Fine and ultrafine particles from indoor sources – Effects on healthy humans in a controlled exposure study and on lung epithelial cells in vitro

In recent years increasing concern has been expressed about the potential adverse health effects of particles from indoor sources. The aims of the EPIA project were: (1) to characterize potentially relevant indoor sources of (ultra)fine particles with respect to their emission levels and composition and (2) to investigate their adverse health effects. We investigated the effects of emissions from candle burning (CB), toasting of bread (TB) and sausage frying (FS) in a randomized, cross-over sham-controlled exposure study in healthy adults as well as in vitro in A549 human lung epithelial cells. Participants were exposed for 2 h to each of these sources at two different exposure levels, and examined before, during and after the exposures at defined time-intervals. We found transient associations between exposures and several respiratory and cardiovascular effects as well as inflammatory changes (e.g. lung function, blood pressure, arterial stiffness, interleukin-8 in nasal lavage/blood). Specific effects were found to depend strongly on the emission source and the selected exposure metric (e.g. size-specific particle mass concentration, size-specific particle number concentration, lung deposited surface area concentration). Evaluation of PM2.5 samples in the A549 cells, revealed an increased interleukin-8 release and DNA strand breakage induction for toasting, whereas candle burning only resulted in DNA damage. The results from our project demonstrate that elevated concentrations from certain indoor emission sources may lead to changes in the lung and cardiovascular systems as well as possibly induce inflammation

Two-level system with a thermally fluctuating transfer matrix element: Application to the problem of DNA charge transfer

Charge transfer along the base-pair stack in DNA is modeled in terms of thermally-assisted tunneling between adjacent base pairs. Central to our approach is the notion that tunneling between fluctuating pairs is rate-limited by the requirement of their optimal alignment. We focus on this aspect of the process by modeling two adjacent base pairs in terms of a classical damped oscillator subject to thermal fluctuations as described by a Fokker-Planck equation. We find that the process is characterized by two time scales, a result that is in accord with experimental findings.Comment: original file is revtex4, 10 pages, three eps figure

Sunny holidays before and after melanoma diagnosis are respectively associated with lower breslow thickness and lower relapse rates in Italy

Background: Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. Methods: A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. Results: Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

What causes hidradenitis suppurativa? - 15 years after

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30?April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as ?the only inflammatory skin disease than can be healed?. This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future

Heavy menstrual bleeding on direct factor Xa inhibitors: Rationale and design of the MEDEA study

Background: In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA). Treatment with the direct oral thrombin inhibitor dabigatran appears to be associated with a reduced risk of HMB compared with VKA. These findings come from small observational studies or post hoc analyses of trials in which HMB was not a primary outcome. Use of tranexamic acid during the menstrual period may be effective in patients with HMB, but prospective data regarding efficacy and safety in patients on anticoagulant treatment are lacking. Rationale and Design: A direct comparison of a factor Xa inhibitor and a thrombin inhibitor with HMB as primary outcome, as well as an evaluation of the effects of adding tranexamic acid in women with anticoagulant-associated HMB is highly relevant for clinical practice. The MEDEA study is a randomized, open-label, pragmatic clinical trial to evaluate management strategies in premenopausal women with HMB associated with factor Xa inhibitor therapy. Outcomes: Women using factor Xa inhibitors with proven HMB, as assessed by a pictorial blood loss assessment chart (PBAC) score of >150, will be randomized to one of three study arms: (i) switch to dabigatran; (ii) continue factor Xa inhibitor with addition of tranexamic acid during the menstrual period; or (iii) continue factor Xa inhibitor without intervention. The primary outcome is the difference in PBAC score before and after randomization. Here, we present the rationale and highlight several unique features in the design of the study

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological PsychiatryBackground: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.publishersversionpublishe

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care