Journal: Lancet

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Abstract

Origins of lifetime health around the time of conception: causes and consequences.

Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, ... Gluckman PD, Godfrey KM
Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.

Lancet: 15 Apr 2018; epub ahead of print
Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, ... Gluckman PD, Godfrey KM
Lancet: 15 Apr 2018; epub ahead of print | PMID: 29673874
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Abstract

Investing in non-communicable diseases: an estimation of the return on investment for prevention and treatment services.

Bertram MY, Sweeny K, Lauer JA, Chisholm D, ... George K, Deane S
The global burden of non-communicable diseases (NCDs) is growing, and there is an urgent need to estimate the costs and benefits of an investment strategy to prevent and control NCDs. Results from an investment-case analysis can provide important new evidence to inform decision making by governments and donors. We propose a methodology for calculating the economic benefits of investing in NCDs during the Sustainable Development Goals (SDGs) era, and we applied this methodology to cardiovascular disease prevention in 20 countries with the highest NCD burden. For a limited set of prevention interventions, we estimated that US$120 billion must be invested in these countries between 2015 and 2030. This investment represents an additional $1·50 per capita per year and would avert 15 million deaths, 8 million incidents of ischaemic heart disease, and 13 million incidents of stroke in the 20 countries. Benefit-cost ratios varied between interventions and country-income levels, with an average ratio of 5·6 for economic returns but a ratio of 10·9 if social returns are included. Investing in cardiovascular disease prevention is integral to achieving SDG target 3.4 (reducing premature mortality from NCDs by a third) and to progress towards SDG target 3.8 (the realisation of universal health coverage). Many countries have implemented cost-effective interventions at low levels, so the potential to achieve these targets and strengthen national income by scaling up these interventions is enormous.

Lancet: 04 Apr 2018; epub ahead of print
Bertram MY, Sweeny K, Lauer JA, Chisholm D, ... George K, Deane S
Lancet: 04 Apr 2018; epub ahead of print | PMID: 29627159
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Abstract

Acute rheumatic fever.

Karthikeyan G, Guilherme L
Acute rheumatic fever is caused by an autoimmune response to throat infection with Streptococcus pyogenes. Cardiac involvement during acute rheumatic fever can result in rheumatic heart disease, which can cause heart failure and premature mortality. Poverty and household overcrowding are associated with an increased prevalence of acute rheumatic fever and rheumatic heart disease, both of which remain a public health problem in many low-income countries. Control efforts are hampered by the scarcity of accurate data on disease burden, and effective approaches to diagnosis, prevention, and treatment. The diagnosis of acute rheumatic fever is entirely clinical, without any laboratory gold standard, and no treatments have been shown to reduce progression to rheumatic heart disease. Prevention mainly relies on the prompt recognition and treatment of streptococcal pharyngitis, and avoidance of recurrent infection using long-term antibiotics. But evidence for the effectiveness of either approach is not strong. High-quality research is urgently needed to guide efforts to reduce acute rheumatic fever incidence and prevent progression to rheumatic heart disease.

Lancet: 13 Jul 2018; 392:161-174
Karthikeyan G, Guilherme L
Lancet: 13 Jul 2018; 392:161-174 | PMID: 30025809
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Abstract

The pathogenesis of psoriatic arthritis.

Veale DJ, Fearon U
Psoriatic arthritis is a chronic, immune-mediated, inflammatory arthropathy that presents with inflammation of the joints and entheses, including those of the axial skeleton, and is associated with increased mortality from cardiovascular disease. Diagnosis is primarily based on clinical phenotype because of the diversity of the associated features, which can include skin and nail disease, dactylitis, uveitis, and osteitis. Improved understanding of the pathogenesis of psoriatic arthritis has led to the development of effective biologics and small-molecular drugs targeting specific cytokines and signalling pathways, which can prevent disease progression and improve quality of life. However, at least 40% of patients with psoriatic arthritis have only a partial response or fail to respond to such treatments. Cytokine inhibitors, mainly those specific for tumour necrosis factor and, more recently, the interleukin 23-T-helper-17 cell pathway, have been highly successful in the treatment of disease manifestations in several different tissues, although targeting the interleukin 23-T-helper-17 cell pathway might be more effective in psoriasis than in arthritis. However, the precise mechanisms underlying the pathogenesis of psoriatic arthritis-which include genetics, environmental factors, and immune-mediated inflammation-are complex, and the relationship between disease of the joint and that of other domains is poorly understood. Improving our understanding of psoriatic arthritis pathogenesis could help to establish validated biomarkers for diagnosis, predict therapeutic response and remission, develop precision medicines, and predict which patients will respond to which therapy. We discuss advances in pathogenetic translational research that could inform these issues.

Lancet: 01 Jun 2018; 391:2273-2284
Veale DJ, Fearon U
Lancet: 01 Jun 2018; 391:2273-2284 | PMID: 29893226
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Abstract

The heart of Africa: succeeding against the odds.

Sliwa K
South Africa and other areas of sub-Saharan Africa have in the past 20 years undergone rapid demographical changes, largely due to urbanisation and changes in lifestyle. This rapid change has led to a marked increase in specific cardiac conditions, such as hypertensive heart disease and coronary artery disease (with the highest prevalence in the middle-aged population), in conjunction with a range of other heart diseases, which are historically common in Africa-eg, rheumatic heart disease, cardiomyopathies, and unoperated congenital heart disease. The short supply of well-equipped screening facilities, late diagnosis, and inadequate care at primary, secondary, and tertiary levels have led to a large burden of patients with poorly treated heart failure. Excellent progress has been made in the understanding of the epidemiology, sociodemographical factors, effect of urbanisation, and pathophysiology of cardiac conditions, such as peripartum cardiomyopathy, rheumatic heart disease, and tuberculous pericarditis, which are common in sub-Saharan Africa. This progress has been achieved largely through several studies, such as the Heart of Soweto, THESUS, REMEDY, BA-HEF, Abeokuta-HF, and the PAPUCO studies. Studies on the suitable therapeutic management of several heart conditions have also been done or are underway. In this Lecture, I provide a personal perspective on the evolving burden of cardiac disease, as witnessed since my appointment at Chris Hani Baragwanath Hospital, in Soweto, South Africa, in 1992, which was also the year that the referendum to end apartheid in South Africa was held. Subsequently, a network of cardiologists was formed under the umbrella of the Heart of Africa Studies and the Pan African Cardiac Society. Furthermore, I summarise the major gaps in the health-care system dealing with the colliding epidemic of communicable and non-communicable heart diseases, including cardiac diseases common in peripartum women. I also touch on the fantastic opportunities available for doing meaningful research with enthusiastic colleagues and, thereby, having a large effect, despite the need to be highly innovative in finding much needed funding support.

Lancet: 28 Oct 2016; epub ahead of print
Sliwa K
Lancet: 28 Oct 2016; epub ahead of print | PMID: 27793430
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Abstract

Age-related macular degeneration.

Mitchell P, Liew G, Gopinath B, Wong TY
Age-related macular degeneration is a leading cause of visual impairment and severe vision loss. Clinically, it is classified as early-stage (medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic). Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids). Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab, aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration, and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no proven therapies for atrophic disease are available, but several agents are being investigated in clinical trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification, personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or other agents, and regenerative therapies.

Lancet: 28 Sep 2018; 392:1147-1159
Mitchell P, Liew G, Gopinath B, Wong TY
Lancet: 28 Sep 2018; 392:1147-1159 | PMID: 30303083
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Abstract

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data.

Heneghan C, Ward A, Perera R, The Self-Monitoring Trialist Collaboration
Background: Uptake of self-testing and self-management of oral coagulation has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. Methods: We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. Findings: Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12 800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. Interpretation: Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. Funding: UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Lancet: 05 Dec 2011; epub ahead of print
Heneghan C, Ward A, Perera R, The Self-Monitoring Trialist Collaboration
Lancet: 05 Dec 2011; epub ahead of print | PMID: 22137798
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Abstract

Land use, transport, and population health: estimating the health benefits of compact cities.

Stevenson M, Thompson J, de Sá TH, Ewing R, ... Wallace M, Woodcock J
Using a health impact assessment framework, we estimated the population health effects arising from alternative land-use and transport policy initiatives in six cities. Land-use changes were modelled to reflect a compact city in which land-use density and diversity were increased and distances to public transport were reduced to produce low motorised mobility, namely a modal shift from private motor vehicles to walking, cycling, and public transport. The modelled compact city scenario resulted in health gains for all cities (for diabetes, cardiovascular disease, and respiratory disease) with overall health gains of 420-826 disability-adjusted life-years (DALYs) per 100 000 population. However, for moderate to highly motorised cities, such as Melbourne, London, and Boston, the compact city scenario predicted a small increase in road trauma for cyclists and pedestrians (health loss of between 34 and 41 DALYs per 100 000 population). The findings suggest that government policies need to actively pursue land-use elements-particularly a focus towards compact cities-that support a modal shift away from private motor vehicles towards walking, cycling, and low-emission public transport. At the same time, these policies need to ensure the provision of safe walking and cycling infrastructure. The findings highlight the opportunities for policy makers to positively influence the overall health of city populations.

Lancet: 26 Sep 2016; epub ahead of print
Stevenson M, Thompson J, de Sá TH, Ewing R, ... Wallace M, Woodcock J
Lancet: 26 Sep 2016; epub ahead of print | PMID: 27671671
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Abstract

PET-guided treatment in patients with advanced-stage Hodgkin\'s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.

Borchmann P, Goergen H, Kobe C, Lohri A, ... Dietlein M, Engert A
The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin\'s lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients.

Lancet: 22 Jan 2018; 390:2790-2802
Borchmann P, Goergen H, Kobe C, Lohri A, ... Dietlein M, Engert A
Lancet: 22 Jan 2018; 390:2790-2802 | PMID: 29061295
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Abstract

Tetanus.

Yen LM, Thwaites CL
Tetanus is a vaccine-preventable disease that still commonly occurs in many low-income and middle-income countries, although it is rare in high-income countries. The disease is caused by the toxin of the bacterium Clostridium tetani and is characterised by muscle spasms and autonomic nervous system dysfunction. Global vaccination initiatives have had considerable success but they continue to face many challenges. Treatment for tetanus aims to control spasms and reduce cardiovascular instability, and consists of wound debridement, antitoxin, antibiotics, and supportive care. Recent research has focused on intravenous magnesium sulphate and intrathecal antitoxin administration as methods of spasm control that can avoid the need for ventilatory support. Nevertheless, without access to mechanical ventilation, mortality from tetanus remains high. Even with such care, patients require several weeks of hospitalisation and are vulnerable to secondary problems, such as hospital-acquired infections.

Lancet: 28 Mar 2019; epub ahead of print
Yen LM, Thwaites CL
Lancet: 28 Mar 2019; epub ahead of print | PMID: 30935736
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Abstract

Sudden unexpected death in epilepsy.

Shorvon S, Tomson T
Sudden unexpected death in epilepsy (SUDEP) refers to the sudden death of a seemingly healthy individual with epilepsy, usually occurring during, or immediately after, a tonic-clonic seizure. The frequency of SUDEP varies depending on the severity of the epilepsy, but overall the risk of sudden death is more than 20 times higher than that in the general population. Several different mechanisms probably exist, and most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction. Data from a pooled analysis of risk factors indicate that the higher the frequency of tonic-clonic seizures, the higher the risk of SUDEP; furthermore, risk of SUDEP is also elevated in male patients, patients with long-duration epilepsy, and those on antiepileptic polytherapy. SUDEP usually occurs when the seizures are not witnessed and often at night. In this Seminar, we provide advice to clinicians on ways to minimise the risk of SUDEP, information to pass on to patients, and medicolegal aspects of these deaths.

Lancet: 08 Jul 2011; epub ahead of print
Shorvon S, Tomson T
Lancet: 08 Jul 2011; epub ahead of print | PMID: 21737136
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Abstract

Multimodality imaging in ischaemic heart failure.

Bax JJ, Di Carli M, Narula J, Delgado V
In heart failure, extensive evaluation with modern non-invasive imaging modalities is needed to assess causes, pathophysiology, and haemodynamics, to determine prognosis and consider therapeutic options. This systematic evaluation includes a stepwise assessment of left ventricular size and function, the presence and severity of coronary artery disease, mitral regurgitation, pulmonary hypertension, right ventricular dilation and dysfunction, and tricuspid regurgitation. Based on this imaging-derived information, the need for specific therapies besides optimised medical therapy can be determined. The need for revascularisation, implantation of an implantable cardiac defibrillator, and mitral or tricuspid valve repair or replacement, can be (partially) guided by non-invasive imaging. Importantly, randomised controlled trials on the use of non-inasive imaging to guide therapy are scarce in this field and most non-pharmacological therapies are based on expert-consensus, but whenever trials are available, they will be addressed in this paper.

Lancet: 08 Mar 2019; 393:1056-1070
Bax JJ, Di Carli M, Narula J, Delgado V
Lancet: 08 Mar 2019; 393:1056-1070 | PMID: 30860031
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Abstract

Rheumatic heart disease.

Marijon E, Mirabel M, Celermajer DS, Jouven X
Rheumatic heart disease, often neglected by media and policy makers, is a major burden in developing countries where it causes most of the cardiovascular morbidity and mortality in young people, leading to about 250,000 deaths per year worldwide. The disease results from an abnormal autoimmune response to a group A streptococcal infection in a genetically susceptible host. Acute rheumatic fever--the precursor to rheumatic heart disease--can affect different organs and lead to irreversible valve damage and heart failure. Although penicillin is effective in the prevention of the disease, treatment of advanced stages uses up a vast amount of resources, which makes disease management especially challenging in emerging nations. Guidelines have therefore emphasised antibiotic prophylaxis against recurrent episodes of acute rheumatic fever, which seems feasible and cost effective. Early detection and targeted treatment might be possible if populations at risk for rheumatic heart disease in endemic areas are screened. In this setting, active surveillance with echocardiography-based screening might become very important.

Lancet: 11 Mar 2012; 379:953-64
Marijon E, Mirabel M, Celermajer DS, Jouven X
Lancet: 11 Mar 2012; 379:953-64 | PMID: 22405798
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Abstract

Chronic non-communicable diseases in Brazil: burden and current challenges.

Schmidt MI, Duncan BB, E Silva GA, Menezes AM, ... Chor D, Menezes PR
Non-communicable diseases (NCDs) have become a major health priority in Brazil-72% of all deaths were attributable to NCDs in 2007. They are also the main source of disease burden, with neuropsychiatric disorders being the single largest contributor. Morbidity and mortality due to NCDs are greatest in the poor population. Although the crude NCD mortality increased 5% between 1996 and 2007, age-standardised mortality declined by 20%. Declines were primarily for cardiovascular and chronic respiratory diseases, in association with the successful implementation of health policies that lead to decreases in smoking and the expansion of access to primary health care. Of note, however, the prevalence of diabetes and hypertension is rising in parallel with that of excess weight; these increases are associated with unfavourable changes of diet and physical activity. Brazil has implemented major policies for the prevention of NCDs, and its age-adjusted NCD mortality is falling by 1·8% per year. However, the unfavourable trends for most major risk factors pose an enormous challenge and call for additional and timely action and policies, especially those of a legislative and regulatory nature and those providing cost-effective chronic care for individuals affected by NCDs.

Lancet: 12 May 2011; epub ahead of print
Schmidt MI, Duncan BB, E Silva GA, Menezes AM, ... Chor D, Menezes PR
Lancet: 12 May 2011; epub ahead of print | PMID: 21561658
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Abstract

Beyond pharmacological treatment: an insight into therapies that target specific aspects of heart failure pathophysiology.

Normand C, Kaye DM, Povsic TJ, Dickstein K
Heart failure is a common syndrome associated with substantial morbidity and mortality. The management of symptoms and the strategies for improving prognosis have largely been based on pharmacological treatments. The pathophysiology of heart failure is complex because of the multiple causes responsible for this syndrome. This Series paper presents some examples of advances in heart failure management, in which the treatment specifically targets the underlying pathophysiological mechanisms responsible for the symptoms. These treatments include treatment of electromechanical dyssynchrony and dysrhythmia by cardiac resynchronisation and implantable cardioverter-defibrillators; neurohumoral modification by baroreflex and vagal stimulation; prevention of adverse cardiac remodelling by interatrial shunts; and finally targeting the myocardium directly by cell therapy in an attempt to regenerate new myocardial cells.

Lancet: 08 Mar 2019; 393:1045-1055
Normand C, Kaye DM, Povsic TJ, Dickstein K
Lancet: 08 Mar 2019; 393:1045-1055 | PMID: 30860030
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Abstract

HIV.

Ghosn J, Taiwo B, Seedat S, Autran B, Katlama C
The benefits of combination antiretroviral therapy (cART) for HIV replication and transmission control have led to its universal recommendation. Many people living with HIV are, however, still undiagnosed or diagnosed late, especially in sub-Saharan Africa, where the HIV disease burden is highest. Further expansion in HIV treatment options, incorporating women-centred approaches, is essential to make individualised care a reality. With a longer life expectancy than before, people living with HIV are at an increased risk of developing non-AIDS comorbidities, such as cardiovascular diseases and cancers. Antiretroviral strategies are evolving towards a decrease in drug burden, and some two-drug combinations have proven efficacy for maintenance therapy. Investigational immune checkpoint inhibitors and broadly neutralising antibodies with effector functions have energised the HIV cure research field as the search for an effective vaccine continues. In this Seminar, we review advances and challenges relating to the goal of an AIDS-free world.

Lancet: 22 Jul 2018; epub ahead of print
Ghosn J, Taiwo B, Seedat S, Autran B, Katlama C
Lancet: 22 Jul 2018; epub ahead of print | PMID: 30049419
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Abstract

Primary ovarian insufficiency.

De Vos M, Devroey P, Fauser BC
Primary ovarian insufficiency is a subclass of ovarian dysfunction in which the cause is within the ovary. In most cases, an unknown mechanism leads to premature exhaustion of the resting pool of primordial follicles. Primary ovarian insufficiency might also result from genetic defects, chemotherapy, radiotherapy, or surgery. The main symptom is absence of regular menstrual cycles, and the diagnosis is confirmed by detection of raised follicle-stimulating hormone and declined oestradiol concentrations in the serum, suggesting a primary ovarian defect. The disorder usually leads to sterility, and has a large effect on reproductive health when it arises at a young age. Fertility-preservation options can be offered to some patients with cancer and those at risk of early menopause, such as those with familial cases of primary ovarian insufficiency. Long-term deprivation of oestrogen has serious implications for female health in general; and for bone density, cardiovascular and neurological systems, wellbeing, and sexual health in particular.

Lancet: 16 Aug 2010; epub ahead of print
De Vos M, Devroey P, Fauser BC
Lancet: 16 Aug 2010; epub ahead of print | PMID: 20708256
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Abstract

Autosomal dominant polycystic kidney disease.

Cornec-Le Gall E, Alam A, Perrone RD
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and one of the most common causes of end-stage kidney disease. Multiple clinical manifestations, such as enlarged kidneys filled with growing cysts, hypertension, and multiple extrarenal complications, including liver cysts, intracranial aneurysms, and cardiac valvular disease, show that ADPKD is a systemic disorder. New information derived from clinical research using molecular genetics and advanced imaging techniques has provided enhanced tools for assessing the diagnosis and prognosis for individual patients and their families. Phase 3 randomised, placebo-controlled clinical trials have clarified aspects of disease management and a disease-modifying therapeutic drug is now available for patients with high risk of rapid disease progression. These developments provide a strong basis on which to make clear recommendations about the management of affected patients and families. Implementation of these advances has the potential to delay kidney failure, reduce the symptom burden, lessen the risk of cardiovascular complications, and prolong life.

Lancet: 24 Feb 2019; epub ahead of print
Cornec-Le Gall E, Alam A, Perrone RD
Lancet: 24 Feb 2019; epub ahead of print | PMID: 30819518
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Abstract

Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.

Fayad ZA, Mani V, Woodward M, Kallend D, ... Tawakol A, for the dal-PLAQUE Investigators
Background: Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods: In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473. Findings: 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation: Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. Funding: F Hoffmann-La Roche Ltd.

Lancet: 12 Sep 2011; epub ahead of print
Fayad ZA, Mani V, Woodward M, Kallend D, ... Tawakol A, for the dal-PLAQUE Investigators
Lancet: 12 Sep 2011; epub ahead of print | PMID: 21908036
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Abstract

Iran in transition.

Danaei G, Farzadfar F, Kelishadi R, Rashidian A, ... Majdzadeh R, Malekzadeh R
Being the second-largest country in the Middle East, Iran has a long history of civilisation during which several dynasties have been overthrown and established and health-related structures have been reorganised. Iran has had the replacement of traditional practices with modern medical treatments, emergence of multiple pioneer scientists and physicians with great contributions to the advancement of science, environmental and ecological changes in addition to large-scale natural disasters, epidemics of multiple communicable diseases, and the shift towards non-communicable diseases in recent decades. Given the lessons learnt from political instabilities in the past centuries and the approaches undertaken to overcome health challenges at the time, Iran has emerged as it is today. Iran is now a country with a population exceeding 80 million, mainly inhabiting urban regions, and has an increasing burden of non-communicable diseases, including cardiovascular diseases, hypertension, diabetes, malignancies, mental disorders, substance abuse, and road injuries.

Lancet: 25 Apr 2019; epub ahead of print
Danaei G, Farzadfar F, Kelishadi R, Rashidian A, ... Majdzadeh R, Malekzadeh R
Lancet: 25 Apr 2019; epub ahead of print | PMID: 31043324
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Abstract

Heart failure drug treatment.

Rossignol P, Hernandez AF, Solomon SD, Zannad F
Heart failure is the most common cardiovascular reason for hospital admission for people older than 60 years of age. Few areas in medicine have progressed as remarkably as heart failure treatment over the past three decades. However, progress has been consistent only for chronic heart failure with reduced ejection fraction. In acutely decompensated heart failure and heart failure with preserved ejection fraction, none of the treatments tested to date have been definitively proven to improve survival. Delaying or preventing heart failure has become increasingly important in patients who are prone to heart failure. The prevention of worsening chronic heart failure and hospitalisations for acute decompensation is also of great importance. The objective of this Series paper is to provide a concise and practical summary of the available drug treatments for heart failure. We support the implementation of the international guidelines. We offer views on the basis of our personal experience in research areas that have insufficient evidence. The best possible evidence-based drug treatment (including inhibitors of the renin-angiotensin-aldosterone system and β blockers) is useful only when optimally implemented. However, implementation might be challenging. We believe that disease management programmes can be helpful in providing a multidisciplinary, holistic approach to the delivery of optimal medical care.

Lancet: 08 Mar 2019; 393:1034-1044
Rossignol P, Hernandez AF, Solomon SD, Zannad F
Lancet: 08 Mar 2019; 393:1034-1044 | PMID: 30860029
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Abstract

Hepatocellular carcinoma.

Forner A, Reig M, Bruix J
Hepatocellular carcinoma appears frequently in patients with cirrhosis. Surveillance by biannual ultrasound is recommended for such patients because it allows diagnosis at an early stage, when effective therapies are feasible. The best candidates for resection are patients with a solitary tumour and preserved liver function. Liver transplantation benefits patients who are not good candidates for surgical resection, and the best candidates are those within Milan criteria (solitary tumour ≤5 cm or up to three nodules ≤3 cm). Image-guided ablation is the most frequently used therapeutic strategy, but its efficacy is limited by the size of the tumour and its localisation. Chemoembolisation has survival benefit in asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread. Finally, sorafenib, lenvatinib, which is non-inferior to sorafenib, and regorafenib increase survival and are the standard treatments in advanced hepatocellular carcinoma. This Seminar summarises the scientific evidence that supports the current recommendations for clinical practice, and discusses the areas in which more research is needed.

Lancet: 03 Jan 2018; epub ahead of print
Forner A, Reig M, Bruix J
Lancet: 03 Jan 2018; epub ahead of print | PMID: 29307467
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Abstract

Coeliac disease.

Lebwohl B, Sanders DS, Green PHR
Coeliac disease occurs in about 1% of people in most populations. Diagnosis rates are increasing, and this seems to be due to a true rise in incidence rather than increased awareness and detection. Coeliac disease develops in genetically susceptible individuals who, in response to unknown environmental factors, develop an immune response that is subsequently triggered by the ingestion of gluten. The disease has many clinical manifestations, ranging from severe malabsorption to minimally symptomatic or non-symptomatic presentations. Diagnosis requires the presence of duodenal villous atrophy, and most patients have circulating antibodies against tissue transglutaminase; in children, European guidelines allow a diagnosis without a duodenal biopsy provided that strict symptomatic and serological criteria are met. Although a gluten-free diet is an effective treatment in most individuals, a substantial minority develop persistent or recurrent symptoms. Difficulties adhering to a gluten-free diet have led to the development of non-dietary therapies, several of which are undergoing trials in human beings.

Lancet: 05 Jan 2018; 391:70-81
Lebwohl B, Sanders DS, Green PHR
Lancet: 05 Jan 2018; 391:70-81 | PMID: 28760445
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Abstract

Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial.

Kuck KH, Schaumann A, Eckardt L, Willems S, ... Hansen PS, for the VTACH study group
Background: In patients with ventricular tachycardia (VT) and a history of myocardial infarction, intervention with an implantable cardioverter defibrillator (ICD) can prevent sudden cardiac death and thereby reduce total mortality. However, ICD shocks are painful and do not provide complete protection against sudden cardiac death. We assessed the potential benefit of catheter ablation before implantation of a cardioverter defibrillator. Methods: The Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study was a prospective, open, randomised controlled trial, undertaken in 16 centres in four European countries. Patients aged 18-80 years were eligible for enrolment if they had stable VT, previous myocardial infarction, and reduced left-ventricular ejection fraction (LVEF; </=50%). 110 patients were randomly allocated in a 1:1 ratio to receive catheter ablation and an ICD (ablation group, n=54) or ICD alone (control group, n=56). Randomisation was done by computer-generated randomly permuted blocks and stratified by centre and LVEF (</=30% or >30%). Patients were followed up for at least 1 year. The primary endpoint was the time to first recurrence of VT or ventricular fibrillation (VF). Analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00919373. Findings: 107 patients were included in the ITT population (ablation group, n=52; control group, n=55). Two patients (one in each group) withdrew consent immediately after randomisation without any follow-up data and one patient (ablation group) was excluded because of a protocol violaton. Mean follow-up was 22.5 months (SD 9.0). Time to recurrence of VT or VF was longer in the ablation group (median 18.6 months [lower quartile 2.4, upper quartile not determinable]) than in the control group (5.9 months [IQR 0.8-26.7]). At 2 years, estimates for survival free from VT or VF were 47% in the ablation group and 29% in the control group (hazard ratio 0.61; 95% CI 0.37-0.99; p=0.045). Complications related to the ablation procedure occurred in two patients; no deaths occurred within 30 days after ablation. 15 device-related complications requiring surgical intervention occurred in 13 patients (ablation group, four; control group, nine). Nine patients died during the study (ablation group, five; control group, four). Interpretation: Prophylactic VT ablation before defibrillator implantation seemed to prolong time to recurrence of VT in patients with stable VT, previous myocardial infarction, and reduced LVEF. Prophylactic catheter ablation should therefore be considered before implantation of a cardioverter defibrillator in such patients. Funding: St Jude Medical.

Lancet: 29 Jan 2010; 375:31-40
Kuck KH, Schaumann A, Eckardt L, Willems S, ... Hansen PS, for the VTACH study group
Lancet: 29 Jan 2010; 375:31-40 | PMID: 20109864
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Abstract

Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments.

Mega JL, Simon T
Antithrombotic drugs, which include antiplatelet and anticoagulant therapies, prevent and treat many cardiovascular disorders and, as such, are some of the most commonly prescribed drugs worldwide. The first drugs designed to inhibit platelets or coagulation factors, such as the antiplatelet clopidogrel and the anticoagulant warfarin, significantly reduced the risk of thrombotic events at the cost of increased bleeding in patients. However, both clopidogrel and warfarin have some pharmacological limitations including interpatient variability in antithrombotic effects in part due to the metabolism, interactions (eg, drug, environment, and genetic), or targets of the drugs. Increased knowledge of the pharmacology of antithrombotic drugs and the mechanisms underlying thrombosis has led to the development of newer drugs with faster onset of action, fewer interactions, and less interpatient variability in their antithrombotic effects than previous antithrombotic drugs. Treatment options now include the next-generation antiplatelet drugs prasugrel and ticagrelor, and, in terms of anticoagulants, inhibitors that directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban) are available. In this Series paper we review the pharmacological properties of these most commonly used oral antithrombotic drugs, and explore the development of antiplatelet and anticoagulant therapies.

Lancet: 16 Mar 2015; epub ahead of print
Mega JL, Simon T
Lancet: 16 Mar 2015; epub ahead of print | PMID: 25777662
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Abstract

Leonardo da Vinci\'s studies of the brain.

Pevsner J
Leonardo da Vinci (1452-1519) contributed to the study of the nervous system. His earliest surviving anatomical drawings (circa 1485-93) included studies of the skull, brain, and cerebral ventricles. These works reflected his efforts to understand medieval psychology, including the localisation of sensory and motor functions to the brain. He was also the first to pith a frog, concluding that piercing the spinal medulla causes immediate death. After a 10-year interval in the early 1500s Leonardo resumed his anatomical studies and developed a method to inject hot wax into the ventricular system, creating a cast that showed the shape and extent of the ventricles. During this period he also progressed in his understanding of the anatomy of the cranial nerves. Besides being the first to identify the olfactory nerve as a cranial nerve, his dissections showed him that contrary to previous theories, the nerves do not converge on the lateral or third ventricles. Leonardo also performed detailed studies of the peripheral nervous system. Although his discoveries had little influence on the development of the field of anatomy, they represent an astonishingly sharp break from the field that had seen little if any progress in the previous 13 centuries. His work reflects the emergence of the modern scientific era and forms a key part of his integrative approach to art and science.

Lancet: 05 Apr 2019; 393:1465-1472
Pevsner J
Lancet: 05 Apr 2019; 393:1465-1472 | PMID: 30967217
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Abstract

Chagas disease.

Pérez-Molina JA, Molina I
Chagas disease is an anthropozoonosis from the American continent that has spread from its original boundaries through migration. It is caused by the protozoan Trypanosoma cruzi, which was identified in the first decade of the 20th century. Once acute infection resolves, patients can develop chronic disease, which in up to 30-40% of cases is characterised by cardiomyopathy, arrhythmias, megaviscera, and, more rarely, polyneuropathy and stroke. Even after more than a century, many challenges remain unresolved, since epidemiological control and diagnostic, therapeutic, and prognostic methods must be improved. In particular, the efficacy and tolerability profile of therapeutic agents is far from ideal. Furthermore, the population affected is older and more complex (eg, immunosuppressed patients and patients with cancer). Nevertheless, in recent years, our knowledge of Chagas disease has expanded, and the international networking needed to change the course of this deadly disease during the 21st century has begun.

Lancet: 05 Jan 2018; 391:82-94
Pérez-Molina JA, Molina I
Lancet: 05 Jan 2018; 391:82-94 | PMID: 28673423
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Abstract

Clinical evidence for oral antiplatelet therapy in acute coronary syndromes.

Wiviott SD, Steg PG
Platelet-mediated thrombosis is a major pathophysiological mechanism that underlies acute coronary syndromes, and therefore, antiplatelet therapy is an important foundation in the treatment and prevention of recurrence of these syndromes. Nearly 30 years ago, aspirin was the first agent to show a benefit for acute coronary syndromes and is still a key therapeutic agent. The landmark CURE trial showed that the addition of a P2Y12 antagonist, clopidogrel, to aspirin was beneficial in the treatment of acute coronary syndromes. Despite substantial benefits with clopidogrel, limitations include the slow speed of onset, variable response, and a modest antiplatelet effect. Next-generation P2Y12 antagonists, prasugrel and ticagrelor, overcome these limitations and have been shown, in large-scale clinical trials for acute coronary syndromes, to reduce ischaemic events more than clopidogrel, at the expense of an increase in bleeding. Additional agents that target platelets by alternate mechanisms, including the protease-activated receptor-1 antagonist vorapaxar, have shown ischaemic benefit. These large-scale trials inform treatment decisions that need to balance ischaemic benefit and bleeding risk in patients with acute coronary syndromes. This Series paper describes major trial results, implications for clinical practice, and summarises continuing controversy.

Lancet: 16 Mar 2015; epub ahead of print
Wiviott SD, Steg PG
Lancet: 16 Mar 2015; epub ahead of print | PMID: 25777663
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Abstract

Acute myeloid leukaemia.

Short NJ, Rytting ME, Cortes JE
For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. In addition to advancing our therapeutic armamentarium, an increased understanding of the biology and genomic architecture of acute myeloid leukaemia has led to refined risk assessment of this disease, with consensus risk stratification guidelines now incorporating a growing number of recurrent molecular aberrations that aid in the selection of risk-adapted management strategies. Despite this promising recent progress, the outcomes of patients with acute myeloid leukaemia remain unsatisfactory, with more than half of patients ultimately dying from their disease. Enrolment of patients into clinical trials that evaluate novel drugs and rational combination therapies is imperative to continuing this progress and further improving the outcomes of patients with acute myeloid leukaemia.

Lancet: 01 Aug 2018; epub ahead of print
Short NJ, Rytting ME, Cortes JE
Lancet: 01 Aug 2018; epub ahead of print | PMID: 30078459
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Abstract

Refractive surgery.

Kim TI, Del Barrio JLA, Wilkins M, Cochener B, Ang M
Refractive surgery has evolved beyond laser refractive techniques over the past decade. Laser refractive surgery procedures (such as laser in-situ keratomileusis), surface ablation techniques (such as laser epithelial keratomileusis), and photorefractive keratectomy have now been established as fairly safe procedures that produce excellent visual outcomes for patients with low-to-moderate amounts of ametropia. Additionally, a broader selection of options are now available to treat a wider range of refractive errors. Small incision lenticule extraction uses a femtosecond laser to shape a refractive lenticule, which is removed through a small wound. The potential advantages of this procedure include greater tectonic strength and less dry eye. In the future, intracorneal implants could be used to treat hyperopia or presbyopia. Phakic intraocular implants and refractive lens exchange might be useful options in carefully selected patients for correcting high degrees of ametropia. Thus, physicians are now able to provide patients with the appropriate refractive corrective option based on the individual\'s risk-benefit profile.

Lancet: 17 May 2019; 393:2085-2098
Kim TI, Del Barrio JLA, Wilkins M, Cochener B, Ang M
Lancet: 17 May 2019; 393:2085-2098 | PMID: 31106754
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Abstract

Type 2 diabetes across generations: from pathophysiology to prevention and management.

Nolan CJ, Damm P, Prentki M
Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.

Lancet: 27 Jun 2011; epub ahead of print
Nolan CJ, Damm P, Prentki M
Lancet: 27 Jun 2011; epub ahead of print | PMID: 21705072
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Abstract

Primary brain tumours in adults.

Lapointe S, Perry A, Butowski NA
Primary CNS tumours refer to a heterogeneous group of tumours arising from cells within the CNS, and can be benign or malignant. Malignant primary brain tumours remain among the most difficult cancers to treat, with a 5 year overall survival no greater than 35%. The most common malignant primary brain tumours in adults are gliomas. Recent advances in molecular biology have improved understanding of glioma pathogenesis, and several clinically significant genetic alterations have been described. A number of these (IDH, 1p/19q codeletion, H3 Lys27Met, and RELA-fusion) are now combined with histology in the revised 2016 WHO classification of CNS tumours. It is likely that understanding such molecular alterations will contribute to the diagnosis, grading, and treatment of brain tumours. This progress in genomics, along with significant advances in cancer and CNS immunology, has defined a new era in neuro-oncology and holds promise for diagntic and therapeutic improvement. The challenge at present is to translate these advances into effective treatments. Current efforts are focused on developing molecular targeted therapies, immunotherapies, gene therapies, and novel drug-delivery technologies. Results with single-agent therapies have been disappointing so far, and combination therapies seem to be required to achieve a broad and durable antitumour response. Biomarker-targeted clinical trials could improve efficiencies of therapeutic development.

Lancet: 26 Jul 2018; epub ahead of print
Lapointe S, Perry A, Butowski NA
Lancet: 26 Jul 2018; epub ahead of print | PMID: 30060998
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Abstract

Short-term and long-term effects of caesarean section on the health of women and children.

Sandall J, Tribe RM, Avery L, Mola G, ... Taylor P, Temmerman M
A caesarean section (CS) can be a life-saving intervention when medically indicated, but this procedure can also lead to short-term and long-term health effects for women and children. Given the increasing use of CS, particularly without medical indication, an increased understanding of its health effects on women and children has become crucial, which we discuss in this Series paper. The prevalence of maternal mortality and maternal morbidity is higher after CS than after vaginal birth. CS is associated with an increased risk of uterine rupture, abnormal placentation, ectopic pregnancy, stillbirth, and preterm birth, and these risks increase in a dose-response manner. There is emerging evidence that babies born by CS have different hormonal, physical, bacterial, and medical exposures, and that these exposures can subtly alter neonatal physiology. Short-term risks of CS include altered immune development, an increased likelihood of allergy, atopy, and asthma, and reduced intestinal gut microbiome diversity. The persistence of these risks into later life is less well investigated, although an association between CS use and greater incidence of late childhood obesity and asthma are frequently reported. There are few studies that focus on the effects of CS on cognitive and educational outcomes. Understanding potential mechanisms that link CS with childhood outcomes, such as the role of the developing neonatal microbiome, has potential to inform novel strategies and research for optimising CS use and promote optimal physiological processes and development.

Lancet: 12 Oct 2018; 392:1349-1357
Sandall J, Tribe RM, Avery L, Mola G, ... Taylor P, Temmerman M
Lancet: 12 Oct 2018; 392:1349-1357 | PMID: 30322585
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Abstract

Autism spectrum disorder.

Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J
Autism spectrum disorder is a term used to describe a constellation of early-appearing social communication deficits and repetitive sensory-motor behaviours associated with a strong genetic component as well as other causes. The outlook for many individuals with autism spectrum disorder today is brighter than it was 50 years ago; more people with the condition are able to speak, read, and live in the community rather than in institutions, and some will be largely free from symptoms of the disorder by adulthood. Nevertheless, most individuals will not work full-time or live independently. Genetics and neuroscience have identified intriguing patterns of risk, but without much practical benefit yet. Considerable work is still needed to understand how and when behavioural and medical treatments can be effective, and for which children, including those with substantial comorbidities. It is also important to implement what we already know and develop services for adults with autism spectrum disorder. Clinicians can make a difference by providing timely and individualised help to families navigating referrals and access to community support systems, by providing accurate information despite often unfiltered media input, and by anticipating transitions such as family changes and school entry and leaving.

Lancet: 01 Aug 2018; epub ahead of print
Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J
Lancet: 01 Aug 2018; epub ahead of print | PMID: 30078460
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Abstract

Interventions to reduce unnecessary caesarean sections in healthy women and babies.

Betrán AP, Temmerman M, Kingdon C, Mohiddin A, ... Gülmezoglu AM, Downe S
Optimising the use of caesarean section (CS) is of global concern. Underuse leads to maternal and perinatal mortality and morbidity. Conversely, overuse of CS has not shown benefits and can create harm. Worldwide, the frequency of CS continues to increase, and interventions to reduce unnecessary CSs have shown little success. Identifying the underlying factors for the continuing increase in CS use could improve the efficacy of interventions. In this Series paper, we describe the factors for CS use that are associated with women, families, health professionals, and health-care organisations and systems, and we examine behavioural, psychosocial, health system, and financial factors. We also outline the type and effects of interventions to reduce CS use that have been investigated. Clinical interventions, such as external cephalic version for breech delivery at term, vaginal breech delivery in appropriately selected women, and vaginal birth after CS, could reduce the frequency of CS use. Approaches such as labour companionship and midwife-led care have been associated with higher proportions of physiological births, safer outcomes, and lower health-care costs relative to control groups without these interventions, and with positive maternal experiences, in high-income countries. Such approaches need to be assessed in middle-income and low-income countries. Educational interventions for women should be complemented with meaningful dialogue with health professionals and effective emotional support for women and families. Investing in the training of health professionals, eliminating financial incentives for CS use, and reducing fear of litigation is fundamental. Safe, private, welcoming, and adequately resourced facilities are needed. At the country level, effective medical leadership is essential to ensure CS is used only when indicated. We conclude that interventions to reduce overuse must be multicomponent and locally tailored, addressing women\'s and health professionals\' concerns, as well as health system and financial factors.

Lancet: 12 Oct 2018; 392:1358-1368
Betrán AP, Temmerman M, Kingdon C, Mohiddin A, ... Gülmezoglu AM, Downe S
Lancet: 12 Oct 2018; 392:1358-1368 | PMID: 30322586
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Abstract

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

IL6R Genetics Consortium Emerging Risk Factors Collaboration
Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Lancet: 15 Mar 2012; epub ahead of print
IL6R Genetics Consortium Emerging Risk Factors Collaboration
Lancet: 15 Mar 2012; epub ahead of print | PMID: 22421339
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Abstract

Global epidemiology of use of and disparities in caesarean sections.

Boerma T, Ronsmans C, Melesse DY, Barros AJD, ... de Lyra Rabello Neto D, Temmerman M
In this Series paper, we describe the frequency of, trends in, determinants of, and inequalities in caesarean section (CS) use, globally, regionally, and in selected countries. On the basis of data from 169 countries that include 98·4% of the world\'s births, we estimate that 29·7 million (21·1%, 95% uncertainty interval 19·9-22·4) births occurred through CS in 2015, which was almost double the number of births by this method in 2000 (16·0 million [12·1%, 10·9-13·3] births). CS use in 2015 was up to ten times more frequent in the Latin America and Caribbean region, where it was used in 44·3% (41·3-47·4) of births, than in the west and central Africa region, where it was used in 4·1% (3·6-4·6) of births. The global and regional increases in CS use were driven both by an increasing proportion of births occurring in health facilities (accounting for 66·5% of the global increase) and increases in CS use within health facilities (33·5%), with considerable variation between regions. Based on the most recent data available for each country, 15% of births in 106 (63%) of 169 countries were by CS, whereas 47 (28%) countries showed CS use in less than 10% of births. National CS use varied from 0·6% in South Sudan to 58·1% in the Dominican Republic. Within-country disparities in CS use were also very large: CS use was almost five times more frequent in births in the richest versus the poorest quintiles in low-income and middle-income countries; markedly high CS use was observed among low obstetric risk births, especially among more educated women in, for example, Brazil and China; and CS use was 1·6 times more frequent in private facilities than in public facilities.

Lancet: 12 Oct 2018; 392:1341-1348
Boerma T, Ronsmans C, Melesse DY, Barros AJD, ... de Lyra Rabello Neto D, Temmerman M
Lancet: 12 Oct 2018; 392:1341-1348 | PMID: 30322584
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Abstract

Principles of DNA methylation and their implications for biology and medicine.

Dor Y, Cedar H
DNA methylation represents an annotation system for marking the genetic text, thus providing instruction as to how and when to read the information and control transcription. Unlike sequence information, which is inherited, methylation patterns are established in a programmed process that continues throughout development, thus setting up stable gene expression profiles. This DNA methylation paradigm is a key player in medicine. Some changes in methylation closely correlate with age providing a marker for biological ageing, and these same sites could also play a part in cancer. The genome continues to undergo programmed variation in methylation after birth in response to environmental inputs, serving as a memory device that could affect ageing and predisposition to various metabolic, autoimmune, and neurological diseases. Taking advantage of tissue-specific differences, methylation can be used to detect cell death and thereby monitor many common diseases with a simple cell-free circulating-DNA blood test.

Lancet: 08 Aug 2018; epub ahead of print
Dor Y, Cedar H
Lancet: 08 Aug 2018; epub ahead of print | PMID: 30100054
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Abstract

Revisiting Alma-Ata: what is the role of primary health care in achieving the Sustainable Development Goals?

Hone T, Macinko J, Millett C
The Sustainable Development Goals (SDGs) are now steering the global health and development agendas. Notably, the SDGs contain no mention of primary health care, reflecting the disappointing implementation of the Alma-Ata declaration of 1978 over the past four decades. The draft Astana declaration (Alma-Ata 2·0), released in June, 2018, restates the key principles of primary health care and renews these as driving forces for achieving the SDGs, emphasising universal health coverage. We use accumulating evidence to show that countries that reoriente their health systems towards primary care are better placed to achieve the SDGs than those with hospital-focused systems or low investment in health. We then argue that an even bolder approach, which fully embraces the Alma-Ata vision of primary health care, could deliver substantially greater SDG progress, by addressing the wider determinants of health, promoting equity and social justice throughout society, empowering communities, and being a catalyst for advancing and amplifying universal health coverage and synergies among SDGs.

Lancet: 19 Oct 2018; 392:1461-1472
Hone T, Macinko J, Millett C
Lancet: 19 Oct 2018; 392:1461-1472 | PMID: 30343860
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Abstract

Effectiveness and sustainability of a diagonal investment approach to strengthen the primary health-care system in Ethiopia.

Assefa Y, Tesfaye D, Damme WV, Hill PS
Weakness of primary health-care (PHC) systems has represented a challenge to the achievement of the targets of disease control programmes (DCPs) despite the availability of substantial development assistance for health, in resource-poor settings. Since 2005, Ethiopia has embraced a diagonal investment approach to strengthen its PHC systems and concurrently scale up DCPs. This approach has led to a substantial improvement in PHC-system capacity that has contributed to increased coverage of DCPs and improved health status, although gaps in equity and quality in health services remain to be addressed. Since 2013, Ethiopia has had a decline in development assistance for health. Nevertheless, the Ethiopian Government has been able to compensate for this decline by increasing domestic resources. We argue that the diagonal investment approach can effectively strengthen PHC systems, achieve DCP targets, and sustain the gains. These goals can be achieved if a visionary and committed leadership coordinates its development partners and mobilises the local community, to ensure financial support to health services and improve population health. The lessons learnt from Ethiopia\'s efforts to improve its health services indicate that global-health initiatives should have a proactive and balanced investment approach to concurrently strengthen PHC systems, achieve programme targets, and sustain the gains, in resource-poor settings.

Lancet: 19 Oct 2018; 392:1473-1481
Assefa Y, Tesfaye D, Damme WV, Hill PS
Lancet: 19 Oct 2018; 392:1473-1481 | PMID: 30343861
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Abstract

Implantable cardioverter defibrillators and cardiac resynchronisation therapy.

Holzmeister J, Leclercq C
Implantable cardioverter defibrillators and cardiac resynchronisation therapy (CRT) have become standard of care in modern treatment for heart failure. Results from trials have provided ample evidence that CRT, in addition to its proven benefits in patients with symptomatic heart failure (New York Heart Association [NYHA] class III), might also reduce morbidity and mortality in those with mildly symptomatic heart failure (NYHA class II). As a result, the 2010 European Society of Cardiology guidelines now recommend CRT for both patient populations. In this review we summarise and critically assess the landmark randomised clinical trials REVERSE, MADIT-CRT, and RAFT. Furthermore, we discuss the rationale and available evidence for other emerging indications of CRT, including its use in patients with a mildly reduced left ventricular ejection fraction (>35%), in those with a narrow QRS complex (≤120 ms), and in those with concomitant bradyarrhythmic pacemaker indications. We also focus on patients who do not respond to CRT, and on CRT optimisation.

Lancet: 22 Aug 2011; 378:722-30
Holzmeister J, Leclercq C
Lancet: 22 Aug 2011; 378:722-30 | PMID: 21856486
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Abstract

Personality disorder across the life course.

Newton-Howes G, Clark LA, Chanen A
The pervasive effect of personality disorder is often overlooked in clinical practice, both as an important moderator of mental state and physical disorders, and as a disorder that should be recognised and managed in its own right. Contemporary research has shown that maladaptive personality (when personality traits are extreme and associated with clinical distress or psychosocial impairment) is common, can be recognised early in life, evolves continuously across the lifespan, and is more plastic than previously believed. These new insights offer opportunities to intervene to support more adaptive development than before, and research shows that such intervention can be effective. Further research is needed to improve classification, assessment, and diagnosis of personality disorder across the lifespan; to understand the complex interplay between changes in personality traits and clinical presentation over time; and to promote more effective intervention at the earliest possible stage of the disorder than is done at present. Recognition of how personality disorder relates to age and developmental stage can improve care of all patients.

Lancet: 23 Feb 2015; 385:727-34
Newton-Howes G, Clark LA, Chanen A
Lancet: 23 Feb 2015; 385:727-34 | PMID: 25706218
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Abstract

Treatment of personality disorder.

Bateman AW, Gunderson J, Mulder R
The evidence base for the effective treatment of personality disorders is insufficient. Most of the existing evidence on personality disorder is for the treatment of borderline personality disorder, but even this is limited by the small sample sizes and short follow-up in clinical trials, the wide range of core outcome measures used by studies, and poor control of coexisting psychopathology. Psychological or psychosocial intervention is recommended as the primary treatment for borderline personality disorder and pharmacotherapy is only advised as an adjunctive treatment. The amount of research about the underlying, abnormal, psychological or biological processes leading to the manifestation of a disordered personality is increasing, which could lead to more effective interventions. The synergistic or antagonistic interaction of psychotherapies and drugs for treating personality disorder should be studied in conjunction with their mechanisms of change throughout the development of each.

Lancet: 23 Feb 2015; 385:735-43
Bateman AW, Gunderson J, Mulder R
Lancet: 23 Feb 2015; 385:735-43 | PMID: 25706219
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Abstract

Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis.

Athyros VG, Tziomalos K, Gossios TD, Griva T, ... Mikhailidis DP, for the GREACE Study Collaborative Group
Background: Long-term statin treatment reduces the frequency of cardiovascular events, but safety and efficacy in patients with abnormal liver tests is unclear. We assessed whether statin therapy is safe and effective for these patients through post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study population. Methods: GREACE was a prospective, intention-to-treat study that randomly assigned by a computer-generated randomisation list 1600 patients with coronary heart disease (aged <75 years, with serum concentrations of LDL cholesterol >2·6 mmol/L and triglycerides <4·5 mmol/L) at the Hippokration University Hospital, Thessaloniki, Greece to receive statin or usual care, which could include statins. The primary outcome of our post-hoc analysis was risk reduction for first recurrent cardiovascular event in patients treated with a statin who had moderately abnormal liver tests (defined as serum alanine aminotransferase or aspartate aminotransferase concentrations of less than three times the upper limit of normal) compared with patients with abnormal liver tests who did not receive a statin. This risk reduction was compared with that for patients treated (or not) with statin and normal liver tests. Findings: Of 437 patients with moderately abnormal liver tests at baseline, which were possibly associated with non-alcoholic fatty liver disease, 227 who were treated with a statin (mainly atorvastatin 24 mg per day) had substantial improvement in liver tests (p<0·0001) whereas 210 not treated with a statin had further increases of liver enzyme concentrations. Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (10·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). This cardiovascular disease benefit was greater (p=0·0074) than it was in patients with normal liver tests (90 [14%] events in 653 patients receiving a statin [4·6 per 100 patient-years] vs 117 [23%] in 510 patients not receiving a statin [7·6 per 100 patient-years]; 39% relative risk reduction, p<0·0001). Seven (<1%) of 880 participants who received a statin discontinued statin treatment because of liver-related adverse effects (transaminase concentrations more than three-times the upper limit of normal). Interpretation: Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease. Funding: None.

Lancet: 26 Nov 2010; epub ahead of print
Athyros VG, Tziomalos K, Gossios TD, Griva T, ... Mikhailidis DP, for the GREACE Study Collaborative Group
Lancet: 26 Nov 2010; epub ahead of print | PMID: 21109302
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Abstract

Pulse oximetry screening for congenital heart defects in newborn infants (PulseOx): a test accuracy study.

Ewer AK, Middleton LJ, Furmston AT, Bhoyar A, ... Khan KS, on behalf of the PulseOx Study Group
Background: Screening for congenital heart defects relies on antenatal ultrasonography and postnatal clinical examination; however, life-threatening defects often are not detected. We prospectively assessed the accuracy of pulse oximetry as a screening test for congenital heart defects. Methods: In six maternity units in the UK, asymptomatic newborn babies (gestation >34 weeks) were screened with pulse oximetry before discharge. Infants who did not achieve predetermined oxygen saturation thresholds underwent echocardiography. All other infants were followed up to 12 months of age by use of regional and national registries and clinical follow-up. The main outcome was the sensitivity and specificity of pulse oximetry for detection of critical congenital heart defects (causing death or requiring invasive intervention before 28 days) or major congenital heart disease (causing death or requiring invasive intervention within 12 months of age). Findings: 20 055 newborn babies were screened and 53 had major congenital heart disease (24 critical), a prevalence of 2·6 per 1000 livebirths. Analyses were done on all babies for whom a pulse oximetry reading was obtained. Sensitivity of pulse oximetry was 75·00% (95% CI 53·29-90·23) for critical cases and 49·06% (35·06-63·16) for all major congenital heart defects. In 35 cases, congenital heart defects were already suspected after antenatal ultrasonography, and exclusion of these reduced the sensitivity to 58·33% (27·67-84·83) for critical cases and 28·57% (14·64-46·30) for all cases of major congenital heart defects. False-positive results were noted for 169 (0·8%) babies (specificity 99·16%, 99·02-99·28), of which six cases were significant, but not major, congenital heart defects, and 40 were other illnesses that required urgent medical intervention. Interpretation: Pulse oximetry is a safe, feasible test that adds value to existing screening. It identifies cases of critical congenital heart defects that go undetected with antenatal ultrasonography. The early detection of other diseases is an additional advantage. Funding: National Institute for Health Research Health Technology Assessment programme.

Lancet: 08 Aug 2011; epub ahead of print
Ewer AK, Middleton LJ, Furmston AT, Bhoyar A, ... Khan KS, on behalf of the PulseOx Study Group
Lancet: 08 Aug 2011; epub ahead of print | PMID: 21820732
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Impact:
Abstract

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.

Cholesterol Treatment Trialists\' Ctt Collaboration
Background: Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. Methods: We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years\' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. Findings: In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations. Interpretation: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%. Funding: UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

Lancet: 11 Nov 2010; epub ahead of print
Cholesterol Treatment Trialists' Ctt Collaboration
Lancet: 11 Nov 2010; epub ahead of print | PMID: 21067804
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Abstract

Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.

Griffin SJ, Borch-Johnsen K, Davies MJ, Khunti K, ... Wareham NJ, Lauritzen T
Background: Intensive treatment of multiple cardiovascular risk factors can halve mortality among people with established type 2 diabetes. We investigated the effect of early multifactorial treatment after diagnosis by screening. Methods: In a pragmatic, cluster-randomised, parallel-group trial done in Denmark, the Netherlands, and the UK, 343 general practices were randomly assigned screening of registered patients aged 40-69 years without known diabetes followed by routine care of diabetes or screening followed by intensive treatment of multiple risk factors. The primary endpoint was first cardiovascular event, including cardiovascular mortality and morbidity, revascularisation, and non-traumatic amputation within 5 years. Patients and staff assessing outcomes were unaware of the practice\'s study group assignment. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00237549. Findings: Primary endpoint data were available for 3055 (99·9%) of 3057 screen-detected patients. The mean age was 60·3 (SD 6·9) years and the mean duration of follow-up was 5·3 (SD 1·6) years. Improvements in cardiovascular risk factors (HbA(1c) and cholesterol concentrations and blood pressure) were slightly but significantly better in the intensive treatment group. The incidence of first cardiovascular event was 7·2% (13·5 per 1000 person-years) in the intensive treatment group and 8·5% (15·9 per 1000 person-years) in the routine care group (hazard ratio 0·83, 95% CI 0·65-1·05), and of all-cause mortality 6·2% (11·6 per 1000 person-years) and 6·7% (12·5 per 1000 person-years; 0·91, 0·69-1·21), respectively. Interpretation: An intervention to promote early intensive management of patients with type 2 diabetes was associated with a small, non-significant reduction in the incidence of cardiovascular events and death. Funding: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Merck.

Lancet: 27 Jun 2011; epub ahead of print
Griffin SJ, Borch-Johnsen K, Davies MJ, Khunti K, ... Wareham NJ, Lauritzen T
Lancet: 27 Jun 2011; epub ahead of print | PMID: 21705063
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Abstract

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
Background: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. Methods: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. Findings: In 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). Interpretation: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. Funding: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.

Lancet: 15 Mar 2012; epub ahead of print
The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
Lancet: 15 Mar 2012; epub ahead of print | PMID: 22421340
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Abstract

Glycaemic control and incidence of heart failure in 20 985 patients with type 1 diabetes: an observational study.

Lind M, Bounias I, Olsson M, Gudbjörnsdottir S, Svensson AM, Rosengren A
Background: Poor glycaemic control is associated with microvascular and macrovascular complications in type 1 diabetes, but whether glycaemic control is associated with heart failure in such patients is not known. We aimed to assess this association in a large cohort of patients with type 1 diabetes identified from the Swedish national diabetes registry. Methods: We identified all patients (aged ≥18 years) with type 1 diabetes and no known heart failure who were registered in the national diabetes registry between January, 1998, and December, 2003. These patients were followed up until hospital admission for heart failure, death, or end of follow-up on Dec 31, 2009. We calculated incidence categorised by glycated haemoglobin A(1c) (HbA(1c)) values, and we assessed the association between patients\' characteristics, including HbA(1c), and heart failure. Findings: In a cohort of 20 985 patients with mean age of 38·6 years (SD 13·3) at baseline, 635 patients (3%) were admitted to hospital with a primary or secondary diagnosis of heart failure during a median follow-up of 9·0 years (IQR 7·3-11·0), with an incidence of 3·38 events per 1000 patient-years (95% CI 3·12-3·65). Incidence increased monotonically with HbA(1c), with a range of 1·42-5·20 per 1000 patient-years between patients in the lowest (<6·5%) and highest (≥10·5%) categories of HbA(1c). In a Cox regression analysis, with adjustment for age, sex, duration of diabetes, cardiovascular risk factors, and baseline or intervening acute myocardial infarction and other comorbidities, the hazard ratio for development of heart failure was 3·98 (95% CI 2·23-7·14) in patients with HbA(1c) of 10·5% or higher compared with a reference group of patients with HbA(1c) of less than 6·5%. Risk of heart failure increased with age and duration of diabetes. Other modifiable factors associated with increased risk of heart failure were smoking, high systolic blood pressure, and raised body-mass index. In a subgroup of 18 281 patients (87%) with data for blood lipids, higher HDL cholesterol was associated with lower risk of heart failure, but there was no association with LDL cholesterol. Interpretation: The positive association between HbA(1c) and risk of heart failure in fairly young patients with type 1 diabetes indicates a potential for prevention of heart failure with improved glycaemic control. Funding: AstraZeneca, Novo Nordisk Scandinavia, Swedish Heart and Lung Foundation, and Swedish Research Council.

Lancet: 27 Jun 2011; epub ahead of print
Lind M, Bounias I, Olsson M, Gudbjörnsdottir S, Svensson AM, Rosengren A
Lancet: 27 Jun 2011; epub ahead of print | PMID: 21705065
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Abstract

The global response and unmet actions for HIV and sex workers.

Shannon K, Crago AL, Baral SD, Bekker LG, ... Strathdee SA, Beyrer C
Female, male, and transgender sex workers continue to have disproportionately high burdens of HIV infection in low-income, middle-income, and high-income countries in 2018. 4 years since our Lancet Series on HIV and sex work, our updated analysis of the global HIV burden among female sex workers shows that HIV prevalence is unacceptably high at 10·4% (95% CI 9·5-11·5) and is largely unchanged. Comprehensive epidemiological data on HIV and antiretroviral therapy (ART) coverage are scarce, particularly among transgender women. Sustained coverage of treatment is markedly uneven and challenged by lack of progress on stigma and criminalisation, and sustained human rights violations. Although important progress has been made in biomedical interventions with pre-exposure prophylaxis and early ART feasibility and demonstration projects, limited coverage and retention suggest that sustained investment in community and structural interventions is required for sex workers to benefit from the preventive interventions and treatments that other key populations have. Evidence-based progress on full decriminalisation grounded in health and human rights-a key recommendation in our Lancet Series-has stalled, with South Africa a notable exception. Additionally, several countries have rolled back rights to sex workers further. Removal of legal barriers through the decriminalisation of sex work, alongside political and funding investments to support community and structural interventions, is urgently needed to reverse the HIV trajectory and ensure health and human rights for all sex workers.

Lancet: 19 Jul 2018; epub ahead of print
Shannon K, Crago AL, Baral SD, Bekker LG, ... Strathdee SA, Beyrer C
Lancet: 19 Jul 2018; epub ahead of print | PMID: 30037733
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Abstract

Leishmaniasis.

Burza S, Croft SL, Boelaert M
Leishmaniasis is a poverty-related disease with two main clinical forms: visceral leishmaniasis and cutaneous leishmaniasis. An estimated 0·7-1 million new cases of leishmaniasis per year are reported from nearly 100 endemic countries. The number of reported visceral leishmaniasis cases has decreased substantially in the past decade as a result of better access to diagnosis and treatment and more intense vector control within an elimination initiative in Asia, although natural cycles in transmission intensity might play a role. In east Africa however, the case numbers of this fatal disease continue to be sustained. Increased conflict in endemic areas of cutaneous leishmaniasis and forced displacement has resulted in a surge in these endemic areas as well as clinics across the world. WHO lists leishmaniasis as one of the neglected tropical diseases for which the development of new treatments is a priority. Major evidence gaps remain, and new tools are needed before leishmaniasis can be definitively controlled.

Lancet: 16 Aug 2018; epub ahead of print
Burza S, Croft SL, Boelaert M
Lancet: 16 Aug 2018; epub ahead of print | PMID: 30126638
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Abstract

Prevention of stroke: a global perspective.

Pandian JD, Gall SL, Kate MP, Silva GS, ... Gandhi DBC, Thrift AG
Along with the rising global burden of disability attributed to stroke, costs of stroke care are rising, providing the impetus to direct our research focus towards effective measures of stroke prevention. In this Series paper, we discuss strategies for reducing the risk of the emergence of disease (primordial prevention), preventing the onset of disease (primary prevention), and preventing the recurrence of disease (secondary prevention). Our focus includes global strategies and campaigns, and measurements of the effectiveness of worldwide preventive interventions, with an emphasis on low-income and middle-income countries. Our findings reveal that effective tobacco control, adequate nutrition, and development of healthy cities are important strategies for primordial prevention, whereas polypill strategies, use of mobile technology (mHealth), along with salt reduction and other dietary interventions, are effective in the primary prevention of stroke. An effective collaboration between various health-care sectors, government policies, and campaigns can successfully implement secondary prevention strategies, through surveillance and registries, such as the WHO\'s non-communicable diseases programmes, across high-income and low-income countries.

Lancet: 05 Oct 2018; 392:1269-1278
Pandian JD, Gall SL, Kate MP, Silva GS, ... Gandhi DBC, Thrift AG
Lancet: 05 Oct 2018; 392:1269-1278 | PMID: 30319114
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Impact:
Abstract

Intracerebral haemorrhage: current approaches to acute management.

Cordonnier C, Demchuk A, Ziai W, Anderson CS
Acute spontaneous intracerebral haemorrhage is a life-threatening illness of global importance, with a poor prognosis and few proven treatments. As a heterogeneous disease, certain clinical and imaging features help identify the cause, prognosis, and how to manage the disease. Survival and recovery from intracerebral haemorrhage are related to the site, mass effect, and intracranial pressure from the underlying haematoma, and by subsequent cerebral oedema from perihaematomal neurotoxicity or inflammation and complications from prolonged neurological dysfunction. A moderate level of evidence supports there being beneficial effects of active management goals with avoidance of early palliative care orders, well-coordinated specialist stroke unit care, targeted neurointensive and surgical interventions, early control of elevated blood pressure, and rapid reversal of abnormal coagulation.

Lancet: 05 Oct 2018; 392:1257-1268
Cordonnier C, Demchuk A, Ziai W, Anderson CS
Lancet: 05 Oct 2018; 392:1257-1268 | PMID: 30319113
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Abstract

New insights into the immunology of chronic obstructive pulmonary disease.

Brusselle GG, Joos GF, Bracke KR
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inflammatory immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses, which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of microRNAs in the persistence of the pulmonary inflammation despite smoking cessation.

Lancet: 12 Sep 2011; 378:1015-26
Brusselle GG, Joos GF, Bracke KR
Lancet: 12 Sep 2011; 378:1015-26 | PMID: 21907865
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Abstract

Current practice and future directions in the diagnosis and acute treatment of ischaemic stroke.

Zerna C, Thomalla G, Campbell BCV, Rha JH, Hill MD
Even though stroke presents as a variety of clinical syndromes, neuroimaging is the most important biomarker to help differentiate between stroke subtypes and assess treatment eligibility. Therapeutic advances have led to intravenous thrombolysis with tissue-type plasminogen activator and endovascular treatment for proximal vessel occlusion in the anterior cerebral circulation being standard care for acute ischaemic stroke. Providing access to this care has implications for existing systems of care for stroke and their organisation and has reintroduced the possibility of adjuvant and neuroprotective treatment strategies in acute ischaemic stroke. The use of neuroimaging for patient selection and speed of diagnosis and delivery of treatment are the dominant themes of modern ischaemic stroke care.

Lancet: 05 Oct 2018; 392:1247-1256
Zerna C, Thomalla G, Campbell BCV, Rha JH, Hill MD
Lancet: 05 Oct 2018; 392:1247-1256 | PMID: 30319112
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Abstract

Depression.

Malhi GS, Mann JJ
Major depression is a common illness that severely limits psychosocial functioning and diminishes quality of life. In 2008, WHO ranked major depression as the third cause of burden of disease worldwide and projected that the disease will rank first by 2030. In practice, its detection, diagnosis, and management often pose challenges for clinicians because of its various presentations, unpredictable course and prognosis, and variable response to treatment.

Lancet: 01 Nov 2018; epub ahead of print
Malhi GS, Mann JJ
Lancet: 01 Nov 2018; epub ahead of print | PMID: 30396512
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Abstract

Primary biliary cirrhosis.

Selmi C, Bowlus CL, Gershwin ME, Coppel RL
Primary biliary cirrhosis is a chronic liver disease characterised by intrahepatic bile-duct destruction, cholestasis, and, in some cases, cirrhosis. Evidence supporting the autoimmune nature of this disorder includes the appearance of highly specific antimitochondrial antibodies (AMAs) and autoreactive T cells. Concordance rates in monozygotic twins, familial prevalence, and genetic associations underscore the importance of genetic factors, whereas findings of epidemiological studies and murine models suggest a possible role for exogenous chemicals and infectious agents through molecular mimicry. The incidence of primary biliary cirrhosis has increased over recent decades, possibly attributable to augmented testing of liver biochemistry rather than a rise in disease incidence. AMAs remain the hallmark of diagnosis in most cases and allow detection of asymptomatic patients. Symptomatic individuals usually present with either pruritus or fatigue and, more rarely, with either jaundice or complications of cirrhosis. The prognosis of primary biliary cirrhosis has improved because of early diagnosis and use of ursodeoxycholic acid, the only established medical treatment for this disorder. Although not a cure, treatment can slow disease progression and delay the need for liver transplantation. However, some patients do not respond adequately to ursodeoxycholic acid and might need alternative therapeutic approaches.

Lancet: 02 May 2011; epub ahead of print
Selmi C, Bowlus CL, Gershwin ME, Coppel RL
Lancet: 02 May 2011; epub ahead of print | PMID: 21529926
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Impact:
Abstract

Small-cell lung cancer.

van Meerbeeck JP, Fennell DA, De Ruysscher DK
The incidence and mortality of small-cell lung cancer worldwide make this disease a notable health-care issue. Diagnosis relies on histology, with the use of immunohistochemical studies to confirm difficult cases. Typical patients are men older than 70 years who are current or past heavy smokers and who have pulmonary and cardiovascular comorbidities. Patients often present with rapid-onset symptoms due to local intrathoracic tumour growth, extrapulmonary distant spread, paraneoplastic syndromes, or a combination of these features. Staging aims ultimately to define disease as metastatic or non-metastatic. Combination chemotherapy, generally platinum-based plus etoposide or irinotecan, is the mainstay first-line treatment for metastatic small-cell lung cancer. For non-metastatic disease, evidence supports early concurrent thoracic radiotherapy. Prophylactic cranial irradiation should be considered for patients with or without metastases whose disease does not progress after induction chemotherapy and radiotherapy. Despite high initial response rates, most patients eventually relapse. Except for topotecan, few treatment options then remain. Signalling pathways have been identified that might yield new drug targets.

Lancet: 13 May 2011; epub ahead of print
van Meerbeeck JP, Fennell DA, De Ruysscher DK
Lancet: 13 May 2011; epub ahead of print | PMID: 21565397
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Abstract

Telemedicine and remote management of patients with heart failure.

Anker SD, Koehler F, Abraham WT
Advances in telecommunication technologies have created new opportunities to provide telemedical care as an adjunct to medical management of patients with heart failure. Meta-analyses suggest that telemedicine can reduce morbidity and mortality in such patients; however, two prospective clinical trials not included in the analyses do not support these findings. Therefore, the effectiveness of telemedicine in heart failure is not established. Telemedicine approaches range from computer-based support systems to programmes led by nurses and physicians. Standardisation and appropriate classification of telemedical systems are needed to enable accurate interpretation of clinical trials. Here we propose a classification of four generations of telemedicine in heart failure. Not all approaches are the same and not every patient with heart failure will need telemedicine. Crisis prevention and treatment, and stabilisation and self-empowerment of patients are focuses of telemedicine in heart failure. The profile of patients who can potentially benefit from telemedicine is unknown and should be investigated in adequately powered randomised clinical trials. We are optimistic that telemedicine is an efficient approach and will become an important feature of management in heart failure.

Lancet: 22 Aug 2011; 378:731-9
Anker SD, Koehler F, Abraham WT
Lancet: 22 Aug 2011; 378:731-9 | PMID: 21856487
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Abstract

Viral gastroenteritis.

Bányai K, Estes MK, Martella V, Parashar UD
Enteric viruses, particularly rotaviruses and noroviruses, are a leading cause of gastroenteritis worldwide. Rotaviruses primarily affect young children, accounting for almost 40% of hospital admissions for diarrhoea and 200 000 deaths worldwide, with the majority of deaths occurring in developing countries. Two vaccines against rotavirus were licensed in 2006 and have been implemented in 95 countries as of April, 2018. Data from eight high-income and middle-income countries showed a 49-89% decline in rotavirus-associated hospital admissions and a 17-55% decline in all-cause gastroenteritis-associated hospital admissions among children younger than 5 years, within 2 years of vaccine introduction. Noroviruses affect people of all ages, and are a leading cause of foodborne disease and outbreaks of gastroenteritis worldwide. Prevention of norovirus infection relies on frequent hand hygiene, limiting contact with people who are infected with the virus, and disinfection of contaminated environmental surfaces. Norovirus vaccine candidates are in clinical trials; whether vaccines will provide durable protection against the range of genetically and antigenically diverse norovirus strains remains unknown. Treatment of viral gastroenteritis is based primarily on replacement of fluid and electrolytes.

Lancet: 13 Jul 2018; 392:175-186
Bányai K, Estes MK, Martella V, Parashar UD
Lancet: 13 Jul 2018; 392:175-186 | PMID: 30025810
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Impact:
Abstract

Myocarditis.

Sagar S, Liu PP, Cooper LT
Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression.

Lancet: 21 Dec 2011; epub ahead of print
Sagar S, Liu PP, Cooper LT
Lancet: 21 Dec 2011; epub ahead of print | PMID: 22185868
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Abstract

Melanoma.

Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, ... Roesch A, Ugurel S
Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF) (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse-free, distant-metastasis-free, and overall survival times.

Lancet: 14 Sep 2018; 392:971-984
Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, ... Roesch A, Ugurel S
Lancet: 14 Sep 2018; 392:971-984 | PMID: 30238891
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Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey.

Yusuf S, Islam S, Chow CK, Rangarajan S, ... Teo KK, on behalf of the Prospective Urban Rural Epidemiology (PURE) Study Investigators
Background: Although most cardiovascular disease occurs in low-income and middle-income countries, little is known about the use of effective secondary prevention medications in these communities. We aimed to assess use of proven effective secondary preventive drugs (antiplatelet drugs, β blockers, angiotensin-converting-enzyme [ACE] inhibitors or angiotensin-receptor blockers [ARBs], and statins) in individuals with a history of coronary heart disease or stroke. Methods: In the Prospective Urban Rural Epidemiological (PURE) study, we recruited individuals aged 35-70 years from rural and urban communities in countries at various stages of economic development. We assessed rates of previous cardiovascular disease (coronary heart disease or stroke) and use of proven effective secondary preventive drugs and blood-pressure-lowering drugs with standardised questionnaires, which were completed by telephone interviews, household visits, or on patient\'s presentation to clinics. We report estimates of drug use at national, community, and individual levels. Findings: We enrolled 153 996 adults from 628 urban and rural communities in countries with incomes classified as high (three countries), upper-middle (seven), lower-middle (three), or low (four) between January, 2003, and December, 2009. 5650 participants had a self-reported coronary heart disease event (median 5·0 years previously [IQR 2·0-10·0]) and 2292 had stroke (4·0 years previously [2·0-8·0]). Overall, few individuals with cardiovascular disease took antiplatelet drugs (25·3%), β blockers (17·4%), ACE inhibitors or ARBs (19·5%), or statins (14·6%). Use was highest in high-income countries (antiplatelet drugs 62·0%, β blockers 40·0%, ACE inhibitors or ARBs 49·8%, and statins 66·5%), lowest in low-income countries (8·8%, 9·7%, 5·2%, and 3·3%, respectively), and decreased in line with reduction of country economic status (p(trend)<0·0001 for every drug type). Fewest patients received no drugs in high-income countries (11·2%), compared with 45·1% in upper middle-income countries, 69·3% in lower middle-income countries, and 80·2% in low-income countries. Drug use was higher in urban than rural areas (antiplatelet drugs 28·7% urban vs 21·3% rural, β blockers 23·5%vs 15·6%, ACE inhibitors or ARBs 22·8%vs 15·5%, and statins 19·9%vs 11·6%; all p<0·0001), with greatest variation in poorest countries (p(interaction)<0·0001 for urban vs rural differences by country economic status). Country-level factors (eg, economic status) affected rates of drug use more than did individual-level factors (eg, age, sex, education, smoking status, body-mass index, and hypertension and diabetes statuses). Interpretation: Because use of secondary prevention medications is low worldwide-especially in low-income countries and rural areas-systematic approaches are needed to improve the long-term use of basic, inexpensive, and effective drugs. Funding: Full funding sources listed at end of paper (see Acknowledgments).

Lancet: 29 Aug 2011; epub ahead of print
Yusuf S, Islam S, Chow CK, Rangarajan S, ... Teo KK, on behalf of the Prospective Urban Rural Epidemiology (PURE) Study Investigators
Lancet: 29 Aug 2011; epub ahead of print | PMID: 21872920
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Abstract

Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.

Jun M, Foote C, Lv J, Neal B, ... Chalmers J, Perkovic V
Background: Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes. Methods: We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events. Findings: We identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0-18) for major cardiovascular events (p=0.048) and a 13% RR reduction (7-19) for coronary events (p<0.0001), but had no benefit on stroke (-3%, -16 to 9; p=0.69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, -8 to 7; p=0.92), cardiovascular mortality (3%, -7 to 12; p=0.59), sudden death (11%, -6 to 26; p=0.19), or non-vascular mortality (-10%, -21 to 0.5; p=0.063). Fibrates reduced the risk of albuminuria progression by 14% (2-25; p=0.028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1.21, 0.91-1.61; p=0.19), although increases in serum creatinine concentrations were common (1.99, 1.46-2.70; p<0.0001). Interpretation: Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia. Funding: National Health and Medical Research Council of Australia.

Lancet: 13 May 2010; epub ahead of print
Jun M, Foote C, Lv J, Neal B, ... Chalmers J, Perkovic V
Lancet: 13 May 2010; epub ahead of print | PMID: 20462635
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Abstract

Rhythm control in atrial fibrillation.

Piccini JP, Fauchier L
Many patients with atrial fibrillation have substantial symptoms despite ventricular rate control and require restoration of sinus rhythm to improve their quality of life. Acute restoration (ie, cardioversion) and maintenance of sinus rhythm in patients with atrial fibrillation are referred to as rhythm control. The decision to pursue rhythm control is based on symptoms, the type of atrial fibrillation (paroxysmal, persistent, or long-standing persistent), patient comorbidities, general health status, and anticoagulation status. Many patients have recurrent atrial fibrillation and require further intervention to maintain long term sinus rhythm. Antiarrhythmic drug therapy is generally recommended as a first-line therapy and drug selection is on the basis of the presence or absence of structural heart disease or heart failure, electrocardiographical variables, renal function, and other comorbidities. In patients who continue to have recurrent atrial fibrillation despite medical therapy, catheter ablation has been shown to substantially reduce recurrent atrial fibrillation, decrease symptoms, and improve quality of life, although recurrence is common despite continued advancement in ablation techniques.

Lancet: 24 Aug 2016; 388:829-840
Piccini JP, Fauchier L
Lancet: 24 Aug 2016; 388:829-840 | PMID: 27560278
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Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial.

Thiele H, Wöhrle J, Hambrecht R, Rittger H, ... Desch S, Schuler G
Background: Intracoronary administration of an abciximab bolus during a primary percutaneous coronary intervention results in a high local drug concentration, improved perfusion, and reduction of infarct size compared with intravenous bolus application. However, the safety and efficacy of intracoronary versus standard intravenous bolus application in patients with ST-elevation myocardial infarction (STEMI) undergoing this intervention has not been tested in a large-scale clinical trial. Methods: The AIDA STEMI trial was a randomised, open-label, multicentre trial. Patients presenting with STEMI in the previous 12 h with no contraindications for abciximab were randomly assigned in a 1:1 ratio by a central web-based randomisation system to intracoronary versus intravenous abciximab bolus (0·25 mg/kg bodyweight) during percutaneous coronary intervention with a subsequent 12 h intravenous infusion 0·125 μg/kg per min (maximum 10 μg/min). The primary endpoint was a composite of all-cause mortality, recurrent infarction, or new congestive heart failure within 90 days of randomisation. Secondary endpoints were the time to occurrence of the primary endpoint, each individual component of that endpoint, early ST-segment resolution, thrombolysis in myocardial infarction (TIMI) flow grade, and enzymatic infarct size. A masked central committee adjudicated the primary outcome and its components. Treatment allocation was not concealed from patients and investigators. This trial is registered with ClinicalTrials.gov, NCT00712101. Findings: Between July, 2008, and April, 2011, 2065 patients were randomly assigned intracoronary abciximab (n=1032) or intravenous abciximab (n=1033). Intracoronary, as compared with intravenous abciximab, resulted in a similar rate of the primary composite clinical endpoint at 90 days in 1876 analysable patients (7·0%vs 7·6%; odds ratio [OR] 0·91; 95% CI 0·64-1·28; p=0·58). The incidence of death (4·5%vs 3·6%; 1·24; 0·78-1·97; p=0·36) and reinfarction (1·8%vs 1·8%; 1·0; 0·51-1·96; p=0·99) did not differ between the treatment groups, whereas less patients in the intracoronary group had new congestive heart failure (2·4%vs 4·1%; 0·57; 0·33-0·97; p=0·04). None of the secondary endpoints or safety measures differed significantly between groups. Interpretation: In patients with STEMI undergoing primary percutaneous coronary intervention, intracoronary as compared to intravenous abciximab did not result in a difference in the combined endpoint of death, reinfarction, or congestive heart failure. Since intracoronary abciximab bolus administration is safe and might be related to reduced rates of congestive heart failure the intracoronary route might be preferred if abciximab is indicated. Funding: Lilly, Germany. University of Leipzig-Heart Centre. University of Leipzig, Clinical Trial Centre Leipzig, supported by the Federal Ministry of Education and Research (BMBF).

Lancet: 22 Feb 2012; epub ahead of print
Thiele H, Wöhrle J, Hambrecht R, Rittger H, ... Desch S, Schuler G
Lancet: 22 Feb 2012; epub ahead of print | PMID: 22357109
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Abstract

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.

Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL, ... Talmud PJ, Danesh J
Background: Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. Methods: We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings: The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride. Interpretation: These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding: British Heart Foundation, UK Medical Research Council, Novartis.

Lancet: 10 May 2010; 375:1634-9
Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL, ... Talmud PJ, Danesh J
Lancet: 10 May 2010; 375:1634-9 | PMID: 20452521
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Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial.

Rasmussen K, Maeng M, Kaltoft A, Thayssen P, ... Lassen JF, on behalf of the SORT OUT III study group
Background: In low-risk patients, the zotarolimus-eluting stent has been shown to reduce rates of restenosis without increasing the risk of stent thrombosis. We compared the efficacy and safety of the zotarolimus-eluting stent versus the sirolimus-eluting stent in patients with coronary artery disease who were receiving routine clinical care with no direct follow-up. Methods: We did a single-blind, all-comer superiority trial in adult patients with chronic stable coronary artery disease or acute coronary syndromes, and at least one target lesion. Patients were treated at one of five percutaneous coronary intervention centres between January, 2006, and August, 2007. Computer-generated block randomisation and a telephone allocation service were used to randomly assign patients to receive the zotarolimus-eluting or the sirolimus-eluting stent. Data for follow-up were obtained from national Danish administrative and health-care registries. The primary endpoint was a composite of major adverse cardiac events within 9 months: cardiac death, myocardial infarction, and target vessel revascularisation. Intention-to-treat analyses were done at 9-month and 18-month follow-up. This trial is registered with ClinicalTrials.gov, number NCT00660478. Findings: 1162 patients (1619 lesions) were assigned to receive the zotarolimus-eluting stent, and 1170 patients (1611 lesions) to receive the sirolimus-eluting stent. 67 patients (72 lesions) had stent failure, and six patients were lost to follow-up. All randomly assigned patients were included in analyses at 9-month follow-up; 2200 patients (94%) had completed 18-month follow-up by the time of our assessment. At 9 months, the primary endpoint had occurred in a higher proportion of patients treated with the zotarolimus-eluting stent than in those treated with the sirolimus-eluting stent (72 [6%] vs 34 [3%]; HR 2.15, 95% CI 1.43-3.23; p=0.0002). At 18-month follow-up, this difference was sustained (113 [10%] vs 53 [5%]; 2.19, 1.58-3.04; p<0.0001). For patients receiving the zotarolimus-eluting stent and those receiving the sirolimus-eluting stent, all cause-mortality was similar at 9-month follow-up (25 [2%] vs 18 [2%]; 1.40, 0.76-2.56; p=0.28), but was significantly different at 18-month follow-up (51 [4%] vs 32 [3%]; 1.61, 1.03-2.50; p=0.035). Interpretation: The sirolimus-eluting stent is superior to the zotarolimus-eluting stent for patients receiving routine clinical care. Funding: Cordis and Medtronic.

Lancet: 16 Mar 2010; epub ahead of print
Rasmussen K, Maeng M, Kaltoft A, Thayssen P, ... Lassen JF, on behalf of the SORT OUT III study group
Lancet: 16 Mar 2010; epub ahead of print | PMID: 20231034
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Abstract

Chronic hepatitis B virus infection.

Seto WK, Lo YR, Pawlotsky JM, Yuen MF
Chronic hepatitis B virus infection is a global public health threat that causes considerable liver-related morbidity and mortality. It is acquired at birth or later via person-to-person transmission. Vaccination effectively prevents infection and chronic hepatitis B virus carriage. In chronically infected patients, an elevated serum hepatitis B virus DNA concentration is the main risk factor for disease progression, although there are other clinical and viral parameters that influence disease outcomes. In addition to liver biochemistry, virological markers, and abdominal ultrasonography, non-invasive assessment of liver fibrosis is emerging as an important assessment modality. Long-term nucleos(t)ide-analogue therapy is safe and well tolerated, achieves potent viral suppression, and reduces the incidence of liver-related complications. However, a need to optimise management remains. Promising novel therapies are at the developmental stage. With current vaccines, therapies, and an emphasis on improving linkage to care, WHO\'s goal of eliminating hepatitis B virus as a global health threat by 2030 is achievable.

Lancet: 23 Nov 2018; 392:2313-2324
Seto WK, Lo YR, Pawlotsky JM, Yuen MF
Lancet: 23 Nov 2018; 392:2313-2324 | PMID: 30496122
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Cardiovascular complications and risk of death in sickle-cell disease.

Gladwin MT
In sickle-cell disease, a point mutation in the β-globin chain causes haemoglobin to polymerise within erythrocytes during deoxygenation, altering red blood cell rheology and causing haemolysis. Improvements in health infrastructure, preventive care, and clinical treatments have reduced the morbidity and mortality of sickle-cell disease in developed countries. However, as these patients live longer, the chronic effects of sustained haemolytic anaemia and episodic vaso-occlusive events drive the development of end-organ complications. Cardiopulmonary organ dysfunction and chronic kidney injury have a large effect on morbidity and premature mortality, and typically accelerate in the second decade of life. These processes culminate in the development of pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, and sudden death. In this Series paper, we review the mechanisms, clinical features, and epidemiology of major cardiovascular complications in patients with sickle-cell disease and discuss how screening and intervention could reduce their incidence.

Lancet: 28 Jun 2016; 387:2565-74
Gladwin MT
Lancet: 28 Jun 2016; 387:2565-74 | PMID: 27353687
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Abstract

Rate control in atrial fibrillation.

Van Gelder IC, Rienstra M, Crijns HJ, Olshansky B
Control of the heart rate (rate control) is central to atrial fibrillation management, even for patients who ultimately require control of the rhythm. We review heart rate control in patients with atrial fibrillation, including the rationale for the intervention, patient selection, and the treatments available. The choice of rate control depends on the symptoms and clinical characteristics of the patient, but for all patients with atrial fibrillation, rate control is part of the management. Choice of drugs is patient-dependent. β blockers, alone or in combination with digoxin, or non-dihydropyridine calcium-channel blockers (not in heart failure) effectively lower the heart rate. Digoxin is least effective, but a reasonable choice for physically inactive patients aged 80 years or older, in whom other treatments are ineffective or are contraindicated, and as an additional drug to other rate-controlling drugs, especially in heart failure when instituted cautiously. Atrioventricular node ablation with pacemaker insertion for rate control should be used as an approach of last resort but is also an option early in the management of patients with atrial fibrillation treated with cardiac resynchronisation therapy. However, catheter ablation of atrial fibrillation should be considered before atrioventricular node ablation. Although rate control is a top priority and one of the first management issues for all patients with atrial fibrillation, many issues remain.

Lancet: 24 Aug 2016; 388:818-828
Van Gelder IC, Rienstra M, Crijns HJ, Olshansky B
Lancet: 24 Aug 2016; 388:818-828 | PMID: 27560277
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Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies.

Huxley RR, Woodward M
Background: Prevalence of smoking is increasing in women in some populations and is a risk factor for coronary heart disease. Whether smoking confers the same excess risk of coronary heart disease for women as it does for men is unknown. Therefore, we aimed to estimate the effect of smoking on coronary heart disease in women compared with men after accounting for sex differences in other major risk factors. Methods: We undertook a systematic review and meta-analysis of prospective cohort studies published between Jan 1, 1966, and Dec 31, 2010, from four online databases. We selected cohort studies that were stratified by sex with measures of relative risk (RR), and associated variability, for coronary heart disease and current smoking compared with not smoking. We pooled data with a random effects model with inverse variance weighting, and estimated RR ratios (RRRs) between men and women. Findings: We reviewed 8005 abstracts and included 26 articles with data for 3 912 809 individuals and 67 075 coronary heart disease events from 86 prospective trials. In 75 cohorts (2·4 million participants) that adjusted for cardiovascular risk factors other than coronary heart disease, the pooled adjusted female-to-male RRR of smoking compared with not smoking for coronary heart disease was 1·25 (95% CI 1·12-1·39, p<0·0001). This outcome was unchanged after adjustment for potential publication bias and there was no evidence of important between-study heterogeneity (p=0·21). The RRR increased by 2% for every additional year of study follow-up (p=0·03). In pooled data from 53 studies, there was no evidence of a sex difference in the RR between participants who had previously smoked compared with those who never had (RRR 0·96, 95% CI 0·86-1·08, p=0·53). Interpretation: Whether mechanisms underlying the sex difference in risk of coronary heart disease are biological or related to differences in smoking behaviour between men and women is unclear. Tobacco-control programmes should consider women, particularly in those countries where smoking among young women is increasing in prevalence. Funding: None.

Lancet: 15 Aug 2011; epub ahead of print
Huxley RR, Woodward M
Lancet: 15 Aug 2011; epub ahead of print | PMID: 21839503
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Clinical features of paediatric pulmonary hypertension: a registry study.

Berger RM, Beghetti M, Humpl T, Raskob GE, ... Schulze-Neick I, Barst RJ
Background: Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension. Methods: Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients\' physicians according to the individual\'s health-care needs. Findings: 362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index ≥3 WU/m(-2)). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3-12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope occurred in 31% (57 of 182) of patients with IPAH or FPAH and in 18% (eight of 45) of those with repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope. Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64%) patients, which is consistent with preserved right-heart function. Interpretation: TOPP identifies important clinical features specific to the care of paediatric pulmonary hypertension, which draw attention to the need for paediatric data rather than extrapolation from adult studies. Funding: Actelion Pharmaceuticals.

Lancet: 13 Jan 2012; epub ahead of print
Berger RM, Beghetti M, Humpl T, Raskob GE, ... Schulze-Neick I, Barst RJ
Lancet: 13 Jan 2012; epub ahead of print | PMID: 22240409
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Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.

Bolli R, Chugh AR, D\'Amario D, Loughran JH, ... Kajstura J, Anversa P
Background: c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. Methods: In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. Findings: This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). Interpretation: These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. Funding: University of Louisville Research Foundation and National Institutes of Health.

Lancet: 17 Nov 2011; epub ahead of print
Bolli R, Chugh AR, D'Amario D, Loughran JH, ... Kajstura J, Anversa P
Lancet: 17 Nov 2011; epub ahead of print | PMID: 22088800
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High-flow oxygen therapy and other inhaled therapies in intensive care units.

Levy SD, Alladina JW, Hibbert KA, Harris RS, Bajwa EK, Hess DR
In this Series paper, we review the current evidence for the use of high-flow oxygen therapy, inhaled gases, and aerosols in the care of critically ill patients. The available evidence supports the use of high-flow nasal cannulae for selected patients with acute hypoxaemic respiratory failure. Heliox might prevent intubation or improve gas flow in mechanically ventilated patients with severe asthma. Additionally, it might improve the delivery of aerosolised bronchodilators in obstructive lung disease in general. Inhaled nitric oxide might improve outcomes in a subset of patients with postoperative pulmonary hypertension who had cardiac surgery; however, it has not been shown to provide long-term benefit in patients with acute respiratory distress syndrome (ARDS). Inhaled prostacyclins, similar to inhaled nitric oxide, are not recommended for routine use in patients with ARDS, but can be used to improve oxygenation in patients who are not adequately stabilised with traditional therapies. Aerosolised bronchodilators are useful in mechanically ventilated patients with asthma and chronic obstructive pulmonary disease, but are not recommended for those with ARDS. Use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis shows promise, but the delivered dose can be highly variable if proper attention is not paid to the delivery method.

Lancet: 19 May 2016; 387:1867-1878
Levy SD, Alladina JW, Hibbert KA, Harris RS, Bajwa EK, Hess DR
Lancet: 19 May 2016; 387:1867-1878 | PMID: 27203510
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Abstract

HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial.

Ridker PM, Genest J, Boekholdt SM, Libby P, ... Kastelein JJ, for the JUPITER Trial Study Group
Background: HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. Methods: Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3.37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT00239681. Findings: For 17 802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0.0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2.80 mmol/L [IQR 2.43-3.24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0.54, 95% CI 0.35-0.83, p=0.0039) and on-treatment (0.55, 0.35-0.87, p=0.0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1.42 mmol/L [IQR 1.14-1.86]), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1.12, 0.62-2.03, p=0.82) or on-treatment (1.03, 0.57-1.87, p=0.97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group. Interpretation: Although measurement of HDL-cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol. Funding: AstraZeneca.

Lancet: 26 Jul 2010; epub ahead of print
Ridker PM, Genest J, Boekholdt SM, Libby P, ... Kastelein JJ, for the JUPITER Trial Study Group
Lancet: 26 Jul 2010; epub ahead of print | PMID: 20655105
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Abstract

Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial.

Kobayashi T, Saji T, Otani T, Takeuchi K, ... Morikawa A, on behalf of the RAISE study group investigators
Background: Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease. Methods: We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940. Findings: We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12-0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group. Interpretation: Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted. Funding: Japanese Ministry of Health, Labour and Welfare.

Lancet: 11 Mar 2012; epub ahead of print
Kobayashi T, Saji T, Otani T, Takeuchi K, ... Morikawa A, on behalf of the RAISE study group investigators
Lancet: 11 Mar 2012; epub ahead of print | PMID: 22405251
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Abstract

Acute myocardial infarction.

Reed GW, Rossi JE, Cannon CP
Acute myocardial infarction has traditionally been divided into ST elevation or non-ST elevation myocardial infarction; however, therapies are similar between the two, and the overall management of acute myocardial infarction can be reviewed for simplicity. Acute myocardial infarction remains a leading cause of morbidity and mortality worldwide, despite substantial improvements in prognosis over the past decade. The progress is a result of several major trends, including improvements in risk stratification, more widespread use of an invasive strategy, implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis), advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins. This seminar discusses the important topics of the pathophysiology, epidemiological trends, and modern management of acute myocardial infarction, focusing on the recent advances in reperfusion strategies and pharmacological treatment approaches.

Lancet: 08 Aug 2016; epub ahead of print
Reed GW, Rossi JE, Cannon CP
Lancet: 08 Aug 2016; epub ahead of print | PMID: 27502078
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Abstract

Anxiety.

Craske MG, Stein MB
Anxiety disorders (separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, agoraphobia, and generalised anxiety disorder) are common and disabling conditions that mostly begin during childhood, adolescence, and early adulthood. They differ from developmentally normative or stress-induced transient anxiety by being marked (ie, out of proportion to the actual threat present) and persistent, and by impairing daily functioning. Most anxiety disorders affect almost twice as many women as men. They often co-occur with major depression, alcohol and other substance-use disorders, and personality disorders. Differential diagnosis from physical conditions-including thyroid, cardiac, and respiratory disorders, and substance intoxication and withdrawal-is imperative. If untreated, anxiety disorders tend to recur chronically. Psychological treatments, particularly cognitive behavioural therapy, and pharmacological treatments, particularly selective serotonin-reuptake inhibitors and serotonin-noradrenaline-reuptake inhibitors, are effective, and their combination could be more effective than is treatment with either individually. More research is needed to increase access to and to develop personalised treatments.

Lancet: 27 Jun 2016; epub ahead of print
Craske MG, Stein MB
Lancet: 27 Jun 2016; epub ahead of print | PMID: 27349358
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Abstract

Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial.

Noman A, Ang DS, Ogston S, Lang CC, Struthers AD
Background: Experimental evidence suggests that xanthine oxidase inhibitors can reduce myocardial oxygen consumption for a particular stroke volume. If such an effect also occurs in man, this class of inhibitors could become a new treatment for ischaemia in patients with angina pectoris. We ascertained whether high-dose allopurinol prolongs exercise capability in patients with chronic stable angina. Methods: 65 patients (aged 18-85 years) with angiographically documented coronary artery disease, a positive exercise tolerance test, and stable chronic angina pectoris (for at least 2 months) were recruited into a double-blind, randomised, placebo-controlled, crossover study in a hospital and two infirmaries in the UK. We used computer-generated randomisation to assign patients to allopurinol (600 mg per day) or placebo for 6 weeks before crossover. Our primary endpoint was the time to ST depression, and the secondary endpoints were total exercise time and time to chest pain. We did a completed case analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 82040078. Findings: In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed. Allopurinol increased the median time to ST depression to 298 s (IQR 211-408) from a baseline of 232 s (182-380), and placebo increased it to 249 s (200-375; p=0.0002). The point estimate (absolute difference between allopurinol and placebo) was 43 s (95% CI 31-58). Allopurinol increased median total exercise time to 393 s (IQR 280-519) from a baseline of 301 s (251-447), and placebo increased it to 307 s (232-430; p=0.0003); the point estimate was 58 s (95% CI 45-77). Allopurinol increased the time to chest pain from a baseline of 234 s (IQR 189-382) to 304 s (222-421), and placebo increased it to 272 s (200-380; p=0.001); the point estimate was 38 s (95% CI 17-55). No adverse effects of treatment were reported. Interpretation: Allopurinol seems to be a useful, inexpensive, well tolerated, and safe anti-ischaemic drug for patients with angina. Funding: British Heart Foundation.

Lancet: 14 Jun 2010; epub ahead of print
Noman A, Ang DS, Ogston S, Lang CC, Struthers AD
Lancet: 14 Jun 2010; epub ahead of print | PMID: 20542554
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Abstract

Bronchiectasis in children: diagnosis and treatment.

Chang AB, Bush A, Grimwood K
Bronchiectasis is conventionally defined as irreversible dilatation of the bronchial tree. Bronchiectasis unrelated to cystic fibrosis is an increasingly appreciated cause of chronic respiratory-related morbidity worldwide. Few randomised controlled trials provide high-level evidence for management strategies to treat the children affected by bronchiectasis. However, both decades-old and more recent studies using technological advances support the notion that prompt diagnosis and optimal management of paediatric bronchiectasis is particularly important in early childhood. Although considered to be of a non-reversible nature, mild bronchiectasis determined by radiography might be reversible at any age if treated early, and the lung function decline associated with disease progression could then be halted. Although some management strategies are extrapolated from cystic fibrosis or adult-based studies, or both, non-cystic fibrosis paediatric-specific data to help diagnose and manage these children still need to be generated. We present current knowledge and an updated definition of bronchiectasis, and review controversies relating to the management of children with bronchiectasis, including applying the concept of so-called treatable traits.

Lancet: 07 Sep 2018; 392:866-879
Chang AB, Bush A, Grimwood K
Lancet: 07 Sep 2018; 392:866-879 | PMID: 30215382
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Abstract

Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity.

Flume PA, Chalmers JD, Olivier KN
Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of bronchiectasis including observations related to the microbiome.

Lancet: 07 Sep 2018; 392:880-890
Flume PA, Chalmers JD, Olivier KN
Lancet: 07 Sep 2018; 392:880-890 | PMID: 30215383
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Abstract

Interpretation of the evidence for the efficacy and safety of statin therapy.

Collins R, Reith C, Emberson J, Armitage J, ... Yusuf S, Peto R
This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual\'s absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.

Lancet: 11 Sep 2016; epub ahead of print
Collins R, Reith C, Emberson J, Armitage J, ... Yusuf S, Peto R
Lancet: 11 Sep 2016; epub ahead of print | PMID: 27616593
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Abstract

Ziconotide for treatment of severe chronic pain.

Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G
Pharmacological management of severe chronic pain is difficult to achieve with currently available analgesic drugs, and remains a large unmet therapeutic need. The synthetic peptide ziconotide has been approved by the US Food and Drug Administration and the European Medicines Agency for intrathecal treatment of patients with severe chronic pain that is refractory to other treatment modalities. Ziconotide is the first member in the new drug class of selective N-type voltage-sensitive calcium-channel blockers. The ziconotide-induced blockade of N-type calcium channels in the spinal cord inhibits release of pain-relevant neurotransmitters from central terminals of primary afferent neurons. By this mechanism, ziconotide can effectively reduce pain. However, ziconotide has a narrow therapeutic window because of substantial CNS side-effects, and thus treatment with ziconotide is appropriate for only a small subset of patients with severe chronic pain. We provide an overview of the benefits and limitations of intrathecal ziconotide treatment and review potential future developments in this new drug class.

Lancet: 23 Apr 2010; epub ahead of print
Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G
Lancet: 23 Apr 2010; epub ahead of print | PMID: 20413151
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Abstract

Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial.

Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, ... Mehran R, on behalf of the HORIZONS-AMI Trial Investigators
Background: Primary results of the HORIZONS-AMI trial have been previously reported. In this final report, we aimed to assess 3-year outcomes. Methods: HORIZONS-AMI was a prospective, open-label, randomised trial undertaken at 123 institutions in 11 countries. Patients aged 18 years or older were eligible for enrolment if they had ST-segment elevation myocardial infarction (STEMI), presented within 12 h after onset of symptoms, and were undergoing primary percutaneous coronary intervention. By use of a computerised interactive voice response system, we randomly allocated patients 1:1 to receive bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI; pharmacological randomisation; stratified by previous and expected drug use and study site) and, if eligible, randomly allocated 3:1 to receive a paclitaxel-eluting stent or a bare metal stent (stent randomisation; stratified by pharmacological group assignment, diabetes mellitus status, lesion length, and study site). We produced Kaplan-Meier estimates of major adverse cardiovascular events at 3 years by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00433966. Findings: Compared with 1802 patients allocated to receive heparin plus a GPI, 1800 patients allocated to bivalirudin monotherapy had lower rates of all-cause mortality (5·9%vs 7·7%, difference -1·9% [-3·5 to -0·2], HR 0·75 [0·58-0·97]; p=0·03), cardiac mortality (2·9%vs 5·1%, -2·2% [-3·5 to -0·9], 0·56 [0·40-0·80]; p=0·001), reinfarction (6·2%vs 8·2%, -1·9% [-3·7 to -0·2], 0·76 [0·59-0·99]; p=0·04), and major bleeding not related to bypass graft surgery (6·9%vs 10·5%, -3·6% [-5·5 to -1·7], 0·64 [0·51-0·80]; p=0·0001) at 3 years, with no significant differences in ischaemia-driven target vessel revascularisation, stent thrombosis, or composite adverse events. Compared with 749 patients who received a bare-metal stent, 2257 patients who received a paclitaxel-eluting stent had lower rates of ischaemia-driven target lesion revascularisation (9·4%vs 15·1%, -5·7% [-8·6 to -2·7], 0·60 [0·48-0·76]; p<0·0001) after 3 years, with no significant differences in the rates of death, reinfarction, stroke or stent thrombosis. Stent thrombosis was high (≥4·5%) in both groups. Interpretation: The effectiveness and safety of bivalirudin monotherapy and paclitaxel-eluting stenting are sustained at 3 years for patients with STEMI undergoing primary percutaneous coronary intervention. Funding: Boston Scientific and The Medicines Company.

Lancet: 13 Jun 2011; epub ahead of print
Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, ... Mehran R, on behalf of the HORIZONS-AMI Trial Investigators
Lancet: 13 Jun 2011; epub ahead of print | PMID: 21665265
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Abstract

The heart and vascular system in dialysis.

Wanner C, Amann K, Shoji T
The heart and the vascular tree undergo major structural and functional changes when kidney function declines and renal replacement therapy is required. The many cardiovascular risk factors and adaptive changes the heart undergoes include left ventricular hypertrophy and dilatation with concomitant systolic and diastolic dysfunction. Myocardial fibrosis is the consequence of impaired angio-adaptation, reduced capillary angiogenesis, myocyte-capillary mismatch, and myocardial micro-arteriopathy. The vascular tree can be affected by both atherosclerosis and arteriosclerosis with both lipid rich plaques and abundant media calcification. Development of cardiac and vascular disease is rapid, especially in young patients, and the phenotype resembles all aspects of an accelerated ageing process and latent cardiac failure. The major cause of left ventricular hypertrophy and failure and the most common problem directly affecting myocardial function is fluid overload and, usually, hypertension. In situations of stress, such as intradialytic hypotension and hypoxaemia, the hearts of these patients are more vulnerable to developing cardiac arrest, especially when such episodes occur frequently. As a result, cardiac and vascular mortality are several times higher in dialysis patients than in the general population. Trials investigating one pharmacological intervention (eg, statins) have shown limitations. Pragmatic designs for large trials on cardio-active interventions are mandatory for adequate cardioprotective renal replacement therapy.

Lancet: 25 May 2016; epub ahead of print
Wanner C, Amann K, Shoji T
Lancet: 25 May 2016; epub ahead of print | PMID: 27226133
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Abstract

Sepsis and septic shock.

Cecconi M, Evans L, Levy M, Rhodes A
Sepsis is a common condition that is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity. Increased awareness of the condition resulting from ongoing campaigns and the evidence arising from research in the past 10 years have increased understanding of this problem among clinicians and lay people, and have led to improved outcomes. The World Health Assembly and WHO made sepsis a global health priority in 2017 and have adopted a resolution to improve the prevention, diagnosis, and management of sepsis. In 2016, a new definition of sepsis (Sepsis-3) was developed. Sepsis is now defined as infection with organ dysfunction. This definition codifies organ dysfunction using the Sequential Organ Failure Assessment score. Ongoing research aims to improve definition of patient populations to allow for individualised management strategies matched to a patient\'s molecular and biochemical profile. The search continues for improved diagnostic techniques that can facilitate this aim, and for a pharmacological agent that can improve outcomes by modifying the disease process. While waiting for this goal to be achieved, improved basic care driven by education and quality-improvement programmes offers the best hope of increasing favourable outcomes.

Lancet: 20 Jun 2018; epub ahead of print
Cecconi M, Evans L, Levy M, Rhodes A
Lancet: 20 Jun 2018; epub ahead of print | PMID: 29937192
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Abstract

Hypertension.

Poulter NR, Prabhakaran D, Caulfield M
Raised blood pressure is the biggest single contributor to the global burden of disease and to global mortality. The numbers of people affected and the prevalence of high blood pressure worldwide are expected to increase over the next decade. Preventive strategies are therefore urgently needed, especially in less developed countries, and management of hypertension must be optimised. Genetic advances in some rare causes of hypertension have been made lately, but the aggregate effect on blood pressure of all the genetic loci identified to date is small. Hence, intervention on key environmental determinants and effective implementation of trial-based therapies are needed. Three-drug combinations can control hypertension in about 90% of patients but only if resources allow identification of patients and drug delivery is affordable. Furthermore, assessment of optimal drug therapy for each ethnic group is needed.

Lancet: 01 Apr 2015; epub ahead of print
Poulter NR, Prabhakaran D, Caulfield M
Lancet: 01 Apr 2015; epub ahead of print | PMID: 25832858
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Abstract

Ventricular septal defect.

Penny DJ, Vick GW
Ventricular septal defects account for up to 40% of all congenital cardiac malformations. The diagnosis encompasses a broad range of anomalies, including isolated defects and those associated with other congenital cardiac malformations. Presentation, symptoms, natural history, and management of ventricular septal defects depend on size and anatomical associations of the anomaly, patient\'s age, and local diagnostic and interventional expertise. In this Seminar, we describe the anatomical range of ventricular septal defects and discuss present management of these malformations. Genetic determinants, diagnostic techniques, physiological considerations, and management challenges are examined in detail. Unfortunately, in many circumstances, evidence on which to guide optimum management is scarce. We present some longer term considerations of ventricular septal defects in adolescents and adults, with particular emphasis on patients with raised pulmonary vascular resistance and Eisenmenger\'s syndrome.

Lancet: 25 Feb 2011; epub ahead of print
Penny DJ, Vick GW
Lancet: 25 Feb 2011; epub ahead of print | PMID: 21349577
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Abstract

Porphyrias.

Puy H, Gouya L, Deybach JC
Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants.

Lancet: 15 Mar 2010; 375:924-37
Puy H, Gouya L, Deybach JC
Lancet: 15 Mar 2010; 375:924-37 | PMID: 20226990
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This program is still in alpha version.