Qualitative Exploration in Exit Interviews of Changes Observed in Clinical Trials for Individuals with Autism Spectrum Disorder Without Intellectual Disability.

Purpose: To explore, from the perspective of Study Partners (SPs; eg, caregivers) of clinical trial participants with autism spectrum disorder (ASD), any changes experienced in socialization and communication over the clinical trial, how these changes manifested, and the impact these changes had on the autistic individual, the SP, and family. This helps interpret whether changes in trial outcomes were meaningful. Patients and Methods: Interviews were conducted with the SPs of individuals with ASD, without intellectual disability, from 2 clinical trials: 86 children (aged 5-12 years) or adolescents (aged 13-17 years) who took part in the aV1ation trial (83.7% male), and 41 adults (aged 18+ years) who took part in the V1aduct trial (80.5% male). The primary endpoint for both trials was change from baseline in the VinelandTM-II two-domain composite, consisting of the mean of the Socialization and Communication domains. In these interviews the participants verbally indicated level of change for each of these key domains on 7-point change scales. Results: Improvements in the Socialization domain enabled greater awareness of the feelings of others and allowed for stronger empathy and kindness. Improvements in the Communication domain allowed for the autistic individual to be better at listening and better at self-expression. Together, changes in these two domains, which were considered most important, allowed for richer, deeper relationships. Study Partners noted that improvements in these domains allowed for better integration within the family unit, decreased stress, and increased optimism about the autistic individual's future. Conclusions: The impacts of changes in either domain were synergistic, combining together to create positive experiences which in turn led to further positive impacts in other skills. These qualitative insights provide context to the changes that were observed during the clinical trial and captured using the VinelandTM-II, illustrating the meaning of these changes to the individuals with ASD without intellectual disability and their families, and the impact that they have on people's everyday lives and overall health-related quality of life.

Quantitative and Qualitative Exploration of Meaningful Change on the Vineland Adaptive Behavior Scales (Vineland™-II) in Children and Adolescents with Autism Without Intellectual Disability Following Participation in a Clinical Trial.

Purpose: The VinelandTM Adaptive Behavior Scale is often used in autism spectrum disorder (ASD) trials. The Adaptive Behavior Composite Score (VABS-ABC) is the standardized overall score (the average of the Socialization, Communication and Daily Living skills domains), and the standardized 2-Domain Composite Score (VABS-2DC) is a novel outcome measure (average of the Socialization and Communication domains). A within-person meaningful change threshold (MCT) has not been established for the VABS-2DC. This paper presents a quantitative and qualitative interpretation of what constitutes a meaningful change in these scores to individuals with ASD without Intellectual Disability (ID; IQ≥70) and their families, as reported by their study partners (SPs). Participants and Methods: Data were obtained from the aV1ation clinical trial in children and adolescents with ASD and associated exit interviews. The intent-to-treat (ITT) clinical trial population included 308 individuals with autism (85.4% male; average age: 12.4 years [standard deviation (SD)=2.97]); 124 in the child cohort (aged 5 to 12 years; average age: 9.4 years [SD=1.86]), and 184 in the adolescent cohort (aged 13 to 17 years; average age: 14.5 years [SD=1.39]). Study partners of 86 trial participants were included in the Exit Interview Population (EIP): participants represented were 83.7% male, average age: 12.3 years [SD=2.98]). Anchor and distribution-based methods were used to estimate within-person change to support a responder definition, to aid interpretation of the clinical trial data; qualitative data were used to contextualize the meaning of changes observed. Results: A within-person MCT range of 4 to 8 points was proposed for both VABS-ABC and VABS-2DC, which was associated with at least a 1-point improvement on 4 different anchors. Evidence for this within-person MCT was further supported by qualitative data, which suggested any change was considered meaningful to the individual with ASD, as reported by their SP, no matter what the magnitude. Conclusion: A change in standardized score of 4 to 8 points constitutes a within-person MCT on both VABS-ABC and novel VABS-2DC in those with ASD and no ID. A change of this, or more, was reported by the SPs in this trial to be meaningful and highly impactful upon the individuals with ASD and their family.

Patient-reported disease impact of systemic lupus erythematosus with active joint symptoms: Results from the systemic lupus erythematosus-update survey.

BACKGROUND: Many people with systemic lupus erythematosus (SLE) experience joint pain, swelling, and stiffness. These joint symptoms are associated with problems in physical functioning and work disability. We used survey data from adults with SLE to explore the burden and impact of joint symptoms. METHODS: SLE-UPDATE was a 2019 cross-sectional US survey of adults with SLE. We compared respondents with "currently active" joint symptoms' and those "without currently active" joint symptoms. The active joint cohort comprised survey respondents who self-reported current "stiffness in joints" or "pain/swelling in joints" and who had moderate to severe joint pain (Worst Joint Pain Numeric Rating Scale [NRS] score ≥ 4). Respondents not fulfilling these criteria were included in the non-active joint cohort. Outcomes included frequency and severity of pain, patient-reported outcomes (LupusPRO™ and Work Productivity and Activity Impairment: Lupus [WPAI-Lupus]), satisfaction with current treatments, and importance of different treatment goals. RESULTS: More respondents in the active joint cohort (N = 285) than in the non-active joint cohort (N = 215) reported pain most or all the time over the preceding 7 days (77.5% vs. 32.1%, p < .0001), fibromyalgia (45% vs. 12%, p < .0001), and higher (worse) mean scores on the Worst Pain NRS (6.5 vs. 4.8, p < .0001) and Worst Joint Pain NRS (6.7 vs. 4.5, p < .0001). Mean Lupus PRO health-related quality of life (HRQoL) total score was lower (worse) in the active joint cohort (48.9 vs. 64.1, p < .0001). WPAI-Lupus scores indicated greater work productivity losses and activity impairment in the active joint cohort. More respondents in the active joint cohort than in the non-active joint cohort were neutral or not satisfied with current treatments and rated reducing pain as a "very important" treatment goal (26.7% vs. 18.1%). CONCLUSIONS: Respondents with SLE and active joint manifestations in addition to having more pain report lower HRQoL and were less satisfied with their current treatments. Comorbid fibromyalgia may play a role in joint symptoms in patient with SLE joint manifestations. There is an unmet need for new therapeutic options to reduce joint symptom burden among patients with SLE.

Independent phenotypic plasticity axes define distinct obesity sub-types.

Studies in genetically 'identical' individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this 'unexplained' phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either 'normal' or 'overgrown'. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent ß-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.

Exome Sequencing of a Portuguese Cohort of Frontotemporal Dementia Patients: Looking Into the ALS-FTD Continuum.

Introduction: Frontotemporal dementia (FTD) is considered to be part of a continuum with amyotrophic lateral sclerosis (ALS). Many genes are associated with both ALS and FTD. Yet, many genes associated with ALS have not been shown to cause FTD. We aimed to study a Portuguese cohort of FTD patients, searching for variants in genes associated with both FTD and/or ALS. Methods: We included 57 thoroughly characterized index FTD patients from our memory clinic, who were not carriers of pathogenic variants in GRN, MAPT or C9orf72. We performed exome sequencing and 1) prioritized potential FTD and ALS causing variants by using Exomiser to annotate and filter results; and 2) looked specifically at rare variability in genes associated with FTD (excluding GRN, MAPT and C9ORF72) and/or ALS. Results: We identified 13 rare missense variants in 10 patients (three patients had two variants) in the following genes: FUS, OPTN, CCNF, DCTN1, TREM2, ERBB4, ANG, CHRNA4, CHRNB4 and SETX. We found an additional frameshift variant on GLT8D1 in one patient. One variant (ERBB4 p.Arg1112His) gathered enough evidence to be classified as likely pathogenic by the ACMG criteria. Discussion: We report, for the first time, an expanded study of genes known to cause FTD-ALS, in the Portuguese population. Potentially pathogenic variants in ERBB4, FUS, SETX, ANG, CHRNA4 and CHRNB4 were identified in FTD patients. These findings provide additional evidence for the potential role of rare variability in ALS-associated genes in FTD, expanding the genetic spectrum between the two diseases.

Genome-wide association of polygenic risk extremes for Alzheimer's disease in the UK Biobank.

In just over a decade, advances in genome-wide association studies (GWAS) have offered an approach to stratify individuals based on genetic risk for disease. Using recent Alzheimer's disease (AD) GWAS results as the base data, we determined each individual's polygenic risk score (PRS) in the UK Biobank dataset. Using individuals within the extreme risk distribution, we performed a GWAS that is agnostic of AD phenotype and is instead based on known genetic risk for disease. To interpret the functions of the new risk factors, we conducted phenotype analyses, including a phenome-wide association study. We identified 246 loci surpassing the significance threshold of which 229 were not reported in the base AD GWAS. These include loci that showed suggestive levels of association in the base GWAS and loci not previously suspected to be associated with AD. Among these, there are loci, such as IL34 and KANSL1, that have since been shown to be associated with AD in recent studies. We also show highly significant genetic correlations with multiple health-related outcomes that provide insights into prodromal symptoms and comorbidities. This is the first study to utilize PRS as a phenotype-agnostic group classification in AD genetic studies. We identify potential new loci for AD and detail phenotypic analysis of these PRS extremes.

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease.

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease.

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer's disease.

The search for rare variants in Alzheimer's disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful.Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs.Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aß pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions.Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs.

Routine provision of feedback from patient-reported outcome measurements to healthcare providers and patients in clinical practice.

BACKGROUND: Patient-reported outcomes measures (PROMs) assess a patient's subjective appraisal of health outcomes from their own perspective. Despite hypothesised benefits that feedback  on PROMs can support decision-making in clinical practice and improve outcomes, there is uncertainty surrounding the effectiveness of PROMs feedback. OBJECTIVES: To assess the effects of PROMs feedback to patients, or healthcare workers, or both on patient-reported health outcomes and processes of care. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, two other databases and two clinical trial registries on 5 October 2020. We searched grey literature and consulted experts in the field. SELECTION CRITERIA: Two review authors independently screened and selected studies for inclusion. We included randomised trials directly comparing the effects on outcomes and processes of care of PROMs feedback to healthcare professionals and patients, or both with the impact of not providing such information. DATA COLLECTION AND ANALYSIS: Two groups of two authors independently extracted data from the included studies and evaluated study quality. We followed standard methodological procedures expected by Cochrane and EPOC. We used the GRADE approach to assess the certainty of the evidence. We conducted meta-analyses of the results where possible. MAIN RESULTS: We identified 116 randomised trials which assessed the effectiveness of PROMs feedback in improving processes or outcomes of care, or both in a broad range of disciplines including psychiatry, primary care, and oncology. Studies were conducted across diverse ambulatory primary and secondary care settings in North America, Europe and Australasia. A total of 49,785 patients were included across all the studies. The certainty of the evidence varied between very low and moderate. Many of the studies included in the review were at risk of performance and detection bias. The evidence suggests moderate certainty that PROMs feedback probably improves quality of life (standardised mean difference (SMD) 0.15, 95% confidence interval (CI) 0.05 to 0.26; 11 studies; 2687 participants), and leads to an increase in patient-physician communication (SMD 0.36, 95% CI 0.21 to 0.52; 5 studies; 658 participants), diagnosis and notation (risk ratio (RR) 1.73, 95% CI 1.44 to 2.08; 21 studies; 7223 participants), and disease control (RR 1.25, 95% CI 1.10 to 1.41; 14 studies; 2806 participants). The intervention probably makes little or no difference for general health perceptions (SMD 0.04, 95% CI -0.17 to 0.24; 2 studies, 552 participants; low-certainty evidence), social functioning (SMD 0.02, 95% CI -0.06 to 0.09; 15 studies; 2632 participants; moderate-certainty evidence), and pain (SMD 0.00, 95% CI -0.09 to 0.08; 9 studies; 2386 participants; moderate-certainty evidence). We are uncertain about the effect of PROMs feedback on physical functioning (14 studies; 2788 participants) and mental functioning (34 studies; 7782 participants), as well as fatigue (4 studies; 741 participants), as the certainty of the evidence was very low. We did not find studies reporting on adverse effects defined as distress following or related to PROM completion. AUTHORS' CONCLUSIONS: PROM feedback probably produces moderate improvements in communication between healthcare professionals and patients as well as in diagnosis and notation, and disease control, and small improvements to quality of life. Our confidence in the effects is limited by the risk of bias, heterogeneity and small number of trials conducted to assess outcomes of interest. It is unclear whether   many of these improvements are clinically meaningful or sustainable in the long term. There is a need for more high-quality studies in this area, particularly studies which employ cluster designs and utilise techniques to maintain allocation concealment.

Factors Associated with the Development, Progression, and Outcome of Dupuytren Disease Treatment: A Systematic Review.

BACKGROUND: The factors typically considered to be associated with Dupuytren disease have been described, such as those in the "Dupuytren diathesis." However, the quality of studies describing them has not been appraised. This systematic review aimed to analyze the evidence for all factors investigated for potential association with the development, progression, outcome of treatment, or recurrence of Dupuytren disease. METHODS: A systematic review of the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature databases was conducted using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant methodology up to September of 2019. Articles were screened in duplicate. Prognostic studies were quality assessed using the Quality in Prognosis Study tool. RESULTS: This study identified 2301 records; 51 met full inclusion criteria reporting data related to 54,491 patients with Dupuytren disease. In total, 46 candidate factors associated with the development of Dupuytren disease were identified. There was inconsistent evidence between the association of Dupuytren disease and the presence of "classic" diathesis factors. The quality of included studies varied, and the generalizability of studies was low. There was little evidence describing the factors associated with functional outcome. CONCLUSIONS: This systematic review challenges conventional notions of diathesis factors. Traditional diathesis factors are associated with disease development and recurrence, although they are not significantly associated with poor outcome following intervention based on the current evidence.

Exploring the use of health and wellbeing measures during pregnancy and the first year following birth in women living with pre-existing long-term conditions: qualitative interviews with women and healthcare professionals.

BACKGROUND: One way in which care for pregnant and postpartum women living with long-term health conditions (LTCs) may be improved is through the adoption of standardised measures to provide evidence of health outcomes and wellbeing from the woman's perspective. AIM: The study explores the views of pregnant and postpartum women living with LTCs, and healthcare professionals to better understand the potential value of using standardised health and wellbeing measures within this patient population. METHODS: Qualitative semi-structured telephone interviews were conducted to explore the perceived value of using measures with pregnant and postpartum women living with LTCs within maternity services. Participants were asked to provide feedback on three exemplar measures: the Long Term Conditions Questionnaire, the Wellbeing in Pregnancy Questionnaire and the EuroQol EQ-5D-5L instrument. Thematic analysis was used in the analysis of the transcripts. RESULTS: Eleven women and 11 healthcare professionals took part in semi-structured interviews. Analysis identified five themes as relevant to the use of measures within maternity services: 1) Improving care, 2) Assessing outcomes, 3) Interpretation and application of data, 4) Engagement challenges and implementation and, 5) Women and healthcare professionals alignment. CONCLUSIONS: Despite varying prior experience and expressing some questions about implementation, respondents were cautiously positive about the use of standardised health and wellbeing measures. Their use offers the opportunity for both affected women and healthcare professionals caring for them to collectively identify and assess important areas of unmet needs and improve outcomes. Incorporating the perspectives of women with LTC's will help bring awareness to elements of women centred care which health services may seek to address.

Use of Patient-Reported Experience Measures in Pediatric Care: A Systematic Review.

Introduction: Patient-reported Experience Measures (PREMs) are validated questionnaires, that gather patients' and families' views of their experience receiving care and are commonly used to measure the quality of care, with the goal to make care more patient and family-centered. PREMs are increasingly being adopted in pediatric population, however knowledge gaps exist around understanding the use of PREMs in pediatrics. Objective: To identify and synthesize evidence on the use of PREMs in pediatric healthcare settings and their characteristics. Evidence Review: Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines governed the conduct and reporting of this review. An exhaustive search strategy was applied to MEDLINE, EMBASE, PsycINFO, Cochrane Library, and CINAHL databases to identify relevant peer-reviewed articles from high-income countries. Additionally, gray literature was searched to capture real-world implementation of PREMs. All the articles were screened independently by two reviewers in two steps. Data was extracted independently, synthesized, and tabulated. Findings from gray literature was synthesized and reported separately. Risk of bias for the studies identified through scientific databases was assessed independently by two reviewers using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: The initial search identified 15,457 articles. After removing duplicates, the title and abstracts of 11,543 articles were screened. Seven hundred ten articles were eligible for full-text review. Finally, 83 articles met the criteria and were included in the analyses. Of the 83 includes studies conducted in 14 countries, 48 were conducted in USA, 25 in European countries and 10 in other countries. These 83 studies reported on the use of 39 different PREMs in pediatric healthcare settings. The gray literature retrieved 10 additional PREMs. The number of items in these PREMs ranged from 7 to 89. Twenty-three PREMs were designed to be completed by proxy, 10 by either pediatric patients or family caregivers, and 6 by pediatric patients themselves. Conclusion and Relevance: This comprehensive review is the first to systematically search evidence around the use of PREMs in pediatrics. The findings of this review can guide health administrators and researchers to use appropriate PREMs to implement patient and family-centered care in pediatrics.

Genetics of synucleins in neurodegenerative diseases.

The SNCA locus currently has an indisputable role in Parkinson's disease and other synucleinopathies. The role of genetic variability in the other members of the synuclein family (SNCB and SNCG) in disease is far less clear. In this review, we critically assess the pathogenicity, main characteristics, and roles of genetic variants in these genes reported to be causative of synucleinopathies. We also summarize the different association signals identified in the SNCA locus that have been associated with risk for disease. We take a bird's eye view of the variability currently reported in the general population for the three genes and use these data to infer on the potential relationship between each of the genes and human disease.

Improving the quality of person-centred healthcare from the patient perspective: development of person-centred quality indicators.

IMPORTANCE: International efforts are being made towards a person-centred care (PCC) model, but there are currently no standardised mechanisms to measure and monitor PCC at a healthcare system level. The use of metrics to measure PCC can help to drive the changes needed to improve the quality of healthcare that is person centred. OBJECTIVE: To develop and validate person-centred care quality indicators (PC-QIs) measuring PCC at a healthcare system level through a synthesis of the evidence and a person-centred consensus approach to ensure the PC-QIs reflect what matters most to people in their care. METHODS: Existing indicators were first identified through a scoping review of the literature and an international environmental scan. Focus group discussions with diverse patients and caregivers and interviews with clinicians and experts in quality improvement allowed us to identify gaps in current measurement of PCC and inform the development of new PC-QIs. A set of identified and newly developed PC-QIs were subsequently refined by Delphi consensus process using a modified RAND/UCLA Appropriateness Method. The international consensus panel consisted of patients, family members, community representatives, clinicians, researchers and healthcare quality experts. RESULTS: From an initial 39 unique evidence-based PC-QIs identified and developed, the consensus process yielded 26 final PC-QIs. These included 7 related to structure, 16 related to process, 2 related to outcome and 1 overall global PC-QI. CONCLUSIONS: The final 26 evidence-based and person-informed PC-QIs can be used to measure and evaluate quality incorporating patient perspectives, empowering jurisdictions to monitor healthcare system performance and evaluate policy and practice related to PCC.

Genetic architecture of common non-Alzheimer's disease dementias.

Frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and vascular dementia (VaD) are the most common forms of dementia after Alzheimer's disease (AD). The heterogeneity of these disorders and/or the clinical overlap with other diseases hinder the study of their genetic components. Even though Mendelian dementias are rare, the study of these forms of disease can have a significant impact in the lives of patients and families and have successfully brought to the fore many of the genes currently known to be involved in FTD and VaD, starting to give us a glimpse of the molecular mechanisms underlying these phenotypes. More recently, genome-wide association studies have also pointed to disease risk-associated loci. This has been particularly important for DLB where familial forms of disease are very rarely described. In this review we systematically describe the Mendelian and risk genes involved in these non-AD dementias in an effort to contribute to a better understanding of their genetic architecture, find differences and commonalities between different dementia phenotypes, and uncover areas that would benefit from more intense research endeavors.

How do frontline staff use patient experience data for service improvement? Findings from an ethnographic case study evaluation.

OBJECTIVES: Improving patient experience is widely regarded as a key component of health care quality. However, while a considerable amount of data are collected about patient experience, there are concerns this information is not always used to improve care. This study explored whether and how frontline staff use patient experience data for service improvement. METHODS: We conducted a year-long ethnographic case study evaluation, including 299 hours of observations and 95 interviews, of how frontline staff in six medical wards at different hospital sites in the United Kingdom used patient experience data for improvement. RESULTS: In every site, staff undertook quality improvement projects using a range of data sources. Teams of health care practitioners and ancillary staff engaged collectively in a process of sense-making using formal and informal sources of patient experience data. While survey data were popular, 'soft' intelligence - such as patients' stories, informal comments and observations - also informed staff's improvement plans, without always being recognized as data. Teams with staff from different professional backgrounds and grades tended to make more progress than less diverse teams, being able to draw on a wider net of practical, organizational and social resources, support and skills, which we describe as team-based capital. CONCLUSIONS: Organizational recognition, or rejection, of specific forms of patient experience intelligence as 'data' affects whether staff feel the data are actionable. Teams combining a diverse range of staff generated higher levels of 'team-based capital' for quality improvement than those adopting a single disciplinary approach. This may be a key mechanism for achieving person-centred improvement in health care.

Systematic Review of Patient-Reported Outcome Measures in Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation. These patients face a unique challenge due to the complexity of GVHD and the toxicity of treatments received. GVHD has significant impact on quality of life (QOL), but this is not routinely evaluated formally. Despite the availability of patient-reported outcome measures (PROMs) to assess QOL, there is currently no consensus regarding the optimal PROMs that should be used to evaluate the impact of GVHD. We undertook a systematic review to determine the current evidence for the use of PROMs in assessment of QOL, symptom burden, and disease severity of patients with GVHD. A comprehensive systematic review based on the COSMIN guidelines was conducted to identify studies using PROMs (including those for QOL and symptom burden) in acute and chronic GVHD (cGVHD) patients. The following databases were searched: OVID Medline, AMED, CINAHL, Embase, PROQOLID, ProQuest, PsychINFO, and Social Sciences Citation Index from inception to May 2018. Hand searches updated the search to December 2018. Articles were screened by 2 independent reviewers, with discrepancies resolved by a third independent reviewer. Included articles were critically appraised using the COSMIN Risk of Bias tool, and relevant data on measurement properties for the included PROMs were extracted from within the target population. A total of 4545 articles were identified, and 64 articles reporting on 27 PROMs were included in this review. PROMs were separated into 5 groups; generic patient-reported measures (n = 7), cancer-specific measures (n = 4), bone marrow transplant-specific measures (n = 2), cGVHD-specific measures (n = 4), and dimension-specific measures (n = 10). Three PROMs (Human Activity Profile, Lee Symptom Scale, National Institutes of Health Eleven Point Scale) had evidence to support strong reliability (including internal consistency), responsiveness, and aspects of validity within the cGVHD population. Only 5 included PROMs were used in patients with acute GVHD. This review summarizes the current evidence regarding the use of 27 included PROMs in the context of GVHD. The choice of the most optimal PROM depends on the clinical or research context of use. Future research should comprehensively validate these tools in the GVHD population, including the testing and possible development of a PROM for use in acute GVHD, which remains a current critical gap in the existing literature.

The Arthroplasty Candidacy Help Engine tool to select candidates for hip and knee replacement surgery: development and economic modelling.

BACKGROUND: There is no good evidence to support the use of patient-reported outcome measures (PROMs) in setting preoperative thresholds for referral for hip and knee replacement surgery. Despite this, the practice is widespread in the NHS. OBJECTIVES/RESEARCH QUESTIONS: Can clinical outcome tools be used to set thresholds for hip or knee replacement? What is the relationship between the choice of threshold and the cost-effectiveness of surgery? METHODS: A systematic review identified PROMs used to assess patients undergoing hip/knee replacement. Their measurement properties were compared and supplemented by analysis of existing data sets. For each candidate score, we calculated the absolute threshold (a preoperative level above which there is no potential for improvement) and relative thresholds (preoperative levels above which individuals are less likely to improve than others). Owing to their measurement properties and the availability of data from their current widespread use in the NHS, the Oxford Knee Score (OKS) and Oxford Hip Score (OHS) were selected as the most appropriate scores to use in developing the Arthroplasty Candidacy Help Engine (ACHE) tool. The change in score and the probability of an improvement were then calculated and modelled using preoperative and postoperative OKS/OHSs and PROM scores, thereby creating the ACHE tool. Markov models were used to assess the cost-effectiveness of total hip/knee arthroplasty in the NHS for different preoperative values of OKS/OHSs over a 10-year period. The threshold values were used to model how the ACHE tool may change the number of referrals in a single UK musculoskeletal hub. A user group was established that included patients, members of the public and health-care representatives, to provide stakeholder feedback throughout the research process. RESULTS: From a shortlist of four scores, the OHS and OKS were selected for the ACHE tool based on their measurement properties, calculated preoperative thresholds and cost-effectiveness data. The absolute threshold was 40 for the OHS and 41 for the OKS using the preferred improvement criterion. A range of relative thresholds were calculated based on the relationship between a patient's preoperative score and their probability of improving after surgery. For example, a preoperative OHS of 35 or an OKS of 30 translates to a 75% probability of achieving a good outcome from surgical intervention. The economic evaluation demonstrated that hip and knee arthroplasty cost of < £20,000 per quality-adjusted life-year for patients with any preoperative score below the absolute thresholds (40 for the OHS and 41 for the OKS). Arthroplasty was most cost-effective for patients with lower preoperative scores. LIMITATIONS: The ACHE tool supports but does not replace the shared decision-making process required before an individual decides whether or not to undergo surgery. CONCLUSION: The OHS and OKS can be used in the ACHE tool to assess an individual patient's suitability for hip/knee replacement surgery. The system enables evidence-based and informed threshold setting in accordance with local resources and policies. At a population level, both hip and knee arthroplasty are highly cost-effective right up to the absolute threshold for intervention. Our stakeholder user group felt that the ACHE tool was a useful evidence-based clinical tool to aid referrals and that it should be trialled in NHS clinical practice to establish its feasibility. FUTURE WORK: Future work could include (1) a real-world study of the ACHE tool to determine its acceptability to patients and general practitioners and (2) a study of the role of the ACHE tool in supporting referral decisions. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Patients with severe hip and knee arthritis may require joint replacement. General practitioners make the decision to refer patients to hospital based on an assessment of their symptoms. Pain and function can be measured using patient questionnaires and the questionnaire scores can indicate whether or not the severity of disease warrants referral (i.e. whether or not the patient is a candidate for joint replacement based on their 'capacity to benefit'). However, we do not know whether or not basing treatment decisions on such scores is correct, nor do we know what exact pain score thresholds should be used for referral. After a thorough search, we found that the Oxford Hip and Knee Scores were the best instruments. A high score (i.e. a maximum score of 48) indicates less pain and better function. The threshold values for referral for surgery were scores of 40 for hips and 41 for knees. The process of evaluating scoring systems, the choice of scoring systems and the threshold values were discussed and agreed by a panel of patients and by doctors throughout the study. Most patients with severe joint pain benefit from joint replacement, and these operations are cost-effective. However, above a certain level (a score of 40 for hips and 41 for knees), patients are not thought to typically benefit from surgery. Below these values, lower presurgery scores indicate a steadily increasing likelihood of benefit in terms of reduced pain and better function. This information provides the basis for a tool to help doctors decide who to refer for joint replacement: the Arthroplasty Candidacy Help Engine (ACHE). Use of the ACHE tool prevents patients who are unlikely to benefit from joint replacement being referred unnecessarily and allows the NHS to concentrate resources on those who will benefit most from arthroplasty treatment.

Development of an International Standard Set of Value-Based Outcome Measures for Patients With Chronic Kidney Disease: A Report of the International Consortium for Health Outcomes Measurement (ICHOM) CKD Working Group.

Value-based health care is increasingly promoted as a strategy for improving care quality by benchmarking outcomes that matter to patients relative to the cost of obtaining those outcomes. To support the shift toward value-based health care in chronic kidney disease (CKD), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international working group of health professionals and patient representatives to develop a standardized minimum set of patient-centered outcomes targeted for clinical use. The considered outcomes and patient-reported outcome measures were generated from systematic literature reviews. Feedback was sought from patients and health professionals. Patients with very high-risk CKD (stages G3a/A3 and G3b/A2-G5, including dialysis, kidney transplantation, and conservative care) were selected as the target population. Using an online modified Delphi process, outcomes important to all patients were selected, such as survival and hospitalization, and to treatment-specific subgroups, such as vascular access survival and kidney allograft survival. Patient-reported outcome measures were included to capture domains of health-related quality of life, which were rated as the most important outcomes by patients. Demographic and clinical variables were identified to be used as case-mix adjusters. Use of these consensus recommendations could enable institutions to monitor, compare, and improve the quality of their CKD care.