Childhood tuberculosis: progress requires an advocacy strategy now

Childhood tuberculosis (TB) is a preventable and curable infectious disease that remains overlooked by public health authorities, health policy makers and TB control programmes. Childhood TB contributes significantly to the burden of disease and represents the failure to control transmission in the community. Furthermore, the pool of infected children constitutes a reservoir of infection for the future burden of TB. It is time to prioritise childhood TB, advocate for addressing the challenges and grasp the opportunities in its prevention and control. Herein, we propose a scientifically informed advocacy agenda developed at the International Childhood TB meeting held in Stockholm, Sweden, from March 17 to 18, 2011, which calls for a renewed effort to improve the situation for children affected by Mycobacterium tuberculosis exposure, infection or disease. The challenges and needs in childhood TB are universal and apply to all settings and must be addressed more effectively by all stakeholders

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.324

Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Funder: Funding details are provided in the Supplementary MaterialAbstractPolygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.</jats:p

Femoral impaction grafting in revision total hip arthroplasty. A follow-up of 540 hips

Between 1987 and 1999, 540 revision total hip replacements in 487 patients were performed at our institution with the femoral impaction grafting technique with a cemented femoral stem. All patients were prospectively followed for 2-15years post-operatively with no loss to follow-up. 494 hips remained successfully in situ at an average 6.7years. The ten year survival rate was 98.0% (95% CI 96.2 to 99.8) with aseptic loosening as the endpoint and 84.2% (95% CI 78.5 to 89.9) for re-operation for any reason. Indication for surgery and the use of any kind of reinforcement significantly influenced outcome (p<0.001). This is the largest known series of revision THR with femoral impaction grafting and the results support continued use of this technique

The long-term results of the original exeter polished cemented femoral component - a follow-up report

We present a long-term follow-up report of the results of the original Exeter polished cemented stems inserted between November 1970 and the end of 1975 at our institution by surgeons of widely differing experience, utilising crude cementing techniques. The results of this series were reported in 1988 [1] and again in 1993 [2]. There have been no failures from aseptic femoral component loosening since the 1993 report. From the original series of 433 hips there were, at the end of 2003, 26 living patients with 33 hips. Of the latter, there were 25 hips in 20 patients with their original femoral components still in situ. 28 hips (6.46%) from the original series have been lost to follow-up, though none since 1992. With the end-point re-operation for aseptic stem loosening, the survivorship is 93.5% (95% CI: 90.0% to 97.0%).The re-operation rate for aseptic femoral component loosening is 3.23% into the 33rd year of follow-up

The concentric all-polyethylene Exeter acetabular component in primary total hip replacement

We report the long term outcome of the flangeless, cemented all polyethylene Exeter cup at a mean of 14.6 years (range 10-17) after operation. Of the 263 hips in 243 patients, 122 hips are still in situ, 112 patients (119 hips) have died, eighteen hips were revised, and three patients (four hips) had moved abroad and were lost to follow-up (1.5%). Radiographs demonstrated two sockets had migrated and six more had radiolucent lines in all three zones. The Kaplan Meier survivorship at 15 years with endpoint revision for all causes is 89.9% (95% CI 84.6 to 95.2%) and for aseptic cup loosening or lysis 91.7% (CI 86.6 to 96.8%). In 210 hips with a diagnosis of primary osteoarthritis survivorship for all causes is 93.2% (95% CI 88.1 to 98.3%), and for aseptic cup loosening 95.0% (CI 90.3 to 99.7%). The cemented all polyethylene Exeter cup has an excellent long-term survivorship

The original Exeter polished femoral component: a study of survivorship into the 33rd year of follow-up

Introduction &amp; Aims: To study the survivorship and subsidence patterns of the first 433 Exeter polished, totally collarless, double tapered, cemented stems that were inserted between November of 1970 and the end of 1975 by 16 different surgeons (13 of them in the training grades) utilising first generation cementing techniques. Method: A survivorship study up to the 33rd year of follow-up, using the Kaplan Meier method, was performed for all 433 hips, the end-point being revision for aseptic stem loosening. Stem subsidence in relation to the cement and the bone was measured in all survivors by a single observer on digitised films (magnified 200%) using the OrthochartTM software. Stem subsidence, the grade of cementing, ‘calcar’ resorption, visible cement fractures, focal lysis and radiolucent lines at the interfaces were assessed. Results: Of the 433 hips, 21 were revisions of previously failed hips. 21.7% patients have had a re-operation, including 3.7% for stem fracture, 3.5% for neck fracture (all from a group of 95 stems with excessively machined necks), 8.5% for aseptic cup loosening, 3.5% for aseptic stem loosening, 1.8% for infection and 0.5% for recurrent dislocation). For the overall series, with revision for aseptic stem loosening as the end-point, the survivorship is 93.5% (95%CL: 90.0% to 97.0%). When all cases lost to follow-up (28 hips) are regarded as failures, survivorship is 85.8% (95% CI of 81.3 to 90.3%). The average age at operation of the survivors was 55.7years. No significant radiological subsidence between the cement and bone was found. Mean subsidence between the stem and cement was 2.15mm, most occurring in the first 5 years and in all but 1 being less than 4. The maximum was 18mm (grade D cementing). Cementing grades were: B-65%, C-27%, D-8%. Resorption of the neck (13%) was associated with excessive socket wear or cement left over the cut surface of the neck (the ‘pseudocollar’). Visible cement fractures were found in 14%, none associated with focal lysis, which was seen in 11%. Conclusions: Although 21.7% of patients in this series of the first 433 Exeter hips to be inserted in Exeter needed a re-operation of some sort, the stem rarely required surgery for aseptic loosening and was associated with benign long-term x-ray appearances in spite of 1st generation cementing

The Exeter Hip: 40 Years of Innovation in Total Hip Arthroplasty

* Propoerties and use of acrylic cement * Design and biomechaniscs of a cemented hip replacement * The science of loosening, lysis and wear * Preparation of patients for surgery * Potential complications and their avoidance * Modern primary surgical techniques and new developments * Complex primary hip replacement and specialist techniques * Outcomes of cemented hip replacement * Principles of revision hip replacement * Basic science of bone grafting in revision surgery * Femoral acetabular impaction bone grafting techniques * Results of revision with bone graft and cemen