Discovery of the Principal Cystic Fibrosis Mutation (F508del) in Ancient DNA from Iron Age Europeans

The most common, life-threatening autosomal recessive disease of Europeans and Euro-Americans, cystic fibrosis (CF), occurs predominately in patients with the F508del mutation.1 Although F508del is currently detectable as a single allele in 1/30-1/40 Europeans2-4 and Euro-Americans,5 it has not been determined what heterozygote selective advantage(s) might account for its relatively high prevalence. Indirect evidence6 suggests that this mutation was present in Brittany at least 3000 years ago, but no direct analyses of ancient DNA have been reported to identify F508del and clarify its frequency in prehistoric inhabitants of Europe. Here we show that F508del was present in 3 of 32 Iron Age inhabitants of Austria from whom DNA could be recovered from molar teeth using procedures that fulfill authenticity criteria.7 Because these individuals, who were buried in cemeteries along the Danube river, were shown by radiocarbon dating of isolated bone collagen to have lived there during 544-255 BC, this indicates that the F508del mutation is definitely more than 2000 years old and that CF (the disease) was present among them. More generally, the apparent enrichment of this Iron Age population in F508del suggests an evolutionary advantage in their environment that can be investigated by interdisciplinary strategies of paleoepidemiology

Volume exclusion effects in perovskite charge transport modeling

Due to their flexible material properties, perovskite materials are a promising candidate for many semiconductor devices such as lasers, memristors, LEDs and solar cells. For example, perovskite-based solar cells have recently become one of the fastest growing photovoltaic technologies. Unfortunately, perovskite devices are far from commercialization due to challenges such as fast degradation. Mathematical models can be used as tools to explain the behavior of such devices, for example drift-diffusion equations portray the ionic and electric motion in perovskites. In this work, we take volume exclusion effects on ion migration within a perovskite crystal lattice into account. This results in the formulation of two different ionic current densities for such a drift-diffusion model -- treating either the mobility or the diffusivity as density-dependent while the other quantity remains constant. The influence of incorporating each current density description into a model for a typical perovskite solar cell configuration is investigated numerically, through simulations performed using two different open source tools. {

Debt income and mental disorder in the general population

Background The association between poor mental health and poverty is well known but its mechanism is not fully understood. This study tests the hypothesis that the association between low income and mental disorder is mediated by debt and its attendant financial hardship. Method The study is a cross-sectional nationally representative survey of private households in England, Scotland and Wales, which assessed 8580 participants aged 16–74 years living in general households. Psychosis, neurosis, alcohol abuse and drug abuse were identified by the Clinical Interview Schedule – Revised, the Schedule for Assessment in Neuropsychiatry (SCAN), the Alcohol Use Disorder Identification Test (AUDIT) and other measures. Detailed questions were asked about income, debt and financial hardship. Results Those with low income were more likely to have mental disorder [odds ratio (OR) 2.09, 95% confidence interval (CI) 1.68–2.59] but this relationship was attenuated after adjustment for debt (OR 1.58, 95% CI 1.25–1.97) and vanished when other sociodemographic variables were also controlled (OR 1.07, 95% CI 0.77–1.48). Of those with mental disorder, 23% were in debt (compared with 8% of those without disorder), and 10% had had a utility disconnected (compared with 3%). The more debts people had, the more likely they were to have some form of mental disorder, even after adjustment for income and other sociodemographic variables. People with six or more separate debts had a six-fold increase in mental disorder after adjustment for income (OR 6.0, 95% CI 3.5–10.3). Conclusions Both low income and debt are associated with mental illness, but the effect of income appears to be mediated largely by debt

Time periods of altered risk for severe injection drug use-associated skin and soft-tissue infections: protocol for a self-controlled case series in New South Wales, Australia, 2001-2018

Injection drug use-associated bacterial and fungal infections (e.g., skin and soft-tissue infections, endocarditis, osteomyelitis, etc.) are common health problems among people who inject drugs, associated with pain, disability, and death. The incidence of these infections is rising, and better understanding of the social and environmental factors that shape individual injecting practices and risk for injecting-related infections is urgently needed. Using a self-controlled study design, the aim of this proposed study is to quantify the risks of injecting-related skin and soft-tissue infections associated with initiation of, exposure to, and discontinuation of incarceration and OAT among a sample of people with opioid use disorder

The Impact of Depression, Anxiety and Personality Disorders on the Outcome of Patients with Functional Limb Weakness – Individual Patient Data Meta-Analysis

Objective: Psychiatric comorbidities such as depression, anxiety, and personality disorders are common in patients with functional limb weakness/paresis (FND-par). The impact of these conditions on the prognosis of FND-par has not been systematically reviewed. The aim of this study was to identify a potential prognostic effect of comorbid depression, anxiety, and/or personality disorder on prognosis in patients with FND-par. Methods: A systematic review was performed to identify studies that reported measures of baseline depression, anxiety, and/or personality disorder, and physical disability. An individual patient data meta-analysis was subsequently performed. Results: Eight studies comprising 348 individuals were included (7 prospective cohorts; 1 case-control study). There was heterogeneity in sample size, follow-up duration, and treatment modality. Depression and anxiety were present in 51.4% and 53.0% of FND-par patients, respectively. In individuals whose FND-par improved, there was no significant difference between those with versus without depression (52.6% vs 47.4%, p = 0.69) or those with versus without anxiety (50.3% vs 49.7%, p = 0.38). Meta-analysis showed no clear impact of baseline depression or anxiety per se [pooled OR for depression 0.85 (95%CI 0.50–1.45; p = 0.40) and anxiety 0.84 (95%CI 0.51–1.38; p = 0.91)]; and of depression or anxiety severity [pooled OR for depression 1.23 (95%CI 0.63–2.39; p = 0.91) and anxiety 1.40 (95%CI 0.70–2.78; p = 0.58)] on FND-par outcome. Insufficient data were available to assess the impact of personality disorders. Conclusion: We found no evidence that depression or anxiety influenced outcome in FND-par. Large-scale, prospective studies in FND-par, and other FND subtypes, are needed to fully contextualize the impact of concurrent mental health concerns on outcomes.</p

Genome-wide profiling in treatment-naive early rheumatoid arthritis reveals DNA methylome changes in T and B lymphocytes

AIM: Although aberrant DNA methylation has been described in rheumatoid arthritis (RA), no studies have interrogated this epigenetic modification in early disease. Following recent investigations of T- and B-lymphocytes in established disease, we now characterize in these cell populations genome-wide DNA methylation in treatment-naive patients with early RA. PATIENTS & METHODS: HumanMethylation450 BeadChips were used to examine genome-wide DNA methylation in lymphocyte populations from 23 early RA patients and 11 healthy individuals. RESULTS: Approximately 2000 CpGs in each cell type were differentially methylated in early RA. Clustering analysis identified a novel methylation signature in each cell type (150 sites in T-lymphocytes, 113 sites in B-lymphocytes) that clustered all patients separately from controls. A subset of sites differentially methylated in early RA displayed similar changes in established disease. CONCLUSION: Treatment-naive early RA patients display novel disease-specific DNA methylation aberrations, supporting a potential role for these changes in the development of RA

Epigenome-wide profiling identifies significant differences in DNA methylation between matched-pairs of T- and B-lymphocytes from healthy individuals

Multiple reports now describe changes to the DNA methylome in rheumatoid arthritis and in many cases have analyzed methylation in mixed cell populations from whole blood. However, these approaches may preclude the identification of cell type-specific methylation, which may subsequently bias identification of disease-specific changes. To address this possibility, we conducted genome-wide DNA methylation profiling using HumanMethylation450 BeadChips to identify differences within matched pairs of T-lymphocytes and B-lymphocytes isolated from the peripheral blood of 10 healthy females. Array data were processed and differential methylation identified using NIMBL software. Validation of array data was performed by bisulfite Pyrosequencing. Genome-wide DNA methylation was initially determined by analysis of LINE-1 sequences and was higher in B-lymphocytes than matched T-lymphocytes (69.8 vs. 65.2%, p ≤ 0.01). Pairwise analysis identified 679 CpGs, representing 250 genes, which were differentially methylated between T-lymphocytes and B-lymphocytes. The majority of sites (76.6%) were hypermethylated in B-lymphocytes. Pyrosequencing of selected candidates confirmed the array data in all cases. Hierarchical clustering revealed perfect segregation of samples into two distinct clusters based on cell type. Differentially methylated genes showed enrichment for biological functions/pathways associated with leukocytes and T-lymphocytes. Our work for the first time shows that T-lymphocytes and B-lymphocytes possess intrinsic differences in DNA methylation within a restricted set of functionally-related genes. These data provide a foundation for investigating DNA methylation in diseases in which these cell types play important and distinct roles

DNA methylation at diagnosis is associated with response to disease-modifying drugs in early rheumatoid arthritis

Aim: A proof-of-concept study to explore whether DNA methylation at first diagnosis is associated with response to disease-modifying antirheumatic drugs (DMARDs) in patients with early rheumatoid arthritis (RA). Patients & methods: DNA methylation was quantified in T-lymphocytes from 46 treatment-naive patients using HumanMethylation450 BeadChips. Treatment response was determined in 6 months using the European League Against Rheumatism (EULAR) response criteria. Results: Initial filtering identified 21 cytosine-phosphate-guanines (CpGs) that were differentially methylated between responders and nonresponders. After conservative adjustment for multiple testing, six sites remained statistically significant, of which four showed high sensitivity and/or specificity (?75%) for response to treatment. Moreover, methylation at two sites in combination was the strongest factor associated with response (80.0% sensitivity, 90.9% specificity, AUC 0.85). Conclusion: DNA methylation at diagnosis is associated with disease-modifying antirheumatic drug treatment response in early RA