Studien mit Surrogatendpunkten: Nutzen und Grenzen in der klinischen Entscheidungsfindung

Zusammenfassung: Therapieentscheidungen sollten im Idealfall auf die Ergebnisse von randomisierten kontrollierten Studien mit patientenrelevanten Endpunkten gestützt sein. Patientenrelevante Endpunkte sind zum Beispiel Lebensqualität, Herzinfarkt oder Tod. Die Durchführung solcher Studien ist jedoch aufwändig, da oft große Patientenzahlen und eine lange Beobachtungszeit benötigt werden. Deshalb werden oft Studien durchgeführt, bei welchen patientenrelevante Endpunkte durch Surrogatendpunkte ersetzt werden, um Patientenzahl und Beobachtungszeit zu verringern. Surrogatendpunkte sind Ersatzmessparameter für die Lebensqualität, den organischen Funktionszustand oder die Überlebenswahrscheinlichkeit eines Patienten. Die Zulassung von neuen Substanzen beruht oft auf den Ergebnissen von Surrogatendpunktstudien. Unerwartete Nebenwirkungen und der Rückzug von Substanzen, welche aufgrund solcher Studien zugelassen wurden, haben in jüngster Zeit eine Kontorverse über die Bedeutung von Surrogatendpunktstudien entfacht. Wir erläutern anhand von Beispielen Kriterien, mit deren Hilfe Kliniker die Ergebnisse von Surrogatendpunktstudien kritisch gewichten könne

Predicting mortality with pneumonia severity scores: importance of model recalibration to local settings

In patients with community-acquired pneumonia (CAP) prediction rules based on individual predicted mortalities are frequently used to support decision-making for in-patient vs. outpatient management. We studied the accuracy and the need for recalibration of three risk prediction scores in a tertiary-care University hospital emergency-department setting in Switzerland. We pooled data from patients with CAP enrolled in two randomized controlled trials. We compared expected mortality from the original pneumonia severity index (PSI), CURB65 and CRB65 scores against observed mortality (calibration) and recalibrated the scores by fitting the intercept α and the calibration slope β from our calibration model. Each of the original models underestimated the observed 30-day mortality of 11%, in 371 patients admitted to the emergency department with CAP (8·4%, 5·5% and 5·0% for the PSI, CURB65 and CRB65 scores, respectively). In particular, we observed a relevant mortality within the low risk classes of the original models (2·6%, 5·3%, and 3·7% for PSI classes I-III, CURB65 classes 0-1, and CRB65 class 0, respectively). Recalibration of the original risk models corrected the miscalibration. After recalibration, however, only PSI class I was sensitive enough to identify patients with a low risk (i.e. <1%) for mortality suitable for outpatient management. In our tertiary-care setting with mostly referred in-patients, CAP risk scores substantially underestimated observed mortalities misclassifying patients with relevant risks of death suitable for outpatient management. Prior to the implementation of CAP risk scores in the clinical setting, the need for recalibration and the accuracy of low-risk re-classification should be studied in order to adhere with discharge guidelines and guarantee patients' safet

Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort.

In Switzerland, organ procurement is well organized at the national-level but transplant outcomes have not been systematically monitored so far. Therefore, a novel project, the Swiss Transplant Cohort Study (STCS), was established. The STCS is a prospective multicentre study, designed as a dynamic cohort, which enrolls all solid organ recipients at the national level. The features of the STCS are a flexible patient-case system that allows capturing all transplant scenarios and collection of patient-specific and allograft-specific data. Beyond comprehensive clinical data, specific focus is directed at psychosocial and behavioral factors, infectious disease development, and bio-banking. Between May 2008 and end of 2011, the six Swiss transplant centers recruited 1,677 patients involving 1,721 transplantations, and a total of 1,800 organs implanted in 15 different transplantation scenarios. 10 % of all patients underwent re-transplantation and 3% had a second transplantation, either in the past or during follow-up. 34% of all kidney allografts originated from living donation. Until the end of 2011 we observed 4,385 infection episodes in our patient population. The STCS showed operative capabilities to collect high-quality data and to adequately reflect the complexity of the post-transplantation process. The STCS represents a promising novel project for comparative effectiveness research in transplantation medicine

Model Kebijakan Penanggulangan Korupsi di Universitas Negeri YOGYAKARTA

Penelitian ini bertujuan untuk mengetahui kebijakan Universitas Negeri Yogyakarta dalam menanggulangi korupsi dan menemukan model kebijakan yang diinginkan Universitas Negeri Yogyakarta dalam menanggulangi korupsi. Penelitian ini adalah penelitian survei dengan pendekatan kuantitatif dan kualitatif. Sampel penelitian ditentukan secara multy stage sampling dengan teknik pengumpulan data dengan angket, dokumen dan diperkuat dengan pengumpulan data melalui Focus Group Discussion (FGD), dan validasi instrumen melalui validitas isi (content validity). Data dianalisis secara deskriptif. Hasil penelitian menunjukkan bahwa kebijakan penanggulangan korupsi di UNY tidak ada secara khusus dikeluarkan. Kebijakan yang ada mengikuti dan mempertahankan kebijakan yang lebih tinggi, yaitu dari Pemerintah. Model kebijakan penangggulangan korupsi di UNY yang digunakan adalah Model Rasional, yaitu kebijakan penanggulangan korupsi yang dikeluarkan merupakan aspirasi semua staf yang ada di unit kerja dan harus menekankan pada aspek efisiensi atas beban kerja pada unit kerja yang bersangkutan. Adapun kebijakan yang sudah ada yang berasal dari Pemerintah pusat dijadikan pedoman

Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials.

BACKGROUND: Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees. METHODS AND FINDINGS: We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements. CONCLUSIONS: Publication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol

Prevalence, characteristics, and publication of discontinued randomized trials.

IMPORTANCE: The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES: To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING: Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES: Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS: After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P &lt; .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P &lt; .001). CONCLUSIONS AND RELEVANCE: In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials

Planck 2015 results. XXVII. The Second Planck Catalogue of Sunyaev-Zeldovich Sources

We present the all-sky Planck catalogue of Sunyaev-Zeldovich (SZ) sources detected from the 29 month full-mission data. The catalogue (PSZ2) is the largest SZ-selected sample of galaxy clusters yet produced and the deepest all-sky catalogue of galaxy clusters. It contains 1653 detections, of which 1203 are confirmed clusters with identified counterparts in external data-sets, and is the first SZ-selected cluster survey containing > $10^3$ confirmed clusters. We present a detailed analysis of the survey selection function in terms of its completeness and statistical reliability, placing a lower limit of 83% on the purity. Using simulations, we find that the Y5R500 estimates are robust to pressure-profile variation and beam systematics, but accurate conversion to Y500 requires. the use of prior information on the cluster extent. We describe the multi-wavelength search for counterparts in ancillary data, which makes use of radio, microwave, infra-red, optical and X-ray data-sets, and which places emphasis on the robustness of the counterpart match. We discuss the physical properties of the new sample and identify a population of low-redshift X-ray under- luminous clusters revealed by SZ selection. These objects appear in optical and SZ surveys with consistent properties for their mass, but are almost absent from ROSAT X-ray selected samples

Prognostic importance of anaemia in HIV type-1-infected patients starting antiretroviral therapy: collaborative analysis of prospective cohort studies

Background: In HIV type-1-infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined. Methods: We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (<8.0 g/dl), 1,120 (9%) had moderate (male 8.0-<11.0 g/dl and female 8.0-<10.0g/dl) and 2,971 (25%) had mild (male 11.0-<13.0g/dl and female 10.0-<12.0 g/dl) anaemia. We separately analysed progression to AIDS or death from baseline and from 6 months using Weibull models, adjusting for CD4+ T-cell count, age, sex and other variables. Results: During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17-1.73), for moderate anaemia 2.56 (2.07-3.18) and for severe anaemia 5.26 (3.55-7.81). Corresponding figures for progression to AIDS were 1.60 (1.37-1.86), 2.00 (1.66-2.40) and 2.24 (1.46-3.42). At 6 months the prevalence of anaemia declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months. Conclusions: Anaemia at the start of HAART is an important factor for short- and long-term prognosis, including in patients whose haemoglobin levels improved or normalized during the first 6 months of HAART

The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals

Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infectio

Obesity trends and body mass index changes after starting antiretroviral treatment : the Swiss HIV Cohort Study

BACKGROUND: The factors that contribute to increasing obesity rates in human immunodeficiency virus (HIV)-positive persons and to body mass index (BMI) increase that typically occurs after starting antiretroviral therapy (ART) are incompletely characterized. METHODS: We describe BMI trends in the entire Swiss HIV Cohort Study (SHCS) population and investigate the effects of demographics, HIV-related factors, and ART on BMI change in participants with data available before and 4 years after first starting ART. RESULTS: In the SHCS, overweight/obesity prevalence increased from 13% in 1990 (n = 1641) to 38% in 2012 (n = 8150). In the participants starting ART (n = 1601), mean BMI increase was 0.92 kg/m(2) per year (95% confidence interval, .83-1.0) during year 0-1 and 0.31 kg/m(2) per year (0.29-0.34) during years 1-4. In multivariable analyses, annualized BMI change during year 0-1 was associated with older age (0.15 [0.06-0.24] kg/m(2)) and CD4 nadir &lt;199 cells/µL compared to nadir &gt;350 (P &lt; .001). Annualized BMI change during years 1-4 was associated with CD4 nadir &lt;100 cells/µL compared to nadir &gt;350 (P = .001) and black compared to white ethnicity (0.28 [0.16-0.37] kg/m(2)). Individual ART combinations differed little in their contribution to BMI change. CONCLUSIONS: Increasing obesity rates in the SHCS over time occurred at the same time as aging of the SHCS population, demographic changes, earlier ART start, and increasingly widespread ART coverage. Body mass index increase after ART start was typically biphasic, the BMI increase in year 0-1 being as large as the increase in years 1-4 combined. The effect of ART regimen on BMI change was limited