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Parkinson’s disease (PD) is typically considered an age-related disease, but the age at disease onset can vary by decades between patients. Aging and aging-associated diseases can affect the movement system independently of PD, and advanced age has previously been proposed to be associated with a more severe PD phenotype with accelerated progression. In this work, we investigated how interactions between PD progression and aging affect a wide range of outcomes related to PD motor and nonmotor symptoms as well as Health Related Quality of Life (HRQoL) and treatment characteristics. This population-based cohort study is based on 1436 PD patients from southern Sweden followed longitudinally for up to approximately 7.5 years from enrollment (3470 visits covering 2285 patient years, average follow-up time 1.7 years). Higher age at onset was generally associated with faster progression of motor symptoms, with a notable exception of dyskinesia and other levodopa-associated motor fluctuations that had less severe trajectories for patients with higher age at onset. Mixed results were observed for emergence of non-motor symptoms, while higher age at onset was generally associated with worse HRQoL trajectories. Accounting for these identified age-associated differences in disease progression could positively impact patient management and drug development efforts.

OBJECTIVES Acute type A aortic dissection (ATAAD) is a rare but severe condition, routinely treated with emergent cardiac surgery. Many surgeons have the notion that patients with ATAAD tend to come in clusters, but no studies have examined these observations. This investigation was undertaken to study the potential association between the lunar cycle and the incidence of ATAAD. METHODS We collected information on 2995 patients who underwent ATAAD surgery at centres from the Nordic Consortium for Acute Type A Aortic Dissection collaboration. We cross-referenced the time of surgery with lunar phase using a case-crossover design with 2 different definitions of full moon (>99% illumination and the 7-day full moon period). RESULTS The period when the moon was illuminated the most (99% definition) did not show any significant increase in incidence for ATAAD surgery. However, when the full moon period was compared with all other moon phases, it yielded a relative risk of 1.08 [95% confidence interval (CI) 1.00–1.17, P = 0.057] and, compared to waxing moon, only the relative risk was 1.11 (95% CI 1.01–1.23, P = 0.027). The peak incidence came 4–6 days after the moon was fully illuminated. CONCLUSIONS This study found an overrepresentation of surgery for ATAAD during the full moon phase. The explanation for this is not known, but we speculate that sleep deprivation during full moon leads to a temporary increase in blood pressure, which in turn could trigger rupture of the aortic wall. While this finding is interesting, it needs to be corroborated and the clinical implications are debateable., The impact our nearest celestial body has on our ecosystem, society and humans has been studied and debated for at least 20 000 years [1] when humans first started to record the lunar cycle.

Exposure to fine particulate air pollution (PM2.5) is emerging as a risk factor for Alzheimer’s disease (AD), but existing studies are still limited and heterogeneous. We have previously studied the association between dementia (AD and vascular dementia) and PM2.5 stemming from vehicle exhaust and wood-smoke in the Betula cohort in Northern Sweden. The aim of this commentary is to estimate the association between total PM2.5 and dementia in the Betula cohort, which is more relevant to include in future meta-estimates than the source-specific estimates. The hazard ratio for incident dementia associated with a 1μg/m3 increase in local PM2.5 was 1.38 (95% confidence interval: 0.99 –1.92). The interpretation of our results is that they indicate an association between local contrasts in concentration of PM2.5 at the residential address and incidence of dementia in a low-level setting.

It is widely known that the apolipoprotein E (APOE) ɛ4 allele imposes a higher risk for Alzheimer's disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOEɛ4 carriers than in non-carriers. Air pollution and interaction with APOEɛ4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOEɛ4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOEɛ4 on the association (p-value for interaction 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOEɛ4 carriers than in the total population.

Background The use of electronic-based devices to measure and to improve adherence of subjects in clinical trials is increasing. AiCure has developed a mobile technology that is claimed to provide visual confirmation of drug ingestion. While there is evidence suggesting that including such self-monitoring device in a study increases adherence, the quality of the data produced by the device may be questionable. Can the mobile technology reliably distinguish whether a subject takes the study drug or not? Methods Adherence was calculated based on exposure, self-reporting and self-monitoring for subjects randomized to an anti-depressant. Levels of adherence and agreement between the three approaches were investigated based on calculation of proportions, two-way tables and receiver operating curves. Results A total of 214 subjects had measured concentrations of study drug at all three time points (end of weeks 3, 4 and 5), along with adherence data to define proportion of days adherent based on self-reporting and the self-monitoring instrument developed by AiCure. Self-reported adherence proportions were higher than self-monitored adherence proportions, although both were high (>90%). Neither self-reported and self-monitored adherence agreed with exposure-based adherence. Conclusion Both self-reported and self-monitored adherence overestimated adherence. Neither the self-reported nor the self-monitored adherence measure reflected subjects’ actual adherence. This prompts for cautiousness when interpreting either of them, and it underlines the need for thorough validation of electronic devices and software that claims to measure adherence. The AiCure instrument may not be able to reliably determine whether the subjects swallow the study medication.

Background Myeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease. Methods MPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN. Results Anti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell-mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb ex vivo-induced apoptotic splenocytes to unmanipulated mice attenuated autoimmunity and GN, whereas deletion of splenic marginal zone macrophages prevented anti-CD20 mAb-induced immunomodulation and treatment efficacy. Six days after administering anti-CD20 mAb to mice with murine anti-MPO GN, cell-mediated anti-MPO responses and GN were attenuated, and Tregs were enhanced, but ANCA levels were unchanged, suggesting humoral autoimmunity was redundant at this time point. Conclusions Collectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20-induced apoptotic B cells.

OBJECTIVES Determine if Mohs micrographic surgery (MMS) is associated with improved overall survival compared to wide local excision (WLE) when treating cutaneous melanoma of the head and neck (CMHN) and to report the proportion of patients treated with MMS versus WLE who also underwent sentinel lymph node biopsy (SLNB). METHODS Retrospective cohort study of the National Cancer Database (NCDB) analyzing the overall survival of patients diagnosed with T1 to T4 CMHN between 2004 and 2016 who were treated with either WLE or MMS. RESULTS On multivariable analysis, treatment with WLE versus MMS was not significantly associated with overall survival (HR, 1.094; 95% CI, 0.997-1.201). On multivariable analysis, lower Charlson-Deyo score (HR, 0.489; 95% CI, 0.427-0.560), negative margins (HR, 0.754; 95% CI, 0.705-0.807), and N0 classification (HR 0.698; 95% CI, 0.668-0.730) were associated with improved overall survival. Seventy-seven percent of patients treated with MMS did not undergo SLNB, while 45% of patients treated with WLE did not undergo SLNB (P

Background Breathlessness is a major cause of suffering and disability globally. The symptom relates to multiple factors including asthma and lung function, which are influenced by hereditary factors. No study has evaluated potential inheritance of breathlessness itself across generations. Methods We analysed the association between breathlessness in parents and their offspring in the Respiratory Health in Northern Europe, Spain and Australia generation study. Data on parents and offspring aged ≥18 years across 10 study centres in seven countries included demographics, self-reported breathlessness, asthma, depression, smoking, physical activity level, measured Body Mass Index and spirometry. Data were analysed using multivariable logistic regression accounting for clustering within centres and between siblings. Results A total of 1720 parents (mean age at assessment 36 years, 55% mothers) and 2476 offspring (mean 30 years, 55% daughters) were included. Breathlessness was reported by 809 (32.7%) parents and 363 (14.7%) offspring. Factors independently associated with breathlessness in parents and offspring included obesity, current smoking, asthma, depression, lower lung function and female sex. After adjusting for potential confounders, parents with breathlessness were more likely to have offspring with breathlessness, adjusted OR 1.8 (95% CI 1.1 to 2.9). The association was not modified by sex of the parent or offspring. Conclusion Parents with breathlessness were more likely to have children who developed breathlessness, after adjusting for asthma, lung function, obesity, smoking, depression and female sex in both generations. The hereditary components of breathlessness need to be further explored., ME was supported by unrestricted grants from the Swedish Society for Medical Research and the Swedish Research Council (Dnr: 2019-02081). Coordination and establishment of the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) study has received funding from the Research Council of Norway (grant numbers 274767, 214123, 228174, 230827 and 273838), ERC StG project BRuSH (#804199), the European Union’s Horizon 2020 research and innovation programme (grant agreement number 633212) (the ALEC Study WP2), the Bergen Medical Research Foundation and the Western Norwegian Regional Health Authorities (grant numbers 912011, 911892 and 911631). Study centres have further received local funding from the following: Bergen: the above grants, World University Network (REF and Sustainability grants), Norwegian Labour Inspection, the Norwegian Asthma and Allergy Association. Albacete and Huelva: Sociedad Española de Patología Respiratoria (SEPAR) Fondo de Investigación Sanitaria (FIS PS09). Göteborg, Umeå and Uppsala: the Swedish Heart and Lung Foundation, the Swedish Asthma and Allergy Association. Reykjavik: Iceland University. Melbourne: NHMRC Project Grant ID1128450, Melbourne University. Tartu: the Estonian Research Council (grant number PUT562). Århus: The Danish Wood Foundation (grant number 444508795), the Danish Working Environment Authority (grant number 20150067134), Aarhus University (PhD scholarship). The RHINE study has received funding from Danish Lung Association, Estonian Science Foundation, Icelandic Research Council, Norwegian Research Council, Norwegian Asthma and Allergy Association, Swedish Asthma and Allergy Association, Swedish Heart and Lung Foundation and Vårdal Foundation for Health Care Science and Allergy Research. The coordination of the ECRHS has been supported by the European Union’s Horizon 2020 research and innovation programme (grant agreement number 633212) (the ALEC study), the Medical Research Council (ECRHS III) and the European Commission FP5 and FP7 (ECRHS I and II). ECRHS IV is being planned and the 10 RHINESSA study centres are funded by ERC StG project BRuSH (#804199) and by the European Union’s Horizon 2020 research and innovation programme (grant agreement number 874703) (the EPHOR project). Further funding agencies for ECRHS are reported elsewhere.

Background Ambient particulate matter is a leading risk factor for disease globally. Particulate matter 10 (PM10) and particulate matter 2.5 (PM2.5) are derived from different sources, including operating motor vehicles as well as from industrial activities. In this study we investigate the association between increased concentrations of PM and total daily visits to the psychiatric emergency unit (PEV). Further, the aim is to identify specific risk groups who are more susceptible to the effects of air pollution exposure by studying sex, age, ongoing psychiatric follow-up and diagnoses of depression/anxiety or substance use. Material and methods The sample was comprised of data from 2740 days to 81 548 PEVs at Sahlgrenska University Hospital in Gothenburg and daily mean concentrations of PM10 and PM2.5. A time-stratified case-crossover design was used to analyse associations between air pollution and PEVs. Results Mean number of daily PEVs were 35 and sex distribution was even. PM exposure was associated with total PEV at lag 0 (the same day), by RR 1.016 (95% confidence interval [CI] 1.004–1.028) and RR 1.020 (95%CI 1.003–1.038) per 10 μg/m3 increase in PM10 and PM2.5, respectively. In females, PEV were increased at lag 0 and lag 1, and in males at lag 1 and lag 2. In the age-stratified analysis, PEVs significantly increased following PM exposure amongst individuals aged 35–65 years by lag 0–2 and in individuals who had contact with outpatient care at lag 0 to lag 1. There were no associations between air pollution and PEVs for any specific diagnostic group evaluated (amongst depression, anxiety and substance use disorder). Conclusions The results indicate that acute exposure to PM10 and PM2.5 may trigger acute worsening in mental health in both males and females, especially among 35–65 year old individuals. However, in subgroups of the most common psychiatric diagnoses, we did not observe statistically significant associations with PM exposure.

Background Alzheimer’s disease (AD) and other dementias currently represent the fifth most common cause of death in the world, according to the World Health Organization, with a projected future increase as the proportion of the elderly in the population is growing. Air pollution has emerged as a plausible risk factor for AD, but studies estimating dementia cases attributable to exposure to fine particulate matter (PM2.5) air pollution and resulting monetary estimates are lacking. Methods We used data on average population-weighted exposure to ambient PM2.5 for the entire population of Sweden above 30 years of age. To estimate the annual number of dementia cases attributable to air pollution in the Swedish population above 60 years of age, we used the latest concentration response functions (CRF) between PM2.5 exposure and dementia incidence, based on ten longitudinal cohort studies, for the population above 60 years of age. To estimate the monetary burden of attributable cases, we calculated total costs related to dementia, including direct and indirect lifetime costs and intangible costs by including quality-adjusted life years (QALYs) lost. Two different monetary valuations of QALYs in Sweden were used to estimate the monetary value of reduced quality-of-life from two different payer perspectives. Results The annual number of dementia cases attributable to PM2.5 exposure was estimated to be 820, which represents 5% of the annual dementia cases in Sweden. Direct and indirect lifetime average cost per dementia case was estimated to correspond € 213,000. A reduction of PM2.5 by 1 μg/m3 was estimated to yield 101 fewer cases of dementia incidences annually, resulting in an estimated monetary benefit ranging up to 0.01% of the Swedish GDP in 2019. Conclusion This study estimated that 5% of annual dementia cases could be attributed to PM2.5 exposure, and that the resulting monetary burden is substantial. These findings suggest the need to consider airborne toxic pollutants associated with dementia incidence in public health policy decisions.

Anti-myeloperoxidase nephritogenic autoimmunity induces severe glomerulonephritis. To assess the therapeutic potential of monoclonal antibodies targeting T helper (Th) subset differentiation determining cytokines, we studied a murine model of anti-myeloperoxidase glomerulonephritis. The temporal participation of T helper subsets was determined by quantitating gene expression of CD4+ T-cells isolated from nephritic kidneys and cytokine production by lymphocytes from nodes draining myeloperoxidase immunization sites. Th17 cytokines (IL-17A and IL-6) rose rapidly but declined as autoimmunity matured when Th1 cytokines (IL-12 and TNF) predominated. Therefore, T helper subset participation in anti-myeloperoxidase autoimmunity is biphasic, with Th17 early and Th1 late. To confirm the functional relevance of this biphasic pattern, we compared systemic anti-myeloperoxidase autoimmunity in wild type, Th17 deficient and Th1 deficient mice. Early, Th1 deficient mice developed similar autoimmunity and glomerulonephritis to wild type mice. However, Th17 deficient mice had significantly reduced anti-myeloperoxidase autoimmunity. In late autoimmunity, Th1 deficient mice developed reduced autoimmunity and were protected from anti-myeloperoxidase glomerulonephritis. The therapeutic potential of these findings were demonstrated by neutralizing monoclonal antibodies. Targeting IL-23p19 attenuated early Th17 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not late phase disease. Targeting IL-12p35 attenuated late phase Th1 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not early autoimmunity or glomerulonephritis. Targeting both T helper subsets with an anti-IL-12p40 monoclonal antibody was effective during both early and late phases of anti-myeloperoxidase glomerulonephritis. Thus, definition of dominant T helper differentiating subsets in anti-myeloperoxidase glomerulonephritis by renal CD4+ T-cell cytokine gene expression allows effective proper phase monoclonal antibody treatment of anti-myeloperoxidase glomerulonephritis.

Evidence of air pollution exposure, namely, ambient particulate matter (PM), during pregnancy and an increased risk of autism spectrum disorders (ASD) in children is growing. Which PM sources contribute to this association is currently unknown, however. The aim of the present study was to investigate local source-specific ambient PM exposure and its association with ASD. A cohort of 48,571 singleton births from 1999 to 2009 in Scania, Sweden, was combined with data on locally emitted PM with an aerodynamic diameter 2.5). A flat, two-dimensional dispersion model was used to model PM2.5 exposure (all-source PM2.5, tailpipe exhaust, vehicle wear-and-tear, and small-scale residential heating- mainly wood burning) at the residential address. Associations were analyzed using binary logistic regression in partially and fully adjusted models. Clear associations were observed between PM2.5 and ASD, with statistical significance for all investigated sources in the partially adjusted model. In the fully adjusted model, only all-source PM2.5 was statistically significant. The results add to existing evidence that exposure to air pollution during pregnancy may be associated with an increased risk for ASD among children. Further, these findings suggest that locally emitted tailpipe exhaust, vehicle wear-and-tear, and small-scale residential heating all contribute to this association.

BACKGROUND Numerous epidemiological studies have highlighted the protective role of immunoglobulin E-mediated allergic diseases on glioblastoma (GBM) susceptibility and prognosis. However, the mechanistic explanations behind these phenomena remain unexplored. Our objective was to set up a preclinical model and investigate the mechanisms underlying such protection to improve our understanding of the crosstalk between immune system and brain tumor development. MATERIAL AND METHODS A mouse model of allergic airway inflammation (AAI) induced by repeated nasal instillation of House Dust Mite extract was initiated before intracranial implantation of GL261 glioma cells, in both immunocompetent (C57BL/6) and immunodeficient (RAG-KO) mice. Tumor take and tumor growth were monitored by MRI. Central (microglia) and peripheral (spleen, bone marrow) immune cells were characterized by flow cytometry. The response of microglia was further assessed by RNA sequencing. Impact of candidate genes on patient survival was characterized by Cox regression analysis using data from TCGA and CGGA. RESULTS Following AAI induction in C57BL/6 mice, engraftment of GL261 cells in the brain was delayed and tumor growth rate was reduced. This correlated with an increase in survival of the mice and was accompanied by increased effector memory T-cells in the circulation. Of note, the survival benefit was lost in RAG-KO mice devoid of adaptive immunity. At the level of the brain, we observed enhanced secretion of TNFα and IL6 in microglia ex vivo. AAI induced a transcriptional reprogramming of microglia towards a pro-inflammatory-like state. We identified an allergy-related microglia gene signature that is associated with improved prognosis of glioma patients. CONCLUSION Our results demonstrate that AAI limits both tumor take and GBM progression in mice, providing a preclinical model to study the role of allergic inflammation in GBM susceptibility and prognosis, respectively. At the functional level, we identify a potentiation of microglial and adaptive anti-tumoral immunity. Further investigations are warranted to shed light on the reciprocal crosstalk between microglial reprogramming and peripheral immunity in the context of allergies and brain tumors.

BackgroundThe response of the Swedish authorities to the COVID-19 pandemic was less restrictive than in most countries during the first year, with infection and death rates substantially higher than in neighbouring Nordic countries. Because access to PCR testing was limited during the first wave (February to June 2020) and regional data were reported with delay, adequate monitoring of community disease spread was hampered. The app-based COVID Symptom Study was launched in Sweden to disseminate real-time estimates of disease spread and to collect prospective data for research. The aim of this study was to describe the research project, develop models for estimation of COVID-19 prevalence and to evaluate it for prediction of hospital admissions for COVID-19. MethodsWe enrolled 143 531 study participants ([≥]18 years) throughout Sweden, who contributed 10{middle dot}6 million daily symptom reports between April 29, 2020 and February 10, 2021. Data from 19 161 self-reported PCR tests were used to create a symptom-based algorithm to estimate daily prevalence of symptomatic COVID-19. The prediction model was validated using external datasets. We further utilized the model estimates to forecast subsequent new hospital admissions. FindingsA prediction model for symptomatic COVID-19 based on 17 symptoms, age, and sex yielded an area under the ROC curve of 0{middle dot}78 (95% CI 0{middle dot}74-0{middle dot}83) in an external validation dataset of 943 PCR-tested symptomatic individuals. App-based surveillance proved particularly useful for predicting hospital trends in times of insufficient testing capacity and registration delays. During the first wave, our prediction model estimates demonstrated a lower mean error (0{middle dot}38 average new daily hospitalizations per 100 000 inhabitants per week (95% CI 0{middle dot}32, 0{middle dot}45)) for subsequent hospitalizations in the ten most populated counties, than a model based on confirmed case data (0{middle dot}72 (0{middle dot}64, 0{middle dot}81)). The model further correctly identified on average three out of five counties (95% CI 2{middle dot}3, 3{middle dot}7) with the highest rates of hospitalizations the following week during the first wave and four out of five (3{middle dot}0, 4{middle dot}6) during the second wave. InterpretationThe experience of the COVID Symptom Study highlights the important role citizens can play in real-time monitoring of infectious diseases, and how app-based data collection may be used for data-driven rapid responses to public health challenges. FundingSwedish Heart-Lung Foundation (20190470, 20140776), Swedish Research Council (EXODIAB, 2009-1039; 2014-03529), European Commission (ERC-2015-CoG - 681742 NASCENT), and Swedish Foundation for Strategic Research (LUDC-IRC, 15-0067) to MG or PF. European Research Council Starting Grant (801965) to TF. NO was financially supported by the Knut and Alice Wallenberg Foundation as part of the National Bioinformatics Infrastructure Sweden at SciLifeLab. ATC was supported in this work through the Massachusetts Consortium on Pathogen Readiness (MassCPR). ZOE Limited provided in-kind support for all aspects of building, running and supporting the app and service to all users worldwide. Support for this study for KCL researchers was provided by the National Institute for Health Research (NIHR)-funded Biomedical Research Centre based at Guys and St Thomas (GSTT) NHS Foundation Trust. This work was supported by the UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value-Based Healthcare. Investigators also received support from the Wellcome Trust, Medical Research Council (MRC), British Heart Foundation (BHF), Alzheimers Society, European Union, NIHR, COVID-19 Driver Relief Fund (CDRF) and the NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre (BRC) based at GSTT NHS Foundation Trust in partnership with KCL. ZOE Limited developed the app for data collection as a not-for-profit endeavour. None of the funding entities had any role in study design, data analysis, data interpretation, or the writing of this manuscript.

Funding Acknowledgements Type of funding sources: None. Aims This study aimed to determine the impact of the volume of epicardial fat on the duration of radiofrequency (RF) energy delivery during the procedure of ablation of atrial fibrillation (AF). Methods The volume of epicardial fat was measured from spiral computerized tomography scan. The primary endpoint was the duration of RF delivery for pulmonary vein isolation (PVI), and the overall total duration of RF application. Secondary endpoint was conversion of AF to sinus rhythm or organisation of the arrhythmia after PVI. Results From March 2015 to May 2018, 222 patients (45,5% with persistent AF) underwent a first RF catheter ablation procedure for AF. The total duration of RF delivery, and the duration of RF delivery specifically for PVI were significantly associated with higher total volume of epicardial fat (p = 0,0002; p = 0,009 respectively), periatrial (p = 0,003; p = 0,045) and periventricular epicardial fat (p = 0,001; p = 0,012). In multivariate analysis, total epicardial fat volume was not significantly associated with total RF delivery duration (p = 0,743). For patients with arrhythmia at the time of the procedure, patients who achieved conversion or organisation of their arrhythmia after PVI had similar levels of total epicardial fat to those whose arrhythmia persisted (65 ± 35,2 vs 74,5 ± 31,2 ml ; p = 0,192). Conclusion We observed a significant relation between total, periatrial, and periventricular epicardial fat, and the duration of RF delivery during ablation of AF. This relation was not significant by multivariate analysis meaning that epicardial fat maybe a marker, but not an independent factor,of ablation complexity.

Triple-negative breast cancer (TNBC) is the most aggressive and deadly subtype of breast cancer, accounting for 30,000 cases annually in the US. While there are several clinical trials ongoing to identify new agents to treat TNBC, the majority of TNBC patients are treated with anthracycline- or taxane-based chemotherapies in the neoadjuvant setting, followed by surgical resection and adjuvant chemotherapy. While many patients respond well to this approach, as many as 25% will suffer local or metastatic recurrence within five years. Understanding the mechanisms that drive recurrence after chemotherapy treatment is critical to improving survival for patients with TNBC. It is well-established that the extracellular matrix, which provides structure and support to tissues, is a major driver of tumor growth, local invasion and dissemination of cancer cells to distant metastatic sites. In the present study, we show that decellularized extracellular matrix (dECM) obtained from chemotherapy-treated mice increases invasion of treatment-naïve breast cancer cells compared to vehicle-treated dECM. Using tandem-mass-tag proteomics, we further demonstrate that anthracycline- and taxane-based chemotherapies induce drug-specific changes in tumor ECM composition. We identify the basement membrane protein collagen IV as significantly upregulated in the ECM of chemotherapy-treated mice and patients treated with neoadjuvant chemotherapy. We show that collagen IV drives invasion via Src/FAK signaling and that inhibiting collagen IV-driven signaling decreases invasion in chemotherapy-treated dECM. These studies provide a novel mechanism by which chemotherapy may induce metastasis via effects on ECM composition.One Sentence SummaryChemotherapy alters the extracellular matrix of breast tumors leading to increased invasion of residual cancer cells.

Background Few studies have assessed the mental health of principals, or studied associations with both organizational and social work environment factors and occupational balance. The purpose of the present study was therefore to investigate associations between supporting and demanding organizational and social work environment factors, occupational balance and stress symptoms in principals. Methods A total of 4309 surveys (2316 from the first round, 1992 from the second round), representing 2781 Swedish principals who had responded to at least one of two surveys, were included in the present study. The surveys include questions about socio-demographic factors, occupational balance, overtime work, and supporting and demanding organizational and social work environment factors, as well as questions about personal stress and exhaustion. Generalized Estimating Equations (GEE) models were used to specify a repeated measures model with a dichotomous outcome (binary logistic regression) and multiple independent factors. Data from two surveys were combined, taking into account dependent observations due to the fact that many study subjects had participated in both surveys. Results Associations were found between occupational balance (Q1: OR 2.52, 95% CI 2.03–3.15; Q2: OR 4.95, 95% CI 3.86–6.35; Q3: OR 9.29, 95% CI 6.99–12.34), overtime work (Once a week: OR 1.51, 95% CI 1.10–2.08; Sometimes a week: OR 1.31, 95% CI 1.03–1.66), supportive private life (OR 1.50, 95% CI 1.36–1.66), supportive colleagues at the leadership level (OR 1.24, 95% CI 1.14–1.36), supportive management (OR 1.17, 95% CI 1.07–1.28) and no or negligible stress symptoms. In addition, role demands (OR 0.72, 95% CI 0.63–0.83), having a container function (OR 0.72, 95% CI 0.64–0.82), collaboration with employees (OR 0.77, 95% CI 0.66–0.89), role conflicts (OR 0.75, 95% CI 0.66–0.89) and having a buffer function (OR 0.86, 95% CI 0.77–0.97) were associated with lower likelihood to rate no or negligible stress symptoms. Conclusions The occupational balance of principals is strongly associated with no or negligible stress symptoms, and thus is a promising venue for promoting well-being. Improvements should be made to several factors in the organizational and social work environments to improve principals’ chances of having occupational balance, and therefore better mental health.

As the leading cause of death in cancer, there is an urgent need to develop treatments to target the dissemination of primary tumor cells to secondary organs, known as metastasis. Bioelectric signaling has emerged in the last century as an important controller of cell growth, and with the development of current molecular tools we are now beginning to identify its role in driving cell migration and metastasis in a variety of cancer types. This review summarizes the currently available research for bioelectric signaling in solid tumor metastasis. We review the steps of metastasis and discuss how these can be controlled by bioelectric cues at the level of a cell, a population of cells, and the tissue. The role of ion channel, pump, and exchanger activity and ion flux is discussed, along with the importance of the membrane potential and the relationship between ion flux and membrane potential. We also provide an overview of the evidence for control of metastasis by external electric fields (EFs) and draw from examples in embryogenesis and regeneration to discuss the implications for endogenous EFs. By increasing our understanding of the dynamic properties of bioelectric signaling, we can develop new strategies that target metastasis to be translated into the clinic.

Background: The increasing prevalence of asthma is linked to westernization and urbanization. Farm environments have been associated with a lower risk of asthma development. However, this may not be universal, as the association differs across birth cohorts and farming methods. The aim of this study was to investigate the associations of farm upbringing with asthma in different generations and at different times in history. Methods: The study population consisted of three generations: 13,868 subjects participating in the ECRHS in 2010, their 9,638 parents, and their 8,885 offspring participating in RHINESSA in 2013. Information on place of upbringing and self-reported ever asthma was provided via questionnaires. Logistic regression was performed including subgroup analysis stratified by generation and birthyear into ten-year-intervals. Results: The prevalence of asthma increased from 8% among grandparents to 13% among parents and to 18% among offspring. An overall analysis showed an inverse association of farm upbringing on the risk of asthma (OR=0.64; 95%CI 0.55-0.74). Subgroup analysis stratified into ten-year-intervals showed a tendency towards a more pronounced inverse association between growing up on a farm and asthma among subjects born in the 1940s (0.74; 0.48-1.12), 1950s (0.70; 0.54-0.90) and 1960s (0.70; 0.52-0.93). For subjects born in 1970 and thereafter this association appeared less consistent.Conclusion: While growing up on a farm was associated with a reduced risk of developing asthma in participants born between 1945-1999, this was mainly driven by generations born from 1945 to 1973.

Background: Studies have shown that ambient air pollution is linked to preeclampsia (PE), possibly via generation of oxidative stress in the placenta. Telomere length and mitochondrial DNA copy number (mtDNAcn) are sensitive to oxidative stress damage.Objective: To study the association between prenatal exposure to ambient nitrogen oxides (NOx, a marker for traffic-related air pollution), and PE, as well as potential mediation effects by placental telomere length and mtDNAcn.Methods: This is a cross-sectional study of 42 preeclamptic and 95 arbitrarily selected normotensive pregnant women with gestational ambient NOx exposure assessment in southern Scania, Sweden. Hourly concentrations of NOx were estimated at the residential addresses by a Gaussian-plume dispersion model with 100 × 100 m spatial resolutions and aggregated into trimester-specific mean concentrations. Placental relative mtDNAcn and telomere length were measured using qPCR. Linear and logistic regression models were used to investigate associations, adjusted for perinatal and seasonal characteristics.Results: Exposure was categorized into low and high exposures by median cut-offs during first [11.9 μg/m3; interquartile range (IQR) 7.9, 17.9], second (11.6 μg/m3; IQR: 7.1, 21.1), third trimesters (11.9 μg/m3; IQR: 7.7, 19.5) and entire pregnancy (12.0 μg/m3; IQR: 7.6, 20.1). Increased risk of PE was found for high prenatal NOx exposure during the first trimester (OR 4.0; 95% CI: 1.4, 11.1; p = 0.008), and entire pregnancy (OR 3.7; 95% CI: 1.3, 10.4; p = 0.012). High exposed group during the first trimester had lower placental relative mtDNAcn compared with low exposed group (−0.20; 95% CI: −0.36, −0.04; p = 0.01). Changes in relative mtDNAcn did not mediate the association between prenatal NOx exposure and PE. No statistically significant association was found between placental relative telomere length, prenatal NOx exposure and PE.Conclusion: In this region with relatively low levels of air pollution, ambient NOx exposure during the first trimester was associated with reduced placental relative mtDNAcn and an increased risk of PE. However, we did not find any evidence that mtDNAcn or TL mediated the association between air pollution and PE. Future research should further investigate the role of mtDNAcn for pregnancy complications in relation to exposure to ambient air pollution during pregnancy.

Background Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse. Objective We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population. Methods We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through linkage to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle confounders, and air pollution. Results During follow-up ( median = 19.5 y ), 11,056 stroke cases were identified. Road traffic noise ( L den ) was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for individual- and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of ≤ 2.5 μ m ( PM 2.5 ) and NO 2 ]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40-50 vs. ≤ 40 dB ) ( HR = 1.12 ; 95% CI: 0.99, 1.27), but not with higher exposure ( ≥ 50 dB , HR = 0.94 ; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke. Discussion In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise. https://doi.org/10.1289/EHP8949.

Introduction Asthma is a complex, heterogeneous disease and one of the most common chronic diseases among children. Exposure to ambient air pollution in early life and childhood may influence asthma aetiology, but it is uncertain which specific components of air pollution and exposure windows are of importance. The role of socio-economic status (SES) is also unclear. The aims of the present study are, therefore, to investigate how various exposure windows of different pollutants affect risk-induced asthma in early life and to explore the possible effect SES has on that relationship. Methods The study population was constructed using register data on all singleton births in the greater Stockholm area between 2006 and 2013. Exposure to ambient black carbon (BC), fine particulate matter (PM2.5), primary organic carbon (pOC) secondary organic aerosols (SOA), secondary inorganic aerosols, and oxidative potential at the residential address was modelled as mean values for the entire pregnancy period, the first year of life and the first three years of life. Swedish national registers were used to define the outcome: asthma diagnosis assessed at hospital during the first six years of life. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were modelled with Cox proportional hazards model with age as the underlying time-scale, adjusting for relevant potential confounding variables. Results An increased risk for developing childhood asthma was observed in association with exposure to PM2.5, pOC and SOA during the first three years of life. With an interquartile range increase in exposure, the HRs were 1.06 (95% CI: 1.01–1.10), 1.05 (95% CI: 1.02–1.09) and 1.02 (95% CI: 1.00–1.04), for PM2.5, pOC and SOA, respectively, in the fully adjusted models. Exposure during foetal life or the first year of life was not associated with asthma risk, and the other pollutants were not statistically significantly associated with increased risk. Furthermore, the increase in risk associated with PM2.5 and the components BC, pOC and SOA were stronger in areas with lower SES. Conclusion Our results suggest that exposure to air pollution during the first three years of life may increase the risk for asthma in early childhood. The findings further imply a possible increased vulnerability to air pollution-attributed asthma among low SES children.

Summary Tumor organoids and patient-derived orthotopic xenografts (PDOXs) are some of the most valuable pre-clinical tools in cancer research. In this protocol, we describe efficient derivation of organoids and PDOX models from glioma patient tumors. We provide detailed steps for organoid culture, intracranial implantation, and detection of tumors in the brain. We further present technical adjustments for standardized functional assays and drug testing. For complete details on the use and execution of this protocol, please refer to Golebiewska et al. (2020)., Graphical abstract, Highlights • Organoids can be generated from diverse glioma patient tumors • High-grade glioma organoids give rise to patient-derived orthotopic xenografts • Serial transplantation in vivo allows for consistent expansion of human tumor cells • The adapted protocol for reconstitution of uniform organoids for functional assays, Tumor organoids and patient-derived orthotopic xenografts (PDOXs) are some of the most valuable pre-clinical tools in cancer research. In this protocol, we describe efficient derivation of organoids and PDOX models from glioma patient tumors. We provide detailed steps for organoid culture, intracranial implantation, and detection of tumors in the brain. We further present technical adjustments for standardized functional assays and drug testing.

Patient-derived cancer models are essential tools for studying tumor biology and for preclinical interventions. Although numerous clinical cancer trials are being conducted, many fail due to inappropriate selection of compounds at the preclinical stage. Therefore, better preclinical models are crucial for predicting successful clinical impact. Orthotropic patient-derived xenograft (PDOX) models are of particular importance for brain cancers, as they allow to better recapitulate the brain tumor environment and the blood brain barrier. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1. PDOX models were based on 3D organoids, derived from mechanically minced patient material. Organoids were implanted in the brain of immunodeficient mice and further propagated by serial intracranial transplantations. High grade glioma PDOX models, starting with viable patient-derived organoids, have generally a high tumor take rate, a reproducible phenotype and tumor development time. PDOXs retain histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models confirmed limited evolution of gliomas upon treatment observed in patient tumors. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. These data indicate that glioma PDOXs represent clinically relevant avatars for personalized treatment. The use of these models should lead to a more realistic evaluation of the efficacy of novel drugs, thereby increasing the success of clinical studies.

Background and objectives: Despite global warming, the climate in Northern Europe is generally cold, and the large number of deaths due to non-optimal temperatures is likely due to cold temperatures. The aim of the current study is to investigate the association between cold temperatures and all-cause mortality, as well as cause-specific mortality, in Tallinn and Riga in North-Eastern Europe. Materials and Methods: We used daily information on deaths from state death registries and minimum temperatures from November to March over the period 1997&ndash, 2015 in Tallinn and 2009&ndash, 2015 in Riga. The relationship between the daily minimum temperature and mortality was investigated using the Poisson regression, combined with a distributed lag non-linear model considering lag times of up to 21 days. Results: We found significantly higher all-cause mortality owing to cold temperatures both in Tallinn (Relative Risk (RR) = 1.28, 95% Confidence Interval (CI) 1.01&ndash, 1.62) and in Riga (RR = 1.41, 95% CI 1.11&ndash, 1.79). In addition, significantly increased mortality due to cold temperatures was observed in the 75+ age group (RR = 1.64, 95% CI 1.17&ndash, 2.31) and in cardiovascular mortality (RR = 1.83, 95% CI 1.31&ndash, 2.55) in Tallinn and in the under 75 age group in Riga (RR = 1.58, 95% CI 1.12&ndash, 2.22). In this study, we found no statistically significant relationship between mortality due to respiratory or external causes and cold days. The cold-related attributable fraction (AF) was 7.4% (95% CI -3.7&ndash, 17.5) in Tallinn and 8.3% (95% CI -0.5&ndash, 16.3) in Riga. This indicates that a relatively large proportion of deaths in cold periods can be related to cold in North-Eastern Europe, where winters are relatively harsh.

High or low ambient temperatures pose a risk factor for the worsening or onset of psychiatric disorders. The aim of this study was to investigate the association between ambient temperature and psychiatric emergency visits in an urban region in a temperate climate. The daily number of visits to a psychiatric emergency room (PEVs) at Sahlgrenska University Hospital, Gothenburg, Sweden and the daily mean temperature were extracted for the study period 1 July 2012 to 31 December 2017. Case-crossover analysis with distributed lag non-linear models was used to analyse the data by season. The warm season was defined as May to August and the cold season as November to February. Shorter lags periods were used for the warm season than the cold season. In the analysis, temperatures at the 95th percentile was associated with 14% (95% confidence interval (CI): 2%, 28%) increase in PEVs at lag 0&ndash, 3 and 22% (95%CI: 6%, 40%) for lags 0&ndash, 14 during the warm season, relative to the seasonal minimum effect temperature (MET). During the cold season temperatures at the 5th percentile were associated with 25% (95% CI: &minus, 8%, 13%) and 18% (95% CI: &minus, 30%, 98%) increase in PEVs at lags 0&ndash, 14 and 0&ndash, 21 respectively. We observed an increased number of PEVs at high and low temperatures, however, not to a statistically significant extent for low temperatures. Our findings are similar to what has been found for somatic diseases and in studies of other mental health outcomes in regions with more extreme climates. This merits the inclusion of individuals with psychiatric disorders in awareness planning for climate warning systems.

Background: Telomere-related genes (TRG) mutations are detected in 30% of familial pulmonary fibrosis (FPF) and are also associated with personal/familial extra-pulmonary disease suggestive of short telomere syndrome (STS). Aim: to evaluate the prevalence of TRG mutations in a national cohort of interstitial lung disease (ILD) with suspected genetic predisposition in Greece and to define patients’ characteristics and impact on outcome.Methods: Genetic diagnoses made between December 2014-September 2019 in patients with FPF, pulmonary fibrosis at young age or personal and/or family extra-pulmonary disease suggestive of STS were analyzed. Results: 150 ILD patients, 73% male, age-at-diagnosis 67 years old, 33% non-smokers, 75% with definite/probable UIP or CPFE, 93% with dyspnea/cough, FVC% pred 75%, DLCO% pred 49% were tested; FPF was 65%, 19% young age, 21% personal and 17% family extra-pulmonary disease suggestive of STS; 21% were tested for more than 1 indication. TRG pathogenic variations were detected in 19 (13%): 13 in a familial, 3 in young age and 3 in extra-pulmonary disease suggestive of STS context as follows: TERT, TERC, RTEL1, PARN, NOP10, NHP2 in 8,5,2,2,1 and 1 respectively. No difference was detected in epidemiological-clinical-radiologic-functional characteristics between patients without and with mutations apart from age-at-diagnosis [69 vs 62 years, p

International audience; Transiently-powered systems featuring non-volatile memory as well as external peripherals enable the development of new low-power sensor applications. However, as programmers, we are ill-equipped to reason about systems where power failures are the norm rather than the exception. A first challenge consists in being able to capture all the volatile state of the application -- external peripherals included -- to ensure progress. A second, more fundamental, challenge consists in specifying how power failures may interact with peripheral operations. In this paper, we propose a formal specification of intermittent computing with peripherals, an axiomatic model of interrupt-based checkpointing as well as its proof of correctness, machine-checked in the Coq proof assistant. We also illustrate our model with several systems proposed in the literature.

We provide first evidence that a heterozygous NOP10 mutation (c.17A>G,p.Tyr6Cys) identified in a large family co-segregates with adult-onset familial PF and predisposes to short telomere syndrome (familial PF, liver, haematological diseases)http://bit.ly/2wvXsUd

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

Many of the plant-derived compounds used in chemotherapies are currently produced by semisynthesis, which results in limited supplies at exorbitant market prices. However, the synthetic biology era, which began ca 15 years ago, has progressively yielded encouraging advances by using engineered microbes for the practical production of cheaper plant anticancer drugs.

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.

Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due to inappropriate preclinical model systems, which do not reflect the complexity of patient tumors. Furthermore, clinically relevant patient-derived models recapitulating the immune compartment are lacking, which represents a bottleneck for adequate immunotherapy testing. Emerging 3D organoid cultures offer innovative possibilities for cancer modeling. Here, we review available GBM organoid models amenable to a large variety of pre-clinical applications including functional bioassays such as proliferation and invasion, drug screening, and the generation of patient-derived orthotopic xenografts (PDOX) for validation of biological responses in vivo. We emphasize advantages and technical challenges in establishing immunocompetent ex vivo models based on co-cultures of GBM organoids and human immune cells. The latter can be isolated either from the tumor or from patient or donor blood as peripheral blood mononuclear cells (PBMCs). We also discuss the challenges to generate GBM PDOXs based on humanized mouse models to validate efficacy of immunotherapies in vivo. A detailed characterization of such models at the cellular and molecular level is needed to understand the potential and limitations for various immune activating strategies. Increasing the availability of immunocompetent GBM models will improve research on emerging immune therapeutic approaches against aggressive brain cancer.

Luftföroreningar står för ett av åtta förtida dödsfall i världen, och utgör därmed ett stort hot mot människors hälsa. HIA (hälsokonsekvensbedömningar) av hypotetiska förändringar i luftföroreningshalter kan användas som ett sätt att bedöma hälsoeffekter, planer och projekt som beslutsfattare behöver för att förhindra sjukdom. Syftet med denna studie var att beräkna hälsoeffekter som kan tillskrivas hypotetisk nedgång i luftföroreningshalter i Malmö i södra Sverige om en policy med avgasfri innerstad skulle genomföras. Air pollution is responsible for one in eight premature deaths worldwide, and thereby a major threat to human health. Health impact assessments of hypothetic changes in air pollution concentrations can be used as a mean of assessing the health impacts of policy, plans and projects, and support decision-makers in choices to prevent disease. The aim of this study was to estimate health impacts attributable to a hypothetical decrease in air pollution concentrations in the city of Malmö in Southern Sweden corresponding to a policy on-road transportations without tail-pipe emissions in the municipality. We used air pollution data modelled for each of the 326,092 inhabitants in Malmö by a Gaussian dispersion model combined with an emission database with >40,000 sources. The dispersion model calculates Nitrogen Oxides (NO) (later transformed into Nitrogen Dioxide (NO)) and particulate matter with an aerodynamic diameter

BACKGROUND High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Recent advances in the molecular characterisation of treatment-naïve HGGs based on next generation sequencing and DNA methylation analyses have led to a better delineation of HGG-subtypes and identification of distinct genomic abnormalities opening opportunities for personalized treatment strategies. METHODS We collected 300 fresh glioma specimen with approximately 100 longitudinal samples of initial and recurrent tumors from 43 matched patients. We succeeded in generating a live-biobank of HGG patient-derived orthotopic xenografts (PDOX) and 3D tumor organoids that neatly recapitulates the mutational spectrum including structural DNA variations and methylation-based subtypes of gliomas. A highlight is the generation of 19 PDOXs of paired initial and relapse HGGs from 9 glioma patients, enabling high-throughput drug screens. We performed comprehensive molecular profiling using arrayCGH, DNA-methylation and targeted DNA sequencing on patient specimen and their derivatives, 3D tumor organoids and PDOXs. RESULTS Detailed analysis of the paired longitudinal samples indicated that PDOXs closely recapitulate the evolutionary trajectory of the parental tumors. Furthermore, targeted genomic sequencing of paired HGGs suggests that relapse tumors also accumulate somatic mutations in epigenetic effectors. Based on patient-derived material we carried out drug response screening on 3D tumor organoids using a compound library matching the majority of genes that were assessed with targeted sequencing. Differential drug responses between initial and recurrent tumors were observed and the prevailing primary drug response profiles were essentially recapitulad in the relapse setting. CONCLUSIONS Response assessment of treatment-naïve gliomas and their recurrences provides crucial information on the differential sensitivity between initial and relapsed HGGs and offers novel personalized therapeutic options for the relapse setting. Furthermore, in depth correlation of the profiled somatic molecular landscape with drug response will enable pharmacogenomic predictions of potential inhibitors in the clinical setting.

There is strong experimental evidence that physiologic stress from high temperatures is greater if humidity is higher. However, heat indices developed to allow for this have not consistently predicted mortality better than dry-bulb temperature.We aimed to clarify the potential contribution of humidity an addition to temperature in predicting daily mortality in summer by using a large multicountry dataset.In 445 cities in 24 countries, we fit a time-series regression model for summer mortality with a distributed lag nonlinear model (DLNM) for temperature (up to lag 3) and supplemented this with a range of terms for relative humidity (RH) and its interaction with temperature. City-specific associations were summarized using meta-analytic techniques.Adding a linear term for RH to the temperature term improved fit slightly, with an increase of 23% in RH (the 99th percentile anomaly) associated with a 1.1% [95% confidence interval (CI): 0.8, 1.3] decrease in mortality. Allowing curvature in the RH term or adding terms for interaction of RH with temperature did not improve the model fit. The humidity-related decreased risk was made up of a positive coefficient at lag 0 outweighed by negative coefficients at lags of 1-3 d. Key results were broadly robust to small model changes and replacing RH with absolute measures of humidity. Replacing temperature with apparent temperature, a metric combining humidity and temperature, reduced goodness of fit slightly.The absence of a positive association of humidity with mortality in summer in this large multinational study is counter to expectations from physiologic studies, though consistent with previous epidemiologic studies finding little evidence for improved prediction by heat indices. The result that there was a small negative average association of humidity with mortality should be interpreted cautiously; the lag structure has unclear interpretation and suggests the need for future work to clarify. https://doi.org/10.1289/EHP5430.

Background The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN. Methods GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20. Results Compared with naive animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon γ (IFNγ) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype. Conclusions OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFNγ production and pro-inflammatory macrophage phenotype in the kidney.

Aims: Cardiovascular disease (CVD) is one of the leading causes of mortality and morbidity worldwide, including in Sweden. The main aim of this study was to explore the temporal trends and spatial patterns of CVD in Sweden using spatial autocorrelation analyses. Methods: The CVD admission rates between 2000 and 2010 throughout Sweden were entered as the input disease data for the analytic processes performed for the Swedish capital, Stockholm, and also for the whole of Sweden. Age-adjusted admission rates were calculated using a direct standardisation approach for men and women, and temporal trends analysis were performed on the standardised rates. Global Moran’s I was used to explore the structure of patterns and Anselin’s local Moran’s I, together with Kulldorff’s scan statistic were applied to explore the geographical patterns of admission rates. Results: The rates followed a spatially clustered pattern in Sweden with differences occurring between sexes. Accordingly, hot spots were identified in northern Sweden, with higher intensity identified for men, together with clusters in central Sweden. Cold spots were identified in the adjacency of the three major Swedish cities of Stockholm, Gothenburg and Malmö. Conclusions: The findings of this study can serve as a basis for distribution of health-care resources, preventive measures and exploration of aetiological factors.

The prevalence of the metabolic syndrome among adults from the French LEA childhood acute leukemia survivors’ cohort was prospectively evaluated considering the type of anti-leukemic treatment received, and compared with that of controls. The metabolic profile of these patients was compared with that of controls. A total of 3203 patients from a French volunteer cohort were age- and sex-matched 3:1 to 1025 leukemia survivors (in both cohorts, mean age: 24.4 years; females: 51%). Metabolic syndrome was defined according to the National Cholesterol Education Program’s Adult Treatment Panel III criteria. Metabolic syndrome was found in 10.3% of patients (mean follow-up duration: 16.3±0.2 years) and 4.5% of controls, (OR=2.49; P

BackgroundCardiovascular disease (CVD) is the main cause of death in most industrialised countries, including those in Europe. The mortality rates due to coronary heart disease (CHD), one of the most serious CVD conditions, have been decreasing in most European countries during the last decades. However, whether the trends over time in CHD mortality rates differ depending on neighbourhood deprivation has rarely been investigated.MethodsFor each year of the study period, 1988–2012, in Sweden, age-standardised mortality rates were calculated for three different types of neighbourhoods, characterised by a Neighbourhood Deprivation Index. Joinpoint regression was used to investigate potential changes in age-standardised mortality rates by neighbourhood deprivation and over time.ResultsOver the study period, age-standardised mortality rates due to CHD were consistently the highest in the deprived neighbourhoods and the lowest in the affluent neighbourhoods. We observed a statistically significant overall decline, ranging from 67% to 59%, in the age-standardised CHD mortality rates for each level of neighbourhood deprivation. Furthermore, the decline for the affluent neighbourhoods was significantly higher compared with the decline in the deprived neighbourhoods.ConclusionAge-standardised CHD mortality rates decreased significantly in Sweden between 1988 and 2012. This decline was more pronounced in the affluent neighbourhoods, which indicates that the improvements in prevention and treatment of CHD have not benefited individuals residing in deprived neighbourhoods to an equal extent. Knowledge of time trends in CHD mortality by level of neighbourhood deprivation may help guide decision-makers in the development of appropriate healthcare policies for deprived neighbourhoods.

Background: Published literature on cognitive functioning in adults with sickle cell disease (SCD) is sparse when compared to children. A few reports describe deficits in processing speed and executive functioning. Some studies suggest that these deficits are more severe in patients with silent cerebral infarcts (SCI). Even in the absence of radiological evidence of ischemic injury, some cognitive deficits have been depicted in adults . We hypothesize that in SCD adults, the cognitive profile varies with the presence of ischemic injury (SCI or overt stroke). The aims of this study were 1) to describe the neuropsychological profiles of SCD adults, and 2) to characterize clusters of patients with similar cognitive profiles. Methods: We conducted a retrospective analysis of all consecutive SCD adults who underwent comprehensive neuropsychological assessment during routine care at the UMGGR clinic at Henri Mondor Hospital, Créteil (France), between January 2017 and April 2021. The Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) were used for cognitive disorder, anxiety and depression screening, respectively. The cognitive battery combined standardized neuropsychological tests with established clinical utility and validity. Educational attainment was scored based on the number of years of schooling for the highest completed diploma. Principal component analysis was performed. ANOVA was used to compare patients' characteristics between clusters. Results: 80 patients, median age 36.5 [range 19-63] years were included. 40 (50.0%) were male. Genotype distribution was 62 patients (77.5%) with SS/Sbeta 0, 12 (15.0%) with SC and 6 (7.5%) with Sbeta +. On Principal Component Analysis, a 5-factor model presented the best fit (Bartlett's sphericity test (χ²(171)=1174; p Conclusions: Overall, these results suggest at least three different cognitive profiles in adults with SCD: 1) few or no cognitive deficits (cluster 3), 2) some cognitive impairment with a sub-cortical cognitive profile (cluster 2) and 3) more global cognitive impairment with cortical/sub-cortical profile and specific deficits of memory, language and constructional praxis, depending on the location of prior overt neurological events (cluster 1). To reduce the long-term cognitive morbidity of SCD, patients can be identified by their distinct cognitive profiles and neurorehabilitation tailored to their unique profile should be applied. The large proportion of childhood stroke in patients with global cognitive impairment in contrast with majority of those with milder to no cognitive impairment having had their stroke in adulthood emphasize the crucial importance of preventing early childhood stroke and implementing early neurorehabilitation. Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer: Research Funding; Novartis: Honoraria. Kuo: Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Bartolucci: Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Emmaus: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding.

Background Cardiac rehabilitation (CR) is associated with improvement of quality of life (QOL) and exercice capacity (EC). Less is known on how EC interplays with QOL. Aim To analyse the correlation between the 36-item Short Form Health Survey (SF-36) and EC. Method We used both dimensions (physical score, PS, and emotional score, ES) of the french validated version of the SF-36 to assess QOL before and after 8 weeks of CR in all patients admitted between January and Mars 2019, in a single ambulatory CR center. Clinical, biological and echocardiographic datas were retrospectively analysed as well as exercice capacity on stress test: performance in Watts and METs, 6 minutes walking test (6-MWT in meters) and aerobic capacity (VO2 in mL/min/kg). Results A total of 129 patients were included (see Table 1 ). Using a dedicated excel file, assessment of SF-36 was fast (less than 1 minute). According to t-test, both EC and QOL improved after CR: the mean EC, PS and ES respectively raised from 113 ± 32 to 134 ± 42 Watts (P Fig. 1 ), METs (r = 0.33, P Conclusion SF-36 is a fast, validated and easy way of assessing global QOL in patient undergoing ambulatory CR, and is positively correlated with exercise capacity and male sex, but not age and LVEF. Its use should be systematic to evaluate efficacy of a CR program on improving QOL.

Despite the identification of pro-metastatic markers and signaling pathways that drive the invasion of triple negative breast cancer (TNBC), there are currently no treatments that directly target invading cells. Recent evidence suggests that the bioelectric state of cancer cells can drive cell proliferation and invasion, creating an opportunity to investigate new therapies that target the bioelectric state of a cell. Our previous data suggests that of the most abundant ions present in the body, potassium (K+) is most important for controlling the bioelectric state of TNBC cells, and that K+ flux affects the invasive properties of TNBC cells. Therefore, we hypothesized that blocking K+ channels would disrupt the bioelectric state and reduce 2D migration and 3D invasion. Four FDA-approved K+ channel blockers (amiodarone, carvedilol, imipramine, and thioridazine) were selected from the Repurposing Drugs in Oncology database based on inhibition target channels and mechanisms of action. Cell viability in human TNBC MDA-MB-231 and MDA-MB-468 cells was investigated and IC50 dose response curves were generated to determine that 5 µM and 10µM were the optimal doses to study further. Interestingly, while we determined that all four drugs reduced cell viability, amiodarone and carvedilol significantly changed the bioelectric state and reduced proliferation of TNBC cells compared to negative controls. Experiments are ongoing to evaluate the effects of these inhibitors on 2D migration, 3D invasion, and in an in vivo mouse xenograft study. Understanding the mechanism behind K+ channel inhibition in TNBC could give rise to new pharmacologic targets. In addition, supplementing existing metastatic TNBC regimens with a repurposed K+ channel blocker could potentially reduce development costs, decrease time to market, and provide a new treatment option to patients. Citation Format: Priyanka Ram, Samantha L. Payne, Madeleine J. Oudin. Repurposing potassium channel blockers to target metastasis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2865.