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Sarcomatoid renal cell carcinoma (sRCC) is a rare variant of renal cell carcinoma (RCC) and is associated with a poor prognosis. We reviewed the outcomes of patients from oncology centers in Turkey. Our aim is to share our real-life experience and to contribute to the literature. The demographic and clinical features, treatment, and survival outcomes of 148 patients with sRCC were analyzed. The median age at the time of diagnosis was 58 years (range: 19-83 years). Most patients (62.8%) had clear-cell histology. Most patients were in the intermediate Memorial Sloan-Kettering Cancer Center (MSKCC) risk group (67.6%) and were stage 4 at the time of diagnosis (63.5%). The most common sites of metastasis were the lung (60.1%), lymph nodes (47.3%), and bone (35.8%). The patients received a median of two lines (range: 0-6) of treatment. The most common side effects were fatigue, hematological side effects, hypertension, and hypothyroidism. The median follow-up was 20.9 months (range: 1-162 months). The median overall survival (OS) was 30.8 months (95% confidence interval: 24.9-36.7 months). In multivariate analysis, high MSKCC scores, sarcomatoid differentiation rates >50%, having stage 4 disease, and having lung metastasis at the time of diagnosis were independent factors for poor prognosis affecting OS. No difference was observed between patients who received tyrosine kinase inhibitor (TKI) as the first or second-line treatments. Similarly, no difference between TKI and immunotherapy as the second-line treatment. In conclusion, sRCC is a rare variant of RCC with a poor prognosis and response to treatment. Larger-scale prospective studies are needed to define an optimal treatment approach for longer survival in this aggressive variant.

Introduction The human population is aging at an astonishing rate. The aim of this study is to capture a situation snapshot revealing the proportion of individuals aged 65 years and over among inpatients in healthcare institutions in Turkey and the prevalence and type of infections in this patient group in order to draw a road map. Materials and Methods Hospitalized patients over 65 years at any of the 62 hospitals in 29 cities across Turkey on February 9, 2017 were included in the study. Web-based SurveyMonkey was used for data recording and evaluation system. Results Of 17,351 patients 5871 (33.8%) were ≥65 years old. The mean age was 75.1 ± 7.2 years; 3075 (52.4%) patients were male. Infection was reason for admission for 1556 (26.5%) patients. Pneumonia was the most common infection. The median length of hospital stay was 5 days (IQR: 2–11 days). The Antibiotic therapy was initiated for 2917 (49.7%) patients at the time of admission, and 23% of the antibiotics prescribed were inappropriate. Healthcare-associated infections developed in 1059 (18%) patients. Urinary catheters were placed in 2388 (40.7%) patients with 7.5% invalid indication. Conclusion This study used real data to reveal the proportion of elderly patients in hospital admissions. The interventions done, infections developed during hospitalization, length of hospital stay, and excessive drug load emphasize the significant impact on health costs and illustrate the importance of preventive medicine in this group of patients.

Consortia for the ALBINO Study Group: Axel R. Franz, Mario Rüdiger, Christian F. Poets, Manon Benders, Frank van Bel, Karel Allegaert, Gunnar Naulaers, Dirk Bassler, Katrin Klebermaß-Schrehof, Maximo Vento, Hercilia Guimarães, Tom Stiris, Luigi Cattarossi, Marjo Metsäranta, Sampsa Vanhatalo, Jan Mazela, Tuuli Metsvaht, Cees van Veldhuizen, Corinna Engel, Christian A. Maiwald, Gabriele von Oldershausen, Iris Bergmann, Monika Weiss, Caroline J. B. R. Wichera, Andreas Eichhorn, Michael Raubuch, Birgit Schuler, Cees K. W. van Veldhuizen, Bas Laméris, Yannique Jacobs, Roselinda van der Vlught-Meijer, Elke Griesmaier, Johannes Brandner, Marie Tackoen, Ruth Reibel, Chantal Lecart, Luc Cornette, Genevieve Malfilatre, Renaud Viellevoye, Tuuli Metsvaht, Mari-Liis Ilmoja, Pille Saik, Ruth Käär, Pille Andresson, Marjo Metsaranta, Axel R. Franz, Rolf Schloesser, Torsten Ott, Stefan Winkler, Thomas Hoehn, Norbert Teig, Michael Schroth, Ulrich H. Thome, Harald Ehrhardt, Luigi Cattarossi, Isabella Mauro, Eugenio Baraldi, Virgilio Carnielli, Giuseppe Paterlini, Marcello Napolitano, Paola Francesca Faldini, Gianluca Lista, Gianluca Visintin, Mario Barbarini, Laura Pagani, Emmanuele Mastretta, Giovanni Vento, Monica Fumagalli, Marco Binotti, Mirjam M. van Weissenbruch, Henrica L. M. van Straaten, Manon J. N. L. Benders, Kim V. Annink, Frank van Bel, Jeroen Dudink, Jan B. Derks, Inge P. de Boer, Clemens B. Meijssen, Timo R. de Haan, Linda G. van Rooij, Jacqueline L. van Hillegersberg, Minouche van Dongen, Jos Bruinenberg, Koen P. Dijkman, Marlies A. van Houten, Sophie R. D. van der Schoor, Tom Stiris, Bodil Salvesen, Moritz Schneider, Eirik Nestaas, Britt Nakstad, Jan Mazela, Lukas Karpinski, Ewa Gulczynska, Barbara Królak-Olejnik, Renata Bokiniec, Ana I. Vilan, Liliana Flores de Pinho, Claudia Ferraz, Almerinda Pereira, Rosalina Barroso, André Mendes da Graça, Teresa Tomé, Filomena Pinto, Maximo Vento, Juan Martínez Rodilla, Simón Lubián, Marta Campubri Camprubí, José Antonio Hurtado Suazo, Eva Valverde, José Ramón Fernández Lorenzo, José Martinez Orgado, Héctor Boix, Francisco Jimenez Parrilla, Maria Teresa Moral-Pumarega, Julia Maletzki, Claudia Knoepfli, Cornelia Hagmann, Sven Schulzke, Martin Stocker, André Birkenmaier, Thomas Riedel, Hans-Jörg Ehni, Annie Janvier & Georg Marckmann., [Background]: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia., [Methods]: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion., [Discussion]: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia., [Trial registration]: NCT03162653, www.ClinicalTrials.gov, May 22, 2017., This study is funded under the Horizon 2020 Framework Program of the European Union, call H2020-PHC-2015-two-stage, grant 667224. Publication of this manuscript was supported by Deutsche Forschungsgemeinschaft and the Open Access Publishing Fund of the University of Tuebingen.

BACKGROUND: Among adults undergoing contemporary noncardiac surgery, little is known about the frequency and timing of death and the associations between perioperative complications and mortality. We aimed to establish the frequency and timing of death and its association with perioperative complications. METHODS: We conducted a prospective cohort study of patients aged 45 years and older who underwent inpatient noncardiac surgery at 28 centres in 14 countries. We monitored patients for complications until 30 days after surgery and determined the relation between these complications and 30-day mortality using a Cox proportional hazards model. RESULTS: We included 40 004 patients. Of those, 715 patients (1.8%) died within 30 days of surgery. Five deaths (0.7%) occurred in the operating room, 500 deaths (69.9%) occurred after surgery during the index admission to hospital and 210 deaths (29.4%) occurred after discharge from the hospital. Eight complications were independently associated with 30-day mortality. The 3 complications with the largest attributable fractions (AF; i.e., potential proportion of deaths attributable to these complications) were major bleeding (6238 patients, 15.6%; adjusted hazard ratio [HR] 2.6, 95% confidence interval [CI] 2.2–3.1; AF 17.0%); myocardial injury after noncardiac surgery [MINS] (5191 patients, 13.0%; adjusted HR 2.2, 95% CI 1.9–2.6; AF 15.9%); and sepsis (1783 patients, 4.5%; adjusted HR 5.6, 95% CI 4.6–6.8; AF 12.0%). INTERPRETATION: Among adults undergoing noncardiac surgery, 99.3% of deaths occurred after the procedure and 44.9% of deaths were associated with 3 complications: major bleeding, MINS and sepsis. Given these findings, focusing on the prevention, early identification and management of these 3 complications holds promise for reducing perioperative mortality. Study registration:ClinicalTrials.gov, no. NCT00512109.

Background Either benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America. Methods The goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20–65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12–18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ≥ 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ≥ 25% with NFX to claim its trypanocidal effect, 60–80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80–90% power; one-sided alpha level 1%). Discussion The EQUITY trial will inform the trypanocidal effect and equivalence of nitroderivative agents NFX and BZN, particularly outside southern cone countries. Its results may challenge current recommendations and inform choices for these agents. Trial registration ClinicalTrials.gov, NCT02369978. Registered on 24 February 2015. Electronic supplementary material The online version of this article (10.1186/s13063-019-3423-3) contains supplementary material, which is available to authorized users.

Purpose: The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury. Methods: We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume. Results: Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01–1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02–1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07–3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT. Conclusions: Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241). © 2018, The Author(s).

Reference intervals (RIs) are fundamental tools used by healthcare and laboratory professionals to interpret patient laboratory test results, ideally enabling differentiation of healthy and unhealthy individuals. Under optimal conditions, a laboratory should perform its own RI study to establish RIs specific for its method and local population. However, the process of developing RIs is often beyond the capabilities of an individual laboratory due to the complex, expensive and time-consuming process to develop them. Therefore, a laboratory can alternatively verify RIs established by an external source. Common RIs can be established by large, multicenter studies and can subsequently be received by local laboratories using various verification procedures. The standard approach to verify RIs recommended by the Clinical Laboratory Standards Institute (CLSI) EP28-A3c guideline for routine clinical laboratories is to collect and analyze a minimum of 20 samples from healthy subjects from the local population. Alternatively, “data mining” techniques using large amounts of patient test results can be used to verify RIs, considering both the laboratory method and local population. Although procedures for verifying RIs in the literature and guidelines are clear in theory, gaps remain for the implementation of these procedures in routine clinical laboratories. Pediatric and geriatric age-groups also continue to pose additional challenges in respect of acquiring and verifying RIs. In this article, we review the current guidelines/approaches and challenges to RI verification and provide a practical guide for routine implementation in clinical laboratories.

PurposeTo compare the functional and anatomical outcomes of eyes with chronic central serous chorioretinopathy treated with yellow micropulse (MP) laser versus half-dose verteporfin photodynamic therapy (PDT).MethodsThis is a multicentre, retrospective comparative study of 92 eyes treated with yellow MP laser (duty cycle of 5%, zero spacing between spots, spot size varied from 100 to 200 µm, power varied from 320 to 660 mW, and the pulse burst duration was 200 ms) and 67 eyes treated with PDT (half-dose verteporfin (3 mg/m2) infused over 10 min), followed by laser activation for 83 s. Spot sizes varied from 400 to 2000 µm.ResultsIn the MP group, at 12 months of follow-up, the mean best corrected visual acuity (BCVA) improved from the logarithm of the minimum angle of resolution (logMAR) of 0.41±0.27 at baseline to 0.21±0.26 (PConclusionsBoth PDT and MP are effective in restoring the macular anatomy. In places where PDT is not available, yellow MP laser may be an adequate treatment alternative.

Chronic hyperglycaemia and glucose variability are associated with the development of chronic diabetes-related complications. We conducted a pooled analysis of patient-level data from three 24-week, randomized, phase III clinical trials to evaluate the impact of lixisenatide (LIXI) on glycaemic variability (GV) vs placebo as add-on to basal insulin. The main outcome GV measures were standard deviation (s.d.), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG) level, area under the curve for fasting glucose (AUC-F), and high (HBGI) and low blood glucose index (LBGI). The change in GV metrics over 24 weeks and relationships among baseline GV, patient characteristics and outcomes were assessed. Data were pooled from 1198 patients (665 LIXI, 533 placebo). Values for s.d., MAG level, MAGE, HBGI, and AUC-F significantly decreased with LIXI vs placebo, while LBGI values were unchanged. Higher baseline GV measures correlated with older age, longer type 2 diabetes duration, lower body mass index, higher baseline glycated/haemogobin, greater reduction in postprandial glucose (PPG) level, and higher rates of symptomatic hypoglycaemia. These data show that LIXI added to basal insulin significantly reduced GV and PPG excursions vs placebo, without increasing the risk of hypoglycaemia (LBGI). © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley and Sons Ltd.

Purpose: To review the available knowledge related to the use of ECCO2R as adjuvant strategy to mechanical ventilation (MV) in various clinical settings of acute respiratory failure (ARF). Methods: Expert opinion and review of the literature. Results: ECCO2R may be a promising adjuvant therapeutic strategy for the management of patients with severe exacerbations of COPD and for the achievement of protective or ultra-protective ventilation in patients with ARDS without life-threatening hypoxemia. Given the observational nature of most of the available clinical data and differences in technical features and performances of current devices, the balance of risks and benefits for or against ECCO2R in such patient populations remains unclear Conclusions: ECCO2R is currently an experimental technique rather than an accepted therapeutic strategy in ARF—its safety and efficacy require confirmation in clinical trials. © 2017, Springer-Verlag Berlin Heidelberg and ESICM.

cited By 2; International audience; What is known and objective: The complex dose regimens of the direct-acting oral anticoagulants (DOAC) make their appropriate prescribing highly challenging. Inappropriate prescribing of the DOAC remains poorly addressed. We studied the patterns of DOAC prescription and estimated the prevalence of drug-related problems (DRPs) associated with their use. Methods: A cross-sectional study was conducted using data from medical records system of the Lyon teaching hospitals. DRPs, identified among patients who received a DOAC, between 1 January 2010 and 31 July 2013, were categorized according to the Pharmaceutical Care Network Europe Classification System. The prevalence of hospital stays with a DRP was estimated, and a subgroup analysis according to DOAC and their indication for use was provided. Clinical outcomes were not assessed. Results: Of the 4154 hospital stays with at least one DOAC administration [3412 patients; median age (range): 71 years (14–98), 57% female], 70·8% were excluded from the analysis mainly due to missing information for renal function and/or patient weight. Of the 1188 hospital stays that were screened, 100 DRPs were identified (prevalence 8·4%; 95% CI, 6·8–10·0). The highest prevalence was found among patients who received rivaroxaban for atrial fibrillation (14·6%; 95% CI, 10·7–18·5). A too low drug dose was the most frequent DRP (n = 56; 4·7%), followed by a too high drug dose (n = 37; 3·1%), contraindication (n = 5; 0·4%), and pharmacokinetic problem requiring dose adjustment (n = 2; 0·2%). What is new and conclusion: Drug-related problems associated with the DOACs occur quite commonly among hospitalized patients. Although these DRPs were considered to be of minor severity, prescribing protocols to support better prescribing should be disseminated to reduce the risk to patients. Renal function and body weight data should be mandatory on prescriptions to allow cross-checking. © 2016 John Wiley & Sons Ltd

"OBJECTIVE: To identify all interventions that increase or reduce mortality in patients with acute kidney injury (AKI) and to establish the agreement between stated beliefs and actual practice in this setting.. . DESIGN AND SETTING: Systematic literature review and international web-based survey.. . PARTICIPANTS: More than 300 physicians from 62 countries.. . INTERVENTIONS: Several databases, including MEDLINE/PubMed, were searched with no time limits (updated February 14, 2012) to identify all the drugs/techniques/strategies that fulfilled all the following criteria: (a) published in a peer-reviewed journal, (b) dealing with critically ill adult patients with or at risk for acute kidney injury, and (c) reporting a statistically significant reduction or increase in mortality.. . MEASUREMENTS AND MAIN RESULTS: Of the 18 identified interventions, 15 reduced mortality and 3 increased mortality. Perioperative hemodynamic optimization, albumin in cirrhotic patients, terlipressin for hepatorenal syndrome type 1, human immunoglobulin, peri-angiography hemofiltration, fenoldopam, plasma exchange in multiple-myeloma-associated AKI, increased intensity of renal replacement therapy (RRT), CVVH in severely burned patients, vasopressin in septic shock, furosemide by continuous infusion, citrate in continuous RRT, N-acetylcysteine, continuous and early RRT might reduce mortality in critically ill patients with or at risk for AKI; positive fluid balance, hydroxyethyl starch and loop diuretics might increase mortality in critically ill patients with or at risk for AKI. Web-based opinion differed from consensus opinion for 30% of interventions and self-reported practice for 3 interventions.. . CONCLUSION: The authors identified all interventions with at least 1 study suggesting a significant effect on mortality in patients with or at risk of AKI and found that there is discordance between participant stated beliefs and actual practice regarding these topics.. . "

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:28:21Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:42:48Z : No. of bitstreams: 1 2-s2.0-84874907173.pdf: 495846 bytes, checksum: 189c6061fc03b14fb90ebe22cd2d8359 (MD5) Made available in DSpace on 2014-05-27T11:28:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-02-01 Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. Conclusions: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth. © 2013 by the authors; licensee MDPI, Basel, Switzerland. Department of Health Management and Policy University of Iowa, Iowa City, IA 52242 Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903 RTI International, Research Triangle Park, NC 27709 Hospital de Reabilitação de Anomalias Craniofaciais, Bauru, Sao Paulo 17.043-900 Department of Epidemiology and Biostatistics University of South Carolina, Columbia, SC 29208 Centro de Atendimento Integral ao Fissurado Lábio Palatal, Curitiba, Paraná 81.050-000 Instituto Materno Infantil Prof. Fernando Figueira-CADEFI/IMIP, Recife, Pernambuco 50070-550 Hospital Santo Antônio: Obras Sociais Irmã Dulce, Salvador, Bahia 40.415-000 Genetic Counseling Service São Paulo State University, Botucatu, Sao Paulo 18618-000 Department of Pediatrics University of Iowa, Iowa City, IA 52242 Genetic Counseling Service São Paulo State University, Botucatu, Sao Paulo 18618-000

OBJECTIVES: This study aimed to assess cost-effectiveness of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided versus symptom-guided therapy in heart failure (HF) patients ≥60 years old. BACKGROUND: Cost-effectiveness of NT-proBNP guidance in HF patients is unclear. It may create additional costs with uncertain benefits. METHODS: In the TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure), patients with left ventricular ejection fraction (LVEF) of ≤45% were randomized to receive intensified NT-proBNP-guided therapy or standard, symptom-guided therapy. For cost-effectiveness analysis, 467 (94%) patients (age 76 ± 7 years, 66% male) were eligible. Incremental cost-effectiveness was calculated as incremental costs per gained life-year and quality-adjusted life-year (QALY) within the 18-month trial period, as defined per protocol. RESULTS: NT-proBNP-guided therapy was dominant (i.e., more effective and less costly) over symptom-guided therapy, saving $2,979 USD (2.5 to 97.5% confidence interval [CI]: $8,758 to $3,265) per patient, with incremental effectiveness of +0.07 life-years and +0.05 QALYs. The probability of NT-proBNP-guided therapy being dominant was 80%, and the probability of saving 1 life-year or QALY at a cost of $50,000 was 97% and 93%, respectively. Exclusion of residence costs resulted in an incremental cost-effectiveness ratio (ICER) of $5,870 per life-year gained. Cost-effectiveness of NT-proBNP-guided therapy was most pronounced in patients

Background: In 2010, the EUPHAS 2 collaborative group created a registry with the purpose of recording data from critically ill patients suffering from severe sepsis and septic shock treated with polymyxin-B hemoperfusion (PMX-HP) for endotoxin removal. The aim of the registry was to verify the application of PMX-HP in the daily clinical practice. Methods: The EUPHAS 2 registry involved 57 centers between January 2010 and December 2014, collecting retrospective data of 357 patients (297 in Europe and 60 in Asia) suffering from severe sepsis and septic shock caused by proved or suspected infection related to Gram negative bacteria. All patients received atleast one cycle of extracorporeal endotoxin removal by PMX-HP. Results: Septic shock was diagnosed in 305 (85.4%) patients. The most common source of infection was abdominal (44.0%) followed by pulmonary (17.6%). Gram negative bacteria represented 60.6% of the pathogens responsible of infection. After 72h from the first cycle of PMX-HP, some of the SOFA score components significantly improved with respect to baseline: cardiovascular (2.16±1.77 from 3.32±1.29, p&nbsp

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome. © 2016, The Author(s).

This study aimed to perform an overview of how ultrasound (US) is being used, implemented, and applied in rheumatologic centers in Latin America (LA). A retrospective, multicenter 1-year experience study was undertaken. Eighteen centers from eight countries were involved. The following information were collected: demographic data, indication to perform an US examination, physician that required the examination, and the anatomical region required for the examination. A total of 7167 patients underwent an US examination. The request for US examinations came most frequently from their own institution (5981 (83.45 %)) than from external referral (1186 (16.55 %)). The services that more frequently requested an US examination were rheumatology 5154 (71.91 %), followed by orthopedic 1016 (14.18 %), and rehabilitation 375 (5.23 %). The most frequently scanned area was the shoulder in 1908 cases (26.62 %), followed by hand 1754 (24.47 %), knee 1518 (21.18 %), ankle 574 (8.01 %), and wrist 394 (5.50 %). Osteoarthritis was the most common disease assessed (2279 patients (31.8 %)), followed by rheumatoid arthritis (2125 patients (29.65 %)), psoriatic arthritis (869 patients (12.1 %)), painful shoulder syndrome (545 (7.6 %)), connective tissue disorders (systemic sclerosis 339 (4.7 %), polymyositis/dermatomyositis 107 (1.4 %), Sjögren’s syndrome 60 (0.8 %), and systemic lupus erythematosus 57 (0.8 %)). US evaluation was more frequently requested for diagnostic purposes (3981 (55.5 %)) compared to follow-up studies (2649 (36.9 %)), research protocols (339 (4.73 %)), and invasive guided procedures (198 (2.76 %)). US registered increasing applications in rheumatology and highlighted its positive impact in daily clinical practice. US increases the accuracy of the musculoskeletal clinical examination, influence the diagnosis, and the disease management. © 2016, International League of Associations for Rheumatology (ILAR).

ObjectivesFollowing up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case–control multi-ancestry population and tested functions of identified variants.MethodsWe performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA.ResultsWe confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10−8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10−3 and 6.8×10−8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=−0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10−5 and 2.0×10−4, respectively).ConclusionWe confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

International audience; Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment. © 2016 Bruder Costa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Purpose The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. Design Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients’ native residual vision compared with their vision with the Argus II. Participants Thirty participants in 10 centers in the United States and Europe. Methods The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. Main Outcome Measures The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. Results Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. Conclusions The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada. © 2016 American Academy of Ophthalmology

Objectives: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged- infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT≥MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of ≥ 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025]. Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Aim The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. Methods Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5mg kg-1 levamisole (or placebo) orally once every other day. One hundred and thirty-six plasma samples were collected from 38 children from India and Europe and included in the analysis. A one compartment model described the data well. Results The apparent clearance rate (CL/F) and distribution volume (V/F) were 44l h-1 70kg-1 and 236l 70kg-1, respectively; estimated interindividual variability was 32-42%. In addition to allometric scaling of CL/F and V/F to body weight, we identified a significant proportional effect of age on CL/F (-10.1% per year). The pharmacokinetics parameters were not affected by gender, tablet strength or study centre. The median (interquartile range) maximum plasma concentration of levamisole was 438.3 (316.5-621.8) ng ml-1, and the median area under the concentration-time curve was 2847 (2267-3761) ng ml-1 h. Median tmax and t1/2; values were 1.65 (1.32-2.0) h and 2.60 (2.06-3.65) h, respectively. Conclusions Here, we present the first pharmacokinetic data regarding levamisole in children with steroid-sensitive nephrotic syndrome. The pharmacokinetic profile of levamisole in children was similar to findings reported in adults, although the elimination rate was slightly higher in children.

Coronary angiography underestimates the magnitude of the atherosclerotic burden and cannot detect the presence of disease in the early phases. Recognition of these inherent limitations of angiography has been an impetus for the development of other coronary imaging techniques. The novel near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) catheters can detect and quantify the presence of lipid core in the atherosclerotic plaque and associate it with other features such as lumen size and plaque architecture. Lipid-rich plaques are known to pose a higher risk of distal embolization during interventions and plaque disruption. The aim of this manuscript is the review of the potential clinical and research applications of this technology as highlighted by recent studies. © 2015 The Author.

Introduction: A large proportion of the coumarin dose variability is explained by environmental factors and by common genetic variants in the VKORC1 and CYP2C9 genes. Genotype-guided coumarin dosing has been proposed for a more accurate prediction of the coumarin dose in order to reduce the incidence of coumarin-related complications.Areas covered: This review discusses the current state of coumarin pharmacogenetics, the evidence from recent randomized controlled trials and economic evaluations regarding the possible clinical implementation of genotype-guided coumarin dosing.Expert opinion: When the VKORC1 and CYP2C9 genotypes are available before the start of coumarin therapy in individuals of European ancestry, a genetic-guided algorithm should be used for dose determination. Ethnicity-specific pharmacogenetic algorithms should be tested in other populations. At this moment the evidence is not sufficient to support genotyping before coumarin therapy initiation. Based on results from recent randomized controlled trials, a clinical dosing algorithm could be considered in the initial phase of coumarin treatment. Current economic studies indicate that genotype-guided dosing could be cost-effective, but the clinical implementation of genetic-guided coumarin therapy will depend on the cost of pharmacogenetic tests and the availability of novel oral anticoagulants.

PubMedID: 25393847 In this multicenter retrospective analysis, we aimed to present clinical, laboratory and treatment results of 94 patients with Hairy cell leukemia diagnosed in 13 centers between 1990 and 2014. Sixty-six of the patients were males and 28 were females, with a median age of 55. Splenomegaly was present in 93.5% of cases at diagnosis. The laboratory findings that came into prominence were pancytopenia with grade 3 bone marrow fibrosis. Most of the patients with an indication for treatment were treated with cladribine as first-line treatment. Total and complete response of cladribine was 97.3% and 80.7%. The relapse rate after cladribine was 16.6%, and treatment related mortality was 2.5%. Most preferred therapy (95%) was again cladribine at second-line, and third line with CR rate of 68.4% and 66.6%, respectively. The 28-month median OS was 91.7% in all patients and 25-month median OS 96% for patients who were given cladribine as first-line therapy. In conclusion, the first multicenter retrospective Turkish study where patients with HCL were followed up for a long period has revealed demographic characteristics of patients with HCL, and confirmed that cladribine treatment might be safe and effective in a relatively large series of the Turkish study population. © 2015 John Wiley & Sons, Ltd.

Aims: We aimed to investigate whether older age leads to limitations in the starting dose of imatinib in daily treatment of chronic myeloid leukemia, and to determine the compliance of elderly patients with tyrosine kinase inhibitors (TKI) therapy. Methods: Data including the clinical characteristics, therapeutic outcomes and compliance with TKI therapy of elderly patients with chronic myeloid leukemia aged >65years were collected from 13 institutions in Turkey, retrospectively. Results: A total of 69 patients (27 [39%] men, 42 [61%] women) were evaluated retrospectively. The median age of the patients was 71years (range 66-85years). Of the patients, 66 (96%) were in the chronic phase and three (4.3%) were in the accelerated phase when diagnosed. A total of 63 (91.3%) patients were receiving imatinib as the first-line therapy. The initial dose of imatinib was 400mg/day in 59 patients (93.6%). Imatinib treatment induced 57 (90.5%) complete hematological responses at 3months, 29 (46%) complete cytogenetic responses at 6months and 49 (77.7%) major molecular responses at 12months. As a result, nilotinib and dasatinib were used in 14 patients as second-line therapy. Second-line TKI induced nine complete hematological responses (64.3%) at 3months, four complete cytogenetic responses (28.6%) at 12months and seven major molecular responses (50%) at 18months. A total of 56 of the patients (81.2%) are still alive. The median overall survival and progression-free survival rates were 35months (range 1-95months) and 17months (range 0.8-95months), respectively. Conclusion: Elderly patients should receive TKI according to the same guidelines that apply to younger patients. © 2014 Japan Geriatrics Society.

WOS: 000355733300008, PubMed ID: 25257190, AimsWe aimed to investigate whether older age leads to limitations in the starting dose of imatinib in daily treatment of chronic myeloid leukemia, and to determine the compliance of elderly patients with tyrosine kinase inhibitors (TKI) therapy. MethodsData including the clinical characteristics, therapeutic outcomes and compliance with TKI therapy of elderly patients with chronic myeloid leukemia aged >65years were collected from 13 institutions in Turkey, retrospectively. ResultsA total of 69 patients (27 [39%] men, 42 [61%] women) were evaluated retrospectively. The median age of the patients was 71years (range 66-85years). Of the patients, 66 (96%) were in the chronic phase and three (4.3%) were in the accelerated phase when diagnosed. A total of 63 (91.3%) patients were receiving imatinib as the first-line therapy. The initial dose of imatinib was 400mg/day in 59 patients (93.6%). Imatinib treatment induced 57 (90.5%) complete hematological responses at 3months, 29 (46%) complete cytogenetic responses at 6months and 49 (77.7%) major molecular responses at 12months. As a result, nilotinib and dasatinib were used in 14 patients as second-line therapy. Second-line TKI induced nine complete hematological responses (64.3%) at 3months, four complete cytogenetic responses (28.6%) at 12months and seven major molecular responses (50%) at 18months. A total of 56 of the patients (81.2%) are still alive. The median overall survival and progression-free survival rates were 35months (range 1-95months) and 17months (range 0.8-95months), respectively. ConclusionElderly patients should receive TKI according to the same guidelines that apply to younger patients. Geriatr Gerontol Int 2015; 15: 729-735.

WOS: 000375337000011, Introduction: During the last three decades, major advances have been made in the therapy of Hodgkin's lymphoma. However, despite these advances, Hodgkin's lymphoma has a poor prognosis in the elderly. The proportion of Hodgkin's lymphoma patients aged > 60 ranges in the different reports between 15% and 35%. This study aimed to examine clinical characteristics, treatment outcomes and prognostic factors affecting patient survival in Hodgkin's lymphoma patients aged 65 years or older. Material methods: Hodgkin's lymphoma patients at 65 years of age and older managed within last 5 years in a total of 5 centers in Turkey were retrospectively assessed. Results: The median age of a total of 32 patients was 71 (65-83) years. Elderly patients presented more frequently with B symptoms, elevated sedimentation rate, mixed cellularity histologic subtype and comorbid disease. Less frequent were bulky disease, bone marrow involvement, and the application of autologous stem cell transplantation. The nodular lymphocyte predominant subtype and lymphocyte rich subtype were not observed at all. Eastern Cooperative Oncology Group, ferritin, total protein, and histological type were significant predictors affecting survival (p

Background: Myelofibrosis is a bone marrow disorder characterized by excessive production of reticulin and collagen fiber deposition caused by hematological and non-hematological disorders. The prognosis of myelofibrosis is poor and treatment is mainly palliative. Janus kinase inhibitors are a novel strategy to treat people with myelofibrosis. Objectives: To determine the clinical benefits and harms of Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis secondary to hematological or non-hematological conditions. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2014, Issue 11), Ovid MEDLINE (from 1946 to 13 November 2014), EMBASE (from 1980 to 12 January 2013), and LILACS (from 1982 to 20 November 2014). We searched WHO International Clinical Trials Registry Platform and The metaRegister of Controlled Trials. We also searched for conference proceedings of the American Society of Hematology (from 2009 to October 2013), European Hematology Association (from 2009 to October 2013), American Society of Clinical Oncology (from 2009 to October 2013), and European Society of Medical Oncology (from 2009 to October 2013). We included searches in FDA, European Medicines Agency, and Epistemonikos. We handsearched the references of all identified included trials, and relevant review articles. We did not apply any language restrictions. Two review authors independently screened search results. Selection criteria: We included randomized clinical trials comparing Janus kinase-1 and Janus kinase-2 inhibitors with placebo or other treatments. Both previously treated and treatment naive patients were included. Data collection and analysis: We used the hazard ratio (HR) and 95% confidence interval (95% CI) for overall survival, progression-free survival and leukemia-free survival, risk ratio (RR) and 95% CI for reduction in spleen size and adverse events binary data, and standardized mean differences (SMD) and 95% CI for continuous data (health-related quality of life). Two review authors independently extracted data and assessed the risk of bias of included trials. Primary outcomes were overall survival, progression-free survival and adverse events. Main results: We included two trials involving 528 participants, comparing ruxolitinib with placebo or best available therapy (BAT). As the two included trials had different comparators we did not pool the data. The confidence in the results estimates of these trials was low due to the bias in their design, and their limited sample sizes that resulted in imprecise results. There is low quality evidence for the effect of ruxolitinib on survival when compared with placebo at 51 weeks of follow-up (HR 0.51, 95% CI 0.27 to 0.98) and compared with BAT at 48 weeks of follow-up (HR 0.70, 95% CI 0.20 to 2.47). Similarly there was very low quality evidence for the effect of ruxolitinib on progression free survival compared with BAT (HR 0.81, 95% CI 0.47 to 1.39). There is low quality evidence for the effect of ruxolitinib in terms of quality of life. Compared with placebo, the drug achieved a greater proportion of patients with a significant reduction of symptom scores (RR 8.82, 95% CI 4.40 to 17.69), and treated patients with ruxolitinib obtained greater MFSAF scores at the end of follow-up (MD -87.90, 95% CI -139.58 to -36.22). An additional trial showed significant differences in EORTC QLQ-C30 scores when compared ruxolitinib with best available therapy (MD 7.60, 95% CI 0.35 to 14.85). The effect of ruxolitinib on reduction in the spleen size of participants compared with placebo or BAT was uncertain (versus placebo: RR 64.58, 95% CI 9.08 to 459.56, low quality evidence; versus BAT: RR 41.78, 95% CI 2.61 to 669.75, low quality evidence). There is low quality evidence for the effect of the drug compared with placebo on anemia (RR 2.35, 95% CI 1.62 to 3.41), neutropenia (RR 3.57, 95% CI 1.02 to 12.55) and thrombocytopenia (RR 9.74, 95% CI 2.32 to 40.96). Ruxolitinib did not result in differences versus BAT in the risk of anemia (RR 1.35, 95% CI 0.91 to 1.99, low quality evidence) or thrombocytopenia (RR 1.20; 95% CI 0.44 to 3.28, low quality evidence). The risk of non-hematologic grade 3 or 4 adverse events (including fatigue, arthralgia, nausea, diarrhea, extremity pain and pyrexia) was similar when ruxolitinib was compared with placebo or BAT. The rate of neutropenia comparing ruxolitinib with standard medical treatment was not reported by the trial. Authors' conclusions: Currently, there is insufficient evidence to allow any conclusions regarding the efficacy and safety of ruxolitinib for treating myelofibrosis. The findings of this Cochrane review should be interpreted with caution as they are based on trials sponsored by industry, and include a small number of patients. Unless powered randomized clinical trials provide strong evidence of a treatment effect, and the trade-offbetween potential benefits and harms is established, clinicians should be cautious when administering ruxolitinib for treating patients with myelofibrosis. © 2015 The Cochrane Collaboration.

Introduction: During the last three decades, major advances have been made in the therapy of Hodgkin's lymphoma. However, despite these advances, Hodgkin's lymphoma has a poor prognosis in the elderly. The proportion of Hodgkin's lymphoma patients aged > 60 ranges in the different reports between 15% and 35%. This study aimed to examine clinical characteristics, treatment outcomes and prognostic factors affecting patient survival in Hodgkin's lymphoma patients aged 65 years or older. Material methods: Hodgkin's lymphoma patients at 65 years of age and older managed within last 5 years in a total of 5 centers in Turkey were retrospectively assessed. Results: The median age of a total of 32 patients was 71 (65-83) years. Elderly patients presented more frequently with B symptoms, elevated sedimentation rate, mixed cellularity histologic subtype and comorbid disease. Less frequent were bulky disease, bone marrow involvement, and the application of autologous stem cell transplantation. The nodular lymphocyte predominant subtype and lymphocyte rich subtype were not observed at all. Eastern Cooperative Oncology Group, ferritin, total protein, and histological type were significant predictors affecting survival (p

Objective: The stability and composition of intestinal flora plays a vital role in human wellbeing throughout life from as early as birth. Over the past 50 years, several studies have been conducted to evaluate the effect of probiotic administration in pediatric gastroenterology. This document aims to provide a recommendation score on probiotic utilization in pediatric gastroenterology, together with a review of current knowledge concerning its benefits, tolerability, and safety. Study Design: Published literature was selected without study design restriction: clinical guidelines, meta-analyses, randomized controlled trials (RCTs), cohort studies, outcomes research and case–controlled studies were selected using the following MESH-validated terms: probiotics, diarrhea, acute diarrhea, antibiotic-associated diarrhea, traveler’s diarrhea, bacterial diarrhea, nosocomial diarrhea, prophylactic diarrhea, Helicobacter pylori infection, colic, infantile colic, necrotizing enterocolitis (NEC), inflammatory bowel disease, constipation, and allergy. Once the validity and the quality of results were evaluated, a recommendation score and level of evidence were assigned for pediatric gastrointestinal-related conditions, according to the updated Evidence-Based Medicine guidelines: 1a for systematic review (SR) of RCTs, 1b for individual RCT, 1c for SR and individual RCT, 2a for SR of cohort studies, 2b for individual cohort studies, 2c for outcomes research, and 3a for SR of case-control studies. Results and Conclusions: The Latin American Expert group consensus recommends the use of the following probiotics for pediatric gastrointestinal conditions: prevention of acute infectious diarrhea (AID): 1b for Bifidobacterium lactis, Lactobacillus rhamnosus GG (LGG), and L. reuteri; prevention of nosocomial diarrhea: 1 b for B. lactis Bb12, B. bifidum, LGG and Streptococcus thermophiles; treatment of AID: 1a for LGG and S. boulardii, 1b for L. reuteri; prevention of antibiotic-associated diarrhea: 1b for LGG and S. boulardii; prevention of traveler’s diarrhea: 1b for S. boulardii; prevention of infantile colic: 1a for L. reuteri DSM 17938; treatment of infantile colic: 1b for L. reuteri DSM 17938; prevention of NEC: 1a for B. breve, mixtures of Bifidobacterium and Streptococcus, LGG, L. acidophilus and L. reuteri DSM 17938; induction and maintenance of remission in ulcerative colitis: 1b for VSL#3; improving symptoms of irritable bowel syndrome: 2c for LGG and VSL#3.

WOS: 000368248400011, PubMed ID: 25393847, In this multicenter retrospective analysis, we aimed to present clinical, laboratory and treatment results of 94 patients with Hairy cell leukemia diagnosed in 13 centers between 1990 and 2014. Sixty-six of the patients were males and 28 were females, with a median age of 55. Splenomegaly was present in 93.5% of cases at diagnosis. The laboratory findings that came into prominence were pancytopenia with grade 3 bone marrow fibrosis. Most of the patients with an indication for treatment were treated with cladribine as first-line treatment. Total and complete response of cladribine was 97.3% and 80.7%. The relapse rate after cladribine was 16.6%, and treatment related mortality was 2.5%. Most preferred therapy ( 95%) was again cladribine at second-line, and third line with CR rate of 68.4% and 66.6%, respectively. The 28-month median OS was 91.7% in all patients and 25-month median OS 96% for patients who were given cladribine as first-line therapy. In conclusion, the first multicenter retrospective Turkish study where patients with HCL were followed up for a long period has revealed demographic characteristics of patients with HCL, and confirmed that cladribine treatment might be safe and effective in a relatively large series of the Turkish study population. Copyright (C) 2014 John Wiley & Sons, Ltd.

Objective: Intra-lesional bony overgrowth (BO) identified during or following cartilage repair treatment is being frequently described through subjective reports focusing primarily on incidence. Our objective was to quantify the exact volume of intra-lesional BO at 12 months post-cartilage repair treatment, to determine if a correlation exists between the extent of BO and clinical outcomes, and to visualize and characterize the BO. Design: MRI scans were systematically obtained during a randomized clinical trial for cartilage repair (Stanish etal., 2013) that compared two microfracture-based treatments in 78 patients. Semi-automated morphological segmentation of pre-treatment, 1 and 12 months post-treatment scans utilizing a programmed anatomical atlas for all knee bone and cartilage structures permitted three-dimensional reconstruction, quantitative analysis, as well as qualitative characterization and artistic visualization ofBO. Results: Limited intra-lesional BO representing only 5.8±5.7% of the original debrided cartilage lesion volume was found in 78 patients with available MRIs at 12 months. The majority (80%) of patients had very little BO (

WOS: 000364114800027, Objective: This retrospective study aimed to investigate the efficacies of colistin and non-colistin monotherapies in multi-drug resistant Acinetobacter baumannii bacteremia (MDR-AB). Materials and methods: Cases with MDR-AB from 27 tertiary-referral hospitals between January 2009 and December 2012 were included. Patients' data that were on either colistin monotherapy (CM) or non-colistin monotherapy (NCM) were compared. Mortality on Day 14 was the primary endpoint, whereas microbiological eradication and clinical outcome were the secondary ones. Results: Eighty-four cases were included in the study with 36 being in the CM group and 48 in the NCM group. Thirty-eight (452%) cases were male and the mean age was 602 years. The mean durations of pre-MDR-AB hospital stay and intensive care unit stay were 25.8 days and 20.9 days, respectively. All of the cases had fever (>38 degrees C). The mean Pitt bacteremia score (PBS) of the patients was calculated as 6.8, APACHE 2 score as 18.9 and the Charlson co-morbidity index (CCI) as 3.7 (CM: 3.6 vs. NCM: 3.9). Twenty (55.6%) cases in the CM group and 26 cases in the NCM group (542%) (p=0.81) died; 9 cases in the CM group (25%) and 16 cases in the NCM group (33 3%) had treatment failure (P=0.55). Bacteriological eradication was achieved in 20 (55.6%) cases in the CM group and in 36 cases (75%) in the NCM group (P=0.061). Conclusions: No significant difference could be identified between the colistin monotherapy and non-colistin monotherapy options in MDR-AB cases with respect to the results of efficacy and 14-day mortality.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, not malignant, disease of the hematopoietic stem cells, associated with significant morbidity and mortality. It is a rare disease with an estimated incidence of 1.3 new cases per one million individuals per year. The treatment of PNH has been largely empirical and symptomatic, with blood transfusions, anticoagulation, and supplementation with folic acid or iron. Eculizumab, a biological agent that inhibits complement cascade, was developed for preventing hemolytic anemia and severe thrombotic episodes. Objectives: To assess the clinical benefits and harms of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria (PNH). Search methods: We conducted a comprehensive search strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 5), Ovid MEDLINE (from 1946 to 15 May 2014), EMBASE (from 1980 to 25 June 2014), and LILACS (from 1982 to 25 June 2014). We did not apply any language restrictions. Selection criteria: We included randomized controlled trials (RCTs) irrespective of their publication status or language. No limits were applied with respect to period of follow-up. We excluded quasi-RCTs. We included trials comparing eculizumab with placebo or best available therapy. We included any patient with a confirmed diagnosis of PNH. Primary outcome was overall survival. Data collection and analysis: We independently performed a duplicate selection of eligible trials, risk of bias assessment, and data extraction. We estimated risk ratios (RRs) and 95% confidence interval (CIs) for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes. We used a random-effects model for analysis. Main results: We identified one multicenter (34 sites) phase III RCT involving 87 participants. The trial compared eculizumab versus placebo, and was conducted in the US, Canada, Europe, and Australia with 26 weeks of follow-up. This small trial had high risk of bias in many domains (attrition and selective reporting). It was sponsored by a pharmaceutical company. No patients died during the study. By using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (scores can range from 0 to 100, with higher scores on the global health status and functioning scales indicating improvement), the trial showed improvement in health-related quality of life in patients treated with eculizumab (mean difference (MD) 19.4, 95% CI 8.25 to 30.55; P = 0.0007; low quality of evidence). By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001; moderate quality of evidence) in the eculizumab group compared with placebo. Eculizumab compared with placebo showed a greater proportion of patients with transfusion independence: 51% (22/43) versus 0% (0/44); risk ratio (RR) 46.02, 95% CI 2.88 to 735.53; P = 0.007; moderate quality of evidence; and withdrawal for any reason: 4.7% (2/43) versus 22.72% (10/44); RR 0.20, 95% CI 0.05 to 0.88; P = 0.03; moderate quality of evidence. Due to the low rate of events observed, the included trial did not show any difference between eculizumab and placebo in terms of serious adverse events: 9.3% (4/43) versus 20.4% (9/44); RR 0.15, 95% CI 0.15 to 1.37; P = 0.16; low quality of evidence. We did not observe any difference between intervention and placebo for the most frequent adverse events. One participant receiving placebo showed an episode of thrombosis. The trial did not assess overall survival, transformation to myelodysplastic syndrome and acute myelogenous leukemia, or development or recurrence of aplastic anemia on treatment. Authors' conclusions: This review has detected an absence of evidence for eculizumab compared with placebo for treating paroxysmal nocturnal hemoglobinuria (PNH), in terms of overall survival, nonfatal thrombotic events, transformation to myelodysplastic syndrome and acute myelogenous leukemia, and development and recurrence of aplastic anemia on treatment. Current evidence indicates that compared with placebo, eculizumab increases health-related quality of life and increases transfusion independence. During the execution of the included trial, no patients died. Furthermore, the intervention seems to reduce fatigue and withdrawals for any reason. The safety profile of eculizumab is unclear. These conclusions are based on one small trial with risk of attrition and selective reporting bias. Therefore, prescription of eculizumab for treating patients with PNH can neither be supported nor rejected, unless new evidence from a large high quality trial alters this conclusion. Therefore, we urge the reader to interpret the trial results with much caution. Future trials on this issue should be conducted according to the SPIRIT statement and reported according to the CONSORT statement by independent investigators, and using the Foundation of Patient-Centered Outcomes Research recommendations. © 2014 The Cochrane Collaboration.

balkan, ilker inanc/0000-0002-8977-5931; KARABAY, OGUZ/0000-0003-1514-1685; Karabay, Oguz/0000-0003-0502-432X WOS: 000364114800027 Objective: This retrospective study aimed to investigate the efficacies of colistin and non-colistin monotherapies in multi-drug resistant Acinetobacter baumannii bacteremia (MDR-AB). Materials and methods: Cases with MDR-AB from 27 tertiary-referral hospitals between January 2009 and December 2012 were included. Patients' data that were on either colistin monotherapy (CM) or non-colistin monotherapy (NCM) were compared. Mortality on Day 14 was the primary endpoint, whereas microbiological eradication and clinical outcome were the secondary ones. Results: Eighty-four cases were included in the study with 36 being in the CM group and 48 in the NCM group. Thirty-eight (452%) cases were male and the mean age was 602 years. The mean durations of pre-MDR-AB hospital stay and intensive care unit stay were 25.8 days and 20.9 days, respectively. All of the cases had fever (>38 degrees C). The mean Pitt bacteremia score (PBS) of the patients was calculated as 6.8, APACHE 2 score as 18.9 and the Charlson co-morbidity index (CCI) as 3.7 (CM: 3.6 vs. NCM: 3.9). Twenty (55.6%) cases in the CM group and 26 cases in the NCM group (542%) (p=0.81) died; 9 cases in the CM group (25%) and 16 cases in the NCM group (33 3%) had treatment failure (P=0.55). Bacteriological eradication was achieved in 20 (55.6%) cases in the CM group and in 36 cases (75%) in the NCM group (P=0.061). Conclusions: No significant difference could be identified between the colistin monotherapy and non-colistin monotherapy options in MDR-AB cases with respect to the results of efficacy and 14-day mortality.

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6(11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (rho=0.79, P = 0.0021) and trough (rho = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients. (C) 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Metastatic gastric cancer is incurable and remains one of the leading causes of cancer-related deaths around the world. Despite the significant progress in its systemic treatment, metastatic gastric cancer is still a major therapeutic challenge for oncologists. Newer chemotherapy regimens and the addition of molecularly targeted agents to chemotherapy seem to provide better clinical outcomes for patients with metastatic gastric cancer. The objective of this article is to review the current treatment approach for this formidable disease.

OBJECTIVES: This study aimed to assess cost-effectiveness of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided versus symptom-guided therapy in heart failure (HF) patients ≥60 years old. BACKGROUND: Cost-effectiveness of NT-proBNP guidance in HF patients is unclear. It may create additional costs with uncertain benefits. METHODS: In the TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure), patients with left ventricular ejection fraction (LVEF) of ≤45% were randomized to receive intensified NT-proBNP-guided therapy or standard, symptom-guided therapy. For cost-effectiveness analysis, 467 (94%) patients (age 76 ± 7 years, 66% male) were eligible. Incremental cost-effectiveness was calculated as incremental costs per gained life-year and quality-adjusted life-year (QALY) within the 18-month trial period, as defined per protocol. RESULTS: NT-proBNP-guided therapy was dominant (i.e., more effective and less costly) over symptom-guided therapy, saving $2,979 USD (2.5 to 97.5% confidence interval [CI]: $8,758 to $3,265) per patient, with incremental effectiveness of +0.07 life-years and +0.05 QALYs. The probability of NT-proBNP-guided therapy being dominant was 80%, and the probability of saving 1 life-year or QALY at a cost of $50,000 was 97% and 93%, respectively. Exclusion of residence costs resulted in an incremental cost-effectiveness ratio (ICER) of $5,870 per life-year gained. Cost-effectiveness of NT-proBNP-guided therapy was most pronounced in patients

WOS: 000317169500016, PubMed ID: 21429771, Background: Testicular self-examination is the easiest and cheapest way to scan testicular cancer. However, the public awareness about testicular self-examination is very low. We aimed to investigate the public awareness of Turkish people about testicular cancer and testicular self-examination. Methods: We performed a survey consisting of 10 questions concerning testicular cancer and testicular self-examination in 799 students in the first year of 12 different medical schools. Aiming for a common method of data collection, the questionnaires were administered to the students during a class just before the lesson started. The whole data from all of the centers were pooled in a common data-base file. Results: Eighty-nine (11.1%) of the participants reported that they had knowledge about testicular cancer, but only 11(1.4%) of them answered all the questions about testicular cancer correctly. Eight (1%) of the participants reported that they had been performing testicular self-examination routinely once a month. Four (0.5%) of them were both well informed about testicular cancer and had been performing testicular self-examination once a month as suggested. Conclusion: The present study showed that awareness on testicular cancer and testicular self-examination is very low and suggests a need for efforts in Turkey to increase public awareness and education. (C) 2013 Elsevier Inc. All rights reserved.

Background: In a planned International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) worldwide study on reference intervals (RIs), a common panel of serum samples is to be measured by laboratories from different countries, and test results are to be compared through conversion using linear regression analysis. This report presents a validation study that was conducted in collaboration with four laboratories. Methods: A panel composed of 80 sera was prepared from healthy individuals, and 45 commonly tested analytes (general chemistry, tumor markers, and hormones) were measured on two occasions 1 week apart in each laboratory. Reduced major-axis linear regression was used to convert reference limits (LL and UL). Precision was expressed as a ratio of the standard error of converted LL or UL to the standard deviation (SD) comprising RI (approx. 1/4 of the RI width corresponding to between-individual SD). The allowable and optimal levels of error for the SD ratio (SDR) were set as

Malignant pleural mesothelioma (MPM) is a relatively rare, but aggressive tumor that causes high mortality. The major risk factor involved in the etiology is environmental and occupational exposure to asbestos. The optimal modality of therapy is controversial. The present study retrospectively evaluated the data pertinent to 282 patients who were examined and treated in 11 different medical oncology centers in Turkey. There were 161 males (57.1 %) and 121 females (42.9 %), with a mean age of 56.38 ± 12.07 years. Surgery was used in 74 patients, 21 patients (28.4 %) received only chemotherapy and 28 patients (37.8 %) received chemoradiotherapy after surgery. The median survival in patients who were administered adjuvant therapy after surgery was 24 months, while the median survival in patients who had only surgery was 6 months (p = 0.029). 106 patients were administered pemetrexed-platinum combination and 35 patients were administered gemcitabine-platinum combination as front-line chemotherapy. Median survival, 1- and 2-year survival rates in patients who received platinum analogues and pemetrexed or gemcitabine combinations were found statistically similar (p = 0.15). The median survival for all patients with MPM in our study was 18 months. The main factors influencing the overall survival were stage of the disease (p = 0.020), performance status (p < 0.001), asbestos exposure (p = 0.030) and mesothelioma histological subtypes (p < 0.001). Results of our study suggest that multi-modality treatment regimens consisting of surgery, radiotherapy and chemotherapy prolong overall survival. Survival rates in patients who received combining platinum analogues with pemetrexed or gemcitabine as front-line chemotherapy were found similar. © 2012 Springer Science+Business Media, LLC.

The reference intervals (RIs) given in laboratory reports have an important role in aiding clinicians in interpreting test results in reference to values of healthy populations. In this report, we present a proposed protocol and standard operating procedures (SOPs) for common use in conducting multicenter RI studies on a national or international scale. The protocols and consensus on their contents were refined through discussions in recent C-RIDL meetings. The protocol describes in detail (1) the scheme and organization of the study, (2) the target population, inclusion/exclusion criteria, ethnicity, and sample size, (3) health status questionnaire, (4) target analytes, (5) blood collection, (6) sample processing and storage, (7) assays, (8) cross-check testing, (9) ethics, (10) data analyses, and (11) reporting of results. In addition, the protocol proposes the common measurement of a panel of sera when no standard materials exist for harmonization of test results. It also describes the requirements of the central laboratory, including the method of cross-check testing between the central laboratory of each country and local laboratories. This protocol and the SOPs remain largely exploratory and may require a reevaluation from the practical point of view after their implementation in the ongoing worldwide study. The paper is mainly intended to be a basis for discussion in the scientific community. Japan Society for the Promotion of Science (24256003)

Background The role of anti-HDV immunoglobulin M (IgM) testing in patients receiving pegylated interferon-α therapy for hepatitis delta is unknown. We performed anti-HDV IgM testing in a well defined cohort of HDV-infected patients who were treated with pegylated interferon-α2a plus adefovir, or either drug alone. Methods Sera from 33 HDV-RNA-positive patients from the international HIDIT-1 trial were available for anti-HDV IgM testing (ETI-DELTA-IGMK-2 assay, DiaSorin, Saluggia, Italy) before therapy, at treatment weeks 24 and 48, and at 24 weeks after the end of treatment. Results Anti-HDV IgM tested positive in 31 out of the 33 patients (94%) prior to treatment. HDV IgM levels correlated with histological inflammatory activity ( r=0.51, PConclusions We suggest that anti-HDV IgM testing might give additional useful information to determine disease activity in hepatitis delta and to predict treatment response to antiviral therapy with type I interferons. However, determination of anti-HDV IgM can not substitute HDV RNA testing, which remains the primary virological marker for response to therapy.

Objective: To determine the prevalence of trial registration in randomized controlled trials (RCTs) published in 2010 (PUBMED/LILACS) from Latin America and the Caribbean's (LAC) and to compare methodological characteristics between registered and nonregistered RCTs. Study Design and Setting: A search for detecting RCTs in which at least the first/contact author had a LAC's affiliation was made. We determined if RCTs were registered in the International Clinical Trial Registry Platform (ICTRP). Data were independently extracted by two authors. The risk of bias (RoB) was assessed in all registered RCTs (n = 89) and in a sample of nonregistered RCTs (n = 237). Results: The search identified 1,695 references; 526 RCTs from 19 countries were included. 16.9% (89/526) of RCTs were registered in the ICTRP; however, only 21 (4.0%) were prospectively registered. A significant difference was found in the overall assessment of the RoB between registered and nonregistered RCTs. Overall, registered RCTs were multinational, had larger sample size and longer follow-up, and reported more frequently information on funding, conflict of interests, and ethic issues. No significant differences were found when analyzing prospectively registered RCTs. Conclusion: This study shows that trial registration rates are still low in LAC and the quality of reporting needs to be improved. © 2012 Elsevier Inc. All rights reserved.

Objective: To evaluate initial combination therapy with metformin plus colesevelam in drug-naïve Hispanic patients with type 2 diabetes mellitus. Research Design and Methods: Patients self-identifed as Hispanic from a previous study were included in this exploratory post hoc analysis. Patients were randomized to metformin plus colesevelam or metformin plus placebo. The primary effcacy parameter was the mean change in glycated hemoglobin (HbA1c) levels from baseline. Results: Metformin plus colesevelam had a greater mean HbA1c reduction (-1.2 ± 0.1%) than metformin plus placebo (-0.8 ± 0.1%; P = 0.001) from mean baselines of 7.7% and 7.6%, respectively. Low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein (apo) B levels were also reduced (P and lt; 0.0001 for all), while triglyceride (P and lt; 0.0001) and apoA-I (P and lt; 0.05) levels were increased with metformin plus colesevelam treatment compared with metformin plus placebo. With metformin plus colesevelam versus metformin plus placebo, more patients achieved an HbA1c of, 7.0% (75% vs 56%) and LDL-C of, 100 mg/dL (49% vs 14%; both P, 0.05). Conclusion: Metformin plus colesevelam may be an effective initial treatment option for Hispanic patients with early type 2 diabetes mellitus. © Postgraduate Medicine.

Aim The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. Methods Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5mg kg-1 levamisole (or placebo) orally once every other day. One hundred and thirty-six plasma samples were collected from 38 children from India and Europe and included in the analysis. A one compartment model described the data well. Results The apparent clearance rate (CL/F) and distribution volume (V/F) were 44l h-1 70kg-1 and 236l 70kg-1, respectively; estimated interindividual variability was 32-42%. In addition to allometric scaling of CL/F and V/F to body weight, we identified a significant proportional effect of age on CL/F (-10.1% per year). The pharmacokinetics parameters were not affected by gender, tablet strength or study centre. The median (interquartile range) maximum plasma concentration of levamisole was 438.3 (316.5-621.8) ng ml-1, and the median area under the concentration-time curve was 2847 (2267-3761) ng ml-1 h. Median tmax and t1/2; values were 1.65 (1.32-2.0) h and 2.60 (2.06-3.65) h, respectively. Conclusions Here, we present the first pharmacokinetic data regarding levamisole in children with steroid-sensitive nephrotic syndrome. The pharmacokinetic profile of levamisole in children was similar to findings reported in adults, although the elimination rate was slightly higher in children.

Introduction: A large proportion of the coumarin dose variability is explained by environmental factors and by common genetic variants in the VKORC1 and CYP2C9 genes. Genotype-guided coumarin dosing has been proposed for a more accurate prediction of the coumarin dose in order to reduce the incidence of coumarin-related complications.Areas covered: This review discusses the current state of coumarin pharmacogenetics, the evidence from recent randomized controlled trials and economic evaluations regarding the possible clinical implementation of genotype-guided coumarin dosing.Expert opinion: When the VKORC1 and CYP2C9 genotypes are available before the start of coumarin therapy in individuals of European ancestry, a genetic-guided algorithm should be used for dose determination. Ethnicity-specific pharmacogenetic algorithms should be tested in other populations. At this moment the evidence is not sufficient to support genotyping before coumarin therapy initiation. Based on results from recent randomized controlled trials, a clinical dosing algorithm could be considered in the initial phase of coumarin treatment. Current economic studies indicate that genotype-guided dosing could be cost-effective, but the clinical implementation of genetic-guided coumarin therapy will depend on the cost of pharmacogenetic tests and the availability of novel oral anticoagulants.