Risk Factors for 1-Year Mortality and Hospital Utilization Patterns in Critical Care Survivors: A Retrospective, Observational, Population-Based Data Linkage Study.

OBJECTIVES: Clear understanding of the long-term consequences of critical care survivorship is essential. We investigated the care process and individual factors associated with long-term mortality among ICU survivors and explored hospital use in this group. DESIGN: Population-based data linkage study using the Secure Anonymised Information Linkage databank. SETTING: All ICUs between 2006 and 2013 in Wales, United Kingdom. PATIENTS: We identified 40,631 patients discharged alive from Welsh adult ICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was 365-day survival. The secondary outcomes were 30- and 90-day survival and hospital utilization in the 365 days following ICU discharge. Kaplan-Meier curves were plotted to compare survival rates. Cox proportional hazards regression models were used to determine risk factors of mortality. Seven-thousand eight-hundred eighty-three patients (19.4%) died during the 1-year follow-up period. In the multivariable Cox regression analysis, advanced age and comorbidities were significant determinants of long-term mortality. Expedited discharge due to ICU bed shortage was associated with higher risk. The rate of hospitalization in the year prior to the critical care admission was 28 hospitalized days/1,000 d; post critical care was 88 hospitalized days/1,000 d for those who were still alive; and 57 hospitalized days/1,000 d and 412 hospitalized days/1,000 d for those who died by the end of the study, respectively. CONCLUSIONS: One in five ICU survivors die within 1 year, with advanced age and comorbidity being significant predictors of outcome, leading to high resource use. Care process factors indicating high system stress were associated with increased risk. More detailed understanding is needed on the effects of the potentially modifiable factors to optimize service delivery and improve long-term outcomes of the critically ill.

All Wales Injury Surveillance System revised: development of a population-based system to evaluate single-level and multilevel interventions.

BACKGROUND: Injury surveillance has been established since the 1990s, but is still largely based upon single-source data from sentinel sites. The growth of electronic health records and developments in privacy protecting linkage technologies provide an opportunity for more sophisticated surveillance systems. OBJECTIVE: To describe the evolution of an injury surveillance system to support the evaluation of interventions, both simple and complex in terms of organisation. METHODS: The paper describes the evolution of the system from one that relied upon data only from emergency departments to one that include multisource data and are now embedded in a total population privacy protecting data linkage system. Injury incidence estimates are compared by source and data linkage used to aid understanding of data quality issues. Examples of applications, challenges and solutions are described. RESULTS: The age profile and estimated incidence of injuries recorded in general practice, emergency departments and hospital admissions differ considerably. Data linkage has enabled the evaluation of complex interventions and measurement of longer-term impact of a wide range of exposures. CONCLUSIONS: Embedding injury surveillance within privacy protecting data linkage environment can transform the utility of a traditional single-source surveillance system to a multisource system. It also facilitates greater involvement in the evaluation of simple and complex healthcare and non-healthcare interventions and contributes to the growing evidence basis underlying the science of injury prevention and control.

PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis.

The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA. IMPLICATIONS: PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.

Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome.

AIM: Coats plus syndrome (CP) is a rare autosomal recessive disorder, characterised by retinal telangiectasia exudates (Coats disease), leukodystrophy, distinctive intracranial calcification and cysts, as well as extra-neurological features including abnormal vasculature of the gastrointestinal tract, portal hypertension and osteopenia with a tendency to fractures. CP most frequently occurs due to loss-of-function mutations in CTC1. The encoded protein CTC1 constitutes part of the CST (CTC1-STN1-TEN1) complex, and three patients have been described with CP due to biallelic mutations in STN1. Together with the identification of homozygosity for a specific loss-of-function mutation in POT1 in a sibling pair, these observations highlight a defect in the maintenance of telomere integrity as the cause of CP, although the precise mechanism leading to the micro-vasculopathy seen at a pathological level remains unclear. Here, we present the investigation of a fourth child who presented to us with retinal exudates, intracranial calcifications and developmental delay, in keeping with a diagnosis of CP, and later went on to develop pancytopenia and gastrointestinal bleeding. Genome sequencing revealed compound heterozygous variants in STN1 as the likely genetic cause of CP in this present case. METHODS: We assessed the phenotype to be CP and undertook targeted sequencing. RESULTS: Whilst sequencing of CTC1 and POT1 was normal, we identified novel compound heterozygous variants in STN1 (previous gene symbol OBFC1): one loss-of-function--c.894dup (p.(Asp299Argfs*58)); and one missense--c.707T>C (p.(Leu236Pro)). CONCLUSION: Given the clinical phenotype and identified variants we suggest that this is only the fourth patient reported to date with CP due to mutations in STN1.

Study protocol for investigating the impact of community home modification services on hospital utilisation for fall injuries: a controlled longitudinal study using data linkage.

INTRODUCTION: This study will evaluate the effectiveness of home adaptations, both in preventing hospital admissions due to falls for older people, and improving timely discharge. Results will provide evidence for services at the interface between health and social care, informing policies seeking to promote healthy ageing through prudent healthcare and fall prevention. METHODS AND ANALYSIS: All individuals living in Wales, UK, aged 60 years and over, will be included in the study using anonymised linked data from the Secure Anonymised Information Linkage Databank. We will use a national database of home modifications implemented by the charity organisation Care & Repair Cymru (C&R) from 2009 to 2017 to define an intervention cohort. We will use the electronic Frailty Index to assign individual levels of frailty (fit, mild, moderate or severe) and use these to create a comparator group (non-C&R) of people who have not received a C&R intervention. Coprimary outcomes will be quarterly numbers of emergency hospital admissions attributed to falls at home, and the associated length of stay. Secondary outcomes include the time in moving to a care home following a fall, and the indicative financial costs of care for individuals who had a fall. We will use appropriate multilevel generalised linear models to analyse the number of hospital admissions related to falls. We will use Cox proportional hazard models to compare the length of stay for fall-related hospital admissions and the time in moving to a care home between the C&R and non-C&R cohorts. We will assess the impact per frailty group, correct for population migration and adjust for confounding variables. Indicative costs will be calculated using financial codes for individual-level hospital stays. Results will provide evidence for services at the interface between health and social care, informing policies seeking to promote healthy ageing through prudent healthcare and prevention. ETHICS AND DISSEMINATION: Information governance requirements for the use of record-linked data have been approved and only anonymised data will be used in our analysis. Our results will be submitted for publication in peer-reviewed journals. We will also work with lay members and the knowledge transfer team at Swansea University to create communication and dissemination materials on key findings.

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis.

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721-32. ©2017 AACR.

The use of secure anonymised data linkage to determine changes in healthcare utilisation following severe open tibial fractures.

Severe open fractures of the lower limbs are complex injuries requiring expert multidisciplinary management in appropriate orthoplastic centres. This study aimed to assess the impact of open fractures on healthcare utilisation and test the null hypotheses that there is no difference in healthcare utilisation between the year before and year after injury, and that there is no difference in healthcare utilisation in the year post-injury between patients admitted directly to an orthoplastic centre in keeping with the joint BOA/BAPRAS standards and those having initial surgery elsewhere. This retrospective cohort study utilising secure anonymised information linkage (SAIL), a novel databank of anonymised nationally pooled health records, recruited patients over 18 years of age sustaining severe open lower limb fractures managed primarily or secondarily at our centre and who had data available in the SAIL databank. 101 patients met inclusion criteria and 90 of these had records in the SAIL databank. The number of days in hospital, number of primary care attendances, number of outpatient attendances and number of emergency department attendances in the years prior and subsequent to injury were recorded. Patients sustaining open fractures had significantly different healthcare utilisation in the year after injury when compared with the year before, in terms of days spent in hospital (23.42 vs. 1.70, p=0.000), outpatient attendances (11.98 vs. 1.05, p=0.000), primary care attendances (29.48 vs. 11.99, p=0.000) and emergency department presentations (0.2 vs. 0.01, p=0.025). Patients admitted directly to orthoplastic centres had significantly fewer operations (1.78 vs. 3.31) and GP attendances (23.6 vs. 33.52) than those transferred in subsequent to initial management in other units. There is a significant increase in healthcare utilisation after open tibial fracture. Adherence to national standards minimises the impact of this on both patients and health services.