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We aimed to evaluate the effect of prolonged targeted temperature management (TTM) in patients with out-of-hospital cardiac arrest (OHCA) on the levels of midregional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) and assess their potential as prognostic biomarkers. A preplanned post hoc analysis of "Targeted temperature management for 48 h vs 24 h and neurologic outcome after out-of-hospital cardiac arrest: A randomized clinical trial (TTH48 trial)," where patients were randomized to TTM at 33°C ± 1°C of standard duration (24 hours) versus prolonged (48 hours). Blood samples were drawn from patients with OHCA at two Scandinavian university hospitals at admission to the ICU and at 24, 48, and 72 hours after reaching the target temperature. Primary outcome was levels of MR-proANP and NT-proBNP. Secondary outcome was cerebral performance category (CPC 1-5) at 6 months. Samples from 114 patients were analyzed. Prolonged TTM significantly decreased the levels of MR-proANP and NT-proBNP at 48 hours compared with standard 24 hours-TTM (p

OBJECTIVES: Although previous studies have examined the effects of exercise training on other International Classification of Functioning, Disability and Health (ICF) component levels in persons with multiple sclerosis (MS), the effects of exercise training on participation remain unclear. The objectives of this review were to: (1) characterize systematically the use of outcome measures that capture participation in exercise training studies; (2) quantify the effect of exercise training on participation in persons with MS.METHODS: A search of 6 electronic databases (CINAHL, Sport Discuss, EMBASE, MEDLINE, Cochrane Central, Scopus) was conducted to identify controlled and noncontrolled trials involving exercise training and participation in persons with MS. Search strings were built from Medical Subject Headings and CINAHL headings. ICF linking rules were used to identify participation chapters and categories captured. Meta-analysis was used to quantify the effect of exercise training on participation in randomized controlled trials comparing exercise effects to no intervention/usual care.RESULTS: We included 49 articles involving controlled and noncontrolled exercise trials in the systematic review of outcome measures. We captured 16 different outcome measures that captured all 9 participation chapters and identified 89 unique participation categories. Across these 16 outcome measures, mobility was the most commonly represented participation chapter, with 108 items. A subsample of 23 randomized controlled trials was included in the meta-analysis. An overall effect of 0.60 (standard error = 0.12, 95% confidence interval: 0.37-0.84, z = 4.9, p < 0.001) was calculated, indicating a moderate, positive effect of exercise training on participation.CONCLUSION: The current review provides information that can be used to guide the selection of outcome measures that capture participation in studies of exercise training in persons with MS. Exercise training has a positive effect on outcomes that capture participation, providing further evidence for the role of exercise training in promoting and maintaining engagement in everyday life.

BACKGROUND: Bone marrow osteoblasts and adipocytes are derived from a common mesenchymal stem cell and have a reciprocal relationship. Peroxisome proliferator-activated receptor gamma (PPARγ), a regulator for adipocyte differentiation, may be a potential target for reducing obesity and increasing bone mass. OBJECTIVES: This study tested the hypothesis that bone-specific Pparg conditional knockout (cKO), via deletion of Pparg from bone marrow stromal cells (BMSC) using Osterix 1 (Osx1)-Cre, would prevent high-fat (HF) diet–induced bone deterioration in mice. METHODS: PPARγ cKO (PPARγ(fl/fl): Osx1-Cre) and floxed littermate control (PPARγ(fl/fl) Osx1-Cre(–) ) mice that were 6 weeks old were randomly assigned to 4 groups (n = 12/group, 6 male and 6 female) and fed ad libitum with either a normal-fat (NF) purified diet (3.85 kcal/g; 10% energy as fat) or an HF diet (4.73 kcal/g; 45% energy as fat) for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured. Data were analyzed by 2-way ANOVA with Tukey post hoc comparison. RESULTS: The HF diet decreased the tibial and lumbar vertebrae trabecular bone volume/total volume (BV/TV) by 28% and 18%, respectively, compared to the NF diet (P

Aims We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7–10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients. Methods and results We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase–DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits. Conclusions The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT., Graphical Abstract Graphical Abstract

Background Sparse evidence exists regarding the feasibility and patients' experiences of exercise programs among older cancer populations. Objective The aim of this study was to explore the experiences of older patients with advanced cancer who participated in a 12-week supervised and multimodal exercise program in a hospital setting. Methods Individual interviews were conducted with 18 participants (≥65 years) with advanced cancer who completed the intervention program regardless of compliance rate. In addition, written evaluation questionnaires were collected. Data were analyzed using thematic analysis. Results Three main themes were identified: (1) Motivated to strengthen body and mind, with the subthemes "Doing what only I can do"and "Reaching goals with support from healthcare professionals and peers"; (2) Exercise as an integrated part of the treatment course; and (3) Overcoming undeniable physical limitations. Conclusions The participants experienced several benefits from participation, including physical improvements, increased energy, reduction of symptoms, and improved social engagement. Goal setting, being positively pushed and cheered on, and integration of fun games increased motivation. In contrast, being pushed beyond physical limitations and experiencing severe symptoms were experienced as barriers toward exercising. Adherence to the exercise program was facilitated by coordinating a tailored program with medical appointments and receiving comprehensive support and guidance. Implications for Practice Multimodal exercise programs seem to be beneficial for older patients with advanced cancer and should be coordinated with oncological treatment in combination with targeted support and advice on symptom management.

Background Understanding consumers’ interpretation of allergy information is crucial for effective food safety policies. We evaluated consumer understanding of allergy information on foods in controlled, experimental studies. Method Using 18 packaged foods, we evaluated consumer understanding of information about allergens in two experiments: First, a comparison of foods with no stated allergen versus allergen as a stated ingredient versus a precautionary allergen label (PAL); second, a comparison of three common variants of PAL. In each experiment, consumers with and without self‐reported food allergy were asked to estimate the risk of allergic reaction and to rate the comprehensibility of the allergen information. In the second experiment, consumers were also asked which form of PAL they preferred. Results Risk of reaction was assessed as high and low for foods with the allergen stated as ingredient, or without any mention of allergen. However, risk assessment for PAL varied and was judged as higher by non‐allergic than allergic participants (82% vs. 58%, p, Food labels are a crucial source of information for allergic consumers, but despite ingredient declaration legislation, allergic reactions frequently occur. We evaluated common allergy information on foods in two controlled experimental studies. Allergic consumers attribute lower risks to products with PAL than consumers without FA, different risks are attributed to different PAL wordings especially by consumers with higher levels of Health Literacy, and less than 50% of participants judge allergy information to be clear. Better allergy information is called for.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., Background: Comedication with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) during treatment with tumour necrosis factor inhibitors (TNFi) is extensively used in psoriatic arthritis (PsA), although the additive benefit remains unclear. We aimed to compare treatment outcomes in patients with PsA treated with TNFi and csDMARD comedication versus TNFi monotherapy. Methods: Patients with PsA from 13 European countries who initiated a first TNFi in 2006-2017 were included. Country-specific comparisons of 1 year TNFi retention were performed by csDMARD comedication status, together with HRs for TNFi discontinuation (comedication vs monotherapy), adjusted for age, sex, calendar year, disease duration and Disease Activity Score with 28 joints (DAS28). Adjusted ORs of clinical remission (based on DAS28) at 12 months were calculated. Between-country heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Secondary analyses stratified according to TNFi subtype (adalimumab/infliximab/etanercept) and restricted to methotrexate as comedication were performed. Results: In total, 15 332 patients were included (62% comedication, 38% monotherapy). TNFi retention varied across countries, with significant heterogeneity precluding a combined estimate. Comedication was associated with better remission rates, pooled OR 1.25 (1.12-1.41). Methotrexate comedication was associated with improved remission for adalimumab (OR 1.45 (1.23-1.72)) and infliximab (OR 1.55 (1.21-1.98)) and improved retention for infliximab. No effect of comedication was demonstrated for etanercept. Conclusion: This large observational study suggests that, as used in clinical practice, csDMARD and TNFi comedication are associated with improved remission rates, and specifically, comedication with methotrexate increases remission rates for both adalimumab and infliximab.

Background More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring’s cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. Methods This study is based on 710 mother–father–newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing. Results Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids. Conclusions Maternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring’s long-term cardiovascular disease risk.

The prevalence of IgE-mediated food allergy diagnosed by clinical history and positive serology in adults across Europe ranges from 0.3-6% (1). Almost half of the food allergic adults are confronted with accidental allergic reactions yearly (2). Especially moderate and severe reactions require medical consultation and treatment, which can have a high impact on economic costs (3).

BackgroundMore than half of women with symptoms suggestive of myocardial ischaemia have no obstructive coronary artery disease (CAD), yet they face a higher risk of cardiovascular mortality and morbidity. Both vital exhaustion (VE) and depression have been linked to adverse cardiovascular prognosis in patients with CAD. We aimed to assess whether symptomatic women with no obstructive CAD are more vitally exhausted compared with asymptomatic women. Furthermore, we investigated the overlap between the constructs of VE and depression.MethodsPrevalence and burden of VE was assessed in symptomatic women with no obstructive CAD (n=1.266) and asymptomatic women (n=2.390). Among symptomatic women, we also assessed chest pain characteristics and symptoms of Hospital Anxiety and Depression Questionnaire.FindingsMedian (IQR) VE score was 4 (1-9) and 2 (0–5) in symptomatic and asymptomatic women, respectively (age adjusted, pConclusionsWomen with chest pain and no obstructive CAD are more vitally exhausted compared with asymptomatic women. PCCA showed that VE is distinct from depression in symptomatic women.Clinical implicationsMental health screening focusing on depressive symptomatology in women with chest pain presenting with symptoms of mental and physical exhaustion may overlook VE in these patients.

BackgroundA significant number of women with angina and no obstructive coronary artery disease (CAD; MethodsStatic CTP with adenosine-induced vasodilation and TTDE of the left anterior descending artery with dipyridamole-induced vasodilation were successfully performed and analysed in 99 women with stable angina and no obstructive CAD and 33 asymptomatic women with no obstructive CAD. CMD was defined as CFVR < 2.ResultsCorrelation between rate-pressure product corrected MPR and CFVR was weak but significant (r = .23; p = .007). MPR was highest among asymptomatic women with normal CFVR (median [interquartile range; IQR] 158 [145–181] %). Symptomatic women with normal CFVR had reduced MPR (148 [134–162] %; age-adjusted p < .001); however, the lowest MPR was found in symptomatic women with CMD (140 [129–164] %; age-adjusted p < .001), independent of cardiovascular risk factors and haemodynamic parameters (p = .017).ConclusionWomen with angina, CMD and no obstructive CAD had markedly diminished MPR compared with asymptomatic women. Correlation between CFVR and MPR was weak, suggesting that CTP and TTDE are not interchangeable for detection of CMD.

ObjectiveThe associations between fatigue and disease activity in patients with rheumatoid arthritis (RA) have not been defined. The present objectives were to explore in RA patients the cross-sectional and longitudinal relation of fatigue with subjective as well as objective assessments of disease activity.MethodsRA patients were consecutively included when initiating biologic disease-modifying anti-rheumatic drugs (DMARDs) and assessed at baseline, 1, 2, 3, 6, and 12 months with investigation of fatigue, patient-reported outcome measures (PROMs; joint pain and patient’s global disease activity, MHAQ, pain catastrophizing, Mental Health score), clinical examinations (examiner’s global disease activity, 28 tender and swollen joint counts), and laboratory variables (ESR, CRP, calprotectin). Ultrasound examinations (semi-quantitative scoring (0–3)) with grey scale and power Doppler were performed of 36 joints and 4 tendons. Statistics included one-way analysis of variance, Pearson’s correlations, and multiple linear and logistic regression analysis.ResultsA total of 208 RA patients (mean (SD) age 53.2 (13.2) years, disease duration 9.8 (8.5) years) were included. Fatigue levels diminished during follow-up (mean (SD) baseline/12 months; 4.8 (2.8)/3.0 (2.5) (p< 0.001)). Substantial correlations were cross-sectionally found between fatigue and PROMs (median (IQR) r=0.61 (0.52-0.71)) but not with the objective inflammatory assessments. During follow-up, baseline fatigue was associated with PROMs (p< 0.001) but not with objective inflammatory assessments. However, change of fatigue was associated with change in all variables. Higher baseline fatigue levels were associated with lower clinical composite score remission rates.ConclusionFatigue was cross-sectionally associated to subjective but not to objective disease assessments. However, change of fatigue during treatment was associated to all assessments of disease activity.Trial registration numberAnzctr.org.auidentifier ACTRN12610000284066, Norwegian Regional Committee for Medical and Health Research Ethics South East reference number 2009/1254Key Points•In this longitudinal study of patients with established RA, fatigue was associated with patient reported outcome measures at each visit, but not with objective assessments of inflammation including calprotectin and comprehensive ultrasound examinations.•Changes in fatigue during biological treatment were associated with changes in patient reported outcome measures, clinical, laboratory and ultrasound assessments.•Baseline fatigue was associated with all patient reported outcome measures, but not objective assessments of inflammation at all the prospective visits.•Higher baseline fatigue levels were associated with lower remission rates as assessed by clinical composite scores.

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Purpose Higher education and its leadership are not yet using their potential impact for a sustainable future. This paper aims to focus on UN developments and the long history of university involvement in sustainability might create more interest and understanding that sustainably oriented universities are actually possible and a much stronger role for higher education is needed when nations are discussing their future. Design/methodology/approach Literature review with a focus on international treaties and declarations on the UN level and international university networks, literature review of the background and potential of the whole-institution approach and the need/suggestions for further research, also to measure advancement. Findings History shows a strong engagement of higher education with sustainability from its beginnings. There have been strong calls/offers from within university networks to take a crucial role in moving towards sustainable development that involves more than teaching about sustainability. The international community calls for higher education to be involved in policymaking rather than simply implementation, have been limited and the full potential of higher education institutions using all opportunities such as being living labs for sustainability has not as yet been realized. Currently, calls for engagement are often still limited to training and providing research when scientific evidence is wanted. Research limitations/implications Literature review focused on UN level treaties/declarations English- and German-language review national developments limited to samples of members of the Sustainable Development Goal (SDG) 4 subcluster in the Higher Education and Research for Sustainable Development (HESD) Global Cluster by the International Association of Universities (IAU). Practical implications Guidance for university leaders and other stakeholders to become aware of and consider a whole-institution approach. Practitioner relevance as countries is encouraged to embed UN recommendations, treaties and declarations. Defining opportunities for further research. Presenting the HESD Cluster by the IAU as a sample for new approaches of higher education to interact with the SDGs. Social implications Strengthening the role of higher education in the pursuit of a better future would focus on science and research as a neutral basis for decision-making and policy development. Sustainability embedded in all streams of university can help universities to be a practical example of the possibilities of sustainability at work. Originality/value Composition of authors with UN background and involvement. Focus on UN treaties/declarations and guidance for academics and practitioners in leadership on adopted UN and other international documents. Summarizing the background of the whole-institution approach as a genuine development over time but including limitations and implications for future roles for higher education leadership. IAU SDG 4 Subcluster is unique in its own approach and with its connections to a global network of higher education institutions and UNESCO.

Objective: To examine the prevalence of self-reported problems with sexual activity among psoriatic arthritis (PsA) patients, and to explore potential associations of such problems with various demographic, musculoskeletal, and dermatological disease variables. Method: Consecutive PsA patients were recruited from an outpatient clinic. Data collected included demographics, measures of musculoskeletal and skin disease activity, and treatments. Perceived effect of health status on sexual activity was assessed using question number 15 from the health-related quality of life instrument 15D; this was explored in univariate and multivariate logistic regression analyses. Results: The study assessed 135 patients (mean age 52.1 years, disease duration 8.7 years, 51.1% male). Mean scores included Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 2.9, Disease Activity index for PSoriatic Arthritis (DAPSA) 18.2, patient global assessment (PGA) 36.0 mm, pain 33.7 mm, fatigue 45.1 mm, modified Health Assessment Questionnaire (mHAQ) 0.42, Psoriasis Area Severity Index (PASI) 2.5, and Dermatology Life Quality Index (DLQI) 3.4. Twenty-four patients (17.8%) reported that their health status had a large negative effect and 111 (82.2%) that it had no or little effect on their sexual activity. In univariate analyses, a statistically significant association with impaired sexual activity was found for longer disease duration and higher MASES, DAPSA, PGA, fatigue, and mHAQ scores, but not for demographic variables or variables reflecting skin psoriasis involvement (PASI, DLQI). In adjusted analyses, only PsA disease duration remained independently associated with impaired sexual activity. Conclusion: One in five PsA patients perceived that their health status had a negative impact on sexual activity. Disease duration and measures reflecting musculoskeletal involvement, but not measures reflecting skin psoriasis involvement, appeared to be associated with impaired sexual activity.

The coronavirus has plunged the global economy into crisis. Since the beginning of March, contact and exit restrictions and bans on business activities have been imposed in Germany, schools have been closed, child care has been suspended, and strict hygiene regulations have been issued. In the meantime, the number of reported new infections has been significantly reduced and the German healthcare system does not appear to be overburdened to date. This is one of the reasons why there is now an intensive debate about easing the regulations, which would allow additional economic activity. The article also examines commuter links and the role they have played in the spread of COVID-19 in Germany as well as bad weather conditions and a high population density.

IntroductionBreast cancer susceptibility gene (BRCA) mutation carriers are recommended to undergo early oophorectomy to prevent ovarian cancer. Premature loss of ovarian hormones may increase the risk of cardiovascular disease. Because women with preventive oophorectomy are mainly young and healthy, they rarely undergo specialized cardiological surveillance. We compared the risk of cardiovascular disease in women after preventive oophorectomy with reference women.MethodsIn an historical cohort study, we included 134 women aged ≤52 years after preventive oophorectomy and 268 age matched premenopausal reference women, aged 52 years or less, from the general population, excluding participants with diabetes or cardiovascular disease. The Norwegian risk assessment tool (NORRISK 2) was used to estimate 10 year cardiovascular risk. This algorithm was validated in a large Norwegian population and is based on age, smoking, systolic blood pressure, total and high density lipoprotein cholesterol, antihypertensive medication, and family history of cardiovascular disease. We also examined cardiometabolic factors (levels of triglycerides and high sensitivity C reactive protein, as well as body mass index and waist circumference) not included in the NORRISK 2 calculation.ResultsMedian age in the preventive oophorectomy and reference groups were 47 (range 33–52) and 46 (31–52) years, respectively. Mean time since surgery in the preventive oophorectomy group was 4.2 years (standard deviation (SD) 2.8). Ten year cardiovascular risk was similar in women after preventive oophorectomy and reference women (mean 1.15% (SD 1.00) vs 1.25 (1.09), respectively, p=0.4). Women in the preventive oophorectomy group had a lower body mass index (24.7 kg/m2 (4.0) vs 26.2 (4.8), p=0.003) and waist circumference (86 cm vs 89, p=0.006). The overall cardiovascular risk estimation was comparable among hormone therapy users and non-users, but hormone therapy users had lower total cholesterol and waist circumference.DiscussionWomen who underwent preventive oophorectomy had a similar risk of cardiovascular disease as population based reference women, estimated according to risk factors easily measured in general practice. Cardiometabolic risks were not increased in the preventive oophorectomy group.

Objective − This paper aims to quantify and compare health care usage among children and adults with and without cerebral palsy (CP). Materials and Methods − A population-based study using public registries with follow-up of children and adults. Persons with CP born from 1950 to 2003 were identified in the Danish Cerebral Palsy Registry (4235 persons). Persons without CP were selected randomly from the Danish Civil Registration System and matched by birth year and gender (22,351 persons). Hospitalizations, visits to specialists, general practitioners and emergency health services were analysed. Children were born 1995-2003 and monitored until 2012 (1996-2012). Adults were born 1950-1985 and monitored for ten years (2003-2012). Results − Significantly fewer adults with CP visited specialists compared with children with CP. At the same time, the differences in use of general practitioners and between persons with and without CP were smaller in adulthood compared to childhood. Persons with CP and the most severe impairments had an unexpected low frequency of acute admissions compared with children with CP. We did not find a high use of acute contact with the health care system among adults with CP. Conclusion − If acute contacts with the health care system could be assumed to be a direct measurement of serious illness, this study does not identify a larger risk of serious illness in adults with CP, but other factors, such as reduced access to the acute health care system may, however, also be a reason for the lower use in adulthood.

Background We aimed to identify a human immunodeficiency virus (HIV)–related microbiota signature, independent of sexual preferences and demographic confounders, in order to assess a possible impact of the microbiome on metabolic comorbid conditions. Methods Bacterial 16S ribosomal RNA analyses were performed on stool samples from 405 HIV-infected and 111 uninfected participants of the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Individuals were stratified according to sexual behavior (men who have sex with men [MSM] vs non-MSM). Results After excluding MSM-associated microbiota traits and adjusting for confounders, we identified an HIV-related microbiota signature, consisting of lower biodiversity, increased relative abundance of the bacterial clades Gammaproteobacteria and Desulfovibrionaceae and decrease in several Clostridia. This microbiota profile was associated with a 2-fold excess risk of metabolic syndrome, driven by increase in Desulfovibrionaceae and decrease in Clostridia (Butyrivibrio, Coprococcus 2, Lachnospiraceae UCG-001 and CAG-56). This association was accentuated (5-fold excess risk) in individuals with previous severe immunodeficiency, which also modified the association between HIV-related microbiota signature and visceral adipose tissue (VAT) area (P for interaction = .01). Accordingly, HIV-related microbiota was associated with 30-cm2 larger VAT in individuals with history of severe immunodeficiency, but not in those without. Conclusion The HIV-related microbiota was associated with increased risk of metabolic syndrome and VAT accumulation, particularly in individuals with previous severe immunodeficiency, driven by increased Desulfovibrionaceae and lower abundance of several Clostridia. Our findings suggest a potential interplay between HIV-related microbiota, immune dysfunction and metabolic comorbid conditions. Interventions targeting the gut microbiome may be warranted to reduce cardiovascular risk, particularly in individuals with previous immunodeficiency.

BACKGROUND Intake of total fat is linked to obesity and inversely associated with bone density in humans. Epidemiologic and animal studies show that long-chain n-3 (ω-3) PUFAs supplied as fish oil (FO) are beneficial to skeletal health. OBJECTIVE This study tested the hypothesis that increasing dietary FO would decrease adiposity and improve bone-related outcomes in growing obese mice. METHODS Male C57BL/6 mice at 6 wk old were assigned to 6 treatment groups and fed either a normal-fat diet (3.85 kcal/g and 10% energy as fat) or a high-fat diet (HF; 4.73 kcal/g and 45% energy as fat) containing either 0%, 3%, or 9% energy as FO (0FO, 3FO, and 9FO, respectively) ad libitum for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured. RESULTS The HF diet increased the expression of the adipose tissue tumor necrosis factor α (Tnfa) and serum concentrations of leptin and tartrate-resistant acid phosphatase (TRAP), and decreased serum concentrations of osteocalcin and bone-specific alkaline phosphatase (P

Objectives The extent to which the human term fetus utilizes cholesterol released from the placenta has remained elusive. Our aims were to estimate the net mass of cholesterol taken up by the uteroplacental unit, released by the placenta and taken up by the fetus. Thereby we aimed to explore the maternal-fetal cholesterol transfer and hypothesized that maternal levels and uteroplacental uptake were correlated to the fetal uptake of cholesterol. Methods A cross-sectional in vivo study of 179 fasting, healthy women with uncomplicated singleton pregnancies. Blood flow in the uterine artery (n = 70) and umbilical vein (n = 125) was measured by Doppler ultrasound. Blood samples from the maternal radial artery, antecubital vein and uterine vein, and the umbilical artery and vein were obtained during cesarean section. Cholesterol was determined enzymatically. Results We found a significant uteroplacental uptake (median [Q1,Q3]) of total (3.50 [-36.8,61.1]) and HDL cholesterol (6.69 [-3.78,17.9]) μmol/min, and a fetal uptake of HDL (8.07 [4.48,12.59]), LDL (5.97 [2.77,8.92]) and total cholesterol (13.2 [8.06,21.58]) μmol/min. Maternal cholesterol levels were not correlated to fetal uptake of cholesterol. There was a correlation between uteroplacental uptake of total (rho 0.35, p 0.003) and LDL cholesterol (rho 0.25, p 0.03) and the fetal uptake of LDL cholesterol from the umbilical circulation. The fetal uptake of cholesterol from HDL was higher than from LDL (p Conclusion Fetal cholesterol uptake is independent of maternal cholesterol levels, but related to the uteroplacental uptake of cholesterol from LDL. This suggests that the placenta influences maternal-fetal cholesterol transfer at term.

Women with angina and no obstructive coronary artery disease (CAD) have worse cardiovascular prognosis than asymptomatic women. Limitation in myocardial perfusion caused by coronary microvascular dysfunction (CMD) is one of the proposed mechanisms contributing to the adverse prognosis. The aim of this study was to assess myocardial perfusion in symptomatic women with no obstructive CAD suspected for CMD compared with asymptomatic sex-matched controls using static CT perfusion (CTP). We performed a semi-quantitative assessment of the left ventricular myocardial perfusion and myocardial perfusion reserve (MPR), using static CTP with adenosine provocation, in 105 female patients with angina and no obstructive CAD (

Inflammation is involved in initiation and progression of aortic stenosis (AS). However, the role of the complement system, a crucial component of innate immunity in AS, is unclear. We hypothesized that circulating levels of complement factor B (FB), an important component of the alternative pathway, are upregulated and could predict outcome in patients with severe symptomatic AS. Therefore, plasma levels of FB, Bb, and terminal complement complex were analyzed in three cohorts of patients with severe symptomatic AS and mild-to-moderate or severe asymptomatic AS (population 1, n = 123; population 2, n = 436; population 3, n = 61) and in healthy controls by enzyme immunoassays. Compared with controls, symptomatic AS patients had significantly elevated levels of FB (2.9- and 2.8-fold increase in population 1 and 2, respectively). FB levels in symptomatic and asymptomatic AS patients were comparable (population 2 and 3), and in asymptomatic patients FB correlated inversely with valve area. FB levels in population 1 and 2 correlated with terminal complement complex levels and measures of systemic inflammation (i.e., CRP), cardiac function (i.e., NT-proBNP), and cardiac necrosis (i.e., Troponin T). High FB levels were significantly associated with mortality also after adjusting for clinical and biochemical covariates (hazard ratio 1.37; p = 0.028, population 2). Plasma levels of the Bb fragment showed a similar pattern in relation to mortality. We concluded that elevated levels of FB and Bb are associated with adverse outcome in patients with symptomatic AS. Increased levels of FB in asymptomatic patients suggest the involvement of FB from the early phase of the disease.

There is generally a mismatch in the land use classification of life cycle inventory (LCI) databases and life cycle impact assessment (LCIA) methods. This mismatch can hinder the proper assessment of land use impacts on biodiversity. To facilitate such assessments, we matched the land use classes of two global LCIA methods to five widely used LCI databases, one LCI nomenclature, and one multi-regional input-output database. In unclear cases, we assumed the worst case. Assumptions were especially necessary for unspecified land use intensity classes. We conclude with recommendations for LCI database and LCIA method developers.

Background: It is challenging to maintain effects of public health interventions. For residential health camps benefits often disappear as the child returns home. Furthermore, long-term effects are often not measured or reported. This paper presents the study protocol for an evaluation of an extended maintenance intervention offered to children who have completed a 10-week residential health camp at one of the five Danish Christmas Seal Houses (DCSH). The target group of DSCH is 7–14-year-olds with social, mental, and/or overweight issues and the overall aim of the camp is to increase life satisfaction and a healthy lifestyle. The primary aim of this study is to assess the effectiveness of the maintenance intervention on children's life satisfaction (primary outcome) and BMI Z-score (secondary outcome) 1 year after health camp.Methods: The extended maintenance intervention is developed by DCSH and delivered to each child and family individually by an intervention coordinator to help children maintain positive benefits of the health camp on life satisfaction and health behaviors after returning to their homes. Intervention activities target the child and the family. The effect will be tested in a quasi-experimental design: The intervention is offered to half of the children at one of the five DSCH (intervention group, N~144) while the other half and the children at the other four DSCH receive a standard maintenance intervention (control group, N~894). Children will complete questionnaires on life satisfaction measured by an adapted version of the Cantril ladder and height and weight prior to health camp, at the end of health camp, 3 months and 1 year after the end of health camp. To enable per protocol analysis and nuanced interpretation of effect estimates, we will monitor the implementation of the intervention by a process evaluation study among children, parents, and follow up coordinators using qualitative and quantitative methods.Discussion: We present a systematic approach to evaluating practice-based interventions in a research design. The study will provide new knowledge on the effectiveness of individualized maintenance interventions on long-term effects on life satisfaction and weight loss among children.Trial registration: Prospectively registered at Current Controlled Trials ISRCTN 13011465 https://www.isrctn.com/ISRCTN13011465

Importance A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n���=���503) or 6 mg/d of intravenous dexamethasone (n���=���497) for up to 10 days. Main Outcomes and Measures The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ���1 serious adverse reactions at 28 days). Results Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P���=���.07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Background The benefits of specific cardiac rehabilitation (CR) programme components on patient outcomes after myocardial infarction (MI) remain unclear, as does their relative predictive strength compared to patient-level predictors. Purpose To identify CR organizational and patient-level predictors for reaching risk factor targets at one-year post-MI. Methods This was an observational survey- and registry-based study. Data on CR organization at all 78 CR centres in Sweden was collected in 2016 and merged with individual patient data from nationwide registries (n=7549, median age 64 years, 24% females). Cross-validation resampled orthogonal partial least squares discriminant analysis identified predictors for reaching treatment targets for low-density lipoprotein-cholesterol (LDL-C0.8 and 95% confidence intervals (CI) excluding zero, were considered meaningful. Results Of the 71 analysed organizational variables, 36 were identified as meaningful predictors for reaching LDL-C and 35 for BP targets (Figure 1). The strongest predictors (VIP [95% CI]) for LDL-C and BP were: offering psychosocial management at initial CR assessment 2.09 [1.70–2.49]; 2.34 [1.90–2.78], having a CR team psychologist 1.59 [1.28–1.91]; 2.00 [1.46–2.55], having extended CR centre opening hours 2.17 [1.95–2.40]; 1.51 [1.03–2.00], staff reporting satisfaction with CR centre facilities 1.55 [1.07–2.04]; 1.96 [1.64–2.28], having a medical director 1.71 [1.45–1.97]; 1.47 [1.07–1.87], nurses using protocols for antihypertensive and/or lipid lowering medication adjustment 1.58 [1.35–1.81]; 1.56 [1.03–2.08], having operational team meetings 1.36 [1.08–1.64]; 1.34 [0.99–1.70], and using audit data for quality improvement 1.00 [0.79–1.20]; 1.27 [0.99–1.56]. Offering pre-exercise-based CR (exCR) assessment and different modes of exCR were predictors for reaching both targets. The strongest patient-level predictor of reaching LDL-C target was low baseline LDL-C 3.90 [3.25–4.56], and for BP it was having no history of hypertension 2.93 [2.74–3.12]. Second, participation in exCR was the strongest predictor for both outcomes 1.60 [0.83–2.37]; 1.50 [1.15–1.86]. For smoking abstinence, 5 organizational variables were identified as meaningful predictors, the strongest being prescription of varenicline by the centre physicians 1.98 [0.13–3.84] (Figure 2). The strongest patient-level predictors were exCR participation 2.51 [2.24–2.79] and socioeconomic status variables e.g., income 1.67 [1.28–2.06], living with partner 1.47 [0.84–2.09] and education 0.80 [0.48–1.12]. Conclusion The study identified multiple CR organizational and patient-level predictors for reaching key risk factor targets one-year post-MI. The results might contribute to defining the optimal composition of comprehensive CR programmes. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1) The Swedish Research Council for Health, Working Life and Welfare (FORTE)2) The Swedish Heart and Lung Foundation (Hjärt Lung Fonden)

Background For smokers who suffer a myocardial infarction (MI), smoking cessation is the most effective measure to reduce recurrent event risk. Still, evidence-based treatment methods for aiding smoking cessation post-MI are underused. Purpose To compare the odds of smoking cessation at two-months post-MI before and after implementing a set of pre-specified routines for optimization of evidence-based treatment methods for smoking cessation, with start during admission. Methods Structured routines for early smoking cessation counselling and treatment optimization were implemented at six cardiac rehabilitation (CR) centres in Sweden. The routines included CR nurses providing current smokers hospitalized for acute MI with short consultation, written material, and optimal dosage of nicotine replacement therapy during admission, increasing early prescription of varenicline for eligible patients, and contacting the patients by telephone 3–5 days after discharge, after which usual care CR follow-up commenced. Centres were also encouraged to strive for continuity in nurse-patient care. Patient data was retrieved from the SWEDEHEART registry and medical records. Using logistic regression, we compared the odds for smoking cessation at two-months post-MI for currently smoking patients admitted with MI (a) before (n=188, median age 60 years, 23% females) and (b) after (n=195, median age 60 years, 29% females) routine implementation. Secondary outcomes included adherence to implemented routines and the association of each routine with smoking cessation odds at two-months. Results In total, 159 (85%) and 179 (92%) of enrolled patients attended the two-month CR follow-up, before and after implementation of the new routines. After implementation, a significantly larger proportion of patients (65% vs 54%) were abstinent from smoking at two-months (crude OR 1.60 [1.04–2.48], p=0.034) (Figure 1). Including only those counselled during admission (n=89), 74% (vs 54%) were abstinent at two-months (crude OR 2.50 [1.42–4.41], p=0.002). After the new routine implementation patients were counselled more frequently during admission (50% vs 6%, p Conclusion Our results support that readily available methods for aiding smoking cessation can be implemented effectively in routine practice, with possible beneficial effects on smoking cessation for the high-risk group of smoking MI patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Swedish Heart and Lung AssociationPfizer AB

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a widely dispersed, broad class of synthetic chemicals with diverse biological effects, including effects on adipose and bone differentiation. PFAS most commonly occur as mixtures and only rarely, if ever, as single environmental contaminants. This poses significant regulatory questions and a pronounced need for chemical risk assessments, analytical methods, and technological solutions to reduce the risk to public and environmental health. The effects of PFAS on biological systems may be complex. Each may have several molecular targets initiating multiple biochemical events leading to a number of different adverse outcomes. An exposure to mixtures or coexposures of PFAS complicates the picture further. This review illustrates how PFAS target peroxisome proliferator–activated receptors. Additionally, we describe how such activation leads to changes in cell differentiation and bone development that contributes to metabolic disorder and bone weakness. This discussion sheds light on the importance of seemingly modest outcomes observed in test animals and highlights why the most sensitive end points identified in some chemical risk assessments are significant from a public health perspective.

Background Complement activation has been associated with atherosclerosis, atherosclerotic plaque destabilization and increased risk of cardiovascular events. Complement component 7 (CC7) binds to the C5bC6 complex which is part of the terminal complement complex (TCC/C5b-9). High-sensitivity C-reactive protein (hsCRP) is a sensitive marker of systemic inflammation and may reflect the increased inflammatory state associated with cardiovascular disease. Aim To evaluate the associations between CC7 and total- and cardiac mortality in patients hospitalized with chest-pain of suspected coronary origin, and whether combining CC7 with hsCRP adds prognostic information. Methods Baseline levels of CC7 were related to 60-months survival in a prospective, observational study of 982 patients hospitalized with a suspected acute coronary syndrome (ACS) at 9 hospitals in Salta, Argentina. A cox regression model, adjusting for conventional cardiovascular risk factors, was fitted with all-cause mortality, cardiac death and sudden cardiac death (SCD) as the dependent variables. A similar Norwegian population of 871 patients was applied to test the reproducibility of results in relation to total death. Results At follow-up, 173 patients (17.7%) in the Argentinean cohort had died, of these 92 (9.4%) were classified as cardiac death and 59 (6.0%) as SCD. In the Norwegian population, a total of 254 patients (30%) died. In multivariable analysis, CC7 was significantly associated with 60-months all-cause mortality [hazard ratio (HR) 1.26 (95% confidence interval (CI), 1.07–1.47) and cardiac death [HR 1.28 (95% CI 1.02–1.60)], but not with SCD. CC7 was only weakly correlated with hsCRP (r = 0.10, p = 0.002), and there was no statistically significant interaction between the two biomarkers in relation to outcome. The significant association of CC7 with total death was reproduced in the Norwegian population. Conclusions CC7 was significantly associated with all-cause mortality and cardiac death at 60-months follow-up in chest-pain patients with suspected ACS. Clinical trial registration ClinicalTrials.gov Identifier: NCT01377402, NCT00521976.

ObjectiveAlthough COVID-19 is primarily a respiratory infection, mounting evidence suggests that the GI tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and could be related to long-term respiratory dysfunction is unknown.DesignFrom the NOR-Solidarity trial (n=181), plasma was collected during hospital admission and after three months, and analyzed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring diffusing capacity of the lungs for carbon monoxide (DLCO), and rectal swabs for gut microbiota analyses were collected (n= 97) and analysed by sequencing of the 16S rRNA gene.ResultsGut microbiota diversity was reduced in COVID-19 patients with persistent respiratory dysfunction, defined as DLCO below lower limit of normal three months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced abundance of Erysipelotrichaceae UCG-003 and increased abundance of Flavonifractor and Veillonella, the latter potentially being linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2-(P/F-ratio)ConclusionPersistent respiratory dysfunction after COVID-19 is associated with reduced biodiversity and gut microbiota alterations, along with persistently elevated LBP levels. Our results point to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.Summary boxWhat is already known about this subject?Mounting evidence suggests that the gastrointestinal tract is involved in the pathogenesis of COVID-19, with the putative SARS-CoV-2 receptor ACE 2 ubiquitously expressed in the gut.In severe COVID-19, the gut-blood barrier is compromised, and leakage of microbial products, such as lipopolysaccharides (LPS), could affect the host’s response to COVID-19 infection.COVID-19 patients exhibit an altered gut microbiota composition, which has been related to disease severity. However, it is currently not known whether dysbiosis or gut barrier dysfunction persist long-term after hospitalization, or whether microbiota-related mechanisms could be related to persistent pulmonary dysfunction.What are the new findings?COVID-19 patients with persistent respiratory dysfunction after three months had a lower microbial diversity and an altered gut microbiota composition at the same time point.The microbiota alterations included reduced abundance of Erysipelotrichaceae UCG-003 and increased abundance of Veillonella and Flavonifractor.During hospitalization, increased plasma levels of LBP were strongly associated with respiratory failure.LBP levels remained elevated during and after hospitalization, and associated significantly with persistent respiratory dysfunction at three-month follow-up.How might it impact on clinical practice in the foreseeable future?Our findings point to a potential gut-lung axis in relation not only to respiratory failure during hospitalization, but also to long-term COVID-19 morbidity. Further studies on gut microbiota composition and gut barrier dysfunction as potential treatment targets and/or disease severity biomarkers in relation to long-term pulmonary dysfunction and long COVID are warranted.

A young man with an unremarkable medical history suffered a seizure with subsequent cardiorespiratory arrest and severe neurological sequelae after ingesting a blotter. Analysis of a similar blotter and a serum sample obtained 3 h after the event detected lysergic acid diethylamide (LSD) at an amount of 300 µg in the blotter and at a concentration of 4.0 ng/mL (12.4 nmol/L) in the serum. No other drugs were present in concentrations which may confer significant effects. In addition, no individual traits which would make the patient particularly susceptible to adverse LSD effects have subsequently been identified. This suggests that LSD may confer toxic effects in previously healthy individuals.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

OBJECTIVES: Obesity is detrimental to bone health in humans and in high-fat diet-induced obese animals. Bone marrow osteoblasts and adipocytes are derived from a common mesenchymal stem cell and have a reciprocal relationship. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a regulator for adipocyte differentiation, may be a potential target for reducing obesity and increasing bone mass. This study tested the hypothesis that bone-specific PPAR gamma conditional knockout (cKO), via deletion of PPAR gamma gene from bone marrow stromal cells (BMSC) using Osterix 1 (Osx1)-Cre, would prevent high-fat diet-induced bone deterioration in mice. METHODS: PPAR gamma cKO (PPAR gammafl/fl: Osx1–Cre) and floxed littermate control (PPAR gammafl/fl Osx1-P-Cre-) mice at 6-wk-old were randomly assigned to 4 groups (n = 12/group, 6 male and 6 female) and fed ad libitum either a normal-fat purified diet (NF, 3.85 kcal/g, 10% energy as fat) or a high-fat diet (HF, 4.73 kcal/g) for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured. RESULTS: Compared to the NF diet, the HF diet increased body mass and fat mass (P

ObjectiveBeyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties.MethodsIn a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase–DNA (MPO–DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1–3).ResultsOur major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all pConclusionsIn patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.

Bovine respiratory disease (BRD) results from interactions between pathogens, environmental stressors, and host factors. Obtaining a diagnosis of the causal pathogens is challenging but the use of high-throughput real-time PCR (rtPCR) may help target preventive and therapeutic interventions. The aim of this study was to improve the interpretation of rtPCR results by analysing their associations with clinical observations. The objective was to develop and illustrate a field-data driven statistical method to guide the selection of relevant quantification cycle cut-off values for pathogens associated with BRD for the high-throughput rtPCR system “Fluidigm BioMark HD” based on nasal swabs from calves. We used data from 36 herds enrolled in a Danish field study where 340 calves within pre-determined age-groups were subject to clinical examination and nasal swabs up to four times. The samples were analysed with the rtPCR system. Each of the 1,025 observation units were classified as sick with BRD or healthy, based on clinical scores. The optimal rtPCR results to predict BRD were investigated for Pasteurella multocida, Mycoplasma bovis, Histophilus somni, Mannheimia haemolytica, and Trueperella pyogenes by interpreting scatterplots and results of mixed effects logistic regression models. The clinically relevant rtPCR cut-off suggested for P. multocida and M. bovis was ≤ 21.3. For H. somni it was ≤ 17.4, while no cut-off could be determined for M. haemolytica and T. pyogenes. The demonstrated approach can provide objective support in the choice of clinically relevant cut-offs. However, for robust performance of the regression model sufficient amounts of suitable data are required. Bovine respiratory disease (BRD) results from interactions between pathogens, environmental stressors, and host factors. Obtaining a diagnosis of the causal pathogens is challenging but the use of high-throughput real-time PCR (rtPCR) may help target preventive and therapeutic interventions. The aim of this study was to improve the interpretation of rtPCR results by analysing their associations with clinical observations. The objective was to develop and illustrate a field-data driven statistical method to guide the selection of relevant quantification cycle cut-off values for pathogens associated with BRD for the high-throughput rtPCR system "Fluidigm BioMark HD" based on nasal swabs from calves. We used data from 36 herds enrolled in a Danish field study where 340 calves within pre-determined age-groups were subject to clinical examination and nasal swabs up to four times. The samples were analysed with the rtPCR system. Each of the 1,025 observation units were classified as sick with BRD or healthy, based on clinical scores. The optimal rtPCR results to predict BRD were investigated for Pasteurella multocida, Mycoplasma bovis, Histophilus somni, Mannheimia haemolytica, and Trueperella pyogenes by interpreting scatterplots and results of mixed effects logistic regression models. The clinically relevant rtPCR cut-off suggested for P. multocida and M. bovis was ≤ 21.3. For H. somni it was ≤ 17.4, while no cut-off could be determined for M. haemolytica and T. pyogenes. The demonstrated approach can provide objective support in the choice of clinically relevant cut-offs. However, for robust performance of the regression model sufficient amounts of suitable data are required.

Background: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, R t, for the two incidence estimates. Findings: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the R t of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, R t fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation: The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding: Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society.

Background While patient performance after participating in cardiac rehabilitation programmes after acute myocardial infarction is regularly reported through registry and survey data, information on cardiac rehabilitation programme characteristics is less well described. Aim The aim of this study was to evaluate Swedish cardiac rehabilitation programme characteristics and adherence to European Guidelines on Cardiovascular Disease Prevention. Method Cardiac rehabilitation programme characteristics at all 78 cardiac rehabilitation centres in Sweden in 2016 were surveyed using a web-based questionnaire (100% response rate). The questions were based on core components of cardiac rehabilitation as recommended by European Guidelines. Results There was a wide variation in programme duration (2–14 months). All programmes reported offering an individual post-discharge visit with a nurse, and 90% ( n = 70) did so within three weeks from discharge. Most programmes offered centre-based exercise training ( n = 76, 97%) and group educational sessions ( n = 61, 78%). All programmes reported to the national audit, SWEDEHEART, and 60% ( n = 47) reported that performance was regularly assessed using audit data, to improve quality of care. Ninety-six per cent ( n = 75) had a core team consisting of a cardiologist, a physiotherapist and a nurse and 76% ( n = 59) reported having a medical director. Having other allied healthcare professionals included in the cardiac rehabilitation team varied. Forty per cent ( n = 31) reported having regular team meetings where nurses, physiotherapists and cardiologist could discuss patient cases. Conclusion The overall quality of cardiac rehabilitation programmes provided in Sweden is high. Still, there are several areas of potential improvement. Monitoring programme characteristics as well as patient outcomes might improve programme quality and patient outcomes both at a local and a national level.

BACKGROUND Improved quality of life (QoL) after oral immunotherapy (OIT) in peanut allergic children is often reported by their parents, while the child's perspective is less clear. OBJECTIVE We aimed to explore whether 2 years of OIT improved QoL in children with peanut allergy and to identify factors influencing change in QoL. METHODS In the open-labeled TAKE-AWAY peanut OIT trial including children with anaphylaxis to peanuts, 57 were randomized to OIT and 20 to observation. The Pediatric Quality of Life Inventory Version 4.0 was completed by parents and children at enrollment (Y0 ), after 1 year (end of updosing; Y1 ) and after 2 years (Y2 ) of OIT. Minimally clinically important difference (MCID) is ≥5.3. Perceived treatment burden was recorded by visual analogue scales, including adverse events (AEs). An open food challenge (OFC) was performed at Y2 . RESULTS At Y2 , 18 children had discontinued OIT and 2 of 39 OIT children refused OFC, while 35 of 37 were desensitized to 7500 mg peanut protein. From Y0 to Y2, the mean change (95% confidence intervals) in QoL was 4.4 (0.5, 8.3) among child self-reports and twice as large among parental proxy reports (9.3 [4.3, 14.3]; both P

ObjectivesJoint swelling and tenderness are considered a proxy for inflammation in patients with rheumatoid arthritis (RA). With ultrasound-detected inflammation as reference, our objectives were to explore on patient and joint level the associations between ultrasound synovitis and joint swelling, tenderness and patient-reported joint pain (PRJP).Methods209 patients with established RA were examined six times during 12 months with assessment of 32 joints in upper/lower extremities for joint swelling/tenderness and Grey scale (GS)/power Doppler (PD) synovitis. PRJP was assessed on a manikin. Correlations between different sum scores were at each examination calculated using Spearman’s rho (r), agreement at joint level was examined by Cohen’s kappa and logistic regression models were used to explore the associations between joint assessment and GS/PD scores.ResultsAt patient level, swollen joints were strongly correlated with GS/PD sum scores (r=0.64–0.88), while tender joints were primarily associated with PRJP (r=0.54–0.68). At joint level, GS/PD pathology had higher agreement with swelling (kappa 0.54–0.57) than tenderness (kappa 0.20–0.21) or PRJP (0.23–0.25). Higher percentages of joints were swollen according to increasing GS/PD scores, independently of joint tenderness. However, joints being tender, but not swollen, were not associated with GS/PD scores. Receiver operating curves showed swollen but not tender joints to be associated with GS/PD scores.ConclusionsSwollen joints were strongly associated with ultrasound detected synovitis at both patient and joint level, while this association was not found for tender joints. These results may question if tender joints reflect ongoing inflammation in established RA.

Background: Quantitative methods and a biomedical concept of the body dominate research in physiotherapy, and physiotherapists’ knowledge of best practices is usually valued higher than patients’ k...

Second generation rent control seeks to prevent negative quantity effects by exempting newly built units. The artificially lowered rent in the controlled segment makes renting attractive for households that would otherwise not have rented in the market, replacing households with higher willingness to pay for housing. These households bid up prices in the free market segment, giving rise to an opposite-sign spillover from the controlled to the free market (Mense, Michelsen, and Kholodilin 2017). This paper documents a positive effect of “second generation” rent control on the value of vacant, buildable land.