Risk for rheumatic disease in relation to ethnicity and admixture

Risk of systemic lupus erythematosus (SLE) is high in west Africans compared with Europeans, and risk of rheumatoid arthritis (RA) is high in Native Americans compared with Europeans. These differences are not accounted for by differences in allele or haplotype frequencies in the human leucocyte antigen (HLA) region or any other loci known to influence risk of rheumatic disease. Where there has been admixture between two or more ethnic groups that differ in risk of disease, studies of the relationship of disease risk to proportionate admixture can help to distinguish between genetic and environmental explanations for ethnic differences in disease risk and to map the genes underlying these differences

Genetic and Molecular Factors in Drug-Induced Liver Injury: A Review

The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic 'dose-dependent' Type A reactions ii) 'idiosyncratic' or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/ toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.

Carpal tunnel syndrome associated with oral bisphosphonates. A population-based cohort study

© 2016 Carvajal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Bisphosphonates are widely used to prevent osteoporotic fractures. Some severe musculoskeletal reactions have been described with this medication; among them, some cases of carpal tunnel syndrome. Thus, the aim of this study was to explore whether bisphosphonates may be associated with this syndrome. Methods: A cohort study was conducted to compare exposed to unexposed women; the exposed group was that composed of women having received at least one prescription of an oral bisphosphonate. For the purpose, we used information from The Health Improvement Network (THIN) database. The outcome of interest was defined as those women diagnosed with carpal tunnel syndrome. A survival analysis was performed; the Cox proportional hazard model was used to calculate hazard ratios and 95% confidence intervals, and to adjust for identified confounding variables. Results: Out of a sample of 59,475 women older than 51 years, 19,825 were treated with bisphosphonates during the period studied. No differences in age distribution or mean follow-up time were observed between the two groups in comparison. Overall, there were 572 women diagnosed with carpal tunnel syndrome, 242 (1.2%) in the group exposed to bisphosphonates, and 330 (0.8%) in the unexposed. An adjusted hazard ratio of developing carpal tunnel syndrome of 1.38 (95%CI, 1.15-1.64) was found for women exposed to bisphosphonates; no significant changes in the hazard ratios were found when considering different levels of bisphosphonate exposure

Risk of Covid-19 in shielded and nursing care home patients: cohort study in general practice

Background: Covid-19 cases were first detected in the UK in January 2020 and vulnerable patients were asked to shield from March to reduce their risk of Covid-19 infection. Aim: To determine the risk and determinants of Covid-19 diagnosis in shielded vs. non-shielded groups adjusted for key comorbidities not explained by shielding. Design: Retrospective cohort study of adults with COVID-19 infection between 1/2/20-15/5/20 in West London. Method: Individuals diagnosed with Covid-19 were identified in SystmOne records using clinical codes. Infection risks were adjusted for socio-demographic factors, nursing home status and comorbidities. Results: Of 57,713 adults, 573 (1%) individuals were identified as shielded and 1,074 adults had documented Covid-19 infections (1.9%). Covid-19 infection rate in the shielded group individuals compared with non-shielded adult individuals was 6.5 % (37/573) vs. 1.8 % (1,037/57, 140), p30kg/m2) 1.39 (1.18-1.63) p<0.001, and age 1.02 (1.01-1.02) p<0.001. Male gender was associated with lower risk of Covid-19 infection: 0.71 (0.62-0.82) p<0.001. Conclusion: Shielded individuals had a higher Covid-19 infection rate compared with non-shielded individuals, after adjusting for socio-demographic factors, nursing home status, and comorbidities

Hypertension and cardiovascular risk factor management in a multi-ethnic cohort of adults with CKD: a cross sectional study in general practice

Background: Hypertension, especially if poorly controlled, is a key determinant of chronic kidney disease (CKD) development and progression to end stage renal disease (ESRD). Aim: To assess hypertension and risk factor management, and determinants of systolic blood pressure control in individuals with CKD and hypertension. Design and setting: Cross-sectional survey using primary care electronic health records from 47/49 general practice clinics in South London. Methods: Known effective interventions, management of hypertension and cardiovascular disease (CVD) risk in patients with CKD Stages 3–5 were investigated. Multivariable logistic regression analysis examined the association of demographic factors, comorbidities, deprivation, and CKD coding, with systolic blood pressure control status as outcome. Individuals with diabetes were excluded. Results: Adults with CKD Stages 3–5 and hypertension represented 4131/286,162 (1.4%) of the total population; 1984 (48%) of these individuals had undiagnosed CKD without a recorded CKD clinical code. Hypertension was undiagnosed in 25% of the total Lambeth population, and in patients with CKD without diagnosed hypertension, 23.0% had systolic blood pressure > 140 mmHg compared with 39.8% hypertensives, p < 0.001. Multivariable logistic regression revealed that factors associated with improved systolic blood pressure control in CKD included diastolic blood pressure control, serious mental illness, history of cardiovascular co-morbidities, CKD diagnostic coding, and age < 60 years. African ethnicity and obesity were associated with poorer systolic blood pressure control. Conclusion: We found both underdiagnosed CKD and underdiagnosed hypertension in patients with CKD. The poor systolic blood pressure control in older age groups ≥ 60 years and in Black African or obese individuals is clinically important as these groups are at increased risk of mortality for cardiovascular diseases

Stratified genome-wide association analysis of type 2 diabetes reveals subgroups with genetic and environmental heterogeneity

Type 2 diabetes (T2D) is a heterogeneous illness caused by genetic and environmental factors. Previous genome wide association studies (GWAS) have identified many genetic variants associated with T2D and found evidence of differing genetic profiles by age-at-onset. This study seeks to explore further the genetic and environmental drivers of T2D by analysing subgroups based on age-at-onset of diabetes and body mass index (BMI). In UK Biobank, 36 494 T2D cases were stratified into 3 subgroups and GWAS performed for all T2D cases and for each subgroup relative to 421 021 controls. Altogether, 18 SNPs significantly associated genome-wide with T2D in one or more subgroups also showed evidence of heterogeneity between the subgroups, (Cochrane's Q p < 0.01) with 2 remaining significant after multiple testing (in CDKN2B and CYTIP). Combined risk scores, based on genetic profile, BMI and age, resulted in excellent diabetes prediction (AUC = 0.92). A modest improvement in prediction (AUC = 0.93) was seen when the contribution of genetic and environmental factors was evaluated separately for each subgroup. Increasing sample sizes of genetic studies enables us to stratify disease cases into subgroups which have sufficient power to highlight areas of genetic heterogeneity. Despite some evidence that optimising combined risk scores by subgroup improves prediction, larger sample sizes are likely needed for prediction when using a stratification approach

Stratified genome-wide association analysis of Type 2 Diabetes reveals subgroups with genetic and environmental heterogeneity

Type 2 diabetes (T2D) is a heterogeneous illness caused by genetic and environmental factors. Previous genome wide association studies (GWAS) have identified many genetic variants associated with T2D and found evidence of differing genetic profiles by age-at-onset. This study seeks to explore further the genetic and environmental drivers of T2D by analysing subgroups based on age-at-onset of diabetes and body mass index (BMI). In UK Biobank, 36 494 T2D cases were stratified into 3 subgroups and GWAS performed for all T2D cases and for each subgroup relative to 421 021 controls. Altogether, 18 SNPs significantly associated genome-wide with T2D in one or more subgroups also showed evidence of heterogeneity between the subgroups, (Cochrane’s Q p < 0.01) with 2 remaining significant after multiple testing (in CDKN2B and CYTIP). Combined risk scores, based on genetic profile, BMI and age, resulted in excellent diabetes prediction (AUC = 0.92). A modest improvement in prediction (AUC = 0.93) was seen when the contribution of genetic and environmental factors was evaluated separately for each subgroup. Increasing sample sizes of genetic studies enables us to stratify disease cases into subgroups which have sufficient power to highlight areas of genetic heterogeneity. Despite some evidence that optimising combined risk scores by subgroup improves prediction, larger sample sizes are likely needed for prediction when using a stratification approach

Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism

Background-Evidence regarding use of direct oral anticoagulants (DOACs) in the elderly, particularly bleeding risks, is unclear despite the presence of greater comorbidities, polypharmacy and altered pharmacokinetics in this age group. Methods and Results-We performed a systematic review and meta-analysis of randomised trials of DOACs (dabigatran, apixaban, rivaroxaban, edoxaban) for efficacy and bleeding outcomes compared to VKA (vitamin k antagonists) in elderly participants (aged ≥75 years) treated for acute venous thromboembolism or stroke prevention in atrial fibrillation. Nineteen studies were eligible for inclusion but only 11 reported data specifically for elderly participants. Efficacy in managing thrombotic risks for each DOAC was similar or superior to VKA in the elderly. A non-significantly, higher risk of major bleeding than VKA was observed with dabigatran 150mg (Odds Ratio 1.18, 95% confidence interval 0.97-1.44) but not with the 110mg dose. Significantly higher gastrointestinal bleeding risks with dabigatran 150mg (1.78, 1.35-2.35) and 110mg (1.40, 1.04-1.90) and lower intracranial bleeding risks than VKA for dabigatran 150mg (0.43, 0.26-0.72) and dabigatran 110mg (0.36, 0.22-0.61) were also observed. A significantly lower major bleeding risk compared to VKA was observed for apixaban (0.63, 0.51-0.77), edoxaban 60mg (0.81, 0.67-0.98) and 30mg (0.46, 0.38-0.57) while rivaroxaban showed similar risk. Conclusion-DOACs demonstrated at least equal efficacy to VKA in managing thrombotic risks in the elderly however bleeding patterns were distinct. In particular, dabigatran was associated with a higher risk of gastrointestinal bleeding than VKA. Insufficient published data for apixaban, edoxaban and rivaroxaban indicates further work is needed to clarify their bleeding risks in the elderly

Theoretical calculations of solvent effects on the adsorption of linear molecules using the multilayer lattice model

Ash, Everett, and Findenegg's model for multilayer polymer adsorption was modified to handle solvent effects upon adsorption behavior. Some of the assumptions of the model are: (1) the segments of the polymer and the solvent monomer are approximately the same size, (2) the segments of the polymer and the solvent monomer occupy only the lattice points of a given geometrical array (close-packed hexagonal) ; (3) the energies of interaction between nonbonded segments are angularly independent, are additive in nature, and extend no further than the nearest neighbors; and (4) the surface has a homogeneous interaction energy for each segment type.The specific polymers examined were the asymmetric dimer (A-B) and the asymmetric tetramer (A-B-B-B) in a solvent (C).Parameters required for computer calculations were the nearest neighbor energies of interaction between all combinations of nonbonded segment pairs (A, A; B, B; C, C; A, B; A, C; and B, C) and interaction energies between the surface and each segment type in each layer near the surface. Analyses were made for the effects of each of these parameters on the surface excess, and on the energy, entropy, and number of each molecular configuration in each layer near the surface.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22027/1/0000444.pd