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Reducing the environmental pressures stemming from food production is central to meeting global sustainability targets. Shifting diets represents one lever for improving food system sustainability, and identifying sustainable diet opportunities requires computational models to represent complex systems and allow users to evaluate counterfactual scenarios. Despite an increase in the number of food system sustainability models, there remains a lack of transparency of data inputs and mathematical formulas to facilitate replication by researchers and application by diverse stakeholders. Further, many models lack the ability to model multiple geographic scales. The present study introduces Foodprint 2.0, which fills both gaps. Foodprint 2.0 is an updated biophysical simulation model that estimates the agricultural resource requirements of diet patterns and can be adapted to suit a variety of research purposes. The objectives of this study are to: 1) describe the new features of Foodprint 2.0, and 2) demonstrate model performance by estimating the agricultural resource requirements of food demand in the United States (US) using nationally representative dietary data from the National Health and Nutrition Examination Survey from 2009-2018. New features of the model include embedded functions to integrate individual-level dietary data that allow for variance estimation; new data and calculations to account for the resource requirements of food trade and farmed aquatic food; updated user interface; expanded output data for over 200 foods that include the use of fertilizer nutrients, pesticides, and irrigation water; supplementary files that include input data for all parameters on an annual basis from 1999-2018; sample programming code; and step-by-step instructions for users. This study demonstrates that animal-sourced foods consumed in the US accounted for the greatest share of total land use, fertilizer nutrient use, pesticide use, and irrigation water use, followed by grains, fruits, and vegetables. Greater adherence to the Dietary Guidelines for Americans was associated with lower use of land and fertilizer nutrients, and greater use of pesticides and irrigation water. Foodprint 2.0 is a highly modifiable model that can be a useful resource for informing sustainable diet policy discussions.

ObjectiveFibromyalgia, a chronic pain disorder, impacts approximately 2% of adults in the US. Gabapentin and pregabalin are common treatments to manage fibromyalgia-related pain. Our recent study showed the risk of adverse cardiovascular events increased in diabetic neuropathy patients who were prescribed gabapentin or pregabalin. Here, we investigated whether the prescription of gabapentin or pregabalin has similar cardiovascular risk in patients with fibromyalgia.MethodsThis retrospective cohort study leveraged electronic health records from 64 US healthcare organizations with 112 million patients. The study population included 105,602 patients first diagnosed with fibromyalgia and followed by a prescription of gabapentin, pregabalin, or other FDA-approved drugs for treating fibromyalgia from 2010 to 2019. Outcomes were deep venous thrombosis (DVT), myocardial infarcts (MI), peripheral vascular disease (PVD), strokes, heart failure, and pulmonary embolism (PE). In propensity-score-matched cohorts, 1-year and 5-year hazard ratios (HRs) were computed with their respective 95% confidence intervals (CIs). Additionally, we conducted sensitivity analyses on the subpopulations without other possible indications.ResultsFor 5-year follow-up, gabapentin increased the risk of PVD (HR = 1.46, 95% CI = 1.17-1.80), MI (HR = 1.31, 95% CI = 1.03-1.66), heart failure (HR = 1.27, 95% CI = 1.10-1.48), DVT (HR = 1.80, 95% CI = 1.33-2.44), and PE (HR = 2.23, 95% CI = 1.62-3.07). Pregabalin increased the risk of DVT (HR = 1.49, 95% CI = 1.01-2.20), and PE (HR = 2.24, 95% CI = 1.43-3.50). For 1-year follow-up, gabapentin increased the risk of PVD (HR = 1.32, 95% CI = 1.11-1.57), DVT (HR = 1.35, 95% CI = 1.09-1.68), and PE (HR = 1.36, 95% CI = 1.17-1.57). Pregabalin increased the risk of PVD (HR = 1.32, 95% CI = 1.06-1.63) and PE (HR = 1.25, 95% CI = 1.03-1.52). Sensitivity analyses showed similar trends.ConclusionIn fibromyalgia patients, the prescription of gabapentin and pregabalin moderately increased the risk of several adverse cardiovascular events. This risk, together with benefits and other adverse reactions, should be considered when prescribing these medications for fibromyalgia patients.

Lung cancer is the second most diagnosed cancer and the first cause of cancer related death for men and women in the United States. Early detection is essential as patient survival is not optimal and recurrence rate is high. Copy number (CN) changes in cancer populations have been broadly investigated to identify CN gains and deletions associated with the cancer. In this research, the similarities between cancer and paired peripheral blood samples are identified using maximal information coefficient (MIC) and the spatial locations with substantially high MIC scores in each chromosome are used for clustering analysis. The results showed that a sizable reduction of feature set can be obtained using only a subset of locations with high MIC values. The clustering performance was evaluated using both true rate and normalized mutual information (NMI). Clustering results using the reduced feature set outperformed the performance of clustering using entire feature set in several chromosomes that are highly associated with lung cancer with several identified oncogenes.

[This corrects the article DOI: 10.1371/journal.pone.0227245.].

BackgroundAnkle-foot orthoses (AFOs) are commonly used to overcome mobility limitations related to lower limb musculoskeletal injury. Despite a multitude of AFOs to choose from, there is scant evidence to guide AFO prescription and limited opportunities for AFO users to provide experiential input during the process. To address these limitations in the current prescription process, this study evaluates a novel, user-centered and personalized 'test-drive' strategy using a robotic exoskeleton ('AFO emulator') to emulate commercial AFO mechanical properties (i.e., stiffness). The study will determine if brief, in-lab trials (with emulated or actual AFOs) can predict longer term preference, satisfaction, and mobility outcomes after community trials (with the actual AFOs). Secondarily, it will compare the in-lab experience of walking between actual vs. emulated AFOs.Methods and analysisIn this participant-blinded, randomized crossover study we will recruit up to fifty-eight individuals with lower limb musculoskeletal injuries who currently use an AFO. Participants will walk on a treadmill with three actual AFOs and corresponding emulated AFOs for the "in-lab" assessments. For the community trial assessment, participants will wear each of the actual AFOs for a two-week period during activities of daily living. Performance-based and user-reported measures of preference and mobility will be compared between short- and long-term trials (i.e., in-lab vs. two-week community trials), and between in-lab trials (emulated vs. actual AFOs).Trial registrationThe study was prospectively registered at www.clininicaltrials.gov (Clinical Trials Study ID: NCT06113159). Date: November 1st 2023. https://classic.clinicaltrials.gov/ct2/show/NCT06113159.

Child impeding packs are difficult for children to open so protect them from unintended access to hazardous contents inside the pack. However, if packs are difficult for adults to open, in normal usage scenarios, this may result in a higher occurrence of packs being left open. This research explores differences in ease of usage and closure compliance between two types of child impeding packs of liquid laundry detergent capsules. The two packs, "Pinch & Lift" and "Press & Lift", had different opening and closing mechanisms. "Press & Lift" also included an audible "click" signal to confirm complete closure to the user. The research was performed across two studies. In both studies, the packs were used in participants' homes according to their usual storage and usage practices as replacements to their current liquid laundry detergent capsule pack. All participants had small children living with them in their household. In Study 1, self-reported closure and ease of use data was collected from 99 adult participants in Germany. They used each package in their home for 10 days. Study 2 extended Study 1 by measuring closure rates with an objective assessment using in pack sensors for a 10-day period for each pack. Self-reported closure and ease of use data were also collected. Study 2 was conducted with 87 participants in the United Kingdom. Results across both studies showed "Press & Lift" with the audible "Click" close signal to be rated by participants to be significantly easier to open and close and have a higher self-reported closure rate than "Pinch & Lift". In addition, Study 2 results demonstrated higher closure rates using "Press & Lift" based on the sensor-measured closure compliance. Together, the results suggest transition to a pack with a mechanism that is child impeding and easier for an adult to use with an audible closure signal, like the "Press & Lift" system, has potential to reduce child access to a capsule from a pack by reducing the likelihood of the pack being left open by the adult user. Ultimately, such packs could protect children from potential poisoning injury across a range of consumer products.

Cardiopulmonary and renal end organ (CPR) complications are associated with early mortality among individuals with sickle cell disease (SCD). However, there is limited knowledge regarding acute care utilization for individuals with SCD and CPR complications. Our objective was to determine the prevalence of CPR complications in a state specific SCD population and compare acute care utilization among individuals with and without CPR complications. We leveraged 2017-2020 data for individuals with SCD identified by the Sickle Cell Data Collection program in Wisconsin. The prevalence of CPR complications is determined for distinct age groups. Generalized linear models adjusted for age compared the rate of acute care visits/person/year among individuals who had cardiopulmonary only, renal only, both cardiopulmonary and renal, or no CPR complications. There were 1378 individuals with SCD, 52% females, mean (SD) age 28.3 (18.5) years; 48% had at least one CPR complication during the study period. The prevalence of CPR complications was higher in adults (69%) compared to pediatric (15%) and transition (51%) groups. Individuals with SCD and cardiopulmonary complications had higher acute visit rates than those without CPR complications (5.4 (IQR 5.0-5.8) vs 2.4 (IQR 2.1-2.5), p

Streptococcus suis (S. suis) infections in weaned pigs are common and responsible for a high consumption of antimicrobials, and their presence is assumed to be multi-factorial. A specific evidence-based veterinary guideline to support the control of S. suis in weaned pigs was developed for veterinary practitioners in the Netherlands in 2014. Adherence to the S. suis clinical practice guideline helps veterinary practitioners to prevent and control the disease in a systematical approach and thereby improve antimicrobial stewardship and contribute to the prevention of antimicrobial resistance in animals and humans. The impact of such a clinical practice guideline on (animal) disease management depends not only on its content, but also largely on the extent to which practitioners adhere to the clinical guideline in practice. When the S. suis guideline was published, no specific activities were undertaken to support veterinarians' uptake and implementation, thereby contributing to suboptimal adherence in clinical practice. As the S. suis guideline was comprehensively written by veterinary experts following an evidence-based approach, our aim was not to judge the (scientific) quality of the guideline but to study the possibility to improve the currently low adherence of this guideline in veterinary practice. This paper describes the systematic development, using Implementation Mapping, of a theory-based intervention program to support swine veterinarians' adherence to the S. suis guideline. The knowledge, skills, beliefs about capabilities, and beliefs about consequences domains are addressed in the program, which includes seven evidence-based methods (modelling, tailoring, feedback, discussion, persuasive communication, active learning, and self-monitoring) for use in program activities such as a peer-learning meeting and an e-learning module. The intervention program has been developed for practicing swine veterinarians, lasts eight months, and is evaluated through a stepped-wedge design. The Implementation Mapping approach ensured that all relevant adopters and implementers were involved, and that outcomes, determinants (influencing factors), and objectives were systematically discussed.

BackgroundFunctional abdominal pain disorders (FAPD) are the most common chronic pain conditions of childhood and are made worse by co-occurring anxiety. Our research team found that the Aim to Decrease Pain and Anxiety Treatment (ADAPT), a six-session coping skills program using cognitive behavioral therapy strategies, was effective in improving pain-related symptoms and anxiety symptoms compared to standard care. In follow-up, this current randomized clinical trial (RCT) aims to test potential neural mechanisms underlying the effect of ADAPT. Specifically, this two-arm RCT will explore changes in amygdalar functional connectivity (primary outcome) following the ADAPT protocol during the water loading symptom provocation task (WL-SPT). Secondary (e.g., changes in regional cerebral blood flow via pulsed arterial spin labeling MRI) and exploratory (e.g., the association between the changes in functional connectivity and clinical symptoms) outcomes will also be investigated.MethodsWe will include patients ages 11 to 16 years presenting to outpatient pediatric gastroenterology care at a midwestern children's hospital with a diagnosis of FAPD plus evidence of clinical anxiety based on a validated screening tool (the Generalized Anxiety Disorder-7 [GAD-7] measure). Eligible participants will undergo baseline neuroimaging involving the WL-SPT, and assessment of self-reported pain, anxiety, and additional symptoms, prior to being randomized to a six-week remotely delivered ADAPT program plus standard medical care or standard medical care alone (waitlist). Thereafter, subjects will complete a post assessment neuroimaging visit similar in nature to their first visit.ConclusionsThis small scale RCT aims to increase understanding of potential neural mechanisms of response to ADAPT.Trial registrationClinicalTrials.gov registration: NCT03518216.

Pannexins are ubiquitously expressed in human and mouse tissues. Pannexin 1 (Panx1), the most thoroughly characterized member of this family, forms plasmalemmal membrane channels permeable to relatively large molecules, such as ATP. Although human and mouse Panx1 amino acid sequences are conserved in the presently known regulatory sites involved in trafficking and modulation of the channel, differences are reported in the N- and C-termini of the protein, and the mechanisms of channel activation by different stimuli remain controversial. Here we used a neuroblastoma cell line to study the activation properties of endogenous mPanx1 and exogenously expressed hPanx1. Dye uptake and electrophysiological recordings revealed that in contrast to mouse Panx1, the human ortholog is insensitive to stimulation with high extracellular [K+] but responds similarly to activation of the purinergic P2X7 receptor. The two most frequent Panx1 polymorphisms found in the human population, Q5H (rs1138800) and E390D (rs74549886), exogenously expressed in Panx1-null N2a cells revealed that regarding P2X7 receptor mediated Panx1 activation, the Q5H mutant is a gain of function whereas the E390D mutant is a loss of function variant. Collectively, we demonstrate differences in the activation between human and mouse Panx1 orthologs and suggest that these differences may have translational implications for studies where Panx1 has been shown to have significant impact.

When designing phylogeographic investigations researchers can choose to collect many different types of molecular markers, including mitochondrial genes or genomes, SNPs from reduced representation protocols, large sequence capture data sets, and even whole genomes. Given that the statistical power and accuracy of various analyses are expected to differ depending on both the type of marker and the amount of data collected, an exploration of the variance across methodological results as a function of marker type should provide valuable information to researchers. Here we collect mitochondrial Cytochrome b sequences, whole mitochondrial genomes, single nucleotide polymorphisms (SNP)s isolated using a genotype by sequencing (GBS) protocol, sequences from ultraconserved elements, and low-coverage nuclear genomes from the North American water vole (Microtus richardsoni). We estimate genetic distances, population genetic structure, and historical demography using data from each of these datasets and compare the results across markers. As anticipated, the results exhibit differences across marker types, particularly in terms of the resolution offered by different analyses. A cost-benefit analysis indicates that SNPs collected using a GBS protocol are the most cost-effective molecular marker, with inferences that mirror those collected from the whole genome data at a fraction of the cost per sample.

BackgroundKetamine at subanaesthetic dosages (≤0.5mg/kg) exhibits rapid onset (over hours to days) antidepressant effects against major depressive disorder in people who are otherwise well. However, its safety, tolerability and efficacy are not known for major depressive disorder in people with advanced life-limiting illnesses.ObjectiveTo determine the feasibility, safety, tolerability, acceptability and any antidepressant signal/activity to justify and inform a fully powered study of subcutaneous ketamine infusions for major depressive disorder in the palliative setting.MethodsThis was a single arm, open-label, phase II feasibility study (Australian New Zealand Clinical Trial Registry Number-ACTRN12618001586202). We recruited adults (≥ 18-years-old) with advanced life-limiting illnesses referred to four palliative care services in Sydney, Australia, diagnosed with major depressive disorder from any care setting. Participants received weekly subcutaneous ketamine infusion (0.1-0.4mg/kg) over two hours using individual dose-titration design. Outcomes assessed were feasibility, safety, tolerability and antidepressant activity.ResultsOut of ninety-nine referrals, ten participants received ketamine and were analysed for responses. Accrual rate was 0.54 participants/month across sites with 50% of treated participants achieving ≥ 50% reduction in baseline Montgomery-Åsberg Depression Rating Scale, meeting feasibility criteria set a priori. There were no clinically relevant harms encountered.ConclusionsA future definitive trial exploring the effectiveness of subcutaneous infusion of ketamine for major depressive disorder in the palliative care setting may be feasible by addressing identified study barriers. Individual dose-titration of subcutaneous ketamine infusions over two hours from 0.1mg/kg can be well-tolerated and appears to produce transient antidepressant signals over hours to days.

BackgroundDespite considerable evidence on a negative association between pregnancy pesticide exposure and child development in high-income countries, evidence from low- and middle-income countries (LMICs) is limited. Therefore, we assessed associations between pregnancy pesticide exposure and child development in rural Bangladesh and summarised existing literature in a systematic review and meta-analysis.MethodsWe used data from 284 mother-child pairs participating in a birth cohort established in 2008. Eight urinary pesticide biomarkers were quantified in early pregnancy (mean gestational age 11.6±2.9 weeks) as an index of pesticide exposure. The Bayley Scales of Infant and Toddler Development, Third Edition were administered at 20-40 months of age. Associations between creatinine-adjusted urinary pesticide biomarker concentrations and child development scores were estimated using multivariable generalised linear models. We searched ten databases up to November 2021 to identify prospective studies on pregnancy pesticide exposure and child development conducted in LMICs. We used a random-effects model to pool similar studies, including our original analysis. The systematic review was pre-registered with PROSPERO: CRD42021292919.ResultsIn the Bangladesh cohort, pregnancy 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPY) concentrations were inversely associated with motor development (-0.66 points [95% CI -1.23, -0.09]). Pregnancy 3,5,6-trichloro-2-pyridinol (TCPY) concentrations were inversely associated with cognitive development, but the association was small: -0.02 points (-0.04, 0.01). We observed no associations between 4-nitrophenol and 3-phenoxybenzoic acid (3-PBA) concentrations and child development. The systematic review included 13 studies from four LMICs. After pooling our results with one other study, we found consistent evidence that pregnancy 3-PBA concentrations were not associated with cognitive, language, or motor development.ConclusionEvidence suggests that pregnancy exposure to some organophosphate pesticides is negatively associated with child development. Interventions to reduce in-utero pesticide exposure in LMICs may help protect child development.

BackgroundClinical utility of routinely measured serial biomarkers in predicting escalation of inpatient care intensity and mortality among hospitalized patients with COVID-19 remains unknown.MethodsThis retrospective cohort study included patients with COVID-19 who admitted to the Massachusetts General Hospital between March and June 2020 and January to March 2021. White blood cell (WBC) count, platelet count, C-reactive protein (CRP), and D-dimer values were measured on days 1, 3, and 7 of admission. Clinical outcomes include 30- and 60-day morality, ICU transfer, and overall survival (OS) over a follow-up period of 90 days. The association between serial biomarkers and outcomes were assessed using multivariable logistic regression and Cox proportional hazards models.Measurements and main resultsOf the 456 patients hospitalized with COVID-19, 199 (43.6%) were ICU, 179 (39.3%) were medical floor, and 78 (17.1%) were initially admitted to the medical floor and then transferred to the ICU. In adjusted analyses, each unit increase in the slope of CRP was associated with a 42% higher odds of ICU transfer after controlling for the initial admission level (OR = 1.42, 95% CI: 1.25-1.65, P < 0.001). Including serial change in CRP levels from initial level on admission achieved the greatest predictive accuracy for ICU transfer (AUC = 0.72, 95% CI: 0.64-0.79).ConclusionsSerial change in CRP levels from admission is associated with escalations of inpatient care intensity and mortality among hospitalized patients with COVID-19.

BackgroundMalignant bowel obstruction is experienced by 15% of people with advanced cancer, preventing them from eating and drinking and causing pain, nausea and vomiting. Surgery is not always appropriate. Management options include tube or stent drainage of intestinal contents and symptom control using medication. Published literature describing palliative interventions uses a broad range of outcome measures, few of which are patient-relevant. This hinders evidence synthesis, and fails to consider the perspectives of people undergoing treatment.AimsTo develop a Core Outcome Set for the assessment of inoperable malignant bowel obstruction with clinician, patient and caregiver involvement, using COMET methodology (Core Outcome Measures in Effectiveness Trials).MethodsA systematic review of clinical trials and observational studies, a rapid review of the qualitative literature and in-depth patient and clinician interviews were conducted to identify a comprehensive list of outcomes. Outcomes were compared and consolidated by the study Steering Group and Patient and Public Involvement contributors, and presented to an international clinical Expert Panel for review. Outcomes from the finalised list were rated for importance in a three-round international Delphi process: results of two survey rounds were circulated to respondents, and two separate consensus meetings were conducted with clinicians and with patients and caregivers via virtual conferencing, using live polling to reach agreement on a Core Outcome Set.Results130 unique outcomes were identified. Following the independent Expert Panel review, 82 outcomes were taken into round 1 of the Delphi survey; 24 outcomes reached criteria for critical importance across all stakeholder groups and none reached criteria for dropping. All outcomes rated critically important were taken forward for re-rating in round 2 and all other outcomes dropped. In round 2, all outcomes were voted critically important by at least one stakeholder group. Round 2 outcomes were presented again at online consensus meetings, categorised as high ranking (n = 9), middle ranking (n = 7) or low ranking (n = 8). Stakeholders reached agreement on 16 core outcomes across four key domains: Symptom control, Life impact, Treatment outcomes, and Communication and patient preferences.ConclusionUse of this Core Outcome Set can help to address current challenges in making sense of the evidence around treatment for inoperable malignant bowel obstruction to date, and underpin a more robust future approach. Clearer communication and an honest understanding between all stakeholders will help to provide a basis for responsible decision-making in this distressing situation in clinical practice.

Many publications lack sufficient background information (e.g. location) to be interpreted, replicated, or reused for synthesis. This impedes scientific progress and the application of science to practice. Reporting guidelines (e.g. checklists) improve reporting standards. They have been widely taken up in the medical sciences, but not in ecological and agricultural research. Here, we use a community-centred approach to develop a reporting checklist (AgroEcoList 1.0) through surveys and workshops with 23 experts and the wider agroecological community. To put AgroEcoList in context, we also assessed the agroecological community's perception of reporting standards in agroecology. A total of 345 researchers, reviewers, and editors, responded to our survey. Although only 32% of respondents had prior knowledge of reporting guidelines, 76% of those that had said guidelines improved reporting standards. Overall, respondents agreed on the need of AgroEcolist 1.0; only 24% of respondents had used reporting guidelines before, but 78% indicated they would use AgroEcoList 1.0. We updated AgroecoList 1.0 based on respondents' feedback and user-testing. AgroecoList 1.0 consists of 42 variables in seven groups: experimental/sampling set-up, study site, soil, livestock management, crop and grassland management, outputs, and finances. It is presented here, and is also available on github (https://github.com/AgroecoList/Agroecolist). AgroEcoList 1.0 can serve as a guide for authors, reviewers, and editors to improve reporting standards in agricultural ecology. Our community-centred approach is a replicable method that could be adapted to develop reporting checklists in other fields. Reporting guidelines such as AgroEcoList can improve reporting standards and therefore the application of research to practice, and we recommend that they are adopted more widely in agriculture and ecology.

Potatoes are a dietary staple consumed by a significant portion of the world, providing valuable carbohydrates and vitamins. However, most commercially produced potatoes have a high content of highly branched amylopectin starch, which generally results in a high glycemic index (GI). Consumption of foods with high levels of amylopectin elicit a rapid spike in blood glucose levels, which is undesirable for individuals who are pre-diabetic, diabetic, or obese. Some cultivars of potatoes with lower amylopectin levels have previously been identified and are commercially available in niche markets in some countries, but they are relatively unavailable in the United States and Latin America. The high glycemic index of widely available potatoes presents a problematic "consumer's dilemma" for individuals and families that may not be able to afford a better-balanced, more favorable diet. Some native communities in the Andes (Bolivia, Chile, and Peru) reportedly embrace a tradition of providing low glycemic tubers to people with obesity or diabetes to help people mitigate what is now understood as the negative effects of high blood sugar and obesity. These cultivars are not widely available on a global market. This study examines 60 potato cultivars to identify potatoes with low amylopectin. Three independent analyses of potato starch were used: microscopic examination of granule structure, water absorption, and spectrophotometric analysis of iodine complexes to identify potato cultivars with low amylopectin Differences among cultivars tested were detected by all three types of analyses. The most promising cultivars are Huckleberry Gold, Muru, Multa, Green Mountain, and an October Blue x Colorado Rose cross. Further work is necessary to document the ability of these low amylopectin cultivars to reduce blood glucose spike levels in human subjects.

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785.

Disturbances to forested watersheds often result in increases of nutrients and light to nearby streams. Such changes are generally expected to produce a shift to a more autotrophic aquatic ecosystem, with measurable increases in algae, and associated implications for food webs and fisheries. Although this paradigm is widely established, results from our 10-year study (2007-2016) in 12 headwater streams and four sites downstream in the Trask River Watershed (Oregon, USA), did not concur. In 2012, one watershed was thinned, three were clearcut harvested with variable buffers and three with uniform riparian buffers. After harvest, light to the stream surface significantly increased at the three watersheds with variable buffers while dissolved inorganic nitrogen (DIN) significantly increased in all of the clearcut harvested streams. Despite the increase in DIN and light, algal standing stocks and chlorophyll a concentrations did not significantly increase. The common assumption of increased autotrophic responses in stream food webs following increases of nitrogen and light was not supported here. We postulate the co-limitation of nutrients, driven by low phosphorus concentrations, which unlike DIN did not increase post-harvest, and the characteristics of the algal community, which were dominated by low light adapted diatoms rather than green algae, contributed to our findings of no responses for standing stocks of epilithic algae or concentrations of chlorophyll a. The inclusion of multiple statistical analyses provided more certainty around our findings. This study documents responses to current forest practices and provides cautionary information for management and restoration activities aiming to increase fish abundance and standing stocks by opening riparian canopies and adding nutrients.

BackgroundAbout 70% of patients with advanced cancer experience pain. Few studies have investigated the use of healthcare in this population and the relationship between pain intensity and costs.MethodsAdults with advanced cancer and scored worst pain ≥ 2/10 on a numeric rating scale (NRS) were recruited from 6 Australian oncology/palliative care outpatient services to the Stop Cancer PAIN trial (08/15-06/19). Out-of-hospital, publicly funded services, prescriptions and costs were estimated for the three months before pain screening. Descriptive statistics summarize the clinico-demographic variables, health services and costs, treatments and pain scores. Relationships with costs were explored using Spearman correlations, Mann-Whitney U and Kruskal-Wallis tests, and a gamma log-link generalized linear model.ResultsOverall, 212 participants had median worst pain scores of five (inter-quartile range 4). The most frequently prescribed medications were opioids (60.1%) and peptic ulcer/gastro-oesophageal reflux disease (GORD) drugs (51.6%). The total average healthcare cost in the three months before the census date was A$6,742 (95% CI $5,637, $7,847), approximately $27,000 annually. Men had higher mean healthcare costs than women, adjusting for age, cancer type and pain levels (men $7,872, women $4,493, pConclusionsIn this population with pain and cancer, there was no clear relationship between healthcare costs and pain severity. These treatment patterns requiring further exploration including the prevalence of peptic ulcer/GORD drugs, and lipid lowering agents and the higher healthcare costs for men.Trial registrationACTRN12615000064505. World Health Organisation unique trial number U1111-1164-4649. Registered 23 January 2015.

BackgroundChildren with congenital heart defects have an increased risk of neurodevelopmental disability. The impact of environmental chemical exposures during daily life on neurodevelopmental outcomes in toddlers with congenital heart defects is unknown.MethodsThis prospective study investigated the impacts of early childhood exposure to mixtures of environmental chemicals on neurodevelopmental outcomes after cardiac surgery. Outcomes were assessed at 18 months of age using The Bayley Scales of Infant and Toddler Development-III. Urinary concentrations of exposure biomarkers of pesticides, phenols, parabens, and phthalates, and blood levels of lead, mercury, and nicotine were measured at the same time point. Bayesian profile regression and weighted quantile sum regression were utilized to assess associations between mixtures of biomarkers and neurodevelopmental scores.ResultsOne-hundred and forty infants were enrolled, and 110 (79%) returned at 18 months of age. Six biomarker exposure clusters were identified from the Bayesian profile regression analysis; and the pattern was driven by 15 of the 30 biomarkers, most notably 13 phthalate biomarkers. Children in the highest exposure cluster had significantly lower adjusted language scores by -9.41 points (95%CI: -17.2, -1.7) and adjusted motor scores by -4.9 points (-9.5, -0.4) compared to the lowest exposure. Weighted quantile sum regression modeling for the overall exposure-response relationship showed a significantly lower adjusted motor score (β = -2.8 points [2.5th and 97.5th percentile: -6.0, -0.6]). The weighted quantile sum regression index weights for several phthalates, one paraben, and one phenol suggest their relevance for poorer neurodevelopmental outcomes.ConclusionsLike other children, infants with congenital heart defects are exposed to complex mixtures of environmental chemicals in daily life. Higher exposure biomarker concentrations were associated with significantly worse performance for language and motor skills in this population.

Determining the dynamics of where and when individuals occur is necessary to understand population declines and identify critical areas for populations of conservation concern. However, there are few examples where a spatially and temporally explicit model has been used to evaluate the migratory dynamics of a bird population across its entire annual cycle. We used geolocator-derived migration tracks of 84 Dunlin (Calidris alpina) on the East Asian-Australasian Flyway (EAAF) to construct a migratory network describing annual subspecies-specific migration patterns in space and time. We found that Dunlin subspecies exhibited unique patterns of spatial and temporal flyway use. Spatially, C. a. arcticola predominated in regions along the eastern edge of the flyway (e.g., western Alaska and central Japan), whereas C. a. sakhalina predominated in regions along the western edge of the flyway (e.g., N China and inland China). No individual Dunlin that wintered in Japan also wintered in the Yellow Sea, China seas, or inland China, and vice-versa. However, similar proportions of the 4 subspecies used many of the same regions at the center of the flyway (e.g., N Sakhalin Island and the Yellow Sea). Temporally, Dunlin subspecies staggered their south migrations and exhibited little temporal overlap among subspecies within shared migration regions. In contrast, Dunlin subspecies migrated simultaneously during north migration. South migration was also characterized by individuals stopping more often and for more days than during north migration. Taken together, these spatial-temporal migration dynamics indicate Dunlin subspecies may be differentially affected by regional habitat change and population declines according to where and when they occur. We suggest that the migration dynamics presented here are useful for guiding on-the-ground survey efforts to quantify subspecies’ use of specific sites, and to estimate subspecies’ population sizes and long-term trends. Such studies would significantly advance our understanding of Dunlin space-time dynamics and the coordination of Dunlin conservation actions across the EAAF.

The reference sequence of structurally complex regions can only be obtained through a highly accurate clone-based approach that we call Single-Haplotype Iterative Mapping and Sequencing (SHIMS). In recent years, improvements to SHIMS have reduced the cost and time required by two orders of magnitude, but internally repetitive clones still require extensive manual effort to transform draft assemblies into reference-quality finished sequences. Here we describe SHIMS 3.0, using ultra-long nanopore reads to augment the Illumina data from SHIMS 2.0 assemblies and resolve internally repetitive structures. This greatly minimizes the need for manual finishing of Illumina-based draft assemblies, allowing a small team with no prior finishing experience to sequence challenging targets with high accuracy. This protocol proceeds from clone-picking to finished assemblies in 2 weeks for about $80 (USD) per clone. We recently used this protocol to produce reference sequence of structurally complex palindromes on chimpanzee and rhesus macaque X chromosomes. Our protocol provides access to structurally complex regions that would otherwise be inaccessible from whole-genome shotgun data or require an impractical amount of manual effort to generate an accurate assembly.

BackgroundHigh-quality care is a clear objective for hospital leaders, but hospitals must balance investing in quality with financial stability. Poor hospital financial health can precipitate closure, limiting patients' access to care. Whether hospital quality is associated with financial health remains poorly understood. The objective of this study was to compare financial performance at high-quality and low-quality hospitals.MethodsWe performed a retrospective observational cohort study of U.S. hospitals using the American Hospital Association and Hospital Compare datasets for years 2013 to 2018. We used multilevel mixed-effects linear and logistic regression models with fixed year effects and random intercepts for hospitals to identify associations between hospitals' measured quality outcomes-30-day hospital-wide readmission rate and the patient safety indicator-90 (PSI-90)-and their financial margins and risk of financial distress in the same year and the subsequent year. Our sample included 20,919 observations from 4,331 unique hospitals.ResultsIn 2018, the median 30-day readmission rate was 15.2 (interquartile range [IQR] 14.8-15.6), the median PSI-90 score was 0.96 (IQR 0.89-1.07), the median operating margin was -1.8 (IQR -9.7-5.9), and 750 (22.7%) hospitals experienced financial distress. Hospitals in the best quintile of readmission rates experienced higher operating margins (+0.95%, 95% CI [0.51-1.39], p < .001) and lower odds of distress (odds ratio [OR] 0.56, 95% CI [0.45-0.70], p < .001) in the same year as compared to hospitals in the worst quintile. Hospitals in the best quintile of PSI-90 had higher operating margins (+0.62%, 95% CI [0.17-1.08], p = .007) and lower odds of financial distress (OR 0.70, 95% CI [0.55-0.89], p = .003) as compared to hospitals in the worst quintile. The results were qualitatively similar for the same-year and lag-year analyses.ConclusionHospitals that deliver high-quality outcomes may experience superior financial performance compared to hospitals with poor-quality outcomes.

Institutions have been described as 'the humanly devised constraints that structure political, economic, and social interactions.' This broad definition of institutions spans social norms, laws, companies, and even scientific theories. We describe a non-equilibrium, multi-scale learning framework supporting institutional quasi-stationarity, periodicity, and switching. Individuals collectively construct ledgers constituting institutions. Agents read only a part of the ledger-positive and negative opinions of an institution-its "public position" whose value biases one agent's preferences over those of rivals. These positions encode collective perception and action relating to laws, the power of parties in political office, and advocacy for scientific theories. We consider a diversity of complex temporal phenomena in the history of social and research culture (e.g. scientific revolutions) and provide a new explanation for ubiquitous cultural resistance to change and novelty-a systemic endowment effect through hysteresis.

In times of crisis, including the current COVID-19 pandemic, the supply chain of filtering facepiece respirators, such as N95 respirators, are disrupted. To combat shortages of N95 respirators, many institutions were forced to decontaminate and reuse respirators. While several reports have evaluated the impact on filtration as a measurement of preservation of respirator function after decontamination, the equally important fact of maintaining proper fit to the users’ face has been understudied. In the current study, we demonstrate the complete inactivation of SARS-CoV-2 and preservation of fit test performance of N95 respirators following treatment with dry heat. We apply scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDS), X-ray diffraction (XRD) measurements, Raman spectroscopy, and contact angle measurements to analyze filter material changes as a consequence of different decontamination treatments. We further compared the integrity of the respirator after autoclaving versus dry heat treatment via quantitative fit testing and found that autoclaving, but not dry heat, causes the fit of the respirator onto the users face to fail, thereby rendering the decontaminated respirator unusable. Our findings highlight the importance to account for both efficacy of disinfection and mask fit when reprocessing respirators to for clinical redeployment.

We investigated sex differences in 473,260 adolescents’ aspirations to work in things-oriented (e.g., mechanic), people-oriented (e.g., nurse), and STEM (e.g., mathematician) careers across 80 countries and economic regions using the 2018 Programme for International Student Assessment (PISA). We analyzed student career aspirations in combination with student achievement in mathematics, reading, and science, as well as parental occupations and family wealth. In each country and region, more boys than girls aspired to a things-oriented or STEM occupation and more girls than boys to a people-oriented occupation. These sex differences were larger in countries with a higher level of women’s empowerment. We explain this counter-intuitive finding through the indirect effect of wealth. Women’s empowerment is associated with relatively high levels of national wealth and this wealth allows more students to aspire to occupations they are intrinsically interested in. Implications for better understanding the sources of sex differences in career aspirations and associated policy are discussed.

The intracellular distribution of copper in the liver has been investigated in dogs and humans. However, this has not been reported in cats. This study aimed to assess the intracellular copper distribution in liver specimens from cats with a range of hepatic copper concentrations. Twenty-nine frozen liver specimens from cats were included. Each liver specimen was divided into two pieces for overall copper quantification and tissue fractionation. The copper concentrations in liver specimens and liver fractions were measured by flame atomic absorption spectroscopy. Five specimens had copper concentrations < 100 μg/g dry weight, eight had copper concentrations between 100 and 180 μg/g, 14 had copper concentrations between 181 and 700 μg/g, and two had copper concentrations >700 μg/g. Only one specimen had positive copper staining. Regardless of the overall concentrations, copper was mostly found in the cytosolic fraction followed by the nuclear, large granule, and microsomal fractions. Our findings indicate that similarly to other species, intracellular copper is predominantly found in the cytosolic and nuclear fractions in cats. The distribution in cats with copper-loaded conditions, such as primary copper hepatopathy, was not assessed but warrants evaluation.

Improving the effectiveness of fishways requires a better understanding of fish behavior near hydraulic structures, especially of upstream orientation. One of the most promising approaches to this problem is the use of model behavioral rules. We developed a three-dimensional individual-based model based on observed brown trout (Salmo trutta fario) movement in a laboratory flume and tested it against two hydraulically different flume setups. We used the model to examine which of five behavioral rule versions would best explain upstream trout orientation. The versions differed in the stimulus for swim angle selection. The baseline stimulus was positive rheotaxis with a random component. It was supplemented by attraction towards either lower velocity magnitude, constant turbulence kinetic energy, increased flow acceleration, or shorter wall distance. We found that the baseline stimulus version already explained large parts of the observed behavior. Mixed results for velocity magnitude, turbulence kinetic energy, and flow acceleration indicated that the brown trout did not orient primarily by means of these flow features. The wall distance version produced significantly improved results, suggesting that wall distance was the dominant orientation stimulus for brown trout in our hydraulic conditions. The absolute root mean square error (RMSE) was small for the best parameter set (RMSE = 9 for setup 1, RMSE = 6 for setup 2). Our best explanation for these results is dominance of the visual sense favored by absence of challenging hydraulic stimuli. We conclude that under similar conditions (moderate flow and visible walls), wall distance could be a relevant stimulus in confined space, particularly for fishway studies and design in IBMs, laboratory, and the field.

Endovascular interventions (EVI) are increasingly performed as minimally-invasive alternatives to surgery and have many advantages, including a decreased need for general anesthesia. However, EVI can be stressful for patients and often lead to anxiety and pain related to the procedure. The use of local anesthetics, anxiolytics, and analgesic drugs can help avoid general anesthesia. Nevertheless, these drugs have potential side effects. Alternative nonpharmacological therapies can improve patients’ experience during conscious interventions and reduce the need for additional medications. The added value of virtually augmented self-hypnosis (VA-HYPO) and its potential to reduce pain and anxiety during peripheral and visceral arterial and venous EVI is unknown. This is a prospective two-arm trial designed to randomize 100 patients in two groups according to the use or not of VA-HYPO during peripheral EVI as a complementary nonpharmacological technique to improve patient comfort. The main objective is to compare per-procedural anxiety, and the secondary aim is to compare the rated per-procedural pain in both groups. The potential significance is that VA-HYPO may improve patients’ experience during peripheral and visceral arterial and venous EVI and other minimally invasive interventions performed under local anesthesia. Trial registration: Our study is registered on clinicaltrials.gov, with trial registration number: NCT04561596.

Prosthetic foot stiffness plays a key role in the functional mobility of lower limb prosthesis users. However, limited objective data exists to guide selection of the optimal prosthetic foot stiffness category for a given individual. Clinicians often must rely solely on manufacturer recommendations, which are typically based on the intended user’s weight and general activity level. Availability of comparable forefoot and heel stiffness data would allow for a better understanding of differences between different commercial prosthetic feet, and also between feet of different stiffness categories and foot sizes. Therefore, this study compared forefoot and heel linear stiffness properties across manufacturer-designated stiffness categories and foot sizes. Mechanical testing was completed for five types of commercial prosthetic feet across a range of stiffness categories and three foot-sizes. Data were collected for 56 prosthetic feet, in total. Testing at two discrete angles was conducted to isolate loading of the heel and forefoot components, respectively. Each prosthetic foot was loaded for six cycles while force and displacement data were collected. Forefoot and heel measured stiffness were both significantly associated with stiffness category (p = .001). There was no evidence that the relationships between stiffness category and measured stiffness differed by foot size (stiffness category by size interaction p = .80). However, there were inconsistencies between the expected and measured stiffness changes across stiffness categories (i.e., magnitude of stiffness changes varied substantially between consecutive stiffness categories of the same feet). While statistical results support that, on average, measured stiffness is positively correlated with stiffness category, force-displacement data suggest substantial variation in measured stiffness across consecutive categories. Published objective mechanical property data for commercial prosthetic feet would likely therefore be helpful to clinicians during prescription.

Background/objectiveTo evaluate the development of intra- and post-operative retinal breaks after pars plana vitrectomy (PPV) for macular hole (MH) and/or vitreomacular traction (VMT).Subjects/methodsMedical records of patients who underwent PPV at Kellogg Eye Center between 1/1/2005-6/30/2018, were evaluated in three groups: group 1, MH/VMT (n = 136); group 2, epiretinal membrane (ERM) without VMT (n = 270); and group 3, diagnostic vitrectomy (DV) or vitreous opacities (n = 35). Statistical analyses were conducted using SAS.Results20.6% of patients with MH/VMT, 8.5% of patients with ERM, and 5.7% of patients with DV or vitreous opacities had either intra-operative or post-operative breaks. Indication of MH/VMT versus ERM was a significant predictor for this outcome (p = .0112). The incidence of retinal breaks was higher in operations using 23-gauge versus 25-gauge PPV (25.0% vs. 7.4%, p < .0001).ConclusionsThe presence of MH and/or VMT is a significant risk factor for retinal breaks from PPV, as is use of 23-gauge vitrectomy.

The endothelium maintains and regulates vascular homeostasis mainly by balancing interplay between vasorelaxation and vasoconstriction via regulating Nitric Oxide (NO) availability. Endothelial nitric oxide synthase (eNOS) is one of three NOS isoforms that catalyses the synthesis of NO to regulate endothelial function. However, eNOS's role in the regulation of endothelial function, such as cell proliferation and migration remain unclear. To gain a better understanding, we genetically knocked down eNOS in cultured endothelial cells using sieNOS and evaluated cell proliferation, migration and also tube forming potential in vitro. To our surprise, loss of eNOS significantly induced endothelial cell proliferation, which was associated with significant downregulation of both cell cycle inhibitor p21 and cell proliferation antigen Ki-67. Knockdown of eNOS induced cell migration but inhibited formation of tube-like structures in vitro. Mechanistically, loss of eNOS was associated with activation of MAPK/ERK and inhibition of PI3-K/AKT signaling pathway. On the contrary, pharmacologic inhibition of eNOS by inhibitors L-NAME or L-NMMA, inhibited cell proliferation. Genetic and pharmacologic inhibition of eNOS, both promoted endothelial cell migration but inhibited tube-forming potential. Our findings confirm that eNOS regulate endothelial function by inversely controlling endothelial cell proliferation and migration, and by directly regulating its tube-forming potential. Differential results obtained following pharmacologic versus genetic inhibition of eNOS indicates a more complex mechanism behind eNOS regulation and activity in endothelial cells, warranting further investigation.

Mobile sensing data processed using machine learning models can passively and remotely assess mental health symptoms from the context of patients' lives. Prior work has trained models using data from single longitudinal studies, collected from demographically homogeneous populations, over short time periods, using a single data collection platform or mobile application. The generalizability of model performance across studies has not been assessed. This study presents a first analysis to understand if models trained using combined longitudinal study data to predict mental health symptoms generalize across current publicly available data. We combined data from the CrossCheck (individuals living with schizophrenia) and StudentLife (university students) studies. In addition to assessing generalizability, we explored if personalizing models to align mobile sensing data, and oversampling less-represented severe symptoms, improved model performance. Leave-one-subject-out cross-validation (LOSO-CV) results were reported. Two symptoms (sleep quality and stress) had similar question-response structures across studies and were used as outcomes to explore cross-dataset prediction. Models trained with combined data were more likely to be predictive (significant improvement over predicting training data mean) than models trained with single-study data. Expected model performance improved if the distance between training and validation feature distributions decreased using combined versus single-study data. Personalization aligned each LOSO-CV participant with training data, but only improved predicting CrossCheck stress. Oversampling significantly improved severe symptom classification sensitivity and positive predictive value, but decreased model specificity. Taken together, these results show that machine learning models trained on combined longitudinal study data may generalize across heterogeneous datasets. We encourage researchers to disseminate collected de-identified mobile sensing and mental health symptom data, and further standardize data types collected across studies to enable better assessment of model generalizability.

Multiple national and international trends and drivers are radically changing what biological security means for the United Kingdom (UK). New technologies present novel opportunities and challenges, and globalisation has created new pathways and increased the speed, volume and routes by which organisms can spread. The UK Biological Security Strategy (2018) acknowledges the importance of research on biological security in the UK. Given the breadth of potential research, a targeted agenda identifying the questions most critical to effective and coordinated progress in different disciplines of biological security is required. We used expert elicitation to generate 80 policy-relevant research questions considered by participants to have the greatest impact on UK biological security. Drawing on a collaboratively-developed set of 450 questions, proposed by 41 experts from academia, industry and the UK government (consulting 168 additional experts) we subdivided the final 80 questions into six categories: bioengineering; communication and behaviour; disease threats (including pandemics); governance and policy; invasive alien species; and securing biological materials and securing against misuse. Initially, the questions were ranked through a voting process and then reduced and refined to 80 during a one-day workshop with 35 participants from a variety of disciplines. Consistently emerging themes included: the nature of current and potential biological security threats, the efficacy of existing management actions, and the most appropriate future options. The resulting questions offer a research agenda for biological security in the UK that can assist the targeting of research resources and inform the implementation of the UK Biological Security Strategy. These questions include research that could aid with the mitigation of Covid-19, and preparation for the next pandemic. We hope that our structured and rigorous approach to creating a biological security research agenda will be replicated in other countries and regions. The world, not just the UK, is in need of a thoughtful approach to directing biological security research to tackle the emerging issues.

Regular surveillance testing of asymptomatic individuals for SARS-CoV-2 has been center to SARS-CoV-2 outbreak prevention on college and university campuses. Here we describe the voluntary saliva testing program instituted at the University of California, Berkeley during an early period of the SARS-CoV-2 pandemic in 2020. The program was administered as a research study ahead of clinical implementation, enabling us to launch surveillance testing while continuing to optimize the assay. Results of both the testing protocol itself and the study participants' experience show how the program succeeded in providing routine, robust testing capable of contributing to outbreak prevention within a campus community and offer strategies for encouraging participation and a sense of civic responsibility.

BackgroundIn order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts.MethodsThe aim of the present study was to compare the 4C mortality score, other measures of the systemic inflammatory response and clinicopathological characteristics in two consecutive cohorts of patients on admission with COVID-19. Electronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17/3/2020-1/5/2020) and (cohort 2: 18/5/2020-6/7/2020) were examined for routine clinical, laboratory and clinical outcome data.ResultsCompared with cohort 1, cohort 2 were older (p70 (p150mg/L (p3) (OR 11.3, 95% C.I. 2.3-96.7, pConclusionIn addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19.Trial registrationclinicaltrials.gov: NCT04484545.

BackgroundPeople with cancer often have unidentified symptoms and social care needs. The Needs Assessment Tool-Cancer (NAT-C) is a validated, structured method of assessing patient/carer concerns and prompting action, to address unmet need.AimsAssess feasibility and acceptability of a definitive two-armed cluster randomised trial of NAT-C in primary care by evaluating: recruitment of GP practices, patients and carers; most effective approach of ensuring NAT-C appointments, acceptability of study measures and follow-up.MethodsNon-blinded, feasibility study in four General Practices, with cluster randomisation to method of NAT-C appointment delivery, and process evaluation. Adults with active cancer were invited to participate with or without carer. Practices cluster randomised (1:1) to Arm I: promotion and use of NAT-C with a NAT-C trained clinician or Arm II: clinician of choice irrespective of training status. Participants completed study questionnaires at: baseline, 1, 3 and 6 months. Patients booked a 20 minute needs-assessment appointment post-baseline. Patients, carers and GP practice staff views regarding the study sought through interviews/focus groups. Quantitative data were analysed descriptively. Qualitative data were analysed thematically, informed by Normalisation Process Theory. Progression to a definitive trial was assessed against feasibility outcomes, relating to: recruitment rate, uptake and delivery of the NAT-C, data collection and quality.ResultsFive GP practices approached, four recruited and trained to use the NAT-C. Forty-seven participants and 17 carers recruited. At baseline, 34/47 (72%) participants reported at least one moderate-severe unmet need, confirming study rationale. 32/47 (68%) participants received a NAT-C-guided consultation, 19 of which on Arm I. Study attrition at one month (n = 44 (94%), n = 16 (94%)), three months (n = 38 (81%), n = 14 (82%)) and six months (n = 32 (68%), n = 10 (59%)). Fifteen patient interviews conducted across the whole study and one focus group at each GP practice. Participants supported a definitive study and found measures acceptable.ConclusionThe feasibility trial indicated that recruitment rate, intervention uptake and data collection were appropriate, with refinements, for a definitive multi-centre cluster randomised controlled trial. Feasibility outcomes informed the design of a 2-armed cluster randomised controlled trial to test the effectiveness and cost-effectiveness of the NAT-C compared with usual care.

A major bottleneck in the study of human liver physiology is the provision of stable liver tissue in sufficient quantity. As a result, current approaches to modelling human drug efficacy and toxicity rely heavily on immortalized human and animal cell lines. These models are informative but do possess significant drawbacks. To address the issues presented by those models, researchers have turned to pluripotent stem cells (PSCs). PSCs can be generated from defined genetic backgrounds, are scalable, and capable of differentiation to all the cell types found in the human body, representing an attractive source of somatic cells for in vitro and in vivo endeavours. Although unlimited numbers of somatic cell types can be generated in vitro, their maturation still remains problematic. In order to develop high fidelity PSC-derived liver tissue, it is necessary to better understand the cell microenvironment in vitro including key elements of liver physiology. In vivo a major driver of zonated liver function is the oxygen gradient that exists from periportal to pericentral regions. In this paper, we demonstrate how cell culture conditions for PSC-derived liver sphere systems can be optimised to recapitulate physiologically relevant oxygen gradients by using mathematical modelling. The mathematical model incorporates some often-understated features and mechanisms of traditional spheroid systems such as cell-specific oxygen uptake, media volume, spheroid size, and well dimensions that can lead to a spatially heterogeneous distribution of oxygen. This mathematical modelling approach allows for the calibration and identification of culture conditions required to generate physiologically realistic function within the microtissue through recapitulation of the in vivo microenvironment.

BackgroundVery few measures are used successfully as part of routine care within national palliative care outcome programs. Only a handful of studies examine these measures. The aim of this study is to evaluate the validity of a measure used in a national outcomes program: the Palliative Care Outcomes Collaboration Symptom Assessment Scale (PCOC SAS).MethodsA retrospective multi-site cohort study with secondary analysis of routinely collected patient-level data to assess PCOC SAS's internal consistency, construct validity, reliability, interpretability, acceptability and sensitivity. The analyses used two sets, with data collected by inpatient and community palliative care services registered with the Australian national PCOC.ResultsDataset one included 1,117 patients receiving palliative care from 21 services. Dataset two included 5,294 patients receiving palliative care from 119 PCOC services. PCOC SAS demonstrated the ability to detect and discriminate distress by palliative care phase, functional status and diagnosis. Excellent and good convergent and discriminant validity were demonstrated. Fair through to substantial inter-rater and intra-rater reliability levels were evidenced. Sufficient interpretability resulted along with necessary levels of acceptability and sensitivity.ConclusionPCOC SAS is a valid and reliable patient-reported outcome measure suitable for use in routine clinical care with patients requiring palliative and or end-of-life care, including in national outcomes programs.

Rationale/study designA major challenge in the development of HIV vaccines is finding immunogens that elicit protection against a broad range of viral strains. Immunity to a narrow range of viral strains may protect infants of HIV-infected women or partners discordant for HIV. We hypothesized that immunization to the relevant viral variants could be achieved by exposure to infectious virus during prophylaxis with antiretroviral drugs. To explore this approach in an animal model, macaques were exposed to live virus (SIVmne or HIV-2287) during prophylaxis with parenteral tenofovir and humoral and cellular immune responses were quantified. Subsequently, experimental animals were challenged with homologous virus to evaluate protection from infection, and if infection occurred, the course of disease was compared to control animals. Experimental animals uninfected with SIVmne were challenged with heterologous HIV-2287 to assess resistance to retroviral infection.Methodology/principal findingsJuvenile female Macaca nemestrina (N = 8) were given ten weekly intravaginal exposures with either moderately (SIVmne) or highly (HIV-2287) pathogenic virus during tenofovir prophylaxis. Tenofovir protected all 8 experimental animals from infection, while all untreated control animals became infected. Specific non-neutralizing antibodies were elicited in blood and vaginal secretions of experimental animals, but no ELISPOT responses were detected. Six weeks following the cessation of tenofovir, intravaginal challenge with homologous virus infected 2/4 (50%) of the SIVmne-immunized animals and 4/4 (100%) of the HIV-2287-immunized animals. The two SIVmne-infected and 3 (75%) HIV-2287-infected had attenuated disease, suggesting partial protection.Conclusions/significanceRepeated exposure to SIVmne or HIV-2287, during antiretroviral prophylaxis that blocked infection, induced binding antibodies in the blood and mucosa, but not neutralizing antibodies or specific cellular immune responses. Studies to determine whether antibodies are similarly induced in breastfeeding infants and sexual partners discordant for HIV infection and receiving pre-exposure antiretroviral prophylaxis are warranted, including whether these antibodies appear to confer partial or complete protection from infection.

Dam removal is an increasingly important method of stream restoration, but most removal efforts are under-studied in their effects. In order to better understand the effects of such removals on the stream ecosystem, we examined changes in stream macroinvertebrate communities from 2011-2016. Comparisons were focused above, below, and before and after the October 2012 removal of the Brown Bridge Dam on the Boardman River in Michigan (USA), as well as to new channel sites created in its former reservoir (2013-2015). Using linear mixed-effect models on the percent abundance of ecologically sensitive taxa (% Ephemeroptera, Plecoptera, Trichoptera (EPT)), total density of all macroinvertebrates, overall taxa richness, and Functional Feeding Groups, along with multivariate analyses on the community matrix, we examined differences in community composition among sites and years. EPT declined downstream of the dam immediately after dam removal, but recovered in the second year, becoming dominant within 2-4 years. Downstream sites before removal had different community composition than upstream sites and downstream sites after removal (p

Pre-exposure prophylaxis (PrEP) is traditionally prescribed by HIV specialist physicians. Given finite specialist resources, there is a need to scale up PrEP delivery by decentralizing services via other healthcare professionals. We aimed to assess the feasibility of delivering PrEP to men who have sex with men (MSM) through primary care physicians and sexual health clinic nurses. We piloted a multi-component, implementation and dissemination research program to increase provision of PrEP through primary care physicians and sexual health clinic nurses in Toronto, Canada. Community-based organizations (CBOs) provided prospective participants with information cards that contained links to an online module on engaging providers in a conversation about PrEP. In our patient-initiated continuing medical education (PICME) strategy, participants saw their family doctors and gave them the card, which also contained a link to a Continuing Medical Education module. In the nurse-led strategy, participants visited one of two participating clinics to obtain PrEP. We administered an optional online questionnaire to patients and providers at baseline and six months. CBOs distributed 3043 cards. At least 339 men accessed the online module and 196 completed baseline questionnaires. Most (55%) intended to visit nurses while 21% intended to consult their physicians. Among 45 men completing follow-up questionnaires at 6 months, 31% reported bringing cards to their physicians and obtaining PrEP through them; sexual health clinics delivered PrEP to 244 patients. Participants who went through the PICME approach reported no changes in relationships with their providers. Nurses showed fidelity to PrEP prescribing guidelines. Nurse-led PrEP and patient-initiated continuing medical education (PICME) for primary care physicians are feasible strategies to increase PrEP uptake. Nurse-led PrEP delivery was preferred by most patients.

Children's movies often provide messages about morally appropriate and inappropriate conduct. In two studies, we draw on Moral Foundations Theory (MFT) to derive predictions about actual depictions of morality, and people's preferences for different moral depictions, within children's movies. According to MFT, people's moral concerns include individualizing foundations of care and fairness and binding foundations of loyalty, authority, and sanctity. Prior work reveals that although there are political differences in the endorsement of these two broad categories-whereby stronger political conservatism predicts stronger binding concerns and weaker individualizing concerns-there nonetheless is broad agreement across political identity in the importance of individualizing concerns. We therefore predicted that heroes would value individualizing foundations more than villains, and that despite political differences in preferences for moral messages, there would be more agreement in the importance of messages promoting individualizing concerns. In Study 1, we coded heroes and villains from popular children's movies for their valuation of moral foundations. Heroes valued individualizing concerns more, and binding concerns less, than villains did. Participants in Study 2 considered moral dilemmas faced by children's movie characters, and rated their preferences for resolutions that promoted either individualizing or binding foundations. Although liberals preferred individualizing-promoting resolutions and conservatives preferred binding-promoting resolutions, there was stronger agreement across political identity in the importance of individualizing concerns. Despite political differences in moral preferences, popular depictions of children's movie characters and people's self-reported moral endorsement suggest a shared belief in the importance of the individualizing moral virtues of care and fairness. Movies are often infused with moral messages. From their exploration of overarching themes, their ascription of particular traits to heroic and villainous characters, and their resolution of pivotal moral dilemmas, movies provide viewers with depictions of morally virtuous (and morally suspect) behavior. Moral messaging in children's movies is of particular importance, since it is targeted at an audience for which morality is actively developing. What moral messages do filmmakers (and consumers, including parents) want children's movies to depict? Are these preferences related to people's political identity? And what are the actual moral depictions presented in movies? In the present two studies, we draw on an influential theory of moral judgment-Moral Foundations Theory-to develop and test predictions about the depiction of morality in children's movies.

During a psychotherapy session, the counselor typically adopts techniques which are codified along specific dimensions (e.g., ‘displays warmth and confidence’, or ‘attempts to set up collaboration’) to facilitate the evaluation of the session. Those constructs, traditionally scored by trained human raters, reflect the complex nature of psychotherapy and highly depend on the context of the interaction. Recent advances in deep contextualized language models offer an avenue for accurate in-domain linguistic representations which can lead to robust recognition and scoring of such psychotherapy-relevant behavioral constructs, and support quality assurance and supervision. In this work, we propose a BERT-based model for automatic behavioral scoring of a specific type of psychotherapy, called Cognitive Behavioral Therapy (CBT), where prior work is limited to frequency-based language features and/or short text excerpts which do not capture the unique elements involved in a spontaneous long conversational interaction. The model focuses on the classification of therapy sessions with respect to the overall score achieved on the widely-used Cognitive Therapy Rating Scale (CTRS), but is trained in a multi-task manner in order to achieve higher interpretability. BERT-based representations are further augmented with available therapy metadata, providing relevant non-linguistic context and leading to consistent performance improvements. We train and evaluate our models on a set of 1,118 real-world therapy sessions, recorded and automatically transcribed. Our best model achieves an F1 score equal to 72.61% on the binary classification task of low vs. high total CTRS.

Personality traits have been found to be related to a variety of health outcomes. The aim of this study was to examine how personality traits were associated with adjustment to the COVID pandemic in college students. The sample included 484 first-year university students (76% female) attending a northeastern university who completed the Big Five Inventory (BFI) personality assessment at the beginning of a semester that was disrupted by the COVID pandemic. Using a phone-based app, students completed daily ratings of mood, perceived stress levels, and engagement in a number of health promotion activities (exercise, mindfulness, adequate sleep, etc.) throughout the semester both before and after the onset of the pandemic (e.g., a within-person longitudinal design). Results, as expected, showed that mood and wellness indices generally declined during the COVID period, although stress levels actually decreased. Further, irrespective of COVID, improved mood, less perceived stress and greater participation in health promotion activities were significantly associated with a number of personality traits including neuroticism (lower), extraversion (higher), agreeableness (higher), and conscientiousness (higher). Of primary interest, mixed-effects models were used to test how major personality traits interacted with any changes in daily ratings from the pre-COVID to COVID period. Significant interactions terms were found suggesting differential impacts of the COVID epidemic for students with low versus high levels of particular traits. Higher levels of extraversion, for example, were found to be related to decreases in mood as the pandemic progressed in contrast to those with lower extraversion, for whom there was a slight increase in mood over time. These data support the conclusion that personality traits are related to mental health and can play a role in a person's ability to cope with major stressful events. Different traits may also be more adaptive to different types of stressors.