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1.  Stress and self-efficacy predict psychological adjustment at diagnosis of prostate cancer 
Scientific Reports  2014;4:5569.
Prostate cancer is the most frequently non-skin cancer diagnosed among men. Diagnosis, a significant burden, generates many challenges which impact on emotional adjustment and so warrants further investigation. Most studies to date however, have been carried out at or post treatment with an emphasis on functional quality of life outcomes. Men recently diagnosed with localised prostate cancer (N = 89) attending a Rapid Access Prostate Clinic to discuss treatment options completed self report questionnaires on stress, self-efficacy, and mood. Information on age and disease status was gathered from hospital records. Self-efficacy and stress together explained more than half of the variance on anxiety and depression. Self-efficacy explained variance on all 6 emotional domains of the POMS (ranging from 5–25%) with high scores linked to good emotional adjustment. Perceived global and cancer specific stress also explained variance on the 6 emotional domains of the POMS (8–31%) with high stress linked to poor mood. These findings extend understanding of the role of efficacy beliefs and stress appraisal in predicting emotional adjustment in men at diagnosis and identify those at risk for poor adaptation at this time. Such identification may lead to more effective patient management.
doi:10.1038/srep05569
PMCID: PMC4081888  PMID: 24993798
2.  Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study): study protocol for a randomized controlled trial 
Trials  2014;15:202.
Background
Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial.
Methods/Design
TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions.
Discussion
This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies.
Trial registration
Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011)
doi:10.1186/1745-6215-15-202
PMCID: PMC4061534  PMID: 24888381
Alzheimer disease; Dementia; Down syndrome; Neuropsychology; Primary prevention; Simvastatin; Statin
3.  Prediction of liver disease in patients whose liver function tests have been checked in primary care: model development and validation using population-based observational cohorts 
BMJ Open  2014;4(6):e004837.
Objective
To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care.
Design
Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2 years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model.
Setting
Primary care, Tayside, Scotland.
Participants
Derivation cohort: LFT results from 310 511 patients. After exclusions (including: patients under 16 years, patients having initial LFTs measured in secondary care, bilirubin >35 μmol/L, liver complications within 6 weeks and history of a liver condition), the derivation cohort contained 95 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11 653 patients.
Primary and secondary outcome measures
Diagnosis of a liver condition within 2 years.
Results
From the derivation cohort (n=95 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20–30% for high-risk patients.
Conclusions
This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk.
doi:10.1136/bmjopen-2014-004837
PMCID: PMC4054629  PMID: 24889852
PRIMARY CARE; EPIDEMIOLOGY
5.  Lessons from Mackenzie that still resonate 
doi:10.3399/bjgp13X664423
PMCID: PMC3582972  PMID: 23561780
7.  Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects 
Background
Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype.
Objective
We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD.
Methods
A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD.
Results
The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Mattft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD.
Conclusion
In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.
doi:10.1016/j.jaci.2013.08.046
PMCID: PMC3834151  PMID: 24084074
Allergy; association; atopic dermatitis; atopy; eczema; filaggrin; flaky tail; Matt; mattrin; mouse; mutation; Tmem79; AD, Atopic dermatitis; DM, Double mutant; FLG, Filaggrin; HDM, House dust mite; hpf, High-power field; MAPEG, Membrane-associated proteins in eicosanoid and glutathione metabolism; OR, Odds ratio; SNP, Single nucleotide polymorphism; TEWL, Transepidermal water loss; WT, Wild-type
8.  Acceptability and perceived barriers and facilitators to creating a national research register to enable ’direct to patient’ enrolment into research: the Scottish Health Research Register (SHARE) 
Background
Difficulties with recruitment pose a major, increasingly recognised challenge to the viability of research. We sought to explore whether a register of volunteers interested in research participation, with data linkage to electronic health records to identify suitable research participants, would prove acceptable to healthcare staff, patients and researchers.
Methods
We undertook a qualitative study in which a maximum variation sampling approach was adopted. Focus groups and interviews were conducted with patients, general practitioners (GP), practice managers and health service researchers in two Scottish health boards. Analysis was primarily thematic to identify a range of issues and concerns for all stakeholder groups.
Results
The concept of a national research register was, in general, acceptable to all stakeholder groups and was widely regarded as beneficial for research and for society. Patients, however, highlighted a number of conditions which should be met in the design of a register to expedite confidence and facilitate recruitment. They also gave their perceptions on how a register should operate and be promoted, favouring a range of media. GPs and practice managers were primarily concerned with the security and confidentiality of patient data and the impact a register may have on their workload. Researchers were supportive of the initiative seeing advantages in more rapid access to a wider pool of patients. They did raise concerns that GPs may be able to block access to personal patient data held in general practice clinical systems and that the register may not be representative of the whole population.
Conclusions
This work suggests that patients, healthcare staff and researchers have a favourable view of the potential benefits of a national register to identify people who are potentially eligible and willing to participate in health related research. It has highlighted a number of issues for the developers to incorporate in the design of research registers.
doi:10.1186/1472-6963-13-422
PMCID: PMC3854488  PMID: 24139174
Research register; Recruitment; Randomised controlled trial; Qualitative
9.  2011 RCGP and Novartis Research Paper of the Year 
doi:10.3399/bjgp12X653697
PMCID: PMC3404322
10.  Impact of clinical trial findings on Bell's palsy management in general practice in the UK 2001–2012: interrupted time series regression analysis 
BMJ Open  2013;3(7):e003121.
Objectives
To measure the incidence of Bell's palsy and determine the impact of clinical trial findings on Bell's palsy management in the UK.
Design
Interrupted time series regression analysis and incidence measures.
Setting
General practices in the UK contributing to the Clinical Practice Research Datalink (CPRD).
Participants
Patients ≥16 years with a diagnosis of Bell's palsy between 2001 and 2012.
Interventions
(1) Publication of the 2004 Cochrane reviews of clinical trials on corticosteroids and antivirals for Bell's palsy, which made no clear recommendation on their use and (2) publication of the 2007 Scottish Bell's Palsy Study (SBPS), which made a clear recommendation that treatment with prednisolone alone improves chances for complete recovery.
Main outcome measures
Incidence of Bell's palsy per 100 000 person-years. Changes in the management of Bell's palsy with either prednisolone therapy, antiviral therapy, combination therapy (prednisolone with antiviral therapy) or untreated cases.
Results
During the 12-year period, 14 460 cases of Bell's palsy were identified with an overall incidence of 37.7/100 000 person-years. The 2004 Cochrane reviews were associated with immediate falls in prednisolone therapy (−6.3% (−11.0 to −1.6)), rising trends in combination therapy (1.1% per quarter (0.5 to 1.7)) and falling trends for untreated cases (−0.8% per quarter (−1.4 to −0.3)). SBPS was associated with immediate increases in prednisolone therapy (5.1% (0.9 to 9.3)) and rising trends in prednisolone therapy (0.7% per quarter (0.4 to 1.2)); falling trends in combination therapy (−1.7% per quarter (−2.2 to −1.3)); and rising trends for untreated cases (1.2% per quarter (0.8 to 1.6)). Despite improvements, 44% still remain untreated.
Conclusions
SBPS was clearly associated with change in management, but a significant proportion of patients failed to receive effective treatment, which cannot be fully explained. Clarity and uncertainty in clinical trial recommendations may change clinical practice. However, better ways are needed to understand and circumvent barriers in implementing clinical trial findings.
doi:10.1136/bmjopen-2013-003121
PMCID: PMC3717449  PMID: 23864211
Epidemiology; Primary Care; Clinical trials < Therapeutics
11.  An ethnographic exploration of influences on prescribing in general practice: why is there variation in prescribing practices? 
Background
Prescribing is a core activity for general practitioners, yet significant variation in the quality of prescribing has been reported. This suggests there may be room for improvement in the application of the current best research evidence. There has been substantial investment in technologies and interventions to address this issue, but effect sizes so far have been small to moderate. This suggests that prescribing is a decision-making process that is not sufficiently understood. By understanding more about prescribing processes and the implementation of research evidence, variation may more easily be understood and more effective interventions proposed.
Methods
An ethnographic study in three Scottish general practices with diverse organizational characteristics. Practices were ranked by their performance against Audit Scotland prescribing quality indicators, incorporating established best research evidence. Two practices of high prescribing quality and one practice of low prescribing quality were recruited. Participant observation, formal and informal interviews, and a review of practice documentation were employed.
Results
Practices ranked as high prescribing quality consistently made and applied macro and micro prescribing decisions, whereas the low-ranking practice only made micro prescribing decisions. Macro prescribing decisions were collective, policy decisions made considering research evidence in light of the average patient, one disease, condition, or drug. Micro prescribing decisions were made in consultation with the patient considering their views, preferences, circumstances and other conditions (if necessary).
Although micro prescribing can operate independently, the implementation of evidence-based, quality prescribing was attributable to an interdependent relationship. Macro prescribing policy enabled prescribing decisions to be based on scientific evidence and applied consistently where possible. Ultimately, this influenced prescribing decisions that occur at the micro level in consultation with patients.
Conclusion
General practitioners in the higher prescribing quality practices made two different ‘types’ of prescribing decision; macro and micro. Macro prescribing informs micro prescribing and without a macro basis to draw upon the low-ranked practice had no effective mechanism to engage with, reflect on and implement relevant evidence. Practices that recognize these two levels of decision making about prescribing are more likely to be able to implement higher quality evidence.
doi:10.1186/1748-5908-8-72
PMCID: PMC3693908  PMID: 23799906
Prescribing; Quality; General practice; Primary care; Ethnographic; Qualitative
12.  Making clinical trials more relevant: improving and validating the PRECIS tool for matching trial design decisions to trial purpose 
Trials  2013;14:115.
Background
If you want to know which of two or more healthcare interventions is most effective, the randomised controlled trial is the design of choice. Randomisation, however, does not itself promote the applicability of the results to situations other than the one in which the trial was done. A tool published in 2009, PRECIS (PRagmatic Explanatory Continuum Indicator Summaries) aimed to help trialists design trials that produced results matched to the aim of the trial, be that supporting clinical decision-making, or increasing knowledge of how an intervention works. Though generally positive, groups evaluating the tool have also found weaknesses, mainly that its inter-rater reliability is not clear, that it needs a scoring system and that some new domains might be needed. The aim of the study is to: Produce an improved and validated version of the PRECIS tool. Use this tool to compare the internal validity of, and effect estimates from, a set of explanatory and pragmatic trials matched by intervention.
Methods
The study has four phases. Phase 1 involves brainstorming and a two-round Delphi survey of authors who cited PRECIS. In Phase 2, the Delphi results will then be discussed and alternative versions of PRECIS-2 developed and user-tested by experienced trialists. Phase 3 will evaluate the validity and reliability of the most promising PRECIS-2 candidate using a sample of 15 to 20 trials rated by 15 international trialists. We will assess inter-rater reliability, and raters’ subjective global ratings of pragmatism compared to PRECIS-2 to assess convergent and face validity. Phase 4, to determine if pragmatic trials sacrifice internal validity in order to achieve applicability, will compare the internal validity and effect estimates of matched explanatory and pragmatic trials of the same intervention, condition and participants. Effect sizes for the trials will then be compared in a meta-regression. The Cochrane Risk of Bias scores will be compared with the PRECIS-2 scores of pragmatism.
Discussion
We have concrete suggestions for improving PRECIS and a growing list of enthusiastic individuals interested in contributing to this work. By early 2014 we expect to have a validated PRECIS-2.
doi:10.1186/1745-6215-14-115
PMCID: PMC3748822  PMID: 23782862
Pragmatic; Explanatory; Clinical trials; Trial design; Applicability
13.  Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis 
BMJ Open  2013;3(2):e002360.
This review is an abridged version of a Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2010, Issue 4, Art. No.: MR000013 DOI: 10.1002/14651858.MR000013.pub5 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review.
Objective
To identify interventions designed to improve recruitment to randomised controlled trials, and to quantify their effect on trial participation.
Design
Systematic review.
Data sources
The Cochrane Methodology Review Group Specialised Register in the Cochrane Library, MEDLINE, EMBASE, ERIC, Science Citation Index, Social Sciences Citation Index, C2-SPECTR, the National Research Register and PubMed. Most searches were undertaken up to 2010; no language restrictions were applied.
Study selection
Randomised and quasi-randomised controlled trials, including those recruiting to hypothetical studies. Studies on retention strategies, examining ways to increase questionnaire response or evaluating the use of incentives for clinicians were excluded. The study population included any potential trial participant (eg, patient, clinician and member of the public), or individual or group of individuals responsible for trial recruitment (eg, clinicians, researchers and recruitment sites). Two authors independently screened identified studies for eligibility.
Results
45 trials with over 43 000 participants were included. Some interventions were effective in increasing recruitment: telephone reminders to non-respondents (risk ratio (RR) 1.66, 95% CI 1.03 to 2.46; two studies, 1058 participants), use of opt-out rather than opt-in procedures for contacting potential participants (RR 1.39, 95% CI 1.06 to 1.84; one study, 152 participants) and open designs where participants know which treatment they are receiving in the trial (RR 1.22, 95% CI 1.09 to 1.36; two studies, 4833 participants). However, the effect of many other strategies is less clear, including the use of video to provide trial information and interventions aimed at recruiters.
Conclusions
There are promising strategies for increasing recruitment to trials, but some methods, such as open-trial designs and opt-out strategies, must be considered carefully as their use may also present methodological or ethical challenges. Questions remain as to the applicability of results originating from hypothetical trials, including those relating to the use of monetary incentives, and there is a clear knowledge gap with regard to effective strategies aimed at recruiters.
doi:10.1136/bmjopen-2012-002360
PMCID: PMC3586125  PMID: 23396504
Statistics & Research Methods; Medical Ethics
14.  Gastrointestinal radiation injury: Symptoms, risk factors and mechanisms 
Ionising radiation therapy is a common treatment modality for different types of cancer and its use is expected to increase with advances in screening and early detection of cancer. Radiation injury to the gastrointestinal tract is important factor working against better utility of this important therapeutic modality. Cancer survivors can suffer a wide variety of acute and chronic symptoms following radiotherapy, which significantly reduces their quality of life as well as adding an extra burden to the cost of health care. The accurate diagnosis and treatment of intestinal radiation injury often represents a clinical challenge to practicing physicians in both gastroenterology and oncology. Despite the growing recognition of the problem and some advances in understanding the cellular and molecular mechanisms of radiation injury, relatively little is known about the pathophysiology of gastrointestinal radiation injury or any possible susceptibility factors that could aggravate its severity. The aims of this review are to examine the various clinical manifestations of post-radiation gastrointestinal symptoms, to discuss possible patient and treatment factors implicated in normal gastrointestinal tissue radiosensitivity and to outline different mechanisms of intestinal tissue injury.
doi:10.3748/wjg.v19.i2.185
PMCID: PMC3547560  PMID: 23345941
Radiation enteritis; Radiation proctitis; Symptoms; Pathophysiology; Risk factors
15.  Gastrointestinal radiation injury: Prevention and treatment 
With the recent advances in detection and treatment of cancer, there is an increasing emphasis on the efficacy and safety aspects of cancer therapy. Radiation therapy is a common treatment for a wide variety of cancers, either alone or in combination with other treatments. Ionising radiation injury to the gastrointestinal tract is a frequent side effect of radiation therapy and a considerable proportion of patients suffer acute or chronic gastrointestinal symptoms as a result. These side effects often cause morbidity and may in some cases lower the efficacy of radiotherapy treatment. Radiation injury to the gastrointestinal tract can be minimised by either of two strategies: technical strategies which aim to physically shift radiation dose away from the normal intestinal tissues, and biological strategies which aim to modulate the normal tissue response to ionising radiation or to increase its resistance to it. Although considerable improvement in the safety of radiotherapy treatment has been achieved through the use of modern optimised planning and delivery techniques, biological techniques may offer additional further promise. Different agents have been used to prevent or minimize the severity of gastrointestinal injury induced by ionising radiation exposure, including biological, chemical and pharmacological agents. In this review we aim to discuss various technical strategies to prevent gastrointestinal injury during cancer radiotherapy, examine the different therapeutic options for acute and chronic gastrointestinal radiation injury and outline some examples of research directions and considerations for prevention at a pre-clinical level.
doi:10.3748/wjg.v19.i2.199
PMCID: PMC3547575  PMID: 23345942
Radiation enteritis; Radiation proctitis; Prevention; Treatment; Gastrointestinal radiation injury
16.  The Utility of Liver Function Tests for Mortality Prediction within One Year in Primary Care Using the Algorithm for Liver Function Investigations (ALFI) 
PLoS ONE  2012;7(12):e50965.
Background
Although liver function tests (LFTs) are routinely measured in primary care, raised levels in patients with no obvious liver disease may trigger a range of subsequent expensive and unnecessary management plans. The aim of this study was to develop and validate a prediction model to guide decision-making by general practitioners, which estimates risk of one year all-cause mortality in patients with no obvious liver disease.
Methods
In this population-based historical cohort study, biochemistry data from patients in Tayside, Scotland, with LFTs performed in primary care were record-linked to secondary care and prescription databases to ascertain baseline characteristics, and to mortality data. Using this derivation cohort a survival model was developed to predict mortality. The model was assessed for calibration, discrimination (using the C-statistic) and performance, and validated using a separate cohort of Scottish primary care practices.
Results
From the derivation cohort (n = 95 977), 2.7% died within one year. Predictors of mortality included: age; male gender; social deprivation; history of cancer, renal disease, stroke, ischaemic heart disease or respiratory disease; statin use; and LFTs (albumin, transaminase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase). The C-statistic for the final model was 0.82 (95% CI 0.80–0.84), and was similar in the validation cohort (n = 11 653) 0.86 (0.79–0.90). As an example of performance, for a 10% predicted probability cut-off, sensitivity = 52.8%, specificity = 94.0%, PPV = 21.0%, NPV = 98.5%. For the model without LFTs the respective values were 43.8%, 92.8%, 15.6%, 98.1%.
Conclusions
The Algorithm for Liver Function Investigations (ALFI) is the first model to successfully estimate the probability of all-cause mortality in patients with no apparent liver disease having LFTs in primary care. While LFTs added to the model's discrimination and sensitivity, the clinical utility of ALFI remains to be established since LFTs did not improve an already high NPV for short term mortality and only modestly improved a very low PPV.
doi:10.1371/journal.pone.0050965
PMCID: PMC3522690  PMID: 23272082
17.  Risk of Cardiovascular Disease and Total Mortality in Adults with Type 1 Diabetes: Scottish Registry Linkage Study 
PLoS Medicine  2012;9(10):e1001321.
Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.
Background
Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.
Methods and Findings
The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p<0.001) than men (2.3: 2.0–2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p<0.001) in men and 2.7 (2.2–3.4, p<0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.
Conclusions
Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background. People with diabetes are more likely to have cardiovascular disease such as heart attacks and strokes. They also have a higher risk of dying prematurely from any cause. Controlling blood sugar (glucose), blood pressure, and cholesterol can help reduce these risks. Some people with type 1 diabetes can achieve tight blood glucose control through a strict regimen that includes a carefully calculated diet, frequent physical activity, regular blood glucose testing several times a day, and multiple daily doses of insulin. Other drugs can reduce blood pressure and cholesterol levels. Keeping one's weight in the normal range and not smoking are important ways in which all people, including those with type 1 diabetes can reduce their risks of heart disease and premature death.
Why Was This Study Done? Researchers and doctors have known for almost two decades what patients with type 1 diabetes can do to minimize the complications from the disease and thereby reduce their risks for cardiovascular disease and early death. So for some time now, patients should have been treated and counseled accordingly. This study was done to evaluate the current risks for have cardiovascular disease and premature death amongst people living with type 1 diabetes in a high-income country (Scotland).
What Did the Researchers Do and Find? From a national register of all people with type 1 diabetes in Scotland, the researchers selected those who were older than 20 years and alive at any time from January 2005 to May 2008. This included about 19,000 people who had been diagnosed with type 1 diabetes before 2005. Another 2,600 were diagnosed between 2005 and 2008. They also obtained data on heart attacks and strokes in these patients from hospital records and on deaths from the natural death register. To obtain a good picture of the current relative risks, they compared the patients with type 1 diabetes with the non-diabetic general Scottish population with regard to the risk of heart attacks/strokes and death from all causes. They also collected information on how well the people with diabetes controlled their blood glucose, on their weight, and whether they smoked.
They found that the current risks compared with the general Scottish population are quite a bit lower than those of people with type 1 diabetes in earlier decades. However, people with type 1 diabetes in Scotland still have much higher (more than twice) the risk of heart attacks, strokes, or premature death than the general population. Moreover, the researchers found a high number of deaths in younger people with diabetes from coma—caused by either too much blood sugar (hyperglycemia) or too little (hypoglycemia). Severe hyperglycemia and hypoglycemia happen when blood glucose control is poor. When the scientists looked at test results for HbA1c levels (a test that is done once or twice a year to see how well patients controlled their blood sugar over the previous 3 months) for all patients, they found that the majority of them did not come close to controlling their blood glucose within the recommended range.
When the researchers compared body mass index (a measure of weight that takes height into account) and smoking between the people with type 1 diabetes and the general population, they found similar proportions of smokers and overweight or obese people.
What Do these Findings Mean? The results represent a snapshot of the recent situation regarding complications from type 1 diabetes in the Scottish population. The results suggest that within this population, strategies over the past two decades to reduce complications from type 1 diabetes that cause cardiovascular disease and death are working, in principle. However, there is much need for further improvement. This includes the urgent need to understand why so few people with type 1 diabetes achieve good control of their blood sugar, and what can be done to improve this situation. It is also important to put more effort into keeping people with diabetes from taking up smoking or getting them to quit, as well as preventing them from getting overweight or promoting weight reduction, because this could further reduce the risks of cardiovascular disease and premature death.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001321
National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on heart disease and diabetes, on general complications of diabetes, and on the HbA1c test (on this site and some others called A1C test) that measures control of blood sugar over the past 3 months
Diabetes.co.uk provides general information on type 1 diabetes, its complications, and what people with the disease can do to reduce their risks
The Canadian Diabetes Association offers a cardiovascular risk self-assessment tool and other relevant information
The American Diabetes Association has information on the benefits and challenges of tight blood sugar control and how it is tested
The Juvenile Diabetes Research Foundation funds research to prevent, cure, and treat type 1 diabetes
Diabetes UK provides extensive information on diabetes for patients, carers, and clinicians
doi:10.1371/journal.pmed.1001321
PMCID: PMC3462745  PMID: 23055834
19.  Protocol for a drugs exposure pregnancy registry for implementation in resource-limited settings 
Background
The absence of robust evidence of safety of medicines in pregnancy, particularly those for major diseases provided by public health programmes in developing countries, has resulted in cautious recommendations on their use. We describe a protocol for a Pregnancy Registry adapted to resource-limited settings aimed at providing evidence on the safety of medicines in pregnancy.
Methods/Design
Sentinel health facilities are chosen where women come for prenatal care and are likely to come for delivery. Staff capacity is improved to provide better care during the pregnancy, to identify visible birth defects at delivery and refer infants with major anomalies for surgical or clinical evaluation and treatment. Consenting women are enrolled at their first antenatal visit and careful medical, obstetric and drug-exposure histories taken; medical record linkage is encouraged. Enrolled women are followed up prospectively and their histories are updated at each subsequent visit. The enrolled woman is encouraged to deliver at the facility, where she and her baby can be assessed.
Discussion
In addition to data pooling into a common WHO database, the WHO Pregnancy Registry has three important features: First is the inclusion of pregnant women coming for antenatal care, enabling comparison of birth outcomes of women who have been exposed to a medicine with those who have not. Second is its applicability to resource-poor settings regardless of drug or disease. Third is improvement of reproductive health care during pregnancies and at delivery. Facility delivery enables better health outcomes, timely evaluation and management of the newborn, and the collection of reliable clinical data. The Registry aims to improves maternal and neonatal care and also provide much needed information on the safety of medicines in pregnancy.
doi:10.1186/1471-2393-12-89
PMCID: PMC3500715  PMID: 22943425
Pregnancy Registry; Congenital anomaly; Pharmacovigilance; Teratogenicity; Drug exposure; Antiretrovirals; Antimalarials; Birth defects; Neonates; Safety; Resource-limited settings
21.  Insightful practice: a reliable measure for medical revalidation 
BMJ quality & safety  2012;21(8):649-656.
Background
Medical revalidation decisions need to be reliable if they are to reassure on the quality and safety of professional practice. This study tested an innovative method in which general practitioners (GPs) were assessed on their reflection and response to a set of externally specified feedback.
Setting and participants
60 GPs and 12 GP appraisers in the Tayside region of Scotland, UK.
Methods
A feedback dataset was specified as (1) GP-specific data collected by GPs themselves (patient and colleague opinion; open book self-evaluated knowledge test; complaints) and (2) Externally collected practice-level data provided to GPs (clinical quality and prescribing safety). GPs' perceptions of whether the feedback covered UK General Medical Council specified attributes of a ‘good doctor’ were examined using a mapping exercise. GPs' professionalism was examined in terms of appraiser assessment of GPs' level of insightful practice, defined as: engagement with, insight into and appropriate action on feedback data. The reliability of assessment of insightful practice and subsequent recommendations on GPs' revalidation by face-to-face and anonymous assessors were investigated using Generalisability G-theory.
Main outcome measures
Coverage of General Medical Council attributes by specified feedback and reliability of assessor recommendations on doctors' suitability for revalidation.
Results
Face-to-face assessment proved unreliable. Anonymous global assessment by three appraisers of insightful practice was highly reliable (G=0.85), as were revalidation decisions using four anonymous assessors (G=0.83).
Conclusions
Unlike face-to-face appraisal, anonymous assessment of insightful practice offers a valid and reliable method to decide GP revalidation. Further validity studies are needed.
doi:10.1136/bmjqs-2011-000429
PMCID: PMC3404544  PMID: 22653078
Audit and feedback; continuous quality improvement; general practice; governance; medical education; evaluation methodology
22.  Using Web Technology to Support Population-Based Diabetes Care 
Background:
Managed clinical networks have been used to coordinate chronic disease management across geographical regions in the United Kingdom. Our objective was to review how clinical networks and multidisciplinary team-working can be supported by Web-based information technology while clinical requirements continually change.
Methods:
A Web-based population information system was developed and implemented in November 2000. The system incorporates local guidelines and shared clinical information based upon a national dataset for multispecialty use. Automated data linkages were developed to link to the master index database, biochemistry, eye screening, and general practice systems and hospital diabetes clinics. Web-based data collection forms were developed where computer systems did not exist. The experience over the first 10 years (to October 2010) was reviewed.
Results:
The number of people with diabetes in Tayside increased from 9694 (2.5% prevalence) in 2001 to 18,355 (4.6%) in 2010. The user base remained stable (~400 users), showing a high level of clinical utility was maintained. Automated processes support a single point of data entry with 10,350 clinical messages containing 40,463 data items sent to external systems during year 10. The system supported quality improvement of diabetes care; for example, foot risk recording increased from 36% in 2007 to 73.3% in 2010.
Conclusions:
Shared-care datasets can improve communication between health care service providers. Web-based technology can support clinical networks in providing comprehensive, seamless care across a geographical region for people with diabetes. While health care requirements evolve, technology can adapt, remain usable, and contribute significantly to quality improvement and working practice.
PMCID: PMC3192619  PMID: 21722568
electronic records; information technology; integrated care; managed clinic networks; shared care
23.  Dermatology research in primary care: why, what, and how? 
doi:10.3399/bjgp11X556173
PMCID: PMC3026146  PMID: 21276334
25.  The Research Paper of the Year Award 2009 
doi:10.3399/bjgp10X515214
PMCID: PMC2913750

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