High Diversity at PRDM9 in Chimpanzees and Bonobos

BACKGROUND: The PRDM9 locus in mammals has increasingly attracted research attention due to its role in mediating chromosomal recombination and possible involvement in hybrid sterility and hence speciation processes. The aim of this study was to characterize sequence variation at the PRDM9 locus in a sample of our closest living relatives, the chimpanzees and bonobos. METHODOLOGY/PRINCIPAL FINDINGS: PRDM9 contains a highly variable and repetitive zinc finger array. We amplified this domain using long-range PCR and determined the DNA sequences using conventional Sanger sequencing. From 17 chimpanzees representing three subspecies and five bonobos we obtained a total of 12 alleles differing at the nucleotide level. Based on a data set consisting of our data and recently published Pan PRDM9 sequences, we found that at the subspecies level, diversity levels did not differ among chimpanzee subspecies or between chimpanzee subspecies and bonobos. In contrast, the sample of chimpanzees harbors significantly more diversity at PRDM9 than samples of humans. Pan PRDM9 shows signs of rapid evolution including no alleles or ZnFs in common with humans as well as signals of positive selection in the residues responsible for DNA binding. CONCLUSIONS AND SIGNIFICANCE: The high number of alleles specific to the genus Pan, signs of positive selection in the DNA binding residues, and reported lack of conservation of recombination hotspots between chimpanzees and humans suggest that PRDM9 could be active in hotspot recruitment in the genus Pan. Chimpanzees and bonobos are considered separate species and do not have overlapping ranges in the wild, making the presence of shared alleles at the amino acid level between the chimpanzee and bonobo species interesting in view of the hypothesis that PRDM9 plays a universal role in interspecific hybrid sterility

NHS Health Checks: Equity and outcomes 2009-17: An observational study.

Background The NHS Health Check cardiovascular prevention programme is now 10 years old. Aim We describe NHS Heath Check attendance, new diagnoses and treatment in relation to equity indicators. Design and Setting Using a nationally representative database derived from 1,500 general practices 2009-17, we compared NHS Health Check attendance and new diagnoses and treatments, by age, gender, ethnic group and deprivation. Results In 2013-17, 590,218 eligible people age 40-74 years attended an NHS Health Check (16.9%) and 2,902,598 (83.1%) did not attend. South Asian ethnic groups were most likely to attend and women more than men. New diagnoses were more likely in attendees than non-attendees; hypertension 25/1000 attendees vs 9/1000 in non-attendees; type 2 diabetes 8/1000 vs 3/1000; chronic kidney disease 7/1000 vs 4/1000. In people aged 65 or older, new atrial fibrillation was diagnosed in 5/1000 attendees and 3/1000 non-attendees and for dementia 2/1000 versus 1/1000 respectively. Type 2 diabetes, hypertension and CKD were more likely in more deprived groups, South Asian and black African/Caribbean ethnic groups. Attendees were more likely to be prescribed statins, 26/1000, than non-attendees 8/1000; and anti-hypertensive medicines, 25/1000 vs 13/1000 non-attendees. However, of the 117,963 people with 10% or greater CVD risk eligible for statins only 9,785 (8.3%) were prescribed them. Conclusions NHS Health Checks uptake remains low. Attendees were more likely than non-attendees to be diagnosed with type 2 diabetes, hypertension and CKD and receive treatment with statins and antihypertensives. Most attendees received neither treatment nor referral. Of those eligible for statins, fewer than 10% were treated

Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients

INTRODUCTION Rheumatoid Arthritis is a systemic inflammatory disease and classical disease-modifying anti-rheumatic drugs (cDMARDs) have proven efficacy. It is unknown what impact cDMARDs might have on dementia as an outcome. METHODS Incident diagnoses of Rheumatoid Arthritis in persons over 18 years from 1995 to 2011 were identified from the UK Clinical Practice Research Datalink. 3,876 cDMARD users were propensity score matched to 1,938 non-users, on a wide range of confounders. Impact on dementia was assessed using survival models. RESULTS cDMARD users were at reduced risk of dementia (hazard ratio: 0.60; 95% confidence intervals: 0.42-0.85). The effect was strongest in Methotrexate users (0.52; 0.34-0.82). DISCUSSION The strong effect of cDMARD use on a halving of dementia risk requires replication in a trial and may provide an important therapeutic pharmacological treatment. </p

Costs of joint replacement in osteoarthritis: A study using the National Joint Registry and Clinical Practice Research Datalink datasets

Objectives: The aim of this study was to estimate the costs of primary hip and knee replacement in individuals with osteoarthritis up to 2 years post-surgery, compare costs before and after the surgery, and identify predictors of hospital costs. Methods: Patients aged 18 years or over with primary planned hip or knee replacements and osteoarthritis in England between 2008 and 2016 were identified from the National Joint Registry and linked with Hospital Episode Statistics data containing inpatient episodes. Primary care data linked with hospital outpatient records were also used to identify patients aged 18 years or over with primary hip or knee replacements between 2008 and 2016. All healthcare resource use was valued using 2016/17 costs and non-parametric censoring methods were used to estimate total 1-year and 2-year costs. Results: We identified 854,866 individuals undergoing hip or knee replacement. The mean censor-adjusted 1-year hospitalisation costs for hip and knee replacement were £7,827 (95% CI £7,813 to £7,842) and £7,805 (95% CI £7,790 to £7,818), respectively. Complications and revisions were associated with up to a three-fold increase in 1-year hospitalisation costs. The censor-adjusted 2-year costs were £9,258 (95 % CI £9,233 to £9,280) and £9,452 (95%CI £9,430 to £9,475) for hip and knee replacement. Adding primary and outpatient care, the mean total hip and knee replacement 2-year costs were £11,987 and £12,578, respectively. Conclusions: There are significant costs following joint replacement. Revisions and complications accounted for considerable costs and there is a significant incentive to identify best approaches to reduce these.</p

Assessment on patient outcomes of primary hip replacement: an interrupted time series analysis from ‘The National Joint Registry of England and Wales’

Objectives Effects of the UK Department of Health’s national Enhanced Recovery After Surgery (ERAS) Programme on outcomes after primary hip replacement. Design Natural experimental study using interrupted time series to assess the changes in trends before, during and after ERAS implementation (April 2009 to March 2011). Setting Surgeries in the UK National Joint Registry were linked with Hospital Episode Statistics containing inpatient episodes from National Health Service trusts in England and patient reported outcome measures. Participants Patients aged ≥18 years from 2008 to 2016. Main outcome measures Regression coefficients of monthly means of length of hospital stay, bed day cost, change in Oxford Hip Scores (OHS) 6 months post-surgery, complications 6 months post-surgery and revision rates 5 years post-surgery. Results 438 921 primary hip replacements were identified. Hospital stays shortened from 5.6 days in April 2008 to 3.6 in December 2016. There were also improvements in bed day costs (£7573 in April 2008 to £5239 in December 2016), positive change in self-reported OHS from baseline to 6 months post-surgery (17.7 points in April 2008 to 22.9 points in December 2016), complication rates (4.1% in April 2008 to 1.7% March 2016) and 5 year revision rates (5.9 per 1000 implant-years (95% CI 4.8 to 7.2) in April 2008 to 2.9 (95% CI 2.2 to 3.9) in December 2011). The positive trends in all outcomes started before ERAS was implemented and continued during and after the programme. Conclusions Patient outcomes after hip replacement have improved over the last decade. A national ERAS programme maintained this improvement but did not alter the existing rate of change.</p

Post-operative determinants of chronic pain after primary knee replacement surgery: analysis of data on 258,386 patients from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR)

Objective: To identify post-operative risk factors for the development of chronic pain after knee replacement. Design: Primary knee replacements in persons aged ≥18 years between April 2008 and December 2016 from the National Joint Registry, linked with English Hospital Episode Statistics data, and Patient Reported Outcome Measures. The outcome was chronic pain 6-months after surgery (Oxford Knee pain score). Logistic regression modelling identified risk factors for chronic pain outcome. Results: 258,386 patients; 56.7% women; average age 70.1 years (SD ±8.8 years). 43,702 (16.9%) were identified as having chronic pain 6-months post-surgery. Within 3 months of surgery complications were uncommon: intra-operative complications 1,224 (0.5%); ≥1 medical complication 6,073 (2.4%)); 32,930 (12.7%) hospital readmissions; 3,848 (1.5%) re-operation; 835 (0.3%) revision. Post-surgical risk factors of chronic pain were: mechanical complication of prosthesis odds ratio (OR) 1.56 (95% Confidence Interval 1.35, 1.80); surgical site infection OR 1.13 (0.99, 1.29); readmission OR 1.47 (1.42, 1.52); re-operation OR 1.39 (1.27, 1.51); revision OR 1.92 (1.64, 2.25); length of stay e.g. 6+ vs. <2 days OR 1.48 (1.35, 1.63), blood transfusion OR 0.47 (0.26, 0.86) and myocardial infarction OR 0.69 (0.49, 0.97). Discriminatory ability of the model was only fair (c-statistic 0.71) indicating that post-surgical predictors explain a limited amount of variability in chronic pain. Conclusions: We identified a number of post-operative factors relating to the operation and early recovery that are associated with chronic pain following primary knee replacement. The model had weak discriminatory ability indicating that there remains considerable unexplained variability in chronic pain outcome