Showing papers by "St Thomas' Hospital published in 2015"

European Society of Contact Dermatitis guideline for diagnostic patch testing – recommendations on best practice

Abstract: The present guideline summarizes all aspects of patch testing for the diagnosis of contact allergy in patients suspected of suffering, or having been suffering, from allergic contact dermatitis or other delayed-type hypersensitivity skin and mucosal conditions. Sections with brief descriptions and discussions of different pertinent topics are followed by a highlighted short practical recommendation. Topics comprise, after an introduction with important definitions, materials, technique, modifications of epicutaneous testing, individual factors influencing the patch test outcome or necessitating special considerations, children, patients with occupational contact dermatitis and drug eruptions as special groups, patch testing of materials brought in by the patient, adverse effects of patch testing, and the final evaluation and patient counselling based on this judgement. Finally, short reference is made to aspects of (continuing) medical education and to electronic collection of data for epidemiological surveillance.

The role of inflammation in perinatal brain injury

Abstract: Neuroinflammation during critical phases of brain development can increase the risk of neurological and neuropsychiatric disorders, even in adulthood. In this Review, Hagberg et al. review the mechanisms through which inflammation can exacerbate perinatal brain injury, and outline how understanding the interplay between inflammation and brain injury can aid the identification of new strategies to alleviate neurological and neuropsychiatric morbidity. Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development. Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity. Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals.

Normal values for cardiovascular magnetic resonance in adults and children

Abstract: Morphological and functional parameters such as chamber size and function, aortic diameters and distensibility, flow and T1 and T2* relaxation time can be assessed and quantified by cardiovascular magnetic resonance (CMR). Knowledge of normal values for quantitative CMR is crucial to interpretation of results and to distinguish normal from disease. In this review, we present normal reference values for morphological and functional CMR parameters of the cardiovascular system based on the peer-reviewed literature and current CMR techniques and sequences.

British Thoracic Society guidelines for the investigation and management of pulmonary nodules: accredited by NICE

Abstract: This guideline is based on a comprehensive review of the literature on pulmonary nodules and expert opinion. Although the management pathway for the majority of nodules detected is straightforward it is sometimes more complex and this is helped by the inclusion of detailed and specific recommendations and the 4 management algorithms below. The Guideline Development Group (GDG) wanted to highlight the new research evidence which has led to significant changes in management recommendations from previously published guidelines. These include the use of two malignancy prediction calculators (section ‘Initial assessment of the probability of malignancy in pulmonary nodules’, algorithm 1) to better characterise risk of malignancy. There are recommendations for a higher nodule size threshold for follow-up (≥5 mm or ≥80 mm3) and a reduction of the follow-up period to 1 year for solid pulmonary nodules; both of these will reduce the number of follow-up CT scans (sections ‘Initial assessment of the probability of malignancy in pulmonary nodules’ and ‘Imaging follow-up’, algorithms 1 and 2). Volumetry is recommended as the preferred measurement method and there are recommendations for the management of nodules with extended volume doubling times (section ‘Imaging follow-up’, algorithm 2). Acknowledging the good prognosis of sub-solid nodules (SSNs), there are recommendations for less aggressive options for their management (section ‘Management of SSNs’, algorithm 3). The guidelines provide more clarity in the use of further imaging, with ordinal scale reporting for PET-CT recommended to facilitate incorporation into risk models (section ‘Further imaging in management of pulmonary nodules’) and more clarity about the place of biopsy (section ‘Non-imaging tests and non-surgical biopsy’, algorithm 4). There are recommendations for the threshold for treatment without histological confirmation (sections ‘Surgical excision biopsy’ and ‘Non-surgical treatment without pathological confirmation of malignancy’, algorithm 4). Finally, and possibly most importantly, there are evidence-based recommendations about the information that people …

EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome

Abstract: Objectives Develop recommendations for women9s health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). Methods Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. Results Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. Conclusions Recommendations for women9s health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

European S3‐Guidelines on the systemic treatment of psoriasis vulgaris – Update 2015 – Short version – EDF in cooperation with EADV and IPC

Abstract: European S3-Guidelines on the systemic treatment of psoriasis vulgaris – Update 2015 – Short version – EDF in cooperation with EADV and IPC A. Nast,* P. Gisondi, A.D. Ormerod, P. Saiag, C. Smith, P.I. Spuls, P. Arenberger, H. Bachelez, J. Barker, E. Dauden, E.M. de Jong, E. Feist, A. Jacobs, R. Jobling, L. Kem eny, M. Maccarone, U. Mrowietz, K.A. Papp, C. Paul, K. Reich, S. Rosumeck, T. Talme, H.B. Thio, P. van de Kerkhof, R.N. Werner, N. Yawalkar Division of Evidence Based Medicine, Department of Dermatology, Charit e – Universit€ atsmedizin Berlin, Berlin, Germany Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, UK Service de Dermatologie, Hôpital Ambroise Par e Universit e Paris V, Boulogne, France Clinical Lead for Dermatology, St Johns Institute of Dermatology, St Thomas’ Hospital, London, UK Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands Third Faculty of Medicine, Department of Dermatology, Charles University, Prague, Czech Republic Department of Dermatology, Hôpital Saint-Louis, Paris, France St. Johns Institute of Dermatology, St. Thomas’ Hospital, London, UK Hospital Universitario de la Princesa, Madrid, Spain University Medical Center Nijmegen St Radboud, Nijmegen, The Netherlands Medizinische Klinik mit Schwerpunkt Rheumatologie u. klinische Immonologie, Charit e – Universit€atsmedizin Berlin, Berlin, Germany Cambridge, UK SZTE Borgyogyaszati Klinika, Szeged, Hungary Roma, Italy Department of Dermatology, Psoriasis-Center University Medical Center Schleswig Holstein, Kiel, Germany Waterloo, Canada Department of Dermatology, Paul Sabatier University, Toulouse, France Dermatologikum Hamburg, Hamburg, Germany Section of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden Department of Dermatology, Erasmus University, Rotterdam, The Netherlands Department of Dermatology, University Hospital Nijmegen, Nijmegen, The Netherlands Department of Dermatology, Inselspital, Universit€ atsklinik f€ ur Dermatologie, Bern, Switzerland *Correspondence: A. Nast. E-mail: alexander.nast@charite.de Received: 22 June 2015; Accepted: 7 July 2015

Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial

Abstract: Summary Background Four previously published randomised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up. We report the long-term follow-up of the IBIS-I trial, in which the participants and investigators remain largely masked to treatment allocation. Methods In the IBIS-I randomised controlled trial, premenopausal and postmenopausal women 35–70 years of age deemed to be at an increased risk of developing breast cancer were randomly assigned (1:1) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years. Patients were randomly assigned to the two treatment groups by telephone or fax according to a block randomisation schedule (permuted block sizes of six or ten). Patients and investigators were masked to treatment assignment by use of central randomisation and coded drug supply. The primary endpoint was the occurrence of breast cancer (invasive breast cancer and ductal carcinoma in situ), analysed by intention to treat. Cox proportional hazard models were used to assess breast cancer occurrence and mortality. The trial is closed to recruitment and active treatment is completed, but long-term follow-up is ongoing. This trial is registered with controlledtrials.com, number ISRCTN91879928. Findings Between April 14, 1992, and March 30, 2001, 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were randomly allocated to the two treatment groups: 3579 to tamoxifen and 3575 to placebo. After a median follow up of 16·0 years (IQR 14·1–17·6), 601 breast cancers have been reported (251 [7·0%] in 3579 patients in the tamoxifen group vs 350 [9·8%] in 3575 women in the placebo group; hazard ratio [HR] 0·71 [95% CI 0·60–0·83], p vs 163 [4·6%] in 3579 women in the tamoxifen group; hazard ratio [HR] 0·72 [95% CI 0·59–0·88], p=0·001) and after 10 years (124 [3·8%] in 3295 women vs 88 [2·6%] in 3343, respectively; HR 0·69 [0·53–0·91], p=0·009). The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer (HR 0·66 [95% CI 0·54–0·81], p Interpretation These results show that tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention. Funding Cancer Research UK (UK) and the National Health and Medical Research Council (Australia).

Prevalence of refractive error in Europe: the European Eye Epidemiology (E(3)) Consortium

Abstract: To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E(3)) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia ≤-0.75 diopters (D), high myopia ≤-6D, hyperopia ≥1D and astigmatism ≥1D. Meta-analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those ≥25 and <90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4-30.9], high myopia 2.7 % (95 % CI 2.69-2.73), hyperopia 25.2 % (95 % CI 25.0-25.4) and astigmatism 23.9 % (95 % CI 23.7-24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8-52.5) in 25-29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe.

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data

Abstract: Summary Background The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD ( DPYD ), including DPYD *2A and c.2846A>T. Three other variants— DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A—have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. Methods We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). Findings 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08–9·30, p A/HapB3 (1·59, 1·29–1·97, p A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86–2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40–23·33, p=0·015; and 2·04, 1·49–2·78, p DPYD *2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75–4·62, p Interpretation DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD *2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. Funding None.

Population genetic differentiation of height and body mass index across Europe

Abstract: Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10(-8); BMI, P < 5.95 × 10(-4)), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria

Abstract: Background:Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts m...

The Impact of Comprehensive Geriatric Assessment Interventions on Tolerance to Chemotherapy in Older People

Abstract: Background Although comorbidities are identified in routine oncology practice, intervention plans for the coexisting needs of older people receiving chemotherapy are rarely made. This study evaluates the impact of geriatrician-delivered comprehensive geriatric assessment (CGA) interventions on chemotherapy toxicity and tolerance for older people with cancer. Methods Comparative study of two cohorts of older patients (aged 70+ years) undergoing chemotherapy in a London Hospital. The observational control group (N=70, October 2010-July 2012) received standard oncology care. The intervention group (N=65, September 2011-February 2013) underwent risk stratification using a patient-completed screening questionnaire and high-risk patients received CGA. Impact of CGA interventions on chemotherapy tolerance outcomes and grade 3+ toxicity rate were evaluated. Outcomes were adjusted for age, comorbidity, metastatic disease and initial dose reductions. Results Intervention participants undergoing CGA received mean of 6.2±2.6 (range 0-15) CGA intervention plans each. They were more likely to complete cancer treatment as planned (odds ratio (OR) 4.14 (95% CI: 1.50-11.42), P=0.006) and fewer required treatment modifications (OR 0.34 (95% CI: 0.16-0.73), P=0.006). Overall grade 3+ toxicity rate was 43.8% in the intervention group and 52.9% in the control (P=0.292). Conclusions Geriatrician-led CGA interventions were associated with improved chemotherapy tolerance. Standard oncology care should shift towards modifying coexisting conditions to optimise chemotherapy outcomes for older people.

A practical guideline for the haematological management of major haemorrhage.

Abstract: The aim of this guideline is to provide recommendations for the haematological management of major haemorrhage in any clinical situation, with practical guidance for Clinical Haematologists and laboratory staff on the content and delivery of major bleeding protocols, including the use of blood components and transfusion alternatives. Management of major haemorrhage in any setting requires a multidisciplinary approach. There have been advances in techniques for resuscitation as well as surgical, radiological and endoscopy interventions, to control bleeding alongside critical care support, but these are beyond the scope of this document. These updated guidelines are based on new studies, which have provoked reassessment of the principles of managing major haemorrhage in all clinical situations, and which mandate much closer working between hospital blood banks and emergency departments to provide timely transfusion support for patients with major bleeding. Alongside changes in the use of blood component therapy, the importance of antifibrinolytics has been demonstrated in the study by the Clinical Randomization of Antifibrinolytics in Significant Haemorrhage (CRASH-2) collaborators (2010). The recognition that tranexamic acid (TA) benefited not only those with massive haemorrhage but also the larger number of patients with, or at risk of, significant haemorrhage (i.e. not only those fulfilling the criteria for massive bleeding) has led to an expansion of our guidelines from massive to major haemorrhage so that we can include this group. Methods

The clinical spectrum of autoimmune congenital heart block

Abstract: Autoimmune congenital heart block is more likely to occur in the babies of women with rheumatic diseases, particularly women seropositive for anti-Ro or anti-La autoantibodies. Here, the authors provide advice for the management of these women and their babies in juxtaposition to a systematic assessment of the epidemiology and classification of the disease.

Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis

Abstract: Background—Evidence regarding the use of direct oral anticoagulants (DOACs) in the elderly, particularly bleeding risks, is unclear despite the presence of greater comorbidities, polypharmacy, and altered pharmacokinetics in this age group. Methods and Results—We performed a systematic review and meta-analysis of randomized trials of DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban) for efficacy and bleeding outcomes in comparison with vitamin K antagonists (VKA) in elderly participants (aged ≥75 years) treated for acute venous thromboembolism or stroke prevention in atrial fibrillation. Nineteen studies were eligible for inclusion, but only 11 reported data specifically for elderly participants. The efficacy in managing thrombotic risks for each DOAC was similar or superior to VKA in elderly patients. A nonsignificantly higher risk of major bleeding than with VKA was observed with dabigatran 150 mg (odds ratio, 1.18; 95% confidence interval, 0.97–1.44) but not with the 110-mg dose. Significantly hi...

Risk factors and effective management of preeclampsia

Abstract: Preeclampsia, a hypertensive disorder of pregnancy is estimated to complicate 2%-8% of pregnancies and remains a principal cause of maternal and fetal morbidity and mortality. Preeclampsia may present at any gestation but is more commonly encountered in the third trimester. Multiple risk factors have been documented, including: family history, nulliparity, egg donation, diabetes, and obesity. Significant progress has been made in developing tests to predict risk of preeclampsia in pregnancy, but these remain confined to clinical trial settings and center around measuring angiogenic profiles, including placental growth factor or newer tests involving metabolomics. Less progress has been made in developing new treatments and therapeutic targets, and aspirin remains one of the few agents shown to consistently reduce the risk of developing preeclampsia. This review serves to discuss recent advances in risk factor identification, prediction techniques, and management of preeclampsia in antenatal, intrapartum, and postnatal patients.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation

Abstract: Background The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

Abstract: Background The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood.

Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial

Abstract: Summary Background Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. Methods In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. Findings Median treatment duration was 16·6 months (IQR 10·1–21·1) in the enzalutamide group and 4·6 months (2·8–9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1–13·9) in the enzalutamide group and 5·6 months (5·5–5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54–0·72]; p vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p vs 257 [42%] of 610; p vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5–not reached) and 31·3 months (95% CI 23·9–not reached) in the placebo group (HR 0·72 [95% CI 0·61–0·84]; p Interpretation In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Funding Astellas Pharma and Medivation.

Na+/Ca2+ exchange and Na+/K+-ATPase in the heart.

Abstract: This paper is the third in a series of reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na(+) channel and Na(+) transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on cardiac Na(+)/Ca(2+) exchange (NCX) and Na(+)/K(+)-ATPase (NKA). While the relevance of Ca(2+) homeostasis in cardiac function has been extensively investigated, the role of Na(+) regulation in shaping heart function is often overlooked. Small changes in the cytoplasmic Na(+) content have multiple effects on the heart by influencing intracellular Ca(2+) and pH levels thereby modulating heart contractility. Therefore it is essential for heart cells to maintain Na(+) homeostasis. Among the proteins that accomplish this task are the Na(+)/Ca(2+) exchanger (NCX) and the Na(+)/K(+) pump (NKA). By transporting three Na(+) ions into the cytoplasm in exchange for one Ca(2+) moved out, NCX is one of the main Na(+) influx mechanisms in cardiomyocytes. Acting in the opposite direction, NKA moves Na(+) ions from the cytoplasm to the extracellular space against their gradient by utilizing the energy released from ATP hydrolysis. A fine balance between these two processes controls the net amount of intracellular Na(+) and aberrations in either of these two systems can have a large impact on cardiac contractility. Due to the relevant role of these two proteins in Na(+) homeostasis, the emphasis of this review is on recent developments regarding the cardiac Na(+)/Ca(2+) exchanger (NCX1) and Na(+)/K(+) pump and the controversies that still persist in the field.