Journal: BMJ

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Abstract

Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications.

England BR, Thiele GM, Anderson DR, Mikuls TR
Rheumatoid arthritis is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. Mechanisms linking rheumatoid arthritis and cardiovascular disease include shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, alterations in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction. Despite a growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown. A multifaceted approach to reduce the burden posed by cardiovascular disease requires optimal management of traditional risk factors in addition to those intrinsic to rheumatoid arthritis such as increased disease activity. Treatments for rheumatoid arthritis seem to exert differential effects on cardiovascular risk as well as the mechanisms linking these conditions. More research is needed to establish whether preferential rheumatoid arthritis therapies exist in terms of prevention of cardiovascular disease. Ultimately, understanding the unique mechanisms for cardiovascular disease in rheumatoid arthritis will aid in risk stratification and the identification of novel targets for meaningful reduction of cardiovascular risk in this patient population.

BMJ: 22 Apr 2018; 361:k1036
England BR, Thiele GM, Anderson DR, Mikuls TR
BMJ: 22 Apr 2018; 361:k1036 | PMID: 29685876
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Abstract

Peripartum cardiomyopathy.

Honigberg MC, Givertz MM
Peripartum cardiomyopathy (PPCM) is a rare, often dilated, cardiomyopathy with systolic dysfunction that presents in late pregnancy or, more commonly, the early postpartum period. Although the condition is prevalent worldwide, women with black ancestry seem to be at greatest risk, and the condition has a particularly high incidence in Nigeria and Haiti. Other risk factors include pre-eclampsia, advanced maternal age, and multiple gestation pregnancy. Although the complete pathophysiology of peripartum cardiomyopathy remains unclear, research over the past decade suggests the importance of vasculo-hormonal pathways in women with underlying susceptibility. At least some women with the condition harbor an underlying sarcomere gene mutation. More than half of affected women recover systolic function, although some are left with a chronic cardiomyopathy, and a minority requires mechanical support or cardiac transplantation (or both). Other potential complications include thromboembolism and arrhythmia. Currently, management entails standard treatments for heart failure with reduced ejection fraction, with attention to minimizing potential adverse effects on the fetus in women who are still pregnant. Bromocriptine is one potential disease specific treatment under investigation. In this review, we summarize the current literature on peripartum cardiomyopathy, as well as gaps in the understanding of this condition and future research directions.

BMJ: 29 Jan 2019; 364:k5287
Honigberg MC, Givertz MM
BMJ: 29 Jan 2019; 364:k5287 | PMID: 30700415
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Abstract

The role of the gut microbiome in systemic inflammatory disease.

Clemente JC, Manasson J, Scher JU
The role of the gut microbiome in models of inflammatory and autoimmune disease is now well characterized. Renewed interest in the human microbiome and its metabolites, as well as notable advances in host mucosal immunology, has opened multiple avenues of research to potentially modulate inflammatory responses. The complexity and interdependence of these diet-microbe-metabolite-host interactions are rapidly being unraveled. Importantly, most of the progress in the field comes from new knowledge about the functional properties of these microorganisms in physiology and their effect in mucosal immunity and distal inflammation. This review summarizes the preclinical and clinical evidence on how dietary, probiotic, prebiotic, and microbiome based therapeutics affect our understanding of wellness and disease, particularly in autoimmunity.

BMJ: 07 Jan 2018; 360:j5145
Clemente JC, Manasson J, Scher JU
BMJ: 07 Jan 2018; 360:j5145 | PMID: 29311119
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Abstract

Newer technologies for detection of atrial fibrillation.

Zungsontiporn N, Link MS
Atrial fibrillation is a common arrhythmia that is associated with increased risk of stroke, which can be reduced with appropriate anticoagulation treatment. However, it remains underdiagnosed in contemporary clinical practice using conventional detection methods, resulting in missed opportunities to implement appropriate treatment. Newer technologies developed in recent years can potentially enhance the detection of atrial fibrillation and overcome certain limitations of the conventional methods. However, uncertainties remain about their use and the significance of atrial fibrillation detected by some of these newer technologies. This review examines the evidence supporting the use of some of these technologies and evaluates their applications in certain clinical scenarios.

BMJ: 16 Oct 2018; 363:k3946
Zungsontiporn N, Link MS
BMJ: 16 Oct 2018; 363:k3946 | PMID: 30333105
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Abstract

Overdiagnosis in primary care: framing the problem and finding solutions.

Kale MS, Korenstein D
Overdiagnosis, is defined as the diagnosis of a condition that, if unrecognized, would not cause symptoms or harm a patient during his or her lifetime, and it is increasingly acknowledged as a consequence of screening for cancer and other conditions. Because preventive care is a crucial component of primary care, which is delivered to the broad population, overdiagnosis in primary care is an important problem from a public health perspective and has far reaching implications. The scope of overdiagnosis as a result of services delivered in primary care is unclear, though overdiagnosis of indolent breast, prostate, thyroid, and lung cancers is well described and overdiagnosis of chronic kidney disease, depression, and attention-deficit/hyperactivity disorder is also recognized. However, overdiagnosis is a known consequence of all screening and can be assumed to occur in many more clinical contexts. Overdiagnosis can harm patients by leading to overtreatment (with associated potential toxicities), diagnosis related anxiety or depression, and labeling, or through financial burden. Many entrenched factors facilitate overdiagnosis, including the growing use of advanced diagnostic technology, financial incentives, a medical culture that encourages greater use of tests and treatments, limitations in the evidence that obscure the understanding of diagnostic utility, use of non-beneficial screening tests, and the broadening of disease definitions. Efforts to reduce overdiagnosis are hindered by physicians\' and patients\' lack of awareness of the problem and by confusion about terminology, with overdiagnosis often conflated with related concepts. Clarity of terminology would facilitate physicians\' understanding of the problem and the growth in evidence regarding its prevalence and downstream consequences in primary care. It is hoped that international coordination regarding diagnostic standards for disease definitions will also help minimize overdiagnosis in the future.

BMJ: 13 Aug 2018; 362:k2820
Kale MS, Korenstein D
BMJ: 13 Aug 2018; 362:k2820 | PMID: 30108054
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Abstract

Palliative care in patients with heart failure.

McIlvennan CK, Allen LA
Despite advances in cardiac therapy, heart failure (HF) remains a progressive, highly symptomatic, and deadly disease that places great demands on patients, caregivers, and healthcare systems. Palliative care is a multidisciplinary approach to care that focuses on communication, shared decision making, and advance care planning; provides relief from pain and other distressing symptoms; integrates psychological and spiritual aspects of care; and offers a support system to help families cope during illness and bereavement. Palliative care has applications across the stages of heart failure, including early in the course of illness, often in conjunction with other therapies that are intended to prolong life. However, the incorporation of palliative care into the management of heart failure has been suboptimal for several reasons: uncertainty in the disease trajectory, failure to reward communication between healthcare providers and patients, siloed care, lack of knowledge, overlay of comorbidity and frailty, life saving devices with complex trade-offs, and a limited evidence base. This review will summarize the current literature on the emerging role of palliative care in patients with heart failure and the challenges and opportunities for its integration into routine care. It will discuss current initiatives and future directions of the collaborative relationship between the palliative care and heart failure disciplines.

BMJ: 14 Apr 2016; 353:i1010
McIlvennan CK, Allen LA
BMJ: 14 Apr 2016; 353:i1010 | PMID: 27079896
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Abstract

Novel therapies for diabetes mellitus in pregnancy.

Feghali MN, Scifres CM
Diabetes is a common complication of pregnancy, and the prevalence of all types of the disease is increasing worldwide. Diabetes in pregnancy is associated with short term and long term adverse effects for mother and child. The goal of treatment of diabetes in pregnancy is to minimize maternal and fetal adverse events related to hyperglycemia. Treatment options vary by type of diabetes, from a focus on lifestyle modifications in gestational diabetes to continuous glucose monitoring and insulin pumps in pregestational diabetes. Nevertheless, given the commonality of hyperglycemia, considerable overlap exists in the treatment of different types of diabetes in pregnancy. Also, despite ongoing research on treatment of diabetes in pregnancy for decades, changes in the characteristics of the patient population have highlighted the limited effectiveness of different therapies. Specifically, despite the co-occurrence of obesity and diabetes, treatment recommendations including glycemic targets are not altered in such cases and a single optimal treatment strategy for each type of diabetes in pregnancy does not seem to exist. Rather, the approach to treating pregnant women with diabetes likely needs to be individualized to maximize the short term and long term health of mother and child. This article will review recent clinical studies to summarize established treatment strategies and introduce novel therapies for diabetes in pregnancy.

BMJ: 15 Jul 2018; 362:k2034
Feghali MN, Scifres CM
BMJ: 15 Jul 2018; 362:k2034 | PMID: 30012851
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Abstract

Intraoperative fluid management guided by oesophageal Doppler monitoring.

Kuper M, Gold SJ, Callow C, Quraishi T, ... Bianchi M, Conway DH
Problem Fluid management during major surgery poses a challenge to the surgical team as postoperative complications are often related to giving the wrong amount of intravenous fluid. Postoperative morbidity can be reduced by using the oesophageal Doppler cardiac output monitor to individualise fluid administration, but this technology has not been widely adopted. Design A campaign for adopting this technology in major surgical specialties explored clinical and managerial barriers throughout the procurement and implementation process. We compared patient outcomes 12 months before implementation and after implementation. Setting: Three large hospitals in England with different size, geographical location, and case mix. Strategies for change Project leads at each site included a consultant anaesthetist, a divisional manager, and an audit facilitator. A business case was prepared by each team with support from NHS Technology Adoption Centre, allowing senior management to overcome the unequal spread of costs versus benefits. A survey of anaesthetists revealed concerns about familiarity with the device, which we dealt with by clinicians volunteering to "champion" the technique, supported by standard training provided by the manufacturer. We encouraged appropriate use of the technology by collecting intraoperative patient related data and postoperative patient outcomes and by giving regular, timely feedback. Key measures for improvement The key outcome measure was length of hospital stay. In-hospital mortality, readmission, and reoperation rates were also recorded. Process measures were use of monitors and change in stroke volume during surgery. Effects of the change We compared 649 patients after implementation across all sites with 658 matched cases before implementation. Use of Doppler increased from 11% to 65% of eligible operations, with a 3.7 day reduction in total length of stay. Length of stay was reduced at each site, and in most specialties. Concurrent improvements in patient care could have contributed to these findings. The only sign of harm from the intervention was one episode of pulmonary oedema. Mortality, readmission, and reoperation rates all fell non-significantly. Lessons learnt Managerial barriers consisted of silo budgeting, difficulties with preparing a business case, and fears about uncontrolled implementation. By collecting outcome data, we convinced senior managers to support and sustain investment. Clinical barriers consisted mainly of scepticism regarding clinical effectiveness and worries about training. Clinicians "championing" the technology took on responsibility for data collection, education, advocacy, and spanning boundaries. When barriers to adoption of oesophageal Doppler monitoring are overcome, outcome improvements suggested by research can be replicated in the real world. The project generated a web based guide (www.howtowhyto.nhs.uk) to provide tools and resources to support implementation.

BMJ: 25 May 2011; 342:d3016
Kuper M, Gold SJ, Callow C, Quraishi T, ... Bianchi M, Conway DH
BMJ: 25 May 2011; 342:d3016 | PMID: 21610051
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Abstract

Management of diabetes mellitus in older people with comorbidities.

Huang ES
Diabetes mellitus is a chronic disease of aging that affects more than 20% of people over 65. In older patients with diabetes, comorbidities are highly prevalent and their presence may alter the relative importance, effectiveness, and safety of treatments for diabetes. Randomized controlled trials have shown that intensive glucose control produces microvascular and cardiovascular benefits but typically after extended treatment periods (five to nine years) and with exposure to short term risks such as mortality (in one trial) and hypoglycemia. Decision analysis, health economics, and observational studies have helped to illustrate the importance of acknowledging life expectancy, hypoglycemia, and treatment burden when setting goals in diabetes. Guidelines recommend that physicians individualize the intensity of glucose control and treatments on the basis of the prognosis (for example, three tiers based on comorbidities and functional impairments) and preferences of individual patients. Very few studies have attempted to formally implement and study these concepts in clinical practice. To better meet the treatment needs of older patients with diabetes and comorbidities, more research is needed to determine the risks and benefits of intensifying, maintaining, or de-intensifying treatments in this population. This research effort should extend to the development and study of decision support tools as well as targeted care management.

BMJ: 15 Jun 2016; 353:i2200
Huang ES
BMJ: 15 Jun 2016; 353:i2200 | PMID: 27307175
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Abstract

Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial.

James SK, Roe MT, Cannon CP, Cornel JH, ... Harrington RA, For the PLATO Study Group
Objective: To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy. Design: Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial. Setting: 862 centres in 43 countries. Participants: 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management. Interventions: Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615). Main outcome measurements Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year. Results: 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel. Conclusions: In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy. Trial registration Clinical trials NCT00391872.

BMJ: 20 Jun 2011; 342:d3527
James SK, Roe MT, Cannon CP, Cornel JH, ... Harrington RA, For the PLATO Study Group
BMJ: 20 Jun 2011; 342:d3527 | PMID: 21685437
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Abstract

Perioperative lung protective ventilation.

O\'Gara B, Talmor D
Perioperative lung injury is a major source of postoperative morbidity, excess healthcare use, and avoidable mortality. Many potential inciting factors can lead to this condition, including intraoperative ventilator induced lung injury. Questions exist as to whether protective ventilation strategies used in the intensive care unit for patients with acute respiratory distress syndrome are equally beneficial for surgical patients, most of whom do not present with any pre-existing lung pathology. Studied both individually and in combination as a package of intraoperative lung protective ventilation, the use of low tidal volumes, moderate positive end expiratory pressure, and recruitment maneuvers have been shown to improve oxygenation and pulmonary physiology and to reduce postoperative pulmonary complications in at risk patient groups. Further work is needed to define the potential contributions of alternative ventilator strategies, limiting excessive intraoperative oxygen supplementation, use of non-invasive techniques in the postoperative period, and personalized mechanical ventilation. Although the weight of evidence strongly suggests a role for lung protective ventilation in moderate risk patient groups, definitive evidence of its benefit for the general surgical population does not exist. However, given the shift in understanding of what is needed for adequate oxygenation and ventilation under anesthesia, the largely historical arguments against the use of intraoperative lung protective ventilation may soon be outdated, on the basis of its expanding track record of safety and efficacy in multiple settings.

BMJ: 09 Sep 2018; 362:k3030
O'Gara B, Talmor D
BMJ: 09 Sep 2018; 362:k3030 | PMID: 30201797
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Abstract

Advances in optimizing the prescription of antibiotics in outpatient settings.

King LM, Fleming-Dutra KE, Hicks LA
The inappropriate use of antibiotics can increase the likelihood of antibiotic resistance and adverse events. In the United States, nearly a third of antibiotic prescriptions in outpatient settings are unnecessary, and the selection of antibiotics and duration of treatment are also often inappropriate. Evidence shows that antibiotic prescribing is influenced by psychosocial factors, including lack of accountability, perceived patient expectations, clinician workload, and habit. A varied and growing body of evidence, including meta-analyses and randomized controlled trials, has evaluated interventions to optimize the use of antibiotics. Interventions informed by behavioral science-such as communication skills training, audit and feedback with peer comparison, public commitment posters, and accountable justification-have been associated with improved antibiotic prescribing. In addition, delayed prescribing, active monitoring, and the use of diagnostics are guideline recommended practices that improve antibiotic use for some conditions. In 2016, the Centers for Disease Control and Prevention released the , which provides a framework for implementing these interventions in outpatient settings. This review summarizes the varied evidence on drivers of inappropriate prescription of antibiotics in outpatient settings and potential interventions to improve their use in such settings.

BMJ: 11 Nov 2018; 363:k3047
King LM, Fleming-Dutra KE, Hicks LA
BMJ: 11 Nov 2018; 363:k3047 | PMID: 30420401
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Abstract

Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database.

Hippisley-Cox J, Coupland C, Robson J, Brindle P
Objective: To develop, validate, and evaluate a new QRISK model to estimate lifetime risk of cardiovascular disease. Design: Prospective cohort study with routinely collected data from general practice. Cox proportional hazards models in the derivation cohort to derive risk equations accounting for competing risks. Measures of calibration and discrimination in the validation cohort. Setting: 563 general practices in England and Wales contributing to the QResearch database. SUBJECTS: Patients aged 30-84 years who were free of cardiovascular disease and not taking statins between 1 January 1994 and 30 April 2010: 2 343 759 in the derivation dataset, and 1 267 159 in the validation dataset. Main outcomes measures Individualised estimate of lifetime risk of cardiovascular disease accounting for smoking status, ethnic group, systolic blood pressure, ratio of total cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative aged <60 years, Townsend deprivation score, treated hypertension, rheumatoid arthritis, chronic renal disease, type 2 diabetes, and atrial fibrillation. Age-sex centile values for lifetime cardiovascular risk compared with 10 year risk estimated using QRISK2 (2010). Results: Across all the 1 267 159 patients in the validation dataset, the 50th, 75th, 90th, and 95th centile values for lifetime risk were 31%, 39%, 50%, and 57% respectively. Of the 10% of patients in the validation cohort classified at highest risk with either the lifetime risk model or the 10 year risk model, only 18 385(14.5%) were at high risk on both measures. Patients identified as high risk with the lifetime risk approach were more likely to be younger, male, from ethnic minority groups, and have a positive family history of premature coronary heart disease than those identified with the 10 year QRISK2 score. The lifetime risk calculator is available at www.qrisk.org/lifetime/. Conclusions: Compared with using a 10 year QRISK2 score, a lifetime risk score will tend to identify patients for intervention at a younger age. Although lifestyle interventions at an earlier age could be advantageous, there would be small gains under the age of 65, and medical interventions carry risks as soon as they are initiated. Research is needed to examine closely the cost effectiveness and acceptability of such an approach.

BMJ: 14 Dec 2010; 341:c6624
Hippisley-Cox J, Coupland C, Robson J, Brindle P
BMJ: 14 Dec 2010; 341:c6624 | PMID: 21148212
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Abstract

Advances in rehabilitation for chronic diseases: improving health outcomes and function.

Richardson CR, Franklin B, Moy ML, Jackson EA
Much of the burden on healthcare systems is related to the management of chronic conditions such as cardiovascular disease and chronic obstructive pulmonary disease. Although conventional outpatient cardiopulmonary rehabilitation programs significantly decrease morbidity and mortality and improve function and health related quality of life for people with chronic diseases, rehabilitation programs are underused. Barriers to enrollment are multifactorial and include failure to recommend and refer patients to these services; poor communication with patients about potential benefits; and patient factors including logistical and financial barriers, comorbidities, and competing demands that make participation in facility based programs difficult. Recent advances in rehabilitation programs that involve remotely delivered technology could help deliver services to more people who might benefit. Problems with intensity, adherence, and safety of home based programs have been investigated in recent clinical trials, and larger dissemination and implementation trials are under way. This review summarizes the evidence for benefit of in-person cardiac and pulmonary rehabilitation programs. It also reviews the literature on newer developments, such as home based remotely mediated exercise programs developed to decrease cost and improve accessibility, high intensity interval training in cardiac rehabilitation, and alternative therapies such as tai chi and yoga for people with chronic obstructive pulmonary disease.

BMJ: 16 Jun 2019; 365:l2191
Richardson CR, Franklin B, Moy ML, Jackson EA
BMJ: 16 Jun 2019; 365:l2191 | PMID: 31208954
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Abstract

Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study.

Phua J, Koh Y, Du B, Tang YQ, ... Chan YH, for the MOSAICS Study Group
ObjectiveS: To assess the compliance of Asian intensive care units and hospitals to the Surviving Sepsis Campaign\'s resuscitation and management bundles. Secondary objectives were to evaluate the impact of compliance on mortality and the organisational characteristics of hospitals that were associated with higher compliance. Design: Prospective cohort study. Setting: 150 intensive care units in 16 Asian countries. Participants: 1285 adult patients with severe sepsis admitted to these intensive care units in July 2009. The organisational characteristics of participating centres, the patients\' baseline characteristics, the achievement of targets within the resuscitation and management bundles, and outcome data were recorded. Main outcome measure: Compliance with the Surviving Sepsis Campaign\'s resuscitation (six hours) and management (24 hours) bundles. Results: Hospital mortality was 44.5% (572/1285). Compliance rates for the resuscitation and management bundles were 7.6% (98/1285) and 3.5% (45/1285), respectively. On logistic regression analysis, compliance with the following bundle targets independently predicted decreased mortality: blood cultures (achieved in 803/1285; 62.5%, 95% confidence interval 59.8% to 65.1%), broad spectrum antibiotics (achieved in 821/1285; 63.9%, 61.3% to 66.5%), and central venous pressure (achieved in 345/870; 39.7%, 36.4% to 42.9%). High income countries, university hospitals, intensive care units with an accredited fellowship programme, and surgical intensive care units were more likely to be compliant with the resuscitation bundle. Conclusions: While mortality from severe sepsis is high, compliance with resuscitation and management bundles is generally poor in much of Asia. As the centres included in this study might not be fully representative, achievement rates reported might overestimate the true degree of compliance with recommended care and should be interpreted with caution. Achievement of targets for blood cultures, antibiotics, and central venous pressure was independently associated with improved survival.

BMJ: 14 Jun 2011; 342:d3245
Phua J, Koh Y, Du B, Tang YQ, ... Chan YH, for the MOSAICS Study Group
BMJ: 14 Jun 2011; 342:d3245 | PMID: 21669950
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Abstract

Effect of retirement on major chronic conditions and fatigue: French GAZEL occupational cohort study.

Westerlund H, Vahtera J, Ferrie JE, Singh-Manoux A, ... Zins M, Kivimäki M
ObjectiveS: To determine, using longitudinal analyses, if retirement is followed by a change in the risk of incident chronic diseases, depressive symptoms, and fatigue. Design Prospective study with repeat measures from 7 years before to 7 years after retirement. Setting: Large French occupational cohort (the GAZEL study), 1989-2007. Participants 11 246 men and 2858 women. Main outcome measures: Respiratory disease, diabetes, coronary heart disease and stroke, mental fatigue, and physical fatigue, measured annually by self report over the 15 year observation period; depressive symptoms measured at four time points. Results: The average number of repeat measurements per participant was 12.1. Repeated measures logistic regression with generalised estimating equations showed that the cumulative prevalence of self reported respiratory disease, diabetes, and coronary heart disease and stroke increased with age, with no break in the trend around retirement. In contrast, retirement was associated with a substantial decrease in the prevalence of both mental fatigue (odds ratio for fatigue one year after versus one year before retirement 0.19, 95% confidence interval 0.18 to 0.21) and physical fatigue (0.27, 0.26 to 0.30). A major decrease was also observed in depressive symptoms (0.60, 0.53 to 0.67). The decrease in fatigue around retirement was more pronounced among people with a chronic disease before retirement. Conclusions: Longitudinal modelling of repeat data showed that retirement did not change the risk of major chronic diseases but was associated with a substantial reduction in mental and physical fatigue and depressive symptoms, particularly among people with chronic diseases.

BMJ: 24 Nov 2010; 341:c6149
Westerlund H, Vahtera J, Ferrie JE, Singh-Manoux A, ... Zins M, Kivimäki M
BMJ: 24 Nov 2010; 341:c6149 | PMID: 21098617
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Abstract

Effect of pay for performance on the management and outcomes of hypertension in the United Kingdom: interrupted time series study.

Serumaga B, Ross-Degnan D, Avery AJ, Elliott RA, ... Zhang F, Soumerai SB
Objective: To assess the impact of a pay for performance incentive on quality of care and outcomes among UK patients with hypertension in primary care. Design: Interrupted time series. Setting: The Health Improvement Network (THIN) database, United Kingdom. Participants: 470 725 patients with hypertension diagnosed between January 2000 and August 2007. Intervention: The UK pay for performance incentive (the Quality and Outcomes Framework), which was implemented in April 2004 and included specific targets for general practitioners to show high quality care for patients with hypertension (and other diseases). Main outcome measures: Centiles of systolic and diastolic blood pressures over time, rates of blood pressure monitoring, blood pressure control, and treatment intensity at monthly intervals for baseline (48 months) and 36 months after the implementation of pay for performance. Cumulative incidence of major hypertension related outcomes and all cause mortality for subgroups of newly treated (treatment started six months before pay for performance) and treatment experienced (started treatment in year before January 2001) patients to examine different stages of illness. Results: After accounting for secular trends, no changes in blood pressure monitoring (level change 0.85, 95% confidence interval -3.04 to 4.74, P=0.669 and trend change -0.01, -0.24 to 0.21, P=0.615), control (-1.19, -2.06 to 1.09, P=0.109 and -0.01, -0.06 to 0.03, P=0.569), or treatment intensity (0.67, -1.27 to 2.81, P=0.412 and 0.02, -0.23 to 0.19, P=0.706) were attributable to pay for performance. Pay for performance had no effect on the cumulative incidence of stroke, myocardial infarction, renal failure, heart failure, or all cause mortality in both treatment experienced and newly treated subgroups. Conclusions: Good quality of care for hypertension was stable or improving before pay for performance was introduced. Pay for performance had no discernible effects on processes of care or on hypertension related clinical outcomes. Generous financial incentives, as designed in the UK pay for performance policy, may not be sufficient to improve quality of care and outcomes for hypertension and other common chronic conditions.

BMJ: 26 Jan 2011; 342:d108
Serumaga B, Ross-Degnan D, Avery AJ, Elliott RA, ... Zhang F, Soumerai SB
BMJ: 26 Jan 2011; 342:d108 | PMID: 21266440
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Abstract

Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study.

Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M, on behalf of UKOSS
ObjectiveS: To follow up a UK national cohort of women admitted to hospital with confirmed 2009/H1N1 influenza in pregnancy in order to obtain a complete picture of pregnancy outcomes and estimate the risks of adverse fetal and infant outcomes. Design: National cohort study. Setting: 221 hospitals with obstetrician led maternity units in the UK. Participants: 256 women admitted to hospital with confirmed 2009/H1N1 in pregnancy during the second wave of pandemic infection between September 2009 and January 2010; 1220 pregnant women for comparison. Main outcome measures: Rates of stillbirth, perinatal mortality, and neonatal mortality; odds ratios for infected versus comparison women. Results: Perinatal mortality was higher in infants born to infected women (10 deaths among 256 infants; rate 39 (95% confidence interval 19 to 71) per 1000 total births) than in infants of uninfected women (9 deaths among 1233 infants; rate 7 (3 to 13) per 1000 total births) (P<0.001). This was principally explained by an increase in the rate of stillbirth (27 per 1000 total births v 6 per 1000 total births; P=0.001). Infants of infected women were also more likely to be born prematurely than were infants of comparison women (adjusted odds ratio 4.0, 95% confidence interval 2.7 to 5.9). Infected women who delivered preterm were more likely to be infected in their third trimester (P=0.046), to have been admitted to an intensive care unit (P<0.001), and to have a secondary pneumonia (P=0.001) than were those who delivered at term. Conclusions: This study suggests an increase in the risk of poor outcomes of pregnancy in women infected with 2009/H1N1, which reinforces the message from studies of maternal risk alone. The health of pregnant women is an important public health priority in future waves of this and other influenza pandemics.

BMJ: 15 Jun 2011; 342:d3214
Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M, on behalf of UKOSS
BMJ: 15 Jun 2011; 342:d3214 | PMID: 21672992
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Abstract

How valuable is physical examination of the cardiovascular system?

Elder A, Japp A, Verghese A
Physical examination of the cardiovascular system is central to contemporary teaching and practice in clinical medicine. Evidence about its value focuses on its diagnostic accuracy and varies widely in methodological quality and statistical power. This makes collation, analysis, and understanding of results difficult and limits their application to daily clinical practice. Specific factors affecting interpretation and clinical application include poor standardisation of observers\' technique and training, the study of single signs rather than multiple signs or signs in combination with symptoms, and the tendency to compare physical examination directly with technological aids to diagnosis rather than explore diagnostic strategies that combine both. Other potential aspects of the value of physical examination, such as cost effectiveness or patients\' perceptions, are poorly studied. This review summarises the evidence for the clinical value of physical examination of the cardiovascular system. The best was judged to relate to the detection and evaluation of valvular heart disease, the diagnosis and treatment of heart failure, the jugular venous pulse in the assessment of central venous pressure, and the detection of atrial fibrillation, peripheral arterial disease, impaired perfusion, and aortic and carotid disease. Although technological aids to diagnosis are likely to become even more widely available at the point of care, the evidence suggests that further research into the value of physical examination of the cardiovascular system is needed, particularly in low resource settings and as a potential means of limiting inappropriate overuse of technological aids to diagnosis.

BMJ: 05 Sep 2016; 354:i3309
Elder A, Japp A, Verghese A
BMJ: 05 Sep 2016; 354:i3309 | PMID: 27598000
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Abstract

Management and prevention of exacerbations of COPD.

Aaron SD
Patients with chronic obstructive pulmonary disease (COPD) are prone to acute respiratory exacerbations, which can develop suddenly or subacutely over the course of several days. Exacerbations have a detrimental effect on patients\' health status and increase the burden on the healthcare system. Initial treatment is unsuccessful in 24-27% of patients, who have a relapse or a second exacerbation within 30 days of the initial event. No obvious benefit has been seen in recent clinical trials of anti-tumour necrosis factor therapy, anti-leukotriene therapy, intensive chest physiotherapy, or early inpatient pulmonary rehabilitation for treatment of exacerbations. By contrast, clinical trials of prevention rather than acute treatment have shown promising results. Long acting β agonist (LABA) or long acting anti-muscarinic (LAMA) bronchodilators and inhaled corticosteroid-LABA combinations prevent exacerbations in patients at risk, with relative risk reductions averaging 14-27% for each of these drugs relative to placebo. Triple therapy with inhaled corticosteroid-LABA plus LAMA may provide additional benefit, although study results to date are heterogeneous and more studies are needed. Pneumonia is an important complication of treatment with inhaled corticosteroid-LABA products, and the risk of pneumonia seems to be doubled in patients with COPD who use fluticasone. The addition of azithromycin to usual COPD therapy prevents exacerbations, although it may prolong the Q-T interval and increase the risk of death from cardiovascular disease in patients prone to arrhythmia. New potential drugs-including mitogen activated protein kinase inhibitors, phosphodiesterase 3 inhibitors, and monoclonal antibodies to the interleukin 1 receptor-offer additional hope for treatments that may prevent exacerbations in the future.

BMJ: 22 Sep 2014; 349:g5237
Aaron SD
BMJ: 22 Sep 2014; 349:g5237 | PMID: 25245156
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Abstract

Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study.

Charlot M, Grove EL, Hansen PR, Olesen JB, ... Torp-Pedersen C, Gislason GH
Objective: To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction. Design: Retrospective nationwide propensity score matched study based on administrative data. Setting All hospitals in Denmark. Participants: All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded. Main outcome measures: The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models. Results 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H(2) receptor blockers (1.04, 0.79 to 1.38; P=0.78). Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events.

BMJ: 12 May 2011; 342:d2690
Charlot M, Grove EL, Hansen PR, Olesen JB, ... Torp-Pedersen C, Gislason GH
BMJ: 12 May 2011; 342:d2690 | PMID: 21562004
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Abstract

Magnitude, impact, and stability of primary headache subtypes: 30 year prospective Swiss cohort study.

Merikangas KR, Cui L, Richardson AK, Isler H, ... Gamma A, Angst J
Objective: To determine the prevalence, impact, and stability of different subtypes of headache in a 30 year prospective follow-up study of a general population sample. Design: Prospective cohort study. Setting: Canton of Zurich, Switzerland. Participants: 591 people aged 19-20 from a cohort of 4547 residents of Zurich, Switzerland, interviewed seven times across 30 years of follow-up. Main outcome measures: Prevalence of headache; stability of the predominant subtype of headache over time; and age of onset, severity, impact, family history, use of healthcare services, and drugs for headache subtypes. Results: The average one year prevalences of subtypes of headache were 0.9% (female:male ratio of 2.8) for migraine with aura, 10.9% (female:male ratio of 2.2) for migraine without aura, and 11.5% (female:male ratio of 1.2) for tension-type headache. Cumulative 30 year prevalences of headache subtypes were 3.0% for migraine with aura, 36.0% for migraine without aura, and 29.3% for tension-type headache. Despite the high prevalence of migraine without aura, most cases were transient and only about 20% continued to have migraine for more than half of the follow-up period. 69% of participants with migraine and 58% of those with tension-type headache manifested the same predominant subtype over time. However, the prospective stability of the predominant headache subtypes was quite low, with substantial crossover among the subtypes and no specific ordinal pattern of progression. A gradient of severity of clinical correlates and service use was present across headache subtypes; the greatest effect was for migraine with aura followed by migraine without aura, and then tension-type headache and unclassified headaches. Conclusions: These findings highlight the importance of prospective follow-up of people with headache. The substantial longitudinal overlap among subtypes of headache shows the developmental heterogeneity of headache syndromes. Studies of the causes of headache that apply diagnostic nomenclature based on distinctions between discrete headache subtypes may not capture the true nature of headache in the general population.

BMJ: 26 Aug 2011; 343:d5076
Merikangas KR, Cui L, Richardson AK, Isler H, ... Gamma A, Angst J
BMJ: 26 Aug 2011; 343:d5076 | PMID: 21868455
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Abstract

Lower urinary tract symptoms in men.

Hollingsworth JM, Wilt TJ
Benign prostatic hyperplasia (BPH) is a highly prevalent and costly condition that affects older men worldwide. Many affected men develop lower urinary tract symptoms, which can have a negative impact on their quality of life. In the past, transurethral resection of the prostate (TURP) was the mainstay of treatment. However, several efficacious drug treatments have been developed, which have transformed BPH from an acute surgical entity to a chronic medical condition. Specifically, multiple clinical trials have shown that α adrenoceptor antagonists can significantly ameliorate lower urinary tract symptoms. Moreover, 5α reductase inhibitors, alone or combined with an α adrenoceptor antagonist, can reverse the natural course of BPH, reducing the risk of urinary retention and the need for surgical intervention. Newer medical regimens including the use of antimuscarinic agents or phosphodiesterase type 5 inhibitors, have shown promise in men with predominantly storage symptoms and concomitant erectile dysfunction, respectively. For men who do not adequately respond to conservative measures or pharmacotherapy, minimally invasive surgical techniques (such as transurethral needle ablation, microwave thermotherapy, and prostatic urethral lift) may be of benefit, although they lack the durability of TURP. A variety of laser procedures have also been introduced, whose improved hemostatic properties abrogate many of the complications associated with traditional surgery.

BMJ: 14 Aug 2014; 349:g4474
Hollingsworth JM, Wilt TJ
BMJ: 14 Aug 2014; 349:g4474 | PMID: 25125424
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Abstract

Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients.

Keene D, Price C, Shun-Shin MJ, Francis DP
To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels.Design: Meta-analysis.STUDIES REVIEWED: Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke).Results: 117 411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference.Conclusions: Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.

BMJ: 18 Jul 2014; 349:g4379
Keene D, Price C, Shun-Shin MJ, Francis DP
BMJ: 18 Jul 2014; 349:g4379 | PMID: 25038074
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Abstract

Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study.

Lawlor DA, Benfield L, Logue J, Tilling K, ... Davey Smith G, Sattar N
ObjectiveS: To examine the prospective associations between body mass index (BMI), waist circumference, and fat mass in childhood and cardiovascular risk factors at age 15-16. Design: Prospective cohort study. Setting: Avon Longitudinal Study of Parents and Children. Participants: 5235 children aged 9-12 at start of study. Main exposures BMI, waist circumference, and fat mass determined by dual energy x ray absorptiometry, assessed at age 9-12 and at age 15-16. Main outcome measures: Systolic and diastolic blood pressure and concentrations of fasting glucose, insulin, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol assessed at age 15-16. Results: In girls a 1 SD greater BMI at age 9-12 was associated with cardiovascular risk factors at age 15-16 in fully adjusted models: odds ratio 1.23 (95% confidence interval 1.10 to 1.38) for high systolic blood pressure (≥130 mm Hg); 1.19 (1.03 to 1.38) for high concentration of low density lipoprotein cholesterol (≥2.79 mmol/l); 1.43 (1.06 to 1.92) for high concentration of triglycerides (≥1.7 mmol/l); 1.25 (1.08 to 1.46) for low concentration of high density lipoprotein cholesterol (<1.03 mmol/l); and 1.45 (1.22 to 1.73) for high concentration of insulin (≥16.95 IU/l). Equivalent results in boys were 1.24 (1.13 to 1.37) for systolic blood pressure; 1.30 (1.07 to 1.59) for low density lipoprotein cholesterol; 1.96 (1.51 to 2.55) for triglycerides; 1.39 (1.22 to 1.57) for high density lipoprotein cholesterol, and 1.84 (1.56 to 2.17) for insulin. BMI was associated with high fasting glucose (≥5.6 mmol/l) only in boys (1.18, 1.03 to 1.36). With these binary outcomes there was statistical evidence that associations differed between girls and boys for fasting glucose (P=0.03) and insulin (P<0.001). When risk factors were examined as continuous outcomes there was evidence for stronger associations of BMI with more adverse levels in boys than girls for fasting insulin, glucose, and triglyceride concentrations (all interaction P≤0.03). BMI, waist circumference, and fat mass were all strongly correlated with each other (r=0.89-0.94), and associations of the three with cardiovascular outcomes were of similar magnitude with statistical evidence of consistency in associations (all P>0.2 for heterogeneity). When waist circumference or fat mass or both were added to models including BMI they did not increase the variation in cardiovascular risk factors already explained by BMI and confounders alone. Girls who were overweight/obese at age 9-12 but were normal weight by 15-16 had similar odds of adverse levels of risk factors to those who were normal weight at both ages. In boys odds of high systolic blood pressure, high concentrations of triglycerides and insulin, and low concentrations of high density lipoprotein cholesterol remained higher in this group compared with those who were normal weight at both ages but were lower than in those who remained overweight/obese at both ages. Conclusions: Measurements of waist circumference or directly assessed fat mass in childhood do not seem to be associated with cardiovascular risk factors in adolescence any more strongly than BMI. Girls who favourably alter their overweight status between childhood and adolescence have cardiovascular risk profiles broadly similar to those who were normal weight at both time points, but boys who change from overweight to normal show risk factor profiles intermediate between those seen in boys who are normal weight at both ages or overweight at both ages.

BMJ: 26 Nov 2010; 341:c6224
Lawlor DA, Benfield L, Logue J, Tilling K, ... Davey Smith G, Sattar N
BMJ: 26 Nov 2010; 341:c6224 | PMID: 21109577
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Abstract

Personalized evidence based medicine: predictive approaches to heterogeneous treatment effects.

Kent DM, Steyerberg E, van Klaveren D
The use of evidence from clinical trials to support decisions for individual patients is a form of \"reference class forecasting\": implicit predictions for an individual are made on the basis of outcomes in a reference class of \"similar\" patients treated with alternative therapies. Evidence based medicine has generally emphasized the broad reference class of patients qualifying for a trial. Yet patients in a trial (and in clinical practice) differ from one another in many ways that can affect the outcome of interest and the potential for benefit. The central goal of personalized medicine, in its various forms, is to narrow the reference class to yield more patient specific effect estimates to support more individualized clinical decision making. This article will review fundamental conceptual problems with the prediction of outcome risk and heterogeneity of treatment effect (HTE), as well as the limitations of conventional (one-variable-at-a-time) subgroup analysis. It will also discuss several regression based approaches to \"predictive\" heterogeneity of treatment effect analysis, including analyses based on \"risk modeling\" (such as stratifying trial populations by their risk of the primary outcome or their risk of serious treatment-related harms) and analysis based on \"effect modeling\" (which incorporates modifiers of relative effect). It will illustrate these approaches with clinical examples and discuss their respective strengths and vulnerabilities.

BMJ: 09 Dec 2018; 363:k4245
Kent DM, Steyerberg E, van Klaveren D
BMJ: 09 Dec 2018; 363:k4245 | PMID: 30530757
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Abstract

Longitudinal analysis of sleep in relation to BMI and body fat in children: the FLAME study.

Carter PJ, Taylor BJ, Williams SM, Taylor RW
ObjectiveS: To determine whether reduced sleep is associated with differences in body composition and the risk of becoming overweight in young children. Design: Longitudinal study with repeated annual measurements. Setting: Dunedin, New Zealand. Participants: 244 children recruited from a birth cohort and followed from age 3 to 7. Main outcome measures: Body mass index (BMI), fat mass (kg), and fat free mass (kg) measured with bioelectrical impedance; dual energy x ray absorptiometry; physical activity and sleep duration measured with accelerometry; dietary intake (fruit and vegetables, non-core foods), television viewing, and family factors (maternal BMI and education, birth weight, smoking during pregnancy) measured with questionnaire. Results: After adjustment for multiple confounders, each additional hour of sleep at ages 3-5 was associated with a reduction in BMI of 0.48 (95% confidence interval 0.01 to 0.96) and a reduced risk of being overweight (BMI ≥85th centile) of 0.39 (0.24 to 0.63) at age 7. Further adjustment for BMI at age 3 strengthened these relations. These differences in BMI were explained by differences in fat mass index (-0.43, -0.82 to -0.03) more than by differences in fat free mass index (-0.21, -0.41 to -0.00). Conclusions: Young children who do not get enough sleep are at increased risk of becoming overweight, even after adjustment for initial weight status and multiple confounding factors. This weight gain is a result of increased fat deposition in both sexes rather than additional accumulation of fat free mass.

BMJ: 30 May 2011; 342:d2712
Carter PJ, Taylor BJ, Williams SM, Taylor RW
BMJ: 30 May 2011; 342:d2712 | PMID: 21622518
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Abstract

Cryotherapy versus salicylic acid for the treatment of plantar warts (verrucae): a randomised controlled trial.

Cockayne S, Hewitt C, Hicks K, Jayakody S, ... Watt I, on behalf of the EVerT Team
Objective: To compare the clinical effectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts. Design: A multicentre, open, two arm randomised controlled trial. Setting: University podiatry school clinics, NHS podiatry clinics, and primary care in England, Scotland, and Ireland. Participants: 240 patients aged 12 years and over, with a plantar wart that in the opinion of the healthcare professional was suitable for treatment with both cryotherapy and salicylic acid. Interventions: Cryotherapy with liquid nitrogen delivered by a healthcare professional, up to four treatments two to three weeks apart. Patient self treatment with 50% salicylic acid (Verrugon) daily up to a maximum of eight weeks. Main outcome measures: Complete clearance of all plantar warts at 12 weeks. Secondary outcomes were (a) complete clearance of all plantar warts at 12 weeks controlling for age, whether the wart had been treated previously, and type of wart, (b) patient self reported clearance of plantar warts at six months, (c) time to clearance of plantar wart, (d) number of plantar warts at 12 weeks, and (e) patient satisfaction with the treatment. Results: There was no evidence of a difference between the salicylic acid and cryotherapy groups in the proportions of participants with complete clearance of all plantar warts at 12 weeks (17/119 (14%) v 15/110 (14%), difference 0.65% (95% CI -8.33 to 9.63), P=0.89). The results did not change when the analysis was repeated but with adjustment for age, whether the wart had been treated previously, and type of plantar wart or for patients\' preferences at baseline. There was no evidence of a difference between the salicylic acid and cryotherapy groups in self reported clearance of plantar warts at six months (29/95 (31%) v 33/98 (34%), difference -3.15% (-16.31 to 10.02), P=0.64) or in time to clearance (hazard ratio 0.80 (95% CI 0.51 to 1.25), P=0.33). There was also no evidence of a difference in the number of plantar warts at 12 weeks (incident rate ratio 1.08 (0.81 to 1.43), P=0.62). Conclusions: Salicylic acid and the cryotherapy were equally effective for clearance of plantar warts. Trial registration Current Controlled Trials ISRCTN18994246, National Research Register N0484189151.

BMJ: 09 Jun 2011; 342:d3271
Cockayne S, Hewitt C, Hicks K, Jayakody S, ... Watt I, on behalf of the EVerT Team
BMJ: 09 Jun 2011; 342:d3271 | PMID: 21652750
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Abstract

Impact of primary health care on mortality from heart and cerebrovascular diseases in Brazil: a nationwide analysis of longitudinal data.

Rasella D, Harhay MO, Pamponet ML, Aquino R, Barreto ML
To evaluate the impact of Brazil\'s recently implemented Family Health Program (FHP), the largest primary health care programme in the world, on heart and cerebrovascular disease mortality across Brazil from 2000 to 2009.Design: Ecological longitudinal design, evaluating the impact of FHP using negative binomial regression models for panel data with fixed effects specifications.Setting: Nationwide analysis of data from Brazilian municipalities covering the period from 2000 to 2009.Data sources: 1622 Brazilian municipalities with vital statistics of adequate quality.Main outcome measures: The annual FHP coverage and the average FHP coverage in previous years were used as main independent variables and classified as none (0%), incipient (<30%), intermediate (30-69%), or consolidated (≥70%). Age standardised mortality rates from causes in the group of cerebrovascular (ICD-10 codes I60-69), ischaemic (ICD-10 I20-25), and other forms of heart diseases (ICD-10 I30-52), which were included in the national list of ambulatory care-sensitive conditions, were calculated for each municipality for each year. They accounted for 40% of all deaths from these groups during the study period.Results: FHP coverage was negatively associated with mortality rates from cerebrovascular and heart diseases (ambulatory care-sensitive conditions) in both unadjusted and adjusted models for demographic, social, and economic confounders. The FHP had no effect on the mortality rate for accidents, used as a control. The rate ratio for the effect of consolidated annual FHP coverage on cerebrovascular disease mortality and on heart disease mortality was 0.82 (95% confidence interval 0.79 to 0.86) and 0.79 (0.75 to 0.80) respectively, reaching the value of 0.69 (0.66 to 0.73) and 0.64 (0.59 to 0.68) when the coverage was consolidated during all the previous eight years. Moreover, FHP coverage increased the number of health education activities, domiciliary visits, and medical consultations and reduced hospitalisation rates for cerebrovascular and heart disease. Several complementary analyses showed quantitatively similar results.Conclusions: Comprehensive and community based primary health care programmes, such as the FHP in Brazil, acting through cardiovascular disease prevention, care, and follow-up can contribute to decreased cardiovascular disease morbidity and mortality in a developing country such as Brazil.

BMJ: 03 Jul 2014; 349:g4014
Rasella D, Harhay MO, Pamponet ML, Aquino R, Barreto ML
BMJ: 03 Jul 2014; 349:g4014 | PMID: 24994807
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Abstract

Autism spectrum disorder: advances in diagnosis and evaluation.

Zwaigenbaum L, Penner M
Autism spectrum disorder (ASD) has a variety of causes, and its clinical expression is generally associated with substantial disability throughout the lifespan. Recent advances have led to earlier diagnosis, and deep phenotyping efforts focused on high risk infants have helped advance the characterization of early behavioral trajectories. Moreover, biomarkers that measure early structural and functional connectivity, visual orienting, and other biological processes have shown promise in detecting the risk of autism spectrum disorder even before the emergence of overt behavioral symptoms. Despite these advances, the mean age of diagnosis is still 4-5 years. Because of the broad consistency in published guidelines, parameters for high quality comprehensive assessments are available; however, such models are resource intensive and high demand can result in greatly increased waiting times. This review describes advances in detecting early behavioral and biological markers, current options and controversies in screening for the disorder, and best practice in its diagnostic evaluation including emerging data on innovative service models.

BMJ: 20 May 2018; 361:k1674
Zwaigenbaum L, Penner M
BMJ: 20 May 2018; 361:k1674 | PMID: 29784657
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Abstract

Anticoagulation in atrial fibrillation.

Steinberg BA, Piccini JP
Atrial fibrillation increases the risk of stroke, which is a leading cause of death and disability worldwide. The use of oral anticoagulation in patients with atrial fibrillation at moderate or high risk of stroke, estimated by established criteria, improves outcomes. However, to ensure that the benefits exceed the risks of bleeding, appropriate patient selection is essential. Vitamin K antagonism has been the mainstay of treatment; however, newer drugs with novel mechanisms are also available. These novel oral anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) obviate many of warfarin\'s shortcomings, and they have demonstrated safety and efficacy in large randomized trials of patients with non-valvular atrial fibrillation. However, the management of patients taking warfarin or novel agents remains a clinical challenge. There are several important considerations when selecting anticoagulant therapy for patients with atrial fibrillation. This review will discuss the rationale for anticoagulation in patients with atrial fibrillation; risk stratification for treatment; available agents; the appropriate implementation of these agents; and additional, specific clinical considerations for treatment.

BMJ: 14 Apr 2014; 348:g2116
Steinberg BA, Piccini JP
BMJ: 14 Apr 2014; 348:g2116 | PMID: 24733535
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Abstract

Secondary peritonitis: principles of diagnosis and intervention.

Ross JT, Matthay MA, Harris HW
Secondary peritonitis accounts for 1% of urgent or emergent hospital admissions and is the second leading cause of sepsis in patients in intensive care units globally. Overall mortality is 6%, but mortality rises to 35% in patients who develop severe sepsis. Despite the dramatic growth in the availability and use of imaging and laboratory tests, the rapid diagnosis and early management of peritonitis remains a challenge for physicians in emergency medicine, surgery, and critical care. In this article, we review the pathophysiology of peritonitis and its potential progression to sepsis, discuss the utility and limitations of the physical examination and laboratory and radiographic tests, and present a paradigm for the management of secondary peritonitis.

BMJ: 17 Jun 2018; 361:k1407
Ross JT, Matthay MA, Harris HW
BMJ: 17 Jun 2018; 361:k1407 | PMID: 29914871
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Abstract

Association between provision of mental illness beds and rate of involuntary admissions in the NHS in England 1988-2008: ecological study.

Keown P, Weich S, Bhui KS, Scott J
Objective: To examine the rise in the rate of involuntary admissions for mental illness in England that has occurred as community alternatives to hospital admission have been introduced. Design: Ecological analysis. Setting: England, 1988-2008. Data source Publicly available data on provision of beds for people with mental illness in the National Health Service from Hospital Activity Statistics and involuntary admission rates from the NHS Information Centre. Main outcome measures: Association between annual changes in provision of mental illness beds in the NHS and involuntary admission rates, using cross correlation. Partial correlation coefficients were calculated and regression analysis carried out for the time lag (interval) over which the largest association between these variables was identified. Results: The rate of involuntary admissions per annum in the NHS increased by more than 60%, whereas the provision of mental illness beds decreased by more than 60% over the same period; these changes seemed to be synchronous. The strongest association between these variables was observed when a time lag of one year was introduced, with bed reductions preceding increases in involuntary admissions (cross correlation -0.60, 95% confidence interval -1.06 to -0.15). This association increased in magnitude when analyses were restricted to civil (non-forensic) involuntary admissions and non-secure mental illness beds. Conclusion: The annual reduction in provision of mental illness beds was associated with the rate of involuntary admissions over the short to medium term, with the closure of two mental illness beds leading to one additional involuntary admission in the subsequent year. This study provides a method for predicting rates of involuntary admissions and what may happen in the future if bed closures continue.

BMJ: 06 Jul 2011; 343:d3736
Keown P, Weich S, Bhui KS, Scott J
BMJ: 06 Jul 2011; 343:d3736 | PMID: 21729994
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Abstract

Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study.

Gwilliam B, Keeley V, Todd C, Gittins M, ... Barclay S, Stone PC
Objective: To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians\' estimates of survival. Design: Prospective multicentre observational cohort study. Setting: 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). Participants: 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. Main outcome measures: Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians\' predictions. Results: On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians\' estimates of survival. Conclusions: In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival.

BMJ: 26 Aug 2011; 343:d4920
Gwilliam B, Keeley V, Todd C, Gittins M, ... Barclay S, Stone PC
BMJ: 26 Aug 2011; 343:d4920 | PMID: 21868477
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Abstract

Prevention of pain on injection of propofol: systematic review and meta-analysis.

Jalota L, Kalira V, George E, Shi YY, ... Apfel CC, On behalf of the Perioperative Clinical Research Core
Objective: To systematically determine the most efficacious approach for preventing pain on injection of propofol. Design: Systematic review and meta-analysis. Data sources: PubMed, Embase, Cochrane Library, www.clinicaltrials.gov, and hand searching from the reference lists of identified papers. Study selection: Randomised controlled trials comparing drug and non-drug interventions with placebo or another intervention to alleviate pain on injection of propofol in adults. Results: Data were analysed from 177 randomised controlled trials totalling 25 260 adults. The overall risk of pain from propofol injection alone was about 60%. Using an antecubital vein instead of a hand vein was the most effective single intervention (relative risk 0.14, 95% confidence interval 0.07 to 0.30). Pretreatment using lidocaine (lignocaine) in conjunction with venous occlusion was similarly effective (0.29, 0.22 to 0.38). Other effective interventions were a lidocaine-propofol admixture (0.40, 0.33 to 0.48); pretreatment with lidocaine (0.47, 0.40 to 0.56), opioids (0.49, 0.41 to 0.59), ketamine (0.52, 0.46 to 0.57), or non-steroidal anti-inflammatory drugs (0.67, 0.49 to 0.91); and propofol emulsions containing medium and long chain triglycerides (0.75, 0.67 to 0.84). Statistical testing of indirect comparisons showed that use of the antecubital vein and pretreatment using lidocaine along with venous occlusion to be more efficacious than the other interventions. Conclusions: The two most efficacious interventions to reduce pain on injection of propofol were use of the antecubital vein, or pretreatment using lidocaine in conjunction with venous occlusion when the hand vein was chosen. Under the assumption of independent efficacy a third practical alternative could be pretreatment of the hand vein with lidocaine or ketamine and use of a propofol emulsion containing medium and long chain triglycerides. Although not the most effective intervention on its own, a small dose of opioids before induction halved the risk of pain from the injection and thus can generally be recommended unless contraindicated.

BMJ: 16 Mar 2011; 342:d1110
Jalota L, Kalira V, George E, Shi YY, ... Apfel CC, On behalf of the Perioperative Clinical Research Core
BMJ: 16 Mar 2011; 342:d1110 | PMID: 21406529
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Abstract

Oxytocin bolus versus oxytocin bolus and infusion for control of blood loss at elective caesarean section: double blind, placebo controlled, randomised trial.

Sheehan SR, Montgomery AA, Carey M, McAuliffe FM, ... Murphy DJ, The ECSSIT Study Group
ObjectiveS: To determine the effects of adding an oxytocin infusion to bolus oxytocin on blood loss at elective caesarean section. Design: Double blind, placebo controlled, randomised trial, conducted from February 2008 to June 2010. Setting: Five maternity hospitals in the Republic of Ireland. Participants: 2069 women booked for elective caesarean section at term with a singleton pregnancy. We excluded women with placenta praevia, thrombocytopenia, coagulopathies, previous major obstetric haemorrhage (>1000 mL), or known fibroids; women receiving anticoagulant treatment; those who did not understand English; and those who were younger than 18 years. Intervention: Intervention group: intravenous slow 5 IU oxytocin bolus over 1 minute and additional 40 IU oxytocin infusion in 500 mL of 0.9% saline solution over 4 hours (bolus and infusion). Placebo group: 5 IU oxytocin bolus over 1 minute and 500 mL of 0.9% saline solution over 4 hours (placebo infusion) (bolus only). Main outcomes Major obstetric haemorrhage (blood loss >1000 mL) and need for an additional uterotonic agent. Results: We found no difference in the occurrence of major obstetric haemorrhage between the groups (bolus and infusion 15.7% (158/1007) v bolus only 16.0% (159/994), adjusted odds ratio 0.98, 95% confidence intervals 0.77 to 1.25, P=0.86). The need for an additional uterotonic agent in the bolus and infusion group was lower than that in the bolus only group (12.2% (126/1033) v 18.4% (189/1025), 0.61, 0.48 to 0.78, P<0.001). Women were less likely to have a major obstetric haemorrhage in the bolus and infusion group than in the bolus only group if the obstetrician was junior rather than senior (0.57, 0.35 to 0.92, P=0.02). Conclusion: The addition of an oxytocin infusion after caesarean delivery reduces the need for additional uterotonic agents but does not affect the overall occurrence of major obstetric haemorrhage. Trial registration Current Controlled Trials ISRCTN17813715.

BMJ: 02 Aug 2011; 343:d4661
Sheehan SR, Montgomery AA, Carey M, McAuliffe FM, ... Murphy DJ, The ECSSIT Study Group
BMJ: 02 Aug 2011; 343:d4661 | PMID: 21807773
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Abstract

Non-cardiovascular effects associated with statins.

Desai CS, Martin SS, Blumenthal RS
Statins form the pharmacologic cornerstone of the primary and secondary prevention of atherosclerotic cardiovascular disease. In addition to beneficial cardiovascular effects, statins seem to have multiple non-cardiovascular effects. Although early concerns about statin induced hepatotoxicity and cancer have subsided owing to reassuring evidence, two of the most common concerns that clinicians have are myopathy and diabetes. Randomized controlled trials suggest that statins are associated with a modest increase in the risk of myositis but not the risk of myalgia. Severe myopathy (rhabdomyolysis) is rare and often linked to a statin regimen that is no longer recommended (simvastatin 80 mg). Randomized controlled trials and meta-analyses suggest an increase in the risk of diabetes with statins, particularly with higher intensity regimens in people with two or more components of the metabolic syndrome. Other non-cardiovascular effects covered in this review are contrast induced nephropathy, cognition, cataracts, erectile dysfunction, and venous thromboembolism. Currently, systematic reviews and clinical practice guidelines indicate that the cardiovascular benefits of statins generally outweigh non-cardiovascular harms in patients above a certain threshold of cardiovascular risk. Literature is also accumulating on the potential non-cardiovascular benefits of statins, which could lead to novel applications of this class of drug in the future.

BMJ: 17 Jul 2014; 349:g3743
Desai CS, Martin SS, Blumenthal RS
BMJ: 17 Jul 2014; 349:g3743 | PMID: 25035309
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Abstract

Portrayal of caesarean section in Brazilian women\'s magazines: 20 year review.

Torloni MR, Daher S, Betrán AP, Widmer M, ... Souza JP, Merialdi M
Objective: To assess the quality and comprehensiveness of the information on caesarean section provided in Brazilian women\'s magazines. Design: Review of articles published during 1988-2008 in top selling women\'s magazines. Setting: Brazil, one of the countries with the highest caesarean section rates in the world. Data sources: Women\'s magazines with the largest distribution during the study period, identified through the official national media indexing organisations. Selection criteria Articles with objective scientific information or advice, comments, opinions, or the experience of ordinary women or celebrities on delivery by caesarean section. Main outcome measures: Sources of information mentioned by the author of the article, the accuracy and completeness of data presented on caesarean section, and alleged reasons why women would prefer to deliver though caesarean section. Results: 118 articles were included. The main cited sources of information were health professionals (78% (n=92) of the articles). 71% (n=84) of the articles reported at least one benefit of caesarean section, and 82% (n=97) reported at least one short term maternal risk of caesarean section. The benefits most often attributed to delivery by caesarean section were reduction of pain and convenience for family or health professionals. The most frequently reported short term maternal risks of caesarean section were increased time to recover and that it is a less natural way of giving birth. Only one third of the articles mentioned any long term maternal risks or perinatal complications associated with caesarean section. Fear of pain was the main reported reason why women would prefer to deliver by caesarean section. Conclusions: Most of the articles published in Brazilian women\'s magazines do not use optimal sources of information. The portrayal of caesarean section is mostly balanced, not explicitly in favour of one or another route of delivery, but incomplete and may be leading women to underestimate the maternal/perinatal risks associated with this route of delivery.

BMJ: 26 Jan 2011; 342:d276
Torloni MR, Daher S, Betrán AP, Widmer M, ... Souza JP, Merialdi M
BMJ: 26 Jan 2011; 342:d276 | PMID: 21266421
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Abstract

Outreach education for integration of HIV/AIDS care, antiretroviral treatment, and tuberculosis care in primary care clinics in South Africa: PALSA PLUS pragmatic cluster randomised trial.

Zwarenstein M, Fairall LR, Lombard C, Mayers P, ... Bachmann MO, Bateman E
Objective: To investigate whether PALSA PLUS, an on-site educational outreach programme of non-didactic, case based, iterative clinical education of staff, led by a trainer, can increase access to and comprehensiveness of care for patients with HIV/AIDS. Design Cluster randomised trial. Setting: Public primary care clinics offering HIV/AIDS care, antiretroviral treatment (ART), tuberculosis care, and ambulatory primary care in Free State province, South Africa. Participants: Fifteen clinics all implementing decentralisation and task shifting were randomised. The clinics cared for 400 000 general primary care patients and 10 136 patients in an HIV/AIDS/ART programme. There were 150 nurses. Intervention: On-site outreach education in eight clinics; no such education in seven (control). Main outcome measures: Provision of co-trimoxazole prophylaxis among patients referred to the HIV/AIDS/ART programme, and detection of cases of tuberculosis among those in the programme. Proportion of patients in the programme enrolled through general primary care consultations. Results: Patients referred to the HIV/AIDS programme through general primary care at intervention clinics were more likely than those at control clinics to receive co-trimoxazole prophylaxis (41%, (2253/5523) v 32% (1340/4210); odds ratio 1.95, 95% confidence interval 1.11 to 3.40), and tuberculosis was more likely to be diagnosed among patients with HIV/AIDS/ART (7% (417/5793) v 6% (245/4343); 1.25, 1.01 to 1.55). Enrolment in the HIV/AIDS and ART programme through HIV testing in general primary care was not significantly increased (53% v 50%; 1.19, 0.51 to 2.77). Secondary outcomes were similar, except for weight gain, which was higher in the intervention group (2.3 kg v 1.9 kg, P<0.001). Conclusion: Though outreach education is an effective and feasible strategy for improving comprehensiveness of care and wellbeing of patients with HIV/AIDS, there is no evidence that it increases access to the ART programme. It is now being widely implemented in South Africa. Trial registration Current Controlled Trials ISRCTN 24820584.

BMJ: 22 Apr 2011; 342:d2022
Zwarenstein M, Fairall LR, Lombard C, Mayers P, ... Bachmann MO, Bateman E
BMJ: 22 Apr 2011; 342:d2022 | PMID: 21511783
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Abstract

Short term effects of temperature on risk of myocardial infarction in England and Wales: time series regression analysis of the Myocardial Ischaemia National Audit Project (MINAP) registry.

Bhaskaran K, Hajat S, Haines A, Herrett E, Wilkinson P, Smeeth L
Objective: To examine the short term relation between ambient temperature and risk of myocardial infarction. Design: Daily time series regression analysis. Setting: 15 conurbations in England and Wales. Participants: 84 010 hospital admissions for myocardial infarction recorded in the Myocardial Ischaemia National Audit Project during 2003-6 (median 57 events a day). Main outcome measures: Change in risk of myocardial infarction associated with a 1 degrees C difference in temperature, including effects delayed by up to 28 days. Results: Smoothed graphs revealed a broadly linear relation between temperature and myocardial infarction, which was well characterised by log-linear models without a temperature threshold: each 1 degrees C reduction in daily mean temperature was associated with a 2.0% (95% confidence interval 1.1% to 2.9%) cumulative increase in risk of myocardial infarction over the current and following 28 days, the strongest effects being estimated at intermediate lags of 2-7 and 8-14 days: increase per 1 degrees C reduction 0.6% (95% confidence interval 0.2% to 1.1%) and 0.7% (0.3% to 1.1%), respectively. Heat had no detrimental effect. Adults aged 75-84 and those with previous coronary heart disease seemed more vulnerable to the effects of cold than other age groups (P for interaction 0.001 or less in each case), whereas those taking aspirin were less vulnerable (P for interaction 0.007). Conclusions: Increases in risk of myocardial infarction at colder ambient temperatures may be one driver of cold related increases in overall mortality, but an increased risk of myocardial infarction at higher temperatures was not detected. The risk of myocardial infarction in vulnerable people might be reduced by the provision of targeted advice or other interventions, triggered by forecasts of lower temperature.

BMJ: 11 Aug 2010; 341:c3823
Bhaskaran K, Hajat S, Haines A, Herrett E, Wilkinson P, Smeeth L
BMJ: 11 Aug 2010; 341:c3823 | PMID: 20699305
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Abstract

Painful diabetic neuropathy.

Peltier A, Goutman SA, Callaghan BC
Diabetes is a worldwide epidemic, and associated neuropathy is its most costly and disabling complication. Given the rising prevalence of painful diabetic neuropathy, it is increasingly important that we understand the best ways to diagnose and treat this condition. Diagnostic tests in this field are evolving rapidly. These include the use of skin biopsies to measure small unmyelinated fibers, as well as even newer techniques that can measure both small unmyelinated fibers and large myelinated fibers in the same biopsy. The main treatments for painful diabetic neuropathy remain management of the underlying diabetes and drugs for the relief of pain. However, emerging evidence points to major differences between type 1 and type 2 diabetes, including the ability of glycemic control to prevent neuropathy. Enhanced glucose control is much more effective at preventing neuropathy in patients with type 2 diabetes than in those with type 1 disease. This dichotomy emphasizes the need to study the pathophysiologic differences between the two types of diabetes, because different treatments may be needed for each condition. The impact of the metabolic syndrome on neuropathy in patients with type 2 diabetes may account for the difference between the two types of diabetes and requires further study. Finally, neuropathic pain is under-recognized and undertreated despite an ever evolving list of effective drugs. Evidence exists to support several drugs, but the optimal sequence and combination of these drugs are still to be determined.

BMJ: 06 May 2014; 348:g1799
Peltier A, Goutman SA, Callaghan BC
BMJ: 06 May 2014; 348:g1799 | PMID: 24803311
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Abstract

Chronic migraine.

Schwedt TJ
Chronic migraine is a disabling neurologic condition that affects 2% of the general population. Patients with chronic migraine have headaches on at least 15 days a month, with at least eight days a month on which their headaches and associated symptoms meet diagnostic criteria for migraine. Chronic migraine places an enormous burden on patients owing to frequent headaches; hypersensitivity to visual, auditory, and olfactory stimuli; nausea; and vomiting. It also affects society through direct and indirect medical costs. Chronic migraine typically develops after a slow increase in headache frequency over months to years. Several factors are associated with an increased risk of transforming to chronic migraine. The diagnosis requires a carefully performed patient interview and neurologic examination, sometimes combined with additional diagnostic tests, to differentiate chronic migraine from secondary headache disorders and other primary chronic headaches of long duration. Treatment takes a multifaceted approach that may include risk factor modification, avoidance of migraine triggers, drug and non-drug based prophylaxis, and abortive migraine treatment, the frequency of which is limited to avoid drug overuse. This article provides an overview of current knowledge regarding chronic migraine, including epidemiology, risk factors for its development, pathophysiology, diagnosis, management, and guidelines. The future of chronic migraine treatment and research is also discussed.

BMJ: 24 Mar 2014; 348:g1416
Schwedt TJ
BMJ: 24 Mar 2014; 348:g1416 | PMID: 24662044
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Abstract

Nature of socioeconomic inequalities in neonatal mortality: population based study.

Smith LK, Manktelow BN, Draper ES, Springett A, Field DJ
Objective: To investigate time trends in socioeconomic inequalities in cause specific neonatal mortality in order to assess changing patterns in mortality due to different causes, particularly prematurity, and identify key areas of focus for future intervention strategies. Design: Retrospective cohort study. Setting: England. Participants: All neonatal deaths in singleton infants born between 1 January 1997 and 31 December 2007. Main outcome measure: Cause specific neonatal mortality per 10 000 births by deprivation tenth (deprivation measured with UK index of multiple deprivation 2004 at super output area level). Results: 18 524 neonatal deaths occurred in singleton infants born in the 11 year study period. Neonatal mortality fell between 1997-9 and 2006-7 (from 31.4 to 25.1 per 10 000 live births). The relative deprivation gap (ratio of mortality in the most deprived tenth compared with the least deprived tenth) increased from 2.08 in 1997-9 to 2.68 in 2003-5, before a fall to 2.35 in 2006-7. The most common causes of death were immaturity and congenital anomalies. Mortality due to immaturity before 24 weeks\' gestation did not decrease over time and showed the widest relative deprivation gap (2.98 in 1997-9; 4.14 in 2003-5; 3.16 in 2006-7). Mortality rates for all other causes fell over time. For congenital anomalies, immaturity, and accidents and other specific causes, the relative deprivation gap widened between 1997-9 and 2003-5, before a slight fall in 2006-7. For intrapartum events and sudden infant deaths (only 13.5% of deaths) the relative deprivation gap narrowed slightly. Conclusions: Almost 80% of the relative deprivation gap in all cause mortality was explained by premature birth and congenital anomalies. To reduce socioeconomic inequalities in mortality, a change in focus is needed to concentrate on these two influential causes of death. Understanding the link between deprivation and preterm birth should be a major research priority to identify interventions to reduce preterm birth.

BMJ: 03 Dec 2010; 341:c6654
Smith LK, Manktelow BN, Draper ES, Springett A, Field DJ
BMJ: 03 Dec 2010; 341:c6654 | PMID: 21127118
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Abstract

Screening for lung cancer using low dose computed tomography.

Tammemagi MC, Lam S
Screening for lung cancer with low dose computed tomography can reduce mortality from the disease by 20% in high risk smokers. This review covers the state of the art knowledge on several aspects of implementing a screening program. The most important are to identify people who are at high enough risk to warrant screening and the appropriate management of lung nodules found at screening. An accurate risk prediction model is more efficient than age and pack years of smoking alone at identifying those who will develop lung cancer and die from the disease. Algorithms are available for assessing people who screen positive to determine who needs additional imaging or invasive investigations. Concerns about low dose computed tomography screening include false positive results, overdiagnosis, radiation exposure, and costs. Further work is needed to define the frequency and duration of screening and to refine risk prediction models so that they can be used to assess the risk of lung cancer in special populations. Another important area is the use of computer vision software tools to facilitate high throughput interpretation of low dose computed tomography images so that costs can be reduced and the consistency of scan interpretation can be improved. Sufficient data are available to support the implementation of screening programs at the population level in stages that can be expanded when found to perform well to improve the outcome of patients with lung cancer.

BMJ: 27 May 2014; 348:g2253
Tammemagi MC, Lam S
BMJ: 27 May 2014; 348:g2253 | PMID: 24865600
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Abstract

Toothbrushing, inflammation, and risk of cardiovascular disease: results from Scottish Health Survey.

de Oliveira C, Watt R, Hamer M
Objective: To examine if self reported toothbrushing behaviour is associated with cardiovascular disease and markers of inflammation (C reactive protein) and coagulation (fibrinogen). Design: National population based survey. Setting: Scottish Health Survey, which draws a nationally representative sample of the general population living in households in Scotland. Participants: 11 869 men and women, mean age 50 (SD 11). Main outcome measures: Oral hygiene assessed from self reported frequency of toothbrushing. Surveys were linked prospectively to clinical hospital records, and Cox proportional hazards models were used to estimate the risk of cardiovascular disease events or death according to oral hygiene. The association between oral hygiene and inflammatory markers and coagulation was examined in a subsample of participants (n=4830) by using general linear models with adjustments. Results: There were a total of 555 cardiovascular disease events over an average of 8.1 (SD 3.4) years of follow-up, of which 170 were fatal. In about 74% (411) of cardiovascular disease events the principal diagnosis was coronary heart disease. Participants who reported poor oral hygiene (never/rarely brushed their teeth) had an increased risk of a cardiovascular disease event (hazard ratio 1.7, 95% confidence interval 1.3 to 2.3; P<0.001) in a fully adjusted model. They also had increased concentrations of both C reactive protein (beta 0.04, 0.01 to 0.08) and fibrinogen (0.08, -0.01 to 0.18). Conclusions: Poor oral hygiene is associated with higher levels of risk of cardiovascular disease and low grade inflammation, though the causal nature of the association is yet to be determined.

BMJ: 28 May 2010; 340:c2451
de Oliveira C, Watt R, Hamer M
BMJ: 28 May 2010; 340:c2451 | PMID: 20508025
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Abstract

Effect of statin treatment on short term mortality after pneumonia episode: cohort study.

Douglas I, Evans S, Smeeth L
Objective To determine whether statins protect against all cause mortality after a diagnosis of pneumonia. Design Cohort study using propensity score based method to control for differences between people prescribed and not prescribed statins. Setting United Kingdom Health Improvement Network database, which contains electronic primary care medical records of more than six million patients. Participants Every patient starting a statin between 1995 and 2006 (129 288) matched with up to five non-statin users (n=600 241); 9073 patients had a recorded diagnosis of pneumonia, of whom 1398 were using a statin. Main outcome measure All cause mortality within six months of diagnosis of pneumonia. Results Among users and non-users of statins with comparable propensity scores, 95/942 users and 686/3615 non-users died on the day that pneumonia was diagnosed. In the following six month period, 109/847 statin users died compared with 578/2927 non-users, giving an adjusted hazard ratio of 0.67 (0.49 to 0.91). If these observed benefits translated into clinical practice, 15 patients would need to be treated with a statin for six months after pneumonia to prevent one death. Conclusions Compared with people who were not taking statins, the risk of dying in the six month period after pneumonia was substantially lower among people who were already established on long term statin treatment when the pneumonia occurred. Whether some or all of this protective effect would be obtained if statin treatment begins when a patient first develops pneumonia is not known. However, given that statins are cheap, safe, and well tolerated, a clinical trial in which people with pneumonia are randomised to a short period of statin treatment is warranted.

BMJ: 07 Apr 2011; 342:d1642
Douglas I, Evans S, Smeeth L
BMJ: 07 Apr 2011; 342:d1642 | PMID: 21471172
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Abstract

Safety of pertussis vaccination in pregnant women in UK: observational study.

Donegan K, King B, Bryan P
To examine the safety of pertussis vaccination in pregnancy.Design: Observational cohort study.Setting: The UK Clinical Practice Research Datalink.Participants: 20 074 pregnant women with a median age of 30 who received the pertussis vaccine and a matched historical unvaccinated control group.Main outcome measure: Adverse events identified from clinical diagnoses during pregnancy, with additional data from the matched child record identified through mother-child linkage. The primary event of interest was stillbirth (intrauterine death after 24 weeks\' gestation).RESULTS : There was no evidence of an increased risk of stillbirth in the 14 days immediately after vaccination (incidence rate ratio 0.69, 95% confidence interval 0.23 to 1.62) or later in pregnancy (0.85, 0.44 to 1.61) compared with historical national rates. Compared with a matched historical cohort of unvaccinated pregnant women, there was no evidence that vaccination accelerated the time to delivery (hazard ratio 1.00, 0.97 to 1.02). Furthermore, there was no evidence of an increased risk of stillbirth, maternal or neonatal death, pre-eclampsia or eclampsia, haemorrhage, fetal distress, uterine rupture, placenta or vasa praevia, caesarean delivery, low birth weight, or neonatal renal failure, all serious events that can occur naturally in pregnancy.Conclusion: In women given pertussis vaccination in the third trimester, there is no evidence of an increased risk of any of an extensive predefined list of adverse events related to pregnancy. In particular, there was no evidence of an increased risk of stillbirth. Given the recent increases in the rate of pertussis infection and morbidity and mortality in neonates, these early data provide initial evidence for evaluating the safety of the vaccine in pregnancy for health professionals and the public and can help to inform vaccination policy making.

BMJ: 11 Jul 2014; 349:g4219
Donegan K, King B, Bryan P
BMJ: 11 Jul 2014; 349:g4219 | PMID: 25015137
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Abstract

Performance of stroke risk scores in older people with atrial fibrillation not taking warfarin: comparative cohort study from BAFTA trial.

Hobbs FD, Roalfe AK, Lip GY, Fletcher K, ... Mant J, on behalf of the Birmingham Atrial Fibrillation in the Aged (BAFTA) investigators and Midland Research Practices Consortium (MidReC) network
Objective To compare the predictive power of the main existing and recently proposed schemes for stratification of risk of stroke in older patients with atrial fibrillation. Design: Comparative cohort study of eight risk stratification scores. Setting Trial of thromboprophylaxis in stroke, the Birmingham Atrial Fibrillation in the Aged (BAFTA) trial. Participants: 665 patients aged 75 or over with atrial fibrillation based in the community who were randomised to the BAFTA trial and were not taking warfarin throughout or for part of the study period. Main outcome measures: Events rates of stroke and thromboembolism. Results: 54 (8%) patients had an ischaemic stroke, four (0.6%) had a systemic embolism, and 13 (2%) had a transient ischaemic attack. The distribution of patients classified into the three risk categories (low, moderate, high) was similar across three of the risk stratification scores (revised CHADS(2), NICE, ACC/AHA/ESC), with most patients categorised as high risk (65-69%, n=460-457) and the remaining classified as moderate risk. The original CHADS(2) (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, previous Stroke) score identified the lowest number as high risk (27%, n=180). The incremental risk scores of CHADS(2), Rietbrock modified CHADS(2), and CHA(2)DS(2)-VASc (CHA(2)DS(2)-Vascular disease, Age 65-74 years, Sex) failed to show an increase in risk at the upper range of scores. The predictive accuracy was similar across the tested schemes with C statistic ranging from 0.55 (original CHADS(2)) to 0.62 (Rietbrock modified CHADS(2)), with all except the original CHADS(2) predicting better than chance. Bootstrapped paired comparisons provided no evidence of significant differences between the discriminatory ability of the schemes. Conclusions: Based on this single trial population, current risk stratification schemes in older people with atrial fibrillation have only limited ability to predict the risk of stroke. Given the systematic undertreatment of older people with anticoagulation, and the relative safety of warfarin versus aspirin in those aged over 70, there could be a pragmatic rationale for classifying all patients over 75 as "high risk" until better tools are available.

BMJ: 24 Jun 2011; 342:d3653
Hobbs FD, Roalfe AK, Lip GY, Fletcher K, ... Mant J, on behalf of the Birmingham Atrial Fibrillation in the Aged (BAFTA) investigators and Midland Research Practices Consortium (MidReC) network
BMJ: 24 Jun 2011; 342:d3653 | PMID: 21700651
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Abstract

Impact of reduction in working hours for doctors in training on postgraduate medical education and patients\' outcomes: systematic review.

Moonesinghe SR, Lowery J, Shahi N, Millen A, Beard JD
Objectives To determine whether a reduction in working hours of doctors in postgraduate medical training has had an effect on objective measures of medical education and clinical outcome. Design Systematic review. Data sources Medline, Embase, ISI Web of Science, Google Scholar, ERIC, and SIGLE were searched without language restriction for articles published between 1990 and December 2010. Reference lists and citations of selected articles. Study selection Studies that assessed the impact of a change in duty hours using any objective measure of outcome related to postgraduate medical training, patient safety, or clinical outcome. Any study design was eligible for inclusion. Results 72 studies were eligible for inclusion: 38 reporting training outcomes, 31 reporting outcomes in patients, and three reporting both. A reduction in working hours from greater than 80 hours a week (in accordance with US recommendations) does not seem to have adversely affected patient safety and has had limited effect on postgraduate training. Reports on the impact of European legislation limiting working hours to less than 56 or 48 a week are of poor quality and have conflicting results, meaning that firm conclusions cannot be made. Conclusions Reducing working hours to less than 80 a week has not adversely affected outcomes in patient or postgraduate training in the US. The impact of reducing hours to less than 56 or 48 a week in the UK has not yet been sufficiently evaluated in high quality studies. Further work is required, particularly in the European Union, using large multicentre evaluations of the impact of duty hours\' legislation on objective educational and clinical outcomes.

BMJ: 23 Mar 2011; 342:d1580
Moonesinghe SR, Lowery J, Shahi N, Millen A, Beard JD
BMJ: 23 Mar 2011; 342:d1580 | PMID: 21427046
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Abstract

Association of echocardiography before major elective non-cardiac surgery with postoperative survival and length of hospital stay: population based cohort study.

Wijeysundera DN, Beattie WS, Karkouti K, Neuman MD, Austin PC, Laupacis A
Objective: To determine the association of resting echocardiography before elective intermediate to high risk non-cardiac surgery with survival and length of hospital stay. Design: Population based retrospective cohort study. Setting: Acute care hospitals in Ontario, Canada, between 1 April 1999 and 31 March 2008. Participants: Patients aged over 40 years who had elective intermediate to high risk non-cardiac surgery. Intervention: Resting echocardiography within 6 months before surgery. Main outcome measures: Postoperative survival (30 days and 1 year) and length of hospital stay; postoperative surgical site infection as an outcome for which no association with echocardiography would be expected. Results: Of the 264 823 patients in the entire cohort, 15.1% (n=40 084) had echocardiography. After use of propensity score methods to assemble a matched cohort (n=70 996) that reduced differences between patients who had or had not had echocardiography, echocardiography was associated with increases in 30 day mortality (relative risk 1.14, 95% confidence interval 1.02 to 1.27), 1 year mortality (1.07, 1.01 to 1.12), and length of hospital stay but no difference in surgical site infections (1.03, 0.98 to 1.06). The association with mortality was influenced (P=0.02) by whether patients had had stress testing or had risk factors for cardiac complications. No association existed between echocardiography and mortality among patients who had stress testing (relative risk 1.01, 0.92 to 1.11) or among patients at high risk who had not had stress testing (1.00, 0.87 to 1.13). However, echocardiography was associated with mortality in patients at low risk (relative risk 1.44, 1.14 to 1.82) and intermediate risk (1.10, 1.02 to 1.18) who had not had stress testing. Conclusions: Preoperative echocardiography was not associated with improved survival or shorter hospital stay after major non-cardiac surgery. These findings highlight the need for further research to guide better use of this common preoperative test.

BMJ: 04 Jul 2011; 342:d3695
Wijeysundera DN, Beattie WS, Karkouti K, Neuman MD, Austin PC, Laupacis A
BMJ: 04 Jul 2011; 342:d3695 | PMID: 21724560
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Abstract

Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis.

Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA
Objective: To determine if vitamin A supplementation is associated with reductions in mortality and morbidity in children aged 6 months to 5 years. Design: Systematic review and meta-analysis. Two reviewers independently assessed studies for inclusion. Data were double extracted; discrepancies were resolved by discussion. Meta-analyses were performed for mortality, illness, vision, and side effects. Data sources: Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, Embase, Global Health, Latin American and Caribbean Health Sciences, metaRegister of Controlled Trials, and African Index Medicus. Databases were searched to April 2010 without restriction by language or publication status. Eligibility criteria for selecting studies Randomised trials of synthetic oral vitamin A supplements in children aged 6 months to 5 years. Studies of children with current illness (such as diarrhoea, measles, and HIV), studies of children in hospital, and studies of food fortification or β carotene were excluded. Results: 43 trials with about 215 633 children were included. Seventeen trials including 194 483 participants reported a 24% reduction in all cause mortality (rate ratio=0.76, 95% confidence interval 0.69 to 0.83). Seven trials reported a 28% reduction in mortality associated with diarrhoea (0.72, 0.57 to 0.91). Vitamin A supplementation was associated with a reduced incidence of diarrhoea (0.85, 0.82 to 0.87) and measles (0.50, 0.37 to 0.67) and a reduced prevalence of vision problems, including night blindness (0.32, 0.21 to 0.50) and xerophthalmia (0.31, 0.22 to 0.45). Three trials reported an increased risk of vomiting within the first 48 hours of supplementation (2.75, 1.81 to 4.19). Conclusions: Vitamin A supplementation is associated with large reductions in mortality, morbidity, and vision problems in a range of settings, and these results cannot be explained by bias. Further placebo controlled trials of vitamin A supplementation in children between 6 and 59 months of age are not required. However, there is a need for further studies comparing different doses and delivery mechanisms (for example, fortification). Until other sources are available, vitamin A supplements should be given to all children at risk of deficiency, particularly in low and middle income countries.

BMJ: 26 Aug 2011; 343:d5094
Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA
BMJ: 26 Aug 2011; 343:d5094 | PMID: 21868478
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Abstract

Comparative safety of anesthetic type for hip fracture surgery in adults: retrospective cohort study.

Patorno E, Neuman MD, Schneeweiss S, Mogun H, Bateman BT
To evaluate the effect of anesthesia type on the risk of in-hospital mortality among adults undergoing hip fracture surgery in the United States.Design: Retrospective cohort study.Setting: Premier research database, United States.Participants: 73 284 adults undergoing hip fracture surgery on hospital day 2 or greater between 2007 and 2011. Of those, 61 554 (84.0%) received general anesthesia, 6939 (9.5%) regional anesthesia, and 4791 (6.5%) combined general and regional anesthesia.Main outcome measure: In-hospital all cause mortality.Results: In-hospital deaths occurred in 1362 (2.2%) patients receiving general anesthesia, 144 (2.1%) receiving regional anesthesia, and 115 (2.4%) receiving combined anesthesia. In the multivariable adjusted analysis, when compared with general anesthesia the mortality risk did not differ significantly between regional anesthesia (risk ratio 0.93, 95% confidence interval 0.78 to 1.11) or combined anesthesia (1.00, 0.82 to 1.22). A mixed effects analysis accounting for differences between hospitals produced similar results: compared with general anesthesia the risk from regional anesthesia was 0.91 (0.75 to 1.10) and from combined anesthesia was 0.98 (0.79 to 1.21). Findings were also consistent in subgroup analyses.Conclusions: In this large nationwide sample of hospital admissions, mortality risk did not differ significantly by anesthesia type among patients undergoing hip fracture surgery. Our results suggest that if the previously posited beneficial effect of regional anesthesia on short term mortality exists, it is likely to be more modest than previously reported.

BMJ: 27 Jun 2014; 348:g4022
Patorno E, Neuman MD, Schneeweiss S, Mogun H, Bateman BT
BMJ: 27 Jun 2014; 348:g4022 | PMID: 24972901
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Abstract

Management of acute upper gastrointestinal bleeding.

Stanley AJ, Laine L
Upper gastrointestinal bleeding (UGIB) is a common medical emergency, with a reported mortality of 2-10%. Patients identified as being at very low risk of either needing an intervention or death can be managed as outpatients. For all other patients, intravenous fluids as needed for resuscitation and red cell transfusion at a hemoglobin threshold of 70-80 g/L are recommended. After resuscitation is initiated, proton pump inhibitors (PPIs) and the prokinetic agent erythromycin may be administered, with antibiotics and vasoactive drugs recommended in patients who have cirrhosis. Endoscopy should be undertaken within 24 hours, with earlier endoscopy considered after resuscitation in patients at high risk, such as those with hemodynamic instability. Endoscopic treatment is used for variceal bleeding (for example, ligation for esophageal varices and tissue glue for gastric varices) and for high risk non-variceal bleeding (for example, injection, thermal probes, or clips for lesions with active bleeding or non-bleeding visible vessel). Patients who require endoscopic therapy for ulcer bleeding should receive high dose proton pump inhibitors after endoscopy, whereas those who have variceal bleeding should continue taking antibiotics and vasoactive drugs. Recurrent ulcer bleeding is treated with repeat endoscopic therapy, with subsequent bleeding managed by interventional radiology or surgery. Recurrent variceal bleeding is generally treated with transjugular intrahepatic portosystemic shunt. In patients who require antithrombotic agents, outcomes appear to be better when these drugs are reintroduced early.

BMJ: 24 Mar 2019; 364:l536
Stanley AJ, Laine L
BMJ: 24 Mar 2019; 364:l536 | PMID: 30910853
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Abstract

Low risk papillary thyroid cancer.

Brito JP, Hay ID, Morris JC
Thyroid cancer is one of the fastest growing diagnoses; more cases of thyroid cancer are found every year than all leukemias and cancers of the liver, pancreas, and stomach. Most of these incident cases are papillary in origin and are both small and localized. Patients with these small localized papillary thyroid cancers have a 99% survival rate at 20 years. In view of the excellent prognosis of these tumors, they have been denoted as low risk. The incidence of these low risk thyroid cancers is growing, probably because of the use of imaging technologies capable of exposing a large reservoir of subclinical disease. Despite their excellent prognosis, these subclinical low risk cancers are often treated aggressively. Although surgery is traditionally viewed as the cornerstone treatment for these tumors, there is less agreement about the extent of surgery (lobectomy v near total thyroidectomy) and whether prophylactic central neck dissection for removal of lymph nodes is needed. Many of these tumors are treated with radioactive iodine ablation and thyrotropin suppressive therapy, which-although effective for more aggressive forms of thyroid cancer-have not been shown to be of benefit in the management of these lesions. This review offers an evidence based approach to managing low risk papillary thyroid cancer. It also looks at the future of promising alternative surgical techniques, non-surgical minimally localized invasive therapies (ethanol ablation and laser ablation), and active surveillance, all of which form part of a more individualized treatment approach for low risk papillary thyroid tumors.

BMJ: 16 Jun 2014; 348:g3045
Brito JP, Hay ID, Morris JC
BMJ: 16 Jun 2014; 348:g3045 | PMID: 24935445
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Abstract

Bariatric surgery for obesity and metabolic conditions in adults.

Arterburn DE, Courcoulas AP
This review summarizes recent evidence related to the safety, efficacy, and metabolic outcomes of bariatric surgery to guide clinical decision making. Several short term randomized controlled trials have demonstrated the effectiveness of bariatric procedures for inducing weight loss and initial remission of type 2 diabetes. Observational studies have linked bariatric procedures with long term improvements in body weight, type 2 diabetes, survival, cardiovascular events, incident cancer, and quality of life. Perioperative mortality for the average patient is low but varies greatly across subgroups. The incidence of major complications after surgery also varies widely, and emerging data show that some procedures are associated with a greater risk of substance misuse disorders, suicide, and nutritional deficiencies. More research is needed to enable long term outcomes to be compared across various procedures and subpopulations, and to identify those most likely to benefit from surgical intervention. Given uncertainties about the balance between the risks and benefits of bariatric surgery in the long term, the decision to undergo surgery should be based on a high quality shared decision making process.

BMJ: 27 Aug 2014; 349:g3961
Arterburn DE, Courcoulas AP
BMJ: 27 Aug 2014; 349:g3961 | PMID: 25164369
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Abstract

Antiviral treatment of hepatitis C.

Feeney ER, Chung RT
Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide.

BMJ: 07 Jul 2014; 349:g3308
Feeney ER, Chung RT
BMJ: 07 Jul 2014; 349:g3308 | PMID: 25002352
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Abstract

Effect of integrated care for sick listed patients with chronic low back pain: economic evaluation alongside a randomised controlled trial.

Lambeek LC, Bosmans JE, Van Royen BJ, Van Tulder MW, Van Mechelen W, Anema JR
Objective: To evaluate the cost effectiveness, cost utility, and cost-benefit of an integrated care programme compared with usual care for sick listed patients with chronic low back pain. Design: Economic evaluation alongside a randomised controlled trial with 12 months\' follow-up. Setting Primary care (10 physiotherapy practices, one occupational health service, one occupational therapy practice) and secondary care (five hospitals) in the Netherlands, 2005-9. Participants: 134 adults aged 18-65 sick listed because of chronic low back pain: 66 were randomised to integrated care and 68 to usual care. Interventions: Integrated care consisted of a workplace intervention based on participatory ergonomics, with involvement of a supervisor, and a graded activity programme based on cognitive behavioural principles. Usual care was provided by general practitioners and occupational physicians according to Dutch guidelines. Main outcome measures: The primary outcome was duration until sustainable return to work. The secondary outcome was quality adjusted life years (QALYs), measured using EuroQol. Results: Total costs in the integrated care group (£13 165, SD £13 600) were significantly lower than in the usual care group (£18 475, SD £13 616). Cost effectiveness planes and acceptability curves showed that integrated care was cost effective compared with usual care for return to work and QALYs gained. The cost-benefit analyses showed that every £1 invested in integrated care would return an estimated £26. The net societal benefit of integrated care compared with usual care was £5744. Conclusions: Implementation of an integrated care programme for patients sick listed with chronic low back pain has a large potential to significantly reduce societal costs, increase effectiveness of care, improve quality of life, and improve function on a broad scale. Integrated care therefore has large gains for patients and society as well as for employers.

BMJ: 01 Dec 2010; 341:c6414
Lambeek LC, Bosmans JE, Van Royen BJ, Van Tulder MW, Van Mechelen W, Anema JR
BMJ: 01 Dec 2010; 341:c6414 | PMID: 21118874
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Abstract

Implications of expanding indications for drug treatment to prevent fracture in older men in United States: cross sectional and longitudinal analysis of prospective cohort study.

Ensrud KE, Taylor BC, Peters KW, Gourlay ML, ... Schousboe J, for the Osteoporotic Fractures in Men (MrOS) Study Group
To quantify incremental effects of applying different criteria to identify men who are candidates for drug treatment to prevent fracture and to examine the extent to which fracture probabilities vary across distinct categories of men defined by these criteria.Design: Cross sectional and longitudinal analysis of a prospective cohort study.Setting: Multicenter Osteoporotic Fractures in Men (MrOS) study in the United States.Participants: 5880 untreated community dwelling men aged 65 years or over classified into four distinct groups: osteoporosis by World Health Organization criteria alone; osteoporosis by National Osteoporosis Foundation (NOF) but not WHO criteria; no osteoporosis but at high fracture risk (at or above NOF derived FRAX intervention thresholds recommended for US); and no osteoporosis and at low fracture risk (below NOF derived FRAX intervention thresholds recommended for US).Main outcome measures: Proportion of men identified for drug treatment; predicted 10 year probabilities of hip and major osteoporotic fracture calculated using FRAX algorithm with femoral neck bone mineral density; observed 10 year probabilities for confirmed incident hip and major osteoporotic (hip, clinical vertebral, wrist, or humerus) fracture events calculated using cumulative incidence estimation, accounting for competing risk of mortality.Results: 130 (2.2%) men were identified as having osteoporosis by using the WHO definition, and an additional 422 were identified by applying the NOF definition (total osteoporosis prevalence 9.4%). Application of NOF derived FRAX intervention thresholds led to 936 (15.9%) additional men without osteoporosis being identified as at high fracture risk, raising the total prevalence of men potentially eligible for drug treatment to 25.3%. Observed 10 year hip fracture probabilities were 20.6% for men with osteoporosis by WHO criteria alone, 6.8% for men with osteoporosis by NOF (but not WHO) criteria, 6.4% for men without osteoporosis but classified as at high fracture risk, and 1.5% for men without osteoporosis and classified as at low fracture risk. A similar pattern was noted in observed fracture probabilities for major osteoporotic fracture. Among men with osteoporosis by WHO criteria, observed fracture probabilities were greater than FRAX predicted probabilities (20.6% v 9.5% for hip fracture and 30.0% v 17.4% for major osteoporotic fracture).CONCLUSIONS AND RELEVANCE: Choice of definition of osteoporosis and use of NOF derived FRAX intervention thresholds have major effects on the proportion of older men identified as warranting drug treatment to prevent fracture. Among men identified with osteoporosis by WHO criteria, who comprised 2% of the study population, actual observed fracture probabilities during 10 years of follow-up were highest and exceeded FRAX predicted fracture probabilities. On the basis of findings from randomized trials in women, these men are most likely to benefit from treatment. Expanding indications for treatment beyond this small group has uncertain value owing to lower observed fracture probabilities and uncertain benefits of treatment among men not selected on the basis of WHO criteria.

BMJ: 03 Jul 2014; 349:g4120
Ensrud KE, Taylor BC, Peters KW, Gourlay ML, ... Schousboe J, for the Osteoporotic Fractures in Men (MrOS) Study Group
BMJ: 03 Jul 2014; 349:g4120 | PMID: 24994809
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Abstract

Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial.

Myles PS, Peyton P, Silbert B, Hunt J, ... Sessler DI, for the ANZCA Trials Group Investigators
Objective: To compare long term recurrence of cancer and survival of patients having major abdominal surgery for cancer. Design: Long term follow-up of prospective randomised controlled clinical trial in which patients were randomly assigned to receive general anaesthesia with or without epidural block for at least three postoperative days. Setting 23 hospitals in Australia, New Zealand, and Asia. Participants: 503 adult patients who had potentially curative surgery for cancer. Main outcome measure: Cancer-free survival (analysis was by intention to treat). Results: Long term follow-up data were available for 94% (n=446) of eligible participants. The median time to recurrence of cancer or death was 2.8 (95% confidence interval 0.7 to 8.7) years in the control group and 2.6 (0.7 to 8.7) years in the epidural group (P=0.61). Recurrence-free survival was similar in both epidural and control groups (hazard ratio 0.95, 95% confidence interval 0.76 to 1.17; P=0.61). Conclusion: Use of epidural block in abdominal surgery for cancer is not associated with improved cancer-free survival. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12607000637448.

BMJ: 30 Mar 2011; 342:d1491
Myles PS, Peyton P, Silbert B, Hunt J, ... Sessler DI, for the ANZCA Trials Group Investigators
BMJ: 30 Mar 2011; 342:d1491 | PMID: 21447587
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Abstract

Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial.

Slagman MC, Waanders F, Hemmelder MH, Woittiez AJ, ... Laverman GD, for the HONEST (HOlland NEphrology STudy) Group
Objective: To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose. Design: Multicentre crossover randomised controlled trial. Setting: Outpatient clinics in the Netherlands. Participants: 52 patients with non-diabetic nephropathy. Interventions: All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na(+)/day) and a regular sodium diet (target 200 mmol Na(+)/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label. Main outcome measures: The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure. Results: Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na(+)/day during a low sodium diet and 184 (6) mmol Na(+)/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was comparable (P=0.009, not significant after Bonferroni correction) to the reduction of proteinuria by the addition of both angiotensin receptor blockade and a low sodium diet to ACE inhibition (62%, 53% to 70%). Mean systolic blood pressure was 134 (3) mm Hg during ACE inhibition plus a regular sodium diet. Mean systolic blood pressure was not significantly altered by the addition of angiotensin receptor blockade (131 (3) mm Hg; P=0.12) but was reduced by the addition of a low sodium diet (123 (2) mm Hg; P<0.001) and angiotensin receptor blockade plus a low sodium diet (121 (3) mm Hg; P<0.001) to ACE inhibition. The reduction of systolic blood pressure by the addition of a low sodium diet (7% (SE 1%)) was significantly larger (P=0.003) than the reduction of systolic blood pressure by the addition of angiotensin receptor blockade (2% (1)) and was similar (P=0.14) to the reduction of systolic blood pressure by the addition of both angiotensin receptor blockade and low sodium diet (9% (1)), to ACE inhibition. Conclusions: Dietary sodium restriction to a level recommended in guidelines was more effective than dual blockade for reduction of proteinuria and blood pressure in non-diabetic nephropathy. The findings support the combined endeavours of patients and health professionals to reduce sodium intake. Trial registration Netherlands Trial Register NTR675.

BMJ: 27 Jul 2011; 343:d4366
Slagman MC, Waanders F, Hemmelder MH, Woittiez AJ, ... Laverman GD, for the HONEST (HOlland NEphrology STudy) Group
BMJ: 27 Jul 2011; 343:d4366 | PMID: 21791491
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Abstract

Time to treatment with recombinant tissue plasminogen activator and outcome of stroke in clinical practice: retrospective analysis of hospital quality assurance data with comparison with results from randomised clinical trials.

Gumbinger C, Reuter B, Stock C, Sauer T, ... Hacke W, for the AG Schlaganfall
To study the time dependent effectiveness of thrombolytic therapy for acute ischaemic stroke in daily clinical practice.Design: A retrospective cohort study using data from a large scale, comprehensive population based state-wide stroke registry in Germany.Setting: All 148 hospitals involved in acute stroke care in a large state in southwest Germany with 10.4 million inhabitants.Participants: Data from 84 439 patients with acute ischaemic stroke were analysed, 10 263 (12%) were treated with thrombolytic therapy and 74 176 (88%) were not treated.Main outcome measures: Primary endpoint was the dichotomised score on a modified Rankin scale at discharge ("favourable outcome" score 0 or 1 or "unfavourable outcome" score 2-6) analysed by binary logistic regression. Patients treated with recombinant tissue plasminogen activator (rtPA) were categorised according to time from onset of stroke to treatment. Analogous analyses were conducted for the association between rtPA treatment of stroke and in-hospital mortality. As a co-primary endpoint the chance of a lower modified Rankin scale score at discharge was analysed by ordinal logistic regression analysis (shift analysis).Results: After adjustment for characteristics of patients, hospitals, and treatment, rtPA was associated with better outcome in a time dependent pattern. The number needed to treat ranged from 4.5 (within first 1.5 hours after onset; odds ratio 2.49) to 18.0 (up to 4.5 hours; odds ratio 1.26), while mortality did not vary up to 4.5 hours. Patients treated with rtPA beyond 4.5 hours (including mismatch based approaches) showed a significantly better outcome only in dichotomised analysis (odds ratio 1.25, 95% confidence interval 1.01 to 1.55) but the mortality risk was higher (1.45, 1.08 to 1.92).Conclusion: The effectiveness of thrombolytic therapy in daily clinical practice might be comparable with the effectiveness shown in randomised clinical trials and pooled analysis. Early treatment was associated with favourable outcome in daily clinical practice, which underlines the importance of speeding up the process for thrombolytic therapy in hospital and before admission to achieve shorter time from door to needle and from onset to treatment for thrombolytic therapy.

BMJ: 30 May 2014; 348:g3429
Gumbinger C, Reuter B, Stock C, Sauer T, ... Hacke W, for the AG Schlaganfall
BMJ: 30 May 2014; 348:g3429 | PMID: 24879819
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Abstract

Thrombolysis in very elderly people: controlled comparison of SITS International Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive.

Mishra NK, Ahmed N, Andersen G, Egido JA, ... Lees KR, for the VISTA and SITS collaborators
Objective: To assess effect of age on response to alteplase in acute ischaemic stroke. Design: Adjusted controlled comparison of outcomes between non-randomised patients who did or did not undergo thrombolysis. Analysis used Cochran-Mantel-Haenszel test and proportional odds logistic regression analysis. Setting: Collaboration between International Stroke Thrombolysis Registry (SITS-ISTR) and Virtual International Stroke Trials Archive (VISTA). Participants: 23 334 patients from SITS-ISTR (December 2002 to November 2009) who underwent thrombolysis and 6166 from VISTA neuroprotection trials (1998-2007) who did not undergo thrombolysis (as controls). Of the 29 500 patients (3472 aged >80 ("elderly," mean 84.6), data on 272 patients were missing for baseline National Institutes of Health stroke severity score, leaving 29 228 patients for analysis adjusted for age and baseline severity. Main outcome measures: Functional outcomes at 90 days measured by score on modified Rankin scale. Results: Median severity at baseline was the same for patients who underwent thrombolysis and controls (median baseline stroke scale score: 12 for each group, P=0.14; n=29 228). The distribution of scores on the modified Rankin scale was better among all thrombolysis patients than controls (odds ratio 1.6, 95% confidence interval 1.5 to 1.7; Cochran-Mantel-Haenszel P<0.001). The association occurred independently among patients aged ≤80 (1.6, 1.5 to 1.7; P<0.001; n=25 789) and in those aged >80 (1.4, 1.3 to 1.6; P<0.001; n=3439). Odds ratios were consistent across all 10 year age ranges above 30, and benefit was significant from age 41 to 90; dichotomised outcomes (score on modified Rankin scale 0-1 v 2-6; 0-2 v 3-6; and 6 (death) v rest) were consistent with the results of the ordinal analysis. Conclusions: Outcome in patients with acute ischaemic stroke is significantly better in those who undergo thrombolysis compared with those who do not. Increasing age is associated with poorer outcome but the association between thrombolysis treatment and improved outcome is maintained in very elderly people. Age alone should not be a barrier to treatment.

BMJ: 24 Nov 2010; 341:c6046
Mishra NK, Ahmed N, Andersen G, Egido JA, ... Lees KR, for the VISTA and SITS collaborators
BMJ: 24 Nov 2010; 341:c6046 | PMID: 21098614
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Abstract

Effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality: systematic review and meta-analysis of randomised controlled trials and observational studies.

Brenner H, Stock C, Hoffmeister M
To review, summarise, and compare the evidence for effectiveness of screening sigmoidoscopy and screening colonoscopy in the prevention of colorectal cancer occurrence and deaths.Design: Systematic review and meta-analysis of randomised controlled trials and observational studies.Data sources: PubMed, Embase, and Web of Science. Two investigators independently extracted characteristics and results of identified studies and performed standardised quality ratings.ELIGIBILITY CRITERIA: Randomised controlled trials and observational studies in English on the impact of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality in the general population at average risk.Results: For screening sigmoidoscopy, four randomised controlled trials and 10 observational studies were identified that consistently found a major reduction in distal but not proximal colorectal cancer incidence and mortality. Summary estimates of reduction in distal colorectal cancer incidence and mortality were 31% (95% confidence intervals 26% to 37%) and 46% (33% to 57%) in intention to screen analysis, 42% (29% to 53%) and 61% (27% to 79%) in per protocol analysis of randomised controlled trials, and 64% (50% to 74%) and 66% (38% to 81%) in observational studies. For screening colonoscopy, evidence was restricted to six observational studies, the results of which suggest tentatively an even stronger reduction in distal colorectal cancer incidence and mortality, along with a significant reduction in mortality from cancer of the proximal colon. Indirect comparisons of results of observational studies on screening sigmoidoscopy and colonoscopy suggest a 40% to 60% lower risk of incident colorectal cancer and death from colorectal cancer after screening colonoscopy even though this incremental risk reduction was statistically significant for deaths from cancer of the proximal colon only.Conclusions: Compelling and consistent evidence from randomised controlled trials and observational studies suggests that screening sigmoidoscopy and screening colonoscopy prevent most deaths from distal colorectal cancer. Observational studies suggest that colonoscopy compared with flexible sigmoidoscopy decreases mortality from cancer of the proximal colon. This added value should be examined in further research and weighed against the higher costs, discomfort, complication rates, capacities needed, and possible differences in compliance.

BMJ: 11 Jun 2014; 348:g2467
Brenner H, Stock C, Hoffmeister M
BMJ: 11 Jun 2014; 348:g2467 | PMID: 24922745
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Abstract

Diagnosis and management of subclinical hypothyroidism in pregnancy.

Negro R, Stagnaro-Green A
In prospective studies, the prevalence of undiagnosed subclinical hypothyroidism in pregnant women ranges from 3% to 15%. Subclinical hypothyroidism is associated with multiple adverse outcomes in the mother and fetus, including spontaneous abortion, pre-eclampsia, gestational hypertension, gestational diabetes, preterm delivery, and decreased IQ in the offspring. Only two prospective studies have evaluated the impact of levothyroxine therapy in pregnant women with subclinical hypothyroidism, and the results were mixed. Subclinical hypothyroidism is defined as raised thyrotropin combined with a normal serum free thyroxine level. The normal range of thyrotropin varies according to geographic region and ethnic background. In the absence of local normative data, the recommended upper limit of thyrotropin in the first trimester of pregnancy is 2.5 mIU/L, and 3.0 mIU/L in the second and third trimester. The thyroid gland needs to produce 50% more thyroid hormone during pregnancy to maintain a euthyroid state. Consequently, most women on levothyroxine therapy before pregnancy require an increase in dose when pregnant to maintain euthyroidism. Ongoing prospective trials that are evaluating the impact of levothyroxine therapy on adverse outcomes in the mother and fetus in women with subclinical hypothyroidism will provide crucial data on the role of thyroid hormone replacement in pregnancy.

BMJ: 06 Oct 2014; 349:g4929
Negro R, Stagnaro-Green A
BMJ: 06 Oct 2014; 349:g4929 | PMID: 25288580
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Abstract

Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data.

Jick SS, Hernandez RK
Objective: To compare the risk of non-fatal venous thromboembolism in women receiving oral contraceptives containing drospirenone with that in women receiving oral contraceptives containing levonorgestrel. Design: Nested case-control and cohort study. Setting: The study was based on information from PharMetrics, a United States based company that collects information on claims paid by managed care plans. Participants: The study encompassed all women aged 15 to 44 years who received an oral contraceptive containing either drospirenone or levonorgestrel after 1 January 2002. Cases were women with current use of a study oral contraceptive and a diagnosis of venous thromboembolism in the absence of identifiable clinical risk factors (idiopathic venous thromboembolism). Up to four controls were matched to each case by age and calendar time. Main outcome measures: Odds ratios comparing the risk of non-fatal venous thromboembolism in users of the two contraceptives; incidence rates and rate ratios of non-fatal venous thromboembolism for users of each of the study contraceptives. Results: 186 newly diagnosed, idiopathic cases of venous thromboembolism were identified in the study population and matched with 681 controls. In the case-control analysis, the conditional odds ratio for venous thromboembolism comparing use of oral contraceptives containing drospirenone with use of those containing levonorgestrel was 2.3 (95% confidence interval 1.6 to 3.2). The incidence rates for venous thromboembolism in the study population were 30.8 (95% confidence interval 25.6 to 36.8) per 100 000 woman years among users of oral contraceptives containing drospirenone and 12.5 (9.61 to 15.9) per 100 000 woman years among users of oral contraceptives containing levonorgestrel. The age adjusted incidence rate ratio for venous thromboembolism for current use of oral contraceptives containing drospirenone compared with those containing levonorgestrel was 2.8 (2.1 to 3.8). Conclusions: The risk of non-fatal venous thromboembolism among users of oral contraceptives containing drospirenone seems to be around twice that of users of oral contraceptives containing levonorgestrel, after the effects of potential confounders and prescribing biases have been taken into account.

BMJ: 22 Apr 2011; 342:d2151
Jick SS, Hernandez RK
BMJ: 22 Apr 2011; 342:d2151 | PMID: 21511805
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Abstract

Urinary incontinence in women.

Wood LN, Anger JT
Urinary incontinence affects women of all ages. History, physical examination, and certain tests can guide specialists in diagnosing stress urinary incontinence, urgency urinary incontinence, and mixed urinary incontinence. First line management includes lifestyle and behavior modification, as well as pelvic floor strength and bladder training. Drug therapy is helpful in the treatment of urgency incontinence that does not respond to conservative measures. In addition, sacral neuromodulation, intravesical onabotulinumtoxinA injections, and posterior tibial nerve stimulation can be used in select patient populations with drug refractory urgency incontinence. Midurethral synthetic slings, including retropubic and transobturator approaches, are safe and efficacious surgical options for stress urinary incontinence and have replaced more invasive bladder neck slings that use autologous or cadaveric fascia. Despite controversy surrounding vaginal mesh for prolapse, synthetic slings for the treatment of stress urinary incontinence are considered safe and minimally invasive.

BMJ: 15 Sep 2014; 349:g4531
Wood LN, Anger JT
BMJ: 15 Sep 2014; 349:g4531 | PMID: 25225003
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Abstract

Urine output on an intensive care unit: case-control study.

Solomon AW, Kirwan CJ, Alexander ND, Nimako K, ... Rahman TM, on behalf of the Prospective Analysis of Renal Compensation for Hypohydration in Exhausted Doctors (PARCHED) Investigators
Objective: To compare urine output between junior doctors in an intensive care unit and the patients for whom they are responsible. Design: Case-control study. Setting: General intensive care unit in a tertiary referral hospital. Participants: 18 junior doctors responsible for clerking patients on weekday day shifts in the unit from 23 March to 23 April 2009 volunteered as "cases." Controls were the patients in the unit clerked by those doctors. Exclusion criteria (for both groups) were pregnancy, baseline estimated glomerular filtration rate <15 ml/min/1.73 m(2), and renal replacement therapy. Main outcome measures: Oliguria (defined as mean urine output <0.5 ml/kg/hour over six or more hours of measurement) and urine output (in ml/kg/hour) as a continuous variable. Results: Doctors were classed as oliguric and "at risk" of acute kidney injury on 19 (22%) of 87 shifts in which urine output was measured, and oliguric to the point of being "in injury" on one (1%) further shift. Data were available for 208 of 209 controls matched to cases in the data collection period; 13 of these were excluded because the control was receiving renal replacement therapy. Doctors were more likely to be oliguric than their patients (odds ratio 1.99, 95% confidence interval 1.08 to 3.68, P=0.03). For each additional 1 ml/kg/hour mean urine output, the odds ratio for being a case rather than a control was 0.27 (0.12 to 0.58, P=0.001). Mortality among doctors was astonishingly low, at 0% (0% to 18%). Conclusions: Managing our own fluid balance is more difficult than managing it in our patients. We should drink more water. Modifications to the criteria for acute kidney injury could be needed for the assessment of junior doctors in an intensive care unit.

BMJ: 15 Dec 2010; 341:c6761
Solomon AW, Kirwan CJ, Alexander ND, Nimako K, ... Rahman TM, on behalf of the Prospective Analysis of Renal Compensation for Hypohydration in Exhausted Doctors (PARCHED) Investigators
BMJ: 15 Dec 2010; 341:c6761 | PMID: 21156738
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Abstract

Living and dying with severe chronic obstructive pulmonary disease: multi-perspective longitudinal qualitative study.

Pinnock H, Kendall M, Murray SA, Worth A, ... Macnee W, Sheikh A
ObjectiveS: To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD. Design: Up to four serial qualitative interviews were conducted with each patient and nominated carer over 18 months. Interviews were transcribed and analysed both thematically and as narratives. Participants: 21 patients, and 13 informal carers (a family member, friend, or neighbour) and 18 professional carers (a key health or social care professional) nominated by the patients. Setting: Primary and secondary care in Lothian, Tayside, and Forth Valley, Scotland, during 2007-9. Results: Eleven patients died during the study period. Our final dataset comprised 92 interviews (23 conducted with patient and informal carer together). Severe symptoms that caused major disruption to normal life were described, often in terms implying acceptance of the situation as a "way of life" rather than an "illness." Patients and their informal carers adapted to and accepted the debilitating symptoms of a lifelong condition. Professional carers\' familiarity with the patients\' condition, typically over many years, and prognostic uncertainty contributed to the difficulty of recognising and actively managing end stage disease. Overall, patients told a "chaos narrative" of their illness that was indistinguishable from their life story, with no clear beginning and an unanticipated end described in terms comparable with attitudes to death in a normal elderly population. Conclusions: Our findings challenge current assumptions underpinning provision of end of life care for people with COPD. The policy focus on identifying a time point for transition to palliative care has little resonance for people with COPD or their clinicians and is counter productive if it distracts from early phased introduction of supportive care. Careful assessment of possible supportive and palliative care needs should be triggered at key disease milestones along a lifetime journey with COPD, in particular after hospital admission for an exacerbation.

BMJ: 25 Jan 2011; 342:d142
Pinnock H, Kendall M, Murray SA, Worth A, ... Macnee W, Sheikh A
BMJ: 25 Jan 2011; 342:d142 | PMID: 21262897
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Abstract

Obamacare: what the Affordable Care Act means for patients and physicians.

Hall MA, Lord R
The Affordable Care Act\'s core achievement is to make all Americans insurable, by requiring insurers to accept all applicants at rates based on population averages regardless of health status. The act also increases coverage by allowing states to expand Medicaid (the social healthcare program for families and people with low income and resources) to cover everyone near the poverty line, and by subsidizing private insurance for people who are not poor but who do not have workplace coverage. The act allows most people to keep the same kind of insurance that they currently have, and it does not change how private insurance pays physicians and hospitals. Although the act falls short of achieving truly universal coverage, nine million uninsured people have received coverage so far. Market reforms have not hurt the insurance industry\'s profitability, prices for individual insurance have been lower than expected, and government costs so far have been less than initially projected. The act expands several ongoing pilot programs in Medicare that reform how doctors and hospitals are paid, but it does not directly change how private insurers pay healthcare providers. Nevertheless, it has set into motion market dynamics that are affecting medical practice, such as limiting insurance networks to fewer providers and requiring patients to pay for more treatment costs out of pocket. In response, many hospitals and physicians are forming closer and larger affiliations. Further time and study are needed to learn whether these evolutionary changes will achieve their goals without harming the doctor-patient relationship.

BMJ: 22 Oct 2014; 349:g5376
Hall MA, Lord R
BMJ: 22 Oct 2014; 349:g5376 | PMID: 25338761
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Abstract

Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database.

Parkin L, Sharples K, Hernandez RK, Jick SS
Objective To examine the risk of non-fatal idiopathic venous thromboembolism in current users of a combined oral contraceptive containing drospirenone, relative to current users of preparations containing levonorgestrel. Design Nested case-control study. Setting UK General Practice Research Database. Participants Women aged 15-44 years without major risk factors for venous thromboembolism who started a new episode of use of an oral contraceptive containing 30 µg oestrogen in combination with either drospirenone or levonorgestrel between May 2002 and September 2009. Cases were women with a first diagnosis of venous thromboembolism; up to four controls, matched by age, duration of recorded information, and general practice, were randomly selected for each case. Main outcome measures Odds ratios and 95% confidence intervals estimated with conditional logistic regression; age adjusted incidence rate ratio estimated with Poisson regression. Results 61 cases of idiopathic venous thromboembolism and 215 matched controls were identified. In the case-control analysis, current use of the drospirenone contraceptive was associated with a threefold higher risk of non-fatal idiopathic venous thromboembolism compared with levonorgestrel use; the odds ratio adjusted for body mass index was 3.3 (95% confidence interval 1.4 to 7.6). Subanalyses suggested that referral, diagnostic, first time user, duration of use, and switching biases were unlikely explanations for this finding. The crude incidence rate was 23.0 (95% confidence interval 13.4 to 36.9) per 100 000 woman years in current users of drospirenone and 9.1 (6.6 to 12.2) per 100 000 woman years in current users of levonorgestrel oral contraceptives. The age adjusted incidence rate ratio was 2.7 (1.5 to 4.7). Conclusions These findings contribute to emerging evidence that the combined oral contraceptive containing drospirenone carries a higher risk of venous thromboembolism than do formulations containing levonorgestrel.

BMJ: 22 Apr 2011; 342:d2139
Parkin L, Sharples K, Hernandez RK, Jick SS
BMJ: 22 Apr 2011; 342:d2139 | PMID: 21511804
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Abstract

Integrated motivational interviewing and cognitive behavioural therapy for people with psychosis and comorbid substance misuse: randomised controlled trial.

Barrowclough C, Haddock G, Wykes T, Beardmore R, ... Steel C, Tarrier N
ObjectiveS: To evaluate the effectiveness of integrated motivational interviewing and cognitive behavioural therapy in addition to standard care for patients with psychosis and a comorbid substance use problem. Design: Two centre, open, rater blind randomised controlled trial. Setting: Secondary care in the United Kingdom. Participants: 327 patients with a clinical diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and a diagnosis of dependence on or misuse of drugs, alcohol, or both according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Intervention: The intervention was integrated motivational interviewing and cognitive behavioural therapy plus standard care, which was compared with standard care alone. Phase one of therapy-"motivation building"-concerns engaging the patient, then exploring and resolving ambivalence for change in substance use. Phase two-"action"-supports and facilitates change using cognitive behavioural approaches. Up to 26 therapy sessions were delivered over one year. Main outcome measures: The primary outcome was death from any cause or admission to hospital in the 12 months after completion of therapy. Secondary outcomes were frequency and amount of substance use (assessed using the timeline followback method), readiness to change, perceived negative consequences of use, psychotic symptom ratings, number and duration of relapses, and global assessment of functioning and deliberate self harm at 12 and 24 months, with additional timeline followback assessments at 6 and 18 months. Analysis was by intention to treat and robust treatment effect estimates were produced. Results: 327 participants were randomly allocated to either the intervention (n=164) or treatment as usual (n=163). At 24 months, 326 (99.7%) were assessed on the primary outcome and 246 (75.2%) on the main secondary outcomes. Treatment had no beneficial effect on hospital admissions or death during follow-up, with 23.3% (38/163) of the therapy group and 20.2% (33/163) of controls deceased or admitted (adjusted odds ratio 1.16, 95% confidence interval 0.68 to 1.99; P=0.579). Therapy had no effect on the frequency of substance use or the perceived negative consequences of misuse, but did have a statistically significant effect on amount used per substance using day (adjusted ORs for main substance 1.50, 95% CI 1.08 to 2.09; P=0.016; and all substances 1.48, 95% CI 1.07 to 2.05; P=0.017). Treatment had a statistically significant effect on readiness to change use at 12 months (adjusted OR 2.05, 95% CI 1.26 to 3.31; P=0.004) that was not maintained at 24 months (0.78, 95% CI 0.48 to 1.28; P=0.320). There were no effects of treatment on clinical outcomes such as relapses, psychotic symptoms, functioning, and self harm. Conclusions: Integrated motivational interviewing and cognitive behavioural therapy for people with psychosis and substance misuse do not improve outcome in terms of hospitalisation, symptom outcomes, or functioning. This approach does reduce the amount of substance used for at least one year after completion of therapy. Trial registration Current Controlled Trials: ISRCTN14404480.

BMJ: 25 Nov 2010; 341:c6325
Barrowclough C, Haddock G, Wykes T, Beardmore R, ... Steel C, Tarrier N
BMJ: 25 Nov 2010; 341:c6325 | PMID: 21106618
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Abstract

Risk of incident diabetes among patients treated with statins: population based study.

Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM
Objective: To examine the risk of new onset diabetes among patients treated with different HMG-CoA reductase inhibitors (statins). Design: Population based cohort study with time to event analyses to estimate the relation between use of particular statins and incident diabetes. Hazard ratios were calculated to determine the effect of dose and type of statin on the risk of incident diabetes. Setting: Ontario, Canada. Participants: All patients aged 66 or older without diabetes who started treatment with statins from 1 August 1997 to 31 March 2010. The analysis was restricted to new users who had not been prescribed a statin in at least the preceding year. Patients with established diabetes before the start of treatment were excluded. Interventions: Treatment with statins. Main outcome measure: Incident diabetes. Results: Compared with pravastatin (the reference drug in all analyses), there was an increased risk of incident diabetes with atorvastatin (adjusted hazard ratio 1.22, 95% confidence interval 1.15 to 1.29), rosuvastatin (1.18, 1.10 to 1.26), and simvastatin (1.10, 1.04 to 1.17). There was no significantly increased risk among people who received fluvastatin (0.95, 0.81 to 1.11) or lovastatin (0.99, 0.86 to 1.14). The absolute risk for incident diabetes was about 31 and 34 events per 1000 person years for atorvastatin and rosuvastatin, respectively. There was a slightly lower absolute risk with simvastatin (26 outcomes per 1000 person years) compared with pravastatin (23 outcomes per 1000 person years). Our findings were consistent regardless of whether statins were used for primary or secondary prevention of cardiovascular disease. Although similar results were observed when statins were grouped by potency, the risk of incident diabetes associated with use of rosuvastatin became non-significant (adjusted hazard ratio 1.01, 0.94 to 1.09) when dose was taken into account. Conclusions: Compared with pravastatin, treatment with higher potency statins, especially atorvastatin and simvastatin, might be associated with an increased risk of new onset diabetes.

BMJ: 23 May 2013; 346:f2610
Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM
BMJ: 23 May 2013; 346:f2610 | PMID: 23704171
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Abstract

The NHS Five Year Forward View: implications for clinicians.

Maruthappu M, Sood HS, Keogh B
The Five Year Forward View is a look at what the NHS could achieve, given the range of resources that may be available. It sets out how the health service needs to change, arguing for a more engaged relationship with patients, carers, and citizens to promote wellbeing and prevent ill health. Here, we outline how the Forward View supports clinicians to provide better, higher quality and more integrated care.New models of care are presented, including multispecialty providers, primary and acute care systems, urgent and emergency care networks, viable smaller hospitals, specialised services, modern maternity services, and enhanced care homes. The commitments to support clinicians are discussed, including specific proposals for primary care, initiatives to improve the health of NHS staff, dealing with gaps in the NHS workforce, and the use of technology and innovation to further enable clinicians.

BMJ: 31 Oct 2014; 349:g6518
Maruthappu M, Sood HS, Keogh B
BMJ: 31 Oct 2014; 349:g6518 | PMID: 25361843
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Abstract

Explaining variation in referral from primary to secondary care: cohort study.

McBride D, Hardoon S, Walters K, Gilmour S, Raine R
ObjectiveS: To determine the extent to which referral for defined symptoms from primary care varies by age, sex, and social deprivation and whether any sociodemographic variations in referral differ according to the presence of national referral guidance and the potential of the symptoms to be life threatening. Design: Cohort study using individual patient data from the health improvement network database in primary care. Setting: United Kingdom. Participants: 5492 patients with postmenopausal bleeding, 23 121 with hip pain, and 101 212 with dyspepsia from 326 general practices, 2001-7. Main outcome measures: Multivariable associations between odds of immediate referral for postmenopausal bleeding and age and social deprivation; hazard rates of referral for hip pain or dyspepsia and age, sex, and social deprivation. Analyses for dyspepsia were stratified for people aged less than and more than 55 years because referral guidance differs by age. Results: 61.4% (3374/5492) of patients with postmenopausal bleeding, 17.4% (4019/23 121) with hip pain, and 13.8% (13 944/101 212) with dyspepsia were referred. The likelihood of referral for postmenopausal bleeding declined with increasing age: the adjusted odds ratio for patients aged 85 or more compared with those aged 55-64 was 0.39 (95% confidence interval 0.31 to 0.49). Patients aged 85 or more with hip pain were also less likely to be referred than those aged 55-64 (0.68, 0.57 to 0.81). Women were less likely than men to be referred for hip pain (hazard ratio 0.90, 95% confidence interval 0.84 to 0.96). More deprived patients with hip pain or dyspepsia (if aged <55) were less likely to be referred. Adjusted hazard ratios for those in the most deprived Townsend fifth compared with the least deprived were 0.72 (95% confidence interval 0.62 to 0.82) and 0.76 (0.68 to 0.85), respectively. No socioeconomic gradient was evident in referral for postmenopausal bleeding. Conclusions: Inequalities in referral associated with socioeconomic circumstances were more likely to occur in the absence of both explicit guidance and potentially life threatening conditions, whereas inequalities with age were evident for all conditions.

BMJ: 01 Dec 2010; 341:c6267
McBride D, Hardoon S, Walters K, Gilmour S, Raine R
BMJ: 01 Dec 2010; 341:c6267 | PMID: 21118873
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Abstract

Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.

Bolland MJ, Avenell A, Baron JA, Grey A, ... Gamble GD, Reid IR
Objective: To investigate whether calcium supplements increase the risk of cardiovascular events. Design: Patient level and trial level meta-analyses. Data sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010. Study selection: Eligible studies were randomised, placebo controlled trials of calcium supplements (>/=500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates. Results: 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038). Conclusions: Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

BMJ: 30 Jul 2010; 341:c3691
Bolland MJ, Avenell A, Baron JA, Grey A, ... Gamble GD, Reid IR
BMJ: 30 Jul 2010; 341:c3691 | PMID: 20671013
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Abstract

An independent and external validation of QRISK2 cardiovascular disease risk score: a prospective open cohort study.

Collins GS, Altman DG
Objective: To evaluate the performance of the QRISK2 score for predicting 10-year cardiovascular disease in an independent UK cohort of patients from general practice records and to compare it with the NICE version of the Framingham equation and QRISK1. Design: Prospective cohort study to validate a cardiovascular risk score. Setting: 365 practices from United Kingdom contributing to The Health Improvement Network (THIN) database. Participants: 1.58 million patients registered with a general practice between 1 January 1993 and 20 June 2008, aged 35-74 years (9.4 million person years) with 71 465 cardiovascular events. Main outcome measures: First diagnosis of cardiovascular disease (myocardial infarction, angina, coronary heart disease, stroke, and transient ischaemic stroke) recorded in general practice records. Results: QRISK2 offered improved prediction of a patient\'s 10-year risk of cardiovascular disease over the NICE version of the Framingham equation. Discrimination and calibration statistics were better with QRISK2. QRISK2 explained 33% of the variation in men and 40% for women, compared with 29% and 34% respectively for the NICE Framingham and 32% and 38% respectively for QRISK1. The incidence rate of cardiovascular events (per 1000 person years) among men in the high risk group was 27.8 (95% CI 27.4 to 28.2) with QRISK2, 21.9 (21.6 to 22.2) with NICE Framingham, and 24.8 (22.8 to 26.9) with QRISK1. Similarly, the incidence rate of cardiovascular events (per 1000 person years) among women in the high risk group was 24.3 (23.8 to 24.9) with QRISK2, 20.6 (20.1 to 21.0) with NICE Framingham, and 21.8 (18.9 to 24.6) with QRISK1. Conclusions: QRISK2 is more accurate in identifying a high risk population for cardiovascular disease in the United Kingdom than the NICE version of the Framingham equation. Differences in performance between QRISK2 and QRISK1 were marginal.

BMJ: 14 May 2010; 340:c2442
Collins GS, Altman DG
BMJ: 14 May 2010; 340:c2442 | PMID: 20466793
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Abstract

Renal cell carcinoma.

Jonasch E, Gao J, Rathmell WK
The treatment of renal cell carcinoma (RCC) has changed greatly over the past 15 years. Progress in the surgical management of the primary tumor and increased understanding of the molecular biology and genomics of the disease have led to the development of new therapeutic agents. The management of the primary tumor has changed owing to the realization that clean margins around the primary lesion are sufficient to prevent local recurrence, as well as the development of more sophisticated tools and techniques that increase the safety of partial nephrectomy. The management of advanced disease has altered even more dramatically as a result of new agents that target the tumor vasculature or that attenuate the activation of intracellular oncogenic pathways. This review summarizes data from prospective randomized phase III studies on the surgical management and systemic treatment of RCC, and provides an up to date summary of the histology, genomics, staging, and prognosis of RCC. It describes the management of the primary tumor and offers an overview of systemic agents that form the mainstay of treatment for advanced disease. The review concludes with an introduction to the exciting new class of immunomodulatory agents that are currently in clinical trials and may form the basis of a new therapeutic approach for patients with advanced RCC.

BMJ: 10 Nov 2014; 349:g4797
Jonasch E, Gao J, Rathmell WK
BMJ: 10 Nov 2014; 349:g4797 | PMID: 25385470
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Abstract

Sepsis associated acute kidney injury.

Poston JT, Koyner JL
Sepsis is defined as organ dysfunction resulting from the host\'s deleterious response to infection. One of the most common organs affected is the kidneys, resulting in sepsis associated acute kidney injury (SA-AKI) that contributes to the morbidity and mortality of sepsis. A growing body of knowledge has illuminated the clinical risk factors, pathobiology, response to treatment, and elements of renal recovery that have advanced our ability to prevent, detect, and treat SA-AKI. Despite these advances, SA-AKI remains an important concern and clinical burden, and further study is needed to reduce the acute and chronic consequences. This review summarizes the relevant evidence, with a focus on the risk factors, early recognition and diagnosis, treatment, and long term consequences of SA-AKI. In addition to literature pertaining to SA-AKI specifically, pertinent sepsis and acute kidney injury literature relevant to SA-AKI was included.

BMJ: 08 Jan 2019; 364:k4891
Poston JT, Koyner JL
BMJ: 08 Jan 2019; 364:k4891 | PMID: 30626586
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Abstract

Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database.

Hippisley-Cox J, Coupland C
Objective: To quantify the unintended effects of statins according to type, dose, and duration of use. Design: Prospective open cohort study using routinely collected data. Setting: 368 general practices in England and Wales supplying data to the QResearch database. Participants: 2 004 692 patients aged 30-84 years of whom 225 922 (10.7%) were new users of statins: 159 790 (70.7%) were prescribed simvastatin, 50 328 (22.3%) atorvastatin, 8103 (3.6%) pravastatin, 4497 (1.9%) rosuvastatin, and 3204 (1.4%) fluvastatin. Methods: Cox proportional hazards models were used to estimate effects of statin type, dose, and duration of use. The number needed to treat (NNT) or number needed to harm (NNH) was calculated and numbers of additional or fewer cases estimated for 10 000 treated patients. Main outcome measure: First recorded occurrence of cardiovascular disease, moderate or serious myopathic events, moderate or serious liver dysfunction, acute renal failure, venous thromboembolism, Parkinson\'s disease, dementia, rheumatoid arthritis, cataract, osteoporotic fracture, gastric cancer, oesophageal cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer. Results: Individual statins were not significantly associated with risk of Parkinson\'s disease, rheumatoid arthritis, venous thromboembolism, dementia, osteoporotic fracture, gastric cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer. Statin use was associated with decreased risks of oesophageal cancer but increased risks of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataract. Adverse effects were similar across statin types for each outcome except liver dysfunction where risks were highest for fluvastatin. A dose-response effect was apparent for acute renal failure and liver dysfunction. All increased risks persisted during treatment and were highest in the first year. After stopping treatment the risk of cataract returned to normal within a year in men and women. Risk of oesophageal cancer returned to normal within a year in women and within 1-3 years in men. Risk of acute renal failure returned to normal within 1-3 years in men and women, and liver dysfunction within 1-3 years in women and from three years in men. Based on the 20% threshold for cardiovascular risk, for women the NNT with any statin to prevent one case of cardiovascular disease over five years was 37 (95% confidence interval 27 to 64) and for oesophageal cancer was 1266 (850 to 3460) and for men the respective values were 33 (24 to 57) and 1082 (711 to 2807). In women the NNH for an additional case of acute renal failure over five years was 434 (284 to 783), of moderate or severe myopathy was 259 (186 to 375), of moderate or severe liver dysfunction was 136 (109 to 175), and of cataract was 33 (28 to 38). Overall, the NNHs and NNTs for men were similar to those for women, except for myopathy where the NNH was 91 (74 to 112). Conclusions: Claims of unintended benefits of statins, except for oesophageal cancer, remain unsubstantiated, although potential adverse effects at population level were confirmed and quantified. Further studies are needed to develop utilities to individualise the risks so that patients at highest risk of adverse events can be monitored closely.

BMJ: 21 May 2010; 340:c2197
Hippisley-Cox J, Coupland C
BMJ: 21 May 2010; 340:c2197 | PMID: 20488911
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Abstract

Initial management of Parkinson\'s disease.

Goetz CG, Pal G
Parkinson\'s disease is one of the most common neurodegenerative disorders seen in the United States and United Kingdom. The disease is characterised by two processes-cellular degeneration and the resulting biochemical deficiency of dopamine. Although these processes are inter-related, they are approached separately in the clinical setting. Currently, no proven neuroprotective or disease modifying treatment is available for Parkinson\'s disease. Several agents can be used to treat the motor symptoms associated with dopamine deficiency, and it is important to choose wisely when starting treatment. Drugs can have mild, moderate, or high potency, and the patient\'s goals, comorbidities, and the short and long term implications of choosing a specific agent should be taken into account when selecting the appropriate agent. Non-motor symptoms, such as depression, fatigue, and disorders of sleep and wakefulness, also need to be evaluated and treated. Research is under way to deliver dopaminergic therapy more effectively, but studies aimed at slowing or stopping disease progression have not shown promise.

BMJ: 19 Dec 2014; 349:g6258
Goetz CG, Pal G
BMJ: 19 Dec 2014; 349:g6258 | PMID: 25527341
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Abstract

Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial.

Aaby P, Martins CL, Garly ML, Balé C, ... Benn CS, Whittle HC
Objective: To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy). Design: Randomised controlled trial. Setting: The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area. Participants: 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation. Intervention: Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C). Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups. Results: In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99). Conclusions: Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children\'s survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations. Trial registration Clinical trials NCT00168558.

BMJ: 01 Dec 2010; 341:c6495
Aaby P, Martins CL, Garly ML, Balé C, ... Benn CS, Whittle HC
BMJ: 01 Dec 2010; 341:c6495 | PMID: 21118875
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Abstract

Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study.

Jentink J, Dolk H, Loane MA, Morris JK, ... de Jong-van den Berg L, for the EUROCAT Antiepileptic Study Working Group
Objective: To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy. Design: A review of all published cohort studies to identify key indications and a population based case-control study to test these indications. Setting: Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005. Participants: The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births. Main outcome measures: Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes. Results: The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect. Conclusion: Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.

BMJ: 03 Dec 2010; 341:c6581
Jentink J, Dolk H, Loane MA, Morris JK, ... de Jong-van den Berg L, for the EUROCAT Antiepileptic Study Working Group
BMJ: 03 Dec 2010; 341:c6581 | PMID: 21127116
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Abstract

Management of perinatal depression with non-drug interventions.

Johansen SL, Robakis TK, Williams KE, Rasgon NL
Perinatal depression is a common disorder that has been associated with serious risks to mother and child. Recently, screening for depression in pregnant and postpartum women has increased, as has the development of new psychotherapy and non-drug treatment modalities. Matching patients to treatments can be challenging, and although research into personalized treatment of major depression in the general population has increased, no published guidelines focus on personalized treatment approaches to perinatal depression. In particular, guidelines on non-drug treatments are lacking. This review summarizes the evidence on personalized non-drug treatment of perinatal depression, how to incorporate patients\' preferences, novel treatments under investigation, and the potential role of biomarkers in matching patients to treatment. The review provides recommendations for future research in personalized care of perinatal depression.

BMJ: 24 Feb 2019; 364:l322
Johansen SL, Robakis TK, Williams KE, Rasgon NL
BMJ: 24 Feb 2019; 364:l322 | PMID: 30803997
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Abstract

Telemonitoring based service redesign for the management of uncontrolled hypertension: multicentre randomised controlled trial.

McKinstry B, Hanley J, Wild S, Pagliari C, ... Stoddart A, Padfield P
Objective: To determine if an intervention consisting of telemonitoring and supervision by usual primary care clinicians of home self measured blood pressure and optional patient decision support leads to clinically important reductions in daytime systolic and diastolic ambulatory blood pressure in patients with uncontrolled blood pressure. Design: Multicentre randomised controlled trial. Setting: 20 primary care practices in south east Scotland. Participants: 401 people aged 29-95 years with uncontrolled blood pressure (mean daytime ambulatory measurement ≥135/85 mm Hg but ≤210/135 mm Hg). Intervention: Self measurement and transmission of blood pressure readings to a secure website for review by the attending nurse or doctor and participant, with optional automated patient decision support by text or email for six months. Main outcome measures: Blinded assessment of mean daytime systolic ambulatory blood pressure six months after randomisation. Results: 200 participants were randomised to the intervention and 201 to usual care; primary outcome data were available for 90% of participants (182 and 177, respectively). The mean difference in daytime systolic ambulatory blood pressure adjusted for baseline and minimisation factors between intervention and usual care was 4.3 mm Hg (95% confidence interval 2.0 to 6.5; P=0.0002) and for daytime diastolic ambulatory blood pressure was 2.3 mm Hg (0.9 to 3.6; P=0.001), with higher values in the usual care group. The intervention was associated with a mean increase of one general practitioner (95% confidence interval 0.5 to 1.6; P=0.0002) and 0.6 (0.1 to 1.0; P=0.01) practice nurse consultations during the course of the study. Conclusions: Supported self monitoring by telemonitoring is an effective method for achieving clinically important reductions in blood pressure in patients with uncontrolled hypertension in primary care settings. However, it was associated with increase in use of National Health Service resources. Further research is required to determine if the reduction in blood pressure is maintained in the longer term and if the intervention is cost effective. Trial registration: Current Controlled Trials ISRCTN72614272.

BMJ: 26 May 2013; 346:f3030
McKinstry B, Hanley J, Wild S, Pagliari C, ... Stoddart A, Padfield P
BMJ: 26 May 2013; 346:f3030 | PMID: 23709583
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Abstract

Opioids for low back pain.

Deyo RA, Von Korff M, Duhrkoop D
Back pain affects most adults, causes disability for some, and is a common reason for seeking healthcare. In the United States, opioid prescription for low back pain has increased, and opioids are now the most commonly prescribed drug class. More than half of regular opioid users report back pain. Rates of opioid prescribing in the US and Canada are two to three times higher than in most European countries. The analgesic efficacy of opioids for acute back pain is inferred from evidence in other acute pain conditions. Opioids do not seem to expedite return to work in injured workers or improve functional outcomes of acute back pain in primary care. For chronic back pain, systematic reviews find scant evidence of efficacy. Randomized controlled trials have high dropout rates, brief duration (four months or less), and highly selected patients. Opioids seem to have short term analgesic efficacy for chronic back pain, but benefits for function are less clear. The magnitude of pain relief across chronic non-cancer pain conditions is about 30%. Given the brevity of randomized controlled trials, the long term effectiveness and safety of opioids are unknown. Loss of long term efficacy could result from drug tolerance and emergence of hyperalgesia. Complications of opioid use include addiction and overdose related mortality, which have risen in parallel with prescription rates. Common short term side effects are constipation, nausea, sedation, and increased risk of falls and fractures. Longer term side effects may include depression and sexual dysfunction. Screening for high risk patients, treatment agreements, and urine testing have not reduced overall rates of opioid prescribing, misuse, or overdose. Newer strategies for reducing risks include more selective prescription of opioids and lower doses; use of prescription monitoring programs; avoidance of co-prescription with sedative hypnotics; and reformulations that make drugs more difficult to snort, smoke, or inject.

BMJ: 05 Jan 2015; 350:g6380
Deyo RA, Von Korff M, Duhrkoop D
BMJ: 05 Jan 2015; 350:g6380 | PMID: 25561513
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Abstract

Asthma: pathogenesis and novel drugs for treatment.

Olin JT, Wechsler ME
Asthma affects almost 20 million people in the United States and more than 300 million people worldwide. Of these, 10-15% have severe asthma, which is refractory to commonly available drugs. New drugs are needed because those that are currently available cannot control symptoms and exacerbations in all patients and can cause adverse reactions. In the past 10 years, there have been substantial advances in the understanding of asthma genetics, airway biology, and immune cell signaling. These advances have led to the development of small molecule therapeutics and biologic agents that may improve asthma care in the future. Several new classes of asthma drugs-including ultra long acting β agonists and modulators of the interleukin 4 (IL-4), IL-5, IL-13, and IL-17 pathways-have been evaluated in randomized controlled trials. Other new drug classes-including dissociated corticosteroids, CXC chemokine receptor 2 antagonists, toll-like receptor 9 agonists, and tyrosine kinase inhibitors-remain in earlier phases of development. Despite some preliminary efficacy data, there is insufficient evidence to make strong recommendations about the use of these newer agents. Future research on the clinical efficacy of these biologic agents, the effect of newer agents on severe asthma in pediatric patients, and the biology of non-eosinophilic and corticosteroid resistant asthma is needed to reduce the morbidity of asthma worldwide.

BMJ: 24 Nov 2014; 349:g5517
Olin JT, Wechsler ME
BMJ: 24 Nov 2014; 349:g5517 | PMID: 25420994
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Abstract

Assessment and management of behavioral and psychological symptoms of dementia.

Kales HC, Gitlin LN, Lyketsos CG
Behavioral and psychological symptoms of dementia include agitation, depression, apathy, repetitive questioning, psychosis, aggression, sleep problems, wandering, and a variety of inappropriate behaviors. One or more of these symptoms will affect nearly all people with dementia over the course of their illness. These symptoms are among the most complex, stressful, and costly aspects of care, and they lead to a myriad of poor patient health outcomes, healthcare problems, and income loss for family care givers. The causes include neurobiologically related disease factors; unmet needs; care giver factors; environmental triggers; and interactions of individual, care giver, and environmental factors. The complexity of these symptoms means that there is no "one size fits all solution," and approaches tailored to the patient and the care giver are needed. Non-pharmacologic approaches should be used first line, although several exceptions are discussed. Non-pharmacologic approaches with the strongest evidence base involve family care giver interventions. Regarding pharmacologic treatments, antipsychotics have the strongest evidence base, although the risk to benefit ratio is a concern. An approach to integrating non-pharmacologic and pharmacologic treatments is described. Finally, the paradigm shift needed to fully institute tailored treatments for people and families dealing with these symptoms in the community is discussed.

BMJ: 02 Mar 2015; 350:h369
Kales HC, Gitlin LN, Lyketsos CG
BMJ: 02 Mar 2015; 350:h369 | PMID: 25731881
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Abstract

Republished: Nicotine and health.

Drug and Therapeutics Bulletin
Nicotine, an alkaloid derived from the leaves of tobacco plants (Nicotiana tabacum and Nicotiana rustica) is the primary addictive agent in tobacco products.(1,2) There are different ways of administering the various products including smoking cigarettes, chewing tobacco, holding moist snuff in the mouth, inhaling dry snuff through the nose, inhaling smoke from a waterpipe and inhaling vapour from an electronic cigarette.(3-6) It can be difficult differentiating the effects of nicotine from the many other toxic substances these products also contain. Here we review the pharmacological effects of nicotine but we will not review the well-known harmful effects of cigarettes, where it is primarily the toxins and carcinogens in tobacco smoke rather than the nicotine that cause illness and death.(7) A future article will consider the use of electronic cigarettes.

BMJ: 26 Nov 2014; 349:2014.7.0264rep
Drug and Therapeutics Bulletin
BMJ: 26 Nov 2014; 349:2014.7.0264rep | PMID: 25428425
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Abstract

Consumers\' estimation of calorie content at fast food restaurants: cross sectional observational study.

Block JP, Condon SK, Kleinman K, Mullen J, ... Rifas-Shiman S, Gillman MW
Objective: To investigate estimation of calorie (energy) content of meals from fast food restaurants in adults, adolescents, and school age children. Design: Cross sectional study of repeated visits to fast food restaurant chains. Setting: 89 fast food restaurants in four cities in New England, United States: McDonald\'s, Burger King, Subway, Wendy\'s, KFC, Dunkin\' Donuts. Participants: 1877 adults and 330 school age children visiting restaurants at dinnertime (evening meal) in 2010 and 2011; 1178 adolescents visiting restaurants after school or at lunchtime in 2010 and 2011. Main outcome measure: Estimated calorie content of purchased meals. Results: Among adults, adolescents, and school age children, the mean actual calorie content of meals was 836 calories (SD 465), 756 calories (SD 455), and 733 calories (SD 359), respectively. A calorie is equivalent to 4.18 kJ. Compared with the actual figures, participants underestimated calorie content by means of 175 calories (95% confidence interval 145 to 205), 259 calories (227 to 291), and 175 calories (108 to 242), respectively. In multivariable linear regression models, underestimation of calorie content increased substantially as the actual meal calorie content increased. Adults and adolescents eating at Subway estimated 20% and 25% lower calorie content than McDonald\'s diners (relative change 0.80, 95% confidence interval 0.66 to 0.96; 0.75, 0.57 to 0.99). Conclusions: People eating at fast food restaurants underestimate the calorie content of meals, especially large meals. Education of consumers through calorie menu labeling and other outreach efforts might reduce the large degree of underestimation.

BMJ: 23 May 2013; 346:f2907
Block JP, Condon SK, Kleinman K, Mullen J, ... Rifas-Shiman S, Gillman MW
BMJ: 23 May 2013; 346:f2907 | PMID: 23704170
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Abstract

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.

Shamseer L, Moher D, Clarke M, Ghersi D, ... Stewart LA, the PRISMA-P Group
Protocols of systematic reviews and meta-analyses allow for planning and documentation of review methods, act as a guard against arbitrary decision making during review conduct, enable readers to assess for the presence of selective reporting against completed reviews, and, when made publicly available, reduce duplication of efforts and potentially prompt collaboration. Evidence documenting the existence of selective reporting and excessive duplication of reviews on the same or similar topics is accumulating and many calls have been made in support of the documentation and public availability of review protocols. Several efforts have emerged in recent years to rectify these problems, including development of an international register for prospective reviews (PROSPERO) and launch of the first open access journal dedicated to the exclusive publication of systematic review products, including protocols (BioMed Central\'s Systematic Reviews). Furthering these efforts and building on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, an international group of experts has created a guideline to improve the transparency, accuracy, completeness, and frequency of documented systematic review and meta-analysis protocols-PRISMA-P (for protocols) 2015. The PRISMA-P checklist contains 17 items considered to be essential and minimum components of a systematic review or meta-analysis protocol.This PRISMA-P 2015 Explanation and Elaboration paper provides readers with a full understanding of and evidence about the necessity of each item as well as a model example from an existing published protocol. This paper should be read together with the PRISMA-P 2015 statement. Systematic review authors and assessors are strongly encouraged to make use of PRISMA-P when drafting and appraising review protocols.

BMJ: 02 Jan 2015; 349:g7647
Shamseer L, Moher D, Clarke M, Ghersi D, ... Stewart LA, the PRISMA-P Group
BMJ: 02 Jan 2015; 349:g7647 | PMID: 25555855
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This program is still in alpha version.