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BackgroundThere is a growing prevalence of nonhealing wounds and chronic diseases in society, and there is an associated need for wound management solutions that include the use of telemedicine. A broad spectrum of factors influences the planning and execution of interventions within telemedicine in chronic wound management, spanning organizations, technologies, and individuals, including professionals and patients. The Telemedicine and Ambulatory Wound Care Team (TELE-AMBUS) project applies a whole-system research approach to account for this spectrum of factors. ObjectiveThe primary objective of this study was to explore and analyze the implementation and consequences of an outpatient wound management model, comprising 2 interconnected quality improvement interventions (ie, telemedicine and ambulatory wound care team) aimed at older and vulnerable patients with chronic wounds, across the specialist and primary health care sectors. Embedded in this objective is the aim to improve the competence levels of health care providers and, consequently, the service quality of outpatient wound management across specialist and primary health care services. MethodsThis project examines the implementation and consequences of an outpatient wound management model through a combined process and economic evaluation research strategy. A sociotechnical system theory approach and multiple work package design support the examination. The project uses observations, conversations, interviews, and economic assessments to gather rich, in-depth insights and understanding on why and how the new wound management model contributes to a change or not compared with the traditional treatment model. ResultsThe project has been funded from 2021 to 2025. Baseline interviews have been conducted since April 2022 and concluded in January 2024. Fieldwork, including nonparticipant observations, semistructured interviews, and informal conversations, has been conducted since November 2022 and is expected to conclude in March 2025. In parallel and as part of the cost-effectiveness analyses, time usage data on the outpatient and regular clinical models are being gathered during the fieldwork. ConclusionsWe applied a whole-system approach in multiple ways, that is, to design or inform our fieldwork and to explore, evaluate, and translate project findings into practice across services. To our knowledge, this approach has not been undertaken in telemedicine in chronic wound management literature and associated human factors and ergonomics research. Thus, our approach can produce both original and novel research and theoretical results internationally. International Registered Report Identifier (IRRID)DERR1-10.2196/55502

Abstract Individuals born with very low birth weight (VLBW;

Objective: Recess contributes meaningfully to physical activity (PA), but recess time has declined. The study’s purpose was to report PA by age, gender, and playground feature to inform potential playground configurations more conducive to PA during recess. Methods: Using the System for Observing Play and Leisure Activity in the Youth, kindergarten through 5th grade recesses were observed on at least four days at four schools in Little Rock, Arkansas, United States during May 2023. Target playground features were ball courts, grass, pavement, play structures, and swings. To provide inferential analysis, a comparison of conditional means across playground features, age, and gender was conducted using linear regression with robust standard errors clustered by school. Results: 3,356 playground scans (intercoder correlation = 0.93) were collected and aggregated by school, day, gender, age (grade), and target feature for a sample size of 292 observations. The gender gap was widest among 4-5th graders, 79 % (95 % CI: 72, 86) for males and 64 % (95 % CI: 58, 70) for females. Among females, PA was highest on swings [82 % (95 % CI: 77, 86)] and lowest on paved areas [56 % (95 % CI: 43, 69)]. Among males, it was highest on both swings [81 % (95 % CI: 75, 86)] and ball courts [83 % (95 % CI: 77, 89)] and lowest on grassy areas [64 % (95 % CI: 60, 67)]. Conclusion: Swings, courts, and play structures were associated with a higher proportion of children being engaged in PA. Research is needed to identify whether physical improvements to facilitate access to these features increase PA.

While the early effects of the COVID-19 pandemic on the United States labor market are well-established, less is known about the long-term impact of SARS-CoV-2 infection and Long COVID on employment. To address this gap, we analyzed self-reported data from a prospective, national cohort study to estimate the effects of SARS-CoV-2 symptoms at three months post-infection on missed workdays and return to work. The analysis included 2,939 adults in the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) study who tested positive for their initial SARS-CoV-2 infection at the time of enrollment, were employed before the pandemic, and completed a baseline and three-month electronic survey. At three months post-infection, 40.8% of participants reported at least one SARS-CoV-2 symptom and 9.6% of participants reported five or more SARS-CoV-2 symptoms. When asked about missed work due to their SARS-CoV-2 infection at three months, 7.2% of participants reported missing ≥10 workdays and 13.9% of participants reported not returning to work since their infection. At three months, participants with ≥5 symptoms had a higher adjusted odds ratio of missing ≥10 workdays (2.96, 95% CI 1.81-4.83) and not returning to work (2.44, 95% CI 1.58-3.76) compared to those with no symptoms. Prolonged SARS-CoV-2 symptoms were common, affecting 4-in-10 participants at three-months post-infection, and were associated with increased odds of work loss, most pronounced among adults with ≥5 symptoms at three months. Despite the end of the federal Public Health Emergency for COVID-19 and efforts to "return to normal", policymakers must consider the clinical and economic implications of the COVID-19 pandemic on people's employment status and work absenteeism, particularly as data characterizing the numerous health and well-being impacts of Long COVID continue to emerge. Improved understanding of risk factors for lost work time may guide efforts to support people in returning to work.

ObjectiveIndividuals born very preterm (Study designCohorts with data on physical activity and cognitive function in adults born very preterm/very low birth weight and term-born controls were recruited from the Research on European Children and Adults Born Preterm, and the Adults Born Preterm International Collaboration Consortia. A systematic literature search was performed in PubMed and Embase.ResultsFive cohorts with 1644 participants aged 22-28 years (595 very preterm/very low birth weight and 1049 controls) were included. Adults born very preterm/very low birth weight reported 1.11 (95% CI: 0.68 to 1.54) hours less moderate to vigorous physical activity per week than controls, adjusted for cohort, age and sex. The difference between individuals born very preterm/very low birth weight and controls was larger among women than among men. Neither intelligence quotient nor self-reported executive function mediated the association between very preterm/very low birth weight and moderate to vigorous physical activity. Results were essentially the same when we excluded individuals with neurosensory impairments.ConclusionAdults born very preterm/very low birth weight, especially women, reported less moderate to vigorous physical activity than their term-born peers. Cognitive function did not mediate this association. Considering the risk of adverse health outcomes among individuals born preterm, physical activity could be a target for intervention.

Abstract There is lack of research on body composition and physical fitness in individuals born small for gestational age (SGA) at term entering mid-adulthood. We aimed to investigate these outcomes in adults born SGA at term. This population-based cohort study included 46 adults born SGA with birth weight

Abstract Based on data collected as part of the contact tracing activity of the City of Helsinki Epidemiological Operations Unit, we evaluated the efficacy and effectiveness of isolating SARS-CoV-2 cases and quarantining their exposed contacts during a mildly growing phase of the COVID-19 epidemic in Finland in autumn 2020. Based on the observed symptom-to-symptom intervals in 1016 pairs of primary and secondary cases, we estimated that without case isolation or quarantine 40 $$\%$$ % (90 $$\%$$ % credible interval, CI 25–59) of transmission would have occurred on the day of or after symptom onset. One third of SARS-CoV-2 cases (N = 1521) had initially been quarantined, with a self-reported time until isolation (quarantine) of 0.8 days before symptom onset. This delay translates into an efficacy of 50 $$\%$$ % (90 $$\%$$ % CI 40–63) of averting secondary infections per quarantined case. Due to later isolation (mean 2.6 days after symptoms), the efficacy was smaller (24 $$\%$$ % ; 90 $$\%$$ % CI 12–41) in those two third of the cases (N = 3101) whose isolation was prompted by their symptoms, i.e. without being previously quarantined. At the population level, we evaluated the effectiveness of case isolation and quarantine on the growth rate of the COVID-19 epidemic in the autumn of 2020. Under a wide range of underlying assumptions, the rate would have been at least 2 times higher without case isolation and quarantine. The numbers needed to isolate or quarantine to prevent one secondary case were 2 and 20, respectively.

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) rates have remained relatively low in Finland. In Southwest Finland, however, annual MRSA incidence increased from 12 to 25/100,000 between 2007 and 2016 with spa t172 strain causing one fourth (237/983) of all cases. This provoked us to study the molecular epidemiology of t172-MRSA, aiming to better understand the transmission of this strain type. We combined epidemiological data and whole genome sequencing (WGS) of a set of 64 (27%, 64/237) t172-MRSA isolates covering 10 years. Isolates represented sporadic and index cases of all identified healthcare-associated outbreaks (HAOs) and family clusters (FCs). Among the included 62 isolates, core-genome MLST analysis revealed eight genomic clusters comprising 24 (38.7%) isolates and 38 (61.3%) non-clustered isolates. Cluster 1 comprised ten and the remaining seven clusters two isolates each, respectively. Two epidemiologically distinct HAOs were linked in cluster 1. FCs were involved in all clusters. All strains were associated with epidemic clonal complex CC59. We were able to confirm the spread of several successful t172-MRSA subclones in regional healthcare and the community. WGS complemented routine surveillance by revealing undetected links between t172-MRSA cases. Targeted, WGS-based typing could enhance MRSA surveillance without the need for routine WGS diagnostics.

Objective Lung cancer is the most common cause of cancer-related death in the USA. While most patients are diagnosed following symptomatic presentation, no studies have compared symptoms and physical examination signs at or prior to diagnosis from electronic health records (EHRs) in the USA. We aimed to identify symptoms and signs in patients prior to diagnosis in EHR data.Design Case–control study.Setting Ambulatory care clinics at a large tertiary care academic health centre in the USA.Participants, outcomes We studied 698 primary lung cancer cases in adults diagnosed between 1 January 2012 and 31 December 2019, and 6841 controls matched by age, sex, smoking status and type of clinic. Coded and free-text data from the EHR were extracted from 2 years prior to diagnosis date for cases and index date for controls. Univariate and multivariable conditional logistic regression were used to identify symptoms and signs associated with lung cancer at time of diagnosis, and 1, 3, 6 and 12 months before the diagnosis/index dates.Results Eleven symptoms and signs recorded during the study period were associated with a significantly higher chance of being a lung cancer case in multivariable analyses. Of these, seven were significantly associated with lung cancer 6 months prior to diagnosis: haemoptysis (OR 3.2, 95% CI 1.9 to 5.3), cough (OR 3.1, 95% CI 2.4 to 4.0), chest crackles or wheeze (OR 3.1, 95% CI 2.3 to 4.1), bone pain (OR 2.7, 95% CI 2.1 to 3.6), back pain (OR 2.5, 95% CI 1.9 to 3.2), weight loss (OR 2.1, 95% CI 1.5 to 2.8) and fatigue (OR 1.6, 95% CI 1.3 to 2.1).Conclusions Patients diagnosed with lung cancer appear to have symptoms and signs recorded in the EHR that distinguish them from similar matched patients in ambulatory care, often 6 months or more before diagnosis. These findings suggest opportunities to improve the diagnostic process for lung cancer.

Abstract We utilized compositional data analysis (CoDA) to study changes in the composition of the 24-h movement behaviors during an activity tracker based physical activity intervention. A total of 231 recently retired Finnish retirees were randomized into intervention and control groups. The intervention participants were requested to use a commercial activity tracker bracelet with daily activity goal and inactivity alerts for 12 months. The controls received no intervention. The 24-h movement behaviors, i.e., sleep, sedentary time (SED), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) were estimated from wrist-worn ActiGraph data using the GGIR R-package. Three balance coordinates describing the composition of movement behaviors were applied: ratio of active vs. passive behaviors, LPA vs. MVPA, and sleep vs. SED. A linear mixed model was used to study changes between the baseline and 6-month time point. Overall, the changes in the 24-h movement behaviors were small and did not differ between the groups. Only the ratio of LPA to MVPA tended to change differently between the groups (group*time interaction p = 0.08) as the intervention group increased LPA similarly to controls but decreased their MVPA. In conclusion, the use of a commercial activity tracker may not be enough to induce changes in the 24-h movement behaviors among retirees.

BackgroundDigital therapeutics are growing as a solution to manage pain for patients; yet, they are underused in primary care where over half of the patients with chronic pain seek care. Little is known about how to successfully engage primary care providers in recommending digital therapeutics to their patients. Exploring provider motivations in chronic pain management would potentially help to improve their engagement and inform the development of digital therapeutics. ObjectiveThis study examined primary care providers’ motivations for chronic pain management, including their strategies and challenges, to inform the future development of chronic pain-related digital therapeutics tailored to primary care settings. MethodsWe conducted qualitative semistructured interviews with health care providers recruited from 3 primary care clinics in Washington and 1 clinic in Colorado between July and October 2021. The sample (N=11) included 7 primary care physicians, 2 behavioral health providers, 1 physician assistant, and 1 nurse. Most providers worked in clinics affiliated with urban academic health systems. Guided by the human-centered design approach and Christensen’s Job-to-be-Done framework, we asked providers their goals and priorities in chronic pain management, their experiences with challenges and strategies used to care for patients, and their perceptions of applying digital therapeutics in clinical practice. Transcripts were analyzed using a thematic analysis approach. ResultsWe found that primary care providers were motivated but challenged to strengthen the patient-provider alliance, provide team-based care, track and monitor patients’ progress, and address social determinants of health in chronic pain management. Specifically, providers desired additional resources to improve patient-centered communication, pain education and counseling, and goal setting with patients. Providers also requested greater accessibility to multidisciplinary care team consultations and nonpharmacological pain treatments. When managing chronic pain at the population level, providers need infrastructure and systems to systematically track and monitor patients’ pain and provide wraparound health and social services for underserved patients. Recommendations on digital therapeutic features that might address provider challenges in achieving these motivations were discussed. ConclusionsGiven the findings, to engage primary care providers, digital therapeutics for chronic pain management need to strengthen the patient-provider alliance, increase access to nonpharmacological treatment options, support population health tracking and management, and provide equitable reach. Leveraging digital therapeutics in a feasible, appropriate, and acceptable way to aid primary care providers in chronic pain management may require multimodal features that address provider motivations at an individual care and clinic or system level.

In Finland, the first wave of the COVID-19 epidemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) took place from March to June 2020, with the majority of COVID-19 cases diagnosed in the Helsinki-Uusimaa region. The magnitude and trend in the incidence of COVID-19 is one way to monitor the course of the epidemic. The diagnosed COVID-19 cases are a subset of the infections and therefore the COVID-19 incidence underestimates the SARS-CoV-2 incidence. The likelihood that an individual with SARS-CoV-2 infection is diagnosed with COVID-19 depends on the clinical manifestation as well as the infection testing policy and capacity. These factors may fluctuate over time and the underreporting of infections changes accordingly. Quantifying the extent of underreporting allows the assessment of the true incidence of infection. To obtain information on the incidence of SARS-CoV-2 infection in Finland, a series of serological surveys was initiated in April 2020. We develop a Bayesian inference approach and apply it to data from the serological surveys, registered COVID-19 cases, and external data on antibody development, to estimate the time-dependent underreporting of SARS-Cov-2 infections during the first wave of the COVID-19 epidemic in Finland. During the entire first wave, there were 1 to 5 (95% probability) SARS-CoV-2 infections for every COVID-19 case. The underreporting was highest before April when there were 4 to 17 (95% probability) infections for every COVID-19 case. It is likely that between 0.5%-1.0% (50% probability) and no more than 1.5% (95% probability) of the adult population in the Helsinki-Uusimaa region were infected with SARS-CoV-2 by the beginning of July 2020.

Abstract Introduction: Several evidence-informed consent practices (ECPs) have been shown to improve informed consent in clinical trials but are not routinely used. These include optimizing consent formatting, using plain language, using validated instruments to assess understanding, and involving legally authorized representatives when appropriate. We hypothesized that participants receiving an implementation science toolkit and a social media push would have increased adoption of ECPs and other outcomes. Methods: We conducted a 1-year trial with clinical research professionals in the USA (n = 1284) who have trials open to older adults or focus on Alzheimer’s disease. We randomized participants to receive information on ECPs via receiving a toolkit with a social media push (intervention) or receiving an online learning module (active control). Participants completed a baseline survey and a follow-up survey after 1 year. A subset of participants was interviewed (n = 43). Results: Participants who engaged more with the toolkit were more likely to have tried to implement an ECP during the trial than participants less engaged with the toolkit or the active control group. However, there were no significant differences in the adoption of ECPs, intention to adopt, or positive attitudes. Participants reported the toolkit and social media push were satisfactory, and participating increased their awareness of ECPs. However, they reported lacking the time needed to engage with the toolkit more fully. Conclusions: Using an implementation science approach to increase the use of ECPs was only modestly successful. Data suggest that having institutional review boards recommend or require ECPs may be an effective way to increase their use.

Abstract Background Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. Methods We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. Discussion This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. Systematic review registration PROSPERO CRD42021234119

Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here, we used gene deletion, blocking Abs, transgene induction, and gene transfer to study how Ang2, its Tie2 receptor, and Tie1 regulate lymphatic vessels. We discovered that VEGF-C–induced Ang2 secretion from lymphatic endothelial cells (LECs) was involved in full Akt activation downstream of phosphoinositide 3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of an Ang2-blocking Ab decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of the PI3K catalytic p110α subunit or with small-molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C–induced lymphangiogenesis also in adult mice. Our results reveal an important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2/Tie/PI3K signaling.

Introduction The burden of Alzheimer’s disease (AD) and AD-related dementias (ADRD) is increasing nationally and globally, with disproportionate impacts on lower-income, lower education and systematically marginalised older adults. Presence of inequalities in neighbourhood factors (eg, social context, physical and built environments) may affect risk of cognitive decline and be key for intervening on AD/ADRD disparities at the population level. However, existing studies are limited by a dearth of longitudinal, detailed neighbourhood measures linked to rich, prospective cohort data. Our main objective is to identify patterns of neighbourhood change related to prevalence of—and disparities in—cognitive decline and dementia.Methods and analyses We describe the process of collecting, processing and linking extensive neighbourhood data to the Multi-Ethnic Study of Atherosclerosis (MESA), creating a 25+ years dataset. Within the MESA parent study, the MESA Neighborhoods and Aging cohort study will characterise dynamic, longitudinal neighbourhood social and built environment variables relevant to cognition for residential addresses of MESA participants. This includes administering new surveys, expanding residential address histories, calculating new measures derived from spatial data and implementing novel deep learning algorithms on street-level imagery. Applying novel statistical techniques, we will examine associations of neighbourhood environmental characteristics with cognition and clinically relevant AD/ADRD outcomes. We will investigate determinants of disparities in outcomes by socioeconomic position and race/ethnicity and assess the contribution of neighbourhood environments to these disparities. This project will provide new evidence about pathways between neighbourhood environments and cognitive outcomes, with implications for policies to support healthy ageing.Ethics and dissemination This project was approved by the University of Washington and Drexel University Institutional Review Boards (protocols #00009029 and #00014523, and #180900605). Data will be distributed through the MESA Coordinating Center. Findings will be disseminated in peer-reviewed scientific journals, briefs, presentations and on the participant website.

Objectives To evaluate variability in life expectancy at birth in small areas, describe the spatial pattern of life expectancy, and examine associations between small-area socioeconomic characteristics and life expectancy in a mid-sized city of a middle-income country.Design Cross-sectional, using data from death registries (2015–2018) and socioeconomic characteristics data from the 2010 national population census.Participants/setting 40 898 death records in 99 small areas of the city of Córdoba, Argentina. We summarised variability in life expectancy at birth by using the difference between the 90th and 10th percentile of the distribution of life expectancy across small areas (P90-P10 gap) and evaluated associations with small-area socioeconomic characteristics by calculating a Slope Index of Inequality in linear regression.Primary outcome Life expectancy at birth.Results The median life expectancy at birth was 80.3 years in women (P90-P10 gap=3.2 years) and 75.1 years in men (P90-P10 gap=4.6 years). We found higher life expectancies in the core and northwest parts of the city, especially among women. We found positive associations between life expectancy and better small-area socioeconomic characteristics, especially among men. Mean differences in life expectancy between the highest versus the lowest decile of area characteristics in men (women) were 3.03 (2.58), 3.52 (2.56) and 2.97 (2.31) years for % adults with high school education or above, % persons aged 15–17 attending school, and % households with water inside the dwelling, respectively. Lower values of % overcrowded households and unemployment rate were associated with longer life expectancy: mean differences comparing the lowest versus the highest decile were 3.03 and 2.73 in men and 2.57 and 2.34 years in women, respectively.Conclusion Life expectancy is substantially heterogeneous and patterned by socioeconomic characteristics in a mid-sized city of a middle-income country, suggesting that small-area inequities in life expectancy are not limited to large cities or high-income countries.

Abstract Models of marine mammal population dynamics have been used extensively to predict abundance. A less common application of these models is to reconstruct historical population dynamics, filling in gaps in observation data by integrating information from multiple sources. We developed an integrated population model for the Florida manatee (Trichechus manatus latirostris) to reconstruct its population dynamics in the southwest region of the state over the past 20 years. Our model improved precision of key parameter estimates and permitted inference on poorly known parameters. Population growth was slow (averaging 1.02; 95% credible interval 1.01–1.03) but not steady, and an unusual mortality event in 2013 led to an estimated net loss of 332 (217–466) manatees. Our analyses showed that precise estimates of abundance could be derived from estimates of vital rates and a few input estimates of abundance, which may mean costly surveys to estimate abundance don’t need to be conducted as frequently. Our study also shows that retrospective analyses can be useful to: (1) model the transient dynamics of age distribution; (2) assess and communicate the conservation status of wild populations; and (3) improve our understanding of environmental effects on population dynamics and thus enhance our ability to forecast.

Abstract Polydextrose (PDX) is a branched glucose polymer, utilized as a soluble dietary fiber. Recently, PDX was found to have hypolipidemic effects and effects on the gut microbiota. To investigate these findings more closely, a non-targeted metabolomics approach, was exploited to determine metabolic alterations in blood and epididymal adipose tissue samples that were collected from C57BL/6 mice fed with a Western diet, with or without oral administration of PDX. Metabolomic analyses revealed significant differences between PDX- and control mice, which could be due to differences in diet or due to altered microbial metabolism in the gut. Some metabolites were found in both plasma and adipose tissue, such as the bile acid derivative deoxycholic acid and the microbiome-derived tryptophan metabolite indoxyl sulfate, both of which increased by PDX. Additionally, PDX increased the levels of glycine betaine and l-carnitine in plasma samples, which correlated negatively with plasma TG and positively correlated with bacterial genera enriched in PDX mice. The results demonstrated that PDX caused differential metabolite patterns in blood and adipose tissues and that one-carbon metabolism, associated with glycine betaine and l-carnitine, and bile acid and tryptophan metabolism are associated with the hypolipidemic effects observed in mice that were given PDX.

Abstract Background Acute otitis media (AOM) is the most frequent indication for antibiotic treatment of children in the United States. Its diagnosis relies on visualization of the tympanic membrane, a clinical skill acquired through a deliberate approach. Instruction in pediatric otoscopy begins in medical school. Medical students receive their primary experience with pediatric otoscopy during the required pediatric clerkship, traditionally relying on an immersion, apprentice-type learning model. A better understanding of their preceptors’ clinical and teaching practices could lead to improved skill acquisition. This study investigates how pediatric preceptors (PP) and members of the Council on Medical Student Education in Pediatrics (COMSEP) perceive teaching otoscopy. Methods A 30-item online survey was administered to a purposeful sample of PP at six institutions in 2017. A comparable 23-item survey was administered to members through the 2018 COMSEP Annual Survey. Only COMSEP members who identified themselves as teaching otoscopy to medical students were asked to complete the otoscopy-related questions on the survey. Results Survey respondents included 58% of PP (180/310) and 44% (152/348) of COMSEP members. Forty-one percent (62/152) of COMSEP member respondents identified themselves as teaching otoscopy and completed the otoscopy-related questions. The majority agreed that standardized curricula are needed (PP 78%, COMSEP members 97%) and that all graduating medical students should be able to perform pediatric otoscopy (PP 95%, COMSEP members 79%). Most respondents reported usefulness of the American Academy of Pediatrics (AAP) AOM guidelines (PP 95%, COMSEP members 100%). More COMSEP members than PP adhered to the AAP’s diagnostic criteria (pediatric preceptors 42%, COMSEP members 93%). The most common barriers to teaching otoscopy were a lack of assistive technology (PP 77%, COMSEP members 56%), presence of cerumen (PP 58%, COMSEP members 60%), time to teach in direct patient care (PP 46%, COMSEP members 48%), and parent anxiety (PP 62%, COMSEP members 54%). Conclusions Our study identified systemic and individual practice patterns and barriers to teaching pediatric otoscopy. These results can inform education leaders in supporting and enabling preceptors in their clinical teaching. This approach can be adapted to ensure graduating medical students obtain intended core clinical skills.

Abstract Background: Opioids are more commonly prescribed for chronic pain in rural settings in the USA, yet little is known about how the rural context influences efforts to improve opioid medication management. Methods: The Six Building Blocks is an evidence-based program that guides primary care practices in making system-based improvements in managing patients using long-term opioid therapy. It was implemented at 6 rural and rural-serving organizations with 20 clinic locations over a 15-month period. To gain further insight about their experience with implementing the program, interviews and focus groups were conducted with staff and clinicians at the six organizations at the end of the 15 months and transcribed. Team members used a template analysis approach, a form of qualitative thematic analysis, to code these data for barriers, facilitators, and corresponding subcodes. Results: Facilitators to making systems-based changes in opioid management within a rural practice context included a desire to help patients and their community, external pressures to make changes in opioid management, a desire to reduce workplace stress, external support for the clinic, supportive clinic leadership, and receptivity of patients. Barriers to making changes included competing demands on clinicians and staff, a culture of clinician autonomy, inadequate data systems, and a lack of patient resources in rural areas. Discussion: The barriers and facilitators identified here point to potentially unique determinants of practice that should be considered when addressing opioid prescribing for chronic pain in the rural setting.

BackgroundTo address the current COVID-19 and any future pandemic, we need robust, real-time, and population-scale collection and analysis of data. Rapid and comprehensive knowledge on the trends in reported symptoms in populations provides an earlier window into the progression of viral spread, and helps to predict the needs and timing of professional health care. ObjectiveThe objective of this study was to use a Conformité Européenne (CE)-marked medical online symptom checker service, Omaolo, and validate the data against the national demand for COVID-19–related care to predict the pandemic progression in Finland. MethodsOur data comprised real-time Omaolo COVID-19 symptom checker responses (414,477 in total) and daily admission counts in nationwide inpatient and outpatient registers provided by the Finnish Institute for Health and Welfare from March 16 to June 15, 2020 (the first wave of the pandemic in Finland). The symptom checker responses provide self-triage information input to a medically qualified algorithm that produces a personalized probability of having COVID-19, and provides graded recommendations for further actions. We trained linear regression and extreme gradient boosting (XGBoost) models together with F-score and mutual information feature preselectors to predict the admissions once a week, 1 week in advance. ResultsOur models reached a mean absolute percentage error between 24.2% and 36.4% in predicting the national daily patient admissions. The best result was achieved by combining both Omaolo and historical patient admission counts. Our best predictor was linear regression with mutual information as the feature preselector. ConclusionsAccurate short-term predictions of COVID-19 patient admissions can be made, and both symptom check questionnaires and daily admissions data contribute to the accuracy of the predictions. Thus, symptom checkers can be used to estimate the progression of the pandemic, which can be considered when predicting the health care burden in a future pandemic.

Research registries are a powerful tool for boosting recruitment into clinical trials. However, little is known about how parents approach the decision to enroll their child in a pediatric participant research registry (PPRR). We conducted in-person, written, or telephone surveys with parents/guardians of children hospitalized at Children's Hospital of Omaha, Nebraska to identify attitudes towards and barriers to enrollment in PPRRs. Overall, our population (N = 36) had positive attitudes toward PPRRs, with 77.8% (CI: 61.6, 88.4) of participants stating they were "somewhat" or "very" likely to enroll their child. Likelihood to enroll differed between various recruitment and enrollment methods, with participants stating they would be more likely to enroll their child in a PPRR if they were recruited by their child's primary care provider or a nurse in clinic (p = 0.02) and less likely to enroll if they were recruited through social media (p

Background Reports on medium and long-term sequelae of SARS-CoV-2 infections largely lack quantification of incidence and relative risk. We describe the rationale and methods of the Innovative Support for Patients with SARS-CoV-2 Registry (INSPIRE) that combines patient-reported outcomes with data from digital health records to understand predictors and impacts of SARS-CoV-2 infection. Methods INSPIRE is a prospective, multicenter, longitudinal study of individuals with symptoms of SARS-CoV-2 infection in eight regions across the US. Adults are eligible for enrollment if they are fluent in English or Spanish, reported symptoms suggestive of acute SARS-CoV-2 infection, and if they are within 42 days of having a SARS-CoV-2 viral test (i.e., nucleic acid amplification test or antigen test), regardless of test results. Recruitment occurs in-person, by phone or email, and through online advertisement. A secure online platform is used to facilitate the collation of consent-related materials, digital health records, and responses to self-administered surveys. Participants are followed for up to 18 months, with patient-reported outcomes collected every three months via survey and linked to concurrent digital health data; follow-up includes no in-person involvement. Our planned enrollment is 4,800 participants, including 2,400 SARS-CoV-2 positive and 2,400 SARS-CoV-2 negative participants (as a concurrent comparison group). These data will allow assessment of longitudinal outcomes from SARS-CoV-2 infection and comparison of the relative risk of outcomes in individuals with and without infection. Patient-reported outcomes include self-reported health function and status, as well as clinical outcomes including health system encounters and new diagnoses. Results Participating sites obtained institutional review board approval. Enrollment and follow-up are ongoing. Conclusions This study will characterize medium and long-term sequelae of SARS-CoV-2 infection among a diverse population, predictors of sequelae, and their relative risk compared to persons with similar symptomatology but without SARS-CoV-2 infection. These data may inform clinical interventions for individuals with sequelae of SARS-CoV-2 infection.

Objectives We investigated the association of healthy food retail presence and cardiovascular mortality, controlling for sociodemographic characteristics. This association could inform efforts to preserve or increase local supermarkets or produce market availability.Design Cohort study, combining Mortality Disparities in American Communities (individual-level data from 2008 American Community Survey linked to National Death Index records from 2008 to 2015) and retail establishment data.Setting Across the continental US area-based sociodemographic and retail characteristics were linked to residential location by ZIP code tabulation area (ZCTA). Sensitivity analyses used census tracts instead, restricted to urbanicity or county-based strata, or accounted for non-independence using frailty models.Participants 2 753 000 individuals age 25+ living in households with full kitchen facilities, excluding group quarters.Primary and secondary outcome measures Cardiovascular mortality (primary) and all-cause mortality (secondary).Results 82% had healthy food retail (supermarket, produce market) within their ZCTA. Density of such retail was correlated with density of unhealthy food sources (eg, fast food, convenience store). Healthy food retail presence was not associated with reduced cardiovascular (HR: 1.03; 95% CI 1.00 to 1.07) or all-cause mortality (HR: 1.05; 95% CI 1.04 to 1.06) in fully adjusted models (with adjustment for gender, age, marital status, nativity, Black race, Hispanic ethnicity, educational attainment, income, median household income, population density, walkable destination density). The null finding for cardiovascular mortality was consistent across adjustment strategies including minimally adjusted models (individual demographics only), sensitivity analyses related to setting, and across gender or household type strata. However, unhealthy food retail presence was associated with elevated all-cause mortality (HR: 1.15; 95% CI 1.11 to 1.20).Conclusions In this study using food establishment locations within administrative areas across the USA, the hypothesised association of healthy food retail availability with reduced cardiovascular mortality was not supported; an association of unhealthy food retail presence with higher mortality was not specific to cardiovascular causes.

Objective: Breast cancer is the most commonly diagnosed form of cancer and the leading cause of cancer-related death among Latina women in the United States. One aspect of recovery that has been underrepresented in the English-language literature is the recovery of Latina women who have developed lymphedema, a debilitating condition characterized by persistent swelling of the arm, hand, chest, and/or breast. To fill this research gap, a study was conducted to examine the lived experiences of Latina women with breast cancer-related lymphedema. Methods: Given the limited scholarship on this topic, qualitative methods were used to obtain a foundational and nuanced understanding of Latina women’s experiences. Semi-structured interviews were conducted with a sample of 10 Latina survivors with breast cancer-related lymphedema. Data were analyzed through thematic analysis and constant comparison methodology. Results: The data analysis yielded three major themes: knowledge of lymphedema, impact of lymphedema diagnosis, and coping with lymphedema. Participants had limited knowledge of lymphedema and its risk factors upon diagnosis, in addition to barriers accessing quality care. They also noted psychological distress related to a significant financial burden as well as social anxiety related to interacting with others while wearing compression gloves or sleeves. A major coping strategy was receiving social support from friends, family, peers in structured support groups, and spiritual/religious groups or practices. Conclusions: Our findings bring to light contextual factors that may place Latina breast cancer survivors at increased risk for lymphedema and for experiencing a high burden managing their condition. Recommendations are provided for primary, secondary, and tertiary prevention.

Given research showing that the very act of communicating side effects can increase their likelihood, how can providers inform patients about side effects while upholding their oath to do no unnecessary harm? An emerging approach provides a potential solution: truthfully describe certain minor side effects as a sign the treatment is active and working in the body. This approach focuses on instilling adaptive mindsets about the meaning of side effects while still keeping patients informed. This article describes existing research suggesting that this approach can be helpful in improving experience and outcomes in treatments for pain, hypertension and allergy. Compared with control groups given a standard, empathetic message about side effects, patients who were informed that side effects are a sign treatment is working were less anxious about side effects and rated them as less threatening and intense. A longitudinal, randomised controlled trial of this approach in patients receiving oral immunotherapy for food allergies found that describing side effects as a sign treatment was working reduced the rate at which patients contacted providers with concerns about side effects and led to greater increases in a biomarker of allergic tolerance from pretreatment to post-treatment (peanut-specific blood IgG4). In unveiling this approach, this article also raises important issues regarding which treatments and symptoms this approach should be applied to. Finally, we outline questions future research should address to further understand and leverage this approach.

Objectives Inspired by the James Lind Alliance (JLA) user involvement approach, the aim of the present study was to identify the top 10 uncertainties for sleep research raised by students in higher education, and to discuss our experiences with adapting the JLA method to a student population.Design The study design is a pragmatic JLA approach, including a priority setting partnership within the field of sleep, collection of sleep-related research uncertainties as reported by students in higher education, sorting of the uncertainties and a final identification of the top 10 uncertainties through collaborative work between researchers, students, stakeholders and experts in the field. Uncertainties were collected using a one-question online survey: ‘as a student, which question(s) do you consider to be important with regards to sleep?’. A variety of approaches were applied to promote the survey to the students, including social media, radio, the university website, stands in university cafeterias and a sleep stunt. NVivo V.12 was used to code and sort the questions.Setting A higher education institution in Norway.Participants 555 students.Results The data collection provided 608 uncertainties, and the following prioritised top 10: (1) screen time, (2) stress, (3) educational achievements, (4) social relations, (5) mental health, (6) physical activity, (7) indoor environment, (8) substance abuse, (9) shift work and (10) sleep quality. Despite successful data collection, we found sleep to be a broad topic, and defining specific questions throughout the sorting and verification process proved difficult.Conclusions We identified the prioritised top 10 research uncertainties as reported by students in higher education, ranking screen time first. However, the process was time and resource consuming. The research uncertainties addressed by the students showed great diversity, characterised by heterogeneity and a lack of specificity, making verification of the uncertainties challenging.

Climate change is expected to increase the frequency and intensity of extreme events in northern ecosystems. The outcome of these events across the landscape, might be mediated by species effects, such as niche construction, with likely consequences on vegetation resilience. To test this hypothesis, we simulated an extreme event by removing aboveground vegetation in tundra heathlands dominated by the allelopathic dwarf shrub Empetrum nigrum, a strong niche constructor. We tested the hypothesis under different climate regimes along a 200-km long gradient from oceanic to continental climate in Northern Norway. We studied the vegetation recovery process over ten years along the climatic gradient. The recovery of E. nigrum and subordinate species was low and flattened out after five years at all locations along the climatic gradient, causing low vegetation cover at the end of the study in extreme event plots. Natural seed recruitment was low at all sites, however, the addition of seeds from faster growing species did not promote vegetation recovery. A soil bioassay from 8 years after the vegetation was removed, suggested the allelopathic effect of E. nigrum was still present in the soil environment. Our results provide evidence of how a common niche constructor species can dramatically affect ecosystem recovery along a climatic gradient after extreme events in habitats where it is dominant. By its extremely slow regrowth and it preventing establishment of faster growing species, this study increases our knowledge on the possible outcomes when extreme events harm niche constructors in the tundra.

BackgroundThe COVID-19 pandemic lead to a sudden shift to online teaching and restricted campus access.AimTo assess how university students experienced the sudden shift to online teaching after closure of campus due to the COVID-19 pandemic.Material and methodsStudents in Public Health Nutrition answered questionnaires two and 12 weeks (N = 79: response rate 20.3% and 26.6%, respectively) after the lockdown in Norway on 12 March 2020 and participated in digital focus group interviews in May 2020 (mixed methods study).Findings and discussionTwo weeks into the lockdown, 75% of students reported that their life had become more difficult and 50% felt that learning outcomes would be harder to achieve due to the sudden shift to online education. Twelve weeks into the lockdown, the corresponding numbers were 57% and 71%, respectively. The most pressing concerns among students were a lack of social interaction, housing situations that were unfit for home office purposes, including insufficient data bandwidth, and an overall sense of reduced motivation and effort. The students collaborated well in digital groups but wanted smaller groups with students they knew rather than being randomly assigned to groups. Most students agreed that pre-recorded and streamed lectures, frequent virtual meetings and student response systems could improve learning outcomes in future digital courses. The preference for written home exams over online versions of previous on-campus exams was likely influenced by student's familiarity with the former. The dropout rate remained unchanged compared to previous years.ConclusionThe sudden shift to digital teaching was challenging for students, but it appears that they adapted quickly to the new situation. Although the concerns described by students in this study may only be representative for the period right after campus lockdown, the study provide the student perspective on a unique period of time in higher education.

In epidemiology, a typical measure of interest is the risk of disease conditional upon exposure. A common source of bias in the estimation of risks and risk ratios is misclassification. Exposure misclassification affects the measurement of exposure, i.e. the variable one conditions on. This article explains how to assess biases under non-differential exposure misclassification when estimating vaccine effectiveness, i.e. the vaccine-induced relative reduction in the risk of disease. The problem can be described in terms of three binary variables: the unobserved true exposure status, the observed but potentially misclassified exposure status, and the observed true disease status. The bias due to exposure misclassification is quantified by the difference between the naïve estimand defined as one minus the risk ratio comparing individuals observed as vaccinated with individuals observed as unvaccinated, and the vaccine effectiveness defined as one minus the risk ratio comparing truly vaccinated with truly unvaccinated. The magnitude of the bias depends on five factors: the risks of disease in the truly vaccinated and the truly unvaccinated, the sensitivity and specificity of exposure measurement, and vaccination coverage. Non-differential exposure misclassification bias is always negative. In practice, if the sensitivity and specificity are known or estimable from external sources, the true risks and the vaccination coverage can be estimated from the observed data and, thus, the estimation of vaccine effectiveness based on the observed risks can be corrected for exposure misclassification. When analysing risks under misclassification, careful consideration of conditional probabilities is crucial.

OBJECTIVES:Type 1 diabetes is a risk factor for coronary heart disease. The underlying mechanism behind the accelerated atherosclerosis formation is not fully understood but may be related to the formation of oxidation products and advanced glycation end-products (AGEs). We aimed to examine the associations between the collagen oxidation product methionine sulfoxide; the collagen AGEs methylglyoxal hydroimidazolone (MG-H1), glucosepane, pentosidine, glucuronidine/LW-1; and serum receptors for AGE (RAGE) with measures of coronary artery disease in patients with long-term type 1 diabetes. METHODS:In this cross-sectional study, 99 participants with type 1 diabetes of ≥ 45-year duration and 63 controls without diabetes had either established coronary heart disease (CHD) or underwent Computed Tomography Coronary Angiography (CTCA) measuring total, calcified and soft/mixed plaque volume. Skin collagen methionine sulfoxide and AGEs were measured by liquid chromatography-mass spectrometry and serum sRAGE/esRAGE by ELISA. RESULTS:In the diabetes group, low levels of methionine sulfoxide (adjusted for age, sex and mean HbA1c) were associated with normal coronary arteries, OR 0.48 (95% CI 0.27-0.88). Glucuronidine/LW-1 was associated with established CHD, OR 2.0 (1.16-3.49). MG-H1 and glucuronidine/LW-1 correlated with calcified plaque volume (r = 0.23-0.28, p

Cellular stress response mechanisms normally function to enhance survival and allow for cells to return to homeostasis following an adverse event. Cancer cells often co-opt these same mechanisms as a means to evade apoptosis and mitigate a state of constant cellular stress. Activating transcription factor 5 (ATF5) is upregulated under diverse stress conditions and is overexpressed in a variety of cancers. It was demonstrated ATF5 is a survival factor in transformed, but not normal cells. However, the regulation of ATF5 is not fully understood. The purpose of the present study was to investigate miRNA regulation at the 3' untranslated region (UTR) of ATF5, with the goal of demonstrating a reversal of the upregulation of ATF5 induced under diverse cellular stress in cancer cells. A multifactorial approach using in silico analysis was employed to identify miRNAs 433-3p, 520b-3p, and 129-5p as potential regulators of ATF5, based on their predicted binding sites over the span of the ATF5 3' UTR. Luciferase reporter assay data validated all three miRNA candidates by demonstrating direct binding to the target ATF5 3'. However, functional studies revealed miR-520b-3p as the sole candidate able to reverse the upregulation of ATF5 protein under diverse cellular stress. Additionally, miR-520b-3p levels were inversely related to ATF5 mRNA under endoplasmic reticulum stress and amino acid deprivation. This is the first evidence that regulation at the 3' UTR is involved in modulating ATF5 levels under cellular stress and suggests an important role for miRNA-520b-3p in the regulation of ATF5.

ObjectiveOur objective is to compare the predictive accuracy of four recently established outcome models of patients hospitalized with coronavirus disease 2019 (COVID-19) published between January 1st and May 1st 2020.MethodsWe used data obtained from the Veterans Affairs Corporate Data Warehouse (CDW) between January 1st, 2020, and May 1st 2020 as an external validation cohort. The outcome measure was hospital mortality. Areas under the ROC (AUC) curves were used to evaluate discrimination of the four predictive models. The Hosmer-Lemeshow (HL) goodness-of-fit test and calibration curves assessed applicability of the models to individual cases.ResultsDuring the study period, 1634 unique patients were identified. The mean age of the study cohort was 68.8±13.4 years. Hypertension, hyperlipidemia, and heart disease were the most common comorbidities. The crude hospital mortality was 29% (95% confidence interval [CI] 0.27-0.31). Evaluation of the predictive models showed an AUC range from 0.63 (95% CI 0.60-0.66) to 0.72 (95% CI 0.69-0.74) indicating fair to poor discrimination across all models. There were no significant differences among the AUC values of the four prognostic systems. All models calibrated poorly by either overestimated or underestimated hospital mortality.ConclusionsAll the four prognostic models examined in this study portend high-risk bias. The performance of these scores needs to be interpreted with caution in hospitalized patients with COVID-19.

Abstract The recent emergence of Zika virus (ZIKV) has been concentrated in the Caribbean, Southeastern United States, and South- and Central America; resulting in travel-based cases being reported around the globe. As multi-disciplinary collaborations are combatting the ZIKV outbreak, the need to validate the sequence of existing strains has become apparent. Here, we report high-quality sequence data for multiple ZIKV strains made publicly available through the National Institutes of Health- (NIH) funded biorepository, BEI Resources (www.beiresources.org). Next-generation sequencing, 3′ rapid amplification of cDNA ends (RACE), and viral genome annotation pipelines generated GenBank sequence records for 16 BEI Resources strains. Minor variants, consensus mutations, and consensus insertions/deletions were identified within the viral stocks using next-generation sequencing (NGS) and consensus changes were confirmed with Sanger sequencing. Bioinformatics analyses of the sequencing results confirm that the virus stocks available to the scientific research community through BEI Resources adequately represent the viral population diversity of ZIKV.

Abstract The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

Abstract Background Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. Discussion Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. Conclusion Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.

During a large outbreak of Shiga toxin−producing Escherichia coli illness associated with an agricultural show in Australia, we used whole-genome sequencing to detect an IS1203v insertion in the Shiga toxin 2c subunit A gene of Shiga toxin−producing E. coli. Our study showed that clinical illness was mild, and hemolytic uremic syndrome was not detected.

Although many studies have reported on physical activity (PA) levels using accelerometers, a thorough description of the PA pattern in preschool children during their stay in the preschool, is lacking in the current literature. Furthermore, there remains a lack of understanding of the PA level and pattern in children in the lower end of the PA continuum. The first aim of this study was therefore to describe the PA pattern during a week-long stay in a preschool in all children born in 2011 (either three or four-year-olds) attending public preschools in a municipality in Norway. The second aim was to describe the PA level and pattern of the children who are the least physically active. This cross-sectional study included baseline data from 95% of children (N = 111) participating in a randomized controlled physical activity intervention (Active Kindergarten – Active Children study). The participants wore an Actigraph accelerometer, in week 39 in 2015, from when they arrived at the preschool on Monday morning and throughout their stay of five consecutive days. The amount of moderate- to vigorous-intensity PA (MVPA) per day ranged from 16 min to 116 min, and sedentary time ranged from 2.7 h to 6.5 h per day in the least and most sedentary child, respectively. The least physically active 25% of children were less active throughout the entire day, and only a few of them managed to achieve the recommended level of MVPA on any weekday. The physical activity levels and patterns among the least active children described in this study may help to inform interventions targeting this group.

Abstract Obesity and dyslipidemia are hallmarks of metabolic and cardiovascular diseases. Polydextrose (PDX), a soluble fiber has lipid lowering effects. We hypothesize that PDX reduces triglycerides and cholesterol by influencing gut microbiota, which in turn modulate intestinal gene expression. C57BL/6 male mice were fed a Western diet (WD) ±75 mg PDX twice daily by oral gavage for 14 days. Body weight and food intake were monitored daily. Fasting plasma lipids, caecal microbiota and gene expression in intestine and liver were measured after 14 days of feeding. PDX supplementation to WD significantly reduced food intake (p

Abstract The collagen- and calcium-binding EGF domains 1 (CCBE1) protein is necessary for lymphangiogenesis. Its C-terminal collagen-like domain was shown to be required for the activation of the major lymphangiogenic growth factor VEGF-C (Vascular Endothelial Growth Factor-C) along with the ADAMTS3 (A Disintegrin And Metalloproteinase with Thrombospondin Motifs-3) protease. However, it remained unclear how the N-terminal domain of CCBE1 contributed to lymphangiogenic signaling. Here, we show that efficient activation of VEGF-C requires its C-terminal domain both in vitro and in a transgenic mouse model. The N-terminal EGF-like domain of CCBE1 increased VEGFR-3 signaling by colocalizing pro-VEGF-C with its activating protease to the lymphatic endothelial cell surface. When the ADAMTS3 amounts were limited, proteolytic activation of pro-VEGF-C was supported by the N-terminal domain of CCBE1, but not by its C-terminal domain. A single amino acid substitution in ADAMTS3, identified from a lymphedema patient, was associated with abnormal CCBE1 localization. These results show that CCBE1 promotes VEGFR-3 signaling and lymphangiogenesis by different mechanisms, which are mediated independently by the two domains of CCBE1: by enhancing the cleavage activity of ADAMTS3 and by facilitating the colocalization of VEGF-C and ADAMTS3. These new insights should be valuable in developing new strategies to therapeutically target VEGF-C/VEGFR-3-induced lymphangiogenesis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ObjectiveTo assess which mental health-related states of being are perceived as diseases by psychiatrists, non-psychiatric physicians, nurses, parliament members and laypeople.Design and settingA population-based, mailed survey in Finland.ParticipantsRespondents from a random sample of 3000 laypeople, 1500 physicians, 1500 nurses and all 200 members of the parliament (MPs) of Finland.Primary outcome measuresRespondents’ perspectives on 20 mental health-related states of being as diseases, measuring the extent of agreement with the claim: ‘[This state of being] is a disease’.ResultsOf the 6200 people approached, we received 3259 eligible responses (53%). Two conditions (schizophrenia and autism) were considered to be diseases by at least 75% and two states (grief and homosexuality) were considered not to be diseases by at least 75% in each group. A majority (at least 50% in each group) considered seven states as diseases (anorexia, attention deficit hyperactivity disorder, bulimia, depression, generalised anxiety disorder, panic disorder and personality disorder) and three not to be diseases (absence of sexual desire, premature ejaculation and transsexualism). In six states, there was a wide divergence of opinion (alcoholism, drug addiction, gambling addiction, insomnia, social anxiety disorder and work exhaustion). Psychiatrists were significantly more inclined to considering states of being as diseases relative to other groups, followed by non-psychiatric physicians, nurses, MPs and laypeople.ConclusionsRespondents agreed that some conditions, such as schizophrenia and autism, are diseases and other states, such as grief and homosexuality, are not; for others, there was considerable disagreement. Psychiatrists are more inclined to consider mental health-related states of being as diseases compared with other physicians, who, in turn, are more inclined than other constituencies. Understanding notions of disease may underlie important debates in public policy and practice in areas of mental health and behaviour, and have implications for resource allocation and stigma.

Climate change is modifying temperature and precipitation regimes across all seasons in northern ecosystems. Summer temperatures are higher, growing seasons extend into spring and fall and snow cover conditions are more variable during winter. The resistance of dominant tundra species to these season-specific changes, with each season potentially having contrasting effects on their growth and survival, can determine the future of tundra plant communities under climate change. In our study, we evaluated the effects of several spring/summer and winter climatic variables (i.e., summer temperature, growing season length, growing degree days, and number of winter freezing days) on the resistance of the dwarf shrub Empetrum nigrum. We measured over six years the ability of E. nigrum to keep a stable shoot growth, berry production, and vegetative cover in five E. nigrum dominated tundra heathlands, in a total of 144 plots covering a 200-km gradient from oceanic to continental climate. Overall, E. nigrum displayed high resistance to climatic variation along the gradient, with positive growth and reproductive output during all years and sites. Climatic conditions varied sharply among sites, especially during the winter months, finding that exposure to freezing temperatures during winter was correlated with reduced shoot length and berry production. These negative effects however, could be compensated if the following growing season was warm and long. Our study demonstrates that E. nigrum is a species resistant to fluctuating climatic conditions during the growing season and winter months in both oceanic and continental areas. Overall, E. nigrum appeared frost hardy and its resistance was determined by interactions among different season-specific climatic conditions with contrasting effects.

The human cell lines HepG2, HuH-7, and Jurkat are commonly used for amplification of the RNA viruses present in environmental samples. To assist with assays by RNAseq, we sequenced these cell lines and developed a subtraction database that contains sequences expected in sequence data from uninfected cells. RNAseq data from cell lines infected with Sendai virus were analyzed to test host subtraction. The process of mapping RNAseq reads to our subtraction database vastly reduced the number non-viral reads in the dataset to allow for efficient secondary analyses.

Vascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, for example in the CNS and immune system. Here we describe a novel, unique VEGF-C form in the human reproductive system produced via cleavage by kallikrein-related peptidase 3 (KLK3), aka prostate-specific antigen (PSA). KLK3 activated VEGF-C specifically and efficiently through cleavage at a novel N-terminal site. We detected VEGF-C in seminal plasma, and sperm liquefaction occurred concurrently with VEGF-C activation, which was enhanced by collagen and calcium binding EGF domains 1 (CCBE1). After plasmin and ADAMTS3, KLK3 is the third protease shown to activate VEGF-C. Since differently activated VEGF-Cs are characterized by successively shorter N-terminal helices, we created an even shorter hypothetical form, which showed preferential binding to VEGFR-3. Using mass spectrometric analysis of the isolated VEGF-C-cleaving activity from human saliva, we identified cathepsin D as a protease that can activate VEGF-C as well as VEGF-D.

BACKGROUND:Vitamin A and D deficiency is prevalent in pregnant women worldwide. Both vitamins are involved in fetal skeletal development. A positive association between maternal vitamin D levels and offspring bone mineral density (BMD) at adulthood has been observed. The impact of maternal vitamin A status in pregnancy on offspring peak bone mass remains unclear. METHOD AND FINDINGS:Forty-one mother-child pairs were recruited from a population-based prospective cohort study in Trondheim, Norway, where pregnant women were followed from gestational week 17. Their term-born infants were followed from birth (1986-88). Regression analyses were performed for vitamin A (retinol), 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in maternal serum (gestational weeks 17, 33, 37) and cord blood. Offspring BMD and spine trabecular bone score (TBS), a measure of bone quality, were analyzed by dual x-ray absorptiometry at 26 years. Average levels during pregnancy of retinol, 25(OH)D and 1,25(OH)2D were 1.66 (0.32) μmol/L, 59.0 (20.6) nmol/L, and 251.3 (62.4) pmol/L, respectively. 1,25(OH)2D levels were similar in those with 25(OH)D levels 75 nmol/L. After adjustment for maternal age, BMI, smoking, and education, and offspring birth weight, maternal serum retinol was positively associated with offspring spine BMD [mean change 30.8 (CI 7.6, 54.0) mg/cm2 per 0.2 μmol/L retinol], and with offspring TBS, although non-significant (p = 0.08). No associations were found between maternal 25(OH)D and 1,25(OH)2D levels and offspring bone parameters. Vitamin levels in cord blood were not associated with offspring BMD or TBS. CONCLUSIONS:This is the first study to show an association between maternal vitamin A status and offspring peak bone mass. Our findings may imply increase future risk for osteoporotic fracture in offspring of mothers with suboptimal vitamin A level. No associations were observed between 25(OH)D and 1,25(OH)2D and offspring BMD.

Blue mold is a postharvest rot of pomaceous fruits caused by Penicillium expansum and a number of other Penicillium species. The genome of the highly aggressive P. expansum strain R19 was re-sequenced and analyzed together with the genome of the less aggressive P. solitum strain RS1. Whole genome scale similarities and differences were examined. A phylogenetic analysis of P. expansum, P. solitum, and several closely related Penicillium species revealed that the two pathogens isolated from decayed apple with blue mold symptoms are not each other’s closest relatives. Among a total of 10,560 and 10,672 protein coding sequences respectively, a comparative genomics analysis revealed 41 genes in P. expansum R19 and 43 genes in P. solitum RS1 that are unique to these two species. These genes may be associated with pome fruit–fungal interactions, subsequent decay processes, and mycotoxin accumulation. An intact patulin gene cluster consisting of 15 biosynthetic genes was identified in the patulin producing P. expansum strain R19, while only a remnant, seven-gene cluster was identified in the patulin-deficient P. solitum strain. However, P. solitum contained a large number of additional secondary metabolite gene clusters, indicating that this species has the potential capacity to produce an array of known as well as not-yet-identified products of possible toxicological or biotechnological interest.

Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). Using this model, we have demonstrated curative ex-vivo gene and cell therapy using a lentiviral vector to express FAH in autologous hepatocytes. To further evaluate the long-term clinical outcomes of this therapeutic approach, we continued to monitor one of these pigs over the course of three years. The animal continued to thrive off the protective drug NTBC, gaining weight appropriately, and maintaining sexual fecundity for the course of his life. The animal was euthanized 31 months after transplantation to perform a thorough biochemical and histological analysis. Biochemically, liver enzymes and alpha-fetoprotein levels remained normal and abhorrent metabolites specific to HT1 remained corrected. Liver histology showed no evidence of tumorigenicity and Masson’s trichrome staining revealed minimal fibrosis and no evidence of cirrhosis. FAH-immunohistochemistry revealed complete repopulation of the liver by transplanted FAH-positive cells. A complete histopathological report on other organs, including kidney, revealed no abnormalities. This study is the first to demonstrate long-term safety and efficacy of hepatocyte-directed gene therapy in a large animal model. We conclude that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1.

Patients with Gorham-Stout disease (GSD) have lymphatic vessels in their bones and their bones gradually disappear. Here, we report that mice that overexpress VEGF-C in bone exhibit a phenotype that resembles GSD. To drive VEGF-C expression in bone, we generated Osx-tTA;TetO-Vegfc double-transgenic mice. In contrast to Osx-tTA mice, Osx-tTA;TetO-Vegfc mice developed lymphatics in their bones. We found that inhibition of VEGFR3, but not VEGFR2, prevented the formation of bone lymphatics in Osx-tTA;TetO-Vegfc mice. Radiological and histological analysis revealed that bones from Osx-tTA;TetO-Vegfc mice were more porous and had more osteoclasts than bones from Osx-tTA mice. Importantly, we found that bone loss in Osx-tTA;TetO-Vegfc mice could be attenuated by an osteoclast inhibitor. We also discovered that the mutant phenotype of Osx-tTA;TetO-Vegfc mice could be reversed by inhibiting the expression of VEGF-C. Taken together, our results indicate that expression of VEGF-C in bone is sufficient to induce the pathologic hallmarks of GSD in mice.