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The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

IntroductionPsychosis spectrum disorders are characterized by both positive and negative symptoms, but whereas there is good effect of treatment on positive symptoms, there is still a scarcity of effective interventions aimed at reducing negative symptoms. Rumination has been proposed as an important and fundamental factor in the development and maintenance of symptoms across psychiatric diagnoses, and there is a need to develop effective interventions targeting rumination behaviors and negative symptoms in patients with psychotic disorders. The aim of the current study is to investigate the feasibility and acceptability of group rumination-focused cognitive behavioral therapy (RFCBT) in the treatment of young people with psychosis spectrum disorders as well as investigating potential indications of treatment efficacy.Methods and analysisThe study is a mixed-method clinical randomized controlled pilot trial with a target sample of 60 patients, who are randomized to either receive 13 weeks of group RFCBT or 13 weeks of treatment as usual (TAU). All patients are examined at the start of the project and at the 13-week follow-up. We will compare changes in outcomes from baseline to posttreatment between group RFCBT and TAU. In addition, qualitative analyzes are carried out to explore feasibility and acceptability and to uncover the patients' experience of receiving the intervention.

Prostate cancer screening using prostate-specific antigen (PSA) testing is controversial but remains prevalent in many countries. There is little information in Sweden or elsewhere on the spatial variation in PSA testing. This study aims to describe the spatio-temporal variation in PSA testing prior to a prostate cancer diagnosis in the Stockholm region at the municipality and small area levels. A population-based register study comprised men aged 40 years and over living in the Stockholm region during 2007-2016. For Stockholm in 2016, we reported the proportion of men who had a PSA test for the preceding one, two, five and ten years by ten-year age groups. The age-standardised proportion of men having a PSA test was reported for municipalities by calendar years. We used spatial smoothing for calculating the age-standardised proportion of men having a PSA test in a small area for each calendar year. In 2016, 74.0% and 77.8% of men aged 60-69 and 70-79 years respectively had taken a PSA test in the previous ten years. The municipalities of Danderyd and Ekerö showed high proportions of PSA testing. A marked heterogeneity in such proportions within each municipality was observed. The odds ratio for having a PSA test for those born in Sweden was 2.22 (95% CI 2.00-2.52). Opportunistic PSA testing is widespread with three quarters of men in their sixties and seventies having had a test in the preceding decade. We found evidence for marked geographical heterogeneity, where more affluent and metropolitan areas had higher levels of testing. Variations in PSA testing was associated with socio-economic position and demographic factors including education, income and country of birth.

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.

[This corrects the article DOI: 10.1371/journal.pone.0300141.].

BackgroundGlobal evidence on psychosis is dominated by studies conducted in Western, high-income countries. The objectives of the Study of Context Of Psychoses to improve outcomes in Ethiopia (SCOPE) are (1) to generate rigorous evidence of psychosis experience, epidemiology and impacts in Ethiopia that will illuminate aetiological understanding and (2) inform development and testing of interventions for earlier identification and improved first contact care that are scalable, inclusive of difficult-to-reach populations and optimise recovery.MethodsThe setting is sub-cities of Addis Ababa and rural districts in south-central Ethiopia covering 1.1 million people and including rural, urban and homeless populations. SCOPE comprises (1) formative work to understand care pathways and community resources (resource mapping); examine family context and communication (ethnography); develop valid measures of family communication and personal recovery; and establish platforms for community engagement and involvement of people with lived experience; (2a) a population-based incidence study, (2b) a case-control study and (2c) a cohort study with 12 months follow-up involving 440 people with psychosis (390 rural/Addis Ababa; 50 who are homeless), 390 relatives and 390 controls. We will test hypotheses about incidence rates in rural vs. urban populations and men vs. women; potential aetiological role of khat (a commonly chewed plant with amphetamine-like properties) and traumatic exposures in psychosis; determine profiles of needs at first contact and predictors of outcome; (3) participatory workshops to develop programme theory and inform co-development of interventions, and (4) evaluation of the impact of early identification strategies on engagement with care (interrupted time series study). Findings will inform development of (5) a protocol for (5a) a feasibility cluster randomised controlled trial of interventions for people with recent-onset psychosis in rural settings and (5b) two uncontrolled pilot studies to test acceptability, feasibility of co-developed interventions in urban and homeless populations.

IntroductionMajor Depressive Disorder (MDD) is one of the most prevalent mental disorders worldwide with significant personal and public health consequences. After an episode of MDD, the likelihood of relapse is high. Therefore, there is a need for interventions that prevent relapse of depression when outpatient mental health care treatment has ended. This scoping review aimed to systematically map the evidence and identify knowledge gaps in interventions that aimed to promote recovery from MDD for patients transitioning from outpatient mental health services to primary care.Materials and methodsWe followed the guidance by Joanna Briggs Institute in tandem with the PRISMA extension for Scoping Reviews checklist. Four electronic databases were systematically searched using controlled index-or thesaurus terms and free text terms, as well as backward and forward citation tracking of included studies. The search strategy was based on the identification of any type of intervention, whether simple, multicomponent, or complex. Three authors independently screened for eligibility and extracted data.Results18 studies were included for review. The studies had high heterogeneity in design, methods, sample size, recovery rating scales, and type of interventions. All studies used several elements in their interventions; however, the majority used cognitive behavioural therapy conducted in outpatient mental health services. No studies addressed the transitioning phase from outpatient mental health services to primary care. Most studies included patients during their outpatient mental health care treatment of MDD.ConclusionsWe identified several knowledge gaps. Recovery interventions for patients with MDD transitioning from outpatient mental health services to primary care are understudied. No studies addressed interventions in this transitioning phase or the patient's experience of the transitioning process. Research is needed to bridge this gap, both regarding interventions for patients transitioning from secondary to primary care, and patients' and health care professionals' experiences of the interventions and of what promotes recovery.RegistrationA protocol was prepared in advance and registered in Open Science Framework (https://osf.io/ah3sv), published in the medRxiv server (https://doi.org/10.1101/2022.10.06.22280499) and in PLOS ONE (https://doi.org/10.1371/journal.pone.0291559).

Arachidonic acid (AA) is involved in inflammation and plays a role in growth and brain development in infants. We previously showed that exposure of mouse sires to AA for three consecutive generations induces a cumulative change in fatty acid (FA) involved in inflammation and an increase in body and liver weight in the offspring. Here, we tested the hypothesis that paternal AA exposure changes the progeny's behavioral response to a proinflammatory insult, and asked whether tissue-specific FA are associated with that response. Male BALB/c mice were supplemented daily with three doses of AA for 10 days and crossed to non-supplemented females (n = 3/dose). Two-month-old unsupplemented male and female offspring (n = 6/paternal AA dose) were exposed to Gram-negative bacteria-derived lipopolysaccharides (LPS) or saline control two hours prior to open field test (OFT) behavioral analysis and subsequent sacrifice. We probed for significant effects of paternal AA exposure on: OFT behaviors; individual FA content of blood, hypothalamus and hypothalamus-free brain; hypothalamic expression profile of genes related to inflammation (Tnfa, Il1b, Cox1, Cox2) and FA synthesis (Scd1, Elovl6). All parameters were affected by paternal AA supplementation in a sex-specific manner. Paternal AA primed the progeny for behavior associated with increased anxiety, with a marked sex dimorphism: high AA doses acted as surrogate of LPS in males, realigning a number of OFT behaviors that in females were differential between saline and LPS groups. Progeny hypothalamic Scd1, a FA metabolism enzyme with documented pro-inflammatory activity, showed a similar pattern of differential expression between saline and LPS groups at high paternal AA dose in females, that was blunted in males. Progeny FA generally were not affected by LPS, but displayed non-linear associations with paternal AA doses. In conclusion, we document that paternal exposure to AA exerts long-term behavioral and biochemical effects in the progeny in a sex-specific manner.

Here we report the results of excavation and interdisciplinary study of the largest child and camelid sacrifice known from the New World. Stratigraphy, associated artifacts, and radiocarbon dating indicate that it was a single mass killing of more than 140 children and over 200 camelids directed by the Chimú state, c. AD 1450. Preliminary DNA analysis indicates that both boys and girls were chosen for sacrifice. Variability in forms of cranial modification (head shaping) and stable isotope analysis of carbon and nitrogen suggest that the children were a heterogeneous sample drawn from multiple regions and ethnic groups throughout the Chimú state. The Huanchaquito-Las Llamas mass sacrifice opens a new window on a previously unknown sacrificial ritual from fifteenth century northern coastal Peru. While the motivation for such a massive sacrifice is a subject for further research, there is archaeological evidence that it was associated with a climatic event (heavy rainfall and flooding) that could have impacted the economic, political and ideological stability of one of the most powerful states in the New World during the fifteenth century A.D.

IntroductionInternet-based interventions are called for within rehabilitation to meet the limited access to support for self-management after stroke. Therefore, a new intervention program, "Strategies for Empowering activities in Everyday life" (SEE) was developed. The aim of this study was to explore and describe how clients with stroke and their occupational therapists experienced the SEE intervention process and whether SEE has the potential to promote an active everyday life.MethodsA qualitative descriptive case study was designed. Four people with stroke (two of each sex, mean age 66,5 years) and their two occupational therapists (one of each sex) were included. A mix of data collection methods as interviews, assessments, registration forms and fieldnotes was used to uncover the participants' experiences and potential changes. Data were analysed with pattern matching.FindingsThe analysed data formed three categories: "Not being able to take on the internet-based intervention", "Being facilitated in the change process of everyday life through the internet-based intervention", and "Providing a new internet-based intervention is a transition from ordinary practice". These categories included two to four subcategories that reflected aspects of SEE feasibility and acceptability with a focus on content and delivery.ConclusionThe first test of the intervention indicates that the content and delivery of SEE can be feasible and acceptable both for clients and occupational therapists. The findings suggest that SEE has the potential to support clients' self-reflections and their adoption of strategies that influence engagement in daily activities and satisfaction with life in various ways. Further research with large-scale studies is needed.

[This corrects the article DOI: 10.1371/journal.pone.0281913.].

[This corrects the article DOI: 10.1371/journal.pone.0277767.].

PurposeMissing data is a key methodological consideration in longitudinal studies of aging. We described missing data challenges and potential methodological solutions using a case example describing five-year frailty state transitions in a cohort of older adults.MethodsWe used longitudinal data from the National Health and Aging Trends Study, a nationally-representative cohort of Medicare beneficiaries. We assessed the five components of the Fried frailty phenotype and classified frailty based on their number of components (robust: 0, prefrail: 1-2, frail: 3-5). One-, two-, and five-year frailty state transitions were defined as movements between frailty states or death. Missing frailty components were imputed using hot deck imputation. Inverse probability weights were used to account for potentially informative loss-to-follow-up. We conducted scenario analyses to test a range of assumptions related to missing data.ResultsMissing data were common for frailty components measured using physical assessments (walking speed, grip strength). At five years, 36% of individuals were lost-to-follow-up, differentially with respect to baseline frailty status. Assumptions for missing data mechanisms impacted inference regarding individuals improving or worsening in frailty.ConclusionsMissing data and loss-to-follow-up are common in longitudinal studies of aging. Robust epidemiologic methods can improve the rigor and interpretability of aging-related research.

BackgroundWater insecurity and inadequate sanitation have adverse impacts on the mental health of individuals.ObjectiveTo review and synthesize evidence on the relationship between water insecurity, inadequate sanitation, and mental health globally.Data sourcesRelevant studies were identified by searching PubMed, PsycINFO, and EMBASE databases from inception up to March 2023.Study eligibility criteriaOnly quantitative studies were included. The exposure was water insecurity and or inadequate sanitation. The outcome was common mental disorders (CMD: depression or anxiety), mental distress, mental health or well-being. There was no restriction on geographical location.ParticipantsGeneral population or people attending health facilities or other services.ExposureWater insecurity and/ or inadequate sanitation.Risk of biasThe effective Public Health Practice Project (EPHPP) assessment tool was used to assess quality of selected studies.Synthesis of resultsA meta-analysis was conducted using a random effects statistical model.ResultsTwenty-five studies were included, with 23,103 participants from 16 countries in three continents: Africa (Kenya, Ethiopia, Ghana, Uganda, South Africa, Malawi, Mozambique, and Lesotho), Asia (Nepal, Bangladesh, India, and Iran) and the Americas (Brazil, Haiti, Bolivia and Vietnam). There was a statistically significant association between water insecurity and CMD symptoms. Nine studies reported a continuous outcome (5,248 participants): overall standardized mean difference (SMD = 1.38; 95% CI = 0.88, 1.87). Five studies reported a binary outcome (5,776 participants): odds ratio 5.03; 95% CI = 2.26, 11.18. There was a statistically significant association between inadequate sanitation and CMD symptoms (7415 participants), overall SMD = 5.36; 95% CI = 2.51, 8.20.LimitationsMost of the included studies were cross-sectional which were unable to examine temporal relationships.ConclusionsWater insecurity and inadequate sanitation contribute to poorer mental health globally.Implications of key findingsInterventions to provide basic water, sanitation and psychosocial support, could substantially contribute to reducing the burden of CMD alongside other health and social benefits.Trial registrationPROSPERO registration number: CRD42022322528.

BackgroundAccess to quality mental health services in Ghana remains poor, yet little is known about the extent of the access gaps and provision of mental health services at the district level in Ghana. We aimed to conduct an analysis of mental health infrastructure and service provision in five districts in Ghana.MethodsA cross-sectional situation analysis was conducted using a standardised tool to collect secondary healthcare data, supplemented by interviews with key informants, across five purposively selected districts in Ghana. The Programme for Improving Mental Health Care (PRIME) situation analysis tool was adapted to the Ghanaian context and used for data collection.ResultsThe districts are predominantly rural (>60%). There were severe challenges with the provision of mental healthcare: there were no mental healthcare plans, supervision of the few mental health professionals was weak and unstructured, access to regular supplies of psychotropic medications was a major challenge, and psychological treatments were extremely limited given the lack of trained clinical psychologists. There were no available data on treatment coverage, but we estimate this to be ConclusionThere is poor mental health infrastructure across the five selected districts of Ghana. There are opportunities for strengthening mental health systems through interventions at the district healthcare organisation, health facility, and community levels. A standardised situation analysis tool is useful for informing district-level mental healthcare planning in low-resource settings in Ghana and potentially other sub-Saharan African countries.

MicroRNAs (miRNAs) are responsible for regulating gene expression post-transcriptionally. Are involved in several biological processes, such as wound healing. Understanding the miRNAs involved in this process is fundamental for the development of new therapies. So, due to the need to understand the role of these molecules, we aimed systematically review the literature in order to identify which miRNAs are involved in the wound healing and determine, through bioinformatics analysis, which signaling pathways are associated with these miRNAs. An electronic search was performed in the following databases: National Library of Medicine National Institutes of Health (PubMed), Science Direct, Scifinder, Scopus and Web of Science, using the descriptors: "(microRNA [MeSH])" and "(skin [MeSH])" and "(wound healing [MeSH])". After the search, two independent and previously calibrated reviewers selected the articles that analyzed the expression pattern of miRNAs in wound healing in in vivo studies, using the software Zotero bibliography manager. Following, bioinformatic analysis was performed using the software DIANA Tools, mirPath v.3 and the data was interpreted. The bioinformatics analysis revealed that on the day 1 there were 13 union pathways, eight of which were statistically significant. Still on the day 1, among the miRNAs that had a decrease in their expression, 12 of 17 union pathways found were statistically significant. On the day 5, among the miRNAs with an increase in expression, 16 union pathways were found, 12 of which were statistically significant. Finally, among the miRNAs with decreased expression, 11 of 15 union pathways found were statistically significant. Although it has been found substantial heterogeneity in the studies, with this systematic review, it was possible to study the panorama of miRNAs that may be altered in the wound healing. The present review summarizes existing evidence of miRNAs associated to wound healing, and these findings can contribute to new therapeutic approaches.

We present a study design and baseline results to establish the impact of interventions on peri-urban water access, security and quality in Kasai Oriental province of the Democratic Republic of the Congo. In standard development practice, program performance is tracked via monitoring and evaluation frameworks of varying sophistication and rigor. Monitoring and evaluation, while usually occurring nearly concurrently with program delivery, may or may not measure parameters that can identify performance with respect to the project's overall goals. Impact evaluations, often using tightly controlled trial designs and conducted over years, challenge iterative program evolution. This study will pilot an implementation science impact evaluation approach in the areas immediately surrounding 14 water service providers, at each surveying 100 randomly-selected households and conducting water quality assessments at 25 randomly-selected households and five water points every three months. We present preliminary point-of-collection and point-of-use baseline data. This study is utilizing a variety of short- and medium-term monitoring and impact evaluation methods to provide feedback at multiple points during the intervention. Rapid feedback monitoring will assess the continuity of water services, point-of-consumption and point-of-collection microbial water quality, household water security, household measures of health status, ability and willingness to pay for water and sanitation service provision, and service performance monitoring. Long-term evaluation will focus on the use of qualitative comparative analysis whereby we will investigate the combination of factors that lead to improved water access, security and quality.

ObjectivesWe examined loop diuretic treatment before and 1-year after transcatheter aortic valve implantation (TAVI), as a proxy for changes in symptom severity and secondly assessed how changes in loop diuretics related to mortality risk.BackgroundRandomized clinical trials suggest that approximately one third of patients undergoing TAVI do not achieve symptom relief, but "all-comer" data are lacking.MethodsUsing Danish nationwide registries, we identified all citizens, who underwent TAVI from 2008 to 2019 and were alive at 1-year post-discharge. Loop diuretic treatment pre-TAVI and at 1-year post-TAVI were assessed and grouped as receiving 1) no-loop diuretics; 2) low: 1-40 mg of furosemide (or equivalent bumetanide) daily; 3) intermediate: 41-120 mg of furosemide daily; or 4) high: >120 mg furosemide daily.ResultsAmong the 4431 patients undergoing TAVI, 2173 (49%) patients were not treated with loop diuretics at the time of TAVI, 918 (21%) had low-loop diuretics, 881 (20%) had intermediate-loop diuretics, and 459 (10%) had high-loop diuretics. At 1-year post-TAVI, 893 (20%) patients had increased, 1010 (23%) had reduced, and 2528 (57%) had unchanged loop diuretic treatment. The cumulative 5-year risk of death in patients surviving one year, was 61% (95% CI: 56.4% to 65.3%) in patients with increased and 47% (95% CI: 44.9% to 49.9%) in patients with reduced/unchanged loop diuretic treatment, respectively. In multivariable Cox proportional hazard analysis, increased loop diuretic treatment was associated with a higher risk of death compared with reduced/unchanged loop diuretic treatment (Hazard ratio: 1.4; 95% CI: 1.22 to 1.52).ConclusionsAmong patients undergoing TAVI, surviving one year, one fifth of patients had increased loop diuretic treatment, and a little over one fifth had reduced loop diuretic treatment 1-year post-procedure. In patients with increased diuretic treatment, the risk of death was higher compared to those with reduced/unchanged loop diuretic treatment.

In solid organ transplantation, donor-derived cell-free DNA (dd-cfDNA) is a promising universal noninvasive biomarker for allograft health, where high levels of dd-cfDNA indicate organ damage. Using Droplet Digital PCR (ddPCR), we aimed to develop an assay setup for monitoring organ health. We aimed to identify the least distinguishable percentage-point increase in the fraction of minute amounts of cfDNA in a large cfDNA background by using assays targeting single nucleotide polymorphisms (SNPs). We mimicked a clinical sample from a recipient in a number of spike-in experiments, where cfDNA from healthy volunteers were mixed. A total of 40 assays were tested and approved by qPCR and ddPCR. Limit of detection (LOD) was demonstrated to be approximately 3 copies per reaction, observed at a fraction of 0.002%, and which would equal 6 copies per mL plasma. Limit of quantification (LOQ) was 35 copies per reaction, estimated to 0.038%. The lowest detectable increase in percentage point of dd-cfDNA was approximately 0.04%. Our results demonstrated that ddPCR has great sensitivity, high precision, and exceptional ability to quantify low levels of cfDNA. The ability to distinguish small differences in mimicking dd-cfDNA was far beyond the desired capability. While these methodological data are promising, further prospective studies are needed to determine the clinical utility of the proposed method.

Common mental disorders (CMDs) and risky alcohol use are highly prevalent among people living with HIV, yet many do not receive treatment for these mental health problems. In Malawi, despite a mental health policy aiming to include mental healthcare into primary health care, many clients with HIV go unscreened and untreated for mental illnesses, indicating missed opportunities to offer mental health care to people living with HIV. The aim of this study was to determine the numbers and types of missed opportunities for screening and treatment of CMDs and risky alcohol use amongst a sample of people living with HIV attending anti-retroviral (ART) clinics in Zomba Malawi. A descriptive cross-sectional clinic survey was used, at three ART clinics in the Zomba district. Random sampling was conducted for all clients attending their ART clinics on specific days. The study surveyed 382 participants living with HIV. Of these participants, the majority were women (N = 247, 64.7%), and 87 (22.8%) screened positive for CMDs and/or alcohol misuse using the self-reporting questionnaire 20 (SRQ-20) and alcohol use disorder identification test (AUDIT). Of these, only 47 (54%) had been screened by health workers for CMDs or risky alcohol use in the past 12 months, and 66 (76%) wanted to receive treatment. Of the total sample of 382 participants, only 92 (24%) and 89 (23%) had been screened for CMDs or risky alcohol use by health workers. Failures by clinical officers and nurses to screen or treat CMDs and risky alcohol use in ART clinics represent missed opportunities to address the mental health of people living with HIV. Providing psychoeducation for staff, guidelines for screening and managing CMDs and alcohol use, increasing human resources, and accelerating implementation of the mental health policy in Malawi may be a few ways of improving mental health service provision at ART clinics in Malawi.

IntroductionBreast cancer is the most common cancer worldwide and the leading cause of cancer related deaths among women. The high incidence and mortality of breast cancer calls for improved prevention, diagnostics, and treatment, including identification of new prognostic and predictive biomarkers for use in precision medicine.Material and methodsWith the aim of compiling a cohort amenable to integrative study designs, we collected detailed epidemiological and clinical data, blood samples, and tumor tissue from a subset of participants from the prospective, population-based Norwegian Women and Cancer (NOWAC) study. These study participants were diagnosed with invasive breast cancer in North Norway before 2013 according to the Cancer Registry of Norway and constitute the Clinical and Multi-omic (CAMO) cohort. Prospectively collected questionnaire data on lifestyle and reproductive factors and blood samples were extracted from the NOWAC study, clinical and histopathological data were manually curated from medical records, and archived tumor tissue collected.ResultsThe lifestyle and reproductive characteristics of the study participants in the CAMO cohort (n = 388) were largely similar to those of the breast cancer patients in NOWAC (n = 10 356). The majority of the cancers in the CAMO cohort were tumor grade 2 and of the luminal A subtype. Approx. 80% were estrogen receptor positive, 13% were HER2 positive, and 12% were triple negative breast cancers. Lymph node metastases were present in 31% at diagnosis. The epidemiological dataset in the CAMO cohort is complemented by mRNA, miRNA, and metabolomics analyses in plasma, as well as miRNA profiling in tumor tissue. Additionally, histological analyses at the level of proteins and miRNAs in tumor tissue are currently ongoing.ConclusionThe CAMO cohort provides data suitable for epidemiological, clinical, molecular, and multi-omics investigations, thereby enabling a systems epidemiology approach to translational breast cancer research.

Questionable authorship practices in scientific publishing are detrimental to research quality and management. The existing literature dealing with the prevalence, and perceptions, of such practices has focused on the medical sciences, and on experienced researchers. In contrast, this study investigated how younger researchers (PhD students) from across the faculties view fair authorship attribution, their experience with granting guest authorships to more powerful researchers and their reasons for doing so. Data for the study were collected in a survey of European PhD students. The final dataset included 1,336 participants from five European countries (Denmark, Hungary, Ireland, Portugal, and Switzerland) representing all major disciplines. Approximately three in ten reported that they had granted at least one guest authorship to "a person in power". Half of these indicated that they had done so because they had been told to do so by the person in power. Participants from the medical, natural and technical sciences were much more likely to state that they had granted a guest authorship than those from other faculties. We identified four general views about what is sufficient for co-authorship. There were two dominant views. The first (inclusive view) considered a broad range of contributions to merit co-authorship. The second (strongly writing-oriented) emphasised that co-authors must have written a piece of the manuscript text. The inclusive view dominated in the natural, technical, and medical sciences. Participants from other faculties were more evenly distributed between the inclusive and writing oriented view. Those with an inclusive view were most likely to indicate that they have granted a guest authorship. According to the experiences of our participants, questionable authorship practices are prevalent among early-career researchers, and they appear to be reinforced through a combination of coercive power relations and dominant norms in some research cultures, particularly in the natural, technical, and medical sciences.

BACKGROUND: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial. METHODS: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed. RESULTS: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH. CONCLUSION: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.

Recordings of smartphone use for contacts are increasingly being used as alternative or supplementary measurement methods for social interactions and social relations in the health sciences. Less work has been done to understand how these measures compare with widely used survey-based information. Using data from the Copenhagen Network Study, we investigated whether derived survey and smartphone measures on two widely studied concepts; Social integration and Tie strength were associated. The study population included 737 college students (mean age 21.6 years, Standard deviation: 2.6), who were followed with surveys and continuous recordings of smartphone usage over a one-month period. We derived self-reported and smartphone measures of social integration (social role diversity, social network size), and tie strength (contact frequency, duration and tie reciprocity). Logistic regression models were used to assess the associations between smartphone derived and self-reported measures adjusting for gender, age and co-habitation. Larger call and text message networks were associated with having a high self-reported social role diversity, and a high self-reported social contact frequency was likewise associated with having both frequent call and text message interactions, longer call duration and a higher level of reciprocity in call and text message communication. Self-reported aspects of social relations and smartphone measures of social interactions have considerable overlap supporting a measurement of similar underlying concepts.

The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme α-galactosidase A. In the present study we present the molecular and biochemical data of the Danish Fabry cohort and report 20 years' (2001-2020) experience in cascade genetic screening at the Danish National Fabry Disease Center. The Danish Fabry cohort consisted of 26 families, 18 index patients (9 males and 9 females, no available data for 8 index-patients) and 97 family members with a pathogenic GLA variant identified by cascade genetic testing (30 males and 67 females). Fourteen patients (5 males and 9 females; mean age of death 47.0 and 64.8 years respectively) died during follow-up. The completeness of the Fabry patient identification in the country has resulted in a cohort of balanced genotypes according to gender (twice number of females compared to males), indicating that the cohort was not biased by referral, and further resulted in earlier diagnosis of the disease by a lower age at diagnosis in family members compared to index-patients (mean age at diagnosis: index-patients 42.2 vs. family members 26.0 years). Six previously unreported disease-causing variants in the GLA gene were discovered. The nationwide screening and registration of Fabry disease families provide a unique possibility to establish a complete cohort of Fabry patients and to advance current knowledge of this inherited rare lysosomal storage disorder.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

Mental disorders often emerge during adolescence and have been associated with age-related differences in connection strengths of brain networks (static functional connectivity), manifesting in non-typical trajectories of brain development. However, little is known about the direction of information flow (directed functional connectivity) in this period of functional brain progression. We employed dynamic graphical models (DGM) to estimate directed functional connectivity from resting state functional magnetic resonance imaging data on 1143 participants, aged 6 to 17 years from the healthy brain network (HBN) sample. We tested for effects of age, sex, cognitive abilities and psychopathology on estimates of direction flow. Across participants, we show a pattern of reciprocal information flow between visual-medial and visual-lateral connections, in line with findings in adults. Investigating directed connectivity patterns between networks, we observed a positive association for age and direction flow from the cerebellar to the auditory network, and for the auditory to the sensorimotor network. Further, higher cognitive abilities were linked to lower information flow from the visual occipital to the default mode network. Additionally, examining the degree networks overall send and receive information to each other, we identified age-related effects implicating the right frontoparietal and sensorimotor network. However, we did not find any associations with psychopathology. Our results suggest that the directed functional connectivity of large-scale resting-state brain networks is sensitive to age and cognition during adolescence, warranting further studies that may explore directed relationships at rest and trajectories in more fine-grained network parcellations and in different populations.

Background and aim Smoking is one of the most important causes of socioeconomic disparities in morbidity and mortality. The aim of this study was to examine if beliefs about harms of smoking differed across gender, smoking status and education among Norwegian adults born between 1899 and 1969. Methods Using data from a nationally representative survey of smoking habits and a multinomial logit/negative binomial two-stage hurdle model design, we examined (first hurdle) the associations between birth cohort, gender, education and smoking status and four beliefs about cigarette smoking: i) smoking is not harmful, ii) do not know if smoking is harmful, iii) any number of cigarettes per day (CPD) is harmful and iv) smoking more than a given nonzero number of CPD is harmful, and (second hurdle) the predicted number of CPD that could be smoked without causing harm (from outcome iv). Results The probability of believing that smoking was not harmful was close to zero, regardless of birth cohort, sex, education and smoking status. The probability of not knowing if smoking was harmful decreased from around 0.7 to almost zero across cohorts. The probability of believing that smoking more than zero CPD was harmful increased from less than 0.1 to around 0.7, while the probability of believing that there is some safe level of smoking increased with cohorts born from 1900 to 1930 before declining. Respondents with primary/secondary education consistently believed smoking to be less harmful compared to respondents with tertiary education, but cohort trajectories were similar. Discussion The similar birth cohort trajectories in beliefs about the harms of smoking do not support the idea that Norwegian adults with lower education has had qualitatively different beliefs about the harmfulness of smoking compared to those with higher education. The persistent and large socioeconomic gradient is likely a result of other factors.

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants for which human exposure remains ubiquitous. This is of concern since these chemicals can perturb development and cause adverse health effects. For instance, DE-71, a technical mixture of PBDEs, can induce liver toxicity as well as reproductive and developmental toxicity. DE-71 can also disrupt the thyroid hormone (TH) system which may induce developmental neurotoxicity indirectly. However, in developmental toxicity studies, it remains unclear how DE-71 exposure affects the offspring’s thyroid hormone system and if this dose-dependently relates to neurodevelopmental effects. To address this, we performed a rat toxicity study by exposing pregnant dams to DE-71 at 0, 40 or 60 mg/kg/day during perinatal development from gestational day 7 to postnatal day 16. We assessed the TH system in both dams and their offspring, as well as potential hearing and neurodevelopmental effects in prepubertal and adult offspring. DE-71 significantly reduced serum T4 and T3 levels in both dams and offspring without a concomitant upregulation of TSH, thus inducing a hypothyroxinemia-like effect. No discernible effects were observed on the offspring’s brain function when assessed in motor activity boxes and in the Morris water maze, or on offspring hearing function. Our results, together with a thorough review of the literature, suggest that DE-71 does not elicit a clear dose-dependent relationship between low serum thyroxine (T4) and effects on the rat brain in standard behavioral assays. However, low serum TH levels are in themselves believed to be detrimental to human brain development, thus we propose that we lack assays to identify developmental neurotoxicity caused by chemicals disrupting the TH system through various mechanisms.

Monitoring specific underlying causes of death in solid organ transplant (SOT) recipients is important in order to identify emerging trends and health challenges. This retrospective cohort study includes all SOT recipients transplanted at Rigshospitalet between January 1st, 2010 and December 31st, 2019. The underlying cause of death was determined using the newly developed Classification of Death Causes after Transplantation (CLASS) method. Cox regression analyses assessed risk factors for all-cause and cause-specific mortality. Of the 1774 SOT recipients included, 299 patients died during a total of 7511 person-years of follow-up (PYFU) with cancer (N = 57, 19%), graft rejection (N = 55, 18%) and infections (N = 52, 17%) being the most frequent causes of death. We observed a lower risk of all-cause death with increasing transplant calendar year (HR 0.91, 95% CI 0.86–0.96 per 1-year increase), alongside death from graft rejection (HR 0.84 per year, 95% CI 0.74–0.95) and death from infections (HR 0.86 per year, 95% CI 0.77–0.97). Further, there was a trend towards lower cumulative incidence of death from cardiovascular disease, graft failure and cancer in more recent years, while death from other organ specific and non-organ specific causes did not decrease. All-cause mortality among SOT recipients has decreased over the past decade, mainly due to a decrease in graft rejection- and infection-related deaths. Conversely, deaths from a broad range of other causes have remained unchanged, suggesting that cause of death among SOT recipients is increasingly diverse and warrants a multidisciplinary effort and attention in the future.

Background Redundancy is an unethical, unscientific, and costly challenge in clinical health research. There is a high risk of redundancy when existing evidence is not used to justify the research question when a new study is initiated. Therefore, the aim of this study was to synthesize meta-research studies evaluating if and how authors of clinical health research studies use systematic reviews when initiating a new study. Methods Seven electronic bibliographic databases were searched (final search June 2021). Meta-research studies assessing the use of systematic reviews when justifying new clinical health studies were included. Screening and data extraction were performed by two reviewers independently. The primary outcome was defined as the percentage of original studies within the included meta-research studies using systematic reviews of previous studies to justify a new study. Results were synthesized narratively and quantitatively using a random-effects meta-analysis. The protocol has been registered in Open Science Framework (https://osf.io/nw7ch/). Results Twenty-one meta-research studies were included, representing 3,621 original studies or protocols. Nineteen of the 21 studies were included in the meta-analysis. The included studies represented different disciplines and exhibited wide variability both in how the use of previous systematic reviews was assessed, and in how this was reported. The use of systematic reviews to justify new studies varied from 16% to 87%. The mean percentage of original studies using systematic reviews to justify their study was 42% (95% CI: 36% to 48%). Conclusion Justification of new studies in clinical health research using systematic reviews is highly variable, and fewer than half of new clinical studies in health science were justified using a systematic review. Research redundancy is a challenge for clinical health researchers, as well as for funders, ethics committees, and journals.

Introduction Temporomandibular disorders (TMD) are comprised by a heterogenous group of diagnoses with multifaceted and complex etiologies. Although diseases of the musculoskeletal system and connective tissue (MSD) have been reported as risk factors for developing TMD, no nationwide population-based registry studies have been conducted to investigate this possible link. The aim of this study was to investigate the association between MSD and TMD in a population-based sample using Swedish registry data, and to further investigate the difference in such association between patients diagnosed with TMD in a hospital setting and patients surgically treated for the condition. Materials and methods Population based case-control study using Swedish nationwide registry data. Data was collected between 1998 and 2016 from 33 315 incident cases and 333 122 controls aged ≥18, matched for sex, age, and living area. Cases were stratified into non-surgical (NS), surgically treated once (ST1) and surgically treated twice or more (ST2). Information on MSD exposure (ICD-10 M00-M99) was collected between 1964 and 2016. Odds ratios were calculated using conditional logistic regression, adjusted for country of birth, educational level, living area, and mental health comorbidity. Results A significant association between MSD and the development of TMD was found for all diagnostic categories: arthropathies (OR 2.0, CI 1.9–2.0); systemic connective tissue disorders (OR 2.3, CI 2.1–2.4); dorsopathies (OR 2.2, CI 2.1–2.2); soft tissue disorders (OR 2.2, CI 2.2–2.3); osteopathies and chondropathies (OR 1.7, CI 1.6–1.8); and other disorders of the musculoskeletal system and connective tissue (OR 1.9, CI 1.8–2.1). The associations were generally much stronger for TMD requiring surgical treatment. The diagnostic group with the strongest association was inflammatory polyarthropathies, M05-M14 (OR 11.7, CI 8.6–15.9), which was seen in the ST2 group. Conclusions Patients with MSD diagnoses have a higher probability of being diagnosed with TMD, in comparison to individuals without MSD. This association is even stronger for TMD that requires surgery. The results are in line with earlier findings, but present new population-based evidence of a possible causal relationship between MSD and TMD, even after adjusting for known confounders. Both dentists and physicians should be aware of this association and be wary of early signs of painful TMD among patients with MSD, to make early referral and timely conservative treatment possible.

Life-time prevalence of low back pain (LBP) in children and adolescents varies from 7% to 72%. Disc changes on magnetic resonance imaging (MRI) have been reported in up to 44% of children with earliest observations around pre-puberty. In this longitudinal cohort study, our objective was to determine the natural history of disc changes from childhood to early adulthood, and the possible association of these changes to LBP. Healthy 8-year-old schoolchildren were recruited for this longitudinal study consisting of a semi-structured interview, a clinical examination, and an MRI investigation at the age of 8-9 (Y8), 11-12 (Y12) and 18-19 (Y19) years. The interview inquired about LBP without trauma. T2-weighted sagittal MRI of the lumbar spine was acquired. Life-long prevalence of LBP was determined, and the disc signal intensity (SI) at the three lowest lumbar levels was assessed both visually using the Schneiderman classification (Bright-Speckled-Dark), and digitally using the disc to cerebrospinal fluid -SI ratio. Possible associations between SI changes and LBP were analyzed. Ninety-four of 208 eligible children were included at Y8 in 1994, 13 and 23 participants were lost to follow-up at Y12 and Y19, respectively. Prevalence of LBP increased after the pubertal growth spurt reaching 54% at Y19. On MRI, 18%, 10% and 38% of participants had disc SI changes at Y8, Y12 and Y19, respectively. No significant associations between self-reported LBP and either qualitative or quantitative disc SI changes were observed at any age. Life-time prevalence of LBP reached 54% by early adulthood. Disc SI changes on MRI traditionally labeled as degenerative were seen earlier than previously reported. Changes in disc SI were not associated with the presence of LBP in childhood, adolescence or early adulthood.

IntroductionManagement of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides.ObjectiveThe aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?.Material and methods45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry.ResultsStudy 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)).ConclusionCGMP can be a relevant supplement for the treatment of PKU.

Since they were first introduced to the United States more than 50 years ago, invasive carp have rapidly colonized rivers of the Mississippi River Basin, with detrimental effects on native aquatic species. Their continued range expansion, and potential for subsequent invasion of the Great Lakes, has led to increased concern for the susceptibility of as-yet uncompromised lotic and lentic systems in the central United States. Because invasive carp eggs and larvae must drift in the river current for the first several days following spawning, numerical drift modeling has emerged as a useful technique for determining whether certain river systems and reaches have the potential to support suspension-to-hatching survival of invasive carp eggs, a critical first step in recruitment. Here we use one such numerical modeling approach, the Fluvial Egg Drift Simulator (FluEgg), to estimate bighead carp (Hypophthalmichthys nobilis) egg hatching success and larval retention in a 47.8-kilometer (km) reach of the multi-thread St. Croix River, Minnesota and Wisconsin, United States. We explore three approaches for obtaining the hydraulic data required by FluEgg, parameterizing the model with either (a) field hydraulic data collected within the main channel during a high-flow event, or hydraulic data output from a one-dimensional hydrodynamic model with both (b) steady, and (c) unsteady flows. We find that the three approaches, along with the range of water temperatures and discharge used in simulations, produce vastly different predictions of streamwise transport and in-river egg hatching probability (0% for field data, 0 to 96% for steady-state hydraulic modeling, and 1.8 to 65% for unsteady modeling). However, all FluEgg simulations, regardless of the source of hydraulic data, predicted that no larvae reach the gas bladder inflation stage within the study reach where nursery habitat is abundant. Overall, these results indicate that the lower St. Croix River is suitable for invasive carp spawning and egg suspension until hatching for a range of discharge and water temperatures. These results highlight the role of complex channel hydraulics and morphology, particularly multi-thread reaches, and their inclusion in ecohydraulic-suitability modeling to determine susceptibility of river systems for invasive carp reproduction. Our work also emphasizes the scientific value of multi-dimensional hydrodynamic models that can capture the spatial heterogeneity of flow fields in geomorphically complex rivers. This work may help to guide management efforts based on the targeted monitoring and control and improve invasive carp egg and larvae sampling efficiency.

Background and aims Alcoholic hepatitis (AH) is characterized by acute liver failure, neurocognitive impairment and renal failure. Severe inflammatory reactions are also known to occur in AH. Inflammation and bacterial translocation in the gut are thought to have major impact on disease development and progression. The mortality rate for AH is close to 50%. We aimed to assess the efficacy of rifaximin in treating AH and its impact on inflammation and metabolism. Methods The trial was approved by relevant authorities (EudraCT no: 2014-02264-33, Scientific Ethics Committee, jr. no: H-1-2014-056). Primary outcomes were changes in metabolic and inflammatory markers. Secondary outcomes were portal hypertension, kidney and neurocognitive function. Results Thirty-two patients were randomized to standard medical therapy (SMT) or SMT plus rifaximin, allocation was concealed. Four patients in the SMT group and five patients in the SMT + rifaximin group died due to AH and liver failure. No adverse events related to the study medication were observed. We found no significant differences in amino acids or inflammation markers (IL-2, IL-6, IL-8, IL-10, TNF-α, interferon-γ) between the groups after 28 and 90 days. Conclusion Rifaximin does not alter inflammation or metabolism in patients with AH.

This study explores the risk for cancer by level of antibodies to the anaerobe oral bacteria of periodontitis Tannerella forsythia (TF), Porphyromonas gingivalis (PG), and Treponema denticola (TD) all three collectively termed the red complex, and the facultative anaerobe bacterium Aggregatibacter actinomycetemcomitans (AA). The prospective cohort, the Oslo II-study from 2000, the second screening of the Oslo study of 1972/73, has been followed for 17 ½ years with regard to cancer incidence and mortality. A random sample of 697 elderly men comprised the study cohort. The antibody results measured by enzyme linked immunosorbent assay (ELISA) were used in the Cox proportional hazards analyses, and quartile risk on cancer incidence in a 17 ½ years follow-up. Among the 621 participants with no prior cancer diagnoses, 221 men developed cancer. The incidence trend was inverse, and the results are shown as 1st quartile of highest value and 4th as lowest of antibody levels. The results of the Cox proportional regression analyses showed that TF inversely predicts bladder cancer (n = 22) by Hazard Ratio (HR) = 1.71 (95% CI: 1.12, 2.61). TD inversely predicts colon cancer (n = 26) by HR = 1.52 (95% CI: 1.06, 2.19) and bladder cancer (n = 22) by HR = 1.60 (95% CI: 1.05, 2.43). Antibodies to two oral bacteria, TF and TD, showed an inverse risk relationship with incidence of specific cancers: TF bladder cancer, TD bladder and colon cancer. Lowered immunological response to the oral infection, periodontitis, is shown to be a risk factor in terms of cancer aetiology.

Accelerated epigenetic ageing, a promising marker of disease risk, has been detected in peripheral blood cells of atherosclerotic patients, but evidence in the vascular wall is lacking. Understanding the trends of epigenetic ageing in the atheroma may provide insights into mechanisms of atherogenesis or identify targets for molecular therapy. We surveyed DNA methylation age in two human artery samples: a set of donor-matched, paired atherosclerotic and healthy aortic portions, and a set of carotid artery atheromas. The well-characterized pan-tissue Horvath epigenetic clock was used, together with the Weidner whole-blood-specific clock as validation. For the first time, we document dynamic DNA methylation age mosaicism of the vascular wall that is atherosclerosis-related, switches from acceleration to deceleration with chronological ageing, and is consistent in human aorta and carotid atheroma. At CpG level, the Horvath epigenetic clock showed modest differential methylation between atherosclerotic and healthy aortic portions, weak association with atheroma histological grade and no clear evidence for participation in atherosclerosis-related cellular pathways. Our data suggest caution when assigning a unidirectional DNA methylation age change to the atherosclerotic arterial wall. Also, the results support previous conclusions that epigenetic ageing reflects non-disease-specific cellular alterations.

Reallocations of time between daily activities such as sleep, sedentary behavior and physical activity are differentially associated with markers of physical, mental and social health. An individual's most desirable allocation of time may differ depending on which outcomes they value most, with these outcomes potentially competing with each other for reallocations. We aimed to develop an interactive app that translates how self-selected time reallocations are associated with multiple health measures. We used data from the Australian Child Health CheckPoint study (n = 1685, 48% female, 11-12 y), with time spent in daily activities derived from a validated 24-h recall instrument, %body fat from bioelectric impedance, psychosocial health from the Pediatric Quality of Life Inventory and academic performance (writing) from national standardized tests. We created a user-interface to the compositional isotemporal substitution model with interactive sliders that can be manipulated to self-select time reallocations between activities. The time-use composition was significantly associated with body fat percentage (F = 2.66, P < .001), psychosocial health (F = 4.02, P < .001), and academic performance (F = 2.76, P < .001). Dragging the sliders on the app shows how self-selected time reallocations are associated with the health measures. For example, reallocating 60 minutes from screen time to physical activity was associated with -0.8 [95% CI -1.0 to -0.5] %body fat, +1.9 [1.4 to 2.5] psychosocial score and +4.5 [1.8 to 7.2] academic performance. Our app allows the health associations of time reallocations to be compared against each other. Interactive interfaces provide flexibility in selecting which time reallocations to investigate, and may transform how research findings are disseminated.

Black soldier fly (Hermetia illucens) larvae can convert biowaste and by-products into body mass high in protein (~40% dry matter, DM) and lipid (~30% DM). However, the type of rearing substrate also affects the larval body composition and thus its nutritional value. Hitherto, it remains unclear how and to what extent the larval body composition can be altered by the substrate. This study was therefore performed to examine the possibilities of modifying larval body composition using different rearing substrates. To investigate this, 5-days old larvae were reared for seven days on different locally available waste and by-products: brewer's spent grain, mitigation mussels (Mytilus edulis), rapeseed cake, and shrimp waste meal (Pandalus borealis). Larval composition and performance were compared to larvae reared on a commercial chicken feed as well as a mixed feed (mixture of chicken feed and by-products, with a similar macronutrient composition to chicken feed). Larval body weight was recorded daily to determine growth over time whereas larvae and substrates were sampled at the start and end of the trial and analysed for their nutritional composition. The type of rearing substrate affected both larval body composition and growth performance. There was a clear relation between the nutritional composition of the substrate and larvae for certain fatty acids. Larvae reared on marine-based waste substrates contained a higher share of omega-3 fatty acids than larvae reared on the other substrates, indicating an accumulation of omega-3 fatty acids from the substrate. There was a strong positive linear correlation between the ash content in the substrate and larvae whereas larval lipid, protein, amino acid, and chitin content seemed more affected by larval development. Overall, this study showed that the rearing substrate affects larval composition and development, and that larval composition of certain nutrients can be tailored depending on further food and feed applications.

The United Nations Convention on the Rights of the Child has substantiated play for play's sake, thus focusing on the doing or being of play rather than any potentially desired outcomes. Examining this type of play from the perspective of the child acknowledges children as meaning-makers. A scoping review was conducted to expose and map the extent of the evidence available in the emerging and diverse field of children's experiences of play in digital spaces. Specifically, the literature was examined with regards to relevance to children's everyday lives, the personal and ecological relevance, and the methods used. A systematic search of the literature over the past fifteen years found thirty-one articles appropriate for inclusion. The analysis of the literature revealed that the articles formed four categories of how play in digital spaces was approached: 'Videogames, behaviours, and societal norms', 'Videogames for its own sake', 'Videogames for learning', and 'Active Videogames for health promotion'. This scoping review has identified a lack of articles focusing on children's experiences of play in a digital space, and these perspectives are essential for parents, professionals, game designers, and policymakers alike to contribute to an enhanced understanding of the role of play in digital spaces.

OBJECTIVES:Low genetic diversity can lead to reduced average fitness in a population or even extinction. Preserving genetic connectivity across fragmented landscapes is therefore vital to counteract the negative consequences of genetic drift and inbreeding. This study aimed to assess the genetic composition and consequently the conservation status of a nationwide sample of European hedgehogs (Erinaceus europaeus) in Denmark. METHODS:We applied an adaptation of the genotyping by sequencing (GBS) technique to 178 individuals from six geographically distinct populations. We used a Bayesian clustering method to subdivide individuals into genetically distinct populations. We estimated individual observed (iHO), observed (HO), and unbiased expected (uHE) heterozygosity, inbreeding coefficient (FIS), percentage of polymorphic loci (P%) and tested for deviations from Hardy-Weinberg equilibrium (HWE). We used linear models to test for potential anthropogenic effects on the genetic variability of hedgehogs with iHO, uHE, P% and FIS as response variables, and assessed the demographic history of the population. RESULTS:The Danish hedgehog population is composed of three genetic clusters. We found a mean P% of 54.44-94.71, a mean uHE of 0.126-0.318 and a mean HO of 0.124-0.293 in the six populations. The FIS was found to be significantly positive for three of the six populations. We detected a large heterogeneity of iHO values within populations, which can be due to inbreeding and/or fragmentation. FIS values decreased with increasing farmland density, but there was no significant association with human population or road density. CONCLUSIONS:We found a low level of genetic variability and evidence for genetic substructure and low effective population size, which are all consequences of habitat fragmentation. We failed to detect signs of a recent population bottleneck or population increase or decline. However, because the test only identifies recent changes in population size, we cannot reject the possibility of a longer-term decline in the Danish hedgehog population.

BACKGROUND:Development of motor competencies and learning of movements in children is dependent on varied physical activity (PA). After-school programs (ASP) might provide opportunities for young schoolchildren to participate in PA. The aim of the current study was to investigate the PA of first graders in ASP and to consider its contribution to the development of motor competencies and the learning of movements. METHODS:The study was performed utilizing a mixed methods design. A total of 42 first graders were sampled from 14 ASPs in Norway. Direct observations of the children's activities were conducted for the duration of one entire ASP day. PA intensity was measured using ActiGraph accelerometers. Qualitative data were analyzed using qualitative content analysis, while the Mann-Whitney U test and the Wilcoxon signed-rank test were used to analyze the quantitative data. RESULTS:The median PA time among the observed children was 61.5 minutes. The median stationary time was 75.9 minutes. There was considerable variation within the sample. Girls were significantly more engaged in stationary behavior than boys. Frequent changes in activity type and intensity were typical features of the children's ASP day. PA duration and intensity were significantly higher outdoors than indoors. Adult-managed time had longer periods of stationary behavior than child-managed time. The PA at all intensity levels contained barrier-breaking movements-especially at light intensity levels. CONCLUSION:Most of the first graders studied were engaged in a variety of activity types of different duration and intensity levels, favorable for the development of motor competencies and for the learning of movements. Hence, it is reasonable to highlight that light PA, in combination with moderate and vigorous PA, is also of great importance for children during the time they spend in ASP. Ultimately, there is a need for staff members who can also stimulate varied PA among the most stationary children.

Background The potential association between level of education and age-related cognitive decline remains an open question, partly because of a lack of studies including large subsamples with low education and follow-up intervals covering a substantial part of the adult lifespan. Objectives To examine cognitive decline assessed by a comprehensive clinical test of intelligence over a 35-year period of follow-up from ages 50 to 85 and to analyze the effect of education on trajectories of cognitive decline, including the effects of selective attrition. Methods A longitudinal cohort study with a 35-year follow-up of community dwelling members of the Glostrup 1914 cohort. The study sample comprised 697 men and women at the 50-year baseline assessment and additional participants recruited at later follow-ups. Verbal, Performance, and Full Scale IQs were assessed using the Wechsler Adult Intelligence Scale at ages 50, 60, 70, 80, and 85. To be able to track cognitive changes between successive WAIS assessments, all IQs were based on the Danish 50-year norms. Information on school education was self-reported. The association between education and cognitive decline over time was examined in growth curve models. Selective attrition was investigated in subsamples of participants who dropped out at early or later follow-ups. Results The trajectories for Verbal, Performance, and Full Scale IQ showed higher initial cognitive performance, but also revealed steeper decline among participants with a formal school exam compared to participants without a formal exam. Verbal IQ showed the largest difference in level between the two educational groups, whereas the interaction between education and age was stronger for Performance IQ than for Verbal IQ. In spite of the difference in trajectories, higher mean IQ was observed among participants with a formal school exam compared to those without across all ages, including the 85-year follow-up. Further analyses revealed that early dropout was associated with steeper decline, but that this effect was unrelated to education. Conclusion Comprehensive cognitive assessment over a 35-year period suggests that higher education is associated with steeper decline in IQ, but also higher mean IQ at all follow-ups. These findings are unlikely to reflect regression towards the mean, other characteristics of the employed test battery or associations between educational level and study dropout.

Objectives In alcoholic hepatitis (AH), dysfunctional T lymphocytes may contribute to the high mortality from infections. T lymphocyte activation is governed by the expression of co-stimulatory receptors such as 4-1BB balanced by inhibitory receptors such as Programmed Death receptor 1 (PD-1). 4-1BB expression is unaccounted for in AH, while PD-1 is elevated. We characterized expression of 4-1BB and PD-1 and the associated T lymphocyte functional status in AH and investigated whether these were associated with short-term mortality. Methods Thirty-five patients with AH (at diagnosis and days 7 and 90) were compared with healthy controls (HC). Spontaneous and in vitro stimulated receptor expression were quantified by flow cytometry, and plasma proteins by ELISA. Results At diagnosis, the patients showed increased stimulated 4-1BB responses of CD4+ T lymphocytes. Also, the frequencies of PD-1+ T lymphocytes both with and without co-expressed 4-1BB were increased. Further, interferon-gamma was predominantly produced in T lymphocytes co-expressing 4-1BB. A decrease in the frequency of spontaneous 4-1BB+ T lymphocytes and an increase in soluble 4-1BB during the first week after diagnosis were associated with higher mortality at day 90 in AH. PD-1 expression showed no systematic dynamics related to mortality. Conclusions We found an increased stimulated 4-1BB response of T lymphocytes in AH and early loss of these lymphocytes was associated with a higher short-term mortality. This suggests a role of T lymphocyte 4-1BB expression in the progression of AH.