Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer : long-term survival results from the STAMPEDE trial

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden

Psychosocial Treatment of Children in Foster Care: A Review

A substantial number of children in foster care exhibit psychiatric difficulties. Recent epidemiologi-cal and historical trends in foster care, clinical findings about the adjustment of children in foster care, and adult outcomes are reviewed, followed by a description of current approaches to treatment and extant empirical support. Available interventions for these children can be categorized as either symptom-focused or systemic, with empirical support for specific methods ranging from scant to substantial. Even with treatment, behavioral and emotional problems often persist into adulthood, resulting in poor functional outcomes. We suggest that self-regulation may be an important mediat-ing factor in the appearance of emotional and behavioral disturbance in these children

Impact of Chlamydia trachomatis in the reproductive setting: British Fertility Society Guidelines for practice

Chlamydia trachomatis infection of the genital tract is the most common sexually transmitted infection and has a world-wide distribution. The consequences of infection have an adverse effect on the reproductive health of women and are a common cause of infertility. Recent evidence also suggests an adverse effect on male reproduction. There is a need to standardise the approach in managing the impact of C. trachomatis infection on reproductive health. We have surveyed current UK practice towards screening and management of Chlamydia infections in the fertility setting. We found that at least 90% of clinicians surveyed offered screening. The literature on this topic was examined and revealed a paucity of solid evidence for estimating the risks of long-term reproductive sequelae following lower genital tract infection with C. trachomatis. The mechanism for the damage that occurs after Chlamydial infections is uncertain. However, instrumentation of the uterus in women with C. trachomatis infection is associated with a high risk of pelvic inflammatory disease, which can be prevented by appropriate antibiotic treatment and may prevent infected women from being at increased risk of the adverse sequelae, such as ectopic pregnancy and tubal factor infertility. Recommendations for practice have been proposed and the need for further studies is identified

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Factors influencing first-service conception and overall pregnancy rates in commercial beef heifers

Commercial beef heifers (n=1863) from 16 different sources were used to evaluate the influence of management practices and biological traits on first-service conception and overall pregnancy rates. Frame score, initial weight, overall ADG, body condition score, reproductive tract score, source, AI technician, and AI sire significantly influenced first-service conception. Overall pregnancy rates were influenced by frame score, body weight, and ADG

Recent developments of precessions polishing for larger components and free-form surfaces

Since the 2003 Annual Meeting, the Precessions process has become accepted as an efficient method for polishing and figuring moderate-sized axially-symmetric aspheric parts in industry. In this paper, we report on some very significant new advances beyond this capability. The first is the demonstration of the process on substantially larger diameter parts than worked hitherto – in particular, a precisionground 500mm diameter deeply-concave aspheric mirror. We describe the consequences of polishing large parts with the axis of the part vertical, in contrast to the horizontal axis of the smaller machines. Issues include slurry puddling and settlement in concave forms, process-uniformity, adequate support of the part and handling. We then report on recent work developing the Precessions process for non axially-symmetric surfaces including free-form. The correct relationship of the process with metrology has proved to be complex on several fronts, one example being differing descriptions of form either along a surface or its projection. We present our experience using profilometry and interferometry on precision-ground and polished surfaces, and in achieving absolute form with known base radius. Finally, we remark on the potential power of a priori predictions of achievable surface quality when optimizing optical system designs