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The objective of this prospective randomized controlled single-center clinical trial was to prove the efficacy of adjunctive photobiomodulation in improving selected outcomes following the use of laterally closed tunnel technique for the management of isolated gingival recession. Nineteen participants (with isolated gingival recession) each treated by laterally closed tunnel technique were randomized to either add on treatment with control (sham laser application) or test group (photobiomodulation with 660 nm diode, 3.5 J/cm2 per point of application). The primary outcome variable was change in recession depth and secondary variables included recession width, width of keratinized gingiva, periodontal biotype, and VAS score for pain assessment and EHS index for early wound healing assessment. Analysis was performed using a linear mixed effects model. There were no significant differences in the gingival recession depth (p = 0.8324) and recession width (p-0.969) at 3-month follow-up. The VAS scores were significantly lower for the test (laterally closed tunnel technique + photobiomodulation) group as compared to control (laterally closed tunnel technique + sham laser) over time (p =

Objective: To validate the capability of the dual wavelength laser (Er,Cr:YSGG and diode 940 nm) and the XP-Endoshaper and finisher in removing the smear layer from curved canals. Methods: Forty cu...

Background Among various design aspects, the choice of randomization procedure have to be agreed on, when planning a clinical trial stratified by center. The aim of the paper is to present a methodological approach to evaluate whether a randomization procedure mitigates the impact of bias on the test decision in clinical trial stratified by center. Methods We use the weighted t test to analyze the data from a clinical trial stratified by center with a two-arm parallel group design, an intended 1:1 allocation ratio, aiming to prove a superiority hypothesis with a continuous normal endpoint without interim analysis and no adaptation in the randomization process. The derivation is based on the weighted t test under misclassification, i.e. ignoring bias. An additive bias model combing selection bias and time-trend bias is linked to different stratified randomization procedures. Results Various aspects to formulate stratified versions of randomization procedures are discussed. A formula for sample size calculation of the weighted t test is derived and used to specify the tolerated imbalance allowed by some randomization procedures. The distribution of the weighted t test under misclassification is deduced, taking the sequence of patient allocation to treatment, i.e. the randomization sequence into account. An additive bias model combining selection bias and time-trend bias at strata level linked to the applied randomization sequence is proposed. With these before mentioned components, the potential impact of bias on the type one error probability depending on the selected randomization sequence and thus the randomization procedure is formally derived and exemplarily calculated within a numerical evaluation study. Conclusion The proposed biasing policy and test distribution are necessary to conduct an evaluation of the comparative performance of (stratified) randomization procedure in multi-center clinical trials with a two-arm parallel group design. It enables the choice of the best practice procedure. The evaluation stimulates the discussion about the level of evidence resulting in those kind of clinical trials.

Summary Background The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia. Methods EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov , NCT02069509 . Findings Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included. Interpretation Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia. Funding European Commission, Voyager Therapeutics, and EuroAtaxia.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Journal of nephrology : JN 33(6), 1231-1239 (2020). doi:10.1007/s40620-020-00836-8, Published by Springer, Milano

Background: Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases.Results: The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients' engagement in study design.Conclusions: Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy's safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered.

Objective Pulmonary hemorrhage (PH) is a severe complication in preterm neonates. This study aims to identify risk factors and comorbidities of PH. Study Design A single-center cohort study on medical records including all preterm neonates of Results In this study, 344 preterm neonates were included, of whom 36 suffered from PH (10.5%). The mean time of the first occurrence was the third day of life (standard deviation [SD]: 1.2). On average, the patients suffered from 1.5 incidents (SD: 0.8) of PH, of whom 50% were severe. Preterm neonates born as multiples (95% confidence interval [CI]: 3.1, 26.9) and those who suffered from IVH (95% CI: 2.7, 18.9) had a significantly increased risk of PH. ICSI was not an independent risk factor. Conclusion PH is significantly associated with IVH and multiple births but not with ICSI. The identification of patients at risk allows to apply prophylactic strategies of ventilation and pharmacological treatment.

Background/Aims: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and still constitutes one of the most important causes of end-stage renal disease. Abnormal T cell responses may play a role in IgAN pathogenesis. Co-stimulatory molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are important for naive T cells to initiate and terminate immune responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 gene locus are associated with several autoimmune diseases. Methods: We aimed to investigate the occurrence of the SNPs -318C/T, +49A/G and CT60 G/A within the CTLA4 locus in healthy blood donors (n=455) and IgAN patients (n=252) recruited from the recently published STOP-IgAN trial. The presence of these SNPs was then associated with baseline proteinuria in IgAN patients. Results: We observed a significantly increased frequency of the CTLA4 -318C/T genotype in IgAN patients as compared to controls (CC vs. CT+TT: OR 1.65, 95%-CI 1.03-2.65, p=0.035). No significant associations, neither with the +49A/G nor for the CT60 G/A SNP, were detected. However, when we stratified for proteinuria at time of inclusion into the STOP-IgAN trial (1 g/day), we observed significant differences in the frequencies of the CT60 G/A genotype, i.e. a significantly increased risk for higher proteinuria in patients carrying the G allele (OR 2.81, 95%-CI 1.03-7.64, p=0.042). Conclusion: The CTLA4 -318/C/T SNP was associated with an increased risk to develop IgAN, while the CT60 G/A genotype significantly associated with the risk for higher proteinuria suggesting a possible role for CTLA-4 in IgAN.

Background/Aims: The addition of immunosuppression to supportive care reduces proteinuria in a subset of patients with IgA nephropathy (IgAN) but is associated with an increased rate of adverse events. The present work investigates whether urinary biomarkers are able to identify subjects who benefit from immunosuppression and to predict the progression of disease in a sub-cohort of the STOP-IgAN trial. Methods: Urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), calprotectin, and the product of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 (TIMP2•IGFBP7) were measured in all available urine samples obtained at the time point of enrollment in the STOP-IgAN trial (n=113). Results: Biomarker concentrations in both the overall study population and the subgroup with additional immunosuppression did not differ in subjects reaching vs. not reaching full clinical remission, eGFR loss ≥ 15, or 30 ml/min/1.73 m2 over the 3-year trial phase (p> 0.05 each). Receiver-operating characteristic curves showed a poor predictive accuracy of each biomarker for the above-mentioned parameters in the overall study population (areas under the curve ≤0.611). Accordingly, there was neither a significant correlation of any biomarker and adverse outcome in linear regression analysis, nor between biomarker concentrations at enrollment and change in the eGFR over the 3-year observation period. Conclusion: NGAL, KIM-1, calprotectin, and [TIMP-2]•[IGFBP7] had neither a prognostic value for the progression of IgAN, nor for the response to immunosuppression in the present sub-cohort of the STOP-IgAN trial. The search for appropriate biomarkers for an individualized treatment strategy in IgAN continues.

The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m2: 6-month corticosteroid monotherapy; GFR=30–59 ml/min per 1.73 m2: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m2 during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; P=0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively; P=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m2 did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.

A retrospective evaluation of maxillary advancement and mandibular setback in class III patients was performed and their aesthetic outcomes compared. Patients with a sella-nasion-A-point angle (SNA) of 80-84° were selected. Pre- and postoperative lateral cephalograms were obtained for 34 class III patients; these were divided into two groups according to the surgical procedure performed: mandibular setback group (n=17) and maxillary advancement group (n=17). The pre- and postoperative cervical length, lip-chin-throat angle, lower/upper lip thickness, distance from the lower/upper lip to the aesthetic line, soft tissue angle, facial contour angle, and nasolabial angle of the two groups were compared. Significant differences were observed for cervical length (P=0.0003) and sex (P=0.003) when comparing maxillary advancement with mandibular setback. Although the preoperative cervical length was similar in the two groups, it increased significantly after maxillary advancement and decreased after mandibular setback. In this study, the differences in aesthetic outcomes depending on the surgical procedure performed were considered. Some aesthetically important parameters proved to be superior after maxillary advancement when compared to mandibular setback, even with the maxilla in the normal position.

The random allocation of patients to treatments is a crucial step in the design and conduct of a randomized controlled trial. For this purpose, a variety of randomization procedures is available. In the case of imperfect blinding, the extent to which a randomization procedure forces balanced group sizes throughout the allocation process affects the predictability of allocations. As a result, some randomization procedures perform superior with respect to selection bias, whereas others are less susceptible to chronological bias. The choice of a suitable randomization procedure therefore depends on the expected risk for selection and chronological bias within the particular study in question. To enable a sound comparison of different randomization procedures, we introduce a model for the combined effect of selection and chronological bias in randomized studies with a survival outcome. We present an evaluation method to quantify the influence of bias on the test decision of the log-rank test in a randomized parallel group trial with a survival outcome. The effect of selection and chronological bias and the dependence on the study setting are illustrated in a sensitivity analysis. We conclude with a case study to showcase the application of our model for comparing different randomization procedures in consideration of the expected type I error probability.

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.

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

BACKGROUND: IDeAl (Integrated designs and analysis of small population clinical trials) is an EU funded project developing new statistical design and analysis methodologies for clinical trials in small population groups. Here we provide an overview of IDeAl findings and give recommendations to applied researchers. METHOD: The description of the findings is broken down by the nine scientific IDeAl work packages and summarizes results from the project's more than 60 publications to date in peer reviewed journals. In addition, we applied text mining to evaluate the publications and the IDeAl work packages' output in relation to the design and analysis terms derived from in the IRDiRC task force report on small population clinical trials. RESULTS: The results are summarized, describing the developments from an applied viewpoint. The main result presented here are 33 practical recommendations drawn from the work, giving researchers a comprehensive guidance to the improved methodology. In particular, the findings will help design and analyse efficient clinical trials in rare diseases with limited number of patients available. We developed a network representation relating the hot topics developed by the IRDiRC task force on small population clinical trials to IDeAl's work as well as relating important methodologies by IDeAl's definition necessary to consider in design and analysis of small-population clinical trials. These network representation establish a new perspective on design and analysis of small-population clinical trials. CONCLUSION: IDeAl has provided a huge number of options to refine the statistical methodology for small-population clinical trials from various perspectives. A total of 33 recommendations developed and related to the work packages help the researcher to design small population clinical trial. The route to improvements is displayed in IDeAl-network representing important statistical methodological skills necessary to design and analysis of small-population clinical trials. The methods are ready for use. ispartof: ORPHANET JOURNAL OF RARE DISEASES vol:13 issue:1 ispartof: location:England status: published

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

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.

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.

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.

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.

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.

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

Purpose: The ‘Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment study’ (SPR study) is a randomized multicentre trial comparing primary vitrectomy (PV) and scleral buckling surgery (SB) for rhegmatogenous retinal detachment (RRD). This subanalysis was conducted to identify risk factors associated with anatomical outcomes. Methods: Relating the anatomical success results at the 1-year follow-up visit to pre- and intraoperative findings using multivariate statistical methods. Results: In the phakic subtrial, anatomical success was negatively associated with the number of breaks (p 1 clock hour (p = 0.0005) and intraoperative use of cryotherapy (p = 0.0484). It was positively associated with retinal breaks with irregular edges (p = 0.0353) and subretinal fluid drainage (p = 0.0155). In the pseudophakic/aphakic subtrial, anatomical success was negatively associated with the number of retinal breaks (p = 0.0004) and previous YAG capsulotomy (p = 0.0256), and the combined effect of the surgical procedure and intraoperative use of laser (p = 0.0229). Conclusion: Primary anatomical success is an important result for patients undergoing RRD surgery. Our data demonstrate that the final anatomical outcome is related to a higher preoperative number of breaks and cryotherapy in phakic eyes. Additional risk factors varied between phakic and pseudophakic subgroups. Our findings may be used to facilitate the prognosis of future patients with RRD.

Background Pneumocystis jiroveci pneumonia (PcP) is a potentially life-threatening complication in renal transplant recipients with increased reports during the past few years. Individual risk factors for susceptibility to PcP are incompletely understood. Methods We retrospectively analysed 60 cases of confirmed PcP, diagnosed in six German transplant centres between 2004 and 2008, as well as 60 matched controls. Results Compared with controls, PcP cases revealed the following significant differences: PcP cases had a poorer renal function (eGFR 31 vs. 42 mL/min in controls), more biopsy-proven rejections (18 vs. 5 patients), more frequent treatment with mycophenolate mofetil (53 vs. 44 patients) and less frequent treatment with interleukin-2 receptor antagonist (20 vs. 32 patients). According to centre policy, in those years, none of the patients or controls had received PcP prophylaxis after transplantation. Of the 60 patients with PcP, 30% developed the disease after the currently recommended duration of prophylactic treatment, 27% died in the course of the disease and 45% required treatment in the ICU. Conclusions Our case-control study reveals a novel risk profile for PcP. Renal transplant recipients with more pronounced renal insufficiency following rejection episodes and treated with intensified immunosuppression are at particular risk for PcP.

Background In this study, we examined the role of superantigen genes and emm genotypes of clinical Streptococcus pyogenes isolates collected in Germany between 1997 and 2003. Methods Multiplex polymerase chain reaction for all 11 currently known superantigen genes and sequencing for emm types were used. Results Using a 2-step explorative data analysis procedure, we found that after combined analysis of superantigen genes and emm types, only the superantigen genes spea1-spea3, spem, and spea4 have a predictive value for invasiveness, with odds ratios of 7.992, 3.209, and 2.323, respectively. The predictive value for invasiveness of emm1 was lost after combined analysis because of the association between emm type and the highly predictive superantigen genes. On the other hand, presence of the superantigen gene ssa and of emm77 are predictors of noninvasiveness, with odds ratios of 0.370 and 0.271, respectively. Conclusions These results indicate that the presence of superantigen genes is more important for the invasiveness of group A Streptococcus infection than emm type and may be the connection between the high-risk HLA type of the host and the pathogen. Furthermore, we found a very clear correlation between the presence of the genes spea1-spea3 and the presence of the gene emm1, which indicates that the relationship between emm1 and invasiveness is based on the superantigen gene profile. Our data suggest that the superantigen gene profile is of high importance for the clinical outcome of group A Streptococcus infections.

Purpose: To identify risk factors that may lead to reoperations following primary vitrectomy (PV) and scleral buckling surgery (SB) for rhegmatogenous retinal detachment (RRD). Methods: Analysis of the association between distinct parameters and the necessity for reoperations in the ‘Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment study’ (SPR Study) using an Andersen–Gill-mean intensity model. Results: The risk for recurrent reoperations is significantly reduced by primary vitrectomy (PV) compared to scleral buckling (SB) in pseudophakic eyes (p = 0.0009) and increased after PV compared to SB in phakic eyes (p < 0.0001). Additional significant risk factors were in the pseudophakic group preoperative deterioration of visual acuity (p = 0.0226), YAG capsulotomy (p = 0.0043), large breaks (p = 0.0290), number of affected quadrants (p = 0.0387), retinal incarceration during surgery (p = 0.0115), number of breaks (p

To evaluate the expression of melanoma cell adhesion molecule (MCAM) as prognostic factor in uveal melanoma patients.Paraffin sections from 35 primary uveal melanomas were analyzed immunhistochemically for the expression of MCAM. Further known prognostic factors such as cell type, ciliary body invasion, tumor stage, and local extension were evaluated. In 16 cases, patients had developed metastatic disease. The patients without metastasis (n = 19) had a mean follow-up of 10.6 (9-13) years.All tumors were positive for MCAM (mean: 57.05%). In the group without metastasis, an average MCAM expression of 35.37% (SD 19.66%) compared to 82.78% (SD 11.73%) in the metastasis group was found. The Cox regression analysis showed a significant association of an enhanced MCAM expression and death due to metastasis (HR: 365.48, 95% CI: 18.51, 7217.85).MCAM expression of primary uveal melanomas can serve as a possible prognostic parameter for metastasis. If further experiments approve the cellular adhesion molecules to account for early micrometastasis of tumor cells, a possible target might be available for future treatment.

Purpose The objective of this study is to characterize the donor-site morbidity after harvesting of nonvascularized and vascularized iliac bone grafts. Patients and Methods Clinical data of 353 patients were collected for analysis. In addition, a questionnaire was sent to all patients asking about their perceptions of different parameters. In an individual age-matched layout, we compared 34 patients with nonvascularized iliac bone grafts with 34 patients with vascularized iliac bone grafts. Results Transplantation of vascularized bone grafts has been increasingly performed at our institution. The mean age was 41.5 years in the nonvascularized group and 48.6 years in the vascularized group. The main reason for the bony defect in the vascularized group was malignancy. The majority of postoperative functional problems were observed in obese patients. No patient had serious or long-term complications at the donor site. The amount of bone graft taken affected postoperative sensitivity disturbance and caused postoperative functional problems and pain. Conclusions We conclude that the iliac crest is a suitable site for harvesting both vascularized and nonvascularized bone grafts measuring up to 10 × 3 cm. For larger defects that require a larger bone graft, a vascularized bone graft is more suitable with a better predictable healing capability. No significant differences in donor-site morbidity were found between the vascularized and nonvascularized bone grafts if a similar amount of bone was taken for transplant.

Objectives: Among the different graft materials being applied in sinus elevation surgery autogenous bone, especially from the iliac crest, is considered to be the graft of choice. The goal of this prospective study was to investigate whether purely cancellous transplants of this donor site lead to significantly better results regarding bone quantity and quality when compared to corticocancellous iliac bone grafts. Material and methods: Fifteen patients suffering from extreme maxillary atrophy underwent bilateral sinus floor augmentation with grafts from the iliac crest consisting of purely cancellous bone (PCB) for the right side and a mixture of 50% cancellous and 50% cortical bone for the left side, respectively. Bone samples that were taken during implant insertion were examined histologically for semiquantitative assessment. In addition, bone density was measured histomorphometrically. Data were statistically analyzed by a repeated measures analysis of covariance model and post hoc paired t-tests as well as Pearson's correlation analysis. Results: Semiquantitative analysis of bone quality resulted in comparable results for both graft preparations while bone density was significantly higher in the PCB group. Without consideration of the different transplant groups, there was neither a significant correlation between patients' age and bone density nor bone quality. Differences between the genders could not be observed either. Conclusions: Because of better bone density, the PCB graft from the iliac crest remains our gold standard. Even in elderly patients, autogenous grafts can be utilized without losses in the properties of the resulting bone.

Purpose: In patients with uveal melanoma, tumor cell dissemination and subsequent formation of metastases are confined mainly to the hematogenous route. Here, we sought to isolate circulating melanoma cells in peripheral blood of patients with primary uveal melanoma and clinically localized disease. Experimental Design: Blood samples from 52 patients with clinically localized uveal melanoma and from 20 control individuals were prospectively collected before therapy of the primary tumor. Tumor cells expressing the melanoma-associated chondroitin sulfate proteoglycan were enriched by immunomagnetic cell sorting and visualized by immunocytologic staining. Results were compared with clinical data at presentation. Results: In 10 of 52 patients [19%; 95% confidence interval (95% CI), 10-33%], between 1 and 5 circulating melanoma cells were detected in 50 mL peripheral blood. No melanoma-associated chondroitin sulfate proteoglycan–positive cells were detected in any of the 20 controls examined. The presence of tumor cells in peripheral blood was associated with ciliary body invasion [odds ratio (OR), 20.0; 95% CI, 3.0-131.7], advanced local tumor stage (OR, 6.7; 95% CI, 1.8-25.4), and anterior tumor localization (OR, 4.0; 95% CI, 1.2-12.7), all established factors for uveal melanoma progression. Conclusions: Immunomagnetic enrichment enables detection of intact melanoma cells in peripheral blood of patients with clinically localized ocular disease. Visualization and capturing of these cells provide a unique tool for characterizing potentially metastasizing tumor cells from a primary melanoma at an early stage of the disease.

Treatment options for persistent diabetic macular edema remain disappointing. ILM peeling and intravitreal triamcinolone have been successfully used in several case series; however, there is no evidence that one of these options is superior for specific groups of patients. The triamcinolone versus ILM peeling in diabetic macular edema study (TIME-study) is designed to investigate the efficacy of these two treatments in patients with persistent diabetic macular edema. Patients with persistent diabetic macular edema are randomised to either the control group (no treatment), ppV + ILM peeling, or triamcinolone (4 mg) injection. One hundred thirty-five patients are to be recruited per group and followed-up for one year. The main endpoints are defined as change in visual acuity (VA) at 12 months compared to baseline and the change in retinal thickness after 3 months follow-up. Secondary endpoints include differences in the functional success and anatomical success and the effect of the treatment on the patient’s quality of life. Twelve institutions (28 surgeons) in 3 European countries agreed to contribute to the study. The design issues and implications of the study are described. The TIME study is the first randomised prospective clinical trial to investigate the effectiveness of the two treatment methods. The results of this study should enable physicians to improve therapy and to select cases according to the most promising treatment option.

A large variety of new treatment options for different forms of age-related macular degeneration (ARMD) are becoming available. Not all new therapies may meet the expectations of patients and ophthalmologists. Despite the given statistical significant priority of treatment investigations, the endpoints may not be relevant to the patient's requirements. Therefore, questions inevitably arise regarding patient's benefit and the validity of the randomized controlled trials. The randomized controlled trial is regarded as the "gold standard" in terms of evaluating the effectiveness of interventions. The external validity of randomized controlled trials may be compromised, if, for example, patients assigned to the study group are unrepresentative of the reference population. This review aims to analyze problems with external validity in the randomized controlled trials on ARMD and surveys the endpoints of clinical studies with respect to the patient benefit.

The trace element zinc is essential for immune function and its regulation. Since zinc deficiency and allergic hyperresponsive reactions are often accompanied, the influence of zinc on allergen-induced cell growth, CD4+ regulatory T (Treg) cell numbers and cytokine expression during allergic immune reactions was investigated. Peripheral blood mononuclear cells (PBMCs) from non-atopic and atopic subjects were treated with timothy grass allergen pre-incubated with or without zinc. Proliferation was determined by analyzing the incorporation of 3H-thymidine. Intracellular zinc and Foxp3 levels and cell surface antigens were measured by FACS, cytokine expression by ELISA and real-time PCR. Incubation with 50 μM zinc sulfate (Zn50) enhances cytosolic zinc concentrations in CD3+ T cells. The data also reveal that the combination of Zn50 plus allergen significantly reduces PBMC proliferation of atopic subjects. Additionally, Zn50 plus allergen enhances Th1 cytokine responses shown by increased interferon (IFN)-γ/interleukin (IL)-10 ratios as well as enhanced tumor necrosis factor-α release. In response to allergen, zinc increases Treg cells and upregulates the mRNA expression of cytotoxic T-lymphocyte antigen-4 in atopic subjects. Interestingly, Zn50 alone leads to an increase of CD4+CD25high(hi)+ cells in atopic and non-atopic subjects. Zinc may regulate unwanted hyperresponsive immune reactions by suppressing proliferation through a significant shift from IL-10 to the Th1 cytokine IFN-γ, and enhanced regulatory T cell numbers. Therefore, zinc supplementation may be a promising tool for the therapy of allergies, without negatively affecting the immune system.

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 WileySons, Ltd.

AIM: To verify the hypothesis that caspase-8 (Casp8), which regulates cellular apoptosis and necroptosis, is critically involved in enterocyte migration. METHODS: Casp8-silenced Caco2 cells were used in migration assays. In addition, enterocyte-specific Casp8 heterozygous (Casp8+/∆int) or homozygous knockout mice (Casp8∆int) were generated by crossing genetically modified mice carrying loxP recombination sites in intron 2 and 4 of the murine Casp8 gene with transgenic animals expressing a cre-transgene under control of the villin promoter in a pure C57/BL6 genetic background. The nucleoside analog BrdU was injected i.p. in male Casp8+/∆int and Casp8∆int animals 4 h, 20 h, or 40 h before performing morphometric studies. Locations of anti-BrdU-immunostained cells (cellmax) in at least 50 hemi-crypts of 6 histoanatomically distinct intestinal mucosal regions were numbered and extracted for statistical procedures. For the mice cohort (n = 28), the walking distance of enterocytes was evaluated from cellmax within crypt (n = 57), plateau (n = 19), and villus (n = 172) positions, resulting in a total of 6838 observations. Data analysis was performed by fitting a three-level mixed effects model to the data. RESULTS: In cell culture experiments with Caco2 cells, Casp8 knockdown efficiency mediated by RNA interference on Casp8 transcripts was 80% controlled as determined by Western blotting. In the scratch assay, migration of Casp8-deleted Caco2 cells was significantly diminished when compared with controls (Casp8∆scramble and Caco2). In BrdU-labeled Casp8∆int mice, cellmax locations were found along the hemi-crypts in a lower position than it was for Casp8+/∆int or control (cre-negative) animals. Statistical data analysis with a three-level mixed effects model revealed that in the six different intestinal locations (distinct segments of the small and large intestine), cell movement between the three mice groups differed widely. Especially in duodenal hemi-crypts, enterocyte movement was different between the groups. At 20 h, duodenal cellmax location was significantly lower in Casp8∆int (25.67 ± 2.49) than in Casp8+/∆int (35.67 ± 4.78; P < 0.05) or control littermates (44.33 ± 0.94; P < 0.01). CONCLUSION: Casp8-dependent migration of enterocytes is likely involved in intestinal physiology and inflammation-related pathophysiology.

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, p0.05). 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.

Statement of Problem. Internal discoloration may occur with the intraoral use of resin-based restoration materials. Water storage and light exposure influence the color properties of microfilled and hybrid composites. Purpose. The purpose of this study was to determine color and translucency changes in a hybrid and a microfilled composite after light exposure with and without water storage. Material and Methods. A hybrid (Tetric) and a microfilled composite (Silux Plus) were subjected to artificial daylight with and without water storage. Tristimulus Yxy values were determined colorimetrically against a black or a white background. Differences from baseline were calculated as ΔE * ab for up to 1 month. After 1 month, ΔL * , Δa * , Δb * , and the contrast ratio ΔC were calculated. Data were analyzed with 2-way analysis of variance ( P Results. The ΔE ab * increased over time for wet and dry stored specimens of both materials. Wet storage for 1 month resulted in significantly higher ΔE ab * and ΔC but lower Δb * than dry storage. The Δa * was significantly higher for Tetric compared with Silux Plus. Both materials showed negative ΔL * values under both storage conditions without significant differences between materials or storage conditions. Conclusion. The results of this in vitro study suggest that resin-based restoration materials undergo measurable changes due to daylight exposure. Increased changes occurred under the influence of water storage. (J Prosthet Dent 2002;87:264-70.)

PURPOSE: To describe the indications, surgical technique, and clinical results of 14 eyes in 13 patients with age-related macular degeneration and foveal choroidal neovascularization, in which subretinal surgery was combined with simultaneous transplantation of autologous retinal pigment epithelial cells. METHODS: Between March 1999 and February 2000, in a prospective study, 14 eyes (13 patients) with age-related macular degeneration underwent subretinal surgery because of foveal choroidal neovascularization with simultaneous transplantation of retinal pigment epithelium harvested from the nasal subretinal area of the same eye. Preoperatively, 1 month postoperatively, 3 months postoperatively and at 3-month intervals thereafter, examinations were performed including best-corrected visual acuity, visual field, biomicroscopy of anterior and posterior segment, tonometry, fluorescein and indocyanine angiographies, autofluorescence, scotometry, and fixation tests. RESULTS: Postoperatively, after median observation of 17 months (range, 12 to 24 months) best-corrected visual acuity was improved 2 or more lines in eight eyes (57.1%), remained the same (± 1 line) in five eyes (35%), and decreased by more than 2 lines in one eye (7.1%). Pairwise t test showed significant improvement after 1 month ( P = .0031, P = .0062) as well as 1 year ( P = .0066, P = .0105). Satisfactory reading vision between Jaeger 1 and 4 was achieved in three eyes (21.2%). No significant intraoperative or postoperative complications occurred in any eye. No recurrence of choroidal neovascularization was observed during the observation period. CONCLUSIONS: In eyes with age-related macular degeneration and foveal choroidal neovascularization, autotransplantation of retinal pigment epithelium was performed in addition to conventional removal of the choroidal neovascularization without significant intraoperative or postoperative complications. Visual acuity improvement of 2 or more lines in 57% of the eyes was achieved. No recurrent choroidal neovascularization formation was observed during the observation period. The results of this pilot study suggest that autologous transplantation of retinal pigment epithelium combined with submacular surgery might be a reasonable treatment option for patients with foveal choroidal neovascularization secondary to age-related macular degeneration.

Autofluorescence devices are widely used to examine oral lesions. The aim of this study was to see whether there were any signs of dysplasia, parakeratosis, or mucosal inflammation in the borders of homogeneous oral leukoplakia using autofluorescence, and we also compared clinically visible extensions with those detected by autofluorescence. Twenty patients with 26 homogeneous areas of oral leukoplakia were included in the study. After the clinically visible extensions of the lesion had been marked, we took a photograph through the autofluorescence device, which showed both borders in one picture. We then used photo-editing software to measure the size of the area of leukoplakia together with the area with loss of autofluorescence. We took 3 punch biopsy specimens: one from the leukoplakia, one 2.5mm from its marked borders, and one from healthy mucosa. Seventy-eight biopsy specimens were examined by an experienced pathologist, and 95% CI calculated to assess the amount of parakeratosis. Spearman's rank correlation was used to assess the association with mucosal inflammation. Ten areas of leukoplakia were surrounded by normal green autofluorescence, and 16 were consistent with loss of autofluorescence with a mean size of 66%, which exceeded the clinically visible size of the area of leukoplakia. We calculated that there was a strong association between these entities and their surrounding areas, with loss of autofluorescence for parakeratosis. Some leukoplakias showed clinically invisible extensions during histopathological examination and autofluorescence. The technique described enables clinicians to measure the extent of these lesions beyond their visible margins. We found no dysplasia, which emphasises that autofluorescence detects non-dysplastic lesions caused by mucosal inflammation and parakeratosis.

SummaryThe publication of a memorandum on improving medication safety by information technology in both the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE) and the journal Methods of Information in Medicine (MIM) gives reason to strengthen cooperation of MIBE and MIM and to report on more publications of MIBE here. The publications in focus deal with simulation-based optimization of emergency processes, handling of research data in publications, open access to research metadata, reliability of digital patient records in medical research, assessment methods for physical activity, using of insurance databases for epidemiological studies, certificates for epidemiological professionals, regression models, computer based training, and performance management in Swiss hospitals. Finally determining factors for scientific careers are discussed.