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Background and Objectives: Drawing causal conclusions from real-world data (RWD) poses methodological challenges and risk of bias. We aimed to systematically assess the type and impact of potential biases that may occur when analyzing RWD using the case of progressive ovarian cancer. Methods: We retrospectively compared overall survival with and without second-line chemotherapy (LOT2) using electronic medical records. Potential biases were determined using directed acyclic graphs. We followed a stepwise analytic approach ranging from crude analysis and multivariable-adjusted Cox model up to a full causal analysis using a marginal structural Cox model with replicates emulating a reference randomized controlled trial (RCT). To assess biases, we compared effect estimates (hazard ratios [HRs]) of each approach to the HR of the reference trial. Results: The reference trial showed an HR for second line vs. delayed therapy of 1.01 (95% confidence interval [95% CI]: 0.82e1.25). The corresponding HRs from the RWD analysis ranged from 0.51 for simple baseline adjustments to 1.41 (95% CI: 1.22e1.64) accounting for immortal time bias with time-varying covariates. Causal trial emulation yielded an HR of 1.12 (95% CI: 0.96e1.28). Conclusion: Our study, using ovarian cancer as an example, shows the importance of a thorough causal design and analysis if one is expecting RWD to emulate clinical trial results.

Zusammenfassung Hintergrund Und Zielsetzung Datenlinkage-Verfahren sind von erheblicher Bedeutung für die Evaluation von Therapieregimes chronischer Erkrankungen, bei denen Patient/inn/en zwischen verschiedenen Versorgungssektoren navigieren. Ein umfassendes Bild langfristiger Effekte und der Kosten-Effektivität der Behandlung kann nur gezeichnet werden, wenn Daten verschiedener Provenienz miteinander verknüpft werden. Methodische Probleme und Herausforderungen Am Beispiel der post-akuten Versorgung des Schlaganfalls veranschaulicht die vorliegende Studie, wie per exaktem deterministischem Datenlinkage klinische Patient/inn/endaten (Primärdaten) mit Routineabrechnungsdaten (Sekundärdaten) der Tiroler Gebietskrankenkasse (TGKK) verknüpft werden können. Die von Datenlinkage-Projekten bekannten Herausforderungen traten auch beim StrokeCard-Projekt der Medizinischen Universität Innsbruck auf, insgesamt jedoch begünstigten die Spezifika des österreichischen Gesundheitssystems (ein Großteil der Population ist in der Gebietskrankenkasse des jeweiligen Bundeslandes pflichtversichert) das Datenlinkage-Vorhaben. Ergebnisse Im Rekrutierungszeitraum 01/2014–12/2015 konnten n=540 Pat. identifiziert und dem operativen Datensatz zugespielt werden. Davon waren n=367 Teil der StrokeCard-Gruppe (d. h. der Interventionsgruppe), n=173 gehörten der Standardversorgungsgruppe an (d. h. der Kontrollgruppe); n=11 Pat. haben das 1-Jahres-Follow-up nicht beendet (n=7 Pat. der Interventionsgruppe vs. n=4 Pat. der Kontrollgruppe); n=7 Pat. verstarben während der Studie (n=5 Pat. der Interventionsgruppe vs. n=2 Pat. der Kontrollgruppe). Für alle 540 Pat. waren TGKK-Routinedaten für 1 Jahr vor Rekrutierung bis 1 Jahr nach Entlassung aus der Klinik verfügbar. Alle Daten konnten für die gesundheitsökonomische Evaluation verwendet werden. Schlussfolgerungen Mit diesem Projekt wurde die Machbarkeit der Verknüpfung von Primär- und Sekundärdaten unterschiedlicher Herkunft untersucht. Trotz günstiger Rahmenbedingungen hat die österreichische Versorgungsforschung nur begrenzte Erfahrungen auf diesem Gebiet. Die Ergebnisse zeigen, dass ein unter Datenschutzkautelen betriebenes Linkage gelingen kann und aufgrund der Verfügbarkeit relevanter Informationen aus Abrechnungsdaten eine empirische Bereicherung insbesondere für gesundheitsökonomische Analysen darstellt. Dies sollte als Anregung verstanden werden, in Evaluationsstudien Datenlinkage-Prozeduren in Zukunft in verstärktem Maße einzusetzen.

Phosphorous magnetic resonance spectroscopy (31P-MRS) allows a non-invasive analysis of phosphorus-containing compounds in vivo. The present study investigated the influence of brain region, hemisphere, age, sex and brain volume on 31P-MRS metabolites in healthy adults.Supratentorial brain 31P-MRS spectra of 125 prospectively recruited healthy volunteers (64 female, 61 male) aged 20 to 85 years (mean: 49.4 ± 16.9 years) were examined with a 3D-31P-MRS sequence at 3T, and the compounds phosphocreatine (PCr), inorganic phosphate (Pi) and adenosine triphosphate (ATP) were measured. From this data, the metabolite ratios PCr/ATP, Pi/ATP and PCr/Pi were calculated for different brain regions. In addition, volumes of gray matter, white matter and cerebrospinal fluid were determined.For all metabolite ratios significant regional differences and in several regions sex differences were found. In some brain regions and for some metabolites hemispheric differences were detected. In addition, changes with aging were found, which differed between women and men.The present results indicate that 31P-MRS metabolism varies throughout the brain, with age and between sexes, and therefore have important practical implications for the design and the interpretation of future 31P-MRS studies under physiological conditions and in patients with various cerebral diseases.

Purpose Human papillomavirus (HPV) can cause condylomata acuminata, also known as genital warts. Our aim was to evaluate the long-term recurrence of genital warts after primary carbon dioxide laser treatment before the introduction of the vaccination against HPV. Methods Recurrence rate and localization of genital warts were analysed in a retrospective study in 1798 women presenting with a new diagnosis of genital warts from 1992 to 2009 at a University hospital and had received laser treatment. Additionally, data on topography, pregnancy status, and cervical smear were available for women treated from 2003 to 2009 (n = 825, data subset 1) and systematic follow-up data for women treated in 2006 and 2007 (n = 242, data subset 2). Results Median time from laser treatment to first recurrence was 14.6 weeks (data subset 2). The site most affected was the vulva (90.7%) followed by the perineum/perianal region (59.3%) and the vagina (47.3%). Abnormal Pap smear was observed in 22.6%. Systematic follow-up with a median follow-up time of 3.1 years revealed at least one recurrence in 68 (28.1%) of 242 women. Women with multifocal genital warts had a 2.9 times increased risk for recurrence compared to women with unifocal lesions (p = 0.01). Conclusions Nearly 30% of women presenting with genital warts experienced at least one recurrence after treatment with carbon dioxide laser. Multifocal lesions are the strongest indicator of recurrence. These data provide an important insight to recurrence rates of genital warts before HPV vaccination and underline the significance of a long-term follow-up and HPV vaccination.

OBJECTIVE: To identify risk factors associated with mortality in critically ill children requiring continuous renal replacement therapy. DESIGN: Retrospective observational study based on a prospective registry. SETTING: Tertiary and quaternary referral 30-bed PICU. PATIENTS: Critically ill children undergoing continuous renal replacement therapy were included in the study. INTERVENTIONS: Continuous renal replacement therapy. MEASUREMENTS AND MAIN RESULTS: Overall mortality was 36% (n = 58) among the 161 patients treated with continuous renal replacement therapy during the study period and was significantly higher in patients on extracorporeal membrane oxygenation (47.5%, 28 of 59) than in patients not requiring extracorporeal membrane oxygenation (28.4%, 29 of 102; p = 0.022). According to the admission diagnosis, we found the highest mortality in patients with onco-hematologic disease (77.8%) and the lowest in patients with renal disease (5.6%). Based on multivariate logistic regression analysis, the presence of higher severity of illness score at admission (adjusted odds ratio, 1.49; 95% CI, 1.18-1.89; p < 0.001), onco-hematologic disease (odds ratio, 17.10; 95% CI, 4.10-72.17; p < 0.001), fluid overload 10%-20% (odds ratio, 3.83; 95% CI, 1.33-11.07; p = 0.013), greater than 20% (odds ratio, 15.03; 95% CI, 4.03-56.05; p < 0.001), and timing of initiation of continuous renal replacement therapy (odds ratio, 1.01; 95% CI, 1.00-1.01; p = 0.040) were independently associated with mortality. In our population, the odds of dying increases by 1% for every hour of delay in continuous renal replacement therapy initiation from ICU admission. CONCLUSIONS: Mortality in children requiring continuous renal replacement therapy remains high and seems to be related to the underlying disease, the severity of illness, and the degree of fluid overload. In critically ill children at high risk for developing acute kidney injury and fluid overload, earlier initiation of continuous renal replacement therapy might result in decreased mortality.

Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich's Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. Methods: Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n = 57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR = 2-9) years and it improved significantly after the introduction of genetic testing (2(IQR = 1-5) years, p < 0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI [5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p = 0.001) as well as in b) patients with late-onset (3(IQR = 1-7) vs 2(IQR = 1-5) years compared to typical onset < 25 years of age, p = 0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r = - 0,6; p < 0,0001), but not in patients with non-neurological presentation (r = - 0,1; p = 0,4). Across 54 siblings' pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r = - 0,14, p = 0,3). Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history., SCOPUS: ar.j, info:eu-repo/semantics/published

Data linkage is of paramount importance in the evaluation of treatment regimens for chronic diseases where different health care sectors are involved. A comprehensive picture of long-term treatment effects and, in particular, the cost-effectiveness ratio of treatment approaches can only be drawn when data from various sources are merged and analyzed together.Regarding post-acute stroke care, the present study gives an example of an exact deterministic data linkage procedure including clinical patient records and claims data of TGKK, the main Tyrolean statutory health insurance fund. Typical problems known from other data linkage projects also emerged in the so-called StrokeCard program conducted at the Medical University of Innsbruck. Distinctive Austrian features (the majority of the Austrian population benefits from a mandatory social insurance system without freedom of choice) facilitated the feasibility of the data linkage procedures.Over the recruitment period 01/2014-12/2015, 540 patients could be assigned to the operative dataset. Of these, 367 patients were part of the StrokeCard group (i. e. the treatment group), and 173 belonged to the usual care group (i. e. the control group); 11 patients did not complete the one-year follow-up period (7 treatment group patients vs. 4 control group patients); 7 of them died during the study (5 treatment group patients vs. 2 control group patients). For all 540 patients, TGKK claims data were available for the time-frames of one year before recruitment and one year after discharge from the University hospital. All data could be used in the health-economic evaluation of the StrokeCard program.The linking of clinical patient records with data collected by SHI funds opens a window of opportunities for analyses of medical care. Counter-intuitively, Austrian health services research activities have limited experience in data linkage approaches, alhough studies based on the linkage of clinical patient records and claims data are indispensable for the evaluation of complex multi-sectoral treatment schemes. The current project proves the feasibility of data linkage mechanisms in the Austrian context. This should be regarded as an impetus for extending data linkage principles to evaluation studies in the future.Datenlinkage-Verfahren sind von erheblicher Bedeutung für die Evaluation von Therapieregimes chronischer Erkrankungen, bei denen Patient/inn/en zwischen verschiedenen Versorgungssektoren navigieren. Ein umfassendes Bild langfristiger Effekte und der Kosten-Effektivität der Behandlung kann nur gezeichnet werden, wenn Daten verschiedener Provenienz miteinander verknüpft werden.Am Beispiel der post-akuten Versorgung des Schlaganfalls veranschaulicht die vorliegende Studie, wie per exaktem deterministischem Datenlinkage klinische Patient/inn/endaten (Primärdaten) mit Routineabrechnungsdaten (Sekundärdaten) der Tiroler Gebietskrankenkasse (TGKK) verknüpft werden können. Die von Datenlinkage-Projekten bekannten Herausforderungen traten auch beim StrokeCard-Projekt der Medizinischen Universität Innsbruck auf, insgesamt jedoch begünstigten die Spezifika des österreichischen Gesundheitssystems (ein Großteil der Population ist in der Gebietskrankenkasse des jeweiligen Bundeslandes pflichtversichert) das Datenlinkage-Vorhaben.Im Rekrutierungszeitraum 01/2014–12/2015 konnten n=540 Pat. identifiziert und dem operativen Datensatz zugespielt werden. Davon waren n=367 Teil der StrokeCard-Gruppe (d. h. der Interventionsgruppe), n=173 gehörten der Standardversorgungsgruppe an (d. h. der Kontrollgruppe); n=11 Pat. haben das 1-Jahres-Follow-up nicht beendet (n=7 Pat. der Interventionsgruppe vs. n=4 Pat. der Kontrollgruppe); n=7 Pat. verstarben während der Studie (n=5 Pat. der Interventionsgruppe vs. n=2 Pat. der Kontrollgruppe). Für alle 540 Pat. waren TGKK-Routinedaten für 1 Jahr vor Rekrutierung bis 1 Jahr nach Entlassung aus der Klinik verfügbar. Alle Daten konnten für die gesundheitsökonomische Evaluation verwendet werden.Mit diesem Projekt wurde die Machbarkeit der Verknüpfung von Primär- und Sekundärdaten unterschiedlicher Herkunft untersucht. Trotz günstiger Rahmenbedingungen hat die österreichische Versorgungsforschung nur begrenzte Erfahrungen auf diesem Gebiet. Die Ergebnisse zeigen, dass ein unter Datenschutzkautelen betriebenes Linkage gelingen kann und aufgrund der Verfügbarkeit relevanter Informationen aus Abrechnungsdaten eine empirische Bereicherung insbesondere für gesundheitsökonomische Analysen darstellt. Dies sollte als Anregung verstanden werden, in Evaluationsstudien Datenlinkage-Prozeduren in Zukunft in verstärktem Maße einzusetzen.

Evaluation of clinical effectiveness of medical devices differs in some aspects from the evaluation of pharmaceuticals. One of the main challenges identified is lack of robust evidence and a will to make use of experimental and observational studies (OSs) in quantitative evidence synthesis accounting for internal and external biases. Using a case study of total hip replacement to compare the risk of revision of cemented and uncemented implant fixation modalities, we pooled treatment effect estimates from OS and RCTs, and simplified existing methods for bias-adjusted evidence synthesis to enhance practical application. We performed an elicitation exercise using methodological and clinical experts to determine the strength of beliefs about the magnitude of internal and external bias affecting estimates of treatment effect. We incorporated the bias-adjusted treatment effects into a generalized evidence synthesis, calculating both frequentist and Bayesian statistical models. We estimated relative risks as summary effect estimates with 95% confidence/credibility intervals to capture uncertainty. When we compared alternative approaches to synthesizing evidence, we found that the pooled effect size strongly depended on the inclusion of observational data as well as on the use bias-adjusted estimates. We demonstrated the feasibility of using observational studies in meta-analyses to complement RCTs and incorporate evidence from a wider spectrum of clinically relevant studies and healthcare settings. To ensure internal validity, OS data require sufficient correction for confounding and selection bias, either through study design and primary analysis, or by applying post-hoc bias adjustments to the results. © 2017 The Authors. Health Economics published by John Wiley & Sons, Ltd.

Objective: To examine the association between grip strength and history of falls among older individuals, and to assess the possible mediating effect of balance problems on this relationship. Method: Data originate from KORA (Cooperative Health Research in the Region of Augsburg)-Age Study of 808 individuals (65 years and above). Follow-up assessment occurred 3 years later. Results: The risk of falls within the last 12 months was reduced on average by 3% (odds ratio [OR] 95% confidence interval [95% CI] = 0.97 [0.94, 0.99]; p value = .026) per 1-kg increase in maximum grip strength after adjusting for age and gender. There was a trend toward an indirect effect of grip strength through the mediator variable balance problems ( p value = .043). Discussion: Increased muscular strength is associated with a reduced risk of falls in older age after adjustment for age and gender. The association is partially mediated by balance problems. Thus, in older adults, muscle-strengthening exercises may decrease the risk of falling.

Purpose: The international multicentre FAME Study (n=1,005) demonstrated significant health benefits for patients undergoing multivessel percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) measurement compared with angiography guidance alone (ANGIO). We determined the cost-effectiveness and the public health/budget impact for Australia. Methods: We performed a prospective economic evaluation comparing FFR vs. ANGIO in patients with multivessel disease based on original patient-level FAME data. We used Australian utilities (EQ-5D) and costs to calculate quality-adjusted life years (QALYs) and incremental cost-effectiveness adopting the societal perspective. The public health and budget impact from the payer's perspective was based on Australian PCI registries. Uncertainty was explored using deterministic sensitivity analyses and the bootstrap method (n=5,000 samples). Results: The cost-effectiveness analysis showed that FFR was cost-saving and reduces costs by 1,776 AUD per patient during one year. Over a two-year time horizon, the public health impact ranged from 7.8 to 73.9 QALYs gained and the budget impact from 1.8 to 14.5 million AUD total cost savings. Sensitivity analyses demonstrated that FFR was cost-saving over a wide range of assumptions. Conclusions: FFR-guided PCI in patients with multivessel coronary disease substantially reduces cardiac events, improves QALYs and is cost-saving in the Australian health care system.

Background Reduced muscular strength in the old age is strongly related to activity impairment and mortality. However, studies evaluating the gender-specific association between muscularity and mortality among older adults are lacking. Thus, the objective of the present study was to examine gender differences in the association between muscular strength and mortality in a prospective population-based cohort study. Methods Data used in this study derived from the Cooperative Health Research in the Region of Augsburg (KORA)-Age Study. The present analysis includes 1,066 individuals (mean age 76 ± 11 SD years) followed up over 3years. Handgrip strength was measured using the Jamar Dynamometer. A Cox proportional hazard model was used to determine adjusted hazard ratios of mortality with 95% confidence intervals (95% CI) for handgrip strength. Potential confounders (i.e. age, nutritional status, number of prescribed drugs, diseases and level of physical activity) were pre-selected according to evidence-based information. Results During the follow-up period, 56 men (11%) and 39 women (7%) died. Age-adjusted mortality rates per 1,000 person years (95% CI) were 77 (59–106), 24 (13–41) and 14 (7–30) for men and 57 (39–81), 14 (7–27) and 1 (0–19) for women for the first, second and third sex-specific tertile of muscular strength, respectively. Low handgrip strength was significantly associated with all-cause mortality among older men and women from the general population after controlling for significant confounders. Hazard ratios (95% CI) comparing the first and second tertile to the third tertle were 3.33 (1.53–7.22) and 1.42 (0.61-3.28), respectively. Respective hazard ratios (95% CI) for mortality were higher in women than in men ((5.23 (0.67–40.91) and 2.17 (0.27–17.68) versus 2.36 (0.97–5.75) and 0.97 (0.36–2.57)). Conclusions Grip strength is inversely associated with mortality risk in older adults, and this association is independent of age, nutritional status, number of prescribed drugs, number of chronic diseases and level of physical activity. The association between muscular strength and all-cause mortality tended to be stronger in women. It seems to be particularly important for the weakest to enhance their levels of muscular strength in order to reduce the risk of dying early. &nbsp

Evaluation of clinical effectiveness of medical devices differs in some aspects from the evaluation of pharmaceuticals. One of the main challenges identified is lack of robust evidence and a will to make use of experimental and observational studies (OSs) in quantitative evidence synthesis accounting for internal and external biases. Using a case study of total hip replacement to compare the risk of revision of cemented and uncemented implant fixation modalities, we pooled treatment effect estimates from OS and RCTs, and simplified existing methods for bias-adjusted evidence synthesis to enhance practical application. We performed an elicitation exercise using methodological and clinical experts to determine the strength of beliefs about the magnitude of internal and external bias affecting estimates of treatment effect. We incorporated the bias-adjusted treatment effects into a generalized evidence synthesis, calculating both frequentist and Bayesian statistical models. We estimated relative risks as summary effect estimates with 95% confidence/credibility intervals to capture uncertainty. When we compared alternative approaches to synthesizing evidence, we found that the pooled effect size strongly depended on the inclusion of observational data as well as on the use bias-adjusted estimates. We demonstrated the feasibility of using observational studies in meta-analyses to complement RCTs and incorporate evidence from a wider spectrum of clinically relevant studies and healthcare settings. To ensure internal validity, OS data require sufficient correction for confounding and selection bias, either through study design and primary analysis, or by applying post-hoc bias adjustments to the results. © 2017 The Authors. Health Economics published by John WileySons, Ltd.

The attitude of nurses influences their application of the Advanced Nursing Process. Studies reveal deficits in the application of the Advanced Nursing Process that is based on valid assessments and nursing classifications. These deficits affect decision-making and – as a result – nursing care quality. In German speaking countries nurses' attitudes towards nursing diagnoses as part of the Advanced Nursing Process were not yet measured.The aim of this study was to evaluate the effects of an educational intervention on nurses' attitude.A quasi-experimental intervention study was carried out in Austria and Germany. Before and after a standardised educational intervention 51 nurses estimated their attitude with the instrument Positions on Nursing Diagnosis (PND). Analyses were performed by Wilcoxon- and U-tests.Before the educational intervention the average attitude score of the Austrian nurses was more positive than in the German group. After the study intervention both groups regarded nursing diagnostics statistically significant more convincing and better understandable. However, both groups still described the application of the Advanced Nursing Process as difficult and demanding to perform.In the future, more attention should be given to the reflexion and development of nurses' attitude towards the Advanced Nursing Process because attitudes lead nurses' actions. In further studies influencing organizational and structural factors in diverse settings will be analysed.

Background The treatment of intracranial aneurysms may be associated with cerebral ischemia. We hypothesize that pre-interventional remote ischemic preconditioning (RIPC) reduces ischemic cerebral tissue damage in patients undergoing elective intracranial aneurysm treatment. Methods/Design This study is a single-center, prospective, randomized, double-blind explorative trial. Patients with an unruptured intracranial aneurysm admitted to Innsbruck Medical University Hospital for coiling or clipping will be consecutively randomized to either the intervention group (= RIPC by inflating an upper extremity blood-pressure cuff for 3 x 5 min to 200 mmHg) or the control group after induction of anesthesia. Participants will be randomized 1:1 to either the preconditioning group or the sham group using a random allocation sequence and block randomization. The precalculated sample size is n = 24 per group. The primary endpoint is the area-under-the-curve concentration of serum biomarkers (S100B, NSE, GFAP, MMP9, MBP, and cellular microparticles) in the first five days after treatment. Secondary endpoints are the number and volume of new ischemic lesions in magnetic resonance imaging and clinical outcome evaluated with the National Institutes of Health Stroke Scale, the modified Rankin Scale, and neuropsychological tests at six and twelve months. All outcome variables will be determined by observers blinded to group allocation. This study was approved by the local institutional Ethics Committee (UN5164), version 3.0 of the study protocol, dated 20 October 2013. Discussion This study uses the elective treatment of intracranial aneurysms as a paradigmatic situation to explore the neuroprotective effects of RIPC. If effects are demonstrable in this pilot trial, a larger, prospective phase III trial will be considered. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1102-6) contains supplementary material, which is available to authorized users.

Background— The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study demonstrated significantly improved health outcomes at 1 year in patients randomized to multivessel percutaneous coronary intervention guided by fractional flow reserve (FFR) compared with percutaneous coronary intervention guided by angiography alone. The economic impact of routine measurement of FFR in this setting is not known. Methods and Results— In this study, 1005 patients were randomly assigned to FFR-guided or angiography-guided percutaneous coronary intervention and followed up for 1 year. A prospective cost-utility analysis comparing costs and quality-adjusted life-years was performed with a time horizon of 1 year. Quality-adjusted life-years were calculated with the use of utilities determined by the EuroQuol 5 dimension health survey with US weights. Direct medical costs included those of the index procedure and hospitalization and costs for major adverse cardiac events during follow-up. Confidence intervals for both quality-adjusted life-years and costs were estimated by the bootstrap percentile method. Major adverse cardiac events at 1 year occurred in 13.2% of those in the FFR-guided arm and 18.3% of those in the angiography-guided arm ( P =0.02). Quality-adjusted life-years were slightly greater in the FFR-guided arm (0.853 versus 0.838; P =0.2). Mean overall costs at 1 year were significantly less in the FFR-guided arm ($14 315 versus $16 700; P Conclusion— Economic evaluation of the FAME study reveals that FFR-guided percutaneous coronary intervention in patients with multivessel coronary disease is one of those rare situations in which a new technology not only improves outcomes but also saves resources. Clinical Trial Registration— URL: http://ClinicalTrials.gov . Unique identifier: NCT00267774.

Surrogate endpoints are attractive in clinical trials when the primary endpoint is difficult to measure because of time, costs, the need to test multiple regimens, ethical considerations, or pressure from patient advocacy groups (27;41). In advanced breast cancer, prolongation of survival and symptom improvement are commonly accepted as evidence of clinical benefit and as appropriate primary endpoints (27;65). However, a validated surrogate endpoint allows for inferences about a treatment’s benefit when primary endpoint data are not available (6;7;26). One potential surrogate endpoint for overall survival (OS) in advanced breast cancer is progression-free survival (PFS), a composite endpoint defined by the United States (U.S.) Food and Drug Administration (FDA) as the time from randomization to documented progression or death from any cause (25;65). However, the association between PFS and OS has not been systematically evaluated in advanced breast cancer for anthracycline and taxane-based chemotherapy. PFS includes death as part of its composite endpoint— and, therefore, differs from other progression-based endpoints. For example, time to progression is defined by the U.S. FDA as the time from randomization until tumor progression (death is censored), and time to treatment failure is a composite endpoint defined as the time from randomization until the patient stops the trial treatment for any reason including progression, toxicity, or preference (death is censored) (25;65). The inclusion of death in PFS may be important in advanced breast cancer because tumor growth, whether or not it is documented, usually precedes death. In other words, background mortality contributes relatively little to the 2-year median survival for advanced breast cancer and death likely reflects the treatment’s ability, or lack thereof, to control disease progression (30;64;65). Therefore, censored deaths may constitute informative censoring and may impact the ability of other progression-based endpoints to predict OS. Because PFS uniquely overcomes this limitation by including death, its ability to predict OS should be evaluated separately from other progression-based endpoints. PFS has additional benefits as an endpoint because it is measured before postprogression treatments are initiated. Therefore, PFS data is not affected by postprotocol agents. Furthermore, PFS is measured earlier and has a higher event frequency compared to OS. Consequently, PFS results may be available sooner and, potentially, with smaller and less costly trials (2;22;33). However, PFS has several potential limitations that it shares with all progression-based endpoints. The need for frequent radiologic studies raises the potential for assessment bias and increases the complexity of data capture and validation (25;65). PFS may be sensitive to differences in the duration between assessments (25;47), unprotocolled assessments (25;47), variations in censoring (25;46), and the use of cytostatic agents (67). Furthermore, variability in PFS measurement may be magnified when it is used to predict OS (20;26). With multiple effective therapies available for advanced breast cancer, the link between PFS and OS may be distorted by nonprotocolled treatments given after the trial regimen (19;22;33). Although PFS has not been systematically evaluated in advanced breast cancer for anthracyclineand taxane-based chemotherapy, studies suggest that time to progression and response rate have a statistically significant association with OS (1;33). However, only 34 to 37 percent of OS variability was explained by variability in time to progression and response rate, respectively (1;33). An abstract suggested a similar result (R2 = .44) for PFS for trials comparing taxane and anthracycline chemotherapy (13). However, cross-validation was not performed for this narrowly defined set of trials. Although there is controversy about the optimal approach for validating surrogate endpoints (12;15;42), one option is to evaluate performance at the trial level (33). The primary aim of this study was to evaluate the association between the direction and magnitude of the treatment effect on PFS compared with the treatment effect on OS for anthracycline- and taxane-based chemotherapy regimens in advanced breast cancer using a trial-based, meta-analytic approach. We limited our analysis (and the generalization of our results) to anthracycline- and taxane-based chemotherapy for advanced breast cancer because the relationship between PFS and OS may differ for different anti-cancer agents and in different cancers due to underlying biologic factors, the interaction of each anti-cancer agent with each cancer, and differences in the availability of active subsequent line treatments (26).

Background The survival of heart transplant patients is limited by cardiac allograft vasculopathy (CAV). Intravascular ultrasound (IVUS) and IVUS-derived radiofrequency plaque composition analysis (IVUS-RF) provide further information about the process of coronary atherosclerosis. Methods In this study we aimed to assess the time-dependent differences in disease progression in patients with CAV. Fifty-six patients were divided into three groups according to time interval after transplantation (Group I: 1 to 3 months, 18 patients; Group II, 1 to 5 years, 20 patients; Group III: 5 to 15 years, 18 patients). Results IVUS-RF revealed time-dependent increases in all plaque components. The largest increase was shown for fibrotic, fibrofatty and necrotic tissue between Groups I and II. Dense calcium area increased uniformly in all groups. IVUS-RF–derived plaque type analysis revealed predominantly fibrotic plaques in all groups with a decrease of frequency over time. Fibrolipidic and fibrotic–calcific plaques increased uniformly. High-risk lesions, such as thick-cap fibroatheromas (FAs), increased in Groups I and II and decreased in Group III. Thin-cap FAs were detected only in Group III. Conclusions IVUS-RF, as compared with gray-scale IVUS, provides better detailed information about the development of CAV by plaque morphology and composition analysis in different stages after heart transplantation. Serial IVUS-RF analysis in these patients may improve the stratification of heart transplant recipients.

Objective The present trial evaluated incorporation of bright light therapy in the treatment of chronic nonspecific back pain (CNBP). Design A prospective, randomized, controlled, multicenter, open design with three parallel trial arms was used. Setting Subjects received a novel therapeutic, an expected therapeutic ineffective low dose, or no light exposure at three different medical centers. Patients A total of 125 CNBP patients reporting pain intensity of ≥3 points on item 5 of the Brief Pain Inventory (BPI) were included. Intervention Over 3 weeks, 36 active treatment, 36 placebo controls, and 33 controls received 3 or no supplementary light exposures of 5.000 lx or 230 lx, respectively. Outcome Measures Changes in self-reported scores of pain intensity (BPI sub-score 1) and depression (Hospital Anxiety and Depression Questionnaire) were the primary outcome measures. Secondary outcome measures were changes in self-reported overall pain sensation (BPI total score), grade of everyday life impairment (BPI sub-score 2), mood (visual analog scale), and well-being (World Health Organization-Five Well-Being Index). Results Changes in pain intensity were higher (1.0 [0.8–1.6]) in the bright light group compared with controls (0.3 [−0.1–0.8]; effect size D = 0.46). Changes in the depression score were also higher in the intervention group (1.5 [0.0–2.5]) compared with controls (0.0 [0.0–2.0]; effect size D = 0.86). No differences were seen in change scores between intervention vs sham group. Conclusion The present randomized controlled trial shows that light therapy even in low dose could improve depressive symptoms and reduce pain intensity in CNBP patients. Further research is needed for optimizing parameters of frequency, dose, and duration of therapeutic light exposure.

Commercialization of trekking tourism enables untrained persons to participate in trekking tours. Because hypoxia is one of the main purported triggers for acute mountain sickness (AMS), pulse oximetry, which measures arterial oxygen saturation (SPO2), is discussed to be a possible and useful tool for the diagnosis of AMS. The purpose of this study was to evaluate possible associations between SPO2 values and the occurrence of AMS. In 204 trekkers, SPO2 values (pulse oximetry) were measured and the Lake Louise Self-assessment Score (LLS) was administered over the first 7 days of their trekking tours. During treks at altitudes of 2500–5500 m in Nepal, India, Africa, and South America, 100 participants suffered from mild AMS, 3 participants suffered from severe AMS, and 9 participants reported both mild and severe AMS. The lowest mean SPO2 was 85.5 (95 % confidence interval (CI), 83.9–86.1 %) on day 5. SPO2 and LLS exhibited a weak to moderate negative correlation for all days of the study (ρ ranging from −0.142 to −0.370). Calculation of time-shifted associations of 24 and 48 h resulted in the disappearance of most associations. Susceptibility to headaches (odds ratio (OR) 2.9–7.2) and a history of AMS (OR 2.2–3.1) were determined to be potential risk factors for the development of AMS. Since there is no strong altitude-independent association between AMS and SPO2 during the first week of high-altitude adaptation, the implementation of pulse oximetry during trekking in order to detect and predict AMS remains questionable.

Objective. Bright light therapy (BLT) is regarded to be an effective treatment against seasonal depression (SAD). Conventional BLT devices are reported to evoke few, but inconvenient symptoms. This study evaluated side effects associated with a new technology for BLT in a healthy population. Methods. In an uncontrolled study design 20 healthy Caucasians received 30 min light exposures on three consecutive mornings. Immediate side effects were evaluated using questionnaires. The new light cabin was equipped with fluorescent lamps (light colour 965 = 6,500 K, CRI >90) with a maximum illumination of 5,000 lux and a maximum luminance of 1,500 cd/m(2). Occurrence of headache was determined to be the main objective. Results. Nineteen volunteers completed the study. No headache was reported at any time. With a prevalence of 21.1% blurring was observed to occur more often after light exposure. Conclusion. With the evaluated light cabin the most prominent short-term side effects of BLT can be minimized, enhancing patients' adherence.

Immobility plus preexisting chronic disease or acute trauma can activate the coagulation system, thus increasing the risk for thromboembolic events. The effects of long-term bed-rest immobility and microgravity on the coagulation system of healthy persons (e.g., during crewed Mars missions) have not yet been studied. The main objective of the second Berlin BedRest Study (BBR2-2) "Coagulation Part" was to investigate adaptations of the hemostatic system during long-term bed rest (60 days) under simulated microgravity (6° head-down-tilt [6°HDT]) and after mobilization in three different volunteer groups (randomly assigned to CTR= inactive control group; RE= resistive exercise only group; and RVE= resistive exercise with whole-body vibration group). In 24 males (aged 21-45 years), before, during, and after long-term bed rest, key parameters of coagulation were measured from venous blood samples: D-dimer (DD), thrombin-antithrombin III complex (TAT), and prothrombin fragment F1 + 2 (PT-F1 + 2). Additionally, modified rotational thrombelastometry (ROTEM (®) ) analysis was performed. Times of exploratory analyses were as follows: baseline data collection 2 days before bed rest (BDC-2); eight different days of 6°HDT bed rest (HDT1-HDT60), and two different days after reambulation (R + 3 and R + 6). We found significant changes in DD, TAT, and PT-F1 + 2 over the total time course, but no consistent effect of physical interventions (RE, RVE) on these parameters. Notably, no parameter reached levels indicative of intravascular thrombin formation. All ROTEM® parameters remained within the normal range and no pathological traces were found. Sixty days of 6°HDT bed rest are not associated with pronounced activation of the coagulation system indicative of intravascular thrombus formation in healthy volunteers independent of the training type during the bed rest.

BACKGROUND Inflammatory bowel disease can decrease the quality of life and induce work disability. We sought to (1) identify and quantify the predictors of disease-specific work disability in patients with inflammatory bowel disease and (2) assess the suitability of using cross-sectional data to predict future outcomes, using the Swiss Inflammatory Bowel Disease Cohort Study data. METHODS A total of 1187 patients were enrolled and followed up for an average of 13 months. Predictors included patient and disease characteristics and drug utilization. Potential predictors were identified through an expert panel and published literature. We estimated adjusted effect estimates with 95% confidence intervals using logistic and zero-inflated Poisson regression. RESULTS Overall, 699 (58.9%) experienced Crohn's disease and 488 (41.1%) had ulcerative colitis. Most important predictors for temporary work disability in patients with Crohn's disease included gender, disease duration, disease activity, C-reactive protein level, smoking, depressive symptoms, fistulas, extraintestinal manifestations, and the use of immunosuppressants/steroids. Temporary work disability in patients with ulcerative colitis was associated with age, disease duration, disease activity, and the use of steroids/antibiotics. In all patients, disease activity emerged as the only predictor of permanent work disability. Comparing data at enrollment versus follow-up yielded substantial differences regarding disability and predictors, with follow-up data showing greater predictor effects. CONCLUSIONS We identified predictors of work disability in patients with Crohn's disease and ulcerative colitis. Our findings can help in forecasting these disease courses and guide the choice of appropriate measures to prevent adverse outcomes. Comparing cross-sectional and longitudinal data showed that the conduction of cohort studies is inevitable for the examination of disability.

UnlabelledDemographic changes and a more active life-style in older age have contributed to an increasing public awareness of the need for lifelong vaccination. Currently many older persons have been vaccinated against selected pathogens during childhood but lack regular booster immunizations. The impact of regular vaccinations when started late in life was analyzed in an open, explorative trial by evaluating the immune response against tetanus and diphtheria in healthy older individuals. 252 persons aged above 60 years received a booster vaccination against tetanus, diphtheria, pertussis and polio and a subcohort (n=87) was recruited to receive a second booster vaccination against tetanus, diphtheria and pertussis 5 years later. The percentage of unprotected individuals at the time of enrollment differed substantially for tetanus (12%) and diphtheria (65%). Despite protective antibody concentrations 4 weeks after the first vaccination in almost all vaccinees, antibodies had again dropped below protective levels in 10% (tetanus) and 45% (diphtheria) of the cohort after 5 years. Protection was restored in almost all vaccinees after the second vaccination. No correlation between tetanus- and diphtheria-specific responses was observed, and antibody concentrations were not associated with age-related changes in the T cell repertoire, inflammatory parameters, or CMV-seropositivity suggesting that there was no general biological "non-responder type." Post-vaccination antibody concentrations depended on pre-existing plasma cells and B cell memory as indicated by a strong positive relationship between post-vaccination antibodies and pre-vaccination antibodies as well as antibody-secreting cells. In contrast, antigen-specific T cell responses were not or only weakly associated with antibody concentrations. In conclusion, our findings demonstrate that single shot vaccinations against tetanus and/or diphtheria do not lead to long-lasting immunity in many elderly persons despite administration at relatively short intervals. Sufficient antigen-specific B cell memory B generated by adequate priming and consecutive booster vaccinations and/or exposure is a prerequisite for long-term protection.Trial registrationEU Clinical Trials Register (EU-CTR); EudraCT number 2009-011742-26; www.clinicaltrialsregister.eu/ctr-search/trial/2009-011742-26/AT.

Background and aims: In many developing countries, gold mining is performed using mercury. Mercury is used to extract gold from ore. Mercury exposure leads to negative health effects. The aim of th...

In many developing countries, mercury is used to extract gold from ore in small-scale mining areas. Exposure through mercury in these small-scale mining communities is a serious health hazard, especially to the children living and working there. Many children begin working with immediate contact to mercury from the very early age of seven. In Indonesia and Zimbabwe, 166 children were clinically examined for mercury. The mercury concentration in the blood, urine, and hair was analyzed. Compared to the control groups, the exposed children showed typical symptoms of mercury intoxication, such as ataxia. The children working with mercury had high levels of this substance in the various biomonitors. The exposure derives mainly from the liquid mercury used to bind gold, forming an amalgam. The amalgam is heated and the smelting amalgam releases mercury vapor plus the wanted gold. Mercury vapor in contrast to liquid mercury is highly toxic. This elemental, vaporized mercury is the main form of exposure. Since in over 50 countries children live in small-scale gold mining areas and are exposed in a similar way to mercury, immediate action is needed to reduce this severe chemical health hazard for children. Child labor with hazardous substances such as mercury must be stopped.