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Patients face numerous health-related decisions once advanced chronic kidney disease (CKD) is diagnosed. Yet, when patients are underprepared to navigate and discuss health-related decisions, they can make choices inconsistent with their expectations for the future. This pilot study, guided by the multiphase optimization strategy and community-engaged research principles, aimed to explore the acceptability of a developed patient component to a decision-support training intervention called ImPart (Improving Decisional Partnership of CKD Dyads). CKD patients and their family caregivers were recruited from an urban, academic medical center. Eligibility criteria for patients included a diagnosis of stage 3 or higher CKD (on chart review), and caregivers participated in interview sessions only. Patients without a caregiver were not eligible. The intervention was lay coach, telephone-delivered, and designed to be administered in 1-2 week intervals for 4 sessions. An interview guide, developed in collaboration with an advisory group, was designed to ascertain participants' experiences with the intervention. Caregiver interviews focused on changes in the patient's decision ability or engagement. Thirteen patients and eleven caregivers were interviewed. The program was viewed as "good" or "beneficial." Three themes capture the intervention's impact- 1) Frequent and deliberate disease-focused communication, 2) Future planning activation, and 3) Coaching relationship. The piloted intervention was successfully delivered, acceptable to use, and found to promote enhanced disease and future planning communication. By undergoing this work, we ensure that the patient component is feasible to use and meets the needs of participants before implementation in a larger factorial trial.

IntroductionChemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global level continues to grow. Because resources are constrained, there is a need to prioritize interventions focused on the greatest health impact. Data, especially related to chemical exposures, are rarely available for most substances of concern, and alternate methods to evaluate their impact are needed.Structured expert judgment (sej) processA Structured Expert Judgment (Research Outreach, 2021) process was performed to provide plausible estimates of health impacts for 16 commonly found pollutants: asbestos, arsenic, benzene, chromium, cadmium, dioxins, fluoride, highly hazardous pesticides (HHPs), lead, mercury, polycyclic-aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Per- and Polyfluorinated Substances (PFAs), phthalates, endocrine disrupting chemicals (EDCs), and brominated flame retardants (BRFs). This process, undertaken by sector experts, weighed individual estimations of the probable global health scale health impacts of each pollutant using objective estimates of the expert opinions' statistical accuracy and informativeness.Main findingsThe foremost substances, in terms of mean projected annual total deaths, were lead, asbestos, arsenic, and HHPs. Lead surpasses the others by a large margin, with an estimated median value of 1.7 million deaths annually. The three other substances averaged between 136,000 and 274,000 deaths per year. Of the 12 other chemicals evaluated, none reached an estimated annual death count exceeding 100,000. These findings underscore the importance of prioritizing available resources on reducing and remediating the impacts of these key pollutants.Range of health impactsBased on the evidence available, experts concluded some of the more notorious chemical pollutants, such as PCBs and dioxin, do not result in high levels of human health impact from a global scale perspective. However, the chemical toxicity of some compounds released in recent decades, such as Endocrine Disrupters and PFAs, cannot be ignored, even if current impacts are limited. Moreover, the impact of some chemicals may be disproportionately large in some geographic areas. Continued research and monitoring are essential; and a preventative approach is needed for chemicals.Future directionsThese results, and potential similar analyses of other chemicals, are provided as inputs to ongoing discussions about priority setting for global chemicals and pollution management. Furthermore, we suggest that this SEJ process be repeated periodically as new information becomes available.

Violence against children in schools harms the affected children, limits their learning and educational attainment, and extends its harms to families and the broader communities. However, to date, comparable cross-country data on violence against children in schools has not been available. We utilize the Violence Against Children and Youth Surveys (VACS) to estimate school-related violence against children in seven countries (Honduras, Kenya, Malawi, Nigeria, Tanzania, Uganda, and Zambia). Leveraging the unique comparability of the surveys, we are able to estimate both physical and sexual violence experienced in childhood and adolescence among youth aged 13-24. Where possible, we also disaggregate by gender and perpetrator type. Overall, within our sample seven countries, we find that 12.11-44.63% of females and 14.28-53.85% of males experienced at least one form of violence. Males experience higher levels of school-related violence and a significant portion of this is due to experiencing physical violence perpetrated by male classmates.

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

Biliary atresia is a neonatal disease characterized by damage, inflammation, and fibrosis of the liver and bile ducts and by abnormal bile metabolism. It likely results from a prenatal environmental exposure that spares the mother and affects the fetus. Our aim was to develop a model of fetal injury by exposing pregnant mice to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock, and then to determine whether there was a hepatobiliary phenotype in their pups. Pregnant mice were treated orally with 15 mg/kg/d biliatresone for 2 days. Histology of the liver and bile ducts, serum bile acids, and liver immune cells of pups from treated mothers were analyzed at P5 and P21. Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal. However, serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at P21. These results suggest that prenatal exposure to low doses of an environmental toxin can cause subclinical disease including liver inflammation and aberrant bile metabolism even in the absence of histological changes. This finding suggests a wide potential spectrum of disease after fetal biliary injury.

ObjectiveGlycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear.MethodsThis study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment.ResultsPCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways.ConclusionsThese findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.

Atlantic tarpon (Megalops atlanticus) are capable of long-distance migrations (hundreds of kilometers) but also exhibit resident behaviors in estuarine and coastal habitats. The aim of this study was to characterize the spatial distribution of juvenile tarpon and identify migration pathways of adult tarpon in the northern Gulf of Mexico. Spatial distribution of juvenile tarpon was investigated using gillnet data collected by Texas Parks and Wildlife Department (TPWD) over the past four decades. Generalized additive models (GAMs) indicated that salinity and water temperature played a significant role in tarpon presence, with tarpon occurrences peaking in the fall and increasing over the past four decades in this region. Adult tarpon caught off Texas (n = 40) and Louisiana (n = 4) were tagged with acoustic transmitters to characterize spatial and temporal trends in their movements and migrations. Of the 44 acoustic transmitters deployed, 18 of the individuals were detected (n = 16 west of the Mississippi River Delta and n = 2 east of the Mississippi River Delta). Tarpon tagged west of the Mississippi River Delta off Texas migrated south in the fall and winter into areas of south Texas and potentially into Mexico, while individuals tagged east of the delta migrated into Florida during the same time period, suggesting the presence of two unique migratory contingents or subpopulations in this region. An improved understanding of the habitat requirements and migratory patterns of tarpon inhabiting the Gulf of Mexico is critically needed by resource managers to assess the vulnerability of each contingent to fishing pressure, and this information will guide multi-state and multi-national conservation efforts to rebuild and sustain tarpon populations.

BackgroundStress during pregnancy is detrimental to maternal health, pregnancy and birth outcomes and various preventive relaxation interventions have been developed. This systematic review and meta-analysis aimed to evaluate their effectiveness in terms of maternal mental health, pregnancy and birth outcomes.MethodThe protocol for this review is published on PROSPERO with registration number CRD42020187443. A systematic search of major databases was conducted. Primary outcomes were maternal mental health problems (stress, anxiety, depression), and pregnancy (gestational age, labour duration, delivery mode) and birth outcomes (birth weight, Apgar score, preterm birth). Randomized controlled trials or quasi-experimental studies were eligible. Meta-analyses using a random-effects model was conducted for outcomes with sufficient data. For other outcomes a narrative review was undertaken.ResultWe reviewed 32 studies comprising 3,979 pregnant women aged 18 to 40 years. Relaxation interventions included yoga, music, Benson relaxation, progressive muscle relaxation (PMR), deep breathing relaxation (BR), guided imagery, mindfulness and hypnosis. Intervention duration ranged from brief experiment (~10 minutes) to 6 months of daily relaxation. Meta-analyses showed relaxation therapy reduced maternal stress (-4.1 points; 95% Confidence Interval (CI): -7.4, -0.9; 9 trials; 1113 participants), anxiety (-5.04 points; 95% CI: -8.2, -1.9; 10 trials; 1965 participants) and depressive symptoms (-2.3 points; 95% CI: -3.4, -1.3; 7 trials; 733 participants). Relaxation has also increased offspring birth weight (80 g, 95% CI: 1, 157; 8 trials; 1239 participants), explained by PMR (165g, 95% CI: 100, 231; 4 trials; 587 participants) in sub-group analysis. In five trials evaluating maternal physiological responses, relaxation therapy optimized blood pressure, heart rate and respiratory rate. Four trials showed relaxation therapy reduced duration of labour. Apgar score only improved significantly in two of six trials. One of three trials showed a significant increase in birth length, and one of three trials showed a significant increase in gestational age. Two of six trials examining delivery mode showed significantly increased spontaneous vaginal delivery and decreased instrumental delivery or cesarean section following a relaxation intervention.DiscussionWe found consistent evidence for beneficial effects of relaxation interventions in reducing maternal stress, improving mental health, and some evidence for improved maternal physiological outcomes. In addition, we found a positive effect of relaxation interventions on birth weight and inconsistent effects on other pregnancy or birth outcomes. High quality adequately powered trials are needed to examine impacts of relaxation interventions on newborns and offspring health outcomes.ConclusionIn addition to benefits for mothers, relaxation interventions provided during pregnancy improved birth weight and hold some promise for improving newborn outcomes; therefore, this approach strongly merits further research.

ObjectivesHeart Failure is a chronic syndrome affecting over 5.7 million in the US and 26 million adults worldwide with nearly 50% experiencing depressive symptoms. The objective of the study is to compare the effects of two evidence-based treatment options for adult patients with depression and advanced heart failure, on depressive symptom severity, physical and mental health related quality of life (HRQoL), heart-failure specific quality of life, caregiver burden, morbidity, and mortality at 3, 6 and 12-months.MethodsTrial design. Pragmatic, randomized, comparative effectiveness trial. Interventions. The treatment interventions are: (1) Behavioral Activation (BA), a patient-centered psychotherapy which emphasizes engagement in enjoyable and valued personalized activities as selected by the patient; or (2) Antidepressant Medication Management administered using the collaborative care model (MEDS). Participants. Adults aged 18 and over with advanced heart failure (defined as New York Heart Association (NYHA) Class II, III, and IV) and depression (defined as a score of 10 or above on the PHQ-9 and confirmed by the MINI International Neuropsychiatric Interview for the DSM-5) selected from all patients at Cedars-Sinai Medical Center who are admitted with heart failure and all patients presenting to the outpatient programs of the Smidt Heart Institute at Cedars-Sinai Medical Center. We plan to randomize 416 patients to BA or MEDS, with an estimated 28% loss to follow-up/inability to collect follow-up data. Thus, we plan to include 150 in each group for a total of 300 participants from which data after randomization will be collected and analyzed.ConclusionsThe current trial is the first to compare the impact of BA and MEDS on depressive symptoms, quality of life, caregiver burden, morbidity, and mortality in patients with depression and advanced heart failure. The trial will provide novel results that will be disseminated and implemented into a wide range of current practice settings.RegistrationClinicalTrials.Gov Identifier: NCT03688100.

Individuals with serious mental illness experience changes in their clinical states over time that are difficult to assess and that result in increased disease burden and care utilization. It is not known if features derived from speech can serve as a transdiagnostic marker of these clinical states. This study evaluates the feasibility of collecting speech samples from people with serious mental illness and explores the potential utility for tracking changes in clinical state over time. Patients (n = 47) were recruited from a community-based mental health clinic with diagnoses of bipolar disorder, major depressive disorder, schizophrenia or schizoaffective disorder. Patients used an interactive voice response system for at least 4 months to provide speech samples. Clinic providers (n = 13) reviewed responses and provided global assessment ratings. We computed features of speech and used machine learning to create models of outcome measures trained using either population data or an individual's own data over time. The system was feasible to use, recording 1101 phone calls and 117 hours of speech. Most (92%) of the patients agreed that it was easy to use. The individually-trained models demonstrated the highest correlation with provider ratings (rho = 0.78, p

ObjectiveA scoping review of studies published in the first year of the COVID-19 pandemic focused on individuals with pre-existing symptoms of depression, anxiety, and specified stressor-related disorders, with the objective of mapping the research conducted.Eligibility criteria(1) direct study of individuals with pre-existing depressive, anxiety, and/or specified stressor-related (i.e., posttraumatic stress, acute stress) disorders/issues; (2) focus on mental health-related pandemic effects, and; (3) direct study of mental health symptoms related to depression, anxiety, or psychological distress.Sources of evidenceDatabase-specific subject headings and natural language keywords were searched in Medline, Embase, APA PsycInfo, and Cumulative Index to Nursing & Allied Health Literature (CINAHL) up to March 3, 2021. Review of potentially relevant studies was conducted by two independent reviewers and proceeded in two stages: (1) title and abstract review, and; (2) full paper review.Data chartingStudy details (i.e., location, design and methodology, sample or population, outcome measures, and key findings) were extracted from included studies by one reviewer and confirmed by the Principal Investigator.Results66 relevant articles from 26 countries were identified. Most studies adopted a cross-sectional design and were conducted via online survey. About half relied on general population samples, with the remainder assessing special populations, primarily mental health patients. The most commonly reported pre-existing category of disorders or symptoms was depression, followed closely by anxiety. Most studies included depressive and anxiety symptoms as outcome measures and demonstrated increased vulnerability to mental health symptoms among individuals with a pre-existing mental health issue.ConclusionThese findings suggest that improved mental health supports are needed during the pandemic and point to future research needs, including reviews of other diagnostic categories and reviews of research published in subsequent years of the pandemic.

The recall of a distant memory may appear satisfying and suggest successful retrieval is inherently rewarding. If the brain incentivizes retrieval attempts on the prospect of an internal retrieval reward, then the desire for that reward might natively reinforce declarative memory access. But what determines the level of retrieval satisfaction? We tested the idea that retrieval attempt uncertainty drives retrieval satisfaction. For instance, the more distant the memory, the more satisfying should it be to successfully retrieve it. Alternatively, the brain issues rewards based on the level of confidence in recall independent of the recall achievement. If so, then more confident retrieval is also more satisfying. In an online experiment containing five Swahili-English word pair study sessions spaced across one week, we tested 30 English-speaking participants' recall satisfaction and memory confidence during learning as well as in a final cued recall test. We hypothesized that retrieval satisfaction should either increase or decrease with retrieval uncertainty as indicated by time since encoding, and how little in overall they recalled from the session. We found that retrieval satisfaction decreased with time since encoding and with study session retrieval performance. Moreover, we found that retrieval confidence and satisfaction ratings were highly related in the experiment. We also found a reliable interaction between confidence and word difficulty indicating that confidently recalled difficult items induced more satisfaction. Thus, the brain appears to reward both retrieval confidence and to a lesser extent, fruitful retrieval effort. Our findings may explain seemingly irrational self-regulated study behavior such as avoiding learning-efficient but difficult training protocols, as effects of a system rationally seeking to accrue intrinsic cognitive reward.

Overdoses are increasing in the province of Ontario, Canada, where northern communities such as Sudbury have witnessed disproportionately elevated rates, with opioid-related deaths double that of the provincial average. To address this issue, governments have implemented supervised consumption services (SCS) where people who use drugs (PWUD) can use their pre-obtained substances onsite under trained supervision. In September 2022, the city of Sudbury opened its first SCS, 'The Spot', but the site's sustainability is contingent on demonstrating benefit to PWUD and the neighboring community. We undertook a qualitative study exploring experiences among clients who used the consumption service inside The Spot. In December 2022, clients of The Spot were invited to participate in a brief survey which collected socio-demographic information and substance use profiles, followed by an in-person semi-structured qualitative interview. Participant survey and interview data were combined with administrative site utilization data provided by site staff of all clients who accessed the consumption service from September 2022 to August 2023 to examine overall service utilization and uptake. Qualitative data were analyzed using iterative thematic analysis techniques, and results were informed by common responses to research questions. The responses were narratively presented. Administrative site utilization data highlighted a relatively stable increase in uptake and utilization of the site since its inception. A total of 20 clients participated in the survey and semi-structured interviews. Participants described the importance of the site in preventing and responding to overdoses, providing a safe and comfortable environment to consume their drugs, and decreasing public drug use, which they suggested may potentially reduce stigmatization in the community. However, clients also suggested challenges, including issues regarding site operational policies that hindered consumption room utilization. Service suggestions made by clients to improve site utilization include the addition of inhalation services, relocating the site to a location in downtown Sudbury where PWUD commonly congregate, and extending operational hours. Positive impacts and recommendations can be drawn on and considered by other northern or rural communities interested in implementing similar harm reduction services.

Climate change and climate variability are affecting marine mammal species and these impacts are projected to continue in the coming decades. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species using currently available information. We conducted a trait-based climate vulnerability assessment using expert elicitation for 108 marine mammal stocks and stock groups in the western North Atlantic, Gulf of Mexico, and Caribbean Sea. Our approach combined the exposure (projected change in environmental conditions) and sensitivity (ability to tolerate and adapt to changing conditions) of marine mammal stocks to estimate vulnerability to climate change, and categorize stocks with a vulnerability index. The climate vulnerability score was very high for 44% (n = 47) of these stocks, high for 29% (n = 31), moderate for 20% (n = 22), and low for 7% (n = 8). The majority of stocks (n = 78; 72%) scored very high exposure, whereas 24% (n = 26) scored high, and 4% (n = 4) scored moderate. The sensitivity score was very high for 33% (n = 36) of these stocks, high for 18% (n = 19), moderate for 34% (n = 37), and low for 15% (n = 16). Vulnerability results were summarized for stocks in five taxonomic groups: pinnipeds (n = 4; 25% high, 75% moderate), mysticetes (n = 7; 29% very high, 57% high, 14% moderate), ziphiids (n = 8; 13% very high, 50% high, 38% moderate), delphinids (n = 84; 52% very high, 23% high, 15% moderate, 10% low), and other odontocetes (n = 5; 60% high, 40% moderate). Factors including temperature, ocean pH, and dissolved oxygen were the primary drivers of high climate exposure, with effects mediated through prey and habitat parameters. We quantified sources of uncertainty by bootstrapping vulnerability scores, conducting leave-one-out analyses of individual attributes and individual scorers, and through scoring data quality for each attribute. These results provide information for researchers, managers, and the public on marine mammal responses to climate change to enhance the development of more effective marine mammal management, restoration, and conservation activities that address current and future environmental variation and biological responses due to climate change.

IntroductionWe developed the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox to address the shortage of school-age assessment tools that combine growth, physical and cognitive function. Here we present i) development, acceptability and feasibility of the SAHARAN toolbox; ii) characteristics of a pilot cohort; and iii) associations between the domains measured in the cohort.MethodsGrowth was measured with anthropometry, knee-heel length and skinfold thicknesses. Bioimpedance analysis measured lean mass index and phase angle. Cognition was assessed using the mental processing index, derived from the Kaufman Assessment Battery for Children version 2, a fine motor finger-tapping task, and School Achievement Test (SAT). Physical function combined grip strength, broad jump and the 20m shuttle-run test to produce a total physical score. A caregiver questionnaire was performed in parallel.ResultsThe SAHARAN toolbox was feasible to implement in rural Zimbabwe, and highly acceptable to children and caregivers following some minor modifications. Eighty children with mean (SD) age 7.6 (0.2) years had mean height-for-age (HAZ) and weight-for-age Z-scores (WAZ) of -0.63 (0.81) and -0.55 (0.85), respectively. Lean mass index and total skinfold thicknesses were related to WAZ and BMI Z-score, but not to HAZ. Total physical score was associated with unit rises in HAZ (1.29, 95% CI 0.75, 1.82, pConclusionsThe SAHARAN toolbox provided a feasible and acceptable holistic assessment of child growth and function in mid-childhood. We found clear associations between growth, height-adjusted lean mass and physical function, but not cognitive function. The SAHARAN toolbox could be deployed to characterise school-age growth, development and function elsewhere in sub-Saharan Africa.

BackgroundOzone (O3) exposure causes respiratory effects including lung function decrements, increased lung permeability, and airway inflammation. Additionally, baseline metabolic state can predispose individuals to adverse health effects from O3. For this reason, we conducted an exploratory study to examine the effect of O3 exposure on derivatives of cholesterol biosynthesis: sterols, oxysterols, and secosteroid (25-hydroxyvitamin D) not only in the lung, but also in circulation.MethodsWe obtained plasma and induced sputum samples from non-asthmatic (n = 12) and asthmatic (n = 12) adult volunteers 6 hours following exposure to 0.4ppm O3 for 2 hours. We quantified the concentrations of 24 cholesterol precursors and derivatives by UPLC-MS and 30 cytokines by ELISA. We use computational analyses including machine learning to determine whether baseline plasma sterols are predictive of O3 responsiveness.ResultsWe observed an overall decrease in the concentration of cholesterol precursors and derivatives (e.g. 27-hydroxycholesterol) and an increase in concentration of autooxidation products (e.g. secosterol-B) in sputum samples. In plasma, we saw a significant increase in the concentration of secosterol-B after O3 exposure. Machine learning algorithms showed that plasma cholesterol was a top predictor of O3 responder status based on decrease in FEV1 (>5%). Further, 25-hydroxyvitamin D was positively associated with lung function in non-asthmatic subjects and with sputum uteroglobin, whereas it was inversely associated with sputum myeloperoxidase and neutrophil counts.ConclusionThis study highlights alterations in sterol metabolites in the airway and circulation as potential contributors to systemic health outcomes and predictors of pulmonary and inflammatory responsiveness following O3 exposure.

Axl, a member of the TAM receptor family has been broadly suggested to play a key role in tumor metastasis. However, the function of Axl in the invasion and metastasis of melanoma, the most lethal skin cancer, remains largely unknown. In the present study, we found that melanoma cell lines present variable protein levels of Axl and Tyro3; interestingly, MerTK is not noted at detectable levels in any of tested MGP (metastatic growth phase) cell lines. Treatment with recombinant human Gas6 significantly activates Akt in the Axl-expressing WM852 and IgR3 lines but just slightly in WM1158. IgR3, WM852 and WM1158 demonstrate different autocrine signaling. Knockdown of Axl by siRNA or the treatment with Axl-specific inhibitor R428 dramatically inhibits the migration and invasion of both IgR3 and WM852 in vitro. These findings suggest that Axl enhances the invasion of melanoma cells.

Prostate specific membrane antigen (PSMA)-based radiotracers have shown promise for prostate cancer assessment. Evaluation of quantitative variability and establishment of reference standards are important for optimal clinical and research utility. This work evaluates the variability of PSMA-based [18F]DCFPyL (PyL) PET quantitative reference standards. Consecutive eligible patients with biochemically recurrent prostate cancer were recruited for study participation from August 2016-October 2017. After PyL tracer injection, whole body PET/CT (wbPET/CT) was obtained with subsequent whole body PET/MR (wbPET/MR). Two readers independently created regions of interest (ROIs) including a 40% standardized uptake value (SUV) threshold ROI of the whole right parotid gland and separate spherical ROIs in the superior, mid, and inferior gland. Additional liver (right lobe) and blood pool spherical ROIs were defined. Bland-Altman analysis, including limits of agreement (LOA), as well as interquartile range (IQR) and coefficient of variance (CoV) was used. Twelve patients with prostate cancer were recruited (mean age, 61.8 yrs; range 54-72 years). One patient did not have wbPET/MR and was excluded. There was minimal inter-reader SUVmean variability (bias±LOA) for blood pool (-0.13±0.42; 0.01±0.41), liver (-0.55±0.82; -0.22±1.3), or whole parotid gland (-0.05±0.31; 0.08±0.24) for wbPET/CT and wbPET/MR, respectively. Greater inter-reader variability for the 1-cm parotid gland ROIs was present, for both wbPET/CT and wbPET/MR. Comparing wbPET/CT to the subsequently acquired wbPET/MR, blood pool had a slight decrease in SUVmean. The liver as well as parotid gland showed a slight increase in activity although the absolute bias only ranged from 0.45-1.28. The magnitude of inter-subject variability was higher for the parotid gland regardless of modality or reader. In conclusion, liver, blood pool, and whole parotid gland quantitation show promise as reliable reference normal organs for clinical/research PET applications. Variability with 1-cm parotid ROIs may limit its use.

Microalgae accumulate lipids in response to nutrient deprivation, and these lipids are a biodiesel fuel stock. Algal cultivation with secondary wastewater effluent is one proposed platform for biofuel production, which provides nutrients to algae while further polishing wastewater effluent. Algal bioreactors were tested using a feast-famine feeding regiment in simulated secondary wastewater effluent to evaluate the effects on lipid content and algal community structure. Algal polycultures were inoculated into reactors fed with synthetic secondary wastewater effluent at pH 7.5 and 9 and operated under a feast-famine nutrient (N, P, and BOD) supply regime in sequencing batch reactors. Fatty acid methyl ester contents of the reactors were assessed, which showed a decrease in lipid content after the feast-famine cycling (from 12.2% initially to 5.2% after four cycles at pH 9). This decrease in lipid content was not correlated with an increase in carbohydrate storage within biomass, nor an increase in bacterial biomass abundance relative to algal biomass in the reactors. The eukaryotic microbial communities from reactors operated at pH 9 diverged from reactors operated at pH 7.5 during cycling, with the pH 9 reactors becoming dominated by a single Operational Taxonomic Unit aligning to the Scenedesmus genus. These results suggest that high pH and feast-famine nutrient cycling may select for a less diverse algal community with a lower lipid content within a secondary wastewater polishing scheme.

The practice of catch and release fishing is common among anglers but has been shown to cause unintended mortalities in some species. Current post-release mortality estimates used in coastal shark stock assessments are typically derived from boat-based shark fisheries, which differ from shore-based operations that expose sharks to potentially more stressful environmental and handling conditions. Recreational post-release mortality rates in shore-based fisheries must be quantified to improve stock assessment models and to create guidelines that protect species from overexploitation. Here, we partnered with experienced anglers acting as citizen scientists to deploy pop-up satellite archival transmitting tags (PSAT, n = 22) and acceleration data loggers (ADLs, n = 22). on four commonly caught sharks including the blacktip shark (Carcharhinus limbatus, n = 11), bull shark (Carcharhinus leucas, n = 14), tiger shark (Galeocerdo cuvier, n = 6), and great hammerheads (Sphyrna mokarran, n = 2). Mortality occurred within minutes to hours post-release. If evidence of mortality occurred after normal diving behavior had been re-established for 10 days, then the mortality was considered natural and not related to the catch-and-release process. Post-release mortality estimates ranged from 0% for bull and tiger sharks to 45.5% for blacktip sharks. Of the two great hammerheads, one died within 30 minutes post-release while the other exhibited mortality characteristics 14 days after release. Moribund blacktip sharks experienced on average 3.4-4.9°C warmer water compared with survivors. Recovery periods were estimated for survivors of each species and were highly variable, differing based on duration of tag deployment. High variability in responses to capture and release between species demonstrates the need for species-specific assessments of post-release mortality in shore-based recreational fisheries.

The Sweepstakes, in Fathom Five National Marine Park, is Ontario's most iconic shipwreck with over 100,000 visitors each summer. Continued exposure to water currents has directly and indirectly affected the integrity of the wreck and resulted in management interventions including efforts to stabilize the wreck and control vessel activity (both duration and speed). Despite these efforts, a scour ring is present in the sediment around the Sweepstakes, raising concerns regarding the prolonged stability of the wreck. An extensive series of field measurements were made during the summer of 2015 with the aim of differentiating between natural hydrological processes present at this site and human-derived water movements during the summer visitor season. There is a high-degree of natural current variability from processes as diverse as wind-induced surface gravity waves, internal gravity waves, and diurnal flows due to differential heating. Our results show that summer circulation driven by internal gravity waves derived from upwelling, surface waves, and differential heating was insignificant with respect to sediment resuspension and thus unlikely to produce the observed scour around the shipwreck. Scour is most likely caused by energetic winter storms, which should be a focus of future studies. While vessel induced currents were detectable at the shipwreck, they were no larger than the normal summer hydrodynamic variability, thus suggesting that management efforts continue to protect the site generally.

Patients face numerous health-related decisions once advanced chronic kidney disease (CKD) is diagnosed. Yet, when patients are underprepared to navigate and discuss health-related decisions, they can make choices inconsistent with their expectations for the future. This pilot study, guided by the multiphase optimization strategy and community-engaged research principles, aimed to explore the acceptability of a developed patient component to a decision-support training intervention called ImPart (Improving Decisional Partnership of CKD Dyads). CKD patients and their family caregivers were recruited from an urban, academic medical center. Eligibility criteria for patients included a diagnosis of stage 3 or higher CKD (on chart review), and caregivers participated in interview sessions only. Patients without a caregiver were not eligible. The intervention was lay coach, telephone-delivered, and designed to be administered in 1–2 week intervals for 4 sessions. An interview guide, developed in collaboration with an advisory group, was designed to ascertain participants' experiences with the intervention. Caregiver interviews focused on changes in the patient's decision ability or engagement. Thirteen patients and eleven caregivers were interviewed. The program was viewed as "good" or "beneficial." Three themes capture the intervention's impact– 1) Frequent and deliberate disease-focused communication, 2) Future planning activation, and 3) Coaching relationship. The piloted intervention was successfully delivered, acceptable to use, and found to promote enhanced disease and future planning communication. By undergoing this work, we ensure that the patient component is feasible to use and meets the needs of participants before implementation in a larger factorial trial. [ABSTRACT FROM AUTHOR]

IntroductionExposure to nature may reduce stress in low-income parents. This prospective randomized trial compares the effect of a physician's counseling about nature with or without facilitated group outings on stress and other outcomes among low-income parents.Materials and methodsParents of patients aged 4-18 years at a clinic serving low-income families were randomized to a supported park prescription versus independent park prescription in a 2:1 ratio. Parents in both groups received physician counseling about nature, maps of local parks, a journal, and pedometer. The supported group received additional phone and text reminders to attend three weekly family nature outings with free transportation, food, and programming. Outcomes measured in parents at baseline, one month and three months post-enrollment included: stress (using the 40-point Perceived Stress Scale [PSS10]); park visits per week (self-report and journaling); loneliness (modified UCLA-Loneliness Scale); physical activity (self-report, journaling, pedometry); physiologic stress (salivary cortisol); and nature affinity (validated scale).ResultsWe enrolled 78 parents, 50 in the supported and 28 in the independent group. One-month follow-up was available for 60 (77%) participants and three-month follow up for 65 (83%). Overall stress decreased by 1.71 points (95% CI, -3.15, -0.26). The improvement in stress did not differ significantly by group assignment, although the independent group had more park visits per week (mean difference 1.75; 95% CI [0.46, 3.04], p = 0.0085). In multivariable analysis, each unit increase in park visits per week was associated with a significant and incremental decrease in stress (change in PSS10-0.53; 95% CI [-0.89, -0.16]; p = 0.005) at three months.ConclusionWhile we were unable to demonstrate the additional benefit of group park visits, we observed an overall decrease in parental stress both overall and as a function of numbers of park visits per week. Paradoxically the park prescription without group park visits led to a greater increase in weekly park visits than the group visits. To understand the benefits of this intervention, larger trials are needed.Trial registrationClinicalTrials.gov NCT02623855.

Introduction: Chemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global level continues to grow. Because resources are constrained, there is a need to prioritize interventions focused on the greatest health impact. Data, especially related to chemical exposures, are rarely available for most substances of concern, and alternate methods to evaluate their impact are needed. Structured expert judgment (SEJ) process: A Structured Expert Judgment (Research Outreach, 2021) process was performed to provide plausible estimates of health impacts for 16 commonly found pollutants: asbestos, arsenic, benzene, chromium, cadmium, dioxins, fluoride, highly hazardous pesticides (HHPs), lead, mercury, polycyclic-aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Per- and Polyfluorinated Substances (PFAs), phthalates, endocrine disrupting chemicals (EDCs), and brominated flame retardants (BRFs). This process, undertaken by sector experts, weighed individual estimations of the probable global health scale health impacts of each pollutant using objective estimates of the expert opinions' statistical accuracy and informativeness. Main findings: The foremost substances, in terms of mean projected annual total deaths, were lead, asbestos, arsenic, and HHPs. Lead surpasses the others by a large margin, with an estimated median value of 1.7 million deaths annually. The three other substances averaged between 136,000 and 274,000 deaths per year. Of the 12 other chemicals evaluated, none reached an estimated annual death count exceeding 100,000. These findings underscore the importance of prioritizing available resources on reducing and remediating the impacts of these key pollutants. Range of health impacts: Based on the evidence available, experts concluded some of the more notorious chemical pollutants, such as PCBs and dioxin, do not result in high levels of human health impact from a global scale perspective. However, the chemical toxicity of some compounds released in recent decades, such as Endocrine Disrupters and PFAs, cannot be ignored, even if current impacts are limited. Moreover, the impact of some chemicals may be disproportionately large in some geographic areas. Continued research and monitoring are essential; and a preventative approach is needed for chemicals. Future directions: These results, and potential similar analyses of other chemicals, are provided as inputs to ongoing discussions about priority setting for global chemicals and pollution management. Furthermore, we suggest that this SEJ process be repeated periodically as new information becomes available. [ABSTRACT FROM AUTHOR]

Biliary atresia is a neonatal disease characterized by damage, inflammation, and fibrosis of the liver and bile ducts and by abnormal bile metabolism. It likely results from a prenatal environmental exposure that spares the mother and affects the fetus. Our aim was to develop a model of fetal injury by exposing pregnant mice to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock, and then to determine whether there was a hepatobiliary phenotype in their pups. Pregnant mice were treated orally with 15 mg/kg/d biliatresone for 2 days. Histology of the liver and bile ducts, serum bile acids, and liver immune cells of pups from treated mothers were analyzed at P5 and P21. Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal. However, serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at P21. These results suggest that prenatal exposure to low doses of an environmental toxin can cause subclinical disease including liver inflammation and aberrant bile metabolism even in the absence of histological changes. This finding suggests a wide potential spectrum of disease after fetal biliary injury. [ABSTRACT FROM AUTHOR]

ObjectivesThe aims of this study were to explore individuals' experiences of contributing to health research and to identify the types of impact that are perceived as important by participants or patient and public advisors. Specifically, research led by NMAHPP clinicians (Nursing, Midwifery, Allied health professions, Healthcare science, Psychology and Pharmacy).MethodsSemi-structured one-to-one interviews were conducted with health research participants and patient or public advisors. Interviewees were recruited from five UK sites and via social media. Interview transcripts were analysed using Thematic Analysis to identify key themes and areas of disagreement.ResultsTwenty-one interviews were completed, and four main themes were identified. The first, optimising research experiences, included personal reflections and broader recommendations to improve participant experiences. The second, connecting health research with healthcare, described research as key for the continued development of healthcare, but illustrated that communication between research teams, participants, and clinicians could be improved. The third theme explored the personal impacts of contributing to research, with interviewees recalling common positive experiences. The final theme discussed capturing research impacts. Interviewees highlighted potential priorities for different stakeholders, but emphasised that financial impacts should not be the sole factor.ConclusionIndividuals who were involved in NMAHPP health research recalled positive experiences and reported good relationships with their research teams. They felt that their contributions were valued. Suggested strategies to optimise the research experience focused on simplifying documentation, clear signposting of the research activities involved, and feedback on the research findings. Routine sharing of relevant research data with clinicians was also recommended. Personal impacts included a deeper understanding of their health condition or health more broadly, and increased confidence interacting with healthcare and other professionals. These findings will be used to inform development of a framework to capture the impact of NMAHPP research.

ObjectiveThe Stress Management and Resilience Training (SMART) program is an evidence-based intervention designed to build resilience in physicians in clinical practice. The objective of the current study was to assess the impact of the SMART program on academic physicians' levels of resilience, subjective happiness, stress, and anxiety, and specifically during the implementation of a new hospital-wide Health Information System (HIS).MethodsA total of 40 physicians in a tertiary care academic hospital were randomized (allocation ratio 1:1) to either the SMART intervention or the control condition. The SMART intervention consisted of one mandatory two-hour in-person workshop and an optional 24-week online program, designed to support the materials delivered in the workshop. Outcome measures were assessed using validated scales administered online at baseline and at 3-months and 6-months follow-up.ResultsAfter adjusting for baseline levels of each outcome, no statistically significant intervention effect was observed for resilience, subjective happiness, stress or anxiety at 3-months or 6-months follow-up. However, physicians in the intervention group demonstrated improvements in resilience, stress and anxiety at follow-up that were within the range of clinically relevant differences.ConclusionsThe findings of this exploratory study provide modest support that the SMART intervention may be beneficial for proactively addressing physician wellness during the implementation of a new HIS and that larger randomized trials are warranted.Trial registrationNCT04384861.

Introduction Bile duct integrity is essential for the maintenance of the structure and function of the biliary tree. We previously showed that cholangiocyte injury in a toxic model of biliary atresia leads to increased monolayer permeability. Increased epithelial permeability was also shown in other cholangiopathies. We hypothesized that after initial cholangiocyte injury, leakage of bile acids into the duct submucosa propagates cholangiocyte damage and fibrosis. We thus aimed to determine the impact of bile acid exposure on cholangiocytes and the potential therapeutic effect of a non-toxic bile acid. Materials and methods Extrahepatic bile duct explants were isolated from adult and neonatal BALB/c mice. Explants were cultured with or without glycochenodeoxycholic acid and ursodeoxycholic acid. They were then fixed and stained. Results Explants treated with glycochenodeoxycholic acid demonstrated cholangiocyte injury with monolayer disruption and partial lumen obstruction compared to control ducts. Masson’s trichrome stains revealed increased collagen fibers. Myofibroblast marker α-SMA stains were significantly elevated in the periductal region. The addition of ursodeoxycholic acid resulted in decreased cholangiocyte injury and reduced fibrosis. Conclusions Bile acid leakage into the submucosa after initial cholangiocyte injury may serve as a possible mechanism of disease propagation and progressive fibrosis in cholangiopathies.

BackgroundAdvances in detection techniques and treatment have increased the diagnosis of breast cancer at early stages; however, recurrence occurs in all breast cancer subtypes, and both recurrent and de novo metastasis are typically treatment resistant. A growing body of evidence supports the notion that metabolic plasticity drives cancer recurrence. RON and DEK are proteins that promote cancer metastasis and synergize mechanistically to activate β-catenin, but the metabolic consequences are unknown.MethodsTo ascertain RON-DEK-β-catenin dependent metabolic pathways, we utilized an NMR-based metabolomics approach to determine steady state levels of metabolites. We also interrogated altered metabolic pathway gene expression for prognostic capacity in breast cancer patient relapse-free and distant metastasis-free survival and discover a metabolic signature that is likely associated with recurrence.ResultsRON-DEK-β-catenin loss showed a consistent metabolite regulation of succinate and phosphocreatine. Consistent metabolite alterations between RON and DEK loss (but not β-catenin) were found in media glucose consumption, lactate secretion, acetate secretion, and intracellular glutamine and glutathione levels. Consistent metabolite alterations between RON and β-catenin loss (and not DEK) were found only in intracellular lactate levels. Further pathway hits include β-catenin include glycolysis, glycosylation, TCA cycle/anaplerosis, NAD+ production, and creatine dynamics. Genes in these pathways epistatic to RON-DEK-β-catenin were used to define a gene signature that prognosticates breast cancer patient survival and response to chemotherapy.ConclusionsThe RON-DEK-β-catenin axis regulates the numerous metabolic pathways with significant associations to breast cancer patient outcomes.

Following the 2010 Deepwater Horizon disaster and subsequent unusual mortality event, adverse health impacts have been reported in bottlenose dolphins in Barataria Bay, LA including impaired stress response and reproductive, pulmonary, cardiac, and immune function. These conditions were primarily diagnosed through hands-on veterinary examinations and analysis of standard diagnostic panels. In human and veterinary medicine, gene expression profiling has been used to identify molecular mechanisms underlying toxic responses and disease states. Identification of molecular markers of exposure or disease may enable earlier detection of health effects or allow for health evaluation when the use of specialized methodologies is not feasible. To date this powerful tool has not been applied to augment the veterinary data collected concurrently during dolphin health assessments. This study examined transcriptomic profiles of blood from 76 dolphins sampled in health assessments during 2013-2018 in the waters near Barataria Bay, LA and Sarasota Bay, FL. Gene expression was analyzed in conjunction with the substantial suite of health data collected using principal component analysis, differential expression testing, over-representation analysis, and weighted gene co-expression network analysis. Broadly, transcript profiles of Barataria Bay dolphins indicated a shift in immune response, cytoskeletal alterations, and mitochondrial dysfunction, most pronounced in dolphins likely exposed to Deepwater Horizon oiling. While gene expression profiles in Barataria Bay dolphins were altered compared to Sarasota Bay for all years, profiles from 2013 exhibited the greatest alteration in gene expression. Differentially expressed transcripts included genes involved in immunity, inflammation, reproductive failure, and lung or cardiac dysfunction, all of which have been documented in dolphins from Barataria Bay following the Deepwater Horizon oil spill. The genes and pathways identified in this study may, with additional research and validation, prove useful as molecular markers of exposure or disease to assist wildlife veterinarians in evaluating the health of dolphins and other cetaceans.

Reward based learning is broadly acknowledged to underpin the development and maintenance of addictive behaviour although the mechanism in sexual compulsivity is less understood. Using a Pavlovian-to-Instrumental Transfer (PIT) task we tested whether the motivational aspect of conditioned Pavlovian conditioned stimulus invigorated instrumental responding in relation to specific compatible monetary rewards. Performance on the task was analysed between two groups of males based on Low (N = 38) and High (N = 41) self-report online sexual behaviour (OSB). Psychometric tests including sexual compulsivity scale and behavioural activation/behavioural inhibition (BIS/BAS) were also administered to determine the relationship between OSB and general reward sensitivity. We show clear evidence of acquisition in the Pavlovian and instrumental conditioning phases. Specific transfer effect was greater in the High-OSB group although the difference compared to the Low-OSB group was non-significant. OSB negatively correlated with both BIS and BAS indicative of introversion and low reward sensitivity. OSB positively correlated with sexual compulsivity although it is unclear whether individuals in the High-OSB group considered their behaviour either excessive or problematic. These findings contribute to the ongoing debate regarding the nature of problematic OSB. Fundamental differences in motivational characteristics and mechanism contributing to compulsive behaviour in relation to high-OSB might indicate incompatibility with behavioural addiction models. PIT was not enhanced in high-OSB by appetitive conditioning, although problematic OSB could stem from failure to inhibit actions. Further research should investigate whether aversive conditioning differentially affects responding in high-OSB individuals, potentially explaining perseverant behaviour despite negative consequences.

Introduction Safe spaces are an alternative to emergency departments, which are often unable to provide optimum care for people experiencing emotional distress and/or suicidal crisis. At present, there are several different safe space models being trialled in Australia. However, research examining the effectiveness of safe space models, especially in community settings, is rare. In this paper, we present a protocol for a study in which we will investigate the implementation, effectiveness, and sustainability of safe space models as genuine alternatives for people who might usually present to the emergency department or choose not to access help due to past negative experiences. Material and methods We will use a mixed methods, co-designed study design, conducted according to the principles of community-based participatory research to obtain deep insights into the benefits of different safe space models, potential challenges, and facilitators of effective practice. We developed the study plan and evaluation framework using the RE-AIM framework, and this will be used to assess key outcomes related to reach, effectiveness, adoption, implementation, and maintenance. Data collection will comprise quantitative measures on access, use, satisfaction, (cost) effectiveness, distress, and suicidal ideation; and qualitative assessments of service implementation, experience, feasibility, acceptability, community awareness, and the fidelity of the models to service co-design. Data will be collected and analysed concurrently throughout the trial period of the initiatives. Discussion This study will enable an extensive investigation of safe spaces that will inform local delivery and provide a broader understanding of the key features of safe spaces as acceptable and effective alternatives to hospital-based care for people experiencing emotional distress and/or suicidal crisis. This study will also contribute to a growing body of research on the role and benefits of peer support and provide critical new knowledge on the successes and challenges of service co-design to inform future practice.

The microbiota gut-brain-axis is a bidirectional circuit that links the neural, endocrine, and immunological systems with gut microbial communities. The gut microbiome plays significant roles in human mind and behavior, specifically pain perception, learning capacity, memory, and temperament. Studies have shown that disruptions in the gut microbiota have been associated with substance use disorders. The interplay of gut microbiota in substance abuse disorders has not been elucidated; however, postmortem microbiome profiles may produce promising avenues for future forensic investigations. The goal of the current study was to determine gut microbiome composition in substance abuse disorder cases using transverse colon tissues of 21 drug overdose versus 19 non-overdose-related cases. We hypothesized that postmortem samples of the same cause of death will reveal similar microbial taxonomic relationships. We compared microbial diversity profiles using amplicon-based sequencing of the 16S rRNA gene V4 hypervariable region. The results demonstrated that the microbial abundance in younger-aged cases were found to have significantly more operational taxonomic units than older cases. Using weighted UniFrac analysis, the influence of substances in overdose cases was found to be a significant factor in determining microbiome similarity. The results also revealed that samples of the same cause of death cluster together, showing a high degree of similarity between samples and a low degree of similarity among samples of different causes of death. In conclusion, our examination of human transverse colon microflora in decomposing remains extends emerging literature on postmortem microbial communities, which will ultimately contribute to advanced knowledge of human putrefaction.

Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are increased in the lungs of rat pups raised in hyperoxia, an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in hyperoxia rat pups. We treated Sprague-Dawley rat pups with tunicamycin or hyperoxia to determine this relationship. ER stress was detected using immunofluorescence, transcriptomic, proteomic, and electron microscopic analyses. Immunofluorescence observed increased ER stress in the lungs of hyperoxic rat BPD and human BPD. Proteomic and morphometric studies showed that tunicamycin directly increased ER stress of rat lungs and decreased lung complexity with a BPD phenotype. Previously, we showed that hyperoxia initiates a cycle of destruction that we hypothesized starts from increasing OS through MPO accumulation and then increases ER stress to cause BPD. To inhibit ER stress, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO, we used N-acetyl-lysyltyrosylcysteine amide (KYC). The fact that TUDCA improved lung complexity in tunicamycin- and hyperoxia-treated rat pups supports the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of tunicamycin- and hyperoxia-treated rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC's inhibition of ER stress in the tunicamycin-treated rat pup's lung provides additional support for the idea that MPO-induced ER stress plays a causal role in the BPD phenotype. ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impair growth and development. The encouraging effect of TUDCA indicates that this compound has the potential for treating BPD.

In recent years, 3D in vitro modeling of human skeletal muscle has emerged as a subject of increasing interest, due to its applicability in basic studies or screening platforms. These models strive to recapitulate key features of muscle architecture and function, such as cell alignment, maturation, and contractility in response to different stimuli. To this end, it is required to culture cells in biomimetic hydrogels suspended between two anchors. Currently available protocols are often complex to produce, have a high rate of breakage, or are not adapted to imaging and stimulation. Therefore, we sought to develop a simplified and reliable protocol, which still enabled versatility in the study of muscle function. In our method, we have used human immortalized myoblasts cultured in a hydrogel composed of MatrigelTM and fibrinogen, to create muscle strips suspended between two VELCROTM anchors. The resulting muscle constructs show a differentiated phenotype and contractile activity in response to electrical, chemical and optical stimulation. This activity is analyzed by two alternative methods, namely contraction analysis and calcium analysis with Fluo-4 AM. In all, our protocol provides an optimized version of previously published methods, enabling individual imaging of muscle bundles and straightforward analysis of muscle response with standard image analysis software. This system provides a start-to-finish guide on how to produce, validate, stimulate, and analyze bioengineered muscle. This ensures that the system can be quickly established by researchers with varying degrees of expertise, while maintaining reliability and similarity to native muscle.

In Australia, telehealth is not new, with several telehealth specialist services being available for those living in rural and remote communities. However, prior to the COVID-19 pandemic, telehealth was not routinely available for primary care or urban specialist appointments. There has been an increased focus in the use of telehealth within primary care, and particularly general practice, but overall, there has been limited research to date to guide telehealth best-practice based on consumer experiences and preferences within these settings. We aimed to capture the consumer experience of telehealth during the COVID-19 pandemic, through a novel Kitchen Table Discussion (KTD) method. This increases access to a broader community consumer cohort, with consumer hosts leading discussions in a safe environment. The KTDs were conducted in May 2021, with 10 community members each hosting a group of up to 10 participants. A total of 90 participants took part from across Australia, with the majority living in major cities, although a significant proportion lived in inner and outer regional areas of Australia, or had experience living in rural, regional or remote areas. Seventy percent of participants reported using telehealth in the past. Data were analysed sequentially using thematic analysis and identified key themes: modality, convenience, access, wait time, existing relationship, communication, connectivity, cost, and privacy. Overall, the future of telehealth looks hopeful from the perspective of the consumer, but significant improvements are required to improve consumer engagement and experience. It is evident that 'one size does not fit all', with results suggesting consumers value the availability of telehealth and having choice and flexibility to use telehealth when appropriate, but do not want to see telehealth replacing face-to-face delivery. Participants tended to agree that telehealth was not a preferred method when physical examination was required but would suit certain points of the patient journey.

We performed whole genome sequencing on SARS-CoV-2 from 59 vaccinated individuals from southwest Pennsylvania who tested positive between February and September, 2021. A comparison of mutations among vaccine breakthrough cases to a time-matched control group identified potential adaptive responses of SARS-CoV-2 to vaccination.

BackgroundGenome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.MethodsWe performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.ResultsThe overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.ConclusionsIn this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Background: Stress during pregnancy is detrimental to maternal health, pregnancy and birth outcomes and various preventive relaxation interventions have been developed. This systematic review and meta-analysis aimed to evaluate their effectiveness in terms of maternal mental health, pregnancy and birth outcomes. Method: The protocol for this review is published on PROSPERO with registration number CRD42020187443. A systematic search of major databases was conducted. Primary outcomes were maternal mental health problems (stress, anxiety, depression), and pregnancy (gestational age, labour duration, delivery mode) and birth outcomes (birth weight, Apgar score, preterm birth). Randomized controlled trials or quasi-experimental studies were eligible. Meta-analyses using a random-effects model was conducted for outcomes with sufficient data. For other outcomes a narrative review was undertaken. Result: We reviewed 32 studies comprising 3,979 pregnant women aged 18 to 40 years. Relaxation interventions included yoga, music, Benson relaxation, progressive muscle relaxation (PMR), deep breathing relaxation (BR), guided imagery, mindfulness and hypnosis. Intervention duration ranged from brief experiment (~10 minutes) to 6 months of daily relaxation. Meta-analyses showed relaxation therapy reduced maternal stress (-4.1 points; 95% Confidence Interval (CI): -7.4, -0.9; 9 trials; 1113 participants), anxiety (-5.04 points; 95% CI: -8.2, -1.9; 10 trials; 1965 participants) and depressive symptoms (-2.3 points; 95% CI: -3.4, -1.3; 7 trials; 733 participants). Relaxation has also increased offspring birth weight (80 g, 95% CI: 1, 157; 8 trials; 1239 participants), explained by PMR (165g, 95% CI: 100, 231; 4 trials; 587 participants) in sub-group analysis. In five trials evaluating maternal physiological responses, relaxation therapy optimized blood pressure, heart rate and respiratory rate. Four trials showed relaxation therapy reduced duration of labour. Apgar score only improved significantly in two of six trials. One of three trials showed a significant increase in birth length, and one of three trials showed a significant increase in gestational age. Two of six trials examining delivery mode showed significantly increased spontaneous vaginal delivery and decreased instrumental delivery or cesarean section following a relaxation intervention. Discussion: We found consistent evidence for beneficial effects of relaxation interventions in reducing maternal stress, improving mental health, and some evidence for improved maternal physiological outcomes. In addition, we found a positive effect of relaxation interventions on birth weight and inconsistent effects on other pregnancy or birth outcomes. High quality adequately powered trials are needed to examine impacts of relaxation interventions on newborns and offspring health outcomes. Conclusion: In addition to benefits for mothers, relaxation interventions provided during pregnancy improved birth weight and hold some promise for improving newborn outcomes; therefore, this approach strongly merits further research. [ABSTRACT FROM AUTHOR]

Public health interventions such as social distancing and mask wearing decrease the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they decrease the viral load of infected patients and whether changes in viral load impact mortality from coronavirus disease 2019 (COVID-19). We evaluated 6923 patients with COVID-19 at six New York City hospitals from March 15-May 14, 2020, corresponding with the implementation of public health interventions in March. We assessed changes in cycle threshold (CT) values from reverse transcription-polymerase chain reaction tests and in-hospital mortality and modeled the impact of viral load on mortality. Mean CT values increased between March and May, with the proportion of patients with high viral load decreasing from 47.7% to 7.8%. In-hospital mortality increased from 14.9% in March to 28.4% in early April, and then decreased to 8.7% by May. Patients with high viral loads had increased mortality compared to those with low viral loads (adjusted odds ratio 2.34). If viral load had not declined, an estimated 69 additional deaths would have occurred (5.8% higher mortality). SARS-CoV-2 viral load steadily declined among hospitalized patients in the setting of public health interventions, and this correlated with decreases in mortality.

Rockfish are an important component of West Coast fisheries and California Current food webs, and recruitment (cohort strength) for rockfish populations has long been characterized as highly variable for most studied populations. Research efforts and fisheries surveys have long sought to provide greater insights on both the environmental drivers, and the fisheries and ecosystem consequences, of this variability. Here, variability in the temporal and spatial abundance and distribution patterns of young-of-the-year (YOY) rockfishes are described based on midwater trawl surveys conducted throughout the coastal waters of California Current between 2001 and 2019. Results confirm that the abundance of winter-spawning rockfish taxa in particular is highly variable over space and time. Although there is considerable spatial coherence in these relative abundance patterns, there are many years in which abundance patterns are very heterogeneous over the scale of the California Current. Results also confirm that the high abundance levels of YOY rockfish observed during the 2014-2016 large marine heatwave were largely coastwide events. Species association patterns of pelagic YOY for over 20 rockfish taxa in space and time are also described. The overall results will help inform future fisheries-independent surveys, and will improve future indices of recruitment strength used to inform stock assessment models and marine ecosystem status reports.

A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF