnivore populations in shared landscapes may require greater tolerance of conflict and more emphasis on effective conflict prevention strategies and compensation programs for affected stakeholders. [ABSTRACT FROM AUTHOR]

Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. 'Diversity Outbred in Australia (DOz)' is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle's contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focusing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform and in vitro assays of insulin action using the Prestwick chemical library. These complementary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation in ex vivo insulin-resistant mouse muscle and palmitate-induced insulin-resistant myotubes demonstrated potent insulin action restoration, potentially via upregulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems-level analysis by identifying potential therapeutics for insulin resistance. [ABSTRACT FROM AUTHOR]

Introduction: Chronic pain is a common, multifactorial condition and pharmacological treatments have limited benefits. Mindfulness is a holistic approach that might be of value in the management of chronic pain. However, attrition rates from mindfulness‐based interventions are high and factors affecting engagement are unknown. The aim of this study was to inform the design of a mindfulness programme that would be accessible and acceptable for people with chronic pain. Methods: Interpretative phenomenological analysis of interview data from people with chronic pain who had taken part in an 8‐week mindfulness programme based on mindfulness‐based stress reduction revealed factors affecting engagement with and suggestions for tailoring the programme. Factors were grouped into physical, psychological and social domains. Further suggestions for tailoring the programme to address these factors were generated through a nominal group of healthcare professionals and a focus group with service users who had chronic pain. Findings: Physical factors included disability and discomfort with some practices; psychological factors included expectations of the mindfulness programme and understanding the relationship between mindfulness and pain; and social factors included loneliness and support from others. The proposed modifications to the mindfulness programme supported by healthcare professionals and/or service users to address these are described in this paper. Public Contribution: This study involved public contributions at a number of stages. The University of Aberdeen Division of Applied Health Sciences Service User Group (who were members of the public with chronic pain) was involved in the design of the study. Patients with chronic pain recruited from general medical practice who took part in the mindfulness programme were interviewed on their experience of the programme. Patients with chronic pain who attended the mindfulness programme, and healthcare professionals with expertise in chronic pain and/or mindfulness, attended meetings to design a tailored mindfulness programme for people with chronic pain. [ABSTRACT FROM AUTHOR]

Ablative fractional resurfacing is clinically an efficient treatment for burn scar management. The aim of this pilot study was to investigate the poorly understood mechanisms underlying ablative fractional CO2 laser (AFL-CO2) therapy in relation to biomarkers S100 and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). S100 stains for Langerhans cells and neuronal cells, potentially representing the pruritus experienced. 11β-HSD1 catalyses the interconversion of cortisol and cortisone in cells, promoting tissue remodelling. Immunohistochemical analysis of S100 and 11β-HSD1 protein expression in the dermis and epidermis of the skin was performed on normal skin, before and after AFL-CO2 therapy. Data assessing outcome parameters was collected concurrently with the skin biopsies. 13 patients were treated with AFL-CO2 therapy. Langerhans cells decreased by 39% after 2nd treatment. Neuronal cells were overexpressed before treatment in the scar tissue by 91% but levels returned to that resembling normal skin. 11β-HSD1 expression in keratinocytes was significantly higher after laser treatment compared to before in scar tissue (p <0.01). No clear correlation was found in dermal fibroblast numbers throughout the treatment course. Whilst the role of the explored mechanisms and their association with clinical outcomes cannot conclusively be stated, this pilot study demonstrates promising trends that encourages investigation into this relationship. • Mechanisms of fractional laser resurfacing of scar healing is not well understood. • Two biomarkers, S100 and 11β-HSD1, investigated in relation to laser therapy. • The data from this pilot study shows promising trends for further investigation [ABSTRACT FROM AUTHOR]

This paper strives to identify the significant and unprecedented challenges in loss prevention and process safety facing industry and its senior leaders due to the social / political / economical changes and unrest of the past few years and the threats to world stability. The pandemic with its travel constraints, price hikes, and economic troubles, reinforced by changing energy markets due to the war in Ukraine is threatening global economic stability. This overall situation has introduced a dramatic step change to the conduct of operations for many manufacturers. On top of that comes the threat of climate change and the ongoing energy and digitalization adjustments that industry will have to make to improve socially responsible and to remain competitive in the face of changing expectations. These Industry 4.0 adjustments introduce a great challenge for the management of multinational companies given the greater range of expectations in its operational jurisdictions. Leadership needs to take stock, re-evaluate their business processes and engage resources not tapped in the past to establish a new foundation on which to remain competitive in the future. Within a rather turbulent world, retirement of experienced staff, the multiplicity of several generations working together with their different attitudes and life styles, posed an additional challenge: the need for skilled and motivated staff to overcome the hurdles. This paper frames these current and future challenges and provides guidance to industry leadership and management to assist in their struggle to meet demands and maintain competitive operations. [ABSTRACT FROM AUTHOR]

A central characteristic of insulin resistance is the impaired ability for insulin to stimulate glucose uptake into skeletal muscle. While insulin resistance can occur distal to the canonical insulin receptor‐PI3k‐Akt signaling pathway, the signaling intermediates involved in the dysfunction are yet to be fully elucidated. β‐catenin is an emerging distal regulator of skeletal muscle and adipocyte insulin‐stimulated GLUT4 trafficking. Here, we investigate its role in skeletal muscle insulin resistance. Short‐term (5‐week) high‐fat diet (HFD) decreased skeletal muscle β‐catenin protein expression 27% (p = 0.03), and perturbed insulin‐stimulated β‐cateninS552 phosphorylation 21% (p = 0.009) without affecting insulin‐stimulated Akt phosphorylation relative to chow‐fed controls. Under chow conditions, mice with muscle‐specific β‐catenin deletion had impaired insulin responsiveness, whereas under HFD, both mice exhibited similar levels of insulin resistance (interaction effect of genotype × diet p < 0.05). Treatment of L6‐GLUT4‐myc myocytes with palmitate lower β‐catenin protein expression by 75% (p = 0.02), and attenuated insulin‐stimulated β‐catenin phosphorylationS552 and actin remodeling (interaction effect of insulin × palmitate p < 0.05). Finally, β‐cateninS552 phosphorylation was 45% lower in muscle biopsies from men with type 2 diabetes while total β‐catenin expression was unchanged. These findings suggest that β‐catenin dysfunction is associated with the development of insulin resistance. [ABSTRACT FROM AUTHOR]

Have you ever wondered about what an organ transplant involves? This article provides a window into the experience of one patient receiving new lungs. My aim is to provide signposts for anyone else who stumbles into lung disease and then struggles for recovery from this mortal threat. Call it a "memoir of resilience"—one person's effort to bend without breaking in response to a series of medical challenges. I hope my experience might help other people with compromised lungs gain a glimmer of what to expect and provide a framework for families, friends, pastors, and others to understand what is happening from outside. [ABSTRACT FROM AUTHOR]

Background: Mobility disability is predictive of further functional decline and can itself compromise older people's capacity (and preference) to live independently. The world's population is also ageing, and multimorbidity is the norm in those aged ≥85. What is unclear in this age group, is the influence of multimorbidity on (a) transitions in mobility disability and (b) mobility disability-free life expectancy (mobDFLE).Methods and Findings: Using multistate modelling in an inception cohort of 714 85-year-olds followed over a 10-year period (aged 85 in 2006 to 95 in 2016), we investigated the association between increasing numbers of long-term conditions and (1) mobility disability incidence, (2) recovery from mobility disability and (3) death, and then explored how this shaped the remaining life expectancy free from mobility disability at age 85. Models were adjusted for age, sex, disease group count, BMI and education. We defined mobility disability based on participants' self-reported ability to get around the house, go up and down stairs/steps, and walk at least 400 yards; participants were defined as having mobility disability if, for one or more these activities, they had any difficulty with them or could not perform them. Data were drawn from the Newcastle 85+ Study: a longitudinal population-based cohort study that recruited community-dwelling and institutionalised individuals from Newcastle upon Tyne and North Tyneside general practices. We observed that each additional disease was associated with a 16% increased risk of incident mobility disability (hazard ratio (HR) 1.16, 95% confidence interval (CI): 1.07 to 1.25, p < 0.001), a 26% decrease in the chance of recovery from this state (HR 0.74, 95% CI: 0.63 to 0.86, p < 0.001), and a 12% increased risk of death with mobility disability (HR: 1.12, 95% CI: 1.07- to .17, p < 0.001). This translated to reductions in mobDFLE with increasing numbers of long-term conditions. However, residual and unmeasured confounding cannot be excluded from these analyses, and there may have been unobserved transitions to/from mobility disability between interviews and prior to death.Conclusions: We suggest 2 implications from this work. (1) Our findings support calls for a greater focus on the prevention of multimorbidity as populations age. (2) As more time spent with mobility disability could potentially lead to greater care needs, maintaining independence with increasing age should also be a key focus for health/social care and reablement services. [ABSTRACT FROM AUTHOR]

Social Scientists have spent decades researching the facilitators and barriers to adopt conservation-based farming practices. Recent reviews of the literature have called on researchers to expand spatial scales to consider social processes at a regional or watershed level. As we look to expand spatial scales for research, the literature associated with regional production offers useful insight. In this perspective, we adapt frameworks that recognize the conceptual alignment of place-making and regionality. By framing regional production as place-making processes, we suggest a model to inform future research and policies that would enhance the compatibility of agriculture and conservation. [ABSTRACT FROM AUTHOR]

Background: Previous research has suggested an association between depression and subsequent acute stroke incidence, but few studies have examined any effect modification by sociodemographic factors. In addition, no studies have investigated this association among primary care recipients with hypertension. Methods: We examined the anonymized records of all public general outpatient visits by patients aged 45+ during January 2007–December 2010 in Hong Kong to extract primary care patients with hypertension for analysis. We took the last consultation date as the baseline and followed them up for 4 years (until 2011–2014) to observe any subsequent acute hospitalization due to stroke. Mixed-effects Cox models (random intercept across 74 included clinics) were implemented to examine the association between depression (ICPC diagnosis or anti-depressant prescription) at baseline and the hazard of acute stroke (ICD-9: 430–437.9). Effect modification by age, sex, and recipient status of social security assistance was examined in extended models with respective interaction terms specified. Results: In total, 396 858 eligible patients were included, with 9099 (2.3%) having depression, and 10 851 (2.7%) eventually hospitalized for stroke. From the adjusted analysis, baseline depression was associated with a 17% increased hazard of acute stroke hospitalization [95% confidence interval (CI) 1.03–1.32]. This association was suggested to be even stronger among men than among women (hazard ratio = 1.29, 95% CI 1.00–1.67). Conclusion: Depression is more strongly associated with acute stroke incidence among male than female primary care patients with hypertension. More integrated services are warranted to address their needs. [ABSTRACT FROM AUTHOR]

Neutrophils accumulate in insulin-sensitive tissues during obesity and may play a role in impairing insulin sensitivity. The major serine protease expressed by neutrophils is neutrophil elastase (NE), which is inhibited endogenously by a1-antitrypsin A (A1AT). We investigated the effect of exogenous (A1AT) treatment on diet-induced metabolic dysfunction. Male C57Bl/6j mice fed a chow or a high-fat diet (HFD) were randomized to receive intraperitoneal injections three times weekly of either Prolastin (human A1AT; 2 mg) or vehicle (PBS) for 10 wk. Prolastin treatment did not affect plasma NE concentration, body weight, glucose tolerance, or insulin sensitivity in chow-fed mice. In contrast, Prolastin treatment attenuated HFD-induced increases in plasma and white adipose tissue (WAT) NE without affecting circulatory neutrophil levels or increases in body weight. Prolastin-treated mice fed a HFD had improved insulin sensitivity, as assessed by insulin tolerance test, and this was associated with higher insulin-dependent IRS-1 (insulin receptor substrate) and AktSer473 phosphorylation, and reduced inflammation markers in WAT but not liver or muscle. In 3T3-L1 adipocytes, Prolastin reversed recombinant NE-induced impairment of insulin-stimulated glucose uptake and IRS-1 phosphorylation. Furthermore, PDGF mediated p-AktSer473 activation and glucose uptake (which is independent of IRS-1) was not affected by recombinant NE treatment. Collectively, our findings suggest that NE infiltration of WAT during metabolic overload contributes to insulin resistance by impairing insulin-induced IRS-1 signaling. [ABSTRACT FROM AUTHOR]

Key points: Loss of β‐catenin impairs in vivo and isolated muscle exercise/contraction‐stimulated glucose uptake.β‐Catenin is required for exercise‐induced skeletal muscle actin cytoskeleton remodelling.β‐Catenin675 phosphorylation during exercise may be intensity dependent. The conserved structural protein β‐catenin is an emerging regulator of vesicle trafficking in multiple tissues and supports insulin‐stimulated glucose transporter 4 (GLUT4) translocation in skeletal muscle by facilitating cortical actin remodelling. Actin remodelling may be a convergence point between insulin and exercise/contraction‐stimulated glucose uptake. Here we investigated whether β‐catenin is involved in regulating exercise/contraction‐stimulated glucose uptake. We report that the muscle‐specific deletion of β‐catenin induced in adult mice (BCAT‐mKO) impairs both exercise‐ and contraction (isolated muscle)‐induced glucose uptake without affecting running performance or canonical exercise signalling pathways. Furthermore, high intensity exercise in mice and contraction of myotubes and isolated muscles led to the phosphorylation of β‐cateninS675, and this was impaired by Rac1 inhibition. Moderate intensity exercise in control and Rac1 muscle‐specific knockout mice did not induce muscle β‐cateninS675 phosphorylation, suggesting exercise intensity‐dependent regulation of β‐cateninS675. Introduction of a non‐phosphorylatable S675A mutant of β‐catenin into myoblasts impaired GLUT4 translocation and actin remodelling stimulated by carbachol, a Rac1 and RhoA activator. Exercise‐induced increases in cross‐sectional phalloidin staining (F‐actin marker) of gastrocnemius muscle was impaired in muscle from BCAT‐mKO mice. Collectively our findings suggest that β‐catenin is required for optimal glucose transport in muscle during exercise/contraction, potentially via facilitating actin cytoskeleton remodelling. Key points: Loss of β‐catenin impairs in vivo and isolated muscle exercise/contraction‐stimulated glucose uptake.β‐Catenin is required for exercise‐induced skeletal muscle actin cytoskeleton remodelling.β‐Catenin675 phosphorylation during exercise may be intensity dependent. [ABSTRACT FROM AUTHOR]

Social factors hold implications for the success or failure of wildlife reintroductions. Potential conflict issues may prevent projects from proceeding or succeeding. The manner in which wildlife managers engage with affected people in conflict scenarios may prevent or contribute toward conflict escalation, so an understanding of how to improve engagement is required. We conducted interviews with individuals who reported conflicts with beavers (Castor fiber) within the case study of a reintroduction trial in England, called the 'River Otter Beaver Trial'. Using a qualitative thematic analysis, we identified five themes to be considered when engaging with affected people in beaver reintroduction conflicts: (1) Proactive Engagement or a Fast Response; (2) Appropriate Communication; (3) Shared Decision-Making; (4) Sense that Humans are Responsible for Conflicts with Reintroduced Species; (5) A Need for Certainty. We conclude that engagement with affected individuals will likely be improved, with reduced conflict potential, where these themes are addressed. [ABSTRACT FROM AUTHOR]

Social factors hold implications for the success or failure of wildlife reintroductions. Potential conflict issues may prevent projects from proceeding or succeeding. The manner in which wildlife managers engage with affected people in conflict scenarios may prevent or contribute toward conflict escalation, so an understanding of how to improve engagement is required. We conducted interviews with individuals who reported conflicts with beavers (Castor fiber) within the case study of a reintroduction trial in England, called the 'River Otter Beaver Trial'. Using a qualitative thematic analysis, we identified five themes to be considered when engaging with affected people in beaver reintroduction conflicts: (1) Proactive Engagement or a Fast Response; (2) Appropriate Communication; (3) Shared Decision-Making; (4) Sense that Humans are Responsible for Conflicts with Reintroduced Species; (5) A Need for Certainty. We conclude that engagement with affected individuals will likely be improved, with reduced conflict potential, where these themes are addressed. [ABSTRACT FROM AUTHOR]

Background Previous work on sickness absence has shown that conversations about return to work can be challenging. The perception of competing interests and multiple stakeholders in the return to work process may also complicate and erode trust, further impacting health and well-being. Aims This study aims to explore the themes arising from the experiences of physicians and patients on the impact of health and return to work. The goal was to use these results to develop a Medical Readers' Theatre workshop focusing on negotiating challenging return to work scenarios to serve as an educational support for stakeholders. Methods Semi-structured interviews were conducted with 19 physicians and 15 patients from the Canadian Maritime Provinces on their experiences in return to work following an injury or illness. Interviews were recorded, transcribed and thematically analysed. Using the emergent themes, an educational workshop in the modality of Readers' Theatre was developed. Results The findings confirm there are multiple stakeholders involved in the return to work process and the factors influencing successful return are not always medically related. Six recurring themes were identified for the patient group and five for the physicians', allowing the development of storylines and four return to work scenarios. The scenarios have been used in teaching sessions. Conclusions The themes reinforced that challenges in return to work are not always medical in nature. This Readers' Theatre adopts perspectives of patients, physicians and other stakeholders whilst focusing on return to work with the goal of providing engagement in reflective and purposeful discussion. [ABSTRACT FROM AUTHOR]

Background: The co-occurrence of mental and physical chronic conditions (mental-physical multimorbidity) is a growing and largely unaddressed challenge for health systems and wider economies in low-and middle-income countries. This study investigated the independent and combined (additive or synergistic) effects of mental and physical chronic conditions on disability, work productivity, and social participation in China.Methods: Panel data study design utilised two waves of the China Health and Retirement Longitudinal Study (2011, 2015), including 5616 participants aged ≥45 years, 12 physical chronic conditions and depression. We used a panel data approach of random-effects regression models to assess the relationships between mental-physical multimorbidity and outcomes.Results: After adjusting for socio-economic and demographic factors, an increased number of physical chronic conditions was independently associated with a higher likelihood of disability (Adjusted odds ratio (AOR) = 1.39; 95% CI: 1.33, 1.45), early retirement (AOR = 1.37 [1.26, 1.49]) and increased sick leave days (1.25 days [1.16, 1.35]). Depression was independently associated with disability (AOR = 3.78 [3.30, 4.34]), increased sick leave days (2.18 days [1.72, 2.77]) and a lower likelihood of social participation (AOR = 0.57 [0.47, 0.70]), but not with early retirement (AOR = 1.24 [0.97, 1.58]). There were small and statistically insignificant interactions between physical chronic conditions and mental health on disability, work productivity and social participation, suggesting an additive effect of mental-physical multimorbidity on productivity loss.Conclusion: Mental-physical multimorbidity poses substantial negative health and economic effects on individuals, health systems, and societies. More research that addresses the challenges of mental-physical multimorbidity is needed to inform the development of interventions that can be applied to the workplace and the wider community in China. [ABSTRACT FROM AUTHOR]

The global challenge of living together peacefully and constructively in the context of deep religious/worldview differences will not be met through bumper-sticker slogans about "tolerance." This essay provides an introductory overview of a richer approach called covenantal pluralism, which has been developed over the last few years at the Templeton Religion Trust. The philosophy of covenantal pluralism is a robust, relational, and non-relativistic paradigm of citizenship that emphasizes both legal equality and neighborly solidarity. It calls not only for a constitutional order characterized by equal rights and responsibilities but also a culture of engagement characterized by relationships of mutual respect and protection. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) are insidious and incurable neurodegenerative diseases that represent a significant burden to affected individuals, caregivers, and an ageing population. Both PD and FTD/ALS are defined at post mortem by the presence of protein aggregates and the loss of specific subsets of neurons. We examine here the crucial role of lysosome dysfunction in these diseases and discuss recent evidence for converging mechanisms. This review draws upon multiple lines of evidence from genetic studies, human tissue, induced pluripotent stem cells (iPSCs), and animal models to argue that lysosomal failure is a primary mechanism of disease, rather than merely reflecting association with protein aggregate end-points. This review provides compelling rationale for targeting lysosomes in future therapeutics for both PD and FTD/ALS. PD and FTD-associated genetic variants are heavily implicated in lysosome function; lysosomal disorder gene variants are associated with increased PD risk, and waste disposal pathways are enriched in both PD and FTD in weighted protein–protein interaction network analyses. Several PD and FTD-associated genes have now been implicated in the regulation of lysosomal pH, a potential underlying mechanism of lysosome dysfunction seen in PD and FTD. LRRK2 and C9ORF72 , the leading genetic causes of PD and FTD, respectively, are both heavily implicated in the regulation of Rabs, suggesting a putative role of Rabs in lysosomal dysfunction in these diseases. Small molecules targeting the lysosome, capable of altering lysosomal pH, have been shown to reverse lysosome dysfunction in models of disease, highlighting future therapeutic targets and potentials. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effect of a primary care-based community-links practitioner (CLP) intervention on patients' quality of life and well-being.Methods: Quasi-experimental cluster-randomized controlled trial in socioeconomically deprived areas of Glasgow, Scotland. Adult patients (aged 18 years or older) referred to CLPs in 7 intervention practices were compared with a random sample of adult patients from 8 comparison practices at baseline and 9 months.Primary Outcome: health-related quality of life (EQ-5D-5L, a standardized measure of self-reported health-related quality of life that assesses 5 dimensions at 5 levels of severity).Secondary Outcomes: well-being (Investigating Choice Experiments for the Preferences of Older People Capability Measure for Adults [ICECAP-A]), depression (Hospital Anxiety and Depression Scale, Depression [HADS-D]), anxiety (Hospital Anxiety and Depression Scale, Anxiety [HADS-A]), and self-reported exercise. Multilevel, multiregression analyses adjusted for baseline differences. Patients were not blinded to the intervention, but outcome analysis was masked.Results: Data were collected on 288 and 214 (74.3%) patients in the intervention practices at baseline and follow-up, respectively, and on 612 and 561 (92%) patients in the comparison practices. Intention-to-treat analysis found no differences between the 2 groups for any outcome. In subgroup analyses, patients who saw the CLP on 3 or more occasions (45% of those referred) had significant improvements in EQ-5D-5L, HADS-D, HADS-A, and exercise levels. There was a high positive correlation between CLP consultation rates and patient uptake of suggested community resources.Conclusions: We were unable to prove the effectiveness of referral to CLPs based in primary care in deprived areas for improving patient outcomes. Future efforts to boost uptake and engagement could improve overall outcomes, although the apparent improvements in those who regularly saw the CLPs may be due to reverse causality. Further research is needed before wide-scale deployment of this approach. [ABSTRACT FROM AUTHOR]

Mexican wolves (Canis lupus baileyi) share their range with a number of sympatric carnivores, many of which are a concern to livestock producers because they can prey on livestock. Determining which predator species is responsible for killing livestock is important for determining appropriate management actions and for the conservation of Mexican wolves. A variety of information can be used to decipher which carnivore species was responsible for making a kill, and mandibular (upper) and maxillary (lower) intercanine width measurements (i.e. bite mark analysis) can aid this process. No research has been conducted to validate the usefulness of bite mark analysis; thus, we used dentition measurements from Mexican wolves, coyotes (Canis latrans), feral dogs (Canis familiaris), bobcats (Lynx rufus), mountain lions (Puma concolor), and gray foxes (Urocyon cinereoargenteus) and an overlap coefficient to evaluate the degree of overlap in intercanine width between these species. We found that larger carnivore species had greater overlap than smaller carnivores, feral dogs overlapped widely with all the medium-to-large carnivores, and upper and lower intercanine width measurements provided similar information. Our data indicated that when investigating livestock depredations for Mexican wolves, bite mark analyses should be evaluated along with additional forensic evidence due to the overlap between many of the carnivore species, and that measurements between 28 and 35 mm have the greatest uncertainty because this range overlaps with feral dogs, mountain lions, and coyotes. [ABSTRACT FROM AUTHOR]

• Uncertainty of cost and schedule for nuclear energy is modeled. • This uncertainty was applied to leading large/small GenIII + designs. • In tight labor markets, single unit SMRs have the least risk. • Reduced cost from Economy of Scale outweighs increased risk in most cases. • Design changes and human errors were the largest drivers for risk. Capital cost and construction schedule estimates for nuclear projects often under-estimate the realized costs upon project completion. Uncertainty quantification of nuclear construction project cost estimates have seldom been used in open-literature and have not shown to effectively bound the realized schedules and costs. Building on recent studies of advanced light water reactor costs and construction schedules, this paper explored the risk of different construction delay drivers and the implication on total installed cost. Using data from previous nuclear projects, as well as other megaprojects and analyses, we modeled the impact of supply chain delays, human error, change orders, and productivity on four different reactor architectures: a large passively safe PWR, a large modular BWR, small modular BWR, and a multi-module PWR. The probability and impact of supply chain delays and change orders were modeled based on the AP1000 construction experience at Vogtle Units 3 & 4, while the human error and productivity models came from non-nuclear sources. The estimated risk to cost overrun and schedule delays were found to be significant. The multi-module plant was the most susceptible to construction delays, and the small modular BWR was the least susceptible. However, the risk mitigation by a small reactor only offset the lost economy of scale in a few scenarios relative to the large reactors, because there was still significant onsite work despite modularization. Access to large labor markets mitigated the upper bound cost and schedule risks significantly for all reactor types. Finally, design changes and the resulting productivity hits were the largest driver of construction delays, and human error was the second largest driver, but supply chain delays only accounted for a small fraction of the delays for the assessed water-cooled concepts. [ABSTRACT FROM AUTHOR]

Background: Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomes remain unclear. Methods: We developed multifaceted proteomic techniques to characterize the dynamic lysosomal biology in living human neurons and fixed mouse brain tissues. Using lysosome proximity labeling and immuno-purification of intact lysosomes, we characterized lysosome compositions and interactome in both human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (i3Neurons) and mouse brains. Using dynamic stable isotope labeling by amino acids in cell culture (dSILAC) proteomics, we measured global protein half-lives in human i3Neurons for the first time. Results: Leveraging the multi-modal proteomics and live-cell imaging techniques, we comprehensively characterized how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes. We found that PGRN loss impairs the lysosome's degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased hydrolases within the lysosome, altered protein regulations related to lysosomal transport, and elevated lysosomal pH. Consistent with impairments in lysosomal function, GRN-null i3Neurons and frontotemporal dementia patient-derived i3Neurons carrying GRN mutation showed pronounced alterations in protein turnover, such as cathepsins and proteins related to supramolecular polymerization and inherited neurodegenerative diseases. Conclusion: This study suggested PGRN as a critical regulator of lysosomal pH and degradative capacity, which influences global proteostasis in neurons. Beyond the study of progranulin deficiency, these newly developed proteomic methods in neurons and brain tissues provided useful tools and data resources for the field to study the highly dynamic neuronal lysosome biology. [ABSTRACT FROM AUTHOR]

Human-carnivore conflict is presently on the rise as human populations continue to grow and carnivore conservation efforts gain precedence. The behaviors exhibited by carnivores that cause conflict are often learned; therefore, reducing learning potential though the use of non-lethal tools is important for coexistence. In this study we measured how prior experience (i.e., conditioning) influenced the motivation and persistence of captive wolves ( Canis lupus ) seeking a food reward by quantifying latency to first behavior and duration of behavior for two behavior groups: investigative and work behaviors. Latency to first behavior was faster in conditioned wolves for both investigative (11 times faster; P = 0.0491) and work (4 times faster; P = 0.0112) behaviors, indicating prior experience motivated wolves to overcome neophobic behaviors and facilitated learning to access rewards more quickly. We found little difference in duration for both investigative (P = 0.3194) and work behaviors (P = 0.7016), indicating conditioned and non-conditioned wolves will spend similar amounts of time trying to obtain a reward once a behavior is initiated. When wolves were unable to attain food rewards, we found that the duration of both investigative (P = 0.0631) and work (P = 0.0609) behavior declined over the course of three weeks for both non-conditioned (37.3% and 92.6% decline in investigative behaviors and work behaviors, respectively) and conditioned (59.5% and 88.2% decline in investigative behaviors and work behaviors, respectively) wolves, indicating decreased persistence with the application of a secure prevention measure. Overall, our results indicate that the use of non-lethal tools that prevent animals from attaining anthropogenic food can effectively curb learning in carnivores and help reduce human-carnivore conflict. [ABSTRACT FROM AUTHOR]

Selection of den sites is a crucial aspect of American black bear (Ursus americanus) life history. High-quality dens provide thermal insulation, protection from disturbance, suitable environment for parturition and cub development, and proximity to available forage upon emergence. Black bears are increasingly coexisting with people in human-dominated landscapes; however, little is known about whether urban environments influence characteristics of dens and den site selection. Our objective was to determine the effect of housing density (a proxy for human activity and availability of anthropogenic resources) on selection of den sites in years of good and poor natural forage. We additionally compared size, shape, and location of dens of males and females to describe den characteristics and explore whether differences existed between males and females. We revisited 34 den locations detected during a 6-year (2005–2010) urban black bear study in Aspen, Colorado, USA, and measured den entrance and den volume. We fit a conditional logistic regression model using a resource selection function framework to determine the importance of housing density and other landscape variables (elevation, slope, aspect, and vegetation type) associated with den site selection. Slope was the best predictor of den site selection and there was no relationship between den selection and housing density, indicating that black bears were neither avoiding nor seeking urban areas for denning. Dens were smaller for females ( = 3.30 m3, SE = 1.94, n = 22) than for males ( = 7.56 m3, SE = 3.31, n = 8), supporting the idea that females have greater constraints in den characteristics, possibly related to cub development and security from predation or because females generally are smaller than males. [ABSTRACT FROM AUTHOR]

Purpose: The influence of multimorbidity on the clinical encounter is poorly understood, especially in areas of high socioeconomic deprivation where burdensome multimorbidity is concentrated. The aim of the current study was to examine the effect of multimorbidity on general practice consultations, in areas of high and low deprivation.Methods: We conducted secondary analyses of 659 video-recorded routine consultations involving 25 general practitioners (GPs) in deprived areas and 22 in affluent areas of Scotland. Patients rated the GP's empathy using the Consultation and Relational Empathy (CARE) measure immediately after the consultation. Videos were analyzed using the Measure of Patient-Centered Communication. Multilevel, multi-regression analysis identified differences between the groups.Results: In affluent areas, patients with multimorbidity received longer consultations than patients without multimorbidity (mean 12.8 minutes vs 9.3, respectively; P = .015), but this was not so in deprived areas (mean 9.9 minutes vs 10.0 respectively; P = .774). In affluent areas, patients with multimorbidity perceived their GP as more empathic (P = .009) than patients without multimorbidity; this difference was not found in deprived areas (P = .344). Video analysis showed that GPs in affluent areas were more attentive to the disease and illness experience in patients with multimorbidity (P < .031) compared with patients without multimorbidity. This was not the case in deprived areas (P = .727).Conclusions: In deprived areas, the greater need of patients with multimorbidity is not reflected in the longer consultation length, higher GP patient centeredness, and higher perceived GP empathy found in affluent areas. Action is required to redress this mismatch of need and service provision for patients with multimorbidity if health inequalities are to be narrowed rather than widened by primary care. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: The purpose of presenting this case is to demonstrate the degree to which the kidney is capable of selectively excreting a massive load of sodium and water when challenged with both of these, without altering the plasma levels of other ions. Case Report: An 8-year-old boy was admitted in severe renal failure. Workup demonstrated a high grade obstruction of a single kidney. Following dialysis, the patient underwent surgery to correct the obstruction and he developed post-obstructive diuresis. Within one week he was receiving 34 liters of essentially 1/2 Na by IV and by mouth and was excreting 70% of his filtered load of water and 50% of his filtered load of sodium. As soon as the administered fluids and Na were cut back, the kidney responded appropriately. Conclusions: While post-obstructive diuresis is a real phenomenon, very frequently it is magnified by forcing diuresis with the administration of too much water. These patients are best treated by administering fluids to equal output for two to three days and then gradually cutting back on fluid intake. If the kidney responds appropriately, then fluids can be given as the patient requests. [ABSTRACT FROM AUTHOR]

The prevalence of complex health and social needs in primary care patients is growing. Furthermore, recent research suggests that the impact of psychosocial distress on the significantly poorer health outcomes in this population may have been underestimated. The potential of social work in primary care settings has been extensively discussed in both health and social work literature and there is evidence that social work interventions in other settings are particularly effective in addressing psychosocial needs. However, the evidence base for specific improved health outcomes related to primary care social work is minimal. This review aimed to identify and synthesise the available evidence on the health benefits of social work interventions in primary care settings. Nine electronic databases were searched from 1990 to 2015 and seven primary research studies were retrieved. Due to the heterogeneity of studies, a narrative synthesis was conducted. Although there is no definitive evidence for effectiveness, results suggest a promising role for primary care social work interventions in improving health outcomes. These include subjective health measures and self-management of long-term conditions, reducing psychosocial morbidity and barriers to treatment and health maintenance. Although few rigorous study designs were found, the contextual detail and clinical settings of studies provide evidence of the practice applicability of social work intervention. Emerging policy on the integration of health and social care may provide an opportunity to develop this model of care. [ABSTRACT FROM AUTHOR]

Martin Luther's social writings (volumes 44-47 in the American edition) provide a robust account of human agency that might help Lutheran social ethics address contemporary crises of confidence. When Luther addresses concrete moral issues, he enriches his two-kingdoms frame with a focus on particular social roles such as ruler, merchant, soldier, parent, etc. This (often tacit) 'three-estates' approach creates room for a distinctly Lutheran contribution to contemporary virtue theory by focusing on the functions served by particular social roles more than on individual self-chosen pathways of moral improvement. It also supports a prophetic affirmation of vocation against the contemporary breakdown of expectations and confidence in social roles. [ABSTRACT FROM AUTHOR]

The use of song by wood-warblers (Parulidae) with multiple song types has received little attention during migration. On the breeding area, the two song types serve to attract mates and defend territory, but the function(s) during migration, if any, are unclear. I studied the singing of Townsend's Warblers (Setophaga townsendi) during spring migration through southern Oregon and northern California. Males preferentially used Type II songs (79%) whether alone or in flocks of up to ~20 individuals. Type 1 songs of wood-warblers tend to be acquired early in the hatch year while Type II songs appear to be subject to modification over an extended period of time. The preference for Type II songs in migration may reflect an important period in the development of Type II song. More than one dialect of Type I song was recorded within flocks indicating that flocks were composed of individuals from different breeding populations. Type II songs are recognizably similar in breeding populations from central Oregon to Alaska. The similarity of Type II songs across the range of the species may result from song refinement through interaction with other singing males while in transit. [ABSTRACT FROM AUTHOR]

The objective of this research was to evaluate effects of replacing sorghum x Sudangrass hay with ground juniper in gestating ewe supplements on pre- and postpartum growth performance, serum metabolites and hormonal concentrations, milk fatty acid composition, and progeny preweaning performance. In a completely randomized design, commercial Rambouillet ewes (age = 3 to 5 yr; initial BW = 65.2 ± 1.6 kg) on a base diet of long-stem sorghum x Sudangrass hay were assigned to 1 of 4 dietary supplements in which ground juniper replaced 0% (CNTL), 33% (18JUN), 66% (36JUN), or 100% (54JUN) of the ground sorghum x Sudangrass hay in a pelleted supplement with ground juniper from d 38 ± 4 of gestation to 2 d postpartum. Treatment DM diet intake overall (g/kg BW) in ewes receiving no juniper was similar (P ≥ 0.38) to that of those receiving increasing concentrations of juniper. Changes in ewe BW and BCS were similar (P ≥ 0.24) in ewes throughout gestation. All serum metabolites and hormones were within normal clinical ranges; however, serum IGF-1 decreased linearly (P = 0.003), alanine increased (linear; P = 0.003), and serum Na decreased (linear; P = 0.049) as the percentage of juniper increased in the diet. Ewe milk fatty acid composition was similar (P > 0.05) for the majority of fatty acids across treatment groups, with the exception of arachidonic acid (C20:4n6) being greater (P < 0.02) in 54JUN vs. CNTL ewe milk. Lamb birth weights were similar (P = 0.13), whereas lamb ADG tended to differ (quadratic; P = 0.06) from d 0 to 14, with 18JUN being the least. At weaning, BW tended (P = 0.09) to linearly decrease in lambs born to ewes consuming greater concentrations of juniper but were not different (P = 0.26) between CNTL and 18JUN, 36JUN, and 54JUN. Results indicated that feeding increasing levels of ground juniper in supplements did not negatively alter ewe performance or serum metabolites and hormones measured pre- and postpartum. Lamb birth weight and preweaning performance appeared unaffected by maternal consumption of ground juniper containing supplements. Results also provide novel information regarding the effects of plant secondary compound consumption throughout pregnancy on ewe and progeny performance and health. [ABSTRACT FROM AUTHOR]

Background: Measurement of multimorbidity in research is variable, including the choice of the data source used to ascertain conditions. We compared the estimated prevalence of multimorbidity and associations with mortality using different data sources. Methods: A cross-sectional study of SAIL Databank data including 2,340,027 individuals of all ages living in Wales on 01 January 2019. Comparison of prevalence of multimorbidity and constituent 47 conditions using data from primary care (PC), hospital inpatient (HI), and linked PC-HI data sources and examination of associations between condition count and 12-month mortality. Results: Using linked PC-HI compared with only HI data, multimorbidity was more prevalent (32.2% versus 16.5%), and the population of people identified as having multimorbidity was younger (mean age 62.5 versus 66.8 years) and included more women (54.2% versus 52.6%). Individuals with multimorbidity in both PC and HI data had stronger associations with mortality than those with multimorbidity only in HI data (adjusted odds ratio 8.34 [95% CI 8.02-8.68] versus 6.95 (95%CI 6.79-7.12] in people with ≥ 4 conditions). The prevalence of conditions identified using only PC versus only HI data was significantly higher for 37/47 and significantly lower for 10/47: the highest PC/HI ratio was for depression (14.2 [95% CI 14.1–14.4]) and the lowest for aneurysm (0.51 [95% CI 0.5–0.5]). Agreement in ascertainment of conditions between the two data sources varied considerably, being slight for five (kappa < 0.20), fair for 12 (kappa 0.21–0.40), moderate for 16 (kappa 0.41–0.60), and substantial for 12 (kappa 0.61–0.80) conditions, and by body system was lowest for mental and behavioural disorders. The percentage agreement, individuals with a condition identified in both PC and HI data, was lowest in anxiety (4.6%) and highest in coronary artery disease (62.9%). Conclusions: The use of single data sources may underestimate prevalence when measuring multimorbidity and many important conditions (especially mental and behavioural disorders). Caution should be used when interpreting findings of research examining individual and multiple long-term conditions using single data sources. Where available, researchers using electronic health data should link primary care and hospital inpatient data to generate more robust evidence to support evidence-based healthcare planning decisions for people with multimorbidity. [ABSTRACT FROM AUTHOR]

We describe the singing behavior of Yellow-rumped Warblers ( Setophaga coronata) in southern Oregon. Males used songs of 2 categories. Type I songs were delivered early in the breeding season before females were observed, and differed from the Type II songs delivered in low-light conditions before sunrise after the arrival of females. Both Type I and Type II songs were used after the dawn chorus. Chip-like call notes did not accompany Type II singing in the dawn chorus unlike some warblers with 2 song categories. Both Type I and Type II songs varied considerably among males, and song sharing was uncommon. Songs of Yellow-rumped Warblers were performance encoded; no obvious features with respect to frequency, duration, or syllable structure united the songs within each song category. Unlike many warblers with performance-encoded songs, Type II song bouts of a given male consisted of a single variant. [ABSTRACT FROM AUTHOR]

Worldwide, native predators are killed to protect livestock, an action that can undermine wildlife conservation efforts and create conflicts among stakeholders. An ongoing example is occurring in the western United States, where wolves (Canis lupus) were eradicated by the 1930s but are again present in parts of their historic range. While livestock losses to wolves represent a small fraction of overall livestock mortality, the response to these depredations has resulted in widespread conflicts including significant efforts at lethal wolf control to reduce impacts on livestock producers, especially those with large-scale grazing operations on public lands. A variety of nonlethal methods have proven effective in reducing livestock losses to wolves in small-scale operations but in large-scale, open-range grazing operations, nonlethal management strategies are often presumed ineffective or infeasible. To demonstrate that nonlethal techniques can be effective at large scales, we report a 7-year case study where we strategically applied nonlethal predator deterrents and animal husbandry techniques on an adaptive basis (i.e., based on terrain, proximity to den or rendezvous sites, avoiding overexposure to techniques such as certain lights or sound devices that could result in wolves losing their fear of that device, etc.) to protect sheep (Ovis aries) and wolves on public grazing lands in Idaho. We collected data on sheep depredation mortalities in the protected demonstration study area and compared these data to an adjacent wolf-occupied area where sheep were grazed without the added nonlethal protection measures. Over the 7-year period, sheep depredation losses to wolves were 3.5 times higher in the Nonprotected Area (NPA) than in the Protected Area (PA). Furthermore, no wolves were lethally controlled within the PA and sheep depredation losses to wolves were just 0.02% of the total number of sheep present, the lowest loss rate among sheep-grazing areas in wolf range statewide, whereas wolves were lethally controlled in the NPA. Our demonstration project provides evidence that proactive use of a variety of nonlethal techniques applied conditionally can help reduce depredation on large open-range operations. [ABSTRACT FROM AUTHOR]

Background The objective of this study was to describe the first US-based study to use the European Position Paper on Rhinosinusitis ( EPOS) criteria to study the prevalence of chronic rhinosinusitis ( CRS) in a general-population sample. Methods A CRS symptom questionnaire was mailed to 23 700 primary care patients from Geisinger Clinic, a health system serving 45 counties in Pennsylvania. CRS cases were categorized into four unique subgroups based on EPOS symptoms: obstruction and discharge with no smell loss or pain/pressure; smell loss without pain/pressure; facial pain and/or pressure without smell loss; and both smell loss and pain/pressure. All cases were required to have nasal obstruction or discharge. Logistic regression was used to evaluate potential factors associated with CRS subgroups. Results We found that 11.9% of patients met criteria for CRS. Prevalence peaked at 15.9% between ages 50 and 59 years and then dropped to 6.8% after age 69. The odds of CRS was higher among patients who were white, younger, smokers, had a history of Medical Assistance, and had other diseases. When CRS subgroups were modeled separately, these associations were no longer significant for some CRS subgroups. Comorbid diseases were most strongly associated with CRS cases who reported smell loss and facial pain and/or pressure and had the weakest associations with CRS cases who did not report these symptoms. Conclusions CRS is a highly prevalent and heterogeneous condition. Differences in risk factors and health outcomes across symptom subgroups may be indicative of differences in etiology that have implications for disease management. [ABSTRACT FROM AUTHOR]

An analytical solution for calculating the contaminant discharge rate in an aquifer following an instantaneous release of reactive contaminant mass to groundwater is used to derive relationships for the time and magnitude of peak concentration in a river receiving the transported material. Relationships are developed for the time of peak concentration relative to the time of travel for the contaminant, and the magnitude of peak concentration relative to the concentration calculated at the time of travel. Both quantities are found to be a function of two dimensionless parameters characterizing advective-dispersive-reactive transport-the Peclet number and the Damkohler number. It is shown that the time to peak concentration may occur before the time of travel, considering advection and retardation only, depending on the magnitudes of the Peclet and Damkohler numbers. Similarly, the magnitude of peak concentration may exceed the concentration calculated assuming that the time of peak concentration coincides with time of travel for the contaminant. For large Damkohler numbers, equating the time of peak concentration with the time of travel for the contaminant can significantly underestimate peak concentrations. [ABSTRACT FROM AUTHOR]

Background: the care of older people with dementia is often complicated by physical comorbidity and polypharmacy, but the extent and patterns of these have not been well described. This paper reports analysis of these factors within a large, cross-sectional primary care data set. Methods: data were extracted for 291,169 people aged 65 years or older registered with 314 general practices in the UK, of whom 10,258 had an electronically recorded dementia diagnosis. Differences in the number and type of 32 physical conditions and the number of repeat prescriptions in those with and without dementia were examined. Age-gender standardised rates were used to calculate odds ratios (ORs) of physical comorbidity and polypharmacy. Results: people with dementia, after controlling for age and sex, had on average more physical conditions than controls (mean number of conditions 2.9 versus 2.4; P < 0.001) and were on more repeat medication (mean number of repeats 5.4 versus 4.2; P < 0.001). Those with dementia were more likely to have 5 or more physical conditions (age-sex standardised OR [sOR] 1.42, 95% confidence interval (CI) 1.35-1.50; P < 0.001) and were also more likely to be on 5 or more (sOR 1.46; 95% CI 1.40-1.52; P < 0.001) or 10 or more repeat prescriptions (sOR 2.01; 95% CI 1.90-2.12; P < 0.001). Conclusions: people with dementia have a higher burden of comorbid physical disease and polypharmacy than those without dementia, even after accounting for age and sex differences. Such complex needs require an integrated response from general health professionals and multidisciplinary dementia specialists. [ABSTRACT FROM AUTHOR]

Urbanization alters landscapes and ecosystem processes that result in negative impacts for many species. However, urbanization also creates novel environments that certain species, including carnivores, are able to exploit. Coyotes (Canis latrans) are 1 example of a species capable of exploiting urban environments throughout North America and, in some cases, becoming involved in human-coyote conflict. As part of a comprehensive study of human-coyote coexistence in the Denver metropolitan area of Colorado, we investigated the spatial ecology of coyotes to determine movement and activity patterns relative to the urban matrix. We examined home-range size, habitat use, and resource selection for 22 coyotes monitored with GPS collars during 2012-2014. Mean (± SD) home-range size of resident coyotes (11.6 ± 11.0 km2) was smaller than ranges of transient coyotes (200.7 ± 232.4 km2). Home-range size did not vary by season or sex, but resident coyotes during the day (7.2 ± 10.5 km2) had smaller home ranges than during the night (11.3 ± 10.8 km2). Coyotes had high percentages of developed lands (44.5 ± 18.9%) within their home ranges, contrary to previous studies of urban coyotes. However, the percentage of coyote locations in natural lands (48.9 ± 22.4%) was higher than in developed lands (20.6 ± 11.7%). Homerange size of residents was not related to either the percentage of developed lands or altered lands within home ranges. Coyotes selected natural lands over developed lands, and they increased activity at night. Although coyotes were able to thrive in home ranges containing large amounts of development, they continued to avoid areas with high human activity by primarily residing in areas with natural land cover. Similar to urban areas throughout the Northern Hemisphere, coyotes in the Denver metropolitan area have become efficiently adapted to a highly developed landscape, reflecting the flexible nature of this opportunistic carnivore. [ABSTRACT FROM AUTHOR]

• Methodology for estimating the construction duration of nuclear projects. • Construction schedules of 3 large and 3 small water reactors are estimated. • Smaller reactors are more insensitive to staffing constraints. • Smaller reactors are more sensitive to modularization assumptions. Recent nuclear construction project schedules in the US and Europe were 2.5x their original estimates due to productivity misses, supply chain challenges, hiring constraints, and other issues. Small modular reactors are proposed as a remedy. Smaller reactors will require one fourth to one third the person-hours of labor and leverage more common supply chains, putting less strain on each step of the construction process. This study presents a methodology for estimating the construction duration of nuclear projects, so the sensitivity of proposed concepts to staffing and labor constraints can be analyzed. The methodology builds on a previous overnight capital cost estimation tool and builds a Gantt chart out of 226 tasks. The genetic algorithm assigns resources to each task to minimize construction time subject to peak staffing and hiring rate constraints. The results were consistently within 15% of seven benchmark durations. Under tighter labor constraints, the construction duration of large reactors increased 42% on average and only 3% for small reactors. Modularization of systems and structures reduced construction durations 60%, but it increased the sensitivity to labor constraints. Small reactors were more sensitive to the modularization assumptions because of the compact structures and layout, and the power specific cost ($/kW) sensitivity was higher, but the total financial impact was smaller because the total costs were lower. [ABSTRACT FROM AUTHOR]

In anthropogenic landscapes, wildlife reintroductions are likely to result in interactions between people and reintroduced species. People living in the vicinity may have little familiarity with the reintroduced species or associated management, so will need to learn to live with the species in a new state of "Renewed Coexistence." In England, Eurasian beavers (Castor fiber) are being reintroduced and U.K. Government agencies are currently considering their national approach to reintroduction and management. Early indications are this will include requirement for "Beaver Management Groups" (BMGs) to engage with local stakeholders. This policy paper reports on qualitative research that captured lessons from the governance of two existing BMGs in Devon (south‐west England), drawing on both a prior study and new interview data. Through the analysis, we identified that BMGs are not a fixed structure, but an adaptive process. This consists of three stages (Formation, Functioning, and Future?), influenced by resource availability and national policy direction. We argue that, where they are used, Species‐specific Management Groups could provide a "front line" for the integration of reintroduced species into modern landscapes, but their role or remit could be scaled back over time and integrated into existing structures or partnerships to reduce pressure on limited resources, as knowledge of reintroduced species (such as beaver) grows and its presence becomes "normalized." There must be sufficient flexibility in forthcoming policy to minimize constraint on the adaptive nature of BMGs and similar groups for other reintroduced species, if they are to facilitate a sustainable coexistence. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity is common in deprived communities and reduces quality of life. Our aim was to evaluate a whole-system primary care-based complex intervention, called CARE Plus, to improve quality of life in multimorbid patients living in areas of very high deprivation.Methods: We used a phase 2 exploratory cluster randomised controlled trial with eight general practices in Glasgow in very deprived areas that involved multimorbid patients aged 30-65 years. The intervention comprised structured longer consultations, relationship continuity, practitioner support, and self-management support. Control practices continued treatment as usual. Primary outcomes were quality of life (EQ-5D-5L utility scores) and well-being (W-BQ12; 3 domains). Cost-effectiveness from a health service perspective, engagement, and retention were assessed. Recruitment and baseline measurements occurred prior to randomisation. Blinding post-randomisation was not possible but outcome measurement and analysis were masked. Analyses were by intention to treat.Results: Of 76 eligible practices contacted, 12 accepted, and eight were selected, randomised and participated for the duration of the trial. Of 225 eligible patients, 152 (68 %) participated and 67/76 (88 %) in each arm completed the 12-month assessment. Two patients died in the control group. CARE Plus significantly improved one domain of well-being (negative well-being), with an effect size of 0.33 (95 % confidence interval [CI] 0.11-0.55) at 12 months (p = 0.0036). Positive well-being, energy, and general well-being (the combined score of the three components) were not significantly influenced by the intervention at 12 months. EQ-5D-5L area under the curve over the 12 months was higher in the CARE Plus group (p = 0.002). The incremental cost in the CARE Plus group was £929 (95 % CI: £86-£1788) per participant with a gain in quality-adjusted life years of 0.076 (95 % CI: 0.028-0.124) over the 12 months of the trial, resulting in a cost-effectiveness ratio of £12,224 per quality-adjusted life year gained. Modelling suggested that cost-effectiveness would continue.Conclusions: It is feasible to conduct a high-quality cluster randomised control trial of a complex intervention with multimorbid patients in primary care in areas of very high deprivation. Enhancing primary care through a whole-system approach may be a cost-effective way to protect quality of life for multimorbid patients in deprived areas.Trial Registration: Trial Registration: ISRCTN 34092919 , assigned 14/1/2013. [ABSTRACT FROM AUTHOR]

We investigated local and regional singing patterns of Nashville Warblers ( Oreothlypis ruficapilla) in southern Oregon. Each male employed a single song, but within local populations individuals sang diverse and distinct variants with a mean of 13.5 ± 1.5 (±SD) variants among 20 males sampled at each of 10 sites. Forty-one variants were recorded among the 200 males, and 17 variants were shared among two or more sites separated from 2-92 km. The mean number of variants shared between pairs of sites was high (7.9 ± 1.6) and did not vary with distance separating them. Neighboring individuals showed no tendency to sing the same variant. The resulting pattern at each site was a mosaic of diverse variants drawn from a restricted pool of variants. Several of the variants recorded in southern Oregon were also recorded >400 km north in incidental sampling, indicating a broad distribution of the variants. High local song diversity implies that an important function of song is to proclaim the identity of the individual. Possible mechanisms for maintenance of high local song diversity are discussed. [ABSTRACT FROM AUTHOR]

The article presents the author's insights on the book of Job which was introduced by the book "The Comforting Whirlwind," by Bill McKibben. Topics include hermeneutic approach to eco-Reformation, interpretation of Job as a heroic figure, and relations of Job's character with the importance of God's design.

The preparation of the C-5′ diastereomers of 5′-homoaristeromycin has been achieved in 6 steps beginning with readily available (3aR,6aR)-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[1,3]dioxol-4-one in a Michael reaction employing chiral Evans N-acyloxazolidinones that served to direct the requisite side chain stereochemistry. The two targets were evaluated against a battery of viruses and found to possess activity only towards yellow fever. Both compounds were non-cytotoxic. [ABSTRACT FROM AUTHOR]

Purpose: We set out to compare patients' expectations, consultation characteristics, and outcomes in areas of high and low socioeconomic deprivation, and to examine whether the same factors predict better outcomes in both settings.Methods: Six hundred fifty-nine patients attending 47 general practitioners in high- and low-deprivation areas of Scotland participated. We assessed patients' expectations of involvement in decision making immediately before the consultation and patients' perceptions of their general practitioners' empathy immediately after. Consultations were video recorded and analyzed for verbal and non-verbal physician behaviors. Symptom severity and related well-being were measured at baseline and 1 month post-consultation. Consultation factors predicting better outcomes at 1 month were identified using backward selection methods.Results: Patients in deprived areas had less desire for shared decision-making (P <.001). They had more problems to discuss (P = .01) within the same consultation time. Patients in deprived areas perceived their general practitioners (GPs) as less empathic (P = .02), and the physicians displayed verbal and nonverbal behaviors that were less patient centered. Outcomes were worse at 1 month in deprived than in affluent groups (70% response rate; P <.001). Perceived physician empathy predicted better outcomes in both groups.Conclusions: Patients' expectations, GPs' behaviors within the consultation, and health outcomes differ substantially between high- and low-deprivation areas. In both settings, patients' perceptions of the physicians' empathy predict health outcomes. These findings are discussed in the context of inequalities and the "inverse care law." [ABSTRACT FROM AUTHOR]

The association between exposure to head injury and increased risk of neurodegenerative disease, specifically chronic traumatic encephalopathy (CTE), is widely recognized. Historically, this was largely considered a phenomenon restricted to boxers, with more recent case series identifying further 'high risk' individuals, such as former American footballers, or military personnel. However, in all cases thus far reported, it is clear that it is the exposure to head injury which is associated with increased dementia risk, and not the circumstances or environment of exposure. As such, there is considerable potential for under-recognition of CTE in patients presenting with neurodegenerative disease, particularly where head injury exposure might have been historical and through sport. This article reviews current understanding of CTE and, via an illustrative case in rugby union, highlights the value of a detailed history on head injury and also draws attention to imaging studies in assessing patients with neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity, the presence of two or more chronic conditions, affects over 60 % of patients in primary care. Due to its association with polypharmacy, the development of interventions to optimise medication management in patients with multimorbidity is a priority. The Behaviour Change Wheel is a new approach for applying behavioural theory to intervention development. Here, we describe how we have used results from a review of previous research, original research of our own and the Behaviour Change Wheel to develop an intervention to improve medication management in multimorbidity by general practitioners (GPs), within the overarching UK Medical Research Council guidance on complex interventions.Methods: Following the steps of the Behaviour Change Wheel, we sought behaviours associated with medication management in multimorbidity by conducting a systematic review and qualitative study with GPs. From the modifiable GP behaviours identified, we selected one and conducted a focused behavioural analysis to explain why GPs were or were not engaging in this behaviour. We used the behavioural analysis to determine the intervention functions, behavioural change techniques and implementation plan most likely to effect behavioural change.Results: We identified numerous modifiable GP behaviours in the systematic review and qualitative study, from which active medication review (rather than passive maintaining the status quo) was chosen as the target behaviour. Behavioural analysis revealed GPs' capabilities, opportunities and motivations relating to active medication review. We combined the three intervention functions deemed most likely to effect behavioural change (enablement, environmental restructuring and incentivisation) to form the MultimorbiditY COllaborative Medication Review And DEcision Making (MY COMRADE) intervention. MY COMRADE primarily involves the technique of social support: two GPs review the medications prescribed to a complex multimorbid patient together. Four other behavioural change techniques are incorporated: restructuring the social environment, prompts/cues, action planning and self-incentives.Conclusions: This study is the first to use the Behaviour Change Wheel to develop an intervention targeting multimorbidity and confirms the usability and usefulness of the approach in a complex area of clinical care. The systematic development of the MY COMRADE intervention will facilitate a thorough evaluation of its effectiveness in the next phase of this work. [ABSTRACT FROM AUTHOR]

Rising feed costs and recurring feed shortages necessitate the investigation into alternative and underutilized feed resources. Nutritional characteristics of Juniperus species are either unknown or limited to leaves and ground material from small stems. Therefore, the objective was to quantify nutritional characteristics, 48-h true IVDMD (tIVDMD), microbial gas production, and secondary compound characteristics of entire woody plant material of 4 Juniperus species-- Juniperus pinchotii, Juniperus monosperma, Juniperus ashei, and Juniperus virginiana--at immature and mature stages of growth. Immature plants had greater CP concentrations and lower NDF concentrations (P < 0.001) than mature plants regardless of species. Mature plants also had greater (P < 0.001) concentrations of ADF compared with immature plants with the exception of J. virginiana. In general, immature J. pinchotii, J. monosperma, and J. ashei had greater (P < 0.02) tIVDMD and total 48-h and asymptotic gas production than mature plants. Immature J. monosperma and J. pinchotii plants were more digested (tIVDMD; P < 0.001) than immature J. virginiana and J. ashei, but tIVDMD did not differ in mature plant material across species. Condensed tannins (CT) were greater (P < 0.001) in immature J. pinchotii and J. ashei than mature plants; differences in CT concentrations among immature species were also detected (P < 0.04). Volatile oil yields were similar across maturity and species with 1 exception: immature J. pinchotii yielded more (P < 0.02) volatile oil than mature material. Volatile oil composition across species varied and contained a range of 65 to 70 terpene compounds. The dominant terpenes across species were generally greater (P < 0.05) in immature vs. mature plant material with the exception of J. virginiana. Labdane acids were negligible in J. pinchotii, J. ashei, and J. virginiana and greater in J. monosperma (P < 0.001). Ground material from mature juniper species, although inferior in nutritional quality compared with immature plants, is comparable to traditional lowquality roughage ingredients. Given that J. pinchotii has been successfully fed in lamb feedlot diets, the similarities of J. pinchotii, J. ashei and J. monosperma suggest that all three species have potential to be effective roughage ingredients. [ABSTRACT FROM AUTHOR]

The preparation of two C-5'-nor-3-deazaaristeromycin diastereomeric analogues possessing a bridgehead nitrogen is described from (3aR,4R,65,6a5)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[ d][1,3]dioxol-4-ol that served as the cyclopentyl unit of the target carbocyclic nucleosides and as the scaffold upon which the compounds were built. The process evolved via a de novo approach for constructing the requisite fused imidazo unit between the aforementioned cyclopentyl ring and a readily available 2,3-dichloropyrazine. The syntheses were accomplished in 11 and 8 steps depending on the diastereomer sought. [ABSTRACT FROM AUTHOR]