Development and evaluation of tools and an intervention to improve patient- and carer-centred outcomes in Longer-Term Stroke care and exploration of adjustment post stroke: the LoTS care research programme

Background: Evidence-based care pathways are required to support stroke patients and their carers in the longer term. Aims: The twofold aim of this programme of four interlinking projects was to enhance the care of stroke survivors and their carers in the first year after stroke and gain insights into the process of adjustment. Methods and results: We updated and further refined a purposely developed system of care (project 1) predicated on a patient-centred structured assessment designed to address areas of importance to patients and carers. The structured assessment is linked to evidence-based treatment algorithms, which we updated using a structured protocol: reviewing available guidelines, Cochrane reviews and randomised trials. A pragmatic cluster randomised controlled trial evaluation of the clinical effectiveness and cost-effectiveness of this system of care was undertaken in 29 community-based UK stroke care co-ordinator services (project 2). In total, 15 services provided the system of care and 14 continued with usual practice. The primary objective was to determine whether the intervention improved patient psychological outcomes (General Health Questionnaire-12) at 6 months; secondary objectives included functional outcomes for patients, outcomes for carers and cost-effectiveness, as measured through self-completed postal questionnaires at 6 and 12 months. A total of 800 patients and 208 carers were recruited; numbers of participants and their baseline characteristics were well balanced between intervention and control services. There was no evidence of statistically significant differences in primary or secondary end points or adverse events between the two groups, nor evidence of cost-effectiveness. Intervention compliance was high, indicating that this is an appropriate approach to implement evidence into clinical practice. A 22-item Longer-term Unmet Needs after Stroke (LUNS) questionnaire was developed and robustly tested (project 3). A pack including the LUNS questionnaire and outcome assessments of mood and social activity was posted to participants 3 or 6 months after stroke to assess acceptability and validity. The LUNS questionnaire was re-sent 1 week after return of the first pack to assess test–retest reliability. In total, 850 patients were recruited and the acceptability, validity and test–retest reliability of the LUNS questionnaire as a screening tool for post-stroke unmet need were confirmed. This tool is now available for clinical use. An in-depth qualitative investigation was undertaken with 22 patients (and carers) at least 1 year after stroke (project 4) to gain further insights into the experience of adjustment. This included initial semistructured interviews, limited observations and solicited diaries with a follow-up interview 3–4 months after the initial interview and highlighted a range of different trajectories for post-stroke recovery. Conclusions: The programme has been completed as planned, including one of the largest ever stroke rehabilitation trials. This work highlights that successfully addressing the needs of a heterogeneous post-stroke population remains problematic. Future work could explore stratifying patients and targeting services towards patients (and carers) with specific needs, leading to a more specialised bespoke service. The newly developed LUNS questionnaire and the qualitative work will help inform such services

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Multiple loci on 8q24 associated with prostate cancer susceptibility

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33)