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Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials.Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1.73 m(2), or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria.Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3.4 years (IQR 2.3-4.2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0.89 (95% Bayesian credible interval [BCI] 0.13-1.70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R-2 0.47, 95% BCI 0.02-0.96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3.4 mg/mmol; R-2 0.72, 0.05-0.99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0.7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0.68, and 95% of sufficiently large studies would have HRs between 0.47 and 0.95.Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

There are various settings in which researchers are interested in the assessment of the correlation between repeated measurements that are taken within the same subject (i.e., reliability). For example, the same rating scale may be used to assess the symptom severity of the same patients by multiple physicians, or the same outcome may be measured repeatedly over time in the same patients. Reliability can be estimated in various ways, for example, using the classical Pearson correlation or the intra-class correlation in clustered data. However, contemporary data often have a complex structure that goes well beyond the restrictive assumptions that are needed with the more conventional methods to estimate reliability. In the current paper, we propose a general and flexible modeling approach that allows for the derivation of reliability estimates, standard errors, and confidence intervals – appropriately taking hierarchies and covariates in the data into account. Our methodology is developed for continuous outcomes together with covariates of an arbitrary type. The methodology is illustrated in a case study, and a Web Appendix is provided which details the computations using the R package CorrMixed and the SAS software. Copyright © 2016 John Wiley & Sons, Ltd.

Background There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. Methods We obtained baseline 6-[ 18 F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence ( n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (k loss ); and the tracer distribution volume (V d ), which is an index of dopamine storage capacity. Results Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, V d significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. Conclusions The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments.

Purpose To report anatomical and functional outcome of 20-gauge versus 25-gauge primary pars plana vitrectomy for management of complex rhegmatogenous retinal detachment in pseudophakic eyes. Methods Prospective single-centre randomized comparative pilot trial. Fifty patients with retinal detachment (RD) not complicated by proliferative vitreoretinopathy grade B or C, who cannot be treated with a single meridional sponge, were randomized (1:1) from November 2006 to January 2010 to either 20-gauge or 25-gauge vitrectomy as first surgical intervention and followed up over a 12-month period, evaluating change in best-corrected visual acuity, anatomical success and intraocular pressure dysregulation. Results Mean visual acuity improved by 0.88 (SD 0.67) from 1.22 logMAR (SD 0.63) to 0.34 logMAR (SD 0.31) in the 20-gauge group and by 0.53 (SD 0.91) from 0.86 logMAR (SD 0.73) to 0.34 logMAR (SD 0.46) in the 25-gauge group. Final anatomical success rate was 100% and primary success rate was 69% at 6 months of follow-up. In the 20-gauge group, the retina was attached after one single procedure in 18 eyes (72%) and in 21 eyes (84%) of the 25-gauge group. Two patients in the 25-gauge group had hypotony at the first postoperative day which normalized within 6 weeks. Conclusion In our series, transconjunctival sutureless 25-gauge and 20-gauge vitrectomy showed comparable results in pseudophakic RD not suitable for single sponge surgery with respect to visual outcome and retinal reattachment. Postoperative hypotony does not seem to be a significant problem of transconjunctival sutureless vitrectomy.

The essential trace element zinc is indispensable for proper immune function as zinc deficiency accompanies immune defects and dysregulations like allergies, autoimmunity and an increased presence of transplant rejection. This point to the importance of the physiological and dietary control of zinc levels for a functioning immune system. This study investigates the capacity of zinc to induce immune tolerance. The beneficial impact of physiological zinc supplementation of 6 mu g/day (0.3 mg/kg body weight) or 30 mu g/day (1.5 mg/kg body weight) on murine experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis with a Th1/Th17 (Th, T helper) cell-dominated immunopathogenesis, was analyzed. Zinc administration diminished EAE scores in C57BL/6 mice in vivo (P

Zinc is an essential trace element, regulating immune function. Its deficiency results in immune dysfunction and transplant rejection. In here, a benefit of zinc supplementation for the induction of tolerance was investigated, focussing on the TH 1-dominated allogeneic immune reaction. Allogeneic immune reaction was modelled by mixed lymphocyte culture (MLC). The effect of zinc supplementation was monitored via expression of cytokines and surface lineage markers using ELISA and flow cytometry. Epigenetic analyses were performed to investigate mechanisms underlying zinc-induced changes in Treg activation. Results reveal that Tregs are induced when MLCs are treated with 50 μM zinc causing a decrease in IFNγ production. IL-2 and IL-10 expression were not affected. The teleology of this effect includes the inhibition of histone deacetylase Sirt-1-mediated Foxp3 deacetylation, resulting in its decreased degradation. In conclusion, zinc should be considered to prevent Graft-versus-Host disease (GVHD) as it is capable of stabilizing iTregs, resulting in increased numbers of this celltype while not suppressing the immune system. This article is protected by copyright. All rights reserved.

BACKGROUND: The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain. METHODS: We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio

Mammography is the gold standard for early breast cancer detection, but shows important limitations. Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography.Potential biomarkers were identified from The Cancer Genome Atlas (TCGA), using HumanMethylation450-BeadChip data. Promoter methylation status was evaluated quantitatively by pyrosequencing in a serum test cohort (Although liquid biopsy remains challenging, a combination of

Journal of statistical software 85(8), 1-22 (2018). doi:10.18637/jss.v085.i08, Published by UCLA, Dept. of Statistics, Los Angeles, Calif.

Background The Oxford classification of IgA nephropathy (IgAN) defines histologic criteria (MEST-C) that provide prognostic information based on the kidney biopsy. There are few data on the predictive impact of this classification in randomized clinical trial settings. Methods We performed an exploratory analysis of MEST-C scores in 70 available renal biopsies from 162 randomized STOP-IgAN trial participants and correlated the results with clinical outcomes. Analyses were performed by researchers blinded to the clinical outcome of the patients. Biopsies had been obtained 6.5 to 95 (median 9.4) months prior to randomization. Results Mesangial hypercellularity (M1) associated with higher annual eGFR-loss during the 3-year trial (M1: − 5.06 ± 5.17 ml/min/1.73 m2, M0: − 0.79 ± 4.50 ml/min/1.73 m2, p = 0.002). An M0-score additionally showed a weak association with full clinical remission, whereas the percentage of patients losing ≥15 ml/min/1.73 m2 over the 3-year trial phase was higher among those scored as M1. Among patients with additional immunosuppression, ESRD occurred more frequently in patients when tubulointerstitial fibrosis (T1/2) was present (T1/2 = 33%, T0 = 0%, p = 0.008). In patients receiving supportive care only, ESRD frequencies were similar (T1/2 = 18%, T0 = 7%, p = 0.603). At randomization, eGFR was significantly lower when tubulointerstitial fibrosis was present (T1/2: 45.2 ± 15.7 ml/min/1.73 m2, T0: 74.6 ± 28.2 ml/min/1.73 m2, p

Multiple lower limits of quantification (MLOQs) result if various laboratories are involved in the analysis of concentration data and some observations are too low to be quantified. For normally distributed data under MLOQs there exists only the multiple regression method of Helsel to estimate the mean and variance. We propose a simple imputation method and two new maximum likelihood estimation methods: the multiple truncated sample method and the multiple censored sample method. A simulation study is conducted to compare the performances of the newly introduced methods to Helsel's via the criteria root mean squared error (RMSE) and bias of the parameter estimates. Two and four lower limits of quantification (LLOQs), various amounts of unquantifiable observations and two sample sizes are studied. Furthermore, the robustness is investigated under model misspecification. The methods perform with decreasing accuracy for increasing rates of unquantified observations. Increasing sample sizes lead to smaller bias. There is almost no change in the performance between two and four LLOQs. The magnitude of the variance impairs the performance of all methods. For a smaller variance, the multiple censored sample method leads to superior estimates regarding the RMSE and bias, whereas Helsel's method is superior regarding the bias for a larger variance. Under model misspecification, Helsel's method was inferior to the other methods. Estimating the mean, the multiple censored sample method performed better, whereas the multiple truncated sample method performs best in estimating the variance. Summarizing, for a large sample size and normally distributed data we recommend to use Helsel's method. Otherwise, the multiple censored sample method should be used to obtain estimates of the mean and variance of data including MLOQs.

The aesthetic outcome of treatment has become increasingly important to patients having orthognathic surgery. The aim of this observational cohort study based on clinical records was to evaluate the effect of maxillary advancement on changes to the soft tissues. We studied 53 patients with class III malocclusion (29 women and 24 men, mean (SD) age 28 (11) years). We identified all patients treated between 1 January 2002 and 30 December 2013 who could be monitored postoperatively for 6 months. To study the effect of maxillary advancement on changes to the soft tissue we distinguished between patients who had had less than 6 mm, and those with 6 mm advancement or more. In those who had had less than 6 mm, we found no significant changes in the soft tissue in the region of the nasolabial angle. However, the lip-chin- throat angle (p=0.016), cervical length (p=0.002), lower lip (p=0.007) and upper lip distance (p=0.0001) from the aesthetic line changed significantly. On the other hand, the changes to the soft tissue in the submental and nasolabial regions were significant in patients with 6 mm advancement or more, and indicated a clear improvement in the aesthetic outcome of this region. This aesthetic change for the good in the submental and nasolabial regions after maxillary advancement of 6 mm or more should be considered when planning treatment, and reduction in the mandibular setback will reduce the risk of development of a double chin.

Patients’ need to improve outcomes and to reduce the number of complications triggers the development of new materials and surgery concepts. Currently, there are many implants and fixation systems dedicated for intraperitoneal onlay mesh procedure. The aim of this study was to compare two different mesh/fixation system concepts (PH: Physiomesh/Securestrap and VS: Ventralight ST/SorbaFix) for laparoscopic ventral hernia repair with respect to pain. A single-center, prospective, randomized study was designed to include 50 patients per group with a planned interim analysis for safety after 25 patients. The endpoints were pain occurrences and intensity, which was measured with the visual analogue scale 7 days, 30 days, 3 months and 6 months after surgery. The safety parameters included the number of recurrences and postoperative complications. During the interim analysis, the study was stopped due to safety reasons. We observed five (20 %) recurrences in the PH group in first 6 months and none in the VS group. We observed a significantly higher pain rate in the PH group after 3 months (p

Summary We provide an asymptotic test to analyze randomized clinical trials that may be subject to selection bias. For normally distributed responses, and under permuted block randomization, we derive a likelihood ratio test of the treatment effect under a selection bias model. A likelihood ratio test of the presence of selection bias arises from the same formulation. We prove that the test is asymptotically chi-square on one degree of freedom. These results correlate well with the likelihood ratio test of Ivanova et al. (2005, Statistics in Medicine 24, 1537–1546) for binary responses, for which they established by simulation that the asymptotic distribution is chi-square. Simulations also show that the test is robust to departures from normality and under another randomization procedure. We illustrate the test by reanalyzing a clinical trial on retinal detachment.

Iliac crest is still regarded as one of the most viable source of autogenous graft materials for extensive sinus floor elevation. Three-dimensional resorption behavior has to be taken into account in anticipation of the subsequent insertion of dental implants. We performed 3-dimensional volume measurements of the inserted bone transplants in 11 patients (6 women and 5 men; mean age = 2.3 years) who underwent bilateral sinus floor elevation with autogenous iliac crest grafts. In order to determine the respective bone graft volumes, cone-beam computerized tomography studies of the maxillary sinuses were carried out directly after the operation (T0), as well as 3 months (T1) and 6 months (T2) postoperatively. The acquired DICOM (Digital Imaging and Communications in Medicine) data sets were evaluated using suitable analysis software. We evaluated statistical significance of graft volumes changes using a linear mixed model with the grouping factors for time, age, side, and sex with a significance level of P = .05. 38.9% of the initial bone graft volume, which amounted to 4.2 cm3, was resorbed until T1. At T2, the average volume again decreased significantly by 18.9 % to finally reach 1.8 cm3. The results show neither age nor side dependency and apply equally to both sexes. Without functional load, iliac bone grafts feature low-volume stability in sinus-augmentation surgery. Further clinical and animal studies should be done to detect the optimal timing for implant placement.

The aim of this in vitro study was to evaluate the effect of combined CO2 laser and tin-containing fluoride treatment on the formation and progression of enamel erosive lesions. Ninety-six human enamel samples were obtained, stored in thymol solution and, after surface polishing, randomly divided into 6 different surface treatment groups (n = 16 in each group) as follows: no treatment, control (C); one CO2 laser irradiation (L1); two CO2 laser irradiations (L2); daily application of fluoride solution (F); combined daily fluoride solution + one CO2 laser irradiation (L1F), and combined daily fluoride solution + two CO2 laser irradiations (L2F). Laser irradiation was performed at 0.3 J/cm2 (5 µs/226 Hz/10.6 µm) on day 1 (L1) and day 6 (L2). The fluoride solution contained AmF/NaF (500 ppm F), and SnCl2 (800 ppm Sn) at pH 4.5. After surface treatment the samples were submitted to an erosive cycling over 10 days, including immersion in citric acid (2 min/0.05 M/pH = 2.3) 6 times daily and storage in remineralization solution (≥1 h) between erosive attacks. At the end of each cycling day, the enamel surface loss (micrometers) was measured using a 3D laser profilometer. Data were statistically analyzed by means of a 2-level mixed effects model and linear contrasts (α = 0.05). Group F (-3.3 ± 2.0 µm) showed significantly lower enamel surface loss than groups C (-27.22 ± 4.1 µm), L1 (-18.3 ± 4.4 µm) and L2 (-16.3 ± 5.3 µm) but higher than L1F (-1.0 ± 4.4 µm) and L2F (1.4 ± 3.2 µm, p < 0.05). Under the conditions of this in vitro study, the tin-containing fluoride solution caused 88% reduction of enamel surface loss, while its combination with CO2 laser irradiation at 0.3 J/cm2 hampered erosive loss almost completely.

Background In trauma patients, acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality. Changes in diagnostics, management, and treatment may have influenced the incidence of ARDS. Therefore, the purpose of this article is to evaluate whether there is a difference in the incidence of posttraumatic ARDS (1) over time, (2) attributable to geographic distribution, and 3) related to admitting surgical subspecialities. Methods A comprehensive search of articles published in English and German language was conducted using PubMed, MEDLINE, and the ISI Web of Science. Search terms included ARDS, acute respiratory distress syndrome, multiple trauma, polytrauma, and surgery. A meta-regression was performed to analyze differences between several decades of patient recruitment (decade 1, 1981-1990; decade 2, 1991-2000; decade 3, 2001-2010), geographic location (North America and Europe), and the type of admitting surgical service (general vs. orthopedic trauma), respectively. Statistical analyses were performed with R (version 3.1.2, metafor package). Results The search included studies between January 1, 1980, and December 31, 2015 and revealed 43 trials from 40 publications (117,951 patients, 7,816 with posttraumatic ARDS). The median incidences over the last three decades were similar between decade 1 (10.4%), decade 2 (7.7%), and decade 3 (8.0%) (p = 0.8322). Geographical observations comparing central Europe and North America revealed no statistically significant difference (Europe 13.0%) and North America (6.9%), (p = 0.0696). The ARDS incidence in patients published based on a general surgery service (9.8%) was comparable to those published by orthopedic trauma surgeons (7.0%) (p = 0.3436). Conclusion The results of this meta-analysis discard the assumption that the following factors have influenced the incidence of posttraumatic ARDS: There was neither a change in the incidence over the last decades, nor a geographical difference within western societies, nor associated with the admitting surgical subspeciality. Level of evidence Systematic review, level III.

Participant timeline: Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) diagram. (PDF 123 kb)

SPIRIT Checklist. (DOC 123 kb)

Background: Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients. Methods: VitaVasK is a prospective, randomized, parallel group, multicentre trial (EudraCT No.: 2010-021264-14) that will include 348 HD patients in an open-label, two-arm design. After baseline multi-slice computed tomography (MSCT) of the heart and thoracic aorta, patients with a coronary calcification volume score of at least 100 will be randomized to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly. Treatment duration will be 18 months, and MSCT scans will be repeated after 12 and 18 months. Primary end points are the progression of thoracic aortic and coronary artery calcification (calculated as absolute changes in the volume scores at the 18-month MSCT versus the baseline MSCT). Secondary end points comprise changes in Agatston score, mitral and aortic valve calcification as well as major adverse cardiovascular events (MACE) and all-cause mortality. VitaVask also aims to record MACE and all-cause mortality in the follow-up period at 3 and 5 years after treatment initiation. This trial may lead to the identification of an inexpensive and safe treatment or prophylaxis of VC in HD patients.

Background Currently, the monitoring of cardiac output (CO) and stroke volume (SV) is mainly performed using invasive techniques. Therefore, performing CO monitoring noninvasively by means of electrical impedance tomography (EIT) would be advantageous for intensive care. Our hypothesis was that, by means of EIT, it is possible to assess heart rate (HR) and to quantify changes in SV due to changes in ventilator settings. Methods CO (HR and SV) of 14 pigs (32-40 kg body weight) was changed by incremental increases in positive end-expiratory pressure levels (0, 5, 10, 15, and 20 cm·H2O; ramp maneuver). This ramp maneuver was applied 4 times in each animal, yielding 43 evaluable single experiments. At each positive end-expiratory pressure level, SV was assessed by transpulmonary thermodilution using a PiCCO device. EIT data were acquired using a Drager EIT Evaluation Kit 2. Results The EIT-based SV-related signal, Z(SV) (in [AU]), showed only a weak correlation (after excluding 2 measurements) with SV(TTD) of r = 0.58 (95% confidence interval, 0.43-0.71). If Z(SV) is calibrated by the reference 1 time for each experiment (defined as SVEIT), the correlation is approximately 0.85 (95% confidence interval, 0.78-0.90). A possible reason for the moderate correlation is the unexpected scaling pattern, leading to amplification of the cardiac impedance signal, found in some animals. The scaling is probably due to the imperfect reconstruction (i.e., a change of sensitivity) of the EIT images or to a change in the position of the heart. Conclusions The hypothesis that EIT can be used to monitor CO and SV was confirmed, but further studies are required before this technique can be applied in clinical practice. HR was determined robustly and accurately. For SV monitoring, promising results were obtained in 80% of the experiments. However, unexpected scaling of the cardiac EIT signal causing inaccurate estimation of SV remains an issue. Before robust assessment of SV by EIT is suitable for clinical practice, the cause of and compensation for undesired scaling effects need to be investigated.

SummaryThe demand for evidence-based health informatics and benchmarking of ‘good’ information systems in health care gives an opportunity to continue reporting on recent papers in the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE) here. The publications in focus deal with a comparison of benchmarking initiatives in German-speaking countries, use of communication standards in telemonitoring scenarios, the estimation of national cancer incidence rates and modifications of parametric tests. Furthermore papers in this issue of MIM are introduced which originally have been presented at the Annual Conference of the German Society of Medical Informatics, Biometry and Epidemiology. They deal as well with evidence and evaluation of ‘good’ information systems but also with data harmonization, surveillance in obstetrics, adaptive designs and parametrical testing in statistical analysis, patient registries and signal processing.

The reduction of central venous line (CVL)-associated bloodstream infections (CLABSIs) is generally advocated. However, despite implementing infection prevention recommendations, CLABSI rates remain high at some institutions. Therefore, a chlorhexidine-containing dressing should be assessed for its potential for infection reduction, adverse events (AEs) and practicability.The number of CVLs, CVL days, CLABSIs and CLABSI rates with regard to the kind of dressing (standard vs. chlorhexidine-containing) were documented from November 2010 to may 2012 (1,298 patients with 12,220 CVL days) at two intensive care units (ICUs) and compared to historical controls. The practicability and safety of the chlorhexidine-containing dressing and reasons for not using this dressing were assessed.Forty CLABSIs occurred in 34 patients, resulting in a significantly lower overall CLABSI rate in patients with the chlorhexidine-containing dressing [1.51/1,000 CVL days; confidence interval (CI): 0.75-2.70] compared to patients with the standard dressing (5.87/1,000 CVL days; CI: 3.93-8.43; p0.0001). The CLABSI rate in historical controls receiving the standard dressing was 6.2/1,000 CVL days. The main reason for not using chlorhexidine-containing dressing was bleeding at the insertion site. AEs occurred in five patients and represented self-healing skin macerations (3 cases) and superficial skin necrosis (2 cases).In case of high CLABSI rates despite the implementation of standard recommendations, our findings suggest that a chlorhexidine-containing dressing safely decreases CLABSI rates.

Two-colour microarray experiments form an important tool in gene expression analysis. Due to the high risk of missing observations in microarray experiments, it is fundamental to concentrate not only on optimal designs but also on designs which are robust against missing observations. As an extension of Latif et al. (2009), we define the optimal breakdown number for a collection of designs to describe the robustness, and we calculate the breakdown number for various D-optimal block designs. We show that, for certain values of the numbers of treatments and arrays, the designs which are D-optimal have the highest breakdown number. Our calculations use methods from graph theory.

Summary Background Compliance with hand hygiene is complicated by indications for hand disinfection in rapid succession during the care of one patient. In such situations, disinfection of gloves could facilitate better workflow and optimize compliance rates. Aim We analysed the efficacy of disinfecting gloves by comparing an individual effect of five different hand disinfectant solutions in combination with three different glove types. Methods The investigation was performed in accordance with DIN EN 1500:2013. For all combinations, ten analyses were performed, including (1) right/left-hand examination disinfection efficacy after the first and fifth contamination with E. coli K12 NCTC 10538, (2) recovery rates after contamination, (3) reduction efficacy, (4) fingertip immersion culture, and (5) check for tightness. Disinfection of the ungloved hands was taken as an additional benchmark. Findings The disinfection efficacy for all disinfectant/glove combinations was better with rather than without gloves. For eight combinations, the disinfection efficacy was always >5.0 log 10 . There were significant differences within the gloves ( P =0.0021) and within the disinfectant product ( P =0.0023), respectively. In detail, Nitril Blue Eco-Plus performed significantly better than Vasco Braun ( P =0.0017) and Latex Med Comfort ( P =0.0493). Descoderm showed a significantly worse performance than Promanum pure ( P =0.043). In the check for tightness, only the Vasco Braun gloves showed no leaks in all samples. There were relevant qualitative differences pertaining to the comfort of disinfecting gloves. Conclusion The disinfection efficacy for the different disinfectant/glove combinations was greater than for the ungloved hands. However, various disinfectant/glove combinations produce relevant differences as regards disinfection efficacy.

Purpose In addition to the transconjunctival approach, the subtarsal incision is one of the most commonly used procedures for surgical exploration of the orbital floor and infraorbital rim. However, available data are limited regarding validity and long-term esthetic and functional outcomes. The aim of this study was to verify the favorable clinical results of the subtarsal approach and compare these results with the transconjunctival procedure. Materials and Methods Forty-five patients (subtarsal group, n = 30; transconjunctival group, n = 15) were examined 6 to 30 months after surgical intervention using a standardized follow-up. Clinically noted complications, such as paresthesia, epiphora, or ocular foreign body sensation, were scored. Postoperative scar formation was investigated using the modified Vancouver Scar Scale (mVSS) and recorded according to standardized photographic documentation procedures. Photographic images were evaluated in a blinded manner by experts and nonexperts according to fixed criteria. Concomitant photographic evaluation was performed by age- and gender-matched healthy controls. Recorded data analyzed by χ2 test and unrelated samples analyzed by the Wilcoxon-Mann-Whitney test were statistically significant (P = .05). Results Comparable complication rates were found for the 2 approaches without any significant differences (P = .29). Using the subtarsal approach, discrete scar formation was discerned in 7 of 30 cases. Moreover, categorization by the mVSS showed that, in 93.3% of cases, the scar was measured as unremarkable hyper- or hypotrophy (mean, 1.7 of 10 possible points). No statistically significant differences in conspicuous scars and asymmetries were observed between the 2 approaches in the nonexpert and expert groups (P > .05). Conclusion The results of the present study confirm that the subtarsal approach is a safe and esthetically favorable method.

Being a secondary outcome in a multicenter randomized controlled trial, the present analysis focused on interdental spacing in the shortened dental arch (SDA). The aim was to evaluate changes in interdental spacing in dependence of two different treatments after an observation period of up to 5 years.Patients were either treated with a partial removable dental prosthesis (PRDP) for molar replacement (PRDP group) or according to the SDA concept aiming at a premolar occlusion (SDA group) in a randomized manner. Interdental spacing in the anterior region was measured with gauges and categorized as "0" (0.1 mm), "1" (0.5 mm), "2" (0.5-1 mm), and "3" (1 mm). The statistical analysis was performed with analysis of variance models followed by linear contrast.Ninety-one patients (SDA n = 41, PRDP n = 50) were included. Changes of interdental spacing were detected in 70.7 % of all cases. A significant difference between the mean score changes was found in the mandible comparing the PRDP group and the SDA group. The respective mean score changes from baseline to 5 years were 0.23 (SD 0.49) for the PRDP group and 0.02 (SD 0.30) for the SDA group (p = 0.023).Major interdental spacing could be observed in neither of the groups. The SDA concept resulted in a slightly better outcome.When deciding whether to replace missing molars, the present results give further support to the SDA concept.

Hedgehog inhibitors, more accurately known as smoothened inhibitors (SIs),were introduced for the treatmentofbasal cell carcinoma(BCC)withmuchsuccess.1Theclinicaldata supported the intriguing rationale of interfering with a tumor driver (overactive Sonic Hedgehog signaling in BCC) thatwas identified 20years ago. Beyond thewell-established surgical or conservative (radiotherapy) treatment options, treatmentwithSIsnowrepresentsanovelavenuethedermatooncologist can take when surgery or radiotherapy of BCC is contraindicated.2This extensionof the therapeutic armamentarium for advanced BCC, which is currently used in patients with highly advanced tumors or basal cell nevus syndrome, has also suggested using vismodegib or sonidegib treatment inaneoadjuvant setting.However,neoadjuvant therapywould be precluded by the development of secondary resistance to vismodegib, which is mediated in the vast majority of cases by secondary mutations in smoothened.3,4 Neoadjuvant treatment may induce regression of advancedBCC in patientswith comorbidities that do not permit surgery at reasonable risk orwhenanatomical limitationspreclude radiotherapy. Intermittent oral treatment for limitedperiods may permit either palliative regression of the tumor or convert a clinical situationnot suitable for surgery to one that would allow less radical surgery. However, such broader use of SIs would immediately have to take into account adverse effects. In particular, the occurrence of secondary independent invasivecutaneoussquamouscell carcinomas (SCCs)during treatment with SIs, which have thus far only been reported in an anecdotal manner, is of great relevance.5,6 In addition, low numbers of cases with putative transdifferentiationofvismodegib-treated tumorhavealsobeendescribed.7 Thesepotential adverse effects need tobe acknowledged, understood, andmanagedbeforewidespreaduse of SIs in aneoadjuvant setting. In this issueof JAMADermatology,Mohanet al8 retrospectively compared the incidenceof secondary skin cancers inpatients with advanced BCC treated with vismodegib vs that in controlpatientsnot treatedwithvismodegib.Although theauthors found an overall higher frequency of secondary cancers in the cohort of patients who did not receive vismodegib, the meanageof thecontrolgroupwassignificantlyhigher thanthat of the treatment group. As age is a strong risk factor for development of cancer, the authors consequently corrected the incidenceof secondarycancers for age.Whenthisdifferencewas accounted for, patients receivingvismodegib vs thosewhodid not receive SI treatment demonstrated ahighly enhancedhazard ratio for developing secondary epithelial skin cancers. The enhancedhazard ratio alsopersistedafter correcting for thediagnosis of basal cell nevus syndrome and for the histologic diagnosis of metatypical BCC. Unavoidably, owing to the nature of a “first-in-class”drug, the studydesignmaybebiasedby selectionand/or chronological biasbecauseof thenonparallel recruitment of the cohorts who received vismodegib and those who did not. In future studies, investigators will need to pay closeattentiontothesimilarityof theresponseanddropoutpatterns between the 2 groups. Thevalidity of the epidemiologic conclusionsdependson whether it was adequate to correct the incidence of secondary cancers for age or whether the adjustment for age within the treatment groups is incorrect. Incidence of cancer in general and of skin cancer specifically is strongly correlatedwith age. In the data set used by Mohan et al,8 the reduced frequency of cancer other than skin tumors in the younger patient cohort receiving vismodegib, compared with the older control group, at least supports this assumption. Still, onemay speculate that patientswhowere treatedwithvismodegibdeveloped advanced BCCs at a younger age owing to increased accumulation of UV light–inducedmutations in sun-exposed skin. Because themutational load is surprisingly high in clinicallynoncancerous skin thathasbeenexposed toUV lightover the long term,9anenhanced incidenceof secondarySCCwould then be independent of vismodegib treatment. Mohan et al8 tried to avoid such bias first by screening their patient database for those with advanced or metastatic BCC and by subsequentstratificationof thecohorts forexposure toknownmutagenic agents as well as for immunosuppression. Yet, the ultimate technique to exclude a bias would have consisted in performing a prospective study that incorporates assessment of mutational loads at multiple skin sites in patients who receivedvismodegib aswell as in the control group. Such elaborated studies may be performed in the future, given today’s increasingly broad accessibility of advanced unbiased ultradeep sequencing technologies that may change our understandingofUV-induced carcinogenesis.9Mohanet al8 laid the groundwork for such studies in future patients treated with vismodegib. Howcould the transition of BCC to SCCor the denovodevelopment of clinically apparent SCC, a tumor-promoting effect, be explained at themolecular level in patients receiving SI treatment? A possible scenario is that suppression of the Hedgehog pathway might select for tumor cells that have overcome Hedgehog pathway dependency by activation of Related article page 527 Opinion

SummaryA national German funding initiative for Medical Informatics focusing at data integration for medicine gives an opportunity to reopen a window to Germany. In the open window appears a best paper selection of the 2015 annual conference of the German Society of Medical Informatics, Biometry and Epidemiology and papers of the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE). The publications in focus deal with data integration by transferring clinical routine data into an electronic data capture (EDC) system, using natural language processing to make unstructured date processable, measuring quality of record linkage, and by using a unified metadata scheme for integrated documentation in laboratories. Two additional papers present methods for data analysis especially for change point detection in binary sequences and for analyzing categorial data.

Summary Background The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich's ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. Methods We enrolled patients with genetically confirmed Friedreich's ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits—baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. Findings Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreich's ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (–0·02 points per year [0·01] per year of age) and lower SARA baseline scores (–0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, −0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and −0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. Interpretation Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreich's ataxia. Funding European Commission.

ispartof: Journal of Rare Diseases Research & Treatment vol:1 issue:1 pages:53-60 status: published

Genome medicine 8(1), 71 (2016). doi:10.1186/s13073-016-0323-y, Published by BioMed Central, London

Two-color microarray experiments form an important tool in gene expression analysis. Due to the high costs of microarray experiments it is fundamental to plan these experiments carefully. Therefore, we propose a method to construct A-optimal block designs which can be adapted to construct nearly optimal microarray experiments. This method can be applied to derive A-optimal designs for arbitrary contrast settings. In this article, we focus on treatment control comparisons and all-to-next contrasts. We will show that our designs are more efficient than the designs currently in practice.

The connection between the randomization procedure and analysis is often ignored in the statistical analysis of clinical trials although regulatory guidelines explicitly call upon (ICH E8). Randomization tests comply with these requirements, as they use the applied random allocation to determine the distribution of the test statistic. However, the impact of missing values on randomization tests is not studied up to now. We explore the use of a randomization test when analyzing data of randomized clinical trials with missing values. We will consider two scenarios leading to a reduced or non-reduced reference set depending on handling missing data. Investigations of p-values of randomization tests under normal approximation and, for small sample sizes, exact randomization tests were conducted.