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This data article curates datasets from Freddie Mac's Single-Family Loan-Level Dataset (SFLLD) quarterly snapshots. The SFLLD tracks loan originations in the USA along with the ensuing repayment trends. This live dataset undergoes quarterly updates. The current work is based on over 50 million fully amortized fixed-rate mortgage loans, which were initiated from 1999 through June 2022. Monthly performance metrics for these loans span from 1999 to September 30, 2022. Loan origination and repayment data were integrated using a unique loan ID, with defaults being identified when three payments were missed within specific performance windows (12-, 24-, 36-, 48-, and 60-months). To ensure rigorous model evaluation, only loans initiated post-2008 and their performance up to 2019 were considered, intentionally sidestepping external influences from the 2007 to 2008 financial crisis and the COVID-19 pandemic. The data was stratified by credit scores, leading to 10 folders with three distinct datasets for model training, out-of-sample testing, and out-of-time testing. We designed the out-of-time testing dataset to mimic real-life conditions as closely as possible. A unique “out-of-universe” test dataset was further constructed from 2019-originated loans, capturing their performance throughout the pandemic. In each dataset, there are 1464 covariates and a binary target label. With the release of these datasets, we hope to empower researchers to utilize common datasets, especially in the credit-scoring area, where access to proprietary datasets is limited.

Abstract Background Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. Methods Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. Results SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. Conclusions This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.

Cancer cell mitochondria are functionally different from those in normal cells and could be targeted to develop novel anticancer agents. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of targeted agents that enhance the production of reactive oxygen species (ROS) that disrupt the outer mitochondrial membrane (OMM) and kill cancer cells. However, the mechanism by which CTU disrupts the inner mitochondrial membrane (IMM) and activates apoptosis is not clear. Here, we show that CTU-mediated ROS selectively dysregulated the OMA1/OPA1 fusion regulatory system located in the IMM. The essential role of ROS was confirmed in experiments with the lipid peroxyl scavenger α-tocopherol, which prevented the dysregulation of OMA1/OPA1 and CTU-mediated MDA-MB-231 cell killing. The disruption of OMA1/OPA1 and IMM fusion by CTU-mediated ROS accounted for the release of cytochrome c from the mitochondria and the activation of apoptosis. Taken together, these findings demonstrate that CTU depolarises the mitochondrial membrane, activates ROS production, and disrupts both the IMM and OMM, which releases cytochrome c and activates apoptosis. Mitochondrial-targeting agents like CTU offer a novel approach to the development of new therapeutics with anticancer activity.

Pancreatic ductal adenocarcinoma (PDAC)’s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized tris(3,5-dimethylphenyl)phosphonium-conjugated palmitic acid. Triphenylphosphonium (TPP) is a lipophilic cationic moiety that promotes the accumulation of conjugated agents in the mitochondrion. Palmitic acid (PA), the most common saturated fatty acid, has pro-apoptotic activity in different types of cancer cells. TPP-PA was prepared by the reaction of 16-bromopalmitic acid with TPP, and its structure was characterized by 1H and 13C NMR and HRMS. We compared the proteomes of TPP-PA-treated and untreated PDAC cells and PCSCs, identifying dysregulated proteins and pathways. Furthermore, assessments of mitochondrial membrane potential, intracellular ROS, cardiolipin content and lipid peroxidation, ER stress, and autophagy markers provided information on the mechanism of action of TPP-PA. The findings showed that TPP-PA reduces PDAC cell proliferation through mitochondrial disruption that leads to increased ROS, activation of ER stress, and autophagy. Hence, TPP-PA might offer a new approach for eliminating both the primary population of cancer cells and PCSCs, which highlights the promise of TPP-derived compounds as anticancer agents for PDAC.

Background: Peripheral artery disease (PAD) impacts more than 200 million people worldwide. The understanding of the genetics of the disease and its clinical implications continue to evolve. This systematic review provides a comprehensive summary of all DNA variants that have been studied in association with the diagnosis and progression of PAD, with a meta-analysis of the ones replicated in the literature. Methods: A systematic review of all studies examining DNA variants associated with the diagnosis and progression of PAD was performed. Candidate gene and genome-wide association studies (GWAS) were included. A meta-analysis of 13 variants derived from earlier smaller candidate gene studies of the diagnosis of PAD was performed. The literature on the progression of PAD was limited, and a meta-analysis was not feasible because of the heterogeneity in the criteria used to characterize it. Results: A total of 231 DNA variants in 112 papers were studied for the association with the diagnosis of PAD. There were significant variations in the definition of PAD and the selection of controls in the various studies. GWAS have established 19 variants associated with the diagnosis of PAD that were replicated in several large patient cohorts. Only variants in intercellular adhesion molecule-1 (rs5498), IL-6 (rs1800795), and hepatic lipase (rs2070895) showed significant association with the diagnosis of PAD. However, these variants were not noted in the published GWAS. Conclusions: Genetic research in the diagnosis of PAD has significant heterogeneity, but recent GWAS have demonstrated variants consistently associated with the disease. More research focusing on the progression of PAD is needed to identify patients at risk of adverse events and develop strategies that would improve their outcomes.

Cross-disciplinary understanding of strategies for stimulating transitional change is critical, in the face of the escalating climate crisis (Newell et al., 2022). If we are to meaningfully stimulate and accelerate transitions toward more sustainable practices, we must foster community and connectivity within and across disciplines. This article presents the findings of a literature review on physical and digital community organization and connectivity strategies, articulating the potential of participation and knowledge sharing within communities to stimulate meaningful change. Eight physical, community-based strategies are reviewed and analysed, alongside four digital strategies. The selection of physical strategies conveys a range of tried-and-tested methods of stimulating change, while the review of digital strategies explores how traditional methods have been adapted into the digital age. The physical strategies reviewed include: community of practice, social entrepreneurship, community of interest, community capacity building, game changers, disruptors, intersectional activism and mass mobilization. The digital strategies reviewed include: digital mobilization, virtual community of practice, digital storytelling and digital artefacts. Middle-out approaches to change are particularly focussed upon, as they are most effective for individual actors within disciplines wishing to stimulate change (Janda & Parag, 2011; Simpson et al., 2020). By bringing together into one place an analysis of a range of existing approaches, this review takes an initial step toward establishing a cross-disciplinary library of community organizing and connectivity strategies. The aspiration is that this will support the collective benefit of all disciplines seeking to accelerate sustainable, transitional change.

Abstract Background Older people living in residential aged care facilities are at high risk of acquiring infections such as influenza, gastroenteritis, and more recently COVID-19. These infections are a major cause of morbidity and mortality among this cohort. Quality infection prevention and control practice in residential aged care is therefore imperative. Although appointment of a dedicated infection prevention and control (IPC) lead in every Australian residential aged care facility is now mandated, all people working in this setting have a role to play in IPC. The COVID-19 pandemic revealed inadequacies in IPC in this sector and highlighted the need for interventions to improve implementation of best practice. Methods Using mixed methods, this four-phase implementation study will use theory-informed approaches to: (1) assess residential aged care facilities’ readiness for IPC practice change, (2) explore current practice using scenario-based assessments, (3) investigate barriers to best practice IPC, and (4) determine and evaluate feasible and locally tailored solutions to overcome the identified barriers. IPC leads will be upskilled and supported to operationalise the selected solutions. Staff working in residential aged care facilities, residents and their families will be recruited for participation in surveys and semi-structured interviews. Data will be analysed and triangulated at each phase, with findings informing the subsequent phases. Stakeholder groups at each facility and the IMMERSE project’s Reference Group will contribute to the interpretation of findings at each phase of the project. Discussion This multi-site study will comprehensively explore infection prevention and control practices in residential aged care. It will inform and support locally appropriate evidence-based strategies for enhancing infection prevention and control practice.

Autophagy is a form of programmed cell degradation that enables the maintenance of homeostasis in response to extracellular stress stimuli. Autophagy is primarily activated by starvation and mediates the degradation, removal, or recycling of cell cytoplasm, organelles, and intracellular components in eukaryotic cells. Autophagy is also involved in the pathogenesis of human diseases, including several cancers. Human uveal melanoma (UM) is the primary intraocular malignancy in adults and has an extremely poor prognosis; at present there are no effective therapies. Several studies have suggested that autophagy is important in UM. By understanding the mechanisms of activation of autophagy in UM it may be possible to develop biomarkers to provide more definitive disease prognoses and to identify potential drug targets for the development of new therapeutic strategies. This article reviews the current information regarding autophagy in UM that could facilitate biomarker and drug development.

Over the past three decades community-based natural resources management (CBNRM) has sought to address the concurrent needs of economic development and ecological protection at the local level, but there is often strong divergence between development and conservation interests and successes. In particular, CBNRM has not always led to expected socioeconomic outcomes, while information of its impact on human well-being at household level is sparse. In Botswana, most communities do not disburse benefits from CBNRM ventures to households. This leads to an inherent scale mismatch that arises because the costs of living with wildlife are felt at the household level, while the benefits are paid out at the community or village level. We use longitudinal data from two household surveys conducted 22 years apart to assess if benefits from the Botswana model of CBNRM have increased household-level adaptive capacity for those living with wildlife. We take a livelihoods capital approach to develop indicators of adaptive capacity and measure how livelihood diversity, inequality, and adaptive capacity have changed in five communities in northern Botswana between 1995 and 2017. Our analyses confirm the findings of qualitative reviews and suggest that CBNRM is under-performing in its contribution to improved household-level adaptive capacity. CBNRM cannot be said to benefit communities if the majority of community members do not experience increased well-being. We therefore recommend restructuring the governance models of CBNRM and other community conservation approaches to ensure that benefits are more directly targeted to actively participating households.

Implementation of evidence-informed rehabilitation of the upper limb is variable, and outcomes for stroke survivors are often suboptimal. We established a national partnership of clinicians, survivors of stroke, researchers, healthcare organizations, and policy makers to facilitate change. The objectives of this study are to increase access to best-evidence rehabilitation of the upper limb and improve outcomes for stroke survivors. This prospective pragmatic, knowledge translation study involves four new specialist therapy centers to deliver best-evidence upper-limb sensory rehabilitation (known as SENSe therapy) for survivors of stroke in the community. A knowledge-transfer intervention will be used to upskill therapists and guide implementation. Specialist centers will deliver SENSe therapy, an effective and recommended therapy, to stroke survivors in the community. Outcomes include number of successful deliveries of SENSe therapy by credentialled therapists; improved somatosensory function for stroke survivors; improved performance in self-selected activities, arm use, and quality of life; treatment fidelity and confidence to deliver therapy; and for future implementation, expert therapist effect and cost-effectiveness. In summary, we will determine the effect of a national partnership to increase access to evidence-based upper-limb sensory rehabilitation following stroke. If effective, this knowledge-transfer intervention could be used to optimize the delivery of other complex, evidence-based rehabilitation interventions.

An opportunistic investigation into ecosystem instability in Kachemak Bay (KBay), Alaska, has led us to investigate exposure to toxic algae in sea otters. We used gene expression to explore the physiological health of sea otters sampled in KBay in May 2019. We found altered levels of gene transcripts in comparison with reference sea otters from clinically normal, oil-exposed, and nutritionally challenged populations sampled over the past decade. KBay sea otters were markedly divergent from the other groups for five genes, which indicated the involvement of neurological, cardiac, immune, and detoxification systems. Further, analyses of urine and fecal samples detected domoic acid in the KBay sea otters. In combination, these results may point to chronic, low-level exposure to an algal toxin, such as domoic acid. With a warming climate, the frequency and severity of harmful algal blooms in marine environments is anticipated to increase, and novel molecular technologies to detect sublethal or chronic exposure to algal toxins will help provide an early warning of threats to the stability of populations and ecosystems.

We evaluated wildlife population health from the perspective of statistical means vs. variances. We outlined the choices necessary to provide the framework for our study. These consisted of spatial and temporal boundaries (e.g., choice of sentinel species, populations, time frame), measurement techniques (molecular to population level), and appropriate statistical analyses. We chose to assess the health of 19 sea otter populations, located in the north Pacific from the Aleutian Islands, AK, to Santa Barbara, CA, and varying in population growth rates and length of occupancy. Our focal metric was gene expression (i.e., mRNA transcripts) data that we had previously generated across sea otter populations as a measure of population health. We used statistical methods with different approaches (i.e., means vs. variances) and examined the subsequent interpretive outcomes and how these influence our assessment of “health.” Interpretations based on analyses using variances versus means overlapped to some degree. In general, sea otter populations with low variation in gene expression were limited by food resources and at or near carrying capacity. In populations where the variation in gene expression was moderate or high, four out of five populations were increasing in abundance, or had been recently increasing. Where we had additional information on sources of stressors at the level of the population, we were able to draw inferences from those stressors to specific gene expression results. For example, gene expression patterns of sea otters from Western Prince William Sound were consistent with long term exposure to petroleum hydrocarbons, whereas in Kachemak Bay, patterns were consistent with exposure to algal toxins. Ultimately, determination of population or ecosystem health will be most informative when multiple metrics are examined across disciplines in the context of specific scenarios and goals.

Summary: Background: Genome-wide association studies (GWAS) for obstructive sleep apnoea (OSA) are limited due to the underdiagnosis of OSA, leading to misclassification of OSA, which consequently reduces statistical power. We performed a GWAS of OSA in the Million Veteran Program (MVP) of the U.S. Department of Veterans Affairs (VA) healthcare system, where OSA prevalence is close to its true population prevalence. Methods: We performed GWAS of 568,576 MVP participants, stratified by biological sex and by harmonized race/ethnicity and genetic ancestry (HARE) groups of White, Black, Hispanic, and Asian individuals. We considered both BMI adjusted (BMI-adj) and unadjusted (BMI-unadj) models. We replicated associations in independent datasets, and analysed the heterogeneity of OSA genetic associations across HARE and sex groups. We finally performed a larger meta-analysis GWAS of MVP, FinnGen, and the MGB Biobank, totalling 916,696 individuals. Findings: MVP participants are 91% male. OSA prevalence is 21%. In MVP there were 18 and 6 genome-wide significant loci in BMI-unadj and BMI-adj analyses, respectively, corresponding to 21 association regions. Of these, 17 were not previously reported in association with OSA, and 13 replicated in FinnGen (False Discovery Rate p-value < 0.05). There were widespread significant differences in genetic effects between men and women, but less so across HARE groups. Meta-analysis of MVP, FinnGen, and MGB biobank revealed 17 additional, previously unreported, genome-wide significant regions. Interpretation: Sex differences in genetic associations with OSA are widespread, likely associated with multiple OSA risk factors. OSA shares genetic underpinnings with several sleep phenotypes, suggesting shared aetiology and causal pathways. Funding: Described in acknowledgements.

Human proton-coupled oligopeptide transporters (PepTs) are important membrane influx transporters that facilitate the cellular uptake of many drugs including ACE inhibitors and antibiotics. PepTs mediate the absorption of di- and tri-peptides from dietary proteins or gastrointestinal secretions, facilitate the reabsorption of peptide-bound amino acids in the kidney, and regulate neuropeptide homeostasis in extracellular fluids. PepT1 and PepT2 have been the most intensively investigated of all PepT isoforms. Modulating the interactions of PepTs and their drug substrates could influence treatment outcomes and adverse effects with certain therapies. In recent studies, topology models and protein structures of PepTs have been developed. The aim of this review was to summarise the current knowledge regarding structure-interaction relationships (SIRs) of PepTs and their substrates as well as the potential applications of this information in therapeutic optimisation and drug development. Such information may provide insights into the efficacy of PepT drug substrates in patients, mechanisms of drug–drug/food interactions and the potential role of PepTs targeting in drug design and development strategies.

Tropical wetlands are a significant but understudied source of methane. Here, methane emissions were measured over three years in a perennial tropical swamp in the Okavango Delta, Botswana, finding phenology was the overarching control of emissions.

Background and study aims Concomitant hiatal hernia (HH) repair with transoral incisionless fundoplication (TIF) is a therapeutic option for patients with HH > 2 cm and gastroesophageal reflux disease (GERD). Data comparing this approach with laparoscopic Nissen fundoplication (LNF) are lacking. We performed an exploratory analysis to compare these two approaches' adverse events (AEs) and clinical outcomes. Patients and methods This was a multicenter retrospective cohort study of HH repair followed by LNF versus HH repair followed by TIF in patients with GERD and moderate HH (2–5 cm). AEs were assessed using the Clavien-Dindo classification. Symptoms (heartburn/regurgitation, bloating, and dysphagia) were compared at 6 and 12 months. Results A total of 125 patients with HH repair with TIF and 70 with HH repair with LNF were compared. There was no difference in rates of discontinuing or decreasing proton pump inhibitor use, dysphagia, esophagitis, disrupted wrap, and HH recurrence between the two groups (P > 0.05). The length of hospital stay (1 day vs. 2 days), 30-day readmission rate (0 vs. 4.3 %), early AE rate (0 vs. 18.6 %), and early serious AE rate (0 vs. 4.3 %) favored TIF (all P

Abstract Purpose Transjugular intrahepatic portosystemic shunt (TIPS) procedure is an established procedure carried out by interventional radiologists to achieve portal decompression and to manage the complications of portal hypertension. The aim of this study was to evaluate the quality and readability of information available online for TIPS procedure. Methods Websites were identified using the search terms “TIPS procedure”, “TIPSS procedure”, “transjugular intrahepatic portosystemic shunt procedure”, with the first 25 pages from the three most popular search engines (Google, Bing and Yahoo) being selected for evaluation with a total of 225. Each Website was grouped by authorship into one of five categories: (1) Physician, (2) Academic, (3) For-profit, (4) Non-profit (including government and public health), or (5) Other (discussion/social media). Readability of each Website was assessed using the Flesch-Reading Ease score, Flesch–Kincaid grade level, Gunning-Fog Index, Coleman–Liau and SMOG index. Quality was calculated using the DISCERN instrument, the Journal of the American Medical Association (JAMA) benchmark criteria and the presence of Health on the Net (HON) code certification. Results After disregarding duplicate and non-accessible Websites a total of 81 were included. The mean DISCERN score assessing the quality of information provided by Websites was “good” (59.3 ± 10.2) with adherence to the JAMA Benchmark being 54.3%. Websites with HON-code certification were statistically significantly higher in terms of DISCERN (p = 0.034) and JAMA scores (p = 0.003) compared to HON-code negative sites. The readability scores of Websites ranged from 10 to 12th grade across calculators. Thirty-two out of the 81 Websites were targeted towards patients (39.5%), 46 towards medical professionals (56.8%) and 3 were aimed at neither (3.7%). The medical professional aimed Websites were statistically significantly more difficulty to read across all readability formulas (all p

Abstract Organic anion transporting polypeptides (OATPs) are important transporter proteins that are expressed at the plasma membrane of cells, where they mediate the influx of endogenous and exogenous substances including hormones, natural compounds and many clinically important drugs. OATP1A2, OATP2B1, OATP1B1 and OATP1B3 are the most important OATP isoforms and influence the pharmacokinetic performance of drugs. These OATPs are highly expressed in the kidney, intestine and liver, where they determine the distribution of drugs to these tissues. Herbal medicines are increasingly popular for their potential health benefits. Humans are also exposed to many natural compounds in fruits, vegetables and other food sources. In consequence, the consumption of herbal medicines or food sources together with a range of important drugs can result in drug-herb/food interactions via competing specific OATPs. Such interactions may lead to adverse clinical outcomes and unexpected toxicities of drug therapies. This review summarises the drug-herb/food interactions of drugs and chemicals that are present in herbal medicines and/or food in relation to human OATPs. This information can contribute to improving clinical outcomes and avoiding unexpected toxicities of drug therapies in patients.

Abstract Background Understanding representations of disease in various art genres provides insights into how patients and health care providers view the diseases. It can also be used to enhance patient care and stimulate patient self-management. Methods This paper reviews how cardiovascular diseases are represented in novels, films, and paintings: myocardial infarction, aneurysm, hypertension, stroke, heart transplantation, Marfan’s disease, congestive heart failure. Various search systems and definitions were used to help identify sources of representations of different cardiovascular diseases. The representations of the different diseases were considered separately. The Common Sense Model was used a theoretical model to outline illness perceptions and self-management in the various identified novels, films, and paintings. Results Myocardial infarction followed by stroke were the most frequently detailed diseases in all three art genres. This reflects their higher prevalence. Representations ranged from biomedical details through to social and psychological consequences of the diseases. Conclusions Artistic representations of cardiovascular diseases reflect cognitions, emotions, and images of prevalent disease. These representations shape views and behaviour of ill and healthy persons regarding heart diseases. As these representations are amenable to change, they deserve further research, which may be instrumental in improving the quality of life of persons struck by cardiovascular diseases. Changing illness perceptions appears to be a method to improve self-management and thereby quality of life in patients with various cardiovascular diseases.

Nasopulmonary mites (NPMs) of the family Halarachnidae are obligate endoparasites that colonize the respiratory tracts of mammals. NPMs damage surface epithelium resulting in mucosal irritation, respiratory illness, and secondary infection, yet the role of NPMs in facilitating pathogen invasion or dissemination between hosts remains unclear. Using 16S rRNA massively parallel amplicon sequencing of six hypervariable regions (or "16S profiling"), we characterized the bacterial community of NPMs from 4 southern sea otters (Enhydra lutris nereis). This data was paired with detection of a priority pathogen, Streptococcus phocae, from NPMs infesting 16 southern sea otters and 9 California sea lions (Zalophus californianus) using nested conventional polymerase chain reaction (nPCR). The bacteriome of assessed NPMs was dominated by Mycoplasmataceae and Vibrionaceae, but at least 16 organisms with pathogenic potential were detected as well. Importantly, S. phocae was detected in 37% of NPM by nPCR and was also detected by 16S profiling. Detection of multiple organisms with pathogenic potential in or on NPMs suggests they may act as mechanical vectors of bacterial infection for marine mammals.

Soil seed banks serve as reservoirs of seeds for subsequent regeneration of plants. Soil seed banks were investigated along the Thamalakane Riparian Woodlands (hereafter referred to as TRWs) of the Okavango Delta, northern Botswana, from January-July 2015 and January-July 2016. The study aimed at examining species richness and diversity, determining densities, assessing the spatial distribution of seeds in the soil and comparing the similarity in species composition between the standing vegetation and soil seed bank flora. The vegetation was sampled in 71 plots (20 × 50 m) and soil samples were collected from 568 subplots. Agglomerative hierarchical cluster analysis was used to determine soil seed bank communities. Indicator species analysis was used to calculate indicator values for species in each community of germinated seeds and across different soil layers. Multi-response permutation procedures (MRPP) were used to compare similarity in soil seed bank composition. Bray-Curtis ordination was used to infer spatial relationships of soil layers in terms of soil seed bank composition. A total of 109 plant species were identified in the litter and top 9 cm soil layers with a mean density of 2101 seeds m−2. Herbs, grasses, sedges and woody plants were represented by 68, 19, 9 and 13 species, respectively, in 30 families and 87 genera. The overall total diversity and evenness of the soil seed bank in the TRWs was 3.25 and 0.69, respectively. Four plant communities were identified from the soil seed bank, namely Setaria verticilata-Amaranthus hybridus, Acanthospermum hispidum-Setaria sagittifolia, Digitaria eriantha-Eclipta prostrata and Cyperus longus-Fimbristylis dichotoma. Bray-Curtis ordination showed that there was overlap between these communities in terms of seed bank composition. However, MRPP analysis showed that there was significant (P

Background and study aims Transoral incisionless fundoplication (TIF) is a safe and effective minimally invasive endoscopic technique for treating gastroesophageal reflux disease (GERD). The learning curve for this technique has not been reported. We studied the learning curve for TIF when performed by a gastroenterologist by identifying the threshold number of procedures needed to achieve consistent technical success or proficiency (consistent creation of TIF valve ≥ 270 degrees in circumference, ≥ 2 cm long) and efficiency after didactic, hands-on and case observation experience. Patients and methods We analyzed prospectively collected data from patients who had TIF performed by a single therapeutic endoscopist within 17 months after basic training. We determined thresholds for procedural learning using cumulative sum of means (CUSUM) analysis to detect changes in achievement rates over time. We used breakpoint analysis to calculate procedure metrics related to proficiency and efficiency. Results A total of 69 patients had 72 TIFs. The most common indications were refractory GERD (44.7 %) and proton pump inhbitor intolerance (23.6 %). Proficiency was achieved at the 18th to 20th procedure. The maximum efficiency for performing a plication was achieved after the 26th procedure, when mean time per plication decreased to 2.7 from 5.1 minutes (P

Background Secure forensic mental health services treat patients with high rates of treatment-resistant psychoses. High rates of obesity and medical comorbidities are common. Population-based studies have identified high-risk groups in the event of SARS-CoV-2 infection, including those with problems such as obesity, lung disease and immune-compromising conditions. Structured assessment tools exist to ascertain the risk of adverse outcome in the event of SARS-CoV-2 infection. Aims To assess risk of adverse outcome in the event of SARS-CoV-2 infection in a complete population of forensic psychiatry patients using structured assessment tools. Method All patients of a national forensic mental health service (n = 141) were rated for risk of adverse outcome in the event of SARS-CoV-2 infection, using two structured tools, the COVID-Age tool and the COVID-Risk tool. Results We found high rates of relevant physical comorbidities. Mean chronological age was 45.5 years (s.d. = 11.4, median 44.1), mean score on the COVID-Age tool was 59.1 years (s.d. = 19.4, median 58.0), mean difference was 13.6 years (s.d. = 15.6), paired t = 10.9, d.f. = 140, P < 0.001. Three patients (2.1%) were chronologically over 70 years of age, compared with 43 (30.5%) with a COVID-Age over 70 (χ2 = 6.99, d.f. = 1, P = 0.008, Fisher's exact test P = 0.027). Conclusions Patients in secure forensic psychiatric services represent a high-risk group for adverse outcomes in the event of SARS-COV-2 infection. Population-based guidance on self-isolation and other precautions based on chronological age may not be sufficient. There is an urgent need for better physical health research and treatment in this group.

Intergenerational practice (IP) is an approach within community health promotion which aims to bring older and younger community members together in collaborative activity. Little research has critically examined the assumptions and values within IP and their implications for these communities. A sample of 15 IP planning documents were analysed using a social constructionist thematic analysis (Braun & Clarke2006) guided by Prior’s (2008) concept of documents as active agents. Three tensions were identified: a community-led model versus a contact model; old and young as targets versus older people as targets; and process-focused versus out­come-focused evaluation. IP has relied on contact theory as a mechanism of change, which has rooted IP to an overly individualistic practice tar­geted at older people (rather than all ages). In contrast, the community-led ethos of IP was also evident alongside values of mutual benefit for old and young, and a desire for more process-focused evaluation.

Capillaria hepatica is a globally distributed zoonotic nematode parasite that most commonly infects feral and native rats. Soil contact, pica, and living in close proximity to rat populations are risk factors for human infection. Larval nematodes and eggs that were morphologically consistent with C. hepatica were observed microscopically in livers of stranded southern sea otters (Enhydra lutris nereis) from California. Large (90–100 × 45–55 μm), barrel-shaped non-embryonated parasite eggs with large polar prominences and a roughened or striated surface, or 105–120 μm diameter larval aphasmid nematode profiles with a prominent stichosome and hypodermal bands were observed in the livers of three otters. The liver of a fourth animal exhibited serpiginous tracts of necrosis, micro-cavitation and pleocellular inflammation, with intralesional linear eosinophilic material that resembled cuticle from degenerating metazoan parasites. Capillaria hepatica-associated hepatitis and capsular adhesions were the cause of death for one otter, and parasite-associated liver lesions were observed in all cases. All infected otters were adult females that stranded from 2006 through 2016 at multiple sites along the central California coast. All cases stranded from December through May; during and soon after peak seasonal precipitation and land-sea runoff in California. This same seasonal pattern has been reported for other land-based parasites infecting southern sea otters. Neither C. hepatica, nor any similar nematodes have been reported from marine mammals, and southern sea otters are not typical hosts for C. hepatica or any other nematode parasites. The most likely route of exposure was via freshwater runoff containing embryonated eggs liberated from predated or decomposing terrestrial hosts, especially rats. Similar to the land-based parasites Toxoplasma gondii and Sarcocystis neurona, C. hepatica eggs may be concentrated and transmitted through filter-feeding marine invertebrates that serve as southern sea otter prey, which may also pose an unrecognized public health risk for people who consume these species.

High-rate anaerobic digestion (AD) is a reliable, efficient process to treat wastewaters and is often operated at temperatures exceeding 30°C, involving energy consumption of biogas in temperate regions, where wastewaters are often discharged at variable temperatures generally below 20°C. High-rate ambient temperature AD, without temperature control, is an economically attractive alternative that has been proven to be feasible at laboratory-scale. In this study, an ambient temperature pilot scale anaerobic reactor (2 m3) was employed to treat real dairy wastewater in situ at a milk processing plant, at organic loading rates of 1.3 ± 0.6 to 10.6 ± 3.7 kg COD/m3/day and hydraulic retention times (HRT) ranging from 36 to 6 h. Consistent high levels of COD removal efficiencies, ranging from 50 to 70% for total COD removal and 70 to 84% for soluble COD removal, were achieved during the trial. Within the reactor biomass, stable active archaeal populations were observed, consisting mainly of Methanothrix (previously Methanosaeta) species, which represented up to 47% of the relative abundant active species in the reactor. The decrease in HRT, combined with increases in the loading rate had a clear effect on shaping the structure and composition of the bacterial fraction of the microbial community, however, without affecting reactor performance. On the other hand, perturbances in influent pH had a strong impact, especially when pH went higher than 8.5, inducing shifts in the microbial community composition and, in some cases, affecting negatively the performance of the reactor in terms of COD removal and biogas methane content. For example, the main pH shock led to a drop in the methane content to 15%, COD removals decreased to 0%, while the archaeal population decreased to ~11% both at DNA and cDNA levels. Functional redundancy in the microbial community underpinned stable reactor performance and rapid reactor recovery after perturbations.

Abstract Introduction Flood recession farming, locally known as molapo farming, is an important livelihood activity for the subsistence farming community around the Okavango Delta. The study was aimed at investigating the influence of cultivation frequency on non-crop species composition. It was carried out in the peripheral settlements of Shorobe, Makalamabedi and Lake Ngami. Methods Vegetation sampling was conducted from March to April 2016 in 36 fields of varying historical cultivation frequencies. The cultivation frequencies were 5, 10 and 15 years with an uncropped control site. Sampling was done in 1-m2 quadrats placed 10 m apart along a line transect. Shannon’s diversity and equitability indices were used to compare diversity for each cultivation frequency within and across the study sites. The Kruskal–Wallis test was used to investigate significant differences in diversity between cultivation frequencies. Rank of abundance was used to determine the association of weeds with the cultivation frequencies. Results Cultivation frequency did not influence species diversity (p > 0.05) at either Lake Ngami or Shorobe. Species evenness was significantly different (p

Sea pigs (Scotoplanes spp.) are deep-sea dwelling sea cucumbers of the phylum Echinodermata, class Holothuroidea, and order Elasipodida. Few reports are available on the microscopic anatomy of these deep-sea animals. This study describes the histologic findings of two, wild, male and female Scotoplanes sp. collected from Monterey Bay, California. Microscopic findings were similar to other holothuroids, with a few notable exceptions. Sea pigs were bilaterally symmetrical with six pairs of greatly enlarged tube feet arising from the lateral body wall and oriented ventrally for walking. Neither a rete mirabile nor respiratory tree was identified, and the large tube feet may function in respiration. Dorsal papillae protrude from the bivium and are histologically similar to tube feet with a large, muscular water vascular canal in the center. There were 10 buccal tentacles, the epidermis of which was highly folded. Only a single gonad was present in each animal; both male and female had histologic evidence of active gametogenesis. In the male, a presumed protozoal cyst was identified in the aboral intestinal mucosa, and was histologically similar to previous reports of coccidians. This work provides control histology for future investigations of sea pigs and related animals using bright field microscopy.

Abstract Background The aim was to assess the feasibility of a single-centre, single-blind, randomized, crossover design to explore the effects of two slow-release dopamine agonists, ropinirole and pramipexole, on cued recall in Parkinson’s disease. As the design required a switch from the prescribed agonist (pramipexole-to-ropinirole, or ropinirole-to-pramipexole), the primary objectives were to (a) examine the efficacy of processes and procedures used to manage symptoms during the washout period and (b) to use cued recall estimates to inform a power calculation for a definitive trial. Secondary objectives were to assess consent and missing data rates, acceptability of clinical support for the OFF sessions, experience of the OFF sessions and of agonist switching, barriers-to-participation for patients and informal caregivers. Methods Patients were randomized in a 1:1 ratio to two treatment arms and stabilized on each agonist for 6 weeks. The arms differed only in the sequence in which the agonists were administered. Cued recall was assessed ON medication and, following a washout period resulting in 93.75% agonist elimination, OFF medication. Results A total of 220 patients were screened: 145 were excluded and 75 invitations to participate were sent to eligible patients. Fifty-three patients declined, 22 consented and 16 completed the study. There were no serious adverse events, and rates of non-serious adverse events were equivalent between the agonists. Using the largest standard deviation (SD) of the ON–OFF difference cued recall score (inflated by ~25% to give a conservative estimate of the SD in a definitive trial) and assuming an effect of at least 10% of the observed range of OFF medication cued recall scores for either agonist to be clinically important, a main trial requires a sample size of just under 150 patients. The consent and missing data rates were 29 and 27% respectively. The washout period and the preparation for the OFF sessions were acceptable, and the sessions were manageable. The experience of switching was also manageable. Barriers to participation included concerns about disease stability, side effects, research process, carer workload and accessibility of the information sheet. Conclusions This study presented challenges to recruitment both in design and execution, and while it was a major aim of the study to assess this, evaluation of these challenges provided the opportunity to explore how they could be overcome for future studies. Trial registration EudraCT 2012-000801-64

Summary: Mitochondrial Ca2+ uniporter (MCU)-mediated Ca2+ uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCUΔhep) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca2+ (mCa2+) uptake, delays cytosolic Ca2+ (cCa2+) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhep were a direct result of extramitochondrial Ca2+-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhep hepatocytes. Conversely, gain-of-function MCU promotes rapid mCa2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+ dynamics to hepatic lipid metabolism. : Hepatic mitochondrial Ca2+ shapes bioenergetics and lipid homeostasis. Tomar et al. demonstrate that MCU-mediated cCa2+ buffering serves as a crucial step in controlling hepatic fuel metabolism through an MCU/PP4/AMPK molecular cascade. Identification of these molecular signaling events aids in understanding how perturbation of mitochondrial ion homeostasis may contribute to the etiology of metabolic disorders. Keywords: mitochondrial Ca2+ uniporter, calcium, bioenergetics, AMPK, MCU, hepatocyte, lipid metabolism, phosphatase, metabolic diseases, diabetes

Growing evidence suggests that the arts may be useful in health care and in the training of health care professionals. Four art genres – novels, films, paintings and music – are examined for their potential contribution to enhancing patient health and/or making better health care providers. Based on a narrative literature review, we examine the effects of passive (e.g. reading, watching, viewing and listening) and active (e.g. writing, producing, painting and performing) exposure to the four art genres, by both patients and health care providers. Overall, an emerging body of empirical evidence indicates positive effects on psychological and physiological outcome measures in patients and some benefits to medical training. Expressive writing/emotional disclosure, psychoneuroimmunology, Theory of Mind and the Common Sense Model of Self-Regulation are considered as possible theoretical frameworks to help incorporate art genres as sources of inspiration for the further development of health psychology research and clinical applications.

Over half of all students enrolling at a particular university in KwaZulu-Natal fail to complete a degree. This article is wanting to determine to what extent the marks they obtain for English and Mathematics at school impact on their probability of graduation at this university. In addressing this problem, other student specific factors associated with their gender, race and the type of school they have attended need also to be properly accounted for. To provide answers for this study, the performance of 24 392 students enrolling at the university over the period 2004 to 2012 was followed until they graduated or dropped out from their studies. A structural equation model was fitted because it allows one to separate a direct effect from that of an indirect effect. Gender, race and school background were found to be very significant with males, Black Africans and students coming from a less privileged school background having a smaller probability associated with eventually graduating from this university. Males tend to perform better than females in Mathematics, with females performing better males in English. More importantly, however, a single percentage point increase in one’s mark for English increases the probability associated with graduating from this university far more than would be the case if their Mathematics mark were to increase by a single percentage point. In the light of these mediated results, perhaps this university should be directing their efforts more towards improving the English (rather than mathematical) literacy of students entering the university.

Background: Hyperammonemia is known to cause neuronal injury, and can result from valproic acid exposure. Prompt reduction of elevated ammonia levels may prevent permanent neurological injury. We report a case of fatal hyperammonemic brain injury in a woman exposed to valproic acid. Case: A 38-year-old woman with schizoaffective disorder and recent increase in valproic acid dosage presented with somnolence and confusion and rapidly progressed to obtundation. Brain MRI showed diffuse bilateral restricted diffusion in nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at 288 µmol/l. Genetic testing showed no mutation in urea cycle enzymes. Despite successful elimination of ammonia with hemodialysis she developed fatal cerebral edema. Conclusion: Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia excretion can be facilitated by initiation of hemodialysis and administration of scavenging agents (sodium phenylacetate and sodium benzoate). Severe hyperammonemia can result from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to check serum ammonia in any patient with encephalopathy who has had recent valproic acid exposure.

The medial prefrontal cortex (mPFC) is involved in a wide range of executive cognitive functions, including reward evaluation, decision-making, memory extinction, mood, and task switching. Manipulation of the mPFC has been shown to alter food intake and food reward valuation, but whether exclusive stimulation of mPFC pyramidal neurons, which form the principle output of the mPFC, is sufficient to mediate food rewarded instrumental behavior is unknown. We sought to determine the behavioral consequences of manipulating mPFC output by exciting pyramidal neurons in mouse mPFC during performance of a panel of behavioral assays, focusing on food reward. We found that increasing mPFC pyramidal cell output using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) enhanced performance in instrumental food reward assays that assess food seeking behavior, while sparing effects in affect and food intake. Specifically, activation of mPFC pyramidal neurons enhanced operant responding for food reward, reinstatement of palatable food seeking, and suppression of impulsive responding for food reward. Conversely, activation of mPFC pyramidal neurons had no effect on unconditioned food intake, social interaction, or behavior in an open field. Furthermore, we found that behavioral outcome is influenced by the degree of mPFC activation, with a low drive sufficient to enhance operant responding and a higher drive required to alter impulsivity. Additionally, we provide data demonstrating that DREADD stimulation involves a nitric oxide synthase dependent pathway, similar to endogenous muscarinic M3 receptor stimulation, a finding that provides novel mechanistic insight into an increasingly widespread method of remote neuronal control.

Whitebark pine (WBP, Pinus albicaulis Engelm.) is an endangered conifer species due to heavy mortality from white pine blister rust (WPBR, caused by Cronartium ribicola) and mountain pine beetle (Dendroctonus ponderosae). Information about genetic diversity and population structure is of fundamental importance for its conservation and restoration. However, current knowledge on the genetic constitution and genomic variation is still limited for WBP. In this study, an integrated genomics approach was applied to characterize seed collections from WBP breeding programs in western North America. RNA-seq analysis was used for de novo assembly of the WBP needle transcriptome, which contains 97,447 protein-coding transcripts. Within the transcriptome, single nucleotide polymorphisms (SNPs) were discovered, and more than 22,000 of them were non-synonymous SNPs (ns-SNPs). Following the annotation of genes with ns-SNPs, 216 ns-SNPs within candidate genes with putative functions in disease resistance and plant defense were selected to design SNP arrays for high-throughput genotyping. Among these SNP loci, 71 were highly polymorphic, with sufficient variation to identify a unique genotype for each of the 371 individuals originating from British Columbia (Canada), Oregon and Washington (USA). A clear genetic differentiation was evident among seed families. Analyses of genetic spatial patterns revealed varying degrees of diversity and the existence of several genetic subgroups in the WBP breeding populations. Genetic components were associated with geographic variables and phenotypic rating of WPBR disease severity across landscapes, which may facilitate further identification of WBP genotypes and gene alleles contributing to local adaptation and quantitative resistance to WPBR. The WBP genomic resources developed here provide an invaluable tool for further studies and for exploitation and utilization of the genetic diversity preserved within this endangered conifer and other five-needle pines.

Lipid-based drugs are emerging as an interesting class of novel anticancer drugs with the potential to target specific cancer cell metabolic pathways linked to their proliferation and invasiveness. In particular, ω-3 polyunsaturated fatty acids (PUFA) derivatives such as epoxides and their bioisosteres have demonstrated the potential to suppress growth and promote apoptosis in triple-negative human breast cancer cells MDA-MB-231. In this study, 16-(4′-chloro-3′-trifluorophenyl)carbamoylamino]hexadecanoic acid (ClFPh-CHA), an anticancer lipid derived from ω-3,17,18-epoxyeicosanoic acid, was formulated as a stable nanoemulsion with size around 150 nm and narrow droplet size distribution (PDI < 0.200) through phase-inversion emulsification process followed by high pressure homogenization in view of an oral administration. The ClFPh-CHA-loaded nanoemulsions were able to significantly decrease the relative tumor volume in mice bearing an intramammary tumor xenograft at all doses tested (2.5, 10 and 40 mg/kg) after 32 days of daily oral administration. Furthermore, absolute tumor weight was decreased to 50% of untreated control at 10 and 40 mg/kg, while intraperitoneal administration could achieve a significant reduction only at the highest dose of 40 mg/kg. Results suggest that oral administration of ClFPh-CHA formulated as a nanoemulsion has a sufficient bioavailability to provide an anticancer effect in mice and that the activity is at least equal if not superior to that obtained by a conventional parenteral administration of equivalent doses of the same drug.

As part of the UK's National Health Service modernisation agenda, the Department of Health, Social Services and Public Safety, Northern Ireland set up a Service Improvement Unit (SIU). The aim of the SIU was to identify key areas in the Health and Social Services that needed improvement and to provide a structured framework in which to achieve the necessary developments. A key area identified was the interface between children in care and the Child and Adolescent Mental Health Services. It was believed that a lot of work needed to be undertaken to identify those children and young people in the "care system" that had "mental health" difficulties and to ensure they received the necessary interventions in an appropriate and timely manner. In order to take forward this improvement, a multi-disciplinary project team was set up under the SIU scheme to look at this issue. The project's title was "Knowing to Care!" which reflects the basic notion that the more we know about the children and young people the better we are caring for them.

The human organic anion transporting polypeptide 1A2 (OATP1A2) is an important membrane protein that mediates the cellular influx of various substances including drugs. Previous studies have shown that PDZ-domain containing proteins, especially PDZK1 and NHERF1, regulate the function of related membrane transporters in other mammalian species. This study investigated the role of PDZK1 and NHERF1 in the regulation of OATP1A2 in an in vitro cell model. Transporter function and protein expression were assessed in OATP1A2-transfected HEK-293 cells that co-expressed PDZK1 or NHERF1. Substrate (estrone-3-sulfate) uptake by OATP1A2 was significantly increased to ∼1.6- (PDZK1) and ∼1.8- (NHERF1) fold of control; this was dependent on the putative PDZ-binding domain within the C-terminus of OATP1A2. The functional increase of OATP1A2 following PDZK1 or NHERF1 over-expression was associated with increased transporter expression at the plasma membrane and in the whole cell, and was reflected by an increase in the apparent maximal velocity of estrone-3-sulfate uptake (V(max): 138.9±4.1 (PDZK1) and 181.4±16.7 (NHERF1) versus 55.5±3.2 pmol*(µg*4 min)⁻¹ in control; P

"Super-blooms" of cyanobacteria that produce potent and environmentally persistent biotoxins (microcystins) are an emerging global health issue in freshwater habitats. Monitoring of the marine environment for secondary impacts has been minimal, although microcystin-contaminated freshwater is known to be entering marine ecosystems. Here we confirm deaths of marine mammals from microcystin intoxication and provide evidence implicating land-sea flow with trophic transfer through marine invertebrates as the most likely route of exposure. This hypothesis was evaluated through environmental detection of potential freshwater and marine microcystin sources, sea otter necropsy with biochemical analysis of tissues and evaluation of bioaccumulation of freshwater microcystins by marine invertebrates. Ocean discharge of freshwater microcystins was confirmed for three nutrient-impaired rivers flowing into the Monterey Bay National Marine Sanctuary, and microcystin concentrations up to 2,900 ppm (2.9 million ppb) were detected in a freshwater lake and downstream tributaries to within 1 km of the ocean. Deaths of 21 southern sea otters, a federally listed threatened species, were linked to microcystin intoxication. Finally, farmed and free-living marine clams, mussels and oysters of species that are often consumed by sea otters and humans exhibited significant biomagnification (to 107 times ambient water levels) and slow depuration of freshwater cyanotoxins, suggesting a potentially serious environmental and public health threat that extends from the lowest trophic levels of nutrient-impaired freshwater habitat to apex marine predators. Microcystin-poisoned sea otters were commonly recovered near river mouths and harbors and contaminated marine bivalves were implicated as the most likely source of this potent hepatotoxin for wild otters. This is the first report of deaths of marine mammals due to cyanotoxins and confirms the existence of a novel class of marine "harmful algal bloom" in the Pacific coastal environment; that of hepatotoxic shellfish poisoning (HSP), suggesting that animals and humans are at risk from microcystin poisoning when consuming shellfish harvested at the land-sea interface.

Pheromone traps in the San Joaquin and Sacramento valleys indicate that seasonal patterns of the tomato fruitworm are similar across large areas. Catches were greatest late in the season. A non-pest species (false corn earworm), also captured at all locations, is easily confused with the pest.