Evaluating an intervention to improve the safety and experience of transitions from hospital to home for older people (Your Care Needs You): a protocol for a cluster randomised controlled trial and process evaluation.

BACKGROUND: Older patients often experience safety issues when transitioning from hospital to home. The 'Your Care Needs You' (YCNY) intervention aims to support older people to 'know more' and 'do more' whilst in hospital so that they are better prepared for managing at home. METHODS: A multi-centre cluster randomised controlled trial (cRCT) will evaluate the effectiveness and cost-effectiveness of the YCNY intervention. Forty acute hospital wards (clusters) in England from varying medical specialities will be randomised to deliver YCNY or care-as-usual on a 1:1 basis. The primary outcome will be unplanned hospital readmission rates within 30 days of discharge. This will be extracted from routinely collected data of at least 5440 patients (aged 75 years and older) discharged to their own homes during the 4- to 5-month YCNY intervention period. A nested cohort of up to 1000 patients will be recruited to the study to collect secondary outcomes via follow-up questionnaires at 5-, 30- and 90-day post-discharge. These will include measures of patient experience of transitions, patient-reported safety events, quality of life and healthcare resource use. Unplanned hospital readmission rates at 60 and 90 days of discharge will be collected from routine data. A process evaluation (primarily interviews and observations with patients, carers and staff) will be conducted to understand the implementation of the intervention and the contextual factors that shape this, as well as the intervention's underlying mechanisms of action. Fidelity of intervention delivery will also be assessed across all intervention wards. DISCUSSION: This study will establish the effectiveness and cost-effectiveness of the YCNY intervention which aims to improve patient safety and experience for older people during transitions of care. The process evaluation will generate insights about how the YCNY intervention was implemented, what elements of the intervention work and for whom, and how to optimise its implementation so that it can be delivered with high fidelity in routine service contexts. TRIAL REGISTRATION: UK Clinical Research Network Portfolio: 44559; ISTCRN: ISRCTN17062524. Registered on 11/02/2020.

Learning does not just happen: establishing learning principles for tools to translate resilience into practice, based on a participatory approach.

BACKGROUND: Theories of learning are of clear importance to resilience in healthcare since the ability to successfully adapt and improve patient care is closely linked to the ability to understand what happens and why. Learning from both positive and negative events is crucial. While several tools and approaches for learning from adverse events have been developed, tools for learning from successful events are scarce. Theoretical anchoring, understanding of learning mechanisms, and establishing foundational principles for learning in resilience are pivotal strategies when designing interventions to develop or strengthen resilient performance. The resilient healthcare literature has called for resilience interventions, and new tools to translate resilience into practice have emerged but without necessarily stipulating foundational learning principles. Unless learning principles are anchored in the literature and based on research evidence, successful innovation in the field is unlikely to occur. The aim of this paper is to explore: What are key learning principles for developing learning tools to help translate resilience into practice? METHODS: This paper reports on a two-phased mixed methods study which took place over a 3-year period. A range of data collection and development activities were conducted including a participatory approach which involved iterative workshops with multiple stakeholders in the Norwegian healthcare system. RESULTS: In total, eight learning principles were generated which can be used to help develop learning tools to translate resilience into practice. The principles are grounded in stakeholder needs and experiences and in the literature. The principles are divided into three groups: collaborative, practical, and content elements. CONCLUSIONS: The establishment of eight learning principles that aim to help develop tools to translate resilience into practice. In turn, this may support the adoption of collaborative learning approaches and the establishment of reflexive spaces which acknowledge system complexity across contexts. They demonstrate easy usability and relevance to practice.

Unpacking the Cinderella black box of complex intervention development through the Partners at Care Transitions (PACT) programme of research.

INTRODUCTION: Complex intervention development has been described as the 'Cinderella' black box in health services research. Greater transparency in the intervention development process is urgently needed to help reduce research waste. METHODS: We applied a new consensus-based framework for complex intervention development to our programme of research, in which we developed an intervention to improve the safety and experience of care transitions for older people. Through this process, we aimed to reflect on the framework's utility for intervention development and identify any important gaps within it to support its continued development. FINDINGS: The framework was a useful tool for transparent reporting of the process of complex intervention development. We identified potential 'action' gaps in the framework including 'consolidation of evidence' and 'development of principles' that could bracket and steer decision-making in the process. CONCLUSIONS: We consider that the level of transparency demonstrated in this report, aided through use of the framework, is essential in the quest for reducing research waste. PATIENT OR PUBLIC CONTRIBUTION: We have involved our dedicated patient and public involvement group in all work packages of this programme of research. Specifically, they attended and contributed to co-design workshops and contributed to finalizing the intervention for the pilot evaluation. Staff also participated by attending co-design workshops, helping us to prioritize content ideas for the intervention and supporting the development of intervention components outside of the workshops.

Improving the safety and experience of transitions from hospital to home: a cluster randomised controlled feasibility trial of the 'Your Care Needs You' intervention versus usual care.

BACKGROUND: The 'Your Care Needs You' (YCNY) intervention aims to increase the safety and experience of transitions for older people through greater patient involvement during the hospital stay. METHODS: A cluster randomised controlled feasibility trial was conducted on NHS inpatient wards (clusters) where ≥ 40% of patients were routinely ≥ 75 years. Wards were randomised to YCNY or usual care using an unequal allocation ratio (3:2). We aimed to recruit up to 20 patients per ward. Follow-up included routine data collection and questionnaires at 5-, 30-, and 90-days post-discharge. Eligible patients were ≥ 75 years, discharged home, stayed overnight on participating wards, and could read and understand English. The trial assessed the feasibility of delivering YCNY and the trial methodology through recruitment rates, outcome completion rates, and a qualitative evaluation. The accuracy of using routinely coded data for the primary outcome in the definitive trial was assessed by extracting discharge information for up to ten nonindividual consenting patients per ward. RESULTS: Ten wards were randomised (6 intervention, 4 control). One ward withdrew, and two wards were unable to deliver the intervention. Seven-hundred twenty-one patients were successfully screened, and 161 were recruited (95 intervention, 66 control). The patient post-discharge attrition rate was 17.4% (n = 28). Primary outcome data were gathered for 91.9% of participants with 75.2% and 59.0% providing secondary outcome data at 5 and 30 days post-discharge respectively. Item completion within questionnaires was generally high. Post-discharge follow-up was terminated early due to the COVID-19 pandemic affecting 90-day response rates (16.8%). Data from 88 nonindividual consenting patients identified an error rate of 15% when using routinely coded data for the primary outcome. No unexpected serious adverse events were identified. Most patients viewed YCNY favourably. Staff agreed with it in principle, but ward pressures and organisational contexts hampered implementation. There was a need to sustain engagement, provide clarity on roles and responsibilities, and account for fluctuations in patients' health, capacity, and preferences. CONCLUSIONS: If implementation challenges can be overcome, YCNY represents a step towards involving older people as partners in their care to improve the safety and experience of their transitions from hospital to home. TRIAL REGISTRATION: ISRCTN: 51154948.

A qualitative formative evaluation of a patient facing intervention to improve care transitions for older people moving from hospital to home.

BACKGROUND: The Partners at Care Transitions (PACTs) intervention was developed to support older people's involvement in hospital to improve outcomes at home. A booklet, question card, record sheet, induction leaflet, and patient-friendly discharge letter support patients to be more involved in their health and wellbeing, medications, activities of daily living and post-discharge care. We aimed to assess intervention acceptability, identify implementation tools, and further develop the intervention. METHODS: This was a qualitative formative evaluation involving three wards from one hospital. We recruited 25 patients aged 75 years and older. Ward staff supported intervention delivery. Data were collected in wards and patients' homes, through semi-structured interviews, observation, and documentary analysis. Data were analysed inductively and iteratively with findings sorted according to the research aims. RESULTS: Patients and staff felt there was a need for, and understood the purpose of, the PACT intervention. Most patients read the booklet but other components were variably used. Implementation challenges included time, awareness, and balancing intervention benefits against risks. Changes to the intervention and implementation included clarifying the booklet's messages, simplifying the discharge letter to reduce staff burden, and using prompts and handouts to promote awareness. CONCLUSION: The PACT intervention offers a promising new way to improve care transitions for older people by supporting patient involvement in their care. After further development of the intervention and implementation package, it will undergo further testing. PATIENT OR PUBLIC CONTRIBUTION: This study regularly consulted a panel representing the local patient community, who supported the development of this intervention and its implementation.

What Do Patients and Their Carers Do to Support the Safety of Cancer Treatment and Care? A Scoping Review.

BACKGROUND: Cancer patients and their carers face a multitude of challenges in the treatment journey; the full scope of how they are involved in promoting safety and supporting resilient healthcare is not known. OBJECTIVE: The study aimed to undertake a scoping review to explore, document, and understand existing research, which explores what cancer patients and their carers do to support the safety of their treatment and care. DESIGN: This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. Five online databases were searched from 2000 to 2021 to identify primary literature exploring perspectives on patient and caregiver involvement in maintaining their safety during cancer care. Narrative synthesis was then conducted on the included literature. RESULTS: Of the 1582 results generated from the initial search, 16 studies were included in the review. Most consisted of qualitative semistructured interviews with patients, as well as carers and healthcare professionals (HCP). Four narrative themes were identified: patient perception of safety and their involvement; patients take charge of their own care and well-being; safety as a dynamic collective responsibility; and carers are an undersupported asset. Patients and their carers involve themselves in a variety of behaviors in physical care, well-being, communication, and care coordination to ensure safety and support system resilience. This review adds a novel perspective on cancer patient and caregiver involvement in supporting resilient healthcare. CONCLUSIONS: Patients and their carers play an important role in promoting safe cancer care and healthcare system resilience. Further research is recommended to realize the full extent of the system gaps encountered and mediated by patients and their carers.

Improving patient experience and safety at transitions of care through the Your Care Needs You (YCNY) intervention: a study protocol for a cluster randomised controlled feasibility trial.

BACKGROUND: Patients, particularly older people, often experience safety issues when transitioning from hospital to home. Although the evidence is currently equivocal as to how we can improve this transition of care, interventions that support patient involvement may be more effective. The 'Your Care Needs You' (YCNY) intervention supports patients to 'know more' and 'do more' whilst in hospital in order that they better understand their health condition and medications, maintain their daily activities, and can seek help at home if required. The intervention aims to reduce emergency hospital readmissions and improve safety and experience during the transition to home. METHODS: As part of the Partners At Care Transitions (PACT) programme of research, a multi-centred cluster randomised controlled trial (cRCT) will be conducted to explore the feasibility of the YCNY intervention and trial methodology. Data will be used to refine the intervention and develop a protocol for a definitive cRCT.Ten acute hospital wards (the clusters) from varying medical specialties including older peoples' medicine, trauma and orthopaedics, cardiology, intermediate care, and stroke will be randomised to deliver YCNY or usual care on a 3:2 basis. Up to 200 patients aged 75 years and over and discharged to their own homes will be recruited to the study. Patients will complete follow-up questionnaires at 5-, 30-, and 90-days post-discharge and readmission data up to 90-days post-discharge will be extracted from their medical records.Study outcomes will include measures of feasibility (e.g. screening, recruitment, and retention data) and processes required to collect routine data at a patient and ward level. In addition, interviews and observations involving up to 24 patients/carers and 28 staff will be conducted to qualitatively assess the acceptability, usefulness, and feasibility of the intervention and implementation package to patients and staff. A separate sub-study will be conducted to explore how accurately primary outcome data (30-day emergency hospital readmissions) can be gathered for the definitive cRCT. DISCUSSION: This study will establish the feasibility of the YCNY intervention which aims to improve safety and experience during transitions of care. It will identify key methodological and implementation issues that need to be addressed prior to assessing the effectiveness of the YCNY intervention in a definitive cluster randomised controlled trial. TRIAL REGISTRATION: UK Clinical Research Network Portfolio: 42191; ISTCRN: ISRCTN51154948. Registered 16/07/2019.

Delivering exceptionally safe transitions of care to older people: a qualitative study of multidisciplinary staff perspectives.

BACKGROUND: Transitions of care are often risky, particularly for older people, and shorter hospital stays mean that patients can go home with ongoing care needs. Most previous research has focused on fundamental system flaws, however, care generally goes right far more often than it goes wrong. We explored staff perceptions of how high performing general practice and hospital specialty teams deliver safe transitional care to older people as they transition from hospital to home. METHODS: We conducted a qualitative study in six general practices and four hospital specialties that demonstrated exceptionally low or reducing readmission rates over time. Data were also collected across four community teams that worked into or with these high-performing teams. In total, 157 multidisciplinary staff participated in semi-structured focus groups or interviews and 9 meetings relating to discharge were observed. A pen portrait approach was used to explore how teams across a variety of different contexts support successful transitions and overcome challenges faced in their daily roles. RESULTS: Across healthcare contexts, staff perceived three key themes to facilitate safe transitions of care: knowing the patient, knowing each other, and bridging gaps in the system. Transitions appeared to be safest when all three themes were in place. However, staff faced various challenges in doing these three things particularly when crossing boundaries between settings. Due to pressures and constraints, staff generally felt they were only able to attempt to overcome these challenges when delivering care to patients with particularly complex transitional care needs. CONCLUSIONS: It is hypothesised that exceptionally safe transitions of care may be delivered to patients who have particularly complex health and/or social care needs. In these situations, staff attempt to know the patient, they exploit existing relationships across care settings, and act to bridge gaps in the system. Systematically reinforcing such enablers may improve the delivery of safe transitional care to a wider range of patients. TRIAL REGISTRATION: The study was registered on the UK Clinical Research Network Study Portfolio (references 35272 and 36174 ).

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.

'Handing over to the patient': A FRAM analysis of transitional care combining multiple stakeholder perspectives.

INTRODUCTION: The period following discharge can present risks for older adults. Most research has focused on hospital discharge with less attention paid to on-going care needs. Despite evidence that patients undertake 'invisible work' to improve care safety, their reported willingness to be involved in care, and the consensus that successful transitions interventions include patient involvement, in reality, this is variable. Further, little research has viewed transitional care as a 'system', with gaps, interdependencies and variability across settings, nor the role of patients and families in supporting the system resilience. RESEARCH OBJECTIVES: 1) model transitional care from multiple perspectives using the Functional Resonance Analysis Method (FRAM); 2) use the model to develop a theory of change to support intervention development. METHOD: We drew data from two studies: i) exploring the perspective of older adults across transitional care, and ii) exploring how health services experience transitional care. We employed the FRAM to develop a model of transitional care, with a system boundary spanning an older patient's admission to hospital, through to thirty days post-discharge. FINDINGS: Modelling transitional care from multiple perspectives was challenging. 27 functions were identified with interdependencies between hospital-based functions and patient-led functions once home, the success of which may impact on transitions 'outcomes' (e.g. safety events, readmissions). The model supported development of a theory of change, to guide future intervention development. CONCLUSIONS: Supporting certain patient-facing upstream hospital functions (e.g. encouraging mobility, supporting a better understanding of medication and condition), may lead to improved outcomes for patients following hospital discharge.

A qualitative positive deviance study to explore exceptionally safe care on medical wards for older people.

BACKGROUND: The positive deviance approach seeks to identify and learn from those who demonstrate exceptional performance. This study sought to explore how multidisciplinary teams deliver exceptionally safe care on medical wards for older people. METHODS: A qualitative positive deviance study was conducted on four positively deviant and four slightly-above-average matched comparator wards, which had been identified using routinely collected NHS Safety Thermometer data. In total, 70 multidisciplinary staff participated in eight focus groups to explore staff perceptions about how their teams deliver safe patient care. A thematic analysis was conducted in two stages: first to identify the tools, processes, strategies, and cultural and social contexts that facilitated safety across all wards; and second to generate hypotheses about the characteristics that facilitated 'positively deviant' patient care. RESULTS: Based on identifiable qualitative differences between the positively deviant and comparison wards, 14 characteristics were hypothesised to facilitate exceptionally safe care on medical wards for older people. This paper explores five positively deviant characteristics that healthcare professionals considered to be most salient. These included the relational aspects of teamworking, specifically regarding staff knowing one another and working together in truly integrated multidisciplinary teams. The cultural and social context of positively deviant wards was perceived to influence the way in which practical tools (eg, safety briefings and bedside boards) were implemented. CONCLUSION: This study exemplifies that there are no 'silver bullets' to achieving exceptionally safe patient care on medical wards for older people. Healthcare leaders should encourage truly integrated multidisciplinary ward teams where staff know each other well and work as a team. Focusing on these underpinning characteristics may facilitate exceptional performances across a broad range of safety outcomes.

Partners at Care Transitions: exploring healthcare professionals' perspectives of excellence at care transitions for older people.

INTRODUCTION: Hospital admissions are shorter than they were 10 years ago. Notwithstanding the benefits of this, patients often leave hospital requiring ongoing care. The transition period can therefore be risky, particularly for older people with complex health and social care needs. Previous research has predominantly focused on the errors and harms that occur during transitions of care. In contrast, this study adopts an asset-based approach to learn from factors that facilitate safe outcomes. It seeks to explore how staff within high-performing ('positively deviant') teams successfully support transitions from hospital to home for older people. METHODS AND ANALYSIS: Six high-performing general practices and six hospital specialties that demonstrate exceptionally low or reducing 30-day emergency hospital readmission rates will be invited to participate in the study. Healthcare staff from these clinical teams will be recruited to take part in focus groups, individual interviews and/or observations of staff meetings. Data collection will explore the ways in which teams successfully deliver exceptionally safe transitional care and how they overcome the challenges faced in their everyday clinical work. Data will be thematically analysed using a pen portrait approach to identify the manifest (explicit) and latent (abstract) factors that facilitate success. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Leeds. The study will help develop our understanding of how multidisciplinary staff within different healthcare settings successfully support care transitions for older people. Findings will be disseminated to academic and clinical audiences through peer-reviewed articles, conferences and workshops. Findings will also inform the development of an intervention to improve the safety and experience of older people during transitions from hospital to home.

Identifying positively deviant elderly medical wards using routinely collected NHS Safety Thermometer data: an observational study.

OBJECTIVE: The positive deviance approach seeks to identify and learn from exceptional performers. Although a framework exists to apply positive deviance within healthcare organisations, there is limited guidance to support its implementation. The approach has also rarely explored exceptional performance on broad outcomes, been implemented at ward level, or applied within the UK. This study develops and critically appraises a pragmatic method for identifying positively deviant wards using a routinely collected, broad measure of patient safety. DESIGN: A two-phased observational study was conducted. During phase 1, cross-sectional and temporal analyses of Safety Thermometer data were conducted to identify a discrete group of positively deviant wards that consistently demonstrated exceptional levels of safety. A group of matched comparison wards with above average performances were also identified. During phase 2, multidisciplinary staff and patients on the positively deviant and comparison wards completed surveys to explore whether their perceptions of safety supported the identification of positively deviant wards. SETTING: 34 elderly medical wards within a northern region of England, UK. PARTICIPANTS: Multidisciplinary staff (n=161) and patients (n=188) clustered within nine positively deviant and comparison wards. RESULTS: Phase 1: A combination of analyses identified five positively deviant wards that performed best in the region, outperformed their organisation and performed consistently well over 12 months. Five above average matched comparator wards were also identified. Phase 2: Staff and patient perceptions of safety generally supported the identification of positively deviant wards using Safety Thermometer data, although patient perceptions of safety were less concordant with the routinely collected data. CONCLUSIONS: This study tentatively supports a pragmatic method of using routinely collected data to identify positively deviant elderly medical wards; however, it also highlights the various challenges that are faced when conducting the first stage of the positive deviance approach. TRIAL REGISTRATION NUMBER: UK Clinical Research Network Portfolio (reference-18050).

Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y POS mouse model.

BACKGROUND: Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes. METHODS: To investigate the relevance of these VUS in regards to the patient's phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (Y POS ) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-Y B6 and undervirilized B6-Y POS gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-Y POS males). RESULTS: We identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-Y POS mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9. CONCLUSION: The use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation.

What methods are used to apply positive deviance within healthcare organisations? A systematic review.

BACKGROUND: The positive deviance approach focuses on those who demonstrate exceptional performance, despite facing the same constraints as others. 'Positive deviants' are identified and hypotheses about how they succeed are generated. These hypotheses are tested and then disseminated within the wider community. The positive deviance approach is being increasingly applied within healthcare organisations, although limited guidance exists and different methods, of varying quality, are used. This paper systematically reviews healthcare applications of the positive deviance approach to explore how positive deviance is defined, the quality of existing applications and the methods used within them, including the extent to which staff and patients are involved. METHODS: Peer-reviewed articles, published prior to September 2014, reporting empirical research on the use of the positive deviance approach within healthcare, were identified from seven electronic databases. A previously defined four-stage process for positive deviance in healthcare was used as the basis for data extraction. Quality assessments were conducted using a validated tool, and a narrative synthesis approach was followed. RESULTS: 37 of 818 articles met the inclusion criteria. The positive deviance approach was most frequently applied within North America, in secondary care, and to address healthcare-associated infections. Research predominantly identified positive deviants and generated hypotheses about how they succeeded. The approach and processes followed were poorly defined. Research quality was low, articles lacked detail and comparison groups were rarely included. Applications of positive deviance typically lacked staff and/or patient involvement, and the methods used often required extensive resources. CONCLUSION: Further research is required to develop high quality yet practical methods which involve staff and patients in all stages of the positive deviance approach. The efficacy and efficiency of positive deviance must be assessed and compared with other quality improvement approaches. PROSPERO REGISTRATION NUMBER: CRD42014009365.

Learning from positively deviant wards to improve patient safety: an observational study protocol.

INTRODUCTION: Positive deviance is an asset-based approach to improvement which has recently been adopted to improve quality and safety within healthcare. The approach assumes that solutions to problems already exist within communities. Certain groups or individuals identify these solutions and succeed despite having the same resources as others. Within healthcare, positive deviance has previously been applied at individual or organisational levels to improve specific clinical outcomes or processes of care. This study explores whether the positive deviance approach can be applied to multidisciplinary ward teams to address the broad issue of patient safety among elderly patients. METHODS AND ANALYSIS: Preliminary work analysed National Health Service (NHS) Safety Thermometer data from 34 elderly medical wards to identify 5 'positively deviant' and 5 matched 'comparison' wards. Researchers are blinded to ward status. This protocol describes a multimethod, observational study which will (1) assess the concurrent validity of identifying positively deviant elderly medical wards using NHS Safety Thermometer data and (2) generate hypotheses about how positively deviant wards succeed. Patient and staff perceptions of safety will be assessed on each ward using validated surveys. Correlation and ranking analyses will explore whether this survey data aligns with the routinely collected NHS Safety Thermometer data. Staff focus groups and researcher fieldwork diaries will be completed and qualitative thematic content analysis will be used to generate hypotheses about the strategies, behaviours, team cultures and dynamics that facilitate the delivery of safe patient care. The acceptability and sustainability of strategies identified will also be explored. ETHICS AND DISSEMINATION: The South East Scotland Research Ethics Committee 01 approved this study (reference: 14/SS/1085) and NHS Permissions were granted from all trusts. Findings will be published in peer-reviewed, scientific journals, and presented at academic conferences. TRIAL REGISTRATION NUMBER: This study is registered on the UK Clinical Research Network Study Portfolio (reference number-18050).

Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities.

BACKGROUND: In humans, Mammalian Target of Rapamycin (MTOR) encodes a 300 kDa serine/ threonine protein kinase that is ubiquitously expressed, particularly at high levels in brain. MTOR functions as an integrator of multiple cellular processes, and in so doing either directly or indirectly regulates the phosphorylation of at least 800 proteins. While somatic MTOR mutations have been recognized in tumors for many years, and more recently in hemimegalencephaly, germline MTOR mutations have rarely been described. CASE PRESENTATION: We report the successful application of family-trio Diagnostic Exome Sequencing (DES) to identify the underlying molecular etiology in two brothers with multiple neurological and developmental lesions, and for whom previous testing was non-diagnostic. The affected brothers, who were 6 and 23 years of age at the time of DES, presented symptoms including but not limited to mild Autism Spectrum Disorder (ASD), megalencephaly, gross motor skill delay, cryptorchidism and bilateral iris coloboma. Importantly, we determined that each affected brother harbored the MTOR missense alteration p.E1799K (c.5395G>A). This exact variant has been previously identified in multiple independent human somatic cancer samples and has been shown to result in increased MTOR activation. Further, recent independent reports describe two unrelated families in whom p.E1799K co-segregated with megalencephaly and intellectual disability (ID); in both cases, p.E1799K was shown to have originated due to germline mosaicism. In the case of the family reported herein, the absence of p.E1799K in genomic DNA extracted from the blood of either parent suggests that this alteration most likely arose due to gonadal mosaicism. Further, the p.E1799K variant exerts its effect by a gain-of-function (GOF), autosomal dominant mechanism. CONCLUSION: Herein, we describe the use of DES to uncover an activating MTOR missense alteration of gonadal mosaic origin that is likely to be the causative mutation in two brothers who present multiple neurological and developmental abnormalities. Our report brings the total number of families who harbor MTOR p.E1799K in association with megalencephaly and ID to three. In each case, evidence suggests that p.E1799K arose in the affected individuals due to gonadal mosaicism. Thus, MTOR p.E1799K can now be classified as a pathogenic GOF mutation that causes megalencephaly and cognitive impairment in humans.

Acceleration of age-associated methylation patterns in HIV-1-infected adults.

Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x 10(-200) and 0.47, p<1 x 10(-200). Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: ßage=0.007088, p=2.08 x 10(-9); ßHIV=0.099574, p=0.0011; Data set 2: ßage=0.008762, p=1.27 x 10(-5); ßHIV=0.128649, p=0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10(-6), odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age-associated patterns and suggest that general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging.

Exome sequencing for the diagnosis of 46,XY disorders of sex development.

CONTEXT: Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (gonadal or genital) sex of an individual. Such conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY gonadal dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available. OBJECTIVE: We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis. DESIGN: Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD. RESULTS: We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding, an additional 12.5% with likely pathogenic findings, and 15% with variants of unknown clinical significance. CONCLUSIONS: Early identification of the genetic cause of a DSD will in many cases streamline and direct the clinical management of the patient, with more focused endocrine and imaging studies and better-informed surgical decisions. Exome sequencing proved an efficient method toward such a goal in 46,XY DSD patients.

Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.

PURPOSE: Diagnostic exome sequencing was immediately successful in diagnosing patients in whom traditional technologies were uninformative. Herein, we provide the results from the first 500 probands referred to a clinical laboratory for diagnostic exome sequencing. METHODS: Family-based exome sequencing included whole-exome sequencing followed by family inheritance-based model filtering, comprehensive medical review, familial cosegregation analysis, and analysis of novel genes. RESULTS: A positive or likely positive result in a characterized gene was identified in 30% of patients (152/500). A novel gene finding was identified in 7.5% of patients (31/416). The highest diagnostic rates were observed among patients with ataxia, multiple congenital anomalies, and epilepsy (44, 36, and 35%, respectively). Twenty-three percent of positive findings were within genes characterized within the past 2 years. The diagnostic rate was significantly higher among families undergoing a trio (37%) as compared with a singleton (21%) whole-exome testing strategy. CONCLUSION: Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date. These data demonstrate the utility of family-based exome sequencing and analysis to obtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease.