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Patient-reported outcomes (PROs) are increasingly used in single-arm cancer studies. We reviewed 60 papers published between 2018 and 2021 of single-arm studies of cancer treatment with PRO data for current practice on design, analysis, reporting, and interpretation. We further examined the studies’ handling of potential bias and how they informed decision making. Most studies (58; 97%) analysed PROs without stating a predefined research hypothesis. 13 (22%) of the 60 studies used a PRO as a primary or co-primary endpoint. Definitions of PRO objectives, study population, endpoints, and missing data strategies varied widely. 23 studies (38%) compared the PRO data with external information, most often by using a clinically important difference value; one study used a historical control group. Appropriateness of methods to handle missing data and intercurrent events (including death) were seldom discussed. Most studies (51; 85%) concluded that PRO results supported treatment. Conducting and reporting of PROs in cancer single-arm studies need standards and a critical discussion of statistical methods and possible biases. These findings will guide the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Data in Cancer Clinical Trials–Innovative Medicines Initiative (SISAQOL-IMI) in developing recommendations for the use of PRO-measures in single-arm studies.

Patient-reported outcomes (PROs), such as symptoms, functioning, and other health-related quality-of-life concepts are gaining a more prominent role in the benefit–risk assessment of cancer therapies. However, varying ways of analysing, presenting, and interpreting PRO data could lead to erroneous and inconsistent decisions on the part of stakeholders, adversely affecting patient care and outcomes. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) Consortium builds on the existing SISAQOL work to establish recommendations on design, analysis, presentation, and interpretation for PRO data in cancer clinical trials, with an expanded set of topics, including more in-depth recommendations for randomised controlled trials and single-arm studies, and for defining clinically meaningful change. This Policy Review presents international stakeholder views on the need for SISAQOL-IMI, the agreed on and prioritised set of PRO objectives, and a roadmap to ensure that international consensus recommendations are achieved.

IntroductionEarly phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements.Methods and analysisA methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions.Ethics and disseminationThis project was approved by ICR’s Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites.Registration detailsSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.

This article summarizes the discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum that took place on December 10, 2020 and was organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group, in coordination with the U.S. FDA Oncology Center of Excellence. Diverse stakeholders including experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on the use of nonconcurrent control in Master Protocols for oncology trials. While the use of nonconcurrent control with the concurrent control may increase the power of detecting the therapeutic difference between a treatment and the control, the panelists had diverse opinion on the statistical approaches for modeling nonconcurrent and concurrent controls. Some were more concerned about the temporality of the nonconcurrent control and bias introduced by different confounders related to time, for example, changes in standard of care, changes in patient population, changes in recruiting strategies, changes in assessment of endpoints. Nevertheless, in some situations such as when the recruitment is extremely challenging for a rare disease, the panelists concluded that the use of a nonconcurrent control can be justified.

IntroductionThe management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) remains challenging in view of the paucity of data and evidence-based treatment recommendations are missing.MethodsIn this single-centre, non-randomised, prospective open-label study, we evaluated and compared the efficacy of oral and parenteral treatments for SUNCT and SUNA in a real-world setting. Additionally, single-arm meta-analyses of the available reports of SUNCT and SUNA treatments were conducted.ResultsThe study cohort comprised 161 patients. Most patients responded to lamotrigine (56%), followed by oxcarbazepine (46%), duloxetine (30%), carbamazepine (26%), topiramate (25%), pregabalin and gabapentin (10%). Mexiletine and lacosamide were effective in a meaningful proportion of patients but poorly tolerated. Intravenous lidocaine given for 7–10 days led to improvement in 90% of patients, whereas only 27% of patients responded to a greater occipital nerve block. No statistically significant differences in responders were observed between SUNCT and SUNA. In the meta-analysis of the pooled data, topiramate was found to be significantly more effective in SUNCT than SUNA patients. However, a higher proportion of SUNA than SUNCT was considered refractory to medications at the time of the topiramate trial, possibly explaining this isolated difference.ConclusionsWe propose a treatment algorithm for SUNCT and SUNA for clinical practice. The response to sodium channel blockers indicates a therapeutic overlap with trigeminal neuralgia, suggesting that sodium channels dysfunction may be a key pathophysiological hallmark in these disorders. Furthermore, the therapeutic similarities between SUNCT and SUNA further support the hypothesis that these conditions are variants of the same disorder.

Novel cell therapies for haematological malignancies and solid tumours address pressing clinical need while offering potentially paradigm shifts in efficacy. However, innovative development risks outflanking information on statutory frameworks, regulatory guidelines and their working application. Meeting this challenge, regulators offer wide-ranging expertise and experience in confidential scientific and regulatory advice. We advocate early incorporation of regulatory perspectives to support strategic development of clinical programmes. We examine critical issues and key advances in clinical oncology trials to highlight practical approaches to optimising the clinical development of cell therapies. We recommend early consideration of collaborative networks, early-access schemes, reducing bias in single-arm trials, adaptive trials, clinical end-points supporting risk/benefit and cost/benefit analyses, companion diagnostics, real-world data and common technical issues. This symbiotic approach between developers and regulators should reduce development risk, safely expedite marketing authorisation, and promote early, wider availability of potentially transformative cell therapies for cancer.

ObjectiveTo compare the clinical characteristics and treatment responses of primary new daily persis- tent headache (NDPH) to transformed chronic daily headache (T-CDH, encompassing chronic migraine and chronic tension-type headache).MethodsAnalysis of prospectively collected clinical data in consecutive patients seen in a headache clinic between 2007 and 2019.ResultsInclusion criteria were met by 366 patients with NDPH and 696 with T-CDH. There was a lower female preponderance in NDPH than T-CDH (62.6% vs. 73.3%, p Nausea, vomiting, photophobia, phonophobia, motion sensitivity, vertigo, and cranial autonomic symptoms were all less common in NDPH than T-CDH (all pAcute treatments were less effective in NDPH, and medication overuse was less common (16% vs. 42%, pConclusionsWhilst there is overlap in the phenotype and response to treatment of NDPH and T-CDH; NDPH appears to be less symptomatically diverse, and less responsive to treatment.

ObjectiveDespite the similar phenotypes, comparison between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic features (SUNA) has hitherto not been possible due to the dearth of studies validating the phenotype of SUNA. Therefore, these 2 syndromes have been kept separate in the International Classification of Headache Disorders. The aim of this study is to characterize and compare the clinical phenotypes of large clinic-based cohorts of patients with SUNA and SUNCT.MethodsThe clinical phenotype of consecutive patients with SUNA identified from a single specialist headache center in the United Kingdom between 2007 and 2012 was studied and compared to that of patients with SUNCT.ResultsSixty-three patients with SUNA (18 male, 28.6%) and 70 patients with SUNCT (32 male, 35.7%) were included. The demographic and clinical characteristics of patients with SUNA were similar to those of patients with SUNCT. Ptosis and rhinorrhea were predictors of SUNCT. The corresponding odds ratios (ORs) (95% confidence interval) were 3.79 (1.64–8.77, p = 0.002) and 2.46 (1.09–5.59, p = 0.031), respectively. The presence of spontaneous only attacks was a predictor for SUNA (OR 2.58 [1.10–6.05], p = 0.029).ConclusionNo major clinical differences have emerged between SUNCT and SUNA, bar the fact that SUNCT is characterized by more prominent cranial autonomic features and triggerability. We propose that the 2 disorders be placed together in a single diagnostic category for which new diagnostic criteria are proposed.

Objective Predictors of psychiatric outcome following TLE surgery have proved elusive and represent a current challenge in the practice of TLE surgery. This prospective study investigated whether frontal lobe dysfunction is predictive of poorer psychiatric outcomes. Methods Forty-nine unilateral TLE surgical patients were assessed using the Beck Depression Inventory–Fast Screen (BDI-FS) and Beck Anxiety Inventory (BAI) preoperatively and 6 and 12 months postoperatively. Measures of intellectual function, semantic knowledge, memory and executive function were completed preoperatively, at 6 and 12 months following surgery. Results Preoperatively, 33 (67%) patients had minimal depressive symptoms, 8 (16%) were mildly depressed, 2 (4%) were moderately depressed, and 6 (12%) reported severe depressive morbidity. Twenty-three (47%) patients reported minimal anxiety, 18 (37%) were mildly anxious, 6 (12%) were moderately anxious and 2 (4%) patients reported severe anxiety symptoms. A mixed-model repeated-measures analysis was performed on the BDI-FS and BAI scores, adjusting for pertinent covariates identified in univariable analyses. At a year following TLE surgery, anxiety symptoms significantly improved but depressive morbidity did not. Indicators of frontal lobe dysfunction moderated the magnitude and direction of mood change. Specifically, pre-surgical cognitive measures of frontal lobe dysfunction predicted increased depression and anxiety symptoms following surgery. There was no relationship between preoperative BDI-FS or BAI scores and seizure outcome at 12 months or change in affective morbidity and seizure outcome. Significance This is the first longitudinal study to provide evidence that specific pre-surgical cognitive and behavioural indices of frontal dysfunction are predictive of poorer psychiatric outcome following TLE surgery. In addition, our findings highlight the potential utility of a dysexecutive behavioural rating scale (DEX) as an assessment tool in epilepsy. Examination of executive functioning in pre-surgical evaluations may lead to an increase in the power of prognostic models used to predict the psychiatric outcome of TLE surgery.

Lambru et al. argue that trigeminal neurovascular contact with morphological changes is involved in the aetiology of both SUNCT and SUNA. The absence of any significant radiological differences between SUNCT and SUNA adds to evidence suggesting they should be considered a single clinical entity., Emerging data-points towards a possible aetiological and therapeutic relevance of trigeminal neurovascular contact in short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and perhaps in short lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). We aimed to assess the prevalence and significance of trigeminal neurovascular contact in a large cohort of consecutive SUNCT and SUNA patients and evaluate the radiological differences between them. The standard imaging protocol included high spatial and nerve-cistern contrast resolution imaging acquisitions of the cisternal segments of the trigeminal nerves and vessels. MRI studies were evaluated blindly by two expert evaluators and graded according to the presence, location and degree of neurovascular contact. The degree of contact was graded as with or without morphological changes. Neurovascular contact with morphological changes was defined as contact with distortion and/or atrophy. A total of 159 patients (SUNCT = 80; SUNA = 79) were included. A total of 165 symptomatic and 153 asymptomatic trigeminal nerves were analysed. The proportion of neurovascular contact on the symptomatic trigeminal nerves was higher (80.0%) compared to the asymptomatic trigeminal nerves (56.9%). The odds on having neurovascular contact over the symptomatic nerves was significantly higher than on the asymptomatic nerves [odds ratio (OR): 3.03, 95% confidence interval (CI) 1.84–4.99; P

Contains fulltext : 229389.pdf (Publisher’s version ) (Closed access) Master protocols have received a growing interest during the last years. By assigning patients to specific substudies, they aim at targeting and accelerating clinical development. Given their complexity, basket, umbrella, and platform designs have raised challenging regulatory and statistical questions, especially the control of multiplicity in confirmatory trials. In basket trials, regulatory assessment of the benefit/risk in pooled populations and choice of the treatment indication is challenging. We provide here our perspectives on these topics. In master protocols, as long as the statistical hypotheses tested between the different substudies are independent, no supplementary adjustment for multiplicity over the different substudies should be required. Moreover, sharing a control arm within an umbrella or a platform trial investigating different drugs would not require a correction for the type I error rate, whereas the chance of multiple false positive regulatory decisions should be recognized. In basket trials, pooling across substudies requires a rationale supporting the intended indication and should be preplanned. Assessment of the benefit/risk in pooled target populations can be complicated by differences in design or in efficacy/safety signals between the substudies. While trials governed by a master protocol can offer logistic and financial advantages, more experience is needed to gain a deeper insight into this novel framework.

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.

BackgroundThere is little evidence to guide pharmacological treatment in adults with Down syndrome and Alzheimer's disease.AimsTo investigate the effect of cholinesterase inhibitors or memantine on survival and function in adults with Down syndrome and Alzheimer's disease.MethodThis was a naturalistic longitudinal follow-up of a clinical cohort of 310 people with Down syndrome diagnosed with Alzheimer's disease collected from specialist community services in England.ResultsMedian survival time (5.59 years, 95% CI 4.67–6.67) for those on medication (n = 145, mainly cholinesterase inhibitors) was significantly greater than for those not prescribed medication (n = 165) (3.45 years, 95% CI 2.91–4.13, log-rank test PConclusionsCholinesterase inhibitors appear to offer benefit for people with Down syndrome and Alzheimer's disease that is comparable with sporadic Alzheimer's disease; a trial to test the effect of earlier treatment (prodromal Alzheimer's disease) in Down syndrome may be indicated.Declaration of interestA.S. has undertaken consulting for Ono Pharmaceuticals, outside the submitted work. Z.W. has received a consultancy fee and grant from GE Healthcare, outside the submitted work.

The vasculature of the brain and kidneys are similarly vulnerable to hypertension, so their microvascular damage may be correlated. We investigated the relationship of renal function to the anatomical distribution of cerebral microbleeds (CMBs), a marker of underlying cerebral small vessel disease (hypertensive arteriopathy or cerebral amyloid angiopathy), in a Western patient cohort. This was a retrospective study of referrals to a hospital stroke service. All patients with clinical data and a T2*-weighted gradient-recalled echo (T2*-GRE) MRI were included. MRI scans were rated for CMBs using the Microbleed Anatomical Rating Scale. Renal function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula. We included 202 patients, 39 with CMBs (19.3 %); 15 had "strictly lobar", 12 had "strictly deep" and 12 had "mixed" CMBs. Patients without CMBs had a higher eGFR than those with CMBs (mean difference 6.50 ml/min/1.73 m(2), 95 % CI -14.73 to 1.72 ml/min/1.73 m(2), p = 0.121). Multivariable analysis found that those with deep and mixed CMBs had a lower eGFR than those without CMBs (mean difference -10.70 ml/min/1.73 m(2), 95 % CI -20.35 to -1.06 ml/min/1.73 m(2), p = 0.030). There was no difference in eGFR found between those with strictly lobar CMBs and those without CMBs (mean difference -1.59 ml/min/1.73 m(2), 95 % CI -13.08 to 9.89 ml/min/1.73 m(2), p = 0.79). In a Western patient cohort, there appears to be an association between eGFR and the presence of deep and mixed CMBs, but not strictly lobar CMBs. This suggests a shared vulnerability of renal afferent and cerebral deep and superficial perforating arterioles to systemic hypertension. The arteriopathy underlying strictly lobar CMBs (i.e. cerebral amyloid angiopathy), appears to be less related to renal impairment.

Background— Exercise testing is performed in patients with hypertrophic cardiomyopathy to evaluate blood pressure response, a risk factor for sudden cardiac death. The prognostic role of exercise gas exchange variables is unknown. Methods and Results— Between 1998 and 2010, 1898 patients (age 47±15 years, range 16–86 years; 67% male) with hypertrophic cardiomyopathy underwent cardiopulmonary exercise testing. A total of 178 (9.4%) patients reached the primary end point of all-cause mortality or heart transplant (death/transplant) during a median follow-up of 5.6 years (interquartile range 2.6–8.9), giving an annual event rate of 1.6% per person year. Peak oxygen consumption (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.77–0.88, P P =0.049), and ventilatory anaerobic threshold (adjusted HR 0.82, 95% CI 0.70–0.96, P =0.016) were predictors of the primary outcome after correction for age, sex, left atrial size, nonsustained ventricular tachycardia, and ejection fraction. The overall adjusted death/transplant estimates for patients in the lowest quartile with peak oxygen consumption ≤15.3 mL/kg/min were 14% at 5 years and 31% at 10 years. Peak oxygen consumption (HR 0.81, 95% CI 0.77–0.86, P P Conclusions— Cardiopulmonary exercise testing provides prognostic information in patients with hypertrophic cardiomyopathy. Submaximal exercise parameters, such as ventilatory efficiency and anaerobic threshold, measured alone or in combination with peak oxygen consumption, predict death from heart failure.

Background: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer’s disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade. Objective: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these. Methods: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated. Results: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment. Conclusion: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.

Background Cerebrovascular disease and neurodegeneration cause cognitive impairment and frequently coexist. Aims Our objectives were to investigate the prevalence and cognitive impact of medial temporal lobe atrophy – a radiological marker often associated with Alzheimer's disease – in a hospital stroke service. Methods Retrospective cohort study of patients from a hospital stroke service. Patients assessed for suspected ischemic stroke or transient ischemic attack, irrespective of final diagnosis, underwent neuropsychological testing and magnetic resonance imaging. medial temporal lobe atrophy, white matter hyperintensities, lacunes, and cerebral microbleeds were rated using established criteria and validated scales. The associations between medial temporal lobe atrophy and cognition were tested using multivariable logistic regression analyses, adjusted for age and imaging markers of cerebrovascular disease. Results Three hundred and ninety-three patients were included, of whom 169 (43%; 95% confidence interval: 38·1–48·1%) had medial temporal lobe atrophy; in 38 patients (9·7%), medial temporal lobe atrophy was severe (mean score ≥2). In unadjusted logistic regression analyses in the whole cohort, mean medial temporal lobe atrophy score was associated with verbal memory, nominal and perceptual skills, executive function, and speed and attention. After adjustment for age, white matter hyperintensities, number of lacunes, presence of cerebral microbleeds, previous ischemic stroke or transient ischemic attack, and premorbid intelligence quotient, mean medial temporal lobe atrophy score remained associated with impairment in verbal memory (odds ratio: 1·64; 95% confidence interval 1·04–2·58) and nominal skills (odds ratio: 1·61; 95% confidence interval 1·04–2·48). Conclusions Medial temporal lobe atrophy is common and has an independent impact on cognitive function in a stroke service population, independent of confounding factors including age and magnetic resonance imaging markers of cerebrovascular disease. Medial temporal lobe atrophy is independently related to verbal memory and nominal skills, while small vessel pathology also contributes to speed and attention, and executive and perceptual functions.

Background Suicidal ideation is more strongly associated with suicidal intent in later life, so risk factors may also differ by age. We investigated whether the relationship between suicidal ideation and established correlates varied by age in a representative population. Methods We used data from the 2007 Adult Psychiatric Morbidity Survey of England to assess the relationship between age and suicidal thoughts across 20-year age bands, using logistic regression, adjusted for survey weights. We used mediation analyses to assess the extent to which other factors mediate the relationship between suicidal thoughts and age. Results Reports of previous-year suicidal thoughts decreased with age. This was partly explained by (1) lower rates of reported child abuse (in those aged 75+), of depression, and of anxiety symptoms (in those aged 55+), factors all strongly associated with suicidal thoughts, and (2) higher rates of protective factors in people aged 35+, specifically homeownership and cohabitation. Rates of phobias, irritability and compulsions also decreased with age, and the association of these symptoms with suicidal thoughts was particularly strong in the youngest (16–34) age group. People who reported experiencing childhood abuse in all age groups reported more suicidal thoughts, suggesting abuse has lifelong negative effects on suicidal ideation. Limitations The response rate was 57%. Older people may be less likely to recall childhood abuse. Conclusions Sexual and physical abuse in childhood are associated with suicidal ideas throughout the lifespan, so screening for suicidal ideas in younger and older people should be routine and vigorous, and cover experiences in early life: management may require appropriate psychological interventions.

Objectives To explore current delays in diagnosis of retinoblastoma (Rb) and effect on outcome with comparison to a study from the 1990s. Setting Primary, secondary, tertiary care: majority from South of England. Participants A retrospective analysis of 93 new referrals of sporadic (non-familial) Rb to a specialist Rb unit in London, UK from January 2006 to February 2014. Primary and secondary outcomes International Intraocular Retinoblastoma Classification, lag times including parental delay and healthcare professional delay, patients requiring enucleation and requirement of adjuvant chemotherapy postenucleation (high-risk Rb). Results During the study period, 29% presented via accident and emergency (A&E). The median referral time from symptom onset to visiting primary care (PC) was 28 days and PC to ophthalmologist 3 days (range 0–181 days). The median time from local ophthalmologist to the Rb Unit was 6 days (0–33). No significant correlation was found between delay and International Classification of Retinoblastoma grade (p>0.05) or between postenucleation adjuvant chemotherapy and enucleation groups (p>0.05). Less enucleations (60%) are being performed compared with the previous study (81%) (p=0.0015). Conclusions Parents are attending A&E more compared with the 1990s and this may reflect the effect of public awareness campaigns. More eyes are being salvaged despite a similar number of children requiring adjuvant chemotherapy. High-risk Rb and Group E eyes do not correlate with increased lag time in the UK. Other determinants such as tumour biology may be more relevant.

Objective: To test the hypothesis that people bereaved by suicide are less likely to receive formal or informal support than people bereaved by other causes of sudden death. Design: National cross-sectional study. Setting: Adults working or studying at any UK Higher Education Institution (HEI) in 2010. Participants: 3,432 eligible respondents aged 18-40 bereaved by the sudden death of a close friend or relative, sampled from approximately 659,572 bereaved and non-bereaved staff and students at 37 of 164 UK HEIs invited to participate. Exposures: Bereavement by suicide (n=614; 18%), by sudden unnatural causes (n=712; 21%) and by sudden natural causes (n=2106; 61%).Main outcome measures: Receipt of formal and of informal support post-bereavement; timing of valued support. Results: 21% (725/3432) of our sample of bereaved adults reported receiving no formal or informal bereavement support, with no evidence for group differences. People bereaved by suicide were less likely to have received informal support than those bereaved by sudden natural causes (adjusted odds ratio (AOR) = 0.79; 95% CI=0.64 to 0.98), or unnatural causes (AOR=0.74; 95% CI=0.58 to 0.96), but did not differ from either comparison group on receipt of formal support. People bereaved by suicide were less likely to have received immediate support (AOR=0.73; 95% CI=0.59 to 0.90) and more likely to report delayed receipt of support (AOR=1.33; 95% CI=1.08 to 1.64) than people bereaved by sudden natural causes. Associations were not modified by gender, or age bereaved, but became non-significant when adjusting for stigma. Conclusions: People bereaved by suicide are less likely to receive informal support than people bereaved by other causes of sudden death, and are more likely to perceive delays in accessing any support. This is concerning given their higher risk of suicide attempt and the recommendations within suicide prevention strategies regarding their need for support. Study registration: http://www.ucl.ac.uk/psychiatry/bereavementstudy/

Purpose – Positive Behaviour Support (PBS) is thought to be an important model for working with people with intellectual disabilities who display behaviours challenging to service. The purpose of this paper is to explore clinical and service user outcomes associated with the delivery of PBS by a Complex Behaviour Service (CBS). Design/methodology/approach – Clinical outcomes of 24 service users treated by the CBS team were assessed at baseline, six and 12 months and compared with those of 22 peers who received usual care. The main outcome was reduction in challenging behaviour measured by the Aberrant Behaviour Checklist (ABC). Secondary outcomes included measures of mental health needs, risk and social care supports. Findings – At six months improvements were seen across all ABC domains in both groups, with greater improvement in the CBS group, compared to usual care in irritability and stereotypy. Between group differences were maintained only for stereotypy at 12 months. No other differences were found. Originality/value – This paper suggests that PBS delivered by trained and dedicated staff may provide clinical benefits to individuals with challenging behaviours. However, there are issues around integration into existing services that need to be addressed in order to maximise efficiency.

Background Pregnancies in women with sickle cell disease (SCD) are known to have high rates of maternal and fetal mortality and morbidity. Given these pregnancy-associated problems for women with SCD, advice both about pregnancy planning and about effective contraception are of paramount importance. This study sought to discover the contraception methods used by women with SCD, what complications women with SCD encounter with contraception, and their experiences of pre-pregnancy counselling and pregnancy planning, and how such issues may have changed over the past two decades. Method The study was a multicentre, interview-based, cross-sectional study. Interviews were carried out with 102 women with SCD, in north and central London during 2010, concerning their current and previous contraceptive use, their pregnancy history, their menstrual history, and the advice they received concerning pregnancy planning and contraception. Patient information was anonymised and ethical approval was obtained. These data were compared with data from a similar study undertaken in 1993. Results There were significant differences in a number of key areas: the number of unplanned pregnancies decreased from 64% in 1993 to 53% in 2010. The number of women with SCD who were advised not to become pregnant also fell, from 36% to 15%. The use of combined oral contraceptive pills declined, from 45% of the women in 1993 to 31% in 2010. Conversely the use of depot medroxyprogesterone acetate contraception (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) both increased. Conclusions Significant changes in the contraceptive methods used by women with SCD are demonstrated in the London population. LNG-IUS use in SCD has not been investigated before. There has been an encouraging decrease in the number of women with SCD who are advised not to become pregnant, perhaps reflecting an improvement in their overall health. Although the number of unplanned pregnancies has fallen, it remains high – emphasising the continuing need for women with SCD to have access to informed advice about pregnancy-associated issues and contraception.

Aims and methodTo develop a programme to help undergraduate medical students and postgraduate trainees to improve their skills in communicating with people with intellectual disabilities through teaching sessions that had input from simulated patients with intellectual disabilities. We conducted four sessions of training for 47 undergraduate 4th-year medical students. The training involved a multiprofessional taught session followed by a clinical scenario role-play with simulated patients who were people with intellectual disabilities. The training was assessed by completing the healthcare provider questionnaire before and after the training.ResultsThere were improvements in the students' perceived skill, comfort and the type of clinical approach across all three scenarios.Clinical implicationsBy involving people with intellectual disabilities in training medical students there has been a significant improvement in students' communication skills in areas of perceived skills, comfort and type of clinical approach which will raise the quality of care provided by them in the future.

Importance Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro–brain natriuretic peptide level, and troponin T level. Results Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, −2.58 to −0.11 mL/kg per minute;P = .03) in the intervention group after 3 months. Conclusions and Relevance In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration ClinicalTrials.gov identifier:NCT01696370

BackgroundDown syndrome is associated with specific cognitive deficits. Alongside this, older adults with Down syndrome are a high risk group for dementia. The Arizona Cognitive Test Battery (ACTB), a cognitive assessment battery specifically developed for use with individuals with Down syndrome, has been proposed for use as outcome measures for clinical trials in this population. It has not been validated in older adults with Down syndrome. This study aims to assess the use and validity of the ACTB in older adults with Down syndrome.MethodsParticipants with Down syndrome aged 45 and over were assessed using the ACTB, standard tabletop tests and informant ratings.ResultsAssessment outcomes of 49 participants were analysed. Of these, 19 (39%) had a diagnosis of dementia or possible dementia. Most participants were able to attempt most of the tasks, although some tasks had high floor effects (including CANTAB Intra-Extra Dimensional shift stages completed and Modified Dots Task). Of the ACTB tasks, statistically significant differences were observed between the dementia and no dementia groups on CANTAB Simple Reaction Time median latency, NEPSY Visuomotor Precision—Car and Motorbike and CANTAB Paired Associates Learning stages completed. No significant differences were observed for CANTAB Intra-Extra Dimensional Shift, Modified Dots Task, Finger Sequencing, NEPSY Visuomotor precision—Train and Car and CANTAB Paired Associates Learning first trial memory score. Several of the tasks in the ACTB can be used in older adults with Down syndrome and have mild to moderate concurrent validity when compared to tabletop tests and informant ratings, although this varies on a test by test basis.ConclusionsOverall, scores for a number of tests in the ACTB were similar when comparing dementia and no dementia groups of older adults with Down syndrome, suggesting that it would not be an appropriate outcome measure of cognitive function for clinical trials of dementia treatments without further modification and validation.

Objective To test the hypothesis that perceived stigma scores in young adults bereaved by suicide are significantly higher than in young adults bereaved by other sudden deaths, whether blood-related to the deceased or not. Methods We conducted a cross-sectional study of all staff and students aged 18–40 at 37 UK higher educational institutions in 2010, and identified 3432 respondents who had experienced a sudden bereavement of a close contact since reaching the age of 10, either due to sudden natural causes, sudden unnatural causes, or suicide. We used multivariable regression to compare scores on the stigma, shame, responsibility and guilt subscales of the Grief Experience Questionnaire, adjusting for socio-demographic factors and pre-bereavement psychopathology. Results People bereaved by suicide (n = 614) had higher stigma scores than people bereaved by sudden natural death (n = 2106; adjusted coefficient = 2.52; 95% CI = 2.13–2.90; p =, Highlights • No studies have confirmed if suicide confers more stigma than other sudden losses. • We compared people bereaved by suicide, sudden natural causes, and sudden unnatural causes. • We found suicide bereavement to be most stigmatising of sudden bereavements. • Suicide bereavement was also associated with shame, guilt, and responsibility. • Associations applied to both relatives and non-relatives.

We conducted a five stage pilot study which initially consisted of a review of 75 case notes of people attending an emergency department (ED) in an inner London Teaching Hospital with musculoskeletal (MSK) low back pain (LBP). This review highlighted inconsistencies in how they were assessed and managed across and within different staff groups. We found patient documentation was often incomplete and that a biomedical model approach to the management of these patients was common. As a result, four further stages in the project were conducted. Our primary aim was to evaluate the impact of implementing a locally developed quality improvement intervention for the assessment and treatment of MSK LBP in this ED. Secondary aims were to explore the user experience of the new pathway, measured by the patient experience questionnaire (PEQ), and any associated health economic costs of changes in practice. The quality improvement intervention consisted of an evidence based low back pain pathway (EBLBPP), a staff educational program, and a patient education booklet. We undertook a retrospective baseline audit of 100 clinical records of patients was undertaken prior to the instigation of the quality improvement intervention, and four months post implementation. The pre-defined variables of interest were: documentation of the case history, examination, classification of back pain (and if correct), prescribed management and if the documentation was compliant with medico-legal standards. All patients in the study were sent a PEQ to complete and return in a self-addressed envelope. Estimated health costs associated with each patient episode of care were calculated including re-attendance episodes for any people presenting with MSK LBP within a four week period. There was a significant improvement in all areas evaluated post implementation in all groups (simple, referred and simple, referred and serious spinal pathology combined). In particular; screening for red flags (22%) and biopsychosocial factors (29%), as well as noting the prevalence of previous symptoms (44%), observation of the painful area (57%), and analysis classification (59%) at a at 95% confidence interval (CI). In terms of management, an increase in adherence to the analgesic ladder, patients receiving reassurance and appropriate referral back to their GP’s increased 45%, 23% and 44% at 95% CI respectively. Unfortunately, there was insufficient data to draw any meaningful conclusions from the patient experience data due to a low response rate. In conclusion, the introduction of the EBLBPP, patient education leaflet and teaching training for staff involved in the treatment of MSK LBP patients has improved the quality and consistency of the documented assessment and subsequent management of MSK LBP patients.

The sudden death of a friend or relative, particularly by suicide, is a risk factor for suicide. People who experience sudden bereavement report feeling highly stigmatised by the loss, potentially influencing access to support. We assessed whether perceived stigma following sudden bereavement is associated with suicidal thoughts and suicide attempt. We analysed cross-sectional survey data on 3387 young adults bereaved by the sudden death of a close contact. We tested the association of high versus low perceived stigma (on the stigma sub-scale of the Grief Experience Questionnaire) with post-bereavement suicidal ideation and suicide attempt, using random effects logistic regression, adjusting for socio-demographic factors, pre-bereavement psychopathology, and mode of sudden bereavement (natural causes/unnatural causes/suicide). Subjects with high perceived stigma scores were significantly more likely to report post-bereavement suicidal thoughts (adjusted odds ratio (AOR) = 2.74; 95% confidence interval (CI) = 1.93–3.89) and suicide attempt (AOR = 2.73; 95% CI = 2.33–3.18) than those with low stigma scores. People who feel highly stigmatised by a sudden bereavement are at increased risk of suicidal thoughts and suicide attempt, even taking into account prior suicidal behaviour. General practitioners, bereavement counsellors, and others who support people bereaved suddenly, should consider inquiring about perceived stigma, mental wellbeing, and suicidal thoughts, and directing them to appropriate sources of support.

Importance: α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. Objectives: To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. Design, Setting, and Participants: We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. Main Outcomes and Measures: We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. Results: We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease–related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively. Conclusions and Relevance: These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.

Falls are a recognised problem for people with long-term neurological conditions but less is known about fall risk in young adults. This study describes fallers' and falls' characteristics in adults less than 60 years old, in a neuro-rehabilitation unit.This single-centre, longitudinal, observational study included 114 consecutive admissions to a UK neuro-rehabilitation unit over 20 months. The demographic and clinical characteristics of eligible patients included age, sex, diagnosis, hospital length of stay and the Functional Independence Measure (FIM). Falls were recorded prospectively in a fall report, using the activities and environmental domains of the International Classification of Functioning (ICF).A total of 34 (30%) patients reported a fall, with 50% experiencing more than one fall. The majority of falls (60%) occurred during the first 2 weeks, during day-time (90%) and during mobile activities (70%). Overall, falls rate (95% confidence interval) was 1.33 (1.04 to 1.67) per 100 d of patient hospital stay. Factors associated with increased falls included becoming a walker during admission or being cognitively impaired. There were no serious fall-related injuries.The first 2 weeks of admission is a high risk time for fallers, in particular those who become walkers or are cognitively impaired. Prevention policies should be put in place based on fall characteristics. Implications for Rehabilitation The ICF is a valuable instrument for describing subject and environmental factors during a fall-event. Falls are frequent events but do not usually cause serious injuries during inpatient rehabilitation. There is an increased fall risk for subjects with cognitive impairments or those relearning how to walk.

Objectives To assess the 2009 National Dementia Strategy's (NDS) impact on dementia diagnosis and treatment. Setting and participants Primary care data for England before and after launch of the NDS. Primary outcome measures We used nationally available data to estimate the trends over time in rates of dementia diagnoses recorded on the Quality Outcomes Framework (QOF) in Primary Care Trusts (PCT) and antidementia medication prescriptions from 2006/2007 (the first available figures) and the associated increase in cost relative to all other prescriptions. To establish PCT general practitioner (GP) QOF dementia recording validity, we correlated it with medication prescription using the NIC (net ingredient cost). Results Regression analysis showed that dementia diagnosis rate was lower prior to launch of the NDS and increased significantly after it was launched. The number of antidementia prescriptions and the cost of antidementia drugs relative to total PCT prescribing costs increased significantly after 2009. GP recording of dementia diagnosis correlated highly with prescription of cholinesterase inhibitors and memantine in the same area (p

Objectives US and UK suicide prevention strategies suggest that bereavement by the suicide of a relative or friend is a risk factor for suicide. However, evidence is lacking that the risk exceeds that of any sudden bereavement, is specific to suicide, or applies to peer suicide. We conducted the first controlled UK-wide study to test the hypothesis that young adults bereaved by suicide have an increased risk of suicidal ideation and suicide attempt compared with young adults bereaved by other sudden deaths. Design National cross-sectional study. Setting Staff and students at 37 UK higher educational institutions in 2010. Participants 3432 eligible respondents aged 18–40 exposed to sudden bereavement of a friend or relative after the age of 10. Exposures Bereavement by suicide (n=614), by sudden unnatural causes (n=712) and by sudden natural causes (n=2106). Primary outcome measures Incident suicidal ideation and suicide attempt. Findings Adults bereaved by suicide had a higher probability of attempting suicide (adjusted OR (AOR)=1.65; 95% CI 1.12 to 2.42; p=0.012) than those bereaved by sudden natural causes. There was no such increased risk in adults bereaved by sudden unnatural causes. There were no group differences in probability of suicidal ideation. The effect of suicide bereavement was similar whether bereaved participants were blood-related to the deceased or not. The significant association between bereavement by suicide and suicide attempt became non-significant when adding perceived stigma (AOR=1.11; 95% CI 0.74 to 1.67; p=0.610). When compared with adults bereaved by sudden unnatural causes, those bereaved by suicide did not show significant differences in suicide attempt (AOR=1.48; 95% CI 0.94 to 2.33; p=0.089). Conclusions Bereavement by suicide is a specific risk factor for suicide attempt among young bereaved adults, whether related to the deceased or not. Suicide risk assessment of young adults should involve screening for a history of suicide in blood relatives, non-blood relatives and friends.

OBJECTIVES: In industrialized countries, there are established programs of childhood vision screening and surveillance, but little is known about their performance. We investigated the patterns of presentation/detection and early treatment of a nationally representative cohort of children with severe visual impairment or blindness (SVI/BL) in 1 year (2000) in the United Kingdom. METHODS: All children who were younger than 16 years and had a new diagnosis of SVI/BL were identified by active surveillance through the British Ophthalmological and Pediatric Surveillance Units. Data that were collected up to 1 year after diagnosis included sociodemographic characteristics, detection of SVI/BL, nonophthalmic disorders/impairments, ophthalmic findings, and early management. RESULTS: Of 439 identified children, 65% were younger than 1 year at diagnosis, 28% were of nonwhite ethnicity, and 40% in the worst quintile of deprivation score. A total of 77% had associated nonophthalmic disorders/impairments. Although 70% had established symptoms or signs at diagnosis by a health professional, parents had suspected blindness in only 47%. A quarter of isolated SVI/BL was detected through routine vision screening; however, 46% of children's SVI/BL and associated nonophthalmic disorders/impairments were diagnosed through a clinical surveillance examination undertaken because of high risk for a specific eye disease. CONCLUSIONS: The “patient journey” of children with visual impairment is markedly influenced by the presence of additional impairments/chronic diseases. Parents' understanding of normal visual development needs to be improved. Increasingly, new evidence-based formal programs of clinical (ophthalmic) surveillance are needed in response to the changing population of children who are at risk for blinding eye disease.

To determine which of two methods of case note review--holistic (implicit) and criterion-based (explicit)--provides the most useful and reliable information for quality and safety of care, and the level of agreement within and between groups of health-care professionals when they use the two methods to review the same record. To explore the process-outcome relationship between holistic and criterion-based quality-of-care measures and hospital-level outcome indicators.Case notes of patients at randomly selected hospitals in England.In the first part of the study, retrospective multiple reviews of 684 case notes were undertaken at nine acute hospitals using both holistic and criterion-based review methods. Quality-of-care measures included evidence-based review criteria and a quality-of-care rating scale. Textual commentary on the quality of care was provided as a component of holistic review. Review teams comprised combinations of: doctors (n = 16), specialist nurses (n = 10) and clinically trained audit staff (n = 3) and non-clinical audit staff (n = 9). In the second part of the study, process (quality and safety) of care data were collected from the case notes of 1565 people with either chronic obstructive pulmonary disease (COPD) or heart failure in 20 hospitals. Doctors collected criterion-based data from case notes and used implicit review methods to derive textual comments on the quality of care provided and score the care overall. Data were analysed for intrarater consistency, inter-rater reliability between pairs of staff using intraclass correlation coefficients (ICCs) and completeness of criterion data capture, and comparisons were made within and between staff groups and between review methods. To explore the process-outcome relationship, a range of publicly available health-care indicator data were used as proxy outcomes in a multilevel analysis.Overall, 1473 holistic and 1389 criterion-based reviews were undertaken in the first part of the study. When same staff-type reviewer pairs/groups reviewed the same record, holistic scale score inter-rater reliability was moderate within each of the three staff groups [intraclass correlation coefficient (ICC) 0.46-0.52], and inter-rater reliability for criterion-based scores was moderate to good (ICC 0.61-0.88). When different staff-type pairs/groups reviewed the same record, agreement between the reviewer pairs/groups was weak to moderate for overall care (ICC 0.24-0.43). Comparison of holistic review score and criterion-based score of case notes reviewed by doctors and by non-clinical audit staff showed a reasonable level of agreement (p-values for difference 0.406 and 0.223, respectively), although results from all three staff types showed no overall level of agreement (p-value for difference 0.057). Detailed qualitative analysis of the textual data indicated that the three staff types tended to provide different forms of commentary on quality of care, although there was some overlap between some groups. In the process-outcome study there generally were high criterion-based scores for all hospitals, whereas there was more interhospital variation between the holistic review overall scale scores. Textual commentary on the quality of care verified the holistic scale scores. Differences among hospitals with regard to the relationship between mortality and quality of care were not statistically significant.Using the holistic approach, the three groups of staff appeared to interpret the recorded care differently when they each reviewed the same record. When the same clinical record was reviewed by doctors and non-clinical audit staff, there was no significant difference between the assessments of quality of care generated by the two groups. All three staff groups performed reasonably well when using criterion-based review, although the quality and type of information provided by doctors was of greater value. Therefore, when measuring quality of care from case notes, consideration needs to be given to the method of review, the type of staff undertaking the review, and the methods of analysis available to the review team. Review can be enhanced using a combination of both criterion-based and structured holistic methods with textual commentary, and variation in quality of care can best be identified from a combination of holistic scale scores and textual data review.

OBJECTIVE. The goal was to measure, by using the Health Utilities Index, the health status of children 6 months after admission to PICUs in the United Kingdom. METHODS. All PICUs in the United Kingdom were invited to participate. Children who were ≥6 months of age at admission and were discharged alive from participating units during a 1-year period were eligible for this study. Children with completed consent forms who had survived to 6 months after admission received the Health Utilities Index questionnaire. RESULTS. Admission data on 7214 admissions to 22 units were collected between March 2001 and February 2002. Of those patients, 6786 survived to unit discharge, and consent for follow-up contact was obtained for 2642. At 6 months after admission, the mortality rate was estimated at 11.1% and 2034 children were still alive and contactable. Of those children, Health Utilities Index questionnaires were returned by 1455. No impairment was indicated for 767, 951, 940, 919, 962, and 939 children with respect to the Health Utilities Index sensation, cognition, emotion, pain, mobility, and self-care attributes, respectively. The mean ± SE Health Utilities Index utility score was 0.73 ± 0.01, with 397 children (27.3%) in full health. CONCLUSIONS. Death after pediatric intensive care in the United Kingdom is uncommon, making assessment of health status important. At 6 months after admission, there is significant morbidity. To assess the impact of strategies to improve or to optimize care on longer-term outcomes, standardized collection of data on preexisting comorbidities and illness severity is required.

Background Exercise testing is commonly performed in patients with hypertrophic cardiomyopathy (HCM) to evaluate blood pressure response, a conventional risk factor for sudden cardiac death. The 2011 ACCF/AHA guidelines state “the role of metabolic stress testing in the evaluation of patients with HCM remains to be decided, particularly with regard to clinical outcome. Methods and results Between 1998 and 2010, 1,898 patients (age 47 ± 15 years, 67% male) with HCM underwent cardiopulmonary exercise testing (CPX). During a mean follow-up of 5.8 ± 4 years, 178 (9.4%) patients reached the primary endpoint of all-cause mortality or orthotropic heart transplant. Peak oxygen consumption, V˙O 2 (HR 0.91 95% CI 0.89–0.93, p 2 (HR 1.08 95% CI 1.06–1.09), and ventilatory anaerobic threshold V˙AT (HR 0.88 95% CI 0.84–0.92) were predictors of the primary outcome. A progressively worse prognosis was associated with higher ventilatory class (Figure 1). V˙EV˙CO 2 was a good predictor of heart failure death or transplantation (HR 1.1 95% CI 1.07–1.14 p Conclusions CPX provides important prognostic information in patients with HCM. Sub-maximal exercise parameters are potentially more useful than peak VO 2 alone. Patients with an enhanced ventilatory response have a substantially higher risk of death or transplantation. Reference 1 Gersh, et al . JACC 2011;58(25):212–60

Background Case reports suggest a causal link between statins and myasthenia gravis (MG). Aims To assess the risk of MG onset and worsening with statin therapy. Methods (1) Retrospective case notes review (2) Linked case–control study. Results 106 patients with MG were studied (56M:50F; mean age at onset 48.8 years ranging 13.4–84.8 years). Eighteen (17.0%) were using a statin at the time of disease onset; however, no cases were temporally associated with starting statin therapy (average time from starting statin to MG onset 5.25 years ranging 2.0–10.3 years). Mean length of follow–up was 7.8 years. Three out of twelve (25.0%) patients who started taking a statin after onset of MG experienced a prompt (within four weeks) worsening of symptoms. In the case–control study, 84 consecutive non–myasthenic patients (25M:59F; mean age at first appointment 43.9 years ranging 17.7–84.1 years) attending Neuro–Ophthalmology clinics were compared with the above 106 cases. Seven controls (8.3%) were taking a statin at the time of their first appointment. Logistic regression analysis (controlling for age differences) did not show a significant association between statin usage and MG onset (OR 1.70; p–value 0.32; 95% CI 0.60–4.87). When the same analysis was applied only to cases of late onset MG (≥40 years) and controls in the same age range, again no significant association was detected (OR 1.58; p–value 0.41; 95% CI 0.53–4.72). Discussion This study supports the hypothesis that statins can aggravate MG. We observed a 25% rate of MG exacerbation in patients who started taking a statin after disease onset. This was higher than the value reported by Oh et al. 1 in a study on 170 patients with MG, where six out 54 (11%) patients given a statin promptly experienced an exacerbation. Neither this, nor our retrospective study identified any cases of statin–induced MG (defined as MG onset within 4 months of starting a statin). Our case–control study did not show a significant association between statin usage and MG onset. This is perhaps because statins do not cause MG; however, insufficient sample sizes may have precluded the detection of a weak causal association. Further research with larger sample sizes is required to support or disprove this hypothesis.