AbstractObjectiveTo establish whether clinical patient characteristics routinely measured in primary care can identify people with differing short-term benefits and risks for SGLT2-inhibitor and DPP4-inhibitor therapies, and to derive and validate a treatment selection algorithm to identify the likely optimal therapy for individual patients.DesignProspective cohort study.SettingRoutine clinical data from United Kingdom general practice (Clinical Practice Research Datalink [CPRD]), and individual-level clinical trial data from 14 multi-country trials of SGLT2-inhibitor and DPP4-inhibitor therapies.Participants26,877 new users of SGLT2-inhibitor and DPP4-inhibitor therapy in CPRD over 2013-2019, and 10,414 participants randomised to SGLT2-inhibitor or DPP4-inhibitor therapy in 14 clinical trials, including 3 head-to-head trials of the two therapies (n=2,499).Main outcome measuresThe primary outcome was achieved HbA1c 6 months after initiating therapy. Clinical features associated with differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies were identified in routine clinical data, with associations then tested in trial data. A multivariable treatment selection algorithm to predict differential HbA1c outcomes was developed in a CPRD derivation cohort (n=14,069), with validation in a CPRD validation cohort (n=9,376) and the head-to-head trials. In CPRD, we further explored the relationship between model predictions and secondary outcomes of weight loss and treatment discontinuation.ResultsThe final treatment selection algorithm included HbA1c, eGFR, ALT, age, and BMI, which were identified as predictors of differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies using both routine and trial data. In validation cohorts, patient strata predicted to have a ≥5 mmol/mol HbA1c reduction with SGLT2-inhibitor therapy compared with DPP4-inhibitor therapy (38.8% of CPRD validation sample) had an observed greater reduction of 8.8 mmol/mol [95%CI 7.8-9.8] in the CPRD validation sample, a 5.8 mmol/mol (95%CI 3.9-7.7) greater reduction in the Cantata D/D2 trials, and a 6.6 mmol/mol [95%CI 2.2-11.0]) greater reduction in the BI1245.20 trial. In CPRD, there was a greater weight reduction with SGLT2-inhibitor therapy regardless of predicted glycaemic benefit. Strata predicted to have greater reduction in HbA1c on SGLT2-inhibitor therapy had a similar risk of discontinuation as on DPP4-inhibitor therapy. In contrast, strata predicted to have greater reduction in HbA1c with DPP4-inhibitor therapy were half as likely to discontinue DPP4-inhibitor therapy than SGLT2-inhibitor therapy.ConclusionsRoutinely measured clinical features are robustly associated with differential glycaemic responses to SGLT2-inhibitor and DPP4-inhibitor therapies. Combining features into a treatment selection algorithm can inform clinical decisions concerning optimal type 2 diabetes treatment choices.Key messagesWhat is already known on this subjectDespite there being multiple glucose-lowering treatment options available for people with type 2 diabetes, current guidelines do not provide clear advice on selecting the optimal treatment for most patients.It is unknown whether routinely measured clinical features modify the risks and benefits of two common treatment options, DPP4-inhibitor or SGLT2-inhibitor therapy, and which could be used to target these treatments to those patients most likely to benefit.What this study addsUsing data from 10,414 participants in 14 randomised trials, and 26,877 patients in UK primary care, we show several routinely available clinical features, notably glycated haemoglobin (HbA1c) and kidney function, are robustly associated with differential HbA1c responses to initiating SGLT2-inhibitor and DPP4-inhibitor therapies.Combining clinical features into a multivariable treatment selection model identifies validated patient strata with 1) a >5 mmol/mol HbA1c benefit for SGLT2-i therapy compared with DPP4-inhibitor therapy ; 2) a 50% reduced risk of early treatment discontinuation with DPP4-inhibitor therapy compared with SGLT2-inhibitor therapy.Our findings demonstrate a precision medicine approach based on routine clinical features can inform clinical decisions concerning optimal type 2 diabetes treatment choices.

Background
Many male prisoners have significant mental health problems,
including anxiety and depression. High proportions struggle with
homelessness and substance misuse.
Aims
This study aims to evaluate whether the Engager intervention
improves mental health outcomes following release.
Method
The design is a parallel randomised superiority trial that was
conducted in the North West and South West of England
(ISRCTN11707331). Men serving a prison sentence of 2 years or
less were individually allocated 1:1 to either the intervention
(Engager plus usual care) or usual care alone. Engager included
psychological and practical support in prison, on release and for
3–5 months in the community. The primary outcome was the
Clinical Outcomes in Routine Evaluation Outcome Measure
(CORE-OM), 6 months after release. Primary analysis compared
groups based on intention-to-treat (ITT).
Results
In total, 280 men were randomised out of the 396 who were
potentially eligible and agreed to participate; 105 did not meet
the mental health inclusion criteria. There was no mean differ ence in the ITT complete case analysis between groups (92 in
each arm) for change in the CORE-OM score (1.1, 95% CI –1.1 to
3.2, P = 0.325) or secondary analyses. There were no consistent
clinically significant between-group differences for secondary
outcomes. Full delivery was not achieved, with 77% (108/140)
receiving community-based contact.
Conclusions
Engager is the first trial of a collaborative care intervention
adapted for prison leavers. The intervention was not shown to
be effective using standard outcome measures. Further testing
of different support strategies for prison with mental health
problems is needed.

Objectives: to identify whether the abolition of prescription fees in Scotland resulted in:
a) increase in the number (cost to NHS) of medicines prescribed for which there had been a fee (inhaled corticosteroids);
b) reduction in hospital admissions for conditions related to those medications for which there had been a fee (asthma or Chronic Obstructive Pulmonary Disease (COPD)) –
when both are compared to prescribed medicines and admissions for a condition (diabetes mellitus) for which prescriptions were historically free.
Design: Natural experimental retrospective General Practice level interrupted time series (ITS) analysis using administrative data
Setting: General Practices, Scotland, United Kingdom
Participants: 732 (73.6%) General Practices across Scotland with valid dispensed medicines and hospital admissions data during the study period (July 2005 – December 2013)
Intervention: Reduction in fees per dispensed item from April 2008 leading to the abolition of the fee in April 2011, resulting in universal free prescriptions
Primary and secondary outcome: Hospital admissions recorded in the Scottish Morbidity Record – 01 Inpatient (SMR01) and dispensed medicines recorded in the Prescriptions Information System (PIS).
Results: the ITS analysis identified marked step reductions in adult (19-59 years) admissions related to asthma or COPD (the intervention group), compared to older or young people with the same conditions or adults with diabetes mellitus (the counterfactual groups). The prescriptions findings were less coherent and subsequent sensitivity analyses found that both the admissions and prescriptions data were highly variable above the annual or seasonal level, limiting the ability to interpret the findings of the ITS analysis.
Conclusions: This study did not find sufficient evidence that universal free prescriptions was a demonstrably effective or ineffective policy, in terms of reducing hospital admissions or reducing socioeconomic inequality in hospital admissions, in the context of a universal, publicly administered medical care system, the National Health Service of Scotland.

Sudden Unexpected Death in Epilepsy (SUDEP) is a major concern for people with epilepsy, their families, their care givers, and medical professionals. There is inconsistency in the SUDEP counselling doctors provide, compared to what is recommended in clinical guidelines. Numerous national and international surveys have highlighted how epilepsy professionals, usually doctors, deliver SUDEP risk counselling, particularly, when they deliver it and to whom. These surveys help understand the unmet need, develop suitable strategies, and raise awareness among clinicians with the eventual goal to reduce SUDEPs. However, there is no standardised survey or essential set of questions identified that can be used to evaluate SUDEP counselling practice globally. This focused review analyses the content of all published SUDEP counselling surveys for medical professionals (n=16) to date covering over 4000 doctors across over 30 countries and five continents. It identifies 36 question themes across three topics. The questions are then reviewed by an expert focus group of SUDEP communication experts including three doctors, an expert statistician and SUDEP Action, an UK based charity specialising in epilepsy deaths with a pre-set criterion. The review and focus group provide ten essential questions that should be included in all future surveys inquiring on SUDEP counselling. They could be used to evaluate current practice and compare findings over time, between services, across countries and between professional groups. They are provided as a template to download and use. The review also explores if there is a continued need in future for similar surveys to justify this activity.

. Background
. Many male prison leavers have significant mental health problems. Prison leavers often have a history of trauma, ongoing substance misuse and housing insecurity. Only a minority of prison leavers receive mental health care on release from prison.
.
.
. Objectives
. The aim of the Engager research programme was to develop and evaluate a theory- and evidence-informed complex intervention designed to support individuals with common mental health problems (e.g. anxiety, depression) and other complex needs, including mental health comorbidity, before and after release from prison.
.
.
. Methods
. In phase 1, the intervention was developed through a set of realist-informed substudies, including a realist review of psychosocial care for individuals with complex needs, case studies within services demonstrating promising intervention features, focus groups with individuals from under-represented groups, a rapid realist review of the intervention implementation literature and a formative process evaluation of the prototype intervention. In a parallel randomised trial, methodological development included selecting outcome measures through reviewing literature, piloting measures and a consensus process, developing ways to quantify intervention receipt, piloting trial procedures and modelling economic outcomes. In phase 2, we conducted an individually randomised superiority trial of the Engager intervention, cost-effectiveness and cost–consequence analyses and an in-depth mixed-methods process evaluation. Patient and public involvement influenced the programme throughout, primarily through a Peer Researcher Group.
.
.
. Results
. In phase 1, the Engager intervention included multiple components. A practitioner offered participants practical support, emotional help (including mentalisation-based approaches) and liaison with other services in prison on the day of the participant’s release and for 3–5 months post release. An intervention delivery platform (i.e. training, manual, supervision) supported implementation. Outcome measures were selected through testing and stakeholder consensus to represent a broad range of domains, with a general mental health outcome as the primary measure for the trial. Procedures for recruitment and follow-up were tested and included flexible approaches to engagement and retention. In phase 2, the trial was conducted in three prison settings, with 280 participants randomised in a 1 : 1 ratio to receive either Engager plus usual care (n = 140) or usual care only (n = 140). We achieved a follow-up rate of 65% at 6 months post release from prison. We found no difference between the two groups for the Clinical Outcomes in Routine Evaluation – Outcome Measure at 6 months. No differences in secondary measures and sensitivity analyses were found beyond those expected by chance. The cost-effectiveness analysis showed that Engager cost significantly more at £2133 (95% of iterations between £997 and £3374) with no difference in quality-adjusted life-years (–0.017, 95% of iterations between –0.042 and 0.007). The mixed-methods process evaluation demonstrated implementation barriers. These barriers included problems with retention of the intervention team, and the adverse health and criminal justice system context. Seventy-seven per cent (108/140) of individuals had at least one community contact. Significant proportions of participants engaging received day release work and practical support. In contrast, there was evidence that the psychological components, mentalisation and developing a shared understanding were used less consistently. When engagement was positive, these components were associated with positive achievement of goals for individuals. We were also able to identify how to improve the intervention programme theory, including how to support individuals who were unrealistic in their perception of their ability to cope with challenges post release.
.
.
. Strengths and limitations
. Our development work provides a worked example of the development of a complex intervention, particularly given little prior evidence or theory specific to male offenders to build on. Our trial methodological development enabled the completion of, to the best of our knowledge, the first fully powered trial of a mental health intervention for prison leavers with common mental health problems. There were potential weaknesses in the trial methodology in terms of follow-up rates and outcome measures, with the latter potentially being insufficiently sensitive to important but highly individual changes in participants who responded to the intervention.
.
.
. Conclusions
. Delivering a randomised controlled trial for prison leavers with acceptable levels of follow-up is possible, despite adverse conditions. Full intervention implementation was challenging, but this is to be expected. Some individuals did respond well to the intervention when both practical and psychological support were flexibly deployed as intended, with evidence that most components were experienced as helpful for some individuals. It is recommended that several key components be developed further and tested, along with improved training and supervision, to support delivery of the Engager intervention within existing teams working with prison leavers.
.
.
. Trial registration
. This trial is registered as ISRCTN11707331.
.
.
. Funding
. This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 10, No. 8. See the NIHR Journals Library website for further project information.
.

IntroductionLong COVID-19 is a distressing, disabling and heterogeneous syndrome often causing severe functional impairment. Predominant symptoms include fatigue, cognitive impairment (‘brain fog’), breathlessness and anxiety or depression. These symptoms are amenable to rehabilitation delivered by skilled healthcare professionals, but COVID-19 has put severe strain on healthcare systems. This study aims to explore whether digitally enabled, remotely supported rehabilitation for people with long COVID-19 can enable healthcare systems to provide high quality care to large numbers of patients within the available resources. Specific objectives are to (1) develop and refine a digital health intervention (DHI) that supports patient assessment, monitoring and remote rehabilitation; (2) develop implementation models that support sustainable deployment at scale; (3) evaluate the impact of the DHI on recovery trajectories and (4) identify and mitigate health inequalities due to the digital divide.Methods and analysisMixed-methods, theoretically informed, single-arm prospective study, combining methods drawn from engineering/computer science with those from biomedicine. There are four work packages (WP), one for each objective. WP1 focuses on identifying user requirements and iteratively developing the intervention to meet them; WP2 combines qualitative data from users with learning from implementation science and normalisation process theory, to promote adoption, scale-up, spread and sustainability of the intervention; WP3 uses quantitative demographic, clinical and resource use data collected by the DHI to determine illness trajectories and how these are affected by use of the DHI; while WP4 focuses on identifying and mitigating health inequalities and overarches the other three WPs.Ethics and disseminationEthical approval obtained from East Midlands – Derby Research Ethics Committee (reference 288199). Our dissemination strategy targets three audiences: (1) Policy makers, Health service managers and clinicians responsible for delivering long COVID-19 services; (2) patients and the public; (3) academics.Trial registration numberResearch Registry number: researchregistry6173.

BACKGROUND: Inhaled corticosteroids (ICS) afford therapeutic benefits in some COPD patients, but their widespread use is cautioned due to an increased risk of developing pneumonia. Subclass variations exist, and the risk profile differs for individual ICS. Formulation particle size has been identified as a potential effect modifier. The present study compared the risk of pneumonia among new COPD users of fixed-dose combination inhalers containing fine-particle fluticasone (fp-FDC-F) versus extrafine particle beclometasone (ef-FDC-BDP). METHODS: a propensity matched historical cohort study was conducted using data from the Optimum Patient Care Research Database. COPD patients aged ≥40 years with ≥1 year of continuous medical data who initiated fp-FDC-F or ef-FDC-BDP were compared. The primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions. RESULTS: a total of 13,316 patients were matched. Initiation of fp-FDC-F (mean dosage furoate 99 µg; propionate 710 µg) was associated with an increased risk of pneumonia versus ef-FDC-BDP (mean beclometasone dose 395 µg), irrespective of definition (sensitive HR 1.38 95% CI 1.14-1.68; specific HR 1.31 95% CI 1.05-1.62). CONCLUSION: in the current investigation, we found that in comparison to extrafine beclomethasone, commencing a formulation containing fluticasone is associated with an increased risk of developing pneumonia. These observations support the idea that not all ICS are equal in their adverse effects and subclass variations exist and should be carefully considered in the treatment choice.

Background
‘Engager’ is an innovative ‘through-the-gate’ complex care intervention for male prison-leavers with common mental health problems. In parallel to the randomised-controlled trial of Engager (Trial registration number: ISRCTN11707331), a set of process evaluation analyses were undertaken. This paper reports on the depth multiple case study analysis part of the process evaluation, exploring how a sub-sample of prison-leavers engaged and responded to the intervention offer of one-to-one support during their re-integration into the community.


Methods
To understand intervention delivery and what response it elicited in individuals, we used a realist-informed qualitative multiple ‘case’ studies approach. We scrutinised how intervention component delivery lead to outcomes by examining underlying causal pathways or ‘mechanisms’ that promoted or hindered progress towards personal outcomes. ‘Cases’ (n = 24) were prison-leavers from the intervention arm of the trial. We collected practitioner activity logs and conducted semi-structured interviews with prison-leavers and Engager/other service practitioners. We mapped data for each case against the intervention logic model and then used Bhaskar’s (2016) ‘DREIC’ analytic process to categorise cases according to extent of intervention delivery, outcomes evidenced, and contributing factors behind engagement or disengagement and progress achieved.


Results
There were variations in the dose and session focus of the intervention delivery, and how different participants responded. Participants sustaining long-term engagement and sustained change reached a state of ‘crises but coping’. We found evidence that several components of the intervention were key to achieving this: trusting relationships, therapeutic work delivered well and over time; and an in-depth shared understanding of needs, concerns, and goals between the practitioner and participants. Those who disengaged were in one of the following states: ‘Crises and chaos’, ‘Resigned acceptance’, ‘Honeymoon’ or ‘Wilful withdrawal’.


Conclusions
We demonstrate that the ‘implementability’ of an intervention can be explained by examining the delivery of core intervention components in relation to the responses elicited in the participants. Core delivery mechanisms often had to be ‘triggered’ numerous times to produce sustained change. The improvements achieved, sustained, and valued by participants were not always reflected in the quantitative measures recorded in the RCT. The compatibility between the practitioner, participant and setting were continually at risk of being undermined by implementation failure as well as changing external circumstances and participants’ own weaknesses.


Trial registration number
ISRCTN11707331, Wales Research Ethics Committee, Registered 02-04-2016—Retrospectively registered https://doi.org/10.1186/ISRCTN11707331.

INTRODUCTION: 'Healthier You', the National Health Service (NHS) diabetes prevention programme (DPP) offers adults in England at high risk of type 2 diabetes (T2DM) an evidence-based behavioral intervention to prevent or delay T2DM onset. This study assesses the impact of a pilot digital stream of the DPP (DDPP) on glycated hemoglobin (HbA1c) and weight. RESEARCH DESIGN AND METHODS: a service evaluation employing prospectively collected data in a prospective cohort design in nine NHS local pilot areas across England. Participants were adults with non-diabetic hyperglycemia (NDH) (HbA1c 42-47 mmol/mol or fasting plasma glucose 5.5-6.9 mmol/L) in the 12 months prior to referral. The DDPP comprised five digital health interventions (DHI). Joint primary outcomes were changes in HbA1c and weight between baseline and 12 months. HbA1c and weight readings were recorded at referral (baseline) by general practices, and then at 12-month postregistration. Demographic data and service variables were collected from the DHI providers. RESULTS: 3623 participants with NDH registered for the DDPP and of these, 2734 (75%) were eligible for inclusion in the analyses. Final (12-month) follow-up data for HbA1c were available for 1799 (50%) and for weight 1817 (50%) of registered participants. Mean change at 12 months was -3.1 (-3.4 to -2.8) kg, p

ObjectiveTransient ischaemic attacks (TIA) and minor strokes are important risk factors for further vascular events. We explored the role of albumin creatinine ratio (ACR) in improving risk prediction after a first event.SettingRapid access stroke clinics in the UK.Participants2202 patients attending with TIA or minor stroke diagnosed by the attending stroke physician, able to provide a urine sample to evaluate ACR using a near-patient testing device.Primary and secondary outcomesPrimary outcome was major adverse cardiac events (MACE: recurrent stroke, myocardial infarction or cardiovascular death) at 90 days. The key secondary outcome was to determine whether urinary ACR could contribute to a risk prediction tool for use in a clinic setting.Results151 MACE occurred in 144 participants within 90 days. Participants with MACE had higher ACR than those without. A composite score awarding a point each for age >80 years, previous stroke/TIA and presence of microalbuminuria identified those at low risk and high risk. 90% of patients were at low risk (scoring 0 or 1). Their 90-day risk of MACE was 5.7%. of the remaining ‘high-risk’ population (scoring 2 or 3) 12.4% experienced MACE over 90 days (p<0.001 compared with the low-risk population). The need for acute admission in the first 7 days was twofold elevated in the high-risk group compared with the low-risk group (3.23% vs 1.43%; p=0.05). These findings were validated in an independent historic sample.ConclusionA risk score comprising age, previous stroke/TIA and microalbuminuria predicts future MACE while identifying those at low risk of a recurrent event. This tool shows promise in the risk stratification of patients to avoid the admission of low-risk patients.

Background
Bacterial infections of the upper and lower respiratory tract are a frequent complication of influenza and contribute to the widespread use of antibiotics. Influenza vaccination may help reduce both appropriate and inappropriate prescribing of antibiotics. Electronic health records provide a rich source of information for assessing secondary effects of influenza vaccination.


Methods
We conducted a retrospective study to estimate effects of influenza vaccine on antibiotic (amoxicillin) prescription in the elderly based on data from the Clinical Practice Research Datalink. The introduction of UK policy to recommend the influenza vaccine to older adults in 2000 led to a substantial increase in uptake, creating a natural experiment. of 259,753 eligible patients that were unvaccinated in 1999 and aged≥65y by January 2000, 88,519 patients received influenza vaccination in 2000. These were propensity score matched 1:1 to unvaccinated patients. Time-to-amoxicillin was analysed using the Prior Event Rate Ratio (PERR) Pairwise method to address bias from time-invariant measured and unmeasured confounders. A simulation study and negative control outcome were used to help strengthen the validity of results.


Results
Compared to unvaccinated patients, those from the vaccinated group were more likely to be prescribed amoxicillin in the year prior to vaccination: hazard ratio (HR) 1.90 (95% confidence interval 1.83, 1.98). Following vaccination, the vaccinated group were again more likely to be prescribed amoxicillin, HR 1.64 (1.58,1.71). After adjusting for prior differences between the two groups using PERR Pairwise, overall vaccine effectiveness was 0.86 (0.81, 0.92). Additional analyses suggested that provided data meet the PERR assumptions, these estimates were robust.


Conclusions
Once differences between groups were taken into account, influenza vaccine had a beneficial effect, lowering the frequency of amoxicillin prescribing in the vaccinated group. Ensuring successful implementation of national programmes of vaccinating older adults against influenza may help contribute to reducing antibiotic resistance.

OBJECTIVE: to undertake meta-analysis and compare treatment effects estimated by the intention-to-treat (ITT) method and per-protocol (PP) method in randomized controlled trials (RCTs). PP excludes trial participants who are non-adherent to trial protocol in terms of eligibility, interventions, or outcome assessment. STUDY DESIGN AND SETTING: Five high impact journals were searched for all RCTs published between July 2017 to June 2019. Primary outcome was a pooled estimate that quantified the difference between the treatment effects estimated by the two methods. Results are presented as ratio of odds ratios (ROR). Meta-regression was used to explore the association between level of trial protocol non-adherence and treatment effect. Sensitivity analyses compared results with varying within-study correlations and across various study characteristics. RESULTS: Random-effects meta-analysis (N = 156) showed that PP estimates were on average 2% greater compared to the ITT estimates (ROR: 1.02, 95% CI: 1.00-1.04, P = 0.03). The divergence further increased with higher degree of protocol non-adherence. Sensitivity analyses reassured consistent results with various within-study correlations and across various study characteristics. CONCLUSION: There was evidence of larger treatment effect with PP compared to ITT analysis. PP analysis should not be used to assess the impact of protocol non-adherence in RCTs. Instead, in addition to ITT, investigators should consider randomization based casual method such as Complier Average Causal Effect (CACE).

BackgroundIschaemic stroke and myocardial infarction (MI) are common after pneumonia and are associated with long-term mortality. Aspirin may attenuate this risk and should be explored as a therapeutic option.MethodsWe extracted all patients with pneumonia (aged over 50�
years) from the Clinical Practice Research Datalink (CPRD), a large UK primary care database, from inception until January 2019. We then performed a prior event rate ratio (PERR) analysis with propensity score matching (PSM), an approach that allows for control of measured and unmeasured confounding, with aspirin usage as the exposure and ischaemic events as the outcome. The primary outcome was the combined outcome of ischaemic stroke and MI. Secondary outcomes were ischaemic stroke and MI individually. Relevant confounders (smoking, comorbidities, age and gender) were included in the analysis.Findings48 743 patients were eligible for matching. of these, 9864 were aspirin users who were matched to 9864 non-users. Aspirin users had a reduced risk of the primary outcome (adjusted hazard ratio 0.64, 95% CI 0.52–0.79) in the PERR analysis. For both secondary outcomes, aspirin use was also associated with a reduced risk for MI (hazard ratio 0.46, 95% CI 0.30–0.72) and stroke (hazard ratio 0.70, 95% CI 0.55–0.91), respectively.InterpretationThis study provides supporting evidence that aspirin use is associated with reduced ischaemic events after pneumonia in a primary care setting. This drug may have a future clinical role in preventing this important complication.

. Background
. Rapid spread of coronavirus disease 2019 (COVID-19) has affected people with intellectual disability disproportionately. Existing data does not provide enough information to understand factors associated with increased deaths in those with intellectual disability. Establishing who is at high risk is important in developing prevention strategies, given risk factors or comorbidities in people with intellectual disability may be different to those in the general population.
.
.
. Aims
. To identify comorbidities, demographic and clinical factors of those individuals with intellectual disability who have died from COVID-19.
.
.
. Method
. An observational descriptive case series looking at deaths because of COVID-19 in people with intellectual disability was conducted. Along with established risk factors observed in the general population, possible specific risk factors and comorbidities in people with intellectual disability for deaths related to COVID-19 were examined. Comparisons between mild and moderate-to-profound intellectual disability subcohorts were undertaken.
.
.
. Results
. Data on 66 deaths in individuals with intellectual disability were analysed. This group was younger (mean age 64 years) compared with the age of death in the general population because of COVID-19. High rates of moderate-to-profound intellectual disability (n = 43), epilepsy (n = 29), mental illness (n = 29), dysphagia (n = 23), Down syndrome (n = 20) and dementia (n = 15) were observed.
.
.
. Conclusions
. This is the first study exploring associations between possible risk factors and comorbidities found in COVID-19 deaths in people with intellectual disability. Our data provides insight into possible factors for deaths in people with intellectual disability. Some of the factors varied between the mild and moderate-to-profound intellectual disability groups. This highlights an urgent need for further systemic inquiry and study of the possible cumulative impact of these factors and comorbidities given the possibility of COVID-19 resurgence.
.

Background: As the prevalence of childhood mental health conditions varies by age and gender, we explored whether there were similar variations in the relationship between psychopathology and exclusion from school in a prospective UK population-based birth cohort. Method: the Avon Longitudinal Study of Parents and Children collected reports of exclusion at 8 years and 16 years. Mental health was assessed at repeated time points using the Strengths and Difficulties Questionnaire (SDQ). Results: Using adjusted linear mixed effects models, we detected a nonlinear interaction between exclusion and age related to poor mental health for boys [adjusted coefficient 1.13 (95% confidence interval 0.55–1.71)] excluded by age 8, but not for girls. The SDQ scores of boys who were excluded in primary school were higher than their peers from age 3, and increasingly diverged over time. As teenagers, these interactions appeared for both genders [boys’ adjusted coefficient 0.18 (0.10–0.27); girls 0.29 (0.17–0.40)]. For teenage girls, exclusion by 16 was followed by deteriorating mental health. Family adversity predicted exclusion in all analyses. Conclusion: Prompt access to effective intervention for children in poor mental health may improve both mental health and access to education. Key Practitioner Message: Children who were subsequently excluded from school often faced family adversity and had poor mental health, which suggests the need for an interdisciplinary response and a multiagency approach. Poor mental health may contribute to and result from exclusion from school, so both mental health and education practitioners have a key role to play. Boys who enter school with poor mental health are at high risk of exclusion in primary school, which prompt assessment and intervention may prevent. Both boys and girls who are excluded between the ages of 15 and 16 years may have poor, and in the case of girls, deteriorating, mental health.

BACKGROUND: Repeat attendances to emergency departments for seizures, impacts on the individual and burdens health care systems. We conducted a review to identify implementable measures which improve the management of people with epilepsy reducing healthcare costs and their supportive evidence. METHODS: a scoping review design using suitable search strategy as outlined by PRISMA-ScR was used to examine seven databases: MEDLINE, EMBASE, CINAHL, AMED, PsychINFO, HMIC and BNI. A manual search of the COCHRANE database and citation searching was also conducted. A thematic analysis was conducted to explore the context and reasons of emergency department attendance for seizures, particularly repeat attendances and the strategies and measures deployed to reduce repeat attendances. RESULTS: Twenty-nine reports were included, comprising of a systematic review, a randomised control study, a multi-method study, quantitative studies (n = 17), qualitative studies (n = 6), an audit, a survey and a quality improvement project. Thematic analysis identified four broad areas for reducing repeat attendances. These were developing care pathways, conducting care and treatment reviews, providing educational interventions and role of ambulance staff. CONCLUSION: the findings indicate varied reasons for attendance at ED following seizure, including mental health and knowledge of seizure management and lack of education. Implementations of care pathways in ED have been found to reduce admission related costs.

IntroductionTo identify risk factors, absolute risk, and impact on treatment discontinuation of genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT2i).Research design and methodsWe assessed the relationship between baseline characteristics and genital infection in 21 004 people with type 2 diabetes initiating SGLT2i and 55 471 controls initiating dipeptidyl peptidase-4 inhibitors (DPP4i) in a UK primary care database. We assessed absolute risk of infection in those with key risk factors and the association between early genital infection and treatment discontinuation.ResultsGenital infection was substantially more common in those treated with SGLT2i (8.1% within 1 year) than DPP4i (1.8%). Key predictors of infection with SGLT2i were female sex (HR 3.64; 95% CI 3.23 to 4.11) and history of genital infection; <1 year before initiation (HR 4.38; 3.73 to 5.13), 1–5 years (HR 3.04; 2.64 to 3.51), and >5 years (HR 1.79; 1.55 to 2.07). Baseline HbA1c was not associated with infection risk for SGLT2i, in contrast to DPP4i where risk increased with higher HbA1c. One-year absolute risk of genital infection with SGLT2i was highest for those with a history of prior infection (females 23.7%, males 12.1%), compared with those without (females 10.8%, males 2.7%). Early genital infection was associated with a similar discontinuation risk for SGLT2i (HR 1.48; 1.21–1.80) and DPP4i (HR 1.58; 1.21–2.07).ConclusionsFemale sex and history of prior infection are simple features that can identify subgroups at greatly increased risk of genital infections with SGLT2i therapy. These data can be used to risk-stratify patients. High HbA1c is not a risk factor for genital infections with SGLT2i.

The COVID-19 pandemic has spawned a rare opportunity to study some latent social structures using data science. The Chinese government and its people have been blamed for the outbreak of the virus. Face mask wearing can signal an embodied stigma and Chinese people living outside China have been subject to discrimination, assault, and other hate crimes, particularly at the early stages of the crisis. However, as we accumulate more evidence surrounding mask use, the stigma is shifting. As more scientific data become available and people leave even more information on social media during the lockdown, data science can help better understand the trajectories of the stigma. The insights generated have implications for anti-stigma interventions for future undesirable conditions and diseases.

IntroductionPharmaceutical treatment options for patients with type 2 diabetes mellitus (T2DM) have increased to include multiple classes of oral glucose-lowering agents but without accompanying guidance on which of these may most benefit individual patients. Clinicians lack information for treatment intensification after first-line metformin therapy. Stratifying patients by simple clinical characteristics may improve care by targeting treatment options to those in whom they are most effective. This academically designed and run three-way crossover trial aims to test a stratification approach using three standard oral glucose-lowering agents.Methods and analysisTriMaster is a randomised, double-blind, crossover trial taking place at up to 25 clinical sites across England, Scotland and Wales. 520 patients with T2DM treated with either metformin alone, or metformin and a sulfonylurea who have glycated haemoglobin (HbA1c) >58 mmol/mol will be randomised to receive 16 weeks each of a dipeptidyl peptidase‐4 inhibitor, sodium-glucose co-transporter-2 inhibitor and thiazolidinedione in random order. Participants will be assessed at the end of each treatment period, providing clinical and biochemical data, and their experience of side effects. Participant preference will be assessed on completion of all three treatments. The primary endpoint is HbA1c after 4 months of therapy (allowing a range of 12–18 weeks for analysis). Secondary endpoints include participant-reported preference between the three treatments, tolerability and prevalence of side effects.Ethical approvalThis study was approved by National Health Service Health Research Authority Research Ethics Committee South Central—Oxford A, study 16/SC/0147. Written informed consent will be obtained from all participants. Results will be submitted to a peer-reviewed journal and presented at relevant scientific meetings. A lay summary of results will be made available to all participants.Trial registration numbers12039221; 2015-002790-38 and NCT02653209.

The prevalence of epileptic seizures is increased in patients in the clinical stages of Alzheimer's disease (AD) when compared to age-matched cognitively normal populations. In previously reported work from the Presentation of Epileptic Seizures in Dementia (PrESIDe) study, we identified a clinical suspicion of epilepsy in between 12.75 and 28.43% of patients with AD recruited from a memory clinic. EEGs were not performed in this study. Patients with epilepsy performed similarly to patients without epilepsy on cognitive testing at the time of recruitment but were more impaired on two measures of everyday functioning [Cambridge Behavioral Inventory-Revised and Clinical Dementia Rating (CBI-R and CDR)]. On repeated testing in this 12-month follow-up study, patients in whom a suspicion of epilepsy was identified performed significantly worse on cognitive function testing (p = 0.028) in addition to maintaining a difference on the informant questionnaires (CBI-R p < 0.001, CDR p = 0.020). These findings suggest that seizures in this population could be a marker of a more rapid decline and worse prognosis.

OBJECTIVE: to undertake a methodological review of statistical methods used in randomized controlled trials (RCTs) for handling intervention nonadherence. STUDY DESIGN AND SETTING: Bibliographic databases were searched using predefined search terms. RESULTS: a substantive number of identified studies (56%) were excluded as they only used naive per protocol analysis for handling nonadherence. Our review included 58 articles published between 1991 and 2015. A total of 88 methodological applications were made by these studies. The two most used methods were complier average causal effect (56%) and instrumental variable (23%) predominantly with the use of maximum likelihood (ML) estimators. These alternative applications typically produced treatment effects greater than the intention-to-treat effect but as their standard errors were larger there was no statistical difference between the methods. CONCLUSION: a substantive proportion of RCTs rely on naive per protocol for handling nonadherence. Recent years have seen an increasing number of applications of more appropriate statistical methods, in particular complier average causal effect and instrumental variable methods. However, these later methods rely on strong underlying assumptions that may be vulnerable to violation. More empirical studies are needed that directly compare the usability and performance of different statistical methods for nonadherence in RCTs.

INTRODUCTION: the prevalence of type 2 diabetes is rising steeply. National Health Service England (NHSE) is exploring the potential of a digital diabetes prevention programme (DDPP) and has commissioned a pilot with embedded evaluation. METHODS AND ANALYSIS: This study aims to determine whether, and if so, how, should NHSE implement a national DDPP, using a mixed-methods pretest and post-test design, underpinned by two theoretical frameworks: the Coventry, Aberdeen and London - Refined (CALO-RE) taxonomy of behavioural change techniques for the digital interventions and the Consolidated Framework for Implementation Research (CFIR) for implementation processes. In eight pilot areas across England, adults with non-diabetic hyperglycaemia (NDH) (glycated haemoglobin (HbA1c) 42-47 mmol/mol or fasting plasma glucose 5.5-6.9 mmol/L) and adults without NDH who are overweight (body mass index (BMI) >25 kg/m2) or obese (BMI >30 kg/m2) will be referred to one of five digitally delivered diabetes prevention interventions. The primary outcomes are reduction in HbA1c and weight (for people with NDH) and reduction in weight (for people who are overweight or obese) at 12 months. Secondary outcomes include use of the intervention, satisfaction, physical activity, patient activation and resources needed for successful implementation. Quantitative data will be collected at baseline, 6 months and 12 months by the digital intervention providers. Qualitative data will be collected through semistructured interviews with commissioners, providers, healthcare professionals and patients. Quantitative data will be analysed descriptively and using generalised linear models to determine whether changes in outcomes are associated with demographic and intervention factors. Qualitative data will be analysed using framework analysis, with data pertaining to implementation mapped onto the CFIR. ETHICS AND DISSEMINATION: the study has received ethical approval from the Public Health England Ethics and Research Governance Group (reference R&D 324). Dissemination will include a report to NHSE to inform future policy and publication in peer-reviewed journals.

Introduction: Fuel poverty affects up to 35% of European homes, which represents a significant burden on society and healthcare systems. Draught proofing homes to prevent heat loss, improved glazing, insulation and heating (energy efficiency measures) can make more homes more affordable to heat. This has prompted significant investment in energy efficiency upgrades for around 40% of UK households to reduce the impact of fuel poverty. Despite some inconsistent evidence, household energy efficiency interventions can improve cardiovascular and respiratory health outcomes. However, the health benefits of these interventions have not been fully explored; this is the focus of this study. Methods: in this cross sectional ecological study, we conducted two sets of analyses at different spatial resolution to explore population data on housing energy efficiency measures and hospital admissions at the area-level (counts grouped over a 3-year period). Housing data were obtained from three data sets covering housing across England (Household Energy Efficiency Database), Energy Performance Certificate (EPC) and, in the South West of England, the Devon Home Analytics Portal. These databases provided data aggregated to Lower Area Super Output Area and postcode level (Home Analytics Portal only). These datasets provided measures of both state (e.g. EPC ratings) and intervention (e.g. number of boiler replacements), aggregated spatially and temporally to enable cross-sectional analyses with health outcome data. Hospital admissions for adult (over 18 years) asthma, chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) were obtained from the Hospital Episode Statistics database for the national (1st April 2011 to 31st March 2014) and Devon, South West of England (1st April 2014 to 31st March 2017) analyses. Descriptive statistics and regression models were used to describe the associations between small area household energy efficiency measures and hospital admissions. Three main analyses were undertaken to investigate the relationships between; 1) household energy efficiency improvements (i.e. improved glazing, insulation and boiler upgrades); 2) higher levels of energy efficiency ratings (measured by Energy Performance Certificate ratings); 3) energy efficiency improvements and ratings (i.e. physical improvements and rating assessed by the Standard Assessment Procedure) and hospital admissions. Results: in the national analyses, household energy performance certificate ratings ranged from 37 to 83 (mean 61.98; Standard Deviation 5.24). There were a total of 312,837 emergency admissions for asthma, 587,770 for COPD and 839,416 for CVD. While analyses for individual energy efficiency metrics (i.e. boiler upgrades, draught proofing, glazing, loft and wall insulation) were mixed; a unit increase in mean energy performance rating was associated with increases of around 0.5% in asthma and CVD admissions, and 1% higher COPD admission rates. Admission rates were also influenced by the type of dwelling, tenure status (e.g. home owner versus renting), living in a rural area, and minimum winter temperature. Discussion: Despite a range of limitations and some mixed and contrasting findings across the national and local analyses, there was some evidence that areas with more energy efficiency improvements resulted in higher admission rates for respiratory and cardiovascular diseases. This builds on existing evidence highlighting the complex relationships between health and housing. While energy efficiency measures can improve health outcomes (especially when targeting those with chronic respiratory illness), reduced household ventilation rates can impact indoor air quality for example and increase the risk of diseases such as asthma. Alternatively, these findings could be due to the ecological study design, reverse causality, or the non-detection of more vulnerable subpopulations, as well as the targeting of areas with poor housing stock, low income households, and the lack of “whole house approaches” when retrofitting the existing housing stock. Conclusion: to be sustainable, household energy efficiency policies and resulting interventions must account for whole house approaches (i.e. consideration of the whole house and occupant lifestyles). These must consider more alternative ‘greener’ and more sustainable measures, which are capable of accounting for variable lifestyles, as well as the need for adequate heating and ventilation. Larger natural experiments and more complex modelling are needed to further investigate the impact of ongoing dramatic changes in the housing stock and health. Study implications: This study supports the need for more holistic approaches to delivering healthier indoor environments, which must consider a dynamic and complex system with multiple interactions between a range of interrelated factors. These need to consider the drivers and pressures (e.g. quality of the built environment and resident behaviours) resulting in environmental exposures and adverse health outcomes.

. Background
. Public health strategies have focused largely on physical health. However, there is increasing recognition that raising mental health awareness and tackling stigma is crucial to reduce disease burden. National campaigns have had some success but tackling issues locally is particularly important.
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. Aims
. To assess the public's awareness and perception of the monthly BBC Cornwall mental health phone-in programmes that have run for 8.5 years in Cornwall, UK (population 530 000).
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. Method
. A consultation, review and feedback process involving a multiagency forum of mental and public health professionals, people with lived experience and local National Health Service trust's media team was used to develop a brief questionnaire. This was offered to all attendees at two local pharmacies covering populations of 27 000 over a 2-week period.
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. Results
. In total, 14% (95% CI 11.9–16.5) were aware of the radio show, 11% (95% CI 9.0–13.1) have listened and the majority (76%) of those who listened did so more than once. The estimated reach is 70 000 people in the local population, of whom approximately 60 000 listen regularly. The show is highly valued among respondents with modal and median scores of 4 out of 5.
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. Conclusions
. Local radio is a successful, cost-effective and impactful way to reach a significant proportion of the population and likely to raise awareness, reduce stigma and be well received. The format has been adopted in other regions thus demonstrating easy transferability. It could form an essential part of a public health strategy to improve a population's mental well-being.
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. Declaration of interest
. W.H. received support from the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. L.R. and D.S. were involved in delivering the programmes but had no role in their evaluation.
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We aimed to explore the levels of agreement about the diagnoses of Autistic Spectrum Conditions between the referrer, CAMHS practitioner and a research diagnosis, as well as the stability of the practitioner’s diagnosis over time in a secondary analysis of data from 302 children attending two Child and Adolescent Mental Health Services over two years. Kappa coefficient was used to assess the agreement between the referrer and research diagnosis. Kendall’s tau b coefficient was used to assess the agreement between the practitioner and the research diagnosis assigned using the Development and Well-Being Assessment, as well as the agreement between the referrer’s indication of presenting problems and the practitioner diagnosis. Diagnostic stability was explored in children with and without a research diagnosis of Autistic Spectrum Condition. There was a moderate level of agreement between the referrer and research diagnosis (Kappa = 0.51) and between practitioner’s and research diagnosis (Kendall’s tau = 0.60) at baseline, which reduced over the subsequent two years. Agreement between the referrer and practitioner’s diagnosis at baseline was fair (Kendall’s tau = 0.36).The greatest diagnostic instability occurred among children who practitioners considered to have possible Autistic Spectrum Conditions but who did not meet research diagnostic criteria. Further studies could explore the approaches used by practitioners to reach diagnoses and the impact these may have on diagnostic stability in Autistic Spectrum Conditions. Standardised assessment using a clinically rated diagnostic framework has a potential role as an adjunct to standard clinical care and might be particularly useful where practitioners are uncertain.

PURPOSE: Comorbid epilepsy is found in 22.5% of people with intellectual disability (ID). Responding to the continuing lack of clarity to the role of the ID psychiatrist in the United Kingdom with regards to epilepsy care, the Royal College of Psychiatrists (RCPsych) published the College Report (CR) 203 in May 2017. This proposed a three-tiered model of competency in ID epilepsy care, with minimum acceptable standards described as Bronze and greater expertise as Silver and Gold. This article documents the perceptions of ID psychiatrists as to their skills and training needs, and the perceived impact of CR203 on the profession. METHODS: an e- questionnaire, matching the standards on CR203 and encouraging comments was designed, reviewed and approved by the RCPsych ID executive faculty. The survey was sent by email to all UK-registered RCPsych ID Faculty members via the RCPsych communications. RESULTS: of the expected 332 ID psychiatrists in the UK, 141 responses were received (42.4%). Key findings included that ID psychiatrists as a group have an interest in epilepsy but Bronze standards were frequently unmet, with variation across the UK. There was a noted lack of agreement on role among ID psychiatrists again linked to geographical variation. Regional disparity correlated to population density and proximity to tertiary neurological centres. CONCLUSION: There are significant implications on training, both pre- and post- accreditation for the ID psychiatry speciality. The CR203 standards appear to be steps in the right direction to help define the role ID psychiatrists have in the delivery of epilepsy care.

IMPORTANCE: There is mixed evidence that blood pressure (BP) stabilizes or decreases in later life. It is also unclear whether BP trajectories reflect advancing age, proximity to end of life, or selective survival of persons free from hypertension. OBJECTIVE: to estimate individual patient BP for each of the 20 years before death and identify potential mechanisms that may explain trajectories. DESIGN, STUDY, AND PARTICIPANTS: We analyzed population-based Clinical Practice Research Datalink primary care and linked hospitalization electronic medical records from the United Kingdom, using retrospective cohort approaches with generalized linear mixed-effects modeling. Participants were all available individuals with BP measures over 20 years, yielding 46 634 participants dying aged at least 60 years, from 2010 to 2014. We also compared BP slopes from 10 to 3 years before death for 20 207 participants who died, plus 20 207 birth-year and sex-matched participants surviving longer than 9 years. MAIN OUTCOMES AND MEASURES: Clinically recorded individual patient repeated systolic BP (SBP) and diastolic BP (DBP). RESULTS: in 46 634 participants (51.7% female; mean [SD] age at death, 82.4 [9.0] years), SBPs and DBPs peaked 18 to 14 years before death and then decreased progressively. Mean changes in SBP from peak values ranged from -8.5 mm Hg (95% CI, -9.4 to -7.7) for those dying aged 60 to 69 years to -22.0 mm Hg (95% CI, -22.6 to -21.4) for those dying at 90 years or older; overall, 64.0% of individuals had SBP changes of greater than -10 mm Hg. Decreases in BP appeared linear from 10 to 3 years before death, with steeper decreases in the last 2 years of life. Decreases in SBP from 10 to 3 years before death were present in individuals not treated with antihypertensive medications, but mean yearly changes were steepest in patients with hypertension (-1.58; 95% CI, -1.56 to -1.60 mm Hg vs -0.70; 95% CI, -0.65 to -0.76 mm Hg), dementia (-1.81; 95% CI, -1.77 to -1.87 mm Hg vs -1.41; 95% CI, -1.38 to -1.43 mm Hg), heart failure (-1.66; 95% CI, -1.62 to -1.69 mm Hg vs -1.37; 95% CI, -1.34 to -1.39 mm Hg), and late-life weight loss. CONCLUSIONS AND RELEVANCE: Mean SBP and DBP decreased for more than a decade before death in patients dying at 60 years and older. These BP decreases are not simply attributable to age, treatment of hypertension, or better survival without hypertension. Late-life BP decreases may have implications for risk estimation, treatment monitoring, and trial design.

BACKGROUND AND PURPOSE: Good practice guidelines highlight the importance of making people with epilepsy aware of the risk of premature mortality in epilepsy particularly due to sudden unexpected death in epilepsy (SUDEP). The SUDEP and Seizure Safety Checklist ('Checklist') is a structured risk communication tool used in UK clinics. It is not known if sharing structured information on risk factors allows individuals to reduce SUDEP and premature mortality risks. The aim of this study was to ascertain if the introduction of the Checklist in epilepsy clinics led to individual risk reduction. METHODS: the Checklist was administered to 130 consecutive people with epilepsy attending a specialized epilepsy neurology clinic and 129 attending an epilepsy intellectual disability (ID) clinic within a 4-month period. At baseline, no attendees at the neurology clinic had received formal risk advice, whereas all those attending the ID clinic had received formal risk advice on multiple occasions for 6 years. The Checklist was readministered 1 year later to each group and scores were compared with baseline and between groups. RESULTS: of 12 risk factors considered, there was an overall reduction in mean risk score for the general (P = 0.0049) but not for the ID (P = 0.322) population. Subanalysis of the 25% of people at most risk in both populations showed that both sets had a significant reduction in risk scores (P < 0.001). CONCLUSION: Structured discussion results in behavioural change that reduces individual risk factors. This impact seems to be higher in those who are at current higher risk. It is important that clinicians share risk information with individuals as a matter of public health and health promotion.

Background: Psychiatric and behavioral side effects (PBSEs) are a major cause of antiepileptic drug (AED) withdrawal. Levetiracetam (LEV) is a recognized first-line AED with good seizure outcomes but recognized with PBSEs. Eslicarbazepine (ESL) is considered to function similarly to an active metabolite of the commonly used carbamazepine (CBZ). Carbamazepine is used as psychotropic medication to assist in various psychiatric illnesses such as mood disorders, aggression, and anxiety. Aim: the aim was to evaluate the psychiatric profile of ESL in people who had LEV withdrawn due to PBSEs in routine clinical practice to see if ESL can be used as a possible alternative to LEV. Methods: a retrospective observational review was conducted in two UK epilepsy centers looking at all cases exposed to ESL since its licensing in 2010. The ESL group was all patients with treatment-resistant epilepsy who developed intolerable PBSEs to LEV, subsequently trialed on ESL. The ESL group was matched to a group who tolerated LEV without intolerable PBSEs. Psychiatric disorders were identified from case notes. The Hamilton Depression Scale (HAM-D) was used to outcome change in mood. Clinical diagnoses of a mental disorder were compared between groups using the Fisher's exact test. Group differences in HAM-D scores were assessed using the independent samples t-test (alpha = 0.05). Results: the total number of people with active epilepsy in the two centers was 2142 of whom 46 had been exposed to ESL. Twenty-six had previous exposure to LEV and had intolerable PBSEs who were matched to a person tolerating LEV. There was no statistical differences in the two groups for mental disorders including mood as measured by HAM-D (Chi-square test: p = 0.28). Conclusion: the ESL was well tolerated and did not produce significant PBSEs in those who had PBSEs with LEV leading to withdrawal of the drug. Though numbers were small, the findings suggest that ESL could be a treatment option in those who develop PBSEs with LEV and possibly other AEDs.

INTRODUCTION: the 'Engager' programme is a 'through-the-gate' intervention designed to support prisoners with common mental health problems as they transition from prison back into the community. The trial will evaluate the clinical and cost-effectiveness of the Engager intervention. METHODS AND ANALYSIS: the study is a parallel two-group randomised controlled trial with 1:1 individual allocation to either: (a) the Engager intervention plus standard care (intervention group) or (b) standard care alone (control group) across two investigation centres (South West and North West of England). Two hundred and eighty prisoners meeting eligibility criteria will take part. Engager is a person-centred complex intervention delivered by practitioners and aimed at addressing offenders' mental health and social care needs. It comprises one-to-one support for participants prior to release from prison and for up to 20 weeks postrelease. The primary outcome is change in psychological distress measured by the Clinical Outcomes in Routine Evaluation-Outcome Measure at 6 months postrelease. Secondary outcomes include: assessment of subjective met/unmet need, drug and alcohol use, health-related quality of life and well-being-related quality of life measured at 3, 6 and 12 months postrelease; change in objective social domains, drug and alcohol dependence, service utilisation and perceived helpfulness of services and change in psychological constructs related to desistence at 6 and 12 months postrelease; and recidivism at 12 months postrelease. A process evaluation will assess fidelity of intervention delivery, test hypothesised mechanisms of action and look for unintended consequences. An economic evaluation will estimate the cost-effectiveness. ETHICS AND DISSEMINATION: This study has been approved by the Wales Research Ethics Committee 3 (ref: 15/WA/0314) and the National Offender Management Service (ref: 2015-283). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations. TRIAL REGISTRATION NUMBER: ISRCTN11707331; Pre-results.

PURPOSE: Multimorbidity is associated with adverse outcomes, yet research on the determinants of its incidence is lacking. We investigated which sociodemographic, health, and individual lifestyle (eg, physical activity, smoking behavior, body mass index) characteristics predict new cases of multimorbidity. METHODS: We used data from 4,564 participants aged 50 years and older in the English Longitudinal Study of Aging that included a 10-year follow-up period. Discrete time-to-event (complementary log-log) models were constructed for exploring the associations of baseline characteristics with outcomes between 2002-2003 and 2012-2013 separately for participants with no initial conditions (n = 1,377) developing multimorbidity, any increase in conditions within 10 years regardless of initial conditions, and the impact of individual conditions on incident multimorbidity. RESULTS: the risks of developing multimorbidity were positively associated with age, and they were greater for the least wealthy, for participants who were obese, and for those who reported the lowest levels of physical activity or an external locus of control (believing that life events are outside of one's control) for all groups regardless of baseline conditions (all linear trends

OBJECTIVES: to estimate associations between long-term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care. DESIGN: Longitudinal analyses of electronic medical records. SETTING: England PARTICIPANTS: Individuals aged 60 and older in primary care receiving PPIs for 1 year or longer (N=75,050) and age- and sex-matched controls (N=75,050). MEASUREMENTS: Net hazard ratios for pneumonia incidence in Year 2 of treatment were estimated using the prior event rate ratio (PERR), which adjusts for pneumonia incidence differences before initiation of treatment. Inverse probability weighted models adjusted for 78 demographic, disease, medication, and healthcare usage measures. RESULTS: During the second year after initiating treatment, PPIs were associated with greater hazard of incident pneumonia (PERR-adjusted hazard ratio=1.82, 95% confidence interval=1.27-2.54), accounting for pretreatment pneumonia rates. Estimates were similar across age and comorbidity subgroups. Similar results were also obtained from propensity score- and inverse probability-weighted models. CONCLUSION: in a large cohort of older adults in primary care, PPI prescription was associated with greater risk of pneumonia in the second year of treatment. Results were robust across alternative analysis approaches. Controversies about the validity of reported short-term harms of PPIs should not divert attention from potential long-term effects of PPI prescriptions on older adults.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death among people with chronic epilepsy. People with intellectual disability (ID) are overrepresented in this population. The SUDEP and Seizure Safety Checklist ("Checklist") is a tool to discuss risk factors influencing seizures and the risk of SUDEP. It includes questions about the availability of nocturnal monitoring. In Cornwall UK, people with epilepsy and ID and their relatives and carers are routinely advised to consider nocturnal surveillance to reduce harm from potential nocturnal seizures. We assessed the retention of advice provided on nocturnal monitoring and if there were differences between those in residential care and those living with their families. METHODS: a postal questionnaire was sent to carers of all people with epilepsy and ID in Cornwall followed by the adult specialist ID epilepsy service. All those who were contacted had received the same advice on SUDEP and nocturnal monitoring at least once in the past year. Each person was categorized into living in a residential setting or with their family group. Intergroup differences were compared using Fisher's exact test. RESULTS: Carers for 170 people were contacted and 121 responded (71%). The family group had statistically more nocturnal seizures than the residential group. While there was no difference in the awareness of SUDEP, the groups differed in their recollection of the person-centered discussion of risk with carers in residential setting being less aware. Where nocturnal monitoring advice was given, it was followed, and previously unknown seizures were identified in 75%. CONCLUSIONS: Carers in residential settings are less likely to recall specific person-centered discussion of risks to the individual they support as compared with those living with families although general awareness of SUDEP and implementing advice such as nocturnal monitoring is present equally in both groups. In improving detection of nocturnal seizures, audio monitoring may be a useful strategy to reduce risk of harm for people with ID.

OBJECTIVE: the choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones. RESEARCH DESIGN AND METHODS: We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2,725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2,222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1,977). RESULTS: in CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups. CONCLUSIONS: Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

Attendance at UK Emergency Departments (EDs) for people with epilepsy (PWE) following a seizure can be unnecessary and costly. The characteristics of PWE attending a UK rural district ED in a 12-month period were examined to foster better understanding of relevant psycho-social factors associated with ED use by conducting cross-sectional interviews using standardized questionnaires. of the total participants (n = 46), approximately one-third of the study cohort attended ED on three or more occasions in the 12-month study period and accounted for 65% of total ED attendances reported. Seizure frequency and lower social deprivation status were associated with increased ED attendance while factors such as knowledge of epilepsy, medication management, and stigma were not. Similarities in frequency of repeat attendees were comparable to a study in urban population but other factors varied considerable. Our findings suggest that regular ED attendees may be appropriate for specific enhanced intervention though consideration needs to be given to the fact that population characteristics may vary across regions.

BackgroundThere has been an increased focus towards improving quality of care within the NHS in the last 15 years; as part of this, there has been an emphasis on the importance of patient feedback within policy, through National Service Frameworks and the Quality and Outcomes Framework. The development and administration of large-scale national patient surveys to gather representative data on patient experience, such as the national GP Patient Survey in primary care, has been one such initiative. However, it remains unclear how the survey is used by patients and what impact the data may have on practice.ObjectivesOur research aimed to gain insight into how different patients use surveys to record experiences of general practice; how primary care staff respond to feedback; and how to engage primary care staff in responding to feedback.MethodsWe used methods including quantitative survey analyses, focus groups, interviews, an exploratory trial and an experimental vignette study.Results(1)Understanding patient experience data. Patients readily criticised their care when reviewing consultations on video, although they were reluctant to be critical when completing questionnaires. When trained raters judged communication during a consultation to be poor, a substantial proportion of patients rated the doctor as ‘good’ or ‘very good’. Absolute scores on questionnaire surveys should be treated with caution; they may present an overoptimistic view of general practitioner (GP) care. However, relative rankings to identify GPs who are better or poorer at communicating may be acceptable, as long as statistically reliable figures are obtained. Most patients have a particular GP whom they prefer to see; however, up to 40% of people who have such a preference are unable regularly to see the doctor of their choice. Users of out-of-hours care reported worse experiences when the service was run by a commercial provider than when it was run by a not-for profit or NHS provider. (2)Understanding patient experience in minority ethnic groups. Asian respondents to the GP Patient Survey tend to be registered with practices with generally low scores, explaining about half of the difference in the poorer reported experiences of South Asian patients than white British patients. We found no evidence that South Asian patients used response scales differently. When viewing the same consultation in an experimental vignette study, South Asian respondents gave higher scores than white British respondents. This suggests that the low scores given by South Asian respondents in patient experience surveys reflect care that is genuinely worse than that experienced by their white British counterparts. We also found that service users of mixed or Asian ethnicity reported lower scores than white respondents when rating out-of-hours services. (3)Using patient experience data. We found that measuring GP–patient communication at practice level masks variation between how good individual doctors are within a practice. In general practices and in out-of-hours centres, staff were sceptical about the value of patient surveys and their ability to support service reconfiguration and quality improvement. In both settings, surveys were deemed necessary but not sufficient. Staff expressed a preference for free-text comments, as these provided more tangible, actionable data. An exploratory trial of real-time feedback (RTF) found that only 2.5% of consulting patients left feedback using touch screens in the waiting room, although more did so when reminded by staff. The representativeness of responding patients remains to be evaluated. Staff were broadly positive about using RTF, and practices valued the ability to include their own questions. Staff benefited from having a facilitated session and protected time to discuss patient feedback.ConclusionsOur findings demonstrate the importance of patient experience feedback as a means of informing NHS care, and confirm that surveys are a valuable resource for monitoring national trends in quality of care. However, surveys may be insufficient in themselves to fully capture patient feedback, and in practice GPs rarely used the results of surveys for quality improvement. The impact of patient surveys appears to be limited and effort should be invested in making the results of surveys more meaningful to practice staff. There were several limitations of this programme of research. Practice recruitment for our in-hours studies took place in two broad geographical areas, which may not be fully representative of practices nationally. Our focus was on patient experience in primary care; secondary care settings may face different challenges in implementing quality improvement initiatives driven by patient feedback. Recommendations for future research include consideration of alternative feedback methods to better support patients to identify poor care; investigation into the factors driving poorer experiences of communication in South Asian patient groups; further investigation of how best to deliver patient feedback to clinicians to engage them and to foster quality improvement; and further research to support the development and implementation of interventions aiming to improve care when deficiencies in patient experience of care are identified.FundingThe National Institute for Health Research Programme Grants for Applied Research programme.

BACKGROUND: Moderate obesity in later life may improve survival, prompting calls to revise obesity control policies. However, this obesity paradox may be due to confounding from smoking, diseases causing weight-loss, plus varying follow-up periods. We aimed to estimate body mass index (BMI) associations with mortality, incident type 2 diabetes, and coronary heart disease in older people with and without the above confounders. METHODS: Cohort analysis in Clinical Practice Research Datalink primary care, hospital and death certificate electronic medical records in England for ages 60 to more than 85 years. Models were adjusted for age, gender, alcohol use, smoking, calendar year, and socioeconomic status. RESULTS: Overall, BMI 30-34.9 (obesity class 1) was associated with lower overall death rates in all age groups. However, after excluding the specific confounders and follow-up less than 4 years, BMI mortality risk curves at age 65-69 were U-shaped, with raised risks at lower BMIs, a nadir between 23 and 26.9 and steeply rising risks above. In older age groups, mortality nadirs were at modestly higher BMIs (all

PURPOSE: There is a shortfall of suitably powered studies to provide evidence for safe prescribing of AEDs to people with Intellectual Disability (ID). We report clinically useful information on differences in response to Perampanel (PER) adjunctive treatment for refractory epilepsy between ID sub-groups and general population from the UK Ep-ID Research Register. METHOD: Pooled retrospective case notes data of consented people with epilepsy (PWE) prescribed PER from 6 UK centres was classified as per WHO guidance into groups of moderate -profound ID, mild ID and General population. Demographics, concomitant AEDs, starting and maximum dosage, exposure length, adverse effects, dropout rates, seizure type and frequency were collected. Group differences were reported as odds ratios estimated from univariable logistic regression models. RESULTS: of the 144 PWE (General population 71, Mild ID 48, Moderate to profound ID 48) examined the association between withdrawal and ID type was marginally statistically significant (p=0.07). Moderate to profound ID PWE were less likely to come off PER compared to mild ID (OR=0.19, CI=0.04-0.92, p=0.04). Differences in mental health side effects by groups was marginally statistically significant (p=0.06). Over 50% seizure improvement was seen in 11% of General population, 24% mild ID and 26% Moderate to profound ID. CONCLUSIONS: PER seems safe in PWE with ID. It is better tolerated by PWE with Moderate to profound ID than PWE with higher functioning. Caution is advised when history of mental health problems is present. The standardised approach of the Ep-ID register UK used confirms that responses to AEDs by different ID groups vary between themselves and General population.

BACKGROUND: There is limited evidence on statin risk and effectiveness for patients aged 80+. We estimated risk of recurrent myocardial infarction, muscle-related and other adverse events, and statin-related incremental costs in "real-world" older patients treated with statins versus no statins. METHODS: We used primary care electronic medical records from the UK Clinical Practice Research Datalink. Subhazard ratios (competing risk of death) for myocardial infarction recurrence (primary end point), falls, fractures, ischemic stroke, and dementia, and hazard ratios (Cox) for all-cause mortality were used to compare older (60+) statin users and 1:1 propensity-score-matched controls (n = 12,156). Participants were followed-up for 10 years. RESULTS: Mean age was 76.5±9.2 years; 45.5% were women. Statins were associated with near significant reduction in myocardial infarction recurrence (subhazard ratio = 0.84, 0.69-1.02, p =. 073), with protective effect in the 60-79 age group (0.73, 0.57-0.94) but a nonsignificant result in the 80+ group (1.06, 0.78-1.44; age interaction p =. 094). No significant associations were found for stroke or dementia. Data suggest an increased risk of falls (1.36, 1.17-1.60) and fractures (1.33, 1.04-1.69) in the first 2 years of treatment, particularly in the 80+ group. Treatment was associated with lower all-cause mortality. Statin use was associated with health care cost savings in the 60-79 group but higher costs in the 80+ group. CONCLUSIONS: Estimates of statin effectiveness for the prevention of recurrent myocardial infarction in patients aged 60-79 years were similar to trial results, but more evidence is needed in the older group. There may be an excess of falls and fractures in very old patients, which deserves further investigation.

BACKGROUND: Older people with common mental health problems (CMHPs) are known to have reduced rates of referral to psychological therapy. AIM: to assess referral rates to the Improving Access to Psychological Therapies (IAPT) services, contact with a therapist, and clinical outcome by age. DESIGN AND SETTING: Empirical research study using patient episodes of care from South West of England IAPT services. METHOD: By analysing 82 513 episodes of care (2010-2011), referral rates and clinical improvement were compared with both total population and estimated prevalence in each age group using IAPT data. Probable recovery of those completing treatment was calculated for each group. RESULTS: Estimated prevalence of CMHPs peaks in 45-49-year-olds (20.59% of population). The proportions of patients identified with CMHPs being referred peaks at 20-24 years (22.95%) and reduces with increase in age thereafter to 6.00% for 70-74-year-olds. Once referred, the proportion of those attending first treatment increases with age between 20 years (57.34%) and 64 years (76.97%). In addition, the percentage of those having a clinical improvement gradually increases from the age of 18 years (12.94%) to 69 years (20.74%). CONCLUSION: Younger adults are more readily referred to IAPT services. However, as a proportion of those referred, probabilities of attending once, attending more than once, and clinical improvement increase with age. It is uncertain whether optimum levels of referral have been reached for young adults. It is important to establish whether changes to service configuration, treatment options, and GP behaviour can increase referrals for middle-aged and older adults.

Purpose - Routine outcome monitoring (ROM) is currently seen as a key driver for service improvement at individual, team and service level. The purpose this paper is to explore the relationships between a patient (parent) reported outcome measure (PROM), a practitioner reported outcome measure, and a patient (parent) reported experience measure (PREM). Design/methodology/approach - a cohort of 302 primary school-age children was recruited and followed for one year from consecutively accepted referrals to three teams within two English Child and Adolescent Mental Health Services (CAMHS). Parents completed the Strengths and Difficulties Questionnaire (a PROM) and practitioners completed the Clinician Global Assessment Scale at baseline, six and 12 months; parents completed the Experience of Services Questionnaire (a PREM) at six and 12 months. Findings - PROM and practitioner reported outcome measure data suggested poor clinical outcome in terms of symptoms, impact and levels of functioning but were accompanied by PREM evidence of high levels of satisfaction. There was an unexpectedly low correlation (o0.2) between both measures of outcome and satisfaction. Originality/value - This paper fulfils a need to explore the relationships between different outcome measures to contribute to the understanding of ROM its validity.

BACKGROUND AND AIMS: Autochthonous hepatitis E virus (HEV) infection is a porcine zoonosis and increasingly recognized in developed countries. In most cases the route of infection is uncertain. A previous study showed that HEV was associated geographically with pig farms and coastal areas. AIM: the aim of the present research was to study the geographical, environmental and social factors in autochthonous HEV infection. METHODS: Cases of HEV genotype 3 infection and controls were identified from 2047 consecutive patients attending a rapid-access hepatology clinic. For each case/control the following were recorded: distance from home to nearest pig farm, distance from home to coast, rainfall levels during the 8 weeks before presentation, and socioeconomic status. RESULTS: a total of 36 acute hepatitis E cases, 170 age/sex-matched controls and 53 hepatitis controls were identified. The geographical spread of hepatitis E cases was not even when compared with both control groups. Cases were more likely to live within 2000 m of the coast (odds ratio=2.32, 95% confidence interval=1.08-5.19, P=0.03). There was no regional difference in the incidence of cases and controls between west and central Cornwall. There was no difference between cases and controls in terms of distance from the nearest pig farm, socioeconomic status or rainfall during the 8 weeks before disease presentation. CONCLUSION: Cases of HEV infection in Cornwall are associated with coastal residence. The reason for this observation is uncertain, but might be related to recreational exposure to beach areas exposed to HEV-contaminated 'run-off' from pig farms. This hypothesis merits further study.

BACKGROUND: a 2014 national audit used the English General Practice Patient Survey (GPPS) to compare service users' experience of out-of-hours general practitioner (GP) services, yet there is no published evidence on the validity of these GPPS items. OBJECTIVES: Establish the construct and concurrent validity of GPPS items evaluating service users' experience of GP out-of-hours care. METHODS: Cross-sectional postal survey of service users (n=1396) of six English out-of-hours providers. Participants reported on four GPPS items evaluating out-of-hours care (three items modified following cognitive interviews with service users), and 14 evaluative items from the Out-of-hours Patient Questionnaire (OPQ). Construct validity was assessed through correlations between any reliable (Cochran's α>0.7) scales, as suggested by a principal component analysis of the modified GPPS items, with the 'entry access' (four items) and 'consultation satisfaction' (10 items) OPQ subscales. Concurrent validity was determined by investigating whether each modified GPPS item was associated with thematically related items from the OPQ using linear regressions. RESULTS: the modified GPPS item-set formed a single scale (α=0.77), which summarised the two-component structure of the OPQ moderately well; explaining 39.7% of variation in the 'entry access' scores (r=0.63) and 44.0% of variation in the 'consultation satisfaction' scores (r=0.66), demonstrating acceptable construct validity. Concurrent validity was verified as each modified GPPS item was highly associated with a distinct set of related items from the OPQ. CONCLUSIONS: Minor modifications are required for the English GPPS items evaluating out-of-hours care to improve comprehension by service users. A modified question set was demonstrated to comprise a valid measure of service users' overall satisfaction with out-of-hours care received. This demonstrates the potential for the use of as few as four items in benchmarking providers and assisting services in identifying, implementing and assessing quality improvement initiatives.

The available oocyte pool is determined before birth, with the majority of oocytes lost before puberty. We hypothesised that events occurring before birth, in childhood or in adolescence ('early-life risk factors') could influence the size of the oocyte pool and thus the timing of menopause. We included cross-sectional data from 273,474 women from the UK Biobank, recruited in 2006-2010 from across the UK. We analysed the association of early menopause with events occurring before adulthood in 11,781 cases (menopause aged under 45) and 173,641 controls (menopause/pre-menopausal at ≥ 45 years), in models controlling for potential confounding variables. Being part of a multiple birth was strongly associated with early menopause (odds ratio = 1.42, confidence interval: 1.11, 1.82, P = 8.0 × 10(-9), fully-adjusted model). Earlier age at menarche (odds ratio = 1.03, confidence interval: 1.01, 1.06, P = 2.5 × 10(-6)) and earlier year of birth were also associated with EM (odds ratio = 1.02, confidence interval: 1.00, 1.04, P = 8.0 × 10(-6)). We also confirmed previously reported associations with smoking, drinking alcohol, educational level and number of births. We identified an association between multiple births and early menopause, which connects events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life.

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (

Observational studies provide a rich source of information for assessing effectiveness of treatment interventions in many situations where it is not ethical or practical to perform randomized controlled trials. However, such studies are prone to bias from hidden (unmeasured) confounding. A promising approach to identifying and reducing the impact of unmeasured confounding is prior event rate ratio (PERR) adjustment, a quasi-experimental analytic method proposed in the context of electronic medical record database studies. In this paper, we present a statistical framework for using a pairwise approach to PERR adjustment that removes bias inherent in the original PERR method. A flexible pairwise Cox likelihood function is derived and used to demonstrate the consistency of the simple and convenient alternative PERR (PERR-ALT) estimator. We show how to estimate standard errors and confidence intervals for treatment effect estimates based on the observed information and provide R code to illustrate how to implement the method. Assumptions required for the pairwise approach (as well as PERR) are clarified, and the consequences of model misspecification are explored. Our results confirm the need for researchers to consider carefully the suitability of the method in the context of each problem. Extensions of the pairwise likelihood to more complex designs involving time-varying covariates or more than two periods are considered. We illustrate the application of the method using data from a longitudinal cohort study of enzyme replacement therapy for lysosomal storage disorders. © 2016 the Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

INTRODUCTION: the Rehabilitation EnAblement in CHronic Heart Failure in patients with Heart Failure (HF) with preserved ejection fraction (REACH-HFpEF) pilot trial is part of a research programme designed to develop and evaluate a facilitated, home-based, self-help rehabilitation intervention to improve self-care and quality of life (QoL) in heart failure patients and their caregivers. We will assess the feasibility of a definitive trial of the REACH-HF intervention in patients with HFpEF and their caregivers. The impact of the REACH-HF intervention on echocardiographic outcomes and bloodborne biomarkers will also be assessed. METHODS AND ANALYSIS: a single-centre parallel two-group randomised controlled trial (RCT) with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention) or usual care alone (control) in 50 HFpEF patients and their caregivers. The REACH-HF intervention comprises a REACH-HF manual with supplementary tools, delivered by trained facilitators over 12�
weeks. A mixed methods approach will be used to assess estimation of recruitment and retention rates; fidelity of REACH-HF manual delivery; identification of barriers to participation and adherence to the intervention and study protocol; feasibility of data collection and outcome burden. We will assess the variance in study outcomes to inform a definitive study sample size and assess methods for the collection of resource use and intervention delivery cost data to develop the cost-effectiveness analyses framework for any future trial. Patient outcomes collected at baseline, 4 and 6�
months include QoL, psychological well-being, exercise capacity, physical activity and HF-related hospitalisation. Caregiver outcomes will also be assessed, and a substudy will evaluate impact of the REACH-HF manual on resting global cardiovascular function and bloodborne biomarkers in HFpEF patients. ETHICS AND DISSEMINATION: the study is approved by the East of Scotland Research Ethics Service (Ref: 15/ES/0036). Findings will be disseminated via journals and presentations to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN78539530; Pre-results.

AIMS: Baseline HbA1c is a major predictor of response to glucose lowering therapy and therefore a potential confounder in studies aiming to identify other predictors. However, baseline adjustment may introduce error if the association between baseline HbA1c and response is substantially due to measurement error and regression to the mean. We aimed to determine whether studies of predictors of response should adjust for baseline HbA1c. METHODS: We assessed the relationship between baseline HbA1c and glycaemic response in 257 participants treated with GLP-1R agonists and assessed whether it reflected measurement error and regression to the mean using duplicate 'pre-baseline' HbA1c measurements not included in the response variable. In this cohort and an additional 2659 participants treated with sulfonylureas we assessed the relationship between covariates associated with baseline HbA1c and treatment response with and without baseline adjustment, and with a bias correction using pre-baseline HbA1c to adjust for the effects of error in baseline HbA1c. RESULTS: Baseline HbA1c was a major predictor of response (R2 = 0.19,β = -0.44,p

OBJECTIVE: Sudden gains were investigated in cognitive-behavioral therapy (CBT) for treatment-resistant depression (TRD). Client and therapist processes in sessions proximal to sudden gains were examined to better understand the antecedents of sudden gains and potential mechanisms linking them to outcome. METHOD: Participants were 156 adults with TRD in a randomized controlled trial of CBT as an adjunct to pharmacotherapy (Wiles et al. 2013). Depression symptoms were assessed by the Beck Depression Inventory-II at each session. In a subsample of 50 clients, audio-recordings of 125 therapy sessions were rated for hope, emotional processing, and therapist competence in case-conceptualization. RESULTS: Sudden gains were experienced by 54% of participants. Those with gains reported significantly lower depression severity at 12-month follow-up and more remission of symptoms than those without gains. Sudden gains also predicted lower depression at follow-up, beyond the slope of linear change in symptoms across treatment. Therapists demonstrated greater competence in case conceptualization with clients who reported sudden gains, and those with gains expressed more hope in sessions prior to a gain. In addition, more hope and emotional processing in the pregain sessions predicted less depression at follow-up, controlling for depression scores in the prior session. Better therapist conceptualization skills and more client hope in the baseline and pregain sessions were also associated with more emotional processing in those same sessions. CONCLUSION: This study extends the phenomenon of sudden gains in CBT for depression to a treatment-resistant population and identified important therapy processes that predicted long-term outcomes: hope and emotional processing. (PsycINFO Database Record

Purpose - the purpose of this paper is to explore the association between children who are at risk of being or who have been excluded from school between the ages of 4 and 12 years and the role of psychopathology, development and attainment. Design/methodology/approach - a case-control approach was conducted. Cases were children who had been excluded from school compared to those who had no reported exclusions and normative data where possible. A range of measures were used to collect information from the parent, child and teacher on areas covering the child's mental health and well-being. Findings - the findings showed the number of difficulties faced by children who are at risk of being or who have been excluded from school compared to gender- nd age-matched controls and normative data increased. Behavioural difficulties were apparent in the majority of the cases and an alarming number of children reported self-harm. Interestingly nearly all the cases had recognised needs, but not all of them were accessing appropriate services. Practical implications - There have been a number of changes regarding the identification and support of children's mental health and well-being. This study highlights gaps in resources and provision, particularly around behavioural difficulties for children who are presenting as not coping in school. Originality/value - the findings from the SKIP study indicate the complexities and compounded difficulties faced by children who are experiencing exclusion from school. By implementing a systematic group of assessments the study was able to identify these complexities of need across a vulnerable group of children.

Emerging evidence suggests that low vitamin D concentrations are potentially involved in the pathogenesis of dementia. This is of particular interest when considering the high prevalence of vitamin D deficiency in elderly adults and the urgent need to identify modifiable risk factors for dementia. Studies have found that vitamin D is implicated in procognitive and neuroprotective functions, including the reduction of Alzheimer's disease hallmarks such as amyloid beta and phosphorylated tau. Cross-sectional studies have consistently found that vitamin D concentrations are significantly lower in individuals with Alzheimer's disease and cognitive impairment compared to healthy controls. Longitudinal studies support an association between low vitamin D concentrations and an increased risk of dementia and cognitive decline. Neuroimaging studies are beginning to uncover the potential neurodegenerative and cerebrovascular mechanisms that underlie these associations such as white matter hyperintensities and enlarged ventricular volume, although there is currently a lack of longitudinal studies. In contrast to observational studies, findings from interventional studies have produced mixed results on the benefits of vitamin D supplementation on dementia and cognitive outcomes. Interpretation of the findings from these studies is hampered by several major methodological limitations, such as small sample sizes, inadequate doses and inclusion of participants unlikely to benefit from vitamin D supplementation. There is a need for large double-blind randomised-control trials investigating whether vitamin D supplementation can halt or delay the risk of dementia-related outcomes in individuals with low vitamin D concentrations.

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown. OBJECTIVE: to investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline. METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively. RESULTS: in the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34). CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer's disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged ≥65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992-93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991-1994 and the second MRI scan was conducted between 1997-1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (

BACKGROUND: High risk medications are commonly prescribed to older US patients. Currently, less is known about high risk medication prescribing in other Western Countries, including the UK. We measured trends and correlates of high risk medication prescribing in a subset of the older UK population (community/institutionalized) to inform harm minimization efforts. METHODS: Three cross-sectional samples from primary care electronic clinical records (UK Clinical Practice Research Datalink, CPRD) in fiscal years 2003/04, 2007/08 and 2011/12 were taken. This yielded a sample of 13,900 people aged 65 years or over from 504 UK general practices. High risk medications were defined by 2012 Beers Criteria adapted for the UK. Using descriptive statistical methods and regression modelling, prevalence of 'any' (drugs prescribed at least once per year) and 'long-term' (drugs prescribed all quarters of year) high risk medication prescribing and correlates were determined. RESULTS: While polypharmacy rates have risen sharply, high risk medication prevalence has remained stable across a decade. A third of older (65+) people are exposed to high risk medications, but only half of the total prevalence was long-term (any = 38.4 % [95 % CI: 36.3, 40.5]; long-term = 17.4 % [15.9, 19.9] in 2011/12). Long-term but not any high risk medication exposure was associated with older ages (85 years or over). Women and people with higher polypharmacy burden were at greater risk of exposure; lower socio-economic status was not associated. Ten drugs/drug classes accounted for most of high risk medication prescribing in 2011/12. CONCLUSIONS: High risk medication prescribing has not increased over time against a background of increasing polypharmacy in the UK. Half of patients receiving high risk medications do so for less than a year. Reducing or optimising the use of a limited number of drugs could dramatically reduce high risk medications in older people. Further research is needed to investigate why the oldest old and women are at greater risk. Interventions to reduce high risk medications may need to target shorter and long-term use separately.

Objective We compared the distribution by wealth of self-reported illness burden (estimated from validated scales, biomarker and reported symptoms) for angina, cataract, depression, diabetes and osteoarthritis, with the distribution of self-reported medical diagnosis and treatment. We aimed to determine if the greater illness burden borne by poorer participants was matched by appropriately higher levels of diagnosis and treatment.Design the English Longitudinal Study of Ageing, a panel study of 12�
765 participants aged 50�
years and older in four waves from 2004 to 2011, selected using a stratified random sample of households in England. Distribution of illness burden, diagnosis and treatment by wealth was estimated using regression analysis.Outcome measures the main outcome measures were ORs for the illness burden, diagnosis and treatment, respectively, adjusted for age, sex and wealth. We estimated the illness burden for angina with the Rose Angina scale, diabetes with fasting glycosylated haemoglobin, depression with the Centre for Epidemiologic Studies Depression Scale, osteoarthritis with self-reported pain and disability and cataract with self-reported poor vision. Medical diagnoses were self-reported for all conditions. Treatment was defined as β-blocker prescription for angina, surgery for osteoarthritis and cataract, and receipt of predefined effective interventions for diabetes and depression.Results Compared with the wealthiest, the least wealthy participant had substantially higher odds for illness burden from any of the five conditions at all four time points, with ORs ranging from 4.2 (95% CI 2.6 to 6.8) for diabetes to 15.1 (11.4 to 20.0) for osteoarthritis. The ORs for diagnosis and treatment were smaller in all five conditions, and ranged from 0.9 (0.5 to 1.4) for diabetes treatment to 4.5 (3.3 to 6.0) for angina diagnosis.Conclusions the substantially higher illness burden in less wealthy participants was not matched by appropriately higher levels of diagnosis and treatment.

INTRODUCTION: Contemporary adolescents are deemed inactive, especially girls, but whether for biological reasons associated with their maturation, changes in their behavior or because of environmental constraints, is uncertain. We examined the trends in physical activity (PA) in relation to both biological and environmental factors in an attempt to establish what drives activity patterns from childhood through adolescence. METHODS: Physical activity (7-d Actigraph accelerometry) was measured annually from 5 to 15 yr in a single cohort of some 300 UK children. Total PA (TPA; in-school and out-of-school separately and combined as whole day) and intensity-specific PA (sedentary, light, and moderate-and-vigorous [MVPA]) were analyzed. Biological age (years before/after measured peak height velocity) and pubertal stage (self-reported pubic hair development-Tanner staging) were also measured as was socioeconomic status (postcode-derived index of multiple deprivation [IMD]). RESULTS: Total PA was stable from 5 to 8 yr (trend P = 0.10) but fell progressively from 9 to 15 yr (by approximately 30% in girls and approximately 20% in boys, both P < 0.001; sex interaction, P < 0.01). Half of this fall was attributable to light intensity PA and only a quarter to MVPA. The decline in PA was related similarly to chronological and biological age, whereas pubertal stage explained the more rapid PA decline in girls (puberty-adjusted sex interaction, P = 0.51). Total PA fell to the same extent for in-school and out-of-school settings (both P < 0.001), and for lower and higher IMD areas (both P < 0.001). Total PA tracked moderately to strongly from childhood into adolescence (r = 0.58; P < 0.001). CONCLUSIONS: the adolescent decline in PA is consistent across different environmental settings, attributable to falls in light-intensity/habitual activity and influenced by puberty, suggesting that the inactivity of adolescence may, in part, be under biological control.

Schools are common sites for obesity prevention interventions. Although many theories suggest that the school context influences weight status, there has been little empirical research. The objective of this study was to explore whether features of the school context were consistently and meaningfully associated with pupil weight status (overweight or obese). Exploratory factor analysis of routinely collected data on 319 primary schools in Devon, England, was used to identify possible school-based contextual factors. Repeated cross-sectional multilevel analysis of five years (2006/07-2010/11) of data from the National Child Measurement Programme was then used to test for consistent and meaningful associations. Four school-based contextual factors were derived which ranked schools according to deprivation, location, resource and prioritisation of physical activity. None of which were meaningfully and consistently associated with pupil weight status, across the five years. The lack of consistent associations between the factors and pupil weight status suggests that the school context is not inherently obesogenic. In contrast, incorporating findings from education research indicates that schools may be equalising weight status, and obesity prevention research, policy and practice might need to address what is happening outside schools and particularly during the school holidays.

INTRODUCTION: Chronically elevated circulating inflammatory markers are common in older persons but mechanisms are unclear. Many blood transcripts (>800 genes) are associated with interleukin-6 protein levels (IL6) independent of age. We aimed to identify gene transcripts statistically mediating, as drivers or responders, the increasing levels of IL6 protein in blood at older ages. METHODS: Blood derived in-vivo RNA from the Framingham Heart Study (FHS, n=2422, ages 40-92 yrs) and InCHIANTI study (n=694, ages 30-104 yrs), with Affymetrix and Illumina expression arrays respectively (>17,000 genes tested), were tested for statistical mediation of the age-IL6 association using resampling techniques, adjusted for confounders and multiple testing. RESULTS: in FHS, IL6 expression was not associated with IL6 protein levels in blood. 102 genes (0.6% of 17,324 expressed) statistically mediated the age-IL6 association of which 25 replicated in InCHIANTI (including 5 of the 10 largest effect genes). The largest effect gene (SLC4A10, coding for NCBE, a sodium bicarbonate transporter) mediated 19% (adjusted CI 8.9 to 34.1%) and replicated by PCR in InCHIANTI (n=194, 35.6% mediated, p=0.01). Other replicated mediators included PRF1 (perforin, a cytolytic protein in cytotoxic T lymphocytes and NK cells) and IL1B (Interleukin 1 beta): few other cytokines were significant mediators. CONCLUSIONS: This transcriptome-wide study on human blood identified a small distinct set of genes that statistically mediate the age-IL6 association. Findings are robust across two cohorts and different expression technologies. Raised IL6 levels may not derive from circulating white cells in age related inflammation.

BACKGROUND: the oldest old (85+) pose complex medical challenges. Both underdiagnosis and overdiagnosis are claimed in this group. OBJECTIVE: to estimate diagnosis, prescribing and hospital admission prevalence from 2003/4 to 2011/12, to monitor trends in medicalisation. DESIGN AND SETTING: observational study of Clinical Practice Research Datalink (CPRD) electronic medical records from general practice populations (eligible; n = 27,109) with oversampling of the oldest old. METHODS: we identified 18 common diseases and five geriatric syndromes (dizziness, incontinence, skin ulcers, falls and fractures) from Read codes. We counted medications prescribed ≥1 time in all quarters of studied years. RESULTS: there were major increases in recorded prevalence of most conditions in the 85+ group, especially chronic kidney disease (stages 3-5: prevalence

Aims
Diabetes complications are potentially avoidable, yet incomplete care is common. Little is known about patient characteristics that predict incomplete care.
Methods
English Longitudinal Study of Ageing participants aged 50 years or older with diabetes reported on four diabetes quality indicators (QIs) in 2008-9 and 2010-11. Annual checks for glycated haemoglobin (HbA1c), proteinuria and foot examination were assessed as a care bundle (n=907). A further QI
assessed whether participants with cardiac risk factors were offered ACE inhibitors/receptor blockers
(n=759). Individual's baseline (2008-9) socio-demographic, lifestyle and health characteristics,
diabetes self-management knowledge and health literacy, and previous QI achievement were assessed
with logistic regressions on outcomes in 2010-11.
Results
A third of participants (2008-9=32.8%; 2010-11=32.2%) did not receive all annual checks in the care
bundle. Nearly half of those eligible were not offered ACE inhibitors/receptor blockers (2008-
9=44.6%; 2010-11=44.5%). Odds of not receiving a complete care bundle were increased for
participants lacking diabetes self-management knowledge (OR=2.05), having poorer cognitive
performance (OR=1.78) or having previously received incomplete care (OR=3.32). Participants who
were single (OR=2.16), had with low health literacy (OR=1.50) and who had received incomplete care
previously (OR=6.94) were less likely to subsequently be offered ACE inhibitors/receptor blockers,
whereas trend test showed that being older (OR=0.76) and increased BMI categorisation (OR=0.70)
improved odds of receiving this aspect of care.
Conclusions
Quality improvement initiatives for diabetes might usefully target patients with characteristics shown
here to predict non-receipt of indicated care, such as poor knowledge of annual diabetes care
processes or previous receipt of incomplete care.

AIMS/HYPOTHESIS: the aim of this work was to test whether the mid-adolescent peak in insulin resistance (IR) and trends in other metabolic markers are influenced by long-term exposure to physical activity. METHODS: Physical activity (7 day ActiGraph accelerometry), HOMA-IR and other metabolic markers (glucose, fasting insulin, HbA1c, lipids and BP) were measured annually from age 9 years to 16 years in 300 children (151 boys) from the EarlyBird study in Plymouth, UK. The activity level of each child was characterised, with 95% reliability, by averaging their eight annual physical activity measures. Age-related trends in IR and metabolic health were analysed by multi-level modelling, with physical activity as the exposure measure (categorical and continuous) and body fat percentage (assessed by dual-energy X-ray absorptiometry) and pubertal status (according to age at peak height velocity and Tanner stage) as covariates. RESULTS: the peak in IR at age 12-13 years was 17% lower (p < 0.001) in the more active adolescents independently of body fat percentage and pubertal status. However, this difference diminished progressively over the next 3 years and had disappeared completely by the age of 16 years (e.g. difference was -14% at 14 years, -8% at 15 years and +1% at 16 years; 'physical activity × age(2), interaction, p < 0.01). Triacylglycerol levels in girls (-9.7%, p = 0.05) and diastolic blood pressure in boys (-1.20 mmHg, p = 0.03) tended to be lower throughout adolescence in the more active group. CONCLUSIONS/INTERPRETATION: Our finding that physical activity attenuates IR during mid-adolescence may be clinically important. It remains to be established whether the temporary attenuation in IR during this period has implications for the development of diabetes in adolescence and for future metabolic health generally.

BACKGROUND: US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. OBJECTIVE: to investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. METHODS: We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests a and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. RESULTS: the multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73-0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail-Making Tests a (RR = 0.85, 95% CI 0.71-1.02) and B (RR = 0.90, 0.79-1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. CONCLUSIONS: High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians.

BackgroundShortfalls in the receipt of recommended health care have been previously reported in England, leading to preventable poor health.ObjectivesTo assess changes over 6 years in the receipt of effective health-care interventions for people aged 50 years or over in England with cardiovascular disease, depression, diabetes or osteoarthritis; to identify how quality varied with participant characteristics; and to compare the distribution of illness burden in the population with the distributions of diagnosis and treatment.Setting and participantsInformation on health-care quality indicators and participant characteristics was collected using face-to-face structured interviews and nurse visits in participants’ homes by the English Longitudinal Study of Ageing in 2004–5, 2006–7, 2008–9 and 2010–11. A total of 16,773 participants aged 50 years or older were interviewed at least once and 5114 were interviewed in all four waves; 5404 reported diagnosis of one or more of four conditions in 2010–11.Main outcome measuresPercentage of indicated health care received by eligible participants for 19 quality indicators: seven for cardiovascular disease, three for depression, five for diabetes and four for osteoarthritis, and condition-level quality indicator achievement, including achievement of a bundle of three diabetes indicators.AnalysisChanges in quality indicator achievement over time and variations in quality with participant characteristics were tested with Pearson’s chi-squared test and logistic regression models. The size of inequality between the hypothetically wealthiest and poorest participants, for illness burden, diagnosis and treatment, was estimated using slope indices of wealth inequality.ResultsAchievement of indicators for cardiovascular disease was 82.7% [95% confidence interval (CI) 79.9% to 85.5%] in 2004–5 and 84.2% (95% CI 82.1% to 86.2%) in 2010–11, for depression 63.3% (95% CI 57.6% to 69.0%) and 59.8% (95% CI 52.4% to 64.3%), for diabetes 76.0% (95% CI 74.1% to 77.8%) and 76.5% (95% CI 74.8% to 78.1%), and for osteoarthritis 31.2% (95% CI 28.5% to 33.8%) and 35.6% (95% CI 34.2% to 37.1%). Achievement of the diabetes care bundle was 67.8% (95% CI 64.5% to 70.9%) in 2010–11. Variations in quality by participant characteristics were generally small. Diabetes indicator achievement was worse in participants with cognitive impairment [odds ratio (OR) 0.5, 95% CI 0.4 to 0.7] and better in those living alone (OR 1.7, 95% CI 1.3 to 2.0). Hypertension care was better for those aged over 74 years (vs. 50–64 years) (OR 3.2, 95% CI 2.0 to 5.3). Osteoarthritis care was better for those with severe (vs. mild) pain (OR 1.8, 95% CI 1.4 to 2.2), limiting illness (OR 1.8, 95% CI 1.5 to 2.1), and obesity (OR 1.6, 95% CI 1.2 to 2.0). Previous non-achievement of the diabetes care bundle was the biggest predictor of non-achievement 2 years later (OR 3.3, 95% CI 2.2 to 4.7). Poorer participants were always more likely than wealthier participants to have illness burden (statistically significant OR 3.9 to 16.0), but not always more likely to be diagnosed or receive treatment (0.2 to 5.3).ConclusionsShortfalls in quality of care for these four conditions have persisted over 6 years, with only half of the level of indicated health care achieved for osteoarthritis, compared with the other three conditions. Quality for osteoarthritis improved slightly over time but remains poor. The relatively high prevalence of specific illness burden in poorer participants was not matched by an equally high prevalence of diagnosis or treatment, suggesting that barriers to equity may exist at the stage at diagnosis. Further research is needed into the association between quality and health system characteristics at the level of clinicians, general practices or hospitals, and regions. Linkage to routinely collected data could provide information on health service characteristics at the individual patient level.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

BACKGROUND: School exclusion is a disciplinary method used to remove a child from the school environment. It is known to affect certain groups disproportionately, including boys, some ethnic minorities, children in care, children in poverty, and children with special educational needs. Population-based studies on wider characteristics of excluded pupils are scarce. The aim of this study was to describe factors associated with school exclusion in the Avon Longitudinal Study of Parents and Children (ALSPAC), focussing on neurodevelopment and mental health. METHODS: ALSPAC is a prospective population-based British birth cohort study, with the initial sample consisting of 14 541 pregnancies. The study has data for whether a child has been permanently excluded from school up to the age of 8 years as reported by parents and also permanent and fixed period exclusions in the preceding 12 months as reported by parents and young people at age 16 years. Upstream risk factors were assessed for associations with exclusion on univariable analysis. The association with social communication difficulties was investigated with multivariable logistic regression. FINDINGS: Data for exclusions up to the age of 8 years were available for 8245 ALSPAC participants and 4482 participants for exclusion at age 16 years. 53 pupils (0·6%) were excluded from school by age 8 years, and 390 (8·7%) at age 16 years. The odds of exclusion by 8 years and at 16 years were increased with male sex (p=0·001 and p

OBJECTIVE: the aim of this study is to examine whether there is a differential impact of primary schools upon children's weight status. METHODS: a repeated cross-sectional study was undertaken using five years (2006/07-2010/11) of National Child Measurement Programme data, comprising 57,976 children (aged 4-5 (Reception) and 10-11 (Year 6) years) from 300 primary schools across Devon, England. Examining each year separately, the schools were ranked according to their observed and residual (having accounted for school and neighbourhood clustering and pupil ethnicity and socioeconomic status) school mean body mass index standard deviation score (BMI-SDS). Subtracting the Reception from the Year 6 mean residuals gave 'value-added' scores for each school which were also ranked. The rankings were compared within and across the years to assess consistency. RESULTS: Although pupil BMI-SDS was high, >97% of the variation in BMI-SDS was attributable to environments other than the school. The 'value-added' by each school was only poorly correlated with the observed and residual pupil BMI-SDS; but none of the rankings were consistent across the five years. CONCLUSION: the inconsistency of the rankings and the small variation in BMI-SDS at the level of the school suggests that there is no systematic differential impact of primary schools upon pupil weight status.

Background Parental longevity confers lower risks for some age-related diseases in offspring. We tested the association between parental longevity and late-life cognitive decline or dementia.

OBJECTIVES: to determine the effectiveness of enzyme replacement therapy (ERT) for adults with late-onset Pompe disease. DESIGN: a longitudinal cohort study including prospective and retrospective clinical outcome data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 62) with a diagnosis of late-onset Pompe disease who attended a specialist treatment centre in England. This cohort represented 83 % of all patients in the UK with a confirmed diagnosis of this rare condition. At study entry, all but three patients were receiving ERT (range of treatment duration, 0 to 3.1 years). OUTCOME MEASURES: Percent predicted forced vital capacity (%FVC); ventilation dependency; mobility; 6 min walk test (6MWT); muscle strength and body mass index (BMI). RESULTS: an association was found between time on ERT and significant increases in the distance walked in the 6MWT (p 

AIMS: Defining responders to glucose lowering therapy can be important for both clinical care and for the development of a stratified approach to diabetes management. Response is commonly defined by either HbA1c change after treatment or whether a target HbA1c is achieved. We aimed to determine the extent to which the individuals identified as responders and non-responders to glucose lowering therapy, and their characteristics, depend on the response definition chosen. METHODS: We prospectively studied 230 participants commencing GLP-1 agonist therapy. We assessed participant characteristics at baseline and repeated HbA1c after 3 months treatment. We defined responders (best quartile of response) based on HbA1c change or HbA1c achieved. We assessed the extent to which these methods identified the same individuals and how this affected the baseline characteristics associated with treatment response. RESULTS: Different definitions of response identified different participants. Only 39% of responders by one definition were also good responders by the other. Characteristics associated with good response depend on the response definition chosen: good response by HbA1c achieved was associated with low baseline HbA1c (p

Background: Child and Adolescent Mental Health services (CAMHS) might benefit from the use of structured diagnostic assessments as an adjunct to clinical assessment. Such assessments will only support clinical practice if their completion avoids too great a burden to parents and services, and if the resulting information is useful to practitioners. Method: Parents were asked to complete the Development and Well-Being Assessment (DAWBA) before their initial appointment at a community CAMHS, and DAWBAs were disclosed to the assessing practitioners in a random half of cases. Parents and Practitioners were asked to complete a questionnaire about their experience of the DAWBA. Parents completed the experience of services questionnaire 6 months after the baseline. Results: Most parents found the interview easy to understand. Many reported that the experience of completing the interview changed the way that they thought about their child's difficulties in a positive manner. Practitioner reports were also mainly positive. The mean helpfulness score adjusted for the clustering of cases within practitioners out of 1-5 for very unhelpful to very helpful was 4.04 (95% Confidence Interval: 3.89-4.18). There was no association between practitioner access to the DAWBA and parent reported satisfaction on the Experiences of Services Questionnaire (mean difference 0.74, 95% confidence interval -0.59-02.06, p0.27). Conclusions: with the right supporting arrangements in place, the DAWBA would be a feasible assessment tool in community CAMHS. © 2013 Association for Child and Adolescent Mental Health.

OBJECTIVES: to determine the effectiveness of enzyme replacement therapy (ERT) for adults and children with Fabry disease. DESIGN: Cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment and untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 289) and children (N = 22) with a confirmed diagnosis of Fabry disease attending a specialist Lysosomal Storage Disorder treatment centre in England. At recruitment 211 adults and seven children were on ERT (range of treatment duration, 0 to 9.7 and 0 to 4.2 years respectively). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression included left ventricular mass index (LVMI); proteinuria; estimated glomerular filtration rate (eGFR); pain; hearing and transient ischaemic attacks (TIA)/stroke. RESULTS: We found evidence of a statistically significant association between time on ERT and a small linear decrease in LVMI (p = 0.01); a reduction in the risk of proteinuria after adjusting for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (p 

OBJECTIVES: to determine the effectiveness of enzyme replacement therapies (ERT) for adults with Gaucher disease (GD). DESIGN: a longitudinal, multi-centre cohort study, including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 150, aged 16 to 83 years) with a diagnosis of GD who attended a specialist treatment centre in England. At recruitment, 131 patients were receiving ERT (mean treatment duration, 10.8 years; range 0-18 years). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin; absence/presence of bone pain; spleen and liver volumes and AST levels. RESULTS: One hundred and fifty adults were recruited. Duration of ERT was associated with statistically significant improvements in platelet count (p 

OBJECTIVES: to determine the effectiveness of enzyme replacement therapies (ERT) for children with Gaucher disease (GD). DESIGN: a longitudinal cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Children on treatment contributed data before and during treatment. Children not on treatment contributed natural history data. PARTICIPANTS: Consenting children (N = 25, aged 1.1 to 15.6 years) with a diagnosis of GD (14 with GD1 and 11 with GD3) who attended a specialist treatment centre in England. At recruitment, 24 patients were receiving ERT (mean treatment duration, 5.57 years; range 0-13.7 years). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin and absence/presence of bone pain. RESULTS: Duration of ERT was associated with statistically significant improvements in platelet count (p 

BACKGROUND: little is known about changes in the quality of medical care for older adults over time. OBJECTIVE: to assess changes in technical quality of care over 6 years, and associations with participants' characteristics. DESIGN: a national cohort survey covering RAND Corporation-derived quality indicators (QIs) in face-to-face structured interviews in participants' households. PARTICIPANTS: a total of 5,114 people aged 50 or more in four waves of the English Longitudinal Study of Ageing. METHODS: the percentage achievement of 24 QIs in 10 general medical and geriatric clinical conditions was calculated for each time point, and associations with participants' characteristics were estimated using logistic regression. RESULTS: participants were eligible for 21,220 QIs. QI achievement for geriatric conditions (cataract, falls, osteoarthritis and osteoporosis) was 41% [95% confidence interval (CI): 38-44] in 2004-05 and 38% (36-39) in 2010-11. Achievement for general medical conditions (depression, diabetes mellitus, hypertension, ischaemic heart disease, pain and cerebrovascular disease) improved from 75% (73-77) in 2004-05 to 80% (79-82) in 2010-11. Achievement ranged from 89% for cerebrovascular disease to 34% for osteoarthritis. Overall achievement was lower for participants who were men, wealthier, infrequent alcohol drinkers, not obese and living alone. CONCLUSION: substantial system-level shortfalls in quality of care for geriatric conditions persisted over 6 years, with relatively small and inconsistent variations in quality by participants' characteristics. The relative lack of variation by participants' characteristics suggests that quality improvement interventions may be more effective when directed at healthcare delivery systems rather than individuals.

Lysosomal storage disorders (LSDs) comprise more than 50 extremely rare, inherited metabolic diseases resulting from a deficiency of specific lysosomal enzymes required for normal macromolecular metabolism. The National Collaborative Study for Lysosomal Storage Disorders (NCS-LSD), was a longitudinal cohort study which collected prospective and retrospective clinical data, and patient-reported data from adults and children with a confirmed diagnosis of Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann Pick disease type C (NPC) in the UK. The study aimed to determine the natural history of these conditions and estimate the effectiveness and cost of therapies. Clinical outcomes were chosen to reflect disease progression. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment while untreated patients contributed natural history data. A total of 711 adults and children were recruited to this study from the seven LSD treatment centres in England. Data was collected from 2008 to 2011. This paper describes the methods used to collect and analyse clinical data for this study. The clinical findings are reported separately in a series of condition-specific articles in this issue.

OBJECTIVE: to investigate the psychometric properties of the Work and Social Adjustment Scale (WSAS) as an outcome measure for the Improving Access to Psychological Therapy programme, assessing its value as an addition to the Patient Health (PHQ-9) and Generalised Anxiety Disorder questionnaires (GAD-7). Little research has investigated these properties to date. METHODS: Reliability and responsiveness to change were assessed using data from 4,835 patients. Principal components analysis was used to determine whether the WSAS measures a factor distinct from the PHQ-9 and GAD-7. RESULTS: the WSAS measures a distinct social functioning factor, has high internal reliability, and is sensitive to treatment effects. CONCLUSIONS: the WSAS, PHQ-9 and GAD-7 perform comparably on measures of reliability and sensitivity. The WSAS also measures a distinct social functioning component suggesting it has potential as an additional outcome measure.

OBJECTIVE: to determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease. METHODS: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria. RESULTS: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (

Low level chronic exposure to toxicants is associated with a range of adverse health effects. Understanding the various factors that influence the chemical burden of an individual is of critical importance to public health strategies. We investigated the relationships between socioeconomic status (SES) and bio-monitored chemical concentration in five cross-sectional waves of the U.S. National Health and Nutrition Examination Survey (NHANES). We utilised adjusted linear regression models to investigate the association between 179 toxicants and the poverty income ratio (PIR) for five NHANES waves. We then selected a subset of chemicals associated with PIR in 3 or more NHANES waves and investigated potential mediating factors using structural equation modelling. PIR was associated with 18 chemicals in 3 or more NHANES waves. Higher SES individuals had higher burdens of serum and urinary mercury, arsenic, caesium, thallium, perfluorooctanoic acid, perfluorononanoic acid, mono(carboxyoctyl) phthalate and benzophenone-3. Inverse associations were noted between PIR and serum and urinary lead and cadmium, antimony, bisphenol a and three phthalates (mono-benzyl, mono-isobutyl, mono-n-butyl). Key mediators included fish and shellfish consumption for the PIR, mercury, arsenic, thallium and perfluorononanoic acid associations. Sunscreen use was an important mediator in the benzophenone-3/PIR relationship. The association between PIR and cadmium or lead was partially mediated by smoking, occupation and diet. These results provide a comprehensive analysis of exposure patterns as a function of socioeconomic status in US adults, providing important information to guide future public health remediation measures to decrease toxicant and disease burdens within society.

Summary: Omission of relevant covariates can lead to bias when estimating treatment or exposure effects from survival data in both randomized controlled trials and observational studies. This paper presents a general approach to assessing bias when covariates are omitted from the Cox model. The proposed method is applicable to both randomized and non-randomized studies. We distinguish between the effects of three possible sources of bias: omission of a balanced covariate, data censoring and unmeasured confounding. Asymptotic formulae for determining the bias are derived from the large sample properties of the maximum likelihood estimator. A simulation study is used to demonstrate the validity of the bias formulae and to characterize the influence of the different sources of bias. It is shown that the bias converges to fixed limits as the effect of the omitted covariate increases, irrespective of the degree of confounding. The bias formulae are used as the basis for developing a new method of sensitivity analysis to assess the impact of omitted covariates on estimates of treatment or exposure effects. In simulation studies, the proposed method gave unbiased treatment estimates and confidence intervals with good coverage when the true sensitivity parameters were known. We describe application of the method to a randomized controlled trial and a non-randomized study. © 2013 the Authors. Biometrics published by the International Biometric Society.

Purpose: While research demands standardized diagnostic assessments as an indication of sufficient methodological rigour, there is debate about their application to clinical practice. The Development and Well-Being Assessment (DAWBA) provides a structured assessment of psychiatric disorder. Since it can be completed on-line, it could be used by Child and Adolescent Mental Health Services with few additional demands on staff. Access to the standardized diagnostic information as an adjunct to clinical assessment could reduce the number of appointments spent on assessment, free up practitioner time to work on engagement and improve clinical outcomes by increasing the accuracy of assessment and thus access to the appropriate evidence-based treatment. Method: Randomized controlled trial of the disclosure of the DAWBA to the assessing practitioner (n = 117) versus assessment at normal (n = 118) and analysed by "intention to disclose". Results: Exposure to the DAWBA may increase agreement between the DAWBA and practitioners about some anxiety disorders, but detected no other statistically significant increased agreement for other disorders, nor a reduced need for further assessment, the number of difficulties recognised or influence on outcomes. Conclusions: the results may be explained by the inadequacy of the DAWBA, lack of statistical power to detect any effects that were present or a reluctance of some practitioners to use the DAWBA in their assessment. Future research might benefit from exploring the use of the DAWBA or similar assessments as a referral rather than an assessment tool, and exploring how practitioners and parents experience and use the DAWBA and what training might optimise the utility of the DAWBA to clinical practice. © 2012 Springer-Verlag.

Locally acquired HEV infection is increasingly recognized in developed countries. Anti-HEV IgG seroprevalence has been shown to be high in haemodialysis patients in a number of previous studies, employing assays of uncertain sensitivity. The aim of this study was to investigate anti-HEV IgG seroprevalence in recipients of haemodialysis and renal transplants compared to a control group using a validated, highly sensitive assay. Eighty-eight patients with functioning renal transplants and 76 receiving chronic haemodialysis were tested for HEV RNA and anti-HEV IgG and IgM. Six hundred seventy controls were tested for anti-HEV IgG. Anti-HEV IgG was positive in 28/76 (36.8%) of haemodialysis and 16/88 (18.2%) of transplant patients. HEV RNA was not found in any patient. 126/670 (18.8%) of control subjects were anti-HEV IgG positive. After adjusting for age and sex, there was a significantly higher anti-HEV IgG seroprevalence amongst haemodialysis patients compared to controls (OR=1.97, 95% CI=1.16-3.31, P=0.01) or transplant recipients (OR=2.63, 95% CI=1.18-6.07, P=0.02). Patients with a functioning transplant showed no difference in anti-HEV IgG seroprevalence compared to controls. The duration of haemodialysis or receipt of blood products were not significant risk factors for HEV IgG positivity. Patients receiving haemodialysis have a higher seroprevalence of anti-HEV IgG than both age- and sex-matched controls and a cohort of renal transplant patients. None of the haemodialysis patients had evidence of chronic infection. The reason haemodialysis patients have a high seroprevalence remains uncertain and merits further study. J. Med. Virol. 85:266-271, 2013. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

BACKGROUND: Children of centenarians have lower cardiovascular disease prevalence and live longer. We aimed to estimate associations between the full range of parental attained ages and health status in a middle-aged U.S. representative sample. METHODS: Using Health and Retirement Study data, models estimated disease incidence and mortality hazards for respondents aged 51-61 years at baseline, followed up for 18 years. Full adjustment included sex, race, smoking, wealth, education, body mass index, and childhood socioeconomic status. Mother's and father's attained age distributions were used to define short-, intermediate-, and long-lived groups, yielding a ranked parental longevity score (n = 6,055, excluding short-long discordance). Linear models (n = 8,340) tested mother's or father's attained ages, adjusted for each other. RESULTS: with increasing mother's or father's survival (>65 years), all-cause mortality declined 19% (hazard ratio [HR] = 0.81, 95% CI: 0.76-0.86, p <. 001) and 14% per decade (HR = 0.87, 95% CI: 0.81-0.92, p <. 001). Estimates changed only modestly when fully adjusted. Parent-in-law survival was not associated with mortality (n = 1,809, HR = 1.00, 95% CI: 0.90-1.12, p =. 98). Offspring with one or two long-lived parents had lower cancer incidence (938 cases, HR per parental longevity score = 0.76, 95% CI: 0.61-0.94, p =. 01) versus two intermediate parents. Similar HRs for diabetes (HR = 0.89, 95% CI: 0.84-0.96, p =. 001), heart disease (HR = 0.88, 95% CI: 0.82-0.93, p <. 001), and stroke (HR = 0.86, 95% CI: 0.78-0.95, p =. 002) were significant, but there was no trend for arthritis. CONCLUSIONS: the results provide the first robust evidence that increasing parental attained age is associated with lower cancer incidence in offspring. Health advantages of having centenarian parents extend to a wider range of parental longevity and may provide a quantitative trait of slower aging.

Background: Depression could be considered to be on a continuum with well-being and some have argued that it is important to measure well-being as well as distress. The Everyday Feelings Questionnaire was designed to measure both these aspects. Its validity has been assessed in a nonclinical population. This project aims to assess the validity and reliability of the EFQ in a clinical population. Methods: the EFQ was completed by 105 clients within a mental health clinical setting. The following aspects of the EFQ were explored: its internal structure, concurrent validity, re-test reliability and internal consistency. Results: the EFQ had good internal consistency and correlated highly with other measures of anxiety and depression. The correlation between total EFQ scores on the two occasions was reasonable and there was no effect of time during completion. A Bland-Altman plot showed no obvious pattern between the difference between EFQ scores and the mean score. A one factor model showed a moderate fit to the data. Limitations: This study does not explore the acceptability or sensitivity to change of the EFQ, and a larger sample size would be needed to extend the analysis conducted. Conclusions: the EFQ is a valid and reliable measure when used in this clinical population. © 2012 Elsevier B.V.

We have previously described a statistical model capable of distinguishing young (age

OBJECTIVES: to estimate the association between uric acid and cardiovascular mortality in older adults, independent of traditional risk factors, and to estimate the risk prediction gain by adding uric acid measurements to the Framingham Cardiovascular Risk Score (FCRS). DESIGN: Longitudinal observational study of two population-based cohorts. SETTING: the Established Populations for Epidemiologic Studies of the Elderly, Iowa (Iowa-EPESE) and the Third National Health and Nutritional Examination Survey (NHANES III). PARTICIPANTS: One thousand twenty-eight Iowa-EPESE participants and 1,316 NHANES III participants. Selected participants were aged 70 and older without overt cardiovascular disease, renal dysfunction, or diuretic use who lived for 3 years or longer after baseline. MEASUREMENTS: Outcome was age at cardiovascular death during follow-up (12–20 years). Uric acid and cardiovascular risk factors such as smoking, systolic blood pressure, diabetes mellitus, obesity, serum cholesterol, and high-density lipoprotein cholesterol were measured at baseline. RESULTS: High serum uric acid (>7.0 mg/dL) was associated with male sex, obesity, lipid levels, and estimated glomerular filtration rate at baseline. Fully adjusted hazard ratios (HRs) for cardiovascular death with high uric acid versus normal were 1.36 (95% confidence interval (CI) = 1.10–1.69) in Iowa-EPESE and 1.43 (95% CI = 1.04–1.99) in NHANES III; pooled HR was 1.38 (95% CI = 1.16–1.61). The net reclassification improvement achieved by adding uric acid measurement to the FCRS was 9% to 20%. CONCLUSION: in individuals aged 70 and older without overt CVD, renal dysfunction, or diuretic use, serum uric acid greater than 7.0 mg/dL was associated with greater CVD mortality independent of classic CVD risk factors. Adding uric acid measurement to the FCRS would improve prediction in older adults.

Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β)-triggered macrophage-mediated muscle fiber regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population. We undertook a genome-wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (aged 30 and 104). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery (SPPB) score tested walk speed, chair stand, and balance. CEBPB expression levels were associated with muscle strength (β coefficient = 0.20560, P = 1.03*10(-6), false discovery rate q = 0.014). The estimated handgrip strength in 70-year-old men in the lowest CEBPB expression tertile was 35.2 kg compared with 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle, and shoulder strength and the SPPB score (P = 0.018). Near-study-wide associations were also noted for TGF-β3 (P = 3.4*10(-5) , q = 0.12) and CEBPD expression (P = 9.7*10(-5) , q = 0.18) but not for CEBPA expression. We report here a novel finding that raised CEBPB expression in circulating leukocyte-derived RNA samples in vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB-triggered muscle repair: if this mechanism is confirmed, it may provide a target for intervention to protect and enhance aging muscle.

The clinical presentation and progression (over 9 months to 13 years) of congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID) in the Cavalier King Charles spaniel dog are described for six new cases and six previously described cases. Cases presented with a congenitally abnormal (rough/curly) coat and signs of KCS from eyelid opening. Persistent scale along the dorsal spine and flanks with a harsh frizzy and alopecic coat was evident in the first few months of life. Ventral abdominal skin was hyperpigmented and hyperkeratinized in adulthood. Footpads were hyperkeratinized from young adulthood with nail growth abnormalities and intermittent sloughing. Long-term follow-up of cases (13/25) is described. Immunomodulatory/lacrimostimulant treatment had no statistically significant effect on Schirmer tear test results, although subjectively, this treatment reduced progression of the keratitis. Histopathological analysis of samples (skin/footpads/lacrimal glands/salivary glands) for three new cases was consistent with an ichthyosiform dermatosis, with no pathology of the salivary or lacrimal glands identified histologically. Pedigree analysis suggests the syndrome is inherited by an autosomal recessive mode.

[This corrects the article on p. e43378 in vol. 7.].

Objective: to determine whether, and to what extent, physical activity interventions affect the overall activity levels of children. Design: Systematic review and meta-analysis. Data sources: Electronic databases (Embase, Medline, PsycINFO, SPORTDiscus) and reference lists of included studies and of relevant review articles. Study selection: Design: randomised controlled trials or controlled clinical trials (cluster and individual) published in peer reviewed journals. Intervention: incorporated a component designed to increase the physical activity of children/adolescents and was at least four weeks in duration. Outcomes: measured whole day physical activity objectively with accelerometers either before or immediately after the end of the intervention period. Data analysis: Intervention effects (standardised mean differences) were calculated for total physical activity, time spent in moderate or vigorous physical activity, or both for each study and pooled using a weighted random effects model. Meta-regression explored the heterogeneity of intervention effects in relation to study participants, design, intervention type, and methodological quality. Results: Thirty studies (involving 14 326 participants; 6153 with accelerometer measured physical activity) met the inclusion criteria and all were eligible for meta-analysis/meta-regression. The pooled intervention effect across all studies was small to negligible for total physical activity (standardised mean difference 0.12, 95% confidence interval 0.04 to 0.20; P

INTRODUCTION: Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample. METHODS: We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models. RESULTS: in genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta=-0.16, p=5.1×10(-6), false discovery rate (FDR; q=0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta=-0.16, p=5.1×10(-6), q=0.003; and beta=-0.13, p=5.5×10(-5), q=0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype. CONCLUSIONS: We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated β-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.

BACKGROUND: the endocrine-disrupting chemical bisphenol a (BPA) is widely used in food and beverage packaging. Higher urinary BPA concentrations were cross-sectionally associated with heart disease in National Health and Nutrition Examination Survey (NHANES) 2003-2004 and NHANES 2005-2006, independent of traditional risk factors. METHODS AND RESULTS: We included 758 incident coronary artery disease (CAD) cases and 861 controls followed for 10.8 years from the European Prospective Investigation of Cancer-Norfolk UK. Respondents aged 40 to 74 years and free of CAD, stroke, or diabetes mellitus provided baseline spot urine samples. Urinary BPA concentrations (median value, 1.3 ng/mL) were low. Per-SD (4.56 ng/mL) increases in urinary BPA concentration were associated with incident CAD in age-, sex-, and urinary creatinine-adjusted models (n=1919; odds ratio=1.13; 95% confidence interval, 1.02-1.24; P=0.017). With CAD risk factor adjustment (including education, occupational social class, body mass index category, systolic blood pressure, lipid concentrations, and exercise), the estimate was similar but narrowly missed 2-sided significance (n=1744; odds ratio=1.11; 95% confidence interval, 1.00-1.23; P=0.058). Sensitivity analyses with the fully adjusted model, excluding those with early CAD (30, or abnormal renal function or with additional adjustment for vitamin C, C-reactive protein, or alcohol consumption, all produced similar estimates, and all showed associations at P≤0.05. CONCLUSIONS: Associations between higher BPA exposure (reflected in higher urinary concentrations) and incident CAD during >10 years of follow-up showed trends similar to previously reported cross-sectional findings in the more highly exposed NHANES respondents. Further work is needed to accurately estimate the prospective exposure-response curve and to establish the underlying mechanisms.

BACKGROUND: Bisphenol a is widely used in food and drinks packaging. There is evidence of associations between raised urinary bisphenol a (uBPA) and increased incidence of reported cardiovascular diagnoses. METHODOLOGY/PRINCIPAL FINDINGS: to estimate associations between BPA exposure and angiographically graded coronary atherosclerosis. 591 patients participating in the Metabonomics and Genomics in Coronary Artery Disease (MaGiCAD) study in Cambridgeshire UK, comparing urinary BPA (uBPA) with grades of severity of coronary artery disease (CAD) on angiography. Linear models were adjusted for BMI, occupational social class and diabetes status. Severe (one to three vessel) CAD was present in 385 patients, 86 had intermediate disease (n=86) and 120 had normal coronary arteries. The (unadjusted) median uBPA concentration was 1.28 ng/mL with normal coronary arteries, and 1.53 ng/mL with severe CAD. Compared to those with normal coronary arteries, uBPA concentration was significantly higher in those with severe CAD (OR per uBPA SD=5.96 ng/ml OR=1.43, CI 1.03 to 1.98, p=0.033), and near significant for intermediate disease (OR=1.69, CI 0.98 to 2.94, p=0.061). There was no significant uBPA difference between patients with severe CAD (needing surgery) and the remaining groups combined. CONCLUSIONS/SIGNIFICANCE: BPA exposure was higher in those with severe coronary artery stenoses compared to those with no vessel disease. Larger studies are needed to estimate true dose response relationships. The mechanisms underlying the association remain to be established.

Objectives: to compare the effectiveness of an exercise programme with usual care in people with Parkinson's disease (PD) who have a history of falls. Design: Pragmatic randomised controlled trial. Setting: Recruitment was from three primary and four secondary care organisations, and PD support groups in South West England. The intervention was delivered in community settings. Participants: People with PD, with a history of two or more falls in the previous year, who were able to mobilise independently. Intervention: 10 week, physiotherapy led, group delivered strength and balance training programme with supplementary home exercises (intervention) or usual care (control). Main outcome measure: Number of falls during the (a) 10 week intervention period and (b) the 10 week followup period. Results: 130 people were recruited and randomised (64 to the intervention; 66 to usual care). Seven participants (5.4%) did not complete the study. The incidence rate ratio for falls was 0.68 (95% CI 0.43 to 1.07, p=0.10) during the intervention period and 0.74 (95% CI 0.41 to 1.33, p=0.31) during the follow-up period. Statistically significant between group differences were observed in Berg balance, Falls Efficacy Scale-International scores and recreational physical activity levels. Conclusions: the study did not demonstrate a statistically significant between group difference in falls although the difference could be considered clinically significant. However, a type 2 error cannot be ruled out. The findings from this trial add to the evidence base for physiotherapy and exercise in the management of people with PD. Trial registration: ISRCTN50793425.

BACKGROUND: Bisphenol a (BPA) is a synthetic estrogen commonly used in polycarbonate plastic and resin-lined food and beverage containers. Exposure of animal and cell models to doses of BPA below the recommended tolerable daily intake (TDI) of 50 μg/kg/day have been shown to alter specific estrogen-responsive gene expression, but this has not previously been shown in humans. OBJECTIVE: We investigated associations between BPA exposure and in vivo estrogenic gene expression in humans. METHODS: We studied 96 adult men from the InCHIANTI population study and examined in vivo expression of six estrogen receptor, estrogen-related receptor, and androgen receptor genes in peripheral blood leukocytes. RESULTS: the geometric mean urinary BPA concentration was 3.65 ng/mL [95% confidence interval (CI): 3.13, 4.28], giving an estimated mean excretion of 5.84 μg/day (95% CI: 5.00, 6.85), significantly below the current TDI. In age-adjusted models, there were positive associations between higher BPA concentrations and higher ESR2 [estrogen receptor 2 (ER beta)] expression (unstandardized linear regression coefficient = 0.1804; 95% CI: 0.0388, 0.3221; p = 0.013) and ESRRA (estrogen related receptor alpha) expression (coefficient = 0.1718; 95% CI: 0.0213, 0.3223; p = 0.026): These associations were little changed after adjusting for potential confounders, including obesity, serum lipid concentrations, and white cell subtype percentages. Upper-tertile BPA excretors (urinary BPA > 4.6 ng/mL) had 65% higher mean ESR2 expression than did lower-tertile BPA excretors (0-2.4 ng/mL). CONCLUSIONS: Because activation of nuclear-receptor-mediated pathways by BPA is consistently found in laboratory studies, such activation in humans provides evidence that BPA is likely to function as a xenoestrogen in this sample of adults.

BACKGROUND: facing the costs of population ageing, many governments aim to keep older people in employment for longer. Summary health measures predict early retirement, but more specific symptoms and conditions need to be identified to guide efforts to delay retirement. OBJECTIVE: to identify common symptoms and conditions that predict early work exit, at the population level. DESIGN: cohort study of community dwelling respondents to the English Longitudinal Study of Ageing. SETTING AND PARTICIPANTS: a total of 1,693 workers aged 50 and over at baseline who were younger than the contemporaneous retirement age (60 for women, 65 for men) at 4-year follow-up. RESULTS: a total of 308 (18.2%) individuals moved out of employment during the follow-up period. Advancing age, female gender, partner retirement, greater pension wealth, high alcohol consumption and fair or poor self-rated health were all associated with work exit. Accounting for these factors, reported difficulty walking a quarter mile was predictive of early work exit (odds ratio (OR) = 2.23; 95% confidence interval (CI) 1.42-3.52), especially where symptoms included lower limb pain and/or shortness of breath. Symptomatic depression (measured by Centre for Epidemiological Studies Depression scale) was also predictive of early work exit (OR = 1.52, CI 1.07, 2.18). About 50.8% of early retirees reported one or more of these specific health symptoms (depression, general pain, mobility limitations and leg pain when walking). CONCLUSION: older workers who report depressive symptoms or impaired physical mobility, especially with lower limb pain and shortness of breath, are at increased risk of early transition out of work. Health interventions targeting these conditions may enable older workers to remain in the labour force.

OBJECTIVE: to establish in children whether inactivity is the cause of fatness or fatness the cause of inactivity. DESIGN: a non-intervention prospective cohort study examining children annually from 7 to 10 years. Baseline versus change to follow-up associations were used to examine the direction of causality. SETTING: Plymouth, England. PARTICIPANTS: 202 children (53% boys, 25% overweight/obese) recruited from 40 Plymouth primary schools as part of the EarlyBird study. MAIN OUTCOME MEASURES: Physical activity (PA) was measured using Actigraph accelerometers. The children wore the accelerometers for 7 consecutive days at each annual time point. Two components of PA were analysed: the total volume of PA and the time spent at moderate and vigorous intensities. Body fat per cent (BF%) was measured annually by dual energy x ray absorptiometry. RESULTS: BF% was predictive of changes in PA over the following 3 years, but PA levels were not predictive of subsequent changes in BF% over the same follow-up period. Accordingly, a 10% higher BF% at age 7 years predicted a relative decrease in daily moderate and vigorous intensities of 4 min from age 7 to 10 years (r=-0.17, p=0.02), yet more PA at 7 years did not predict a relative decrease in BF% between 7 and 10 years (r=-0.01, p=0.8). CONCLUSIONS: Physical inactivity appears to be the result of fatness rather than its cause. This reverse causality may explain why attempts to tackle childhood obesity by promoting PA have been largely unsuccessful.

INTRODUCTION: in developed countries autochthonous hepatitis E infection is caused by hepatitis E virus (HEV) genotype 3 or 4 and mainly affects middle aged/elderly men. Host factors might explain why older men develop clinically overt disease. METHODS: Retrospective review of 53 patients with symptomatic autochthonous hepatitis E infection to determine putative host risk factors. Patients were compared with 564 controls with adjustment for age and sex. Anti-HEV seroprevalence was determined in controls and 189 patients with chronic liver disease. RESULTS: Mean age of the patients was 62.4 years, 73.6% were men. Compared with controls, patients with hepatitis E were more likely to drink at least 22 U alcohol/week (OR=9.4; 95% confidence interval=3.8-25.0; P

Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30-104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n= 58), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P

BACKGROUND: Mean costs and quality-adjusted-life-years are central to the cost-effectiveness of health technologies. They are often calculated from time to event curves such as for overall survival and progression-free survival. Ideally, estimates should be obtained from fitting an appropriate parametric model to individual patient data. However, such data are usually not available to independent researchers. Instead, it is common to fit curves to summary Kaplan-Meier graphs, either by regression or by least squares. Here, a more accurate method of fitting survival curves to summary survival data is described. METHODS: First, the underlying individual patient data are estimated from the numbers of patients at risk (or other published information) and from the Kaplan-Meier graph. The survival curve can then be fit by maximum likelihood estimation or other suitable approach applied to the estimated individual patient data. The accuracy of the proposed method was compared against that of the regression and least squares methods and the use of the actual individual patient data by simulating the survival of patients in many thousands of trials. The cost-effectiveness of sunitinib versus interferon-alpha for metastatic renal cell carcinoma, as recently calculated for NICE in the UK, is reassessed under several methods, including the proposed method. RESULTS: Simulation shows that the proposed method gives more accurate curve fits than the traditional methods under realistic scenarios. Furthermore, the proposed method achieves similar bias and mean square error when estimating the mean survival time to that achieved by analysis of the complete underlying individual patient data. The proposed method also naturally yields estimates of the uncertainty in curve fits, which are not available using the traditional methods. The cost-effectiveness of sunitinib versus interferon-alpha is substantially altered when the proposed method is used. CONCLUSIONS: the method is recommended for cost-effectiveness analysis when only summary survival data are available. An easy-to-use Excel spreadsheet to implement the method is provided.

OBJECTIVES: to identify predictors of extraordinary survival. DESIGN: Longitudinal study of a cohort of elderly people followed up until almost all have died. SETTING: Two counties in Iowa; a part of the Established Populations for Epidemiologic Study of the Elderly. PARTICIPANTS: Two thousand eight hundred ninety community-dwelling citizens aged 65 to 85 at baseline and surviving at least 3 years. MEASUREMENTS: Data relating to age, sex, birth order, parental longevity, marital status, education, family income, social support, self-reported health, chronic diseases, blood pressure, body mass index, physical ability, exercise, life attitude and mental health were obtained. Extraordinary survivors (ESs) were defined to include approximately 10% of the longest survivors in their sex group. RESULTS: the 253 ESs were far more likely never to have smoked. In models adjusted for age, sex, and smoking, the earlier-life factors such as parental longevity, being earlier in the birth order (in women only), and body mass index at age 50 were associated with extraordinary survival. In similar models for predictors at age 65 to 85, extraordinary survival was associated with excellent self-reported health, fewer chronic diseases, better physical mobility and memory, and positive attitude toward life, but it was not associated with depression, anxiety, or sleep quality. In multivariable models, attitude toward life was not an independent predictor. Women in the top third of a cumulative score of independent predictors were 9.3 (95% confidence interval=4.4-19.6, P

BACKGROUND: Self-care is a key component of current policies to manage long term conditions. Although most people with long-term health problems care for themselves within lay networks, consultation rates for long-term undifferentiated illness remain high. Promotion of self-care in these individuals requires an understanding of their own self-care practices and needs to be understood in the context of health care pluralism. The aim was to investigate the extent and nature of self-care practices in patients experiencing long term health problems, sources of information used for self-care, and use of other forms of health care (conventional health care and complementary and alternative medicine). METHODS: the study involved a cross-sectional community-based survey set in three general practices in South West England: two in urban areas, one in a rural area. Data were collected using a postal questionnaire sent to a random sample of 3,060 registered adult patients. Respondents were asked to indicate which of six long term health problems they were experiencing, and to complete the questionnaire in reference to a single (most bothersome) problem only. RESULTS: of the 1,347 (45% unadjusted response rate) who responded, 583 reported having one or more of the six long term health problems and 572 completed the survey questionnaire. Use of self-care was notably more prevalent than other forms of health care. Nearly all respondents reported using self-care (mean of four self-care practices each). Predictors of high self-care reported in regression analysis included the reported number of health problems, bothersomeness of the health problem and having received a diagnosis. Although GPs were the most frequently used and trusted source of information, their advice was not associated with greater use of self-care. CONCLUSIONS: This study reveals both the high level and wide range of self-care practices undertaken by this population. It also highlights the importance of GPs as a source of trusted information and advice. Our findings suggest that in order to increase self-care without increasing consultation rates, GPs and other health care providers may need more resources to help them to endorse appropriate self-care practices and signpost patients to trusted sources of self-care support.

BACKGROUND: Common variation at chromosome 9p21 (marked by rs10757278 or rs1333049) is associated with coronary artery disease (CAD) and peripheral vascular disease. A decreasing effect at older age was suggested, and effects on long-term mortality are unclear. We estimated 9p21 associations with CAD and all-cause mortality in a CAD diagnosis-free older population. We also estimated classification gains on adding the variant to the Framingham Risk Score (FRS) for CAD. METHODS AND RESULTS: DNA was from an Established Populations for Epidemiological Study of the Elderly-Iowa cohort from 1988 (participants >71 years), with death certificates obtained to 2008 for 92% of participants. Cox regression models were adjusted for confounders and CAD risk factors. of 1095 CAD diagnosis-free participants, 52% were heterozygous (CG) and 22% were homozygous (CC) for the risk C allele rs1333049. Unadjusted CAD-attributed death rates in the CC group were 30 vs 22 per 1000 person-years for the GG group. The C allele was associated with all-cause (hazard ratio, 1.19; 95% CI, 1.08-1.30) and CAD (hazard ratio, 1.29; 95% CI, 1.08-1.56) mortality, independent of CAD risk factors. There was no association with stroke deaths. Variant associations with CAD mortality were attenuated after the age of 80 years (age-interaction term P=0.05). In age group 71 to 80 years, FRS classified as high risk 21% of respondents who died of CAD within 10 years; adding 9p21 identified 27% of respondents. CONCLUSIONS: in 71- to 80-year-old subjects free of CAD diagnoses, 9p21 is associated with excess mortality, mainly attributed to CAD mortality. Adding 9p21 to the FRS may improve the targeting of CAD prevention in older people, but validation in independent samples is needed for confirmation.

BACKGROUND: Perfluorooctanoic acid (PFOA, also known as C8) and perfluorooctane sulfonate (PFOS) are stable compounds with many industrial and consumer uses. Their persistence in the environment plus toxicity in animal models has raised concern over low-level chronic exposure effects on human health. OBJECTIVES: We estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population. METHODS: Analyses of PFOA/PFOS versus disease status in the National Health and Nutrition Examination Survey (NHANES) for 1999-2000, 2003-2004, and 2005-2006 included 3,974 adults with measured concentrations for perfluorinated chemicals. Regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and alcohol intake. RESULTS: the NHANES-weighted prevalence of reporting any thyroid disease was 16.18% (n = 292) in women and 3.06% (n = 69) in men; prevalence of current thyroid disease with related medication was 9.89% (n = 163) in women and 1.88% (n = 46) in men. In fully adjusted logistic models, women with PFOA >or= 5.7 ng/mL [fourth (highest) population quartile] were more likely to report current treated thyroid disease [odds ratio (OR) = 2.24; 95% confidence interval (CI), 1.38-3.65; p = 0.002] compared with PFOA or= 36.8 ng/mL (quartile 4) versus

BACKGROUND: Bisphenol a (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years. METHODOLOGY AND FINDINGS: a cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18-74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant. CONCLUSIONS: Higher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.

BACKGROUND: the baby-boom generation is entering retirement. Having experienced unprecedented prosperity and improved medical technology, they should be the healthiest generation ever. METHODS: We compared prevalence of disease and risk factors at ages 50-61 years in baby boomers with the preceding generation and attributed differences to period or cohort effects. Data were from the Health Survey for England (HSE) from 1994 to 2007 (n = 48,563). Logistic regression models compared health status between birth cohorts. Age-period-cohort models identified cohort and period effects separately. RESULTS: Compared to the wartime generation, the baby-boomer group was heavier (3.02 kg; 95% confidence interval [CI], 2.42-3.63; p < 0.001) and reported more diagnoses of hypertension (odds ratio [OR] = 1.48; CI, 1.27-1.72; p < 0.001), diabetes (OR = 1.71; CI, 1.37-2.12; p < 0.001), and mental illness (OR = 1.90; CI, 1.54-2.53; p < 0.001). Baby boomers reported fewer heart attacks (OR = 0.61; CI, 0.47-0.79; p < 0.001) and had lower measured blood pressures (systolic -9.51 mmHg; CI, -8.7 to -10.31; p

BACKGROUND & AIMS: in adults, adjustments in resting energy expenditure (REE) are used to defend energy balance against disturbance caused by over-and under-nutrition, and may be linked to changes in insulin resistance and leptin. Little is known of these associations in children. Our aim was to test the hypothesis that long-term weight gain in children is met with adaptive changes in resting energy expenditure, mediated by insulin resistance and/or leptin. METHODS: REE by indirect calorimetry, anthropometry, body composition by DEXA, insulin resistance (HOMA-IR) and serum leptin were measured annually in 232 children from the age of 7-10 y. RESULTS: REE rose from 7 to 10 y, and the rise exceeded that predicted by the concurrent rise in fat and fat-free mass by 184 kcal/day in the boys and by 160 kcal/day in the girls. However, there were no significant relationships in either gender between this 'excess' rise in REE and change in body composition (r < or = 0.08, p > or = 0.42). The rise in both boys and girls was associated with, but not explained by, a rise in insulin resistance (p < or = 0.002). There was no association with serum leptin (p > or = 0.32). CONCLUSIONS: the data do not support the hypothesis of adaptive changes in REE in pre-pubertal children, and insulin resistance explains very little of the pre-pubertal rise in REE. The rise in REE beyond that explained by changes in body composition may reflect an increase in energy requirements prior to puberty.

A correlation between national pig-meat consumption and mortality rates from chronic liver disease (CLD) across developed countries was reported in 1985. One possible mechanism explaining this may be hepatitis E infection spread via pig meat. We aimed to re-examine the original association in more recent international data. Regression models were used to estimate associations between national pig-meat consumption and CLD mortality, adjusting for confounders. Data on CLD mortality, alcohol consumption, hepatitis B virus (HBV) and hepatitis C virus (HCV) seroprevalence for 18 developed countries (1990-2000) were obtained from WHO databases. Data on national pig-meat and beef consumption were obtained from the UN database. Univariate regression showed that alcohol and pig-meat consumption were associated with mortality from CLD, but beef consumption, HBV and HCV seroprevalence were not. A 1 litre per capita increase in alcohol consumption was associated with an increase in mortality from CLD in excess of 1.6 deaths/100,000 population. A 10 kg higher national annual average per capita consumption of pork meat was associated with an increase in mortality from CLD of between 4 and 5 deaths/100,000 population. Multivariate regression showed that alcohol, pig-meat consumption and HBV seroprevalence were independently associated with mortality from CLD, but HCV seroprevalence was not. Pig-meat consumption remained independently associated with mortality from CLD in developed countries in the 1990-2000 period. Further work is needed to establish the mechanism.

A recent genome-wide association (GWA) study of late-onset Alzheimer's disease (LOAD) identified 15 novel single nucleotide polymorphisms (SNPs) independent of ApoE. We hypothesised that variants associated with LOAD are also associated with poor cognitive function in elderly populations. We measured additive associations between the five most strongly associated LOAD SNPs and grouped Mini Mental State Examination (MMSE) scores. Variants were genotyped in respondents (mean age 79 years) from the Oxford Healthy Ageing project (OHAP) and other sites of the MRC Cognitive Function and Ageing Study (MRC-CFAS). In adjusted ordinal logistic models, two variants were associated with poorer cognitive function: rs11622883 (OR=1.14, 95% CI: 1.01-1.28, p=0.040) and rs505058 (OR=1.29, 95% CI: 1.02-1.64, p=0.036). These SNPs are close to a SERPINA gene cluster and within LMNA, respectively. The mechanisms underlying the associations with cognitive impairment and LOAD require further elucidation, but both genes are interesting candidates for involvement in age-related cognitive impairment.

Studies investigating the role of oxidative stress in both the ageing process and osteoarthritis (OA) in human beings are limited by the unavailability of samples from healthy subjects. OA occurs naturally in the horse and has been used as a model of human OA. The objective of this study was to determine the effect of ageing and OA on the non-enzymatic synovial fluid antioxidant status of the horse. The concentrations of ascorbic acid, dehydroascorbate (DHA, oxidized ascorbic acid), uric acid, glutathione, α-tocopherol and thiobarbituric acid reactive substances (TBARS) were determined in paired synovial fluid and plasma samples from 25 horses aged between 3 and 25 years. Osteoarthritic lesions were scored from 0 (healthy) to 4 (severe OA). Glutathione was not detectable in synovial fluid. Neither plasma nor synovial fluid antioxidant concentrations were affected by age. Ascorbic acid concentrations in plasma correlated strongly with those in synovial fluid from both healthy (P 

OBJECTIVES: We sought to identify the income-disability prevalence relationship among older Brazilians. METHODS: Data were from 63,985 individuals 60 years and older from the 1998 and 2003 Brazilian National Household Surveys. Generalized additive logistic models with cubic regression splines were used to estimate the disability-income relationships. RESULTS: There was a strong linear relationship between increased income and reduced disability prevalence for most of the income distribution. Benefits were still present above the 90th percentile of income but were more modest. Because incomes among the wealthiest few are disproportionately large, odds ratios of disability nevertheless showed marked improvements, even across the very highest income groups. CONCLUSIONS: Among older Brazilians, reduced disability is associated with higher income, and these associations are present even above the 90th percentile of income. In addition to understanding mechanisms of disability reduction among impoverished individuals, work is needed to understand these mechanisms in middle- and high-income groups.

BACKGROUND: a common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 single-nucleotide polymorphism) is strongly associated with myocardial infarction and major arterial aneurysms. An association with peripheral arterial disease (PAD) was also reported in a sample younger than 75 years, but this disappeared on removal of respondents with a myocardial infarction history, resulting in an odds ratio of 1.09 for PAD (P=0.075). We aimed at estimating the association of this variant with an Ankle-Brachial Index (ABI) and PAD in 3 older populations. METHODS AND RESULTS: We used data from the InCHIANTI, Baltimore Longitudinal Study of Aging, and Health, Aging, and Body Composition studies. In 2630 white individuals (mean age, 76.4 years), the C allele at rs1333049 was associated with lower mean ABI measures and with an increased prevalence of PAD. These associations remained after removal of baseline and incident myocardial infarction cases over a 6-year follow-up for both ABI (-0.017 ABI units; 95% CI, -0.03 to -0.01; P = 1.3 x 10(-4)) and PAD (per allele odds ratio, 1.29; 95% CI, 1.06 to 1.56; P = 0.012). These associations also remained after adjustment for known atherosclerosis risk factors, including diabetes mellitus, smoking, hypercholesterolemia, and hypertension. CONCLUSIONS: the C allele at rs1333049 is associated with an increased prevalence of PAD and lower mean ABI. This association was independent of the presence of diagnosed myocardial infarction and atherosclerotic risk factors in 3 older white populations.

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

CONTEXT: Bisphenol a (BPA) is widely used in epoxy resins lining food and beverage containers. Evidence of effects in animals has generated concern over low-level chronic exposures in humans. OBJECTIVE: to examine associations between urinary BPA concentrations and adult health status. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States, using data from the National Health and Nutrition Examination Survey 2003-2004. Participants were 1455 adults aged 18 through 74 years with measured urinary BPA and urine creatinine concentrations. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration. The sample provided 80% power to detect unadjusted odds ratios (ORs) of 1.4 for diagnoses of 5% prevalence per 1-SD change in BPA concentration, or standardized regression coefficients of 0.075 for liver enzyme concentrations, at a significance level of P <. 05. MAIN OUTCOME MEASURES: Chronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes. RESULTS: Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P =. 001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P <. 001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes gamma-glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14-1.46; P <. 001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18-1.85; P =. 002). CONCLUSION: Higher BPA exposure, reflected in higher urinary concentrations of BPA, may be associated with avoidable morbidity in the community-dwelling adult population.

OBJECTIVES: to assess factors associated with granting of the Disability Living Allowance (DLA) for Down syndrome. DESIGN: Cross-sectional survey. SETTING: Families with a child with Down syndrome enrolled in a community-based trial of vitamin supplementation. PARTICIPANTS: 156 children with trisomy 21 (59% male, 20% non-white) were enrolled before 7 months of age and 138 completed follow-up. MAIN OUTCOME MEASURES: Before the child was 2 years old, we surveyed parents about applications for the DLA and socioeconomic factors, and assessed the child's development. RESULTS: Application for the DLA was not associated with ethnicity or speaking English. Significantly fewer ethnic minority parents (OR = 0.10; 95% CI 0.03 to 0.35; 69% vs 96%, risk difference 27%) and parents with English as a second language (OR = 0.15: 95% CI 0.04 to 0.62; 67% vs 93%, risk difference 26%) were granted the DLA. Amongst those granted the DLA, ethnic minority families were significantly less likely to be granted a higher monetary award (OR = 0.19; 95% CI 0.06 to 0.55). Severity of disability, reflected by quartile of Griffiths Developmental Quotient or the presence of severe cardiac disease requiring surgery, was not associated with application, granting or level of the DLA award. CONCLUSIONS: Although all children with Down syndrome meet some of the criteria for the DLA, only 80% were receiving this benefit. The decision to award the DLA and the monetary level of the award favoured white, English speaking parents and was not related to severity of disability. Routine monitoring of awards by ethnicity and language spoken is needed. TRIAL REGISTRATION NUMBER: NCT00378456.

Feline upper respiratory tract disease (URTD), mainly caused by feline calicivirus (FCV) and feline herpesvirus, is a major cause of disease outbreaks in feline accommodation such as animal shelters, catteries and multi-cat households. We conducted a longitudinal, yearlong study in five UK feline animal shelters to identify risk factors for the time to diagnosis of URTD. We were especially interested in risk factors that could be identified at the time the cat entered the shelter. Shelter staff recorded data for 1,434 cats during 2002-2003. Most of the cats were domestic shorthair cats and were from private households, or were stray or abandoned. Sixty cats without clinical signs of URTD at entry had URTD diagnosed (typically within the first month at the centre). We used two multivariable models: one was a Cox proportional-hazards model, and the other a regression analyses with complementary log-log model. The hazard varied substantially between shelters and was considerably lower for the shelter that had a purpose-built admissions unit with its own isolation facilities. The hazard was greater for purebred cats (HR 4.3-5.0) and for neutered cats (HR 2.0). The hazard was also typically greater if the centre had a greater proportion of cats present with URTD. The analyses suggested that the centre-level risk factors were more important in determining hazard than cat-level risk factors.

OBJECTIVES: to assess whether supplementation with antioxidants, folinic acid, or both improves the psychomotor and language development of children with Down's syndrome. DESIGN: Randomised controlled trial with two by two factorial design. SETTING: Children living in the Midlands, Greater London, and the south west of England. PARTICIPANTS: 156 infants aged under 7 months with trisomy 21. INTERVENTION: Daily oral supplementation with antioxidants (selenium 10 mug, zinc 5 mg, vitamin a 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg), antioxidants and folinic acid combined, or placebo. MAIN OUTCOME MEASURES: Griffiths developmental quotient and an adapted MacArthur communicative development inventory 18 months after starting supplementation; biochemical markers in blood and urine at age 12 months. RESULTS: Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval -2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, -1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results. CONCLUSIONS: This study provides no evidence to support the use of antioxidant or folinic acid supplements in children with Down's syndrome. TRIAL REGISTRATION: Clinical trials NCT00378456.

Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with interleukin 6 receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r(2)=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13-140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35-71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 x 10(-62). The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 x 10(-4)). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.

BACKGROUND: the proinflammatory cytokine interleukin-18 (IL-18) is associated with major disabling conditions, although whether as byproduct or driver is unclear. The role of common variation in the IL-18 gene on serum concentrations and functioning in old age is unknown. METHODS: We used 1671 participants aged 65-80 years from two studies: the InCHIANTI study and wave 6 of the Iowa-Established Populations for Epidemiological Study of the Elderly (EPESE). We tested three common polymorphisms against IL-18 concentration and measures of functioning. RESULTS: in the InCHIANTI study, a 1 standard deviation increase in serum IL-18 concentrations was associated with an increased chance of being in the 20% of slowest walkers (odds ratio 1.45; 95% confidence interval, 1.17-1.80; p =.0007) and 20% of those with poorest function based on the Short Physical Performance Battery Score (odds ratio 1.52; 95% confidence interval, 1.22-1.89; p =.00016) in age sex adjusted logistic regression models. There was no association with Activities of Daily Living (p =.26) or Mini-Mental State Examination score (p =.66). The C allele of the IL-18 polymorphism rs5744256 reduced serum concentrations of IL-18 by 39 pmol/mL per allele (p =.00001). The rs5744256 single nucleotide polymorphism was also associated with shorter walk times in InCHIANTI (n = 662, p =.016) and Iowa-EPESE (n = 995, p =.026). In pooled ranked models rs5744256 was also associated with higher SPPB scores (n = 1671, p =.019). Instead of adjusting for confounders in the IL-18 walk time association, we used rs5744256 in a Mendelian randomization analysis: the association remained in instrumental variable models (p =.021). CONCLUSION: IL-18 concentrations are associated with physical function in 65- to 80-year-olds. A polymorphism in the IL-18 gene alters IL-18 concentrations and is associated with an improvement in walk speed. IL-18 may play an active role in age-related functional impairment, but these findings need independent replication.

Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range=0.016-4.9 x 10(-5)). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r(2)=0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r(2)=0.91), may also be independently associated with IL-1RA levels (P=0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1beta (P=0.03) level and may also be associated with interferon -gamma (P=0.03), alpha-2 macroglobulin (P=0.008) and adiponectin (P=0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.

Survival analysis was used to assess risk factors for fatal injuries on UK race courses. This allowed assessment of variation due to temporal horse-level effects, including previous racing intensity and historical distribution of race types, as well as race-level factors. Comparisons were made between measuring survival time as number of days and as number of races to injury from the first race. Two related models were presented for time as number of races to injury: a Cox regression model fitted using partial likelihood, with the Efron approximation to handling ties, and a discrete-time logit model fitted using maximum likelihood. The latter approach had the advantages of being computationally more efficient and enabling the testing of different functional forms for the dependence of hazard on time. Retrospective data were available from all race starts on the 59 courses in Britain from 1990 to the end of 1999, as analysed by. The analysis was conducted on the data for the 47,424 horses that had started racing in the UK: 538,895 starts with 1,228 fatal injuries. Horses starting racing abroad were excluded, but some included horses would have raced abroad at some stage during their racing career. The results for the selected models were broadly consistent with each other and with previously published studies. Steeplechase and hurdle races had a higher risk of fatal injury than flat races (relative hazards 1.5 and 1.7, respectively). Risk increased with the firmness of surface, age and race distance (reaching a plateau at 20 furlongs) and decreased with previous racing intensity (reaching a plateau after seven races run in the last 12 months). Horses running their first race of a new type were also found to be at higher risk (relative hazard 1.5). The main difference between the models for time as number of days and number of races concerned the role of age: age at race was identified as the more important factor in the latter model, whereas, age at first race was more significant in the former model.

This study was based on a convenience-sampling questionnaire study of pedigree cat breeding in the UK. Data were collated for the births of 1,056 litters from 14 different pedigree breeds and 942 different households. Significant relationships between various outcomes and relevant predictors were assessed by multiple linear regression or logistic regression as appropriate. The overall mean gestation length of 65.1 days varied significantly between the breeds (P

The Patnaik histologic grading system is commonly used to predict the behavior of cutaneous mast cell tumors (MCTs) in dogs, but it is less useful for grade 2 MCTs because they exhibit considerable variation in biological behavior. In this retrospective study, immunohistochemical staining for Ki-67, proliferating cell nuclear antigen (PCNA), and survivin and a standardized argyrophilic staining of nucleolar organizer regions (AgNOR) protocol were performed on 121 archived paraffin-embedded specimens of canine cutaneous MCTs, for which clinical follow-up data were available. Cox regression models indicated that the Ki-67 score (hazard ratio, 1.92; P <. 001) and mean AgNOR score (hazard ratio, 2.57; P <. 001) were significantly associated with Patnaik grade and survival time. A binary Ki-67 variable (cutoff point Ki-67 score = 1.8) was a significant predictor of survival for dogs with grade 2 MCTs. The estimated 1-, 2-, and 3-year survival probabilities for dogs with grade 2 MCTs and Ki-67 scores less than 1.8 were 0.92, 0.86, and 0.77, respectively (SEs, 0.08, 0.14, and 0.23, respectively; median not estimable). The corresponding survival probabilities for dogs with grade 2 MCTs and Ki-67 scores higher than 1.8 were 0.43, 0.21, and 0.21, respectively (SEs, 0.19, 0.18, and 0.18, respectively; median survival time, 395 days). No significant association was identified between survival and survivin score or PCNA score. This study shows that both mean AgNOR score and Ki-67 score are prognostic markers for canine MCTs. The Ki-67 score can be used to divide Patnaik grade 2 MCTs into 2 groups with markedly different expected survival times.

BACKGROUND: Congenital sensorineural deafness (CSD) occurs in Border Collies, but its prevalence and inheritance are unknown. This study estimated the prevalence of CSD in Border Collies and investigated its association with phenotypic attributes linked to the merle gene, including coat pigmentation and iris color. HYPOTHESIS: Deafness in Border Collies is associated with pigmentation patterns linked to the merle gene. ANIMALS: a total of 2597 Border Collies from the United Kingdom. METHODS: a retrospective study of Border Collies tested, during 1994-2002, by using brainstem auditory evoked responses. Associations between deafness and phenotypic attributes were assessed by using generalized logistic regression. RESULTS: the prevalence of CSD in puppies was estimated as 2.8%. The corresponding rates of unilateral and bilateral CSD were 2.3 and 0.5%, respectively. Adjustment for clustering of hearing status by litter reduced the overall prevalence estimate to 1.6%. There was no association between CSD and sex (P =. 2). Deaf Border Collies had higher rates of merle coat pigmentation, blue iris pigment, and excess white on the head than normal hearing Border Collies (all P <. 001). The odds of deafness were increased by a factor of 14 for Border Collies with deaf dams, relative to the odds for dogs with normal dams (P =. 007), after adjustment for phenotypic attributes. CONCLUSIONS AND CLINICAL IMPORTANCE: Associations between CSD and pigmentation patterns linked to the merle gene were demonstrated for Border Collies. Evidence for an inherited component to CSD in Border Collies supports selective breeding from only tested and normal parents to reduce the prevalence of this disease.

Pulmonary capillary stress failure, largely as a result of high pulmonary vascular pressures, has been implicated in the aetiology of EIPH. However, the role of the respiratory system in determining the magnitude of EIPH has received little attention. Horses breathing a gas of greater density than air will exhibit greater transmural pulmonary arterial pressures (TPAP) and more severe EIPH, and horses breathing a gas of lower density than air will exhibit lower TPAP and less severe EIPH, both compared with horses breathing air. Following a warm-up, 8 Thoroughbred horses were exercised for 1 min at 10, 11 and 12 m/sec (5 degrees incline) breathing air or 21% oxygen/79% helium or 21% oxygen/79% argon in a randomised order. Heart rate, respiratory rate, pulmonary arterial pressure and oesophageal pressure were measured during exercise. Bronchoalveolar lavage fluid (BALF) was collected from the dorsocaudal regions of the left and right lungs 40 min post exercise and red blood cell (RBC) counts were performed. The exercise tests induced mild EIPH. Maximum changes in oesophageal pressure were lower on helium-oxygen compared to argon-oxygen (P < 0.001). TPAP and median RBC counts did not differ between gas mixtures. BALF RBC counts from the left lung correlated with counts from the right lung (P < 0.0001). However BALF RBC counts from the left lung were higher than those from the right lung (P = 0.004). As alterations in pulmonary arterial and oesophageal pressure caused by changes in inspired gas density were of similar magnitude, TPAP remained unchanged and there was no significant effect on EIPH severity. Manipulations that decrease swings in intrapleural pressure may only decrease the degree of EIPH in horses severely affected by the condition.

BACKGROUND: Experimental studies in adult horses have shown that general anaesthesia maintained with isoflurane is associated with less depression of cardiovascular function compared with halothane anaesthesia. Adverse effects of intermittent positive-pressure ventilation (IPPV) have also been demonstrated. Nevertheless, the haemodynamic effects of these agents and the effects of differing modes of ventilation have not been assessed during clinical anaesthesia in horses undergoing surgery. METHODS: the haemodynamic effects of isoflurane or halothane anaesthesia during spontaneous or IPPV were studied non-invasively in 32 laterally recumbent horses undergoing elective surgery. Indices of cardiac function and measurements of femoral arterial blood flow and resistance were recorded using transoesophageal and transcutaneous Doppler echocardiography, respectively. Arterial pressure was measured directly using a facial artery catheter. RESULTS: Cardiac index (CI) was significantly higher during isoflurane anaesthesia than during halothane anaesthesia and was also higher during spontaneous ventilation with isoflurane. CI decreased significantly over time and an inverse relationship was observed between CI and mean arterial pressure (MAP). Horses with higher MAP had a significantly lower CI. During isoflurane anaesthesia, femoral arterial blood flow was significantly higher in both pelvic limbs compared with halothane anaesthesia, and flow in the lower limb was significantly higher during spontaneous ventilation than during IPPV. No significant change in femoral blood flow was observed over time. CONCLUSION: the effects of anaesthetics and mode of ventilation on cardiovascular function recorded under surgical conditions in horses are similar to those reported under experimental conditions. However, in contrast with previous experimental studies, CI progressively decreased over time regardless of agent used or mode of ventilation employed.

In horses, natural infection confers long lasting protective immunity characterised by mucosal IgA and humoral IgGa and IgGb responses. In order to investigate the potential of locally administered vaccine to induce a protective IgA response, responses generated by vaccination with an immunostimulating complex (ISCOM)-based vaccine for equine influenza (EQUIP F) containing A/eq/Newmarket/77 (H7N7), A/eq/Borlänge/91 (H3N8) and A/eq/Kentucky/98 (H3N8) using a systemic prime/mucosal boost strategy were studied. Seven ponies in the vaccine group received EQUIP F vaccine intranasally 6 weeks after an initial intramuscular immunisation. Following intranasal boosting a transient increase in virus-specific IgA was detected in nasal wash secretions. Aerosol challenge with the A/eq/Newmarket/1/93 reference strain 4 weeks after the intranasal booster resulted in clinical signs of infection and viral shedding in seven of seven influenza-naive control animals whereas the seven vaccinated ponies had statistically significantly reduced clinical signs and duration of virus excretion. Furthermore, following this challenge, significantly enhanced levels of virus-specific IgA were detected in the nasal washes from vaccinated ponies compared with the unvaccinated control animals. These data indicate that the intranasal administration of EQUIP F vaccine primes the mucosal system for an enhanced IgA response following exposure to live influenza virus. © 2005 Elsevier B.V. All rights reserved.

REASONS FOR PERFORMING STUDY: Dorsometacarpal disease (DMD) is common in young Thoroughbred (TB) racehorses, often interfering with their training programme. No reports exist on incidence rate or associated risk factors in the UK. OBJECTIVES: to estimate the incidence rate of DMD in TB horses in training for flat racing in the UK and identify associated risk factors, particularly in relation to training regimens. METHODS: Data were drawn from a large prospective study in which TB horses in 13 training yards were monitored for a period of up to 2 years, recording daily training information and details of musculoskeletal injury, including DMD. The incidence of DMD was calculated and survival analysis performed to determine features of the training regimen related to the risk of disease. RESULTS: a total of 335 horses provided 4235 months at risk of DMD. Seventy-nine first episodes were recorded, resulting in an incidence rate of 1.87/100 horse months (95% confidence interval 1.50-2.33). Increasing exercise distances at canter and high speed in short periods (up to 1 month) were associated with an increasing risk of DMD. However, increasing cumulative exercise distances since entering training were associated with a decreasing risk of the disease. CONCLUSIONS: the risk of DMD in young TBs decreases with accumulation of distances exercised at canter and high speed; this reflects the adaptive response of the third metacarpal bone to the loads placed upon it. However, increasing exercise distances in short periods (up to 1 month) increases the risk of DMD, probably as a consequence of microdamage and its associated remodelling response, and should therefore be avoided. POTENTIAL RELEVANCE: Training regimens for young TBs can be adjusted to prevent the occurrence of DMD. Early but gradual introduction of small amounts of high-speed exercise may be beneficial. Canter exercise should be kept minimal on high-speed work days and large amounts of both cantering and high-speed work per week, 2 weeks or per month should be avoided, particularly during the early stages of training, in order to minimise the risk of DMD.

This paper reviews recent epidemiological research in the United Kingdom for controlling deafness in Dalmatians, glaucoma in flat coated retrievers and great Danes and hip dysplasia in flat coated retrievers, Newfoundlands, Gordon setters and Labrador retrievers. These studies assessed the prevalence of the disease, identified the factors affecting prevalence, and developed predictive statistical models of offspring/parent relationships. For each disease/breed combination, the research identified those sires and dams that might justifiably be regarded as suitable/unsuitable as potential parents in a selective breeding strategy to control or prevent the disease. Future progress in the control of these diseases is likely to come from greater understanding of their mode of inheritance. Insight, even for these complex diseases, can be derived from further detailed statistical evaluation of datasets such as those described in this paper.

Two lineages of antigenically distinct equine influenza a H3N8 subtype viruses, American and European, co-circulate. Experiments were conducted in ponies to investigate the protection induced by vaccines containing virus from one lineage against challenge infection with homologous or heterologous virus. Regression analysis showed that vaccinated ponies with average pre-challenge single radial haemolysis (SRH) antibody levels (i.e. 45-190mm2) had a higher probability of becoming infected if they were vaccinated with virus heterologous to the challenge strain than if they were vaccinated with homologous virus. Field studies in Thoroughbred racehorses also showed that SRH antibody levels of >/= 150mm2 induced by vaccines containing a European lineage strain are protective against infection with a virus from the same lineage, but that the same or higher antibody levels may not be protective against an American lineage virus. In conclusion, vaccines should contain virus strains representative of both H3N8 subtype lineages to maximise protection against infection.

Medical records of 81 dogs with severe pulmonic stenosis from 2 referral centers were examined retrospectively. Forty dogs underwent balloon valvuloplasty (BV), which was performed by 1 operator, whereas 41 did not. The mean age at latest follow-up was 41.5 months. A statistical comparison of the clinical outcome and survival was performed. Dogs revealing clinical signs at presentation showed a 16-fold increase in risk of death compared with asymptomatic dogs (P <. 001). Statistical analyses demonstrated that an increase of 1 mm Hg in transstenotic pressure gradient (PG) at presentation was associated with a 3% increase in hazard rate (P <. 001). Thirty-seven dogs survived BV with a median reduction in PG of 46%. The median preoperative PG was 120 mm Hg, and median PG 24 hours postoperatively was 55 mm Hg with a median of 55 mm Hg 6 months post-BV. Twenty (49%) of the non-BV (NBV) dogs remained asymptomatic at last follow-up. Fourteen (34%) of the NBV dogs died or were euthanized because of heart disease related to pulmonic stenosis. Twelve of these dogs died suddenly, whereas only 1 of the BV dogs died suddenly. After adjusting for PG, clinical signs at presentation, and age, BV or dilation was associated with a 53% reduction in hazard rate (P =. 005). This study indicates that BV, when performed by an experienced operator, appears to be successful both in alleviating clinical signs and in prolonging survival in dogs with severe pulmonic stenosis.

We assess the effects of strain heterology (strains that are immunologically similar but not identical) on equine influenza in a vaccinated population. Using data relating to individual animals, for both homologous and heterologous vaccinees, we estimate distributions for the latent and infectious periods, quantify the risk of becoming infected in terms of the quantity of cross-reactive antibodies to a key surface protein of the virus (haemagglutinin) and estimate the probability of excreting virus (i.e. becoming infectious) given that infection has occurred. The data suggest that the infectious period, the risk of becoming infected (for a given vaccine-induced level of cross-reactive antibodies) and the probability of excreting virus are increased for heterologously vaccinated animals when compared with homologously vaccinated animals. The data are used to parameterize a modified susceptible, exposed, infectious and recovered/resistant (SEIR) model, which shows that these relatively small differences combine to have a large effect at the population level, where populations of heterologous vaccinees face a significantly increased risk of an epidemic occurring.

Following concerns raised over the safety of canine vaccines, an epidemiological investigation was conducted to evaluate the evidence for a temporal association between vaccination and ill-health in dogs. The owners of a randomly selected population of dogs were sent 9055 postal questionnaires, 4040 of which were returned. No temporal association was found between vaccination and ill-health in dogs after adjusting for potential confounders, such as age. However, reliable inferences from non-significant test results are limited and so equivalence-testing methods were also used to make informative inferences. Results demonstrated that recent vaccination (< 3 months) does not increase signs of ill-health by more than 0.5% and may actually decrease it by as much as 5%. This general approach should be used in all field studies of vaccine safety.

Canine lymphoma is one of the commonest forms of spontaneous canine neoplasia. Improved understanding of the genetic and environmental risk factors for canine lymphoma, including breed differences, may have comparative benefits for the study of non-Hodgkin's lymphoma in humans. In this study, data from a pet insurance company were used to estimate the incidences of canine lymphoma for pedigree breeds in the UK. Out of a total of 130,684 insured dogs, 103 had a diagnosis of lymphoma recorded. A significant breed effect was found with the boxer, bulldog and bull mastiff breeds, all having a high incidence of lymphoma. The small number of lymphoma cases recorded may have limited our ability to detect other breeds with an elevated risk. Incidence of lymphoma was found to increase with age, peaking at 10 years of age.

Objectives: to compare the effectiveness of first protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. Methods: Data were analysed from three large HIV patient databases: Apache HIV Insight™ (APACHE), Target Management Services (TMS) and Clinical Partners (CP). The effectiveness of therapy was the time taken for HIV-1 RNA to fall below detectable levels on first highly active antiretroviral therapy regimen (PI- or NNRTI-containing) and the subsequent time to failure (two consecutive detectable measurements). Comparisons were made using proportional hazards models, adjusting for differences in age, sex, previous reverse transcriptase inhibitor use, calendar year and baseline viral load and CD4 T-cell count. Results: the type of regimen was not associated with time to undetectable viral load in any of the three databases, all of which had high power to detect a difference. PI-containing regimens were significantly less likely to fail after reaching undetectable viral loads for APACHE and CP patients (relative hazard, 1.7; 95% confidence interval, 1.3-2.1 and relative hazard, 1.6; 95% confidence interval, 1.0-2.5 respectively). These results remained significant after allowing for an unmeasured confounder with moderate effect on risk. No significant association between time to failure and regimen was found for TMS patients, possibly due to low power (67% to detect a relative hazard of 1.5). No difference was found between regimens in the time taken for an increase of > 100 × 109cells/I in CD4 T-cell count. In the APACHE database, those on NNRTI-containing regimens were more likely to have a failing CD4 T-cell response. Conclusions: PI-containing regimens have a lower risk of treatment failure than NNRTI-containing regimens. © 2001 Lippincott Williams & Wilkins.

This paper describes the construction of a credit-scoring system using the k-nearest-neighbour method, a standard technique in pattern recognition and non-parametric statistics. An important part of our analysis is the selection of distance metrics. We propose using an adjusted version of the euclidean distance metric, which incorporates an estimate of underlying equiprobability contours for class membership. This approach was used to classify a sample of applications for mail-order credit from the Littlewoods Organisation. We describe the results of comparison experiments with a range of discrimination techniques, including logistic regression, projection-pursuit regression, and decision trees. © 1997 Oxford University Press 1997.

The last 30 years have seen the development of credit scoring techniques for assessing the creditworthiness of consumer loan applicants. Traditional credit scoring methodology has involved the use of techniques such as discriminant analysis, linear or logistic regression, linear programming and decision trees. In this paper we look at the application of the k-nearest-neighbour (k-NN) method, a standard technique in pattern recognition and nonparametric statistics, to the credit scoring problem. We propose an adjusted version of the Euclidean distance metric which attempts to incorporate knowledge of class separation contained in the data. Our &-NN methodology is applied to a real data set and we discuss the selection of optimal values of the parameters k and D included in the method. To assess the potential of the method we make comparisons with linear and logistic regression and decision trees and graphs. We end by discussing a practical implementation of the proposed k-NN classifier.

The true good/bad status of applicants accepted for credit is ultimately known. However, the status of rejected applicants will never be known. 'Reject inference' is the process of inferring the status of applicants who have been rejected. This paper reviews methods of reject inference, and describes some new approaches. Three classes of method are described: (i) methods based on extrapolating a model built on the accepted applicants into the reject region; (ii) methods based on the distribution of the rejected applicants; (iii) methods using supplementary information. In particular, we conclude that the distribution of the rejected applicants cannot assist reject inference unless additional assumptions are made. © 1993 Oxford University Press.