A Comparison of Additional Benefit Assessment Methods for Time-to-Event Endpoints Using Hazard Ratio Point Estimates or Confidence Interval Limits by Means of a Simulation Study.

BACKGROUND: For time-to-event endpoints, three additional benefit assessment methods have been developed aiming at an unbiased knowledge about the magnitude of clinical benefit of newly approved treatments. The American Society of Clinical Oncology (ASCO) defines a continuous score using the hazard ratio point estimate (HR-PE). The European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) developed methods with an ordinal outcome using lower and upper limits of the 95% HR confidence interval (HR-CI), respectively. We describe all three frameworks for additional benefit assessment aiming at a fair comparison across different stakeholders. Furthermore, we determine which ASCO score is consistent with which ESMO/IQWiG category. METHODS: In a comprehensive simulation study with different failure time distributions and treatment effects, we compare all methods using Spearman's correlation and descriptive measures. For determination of ASCO values consistent with categories of ESMO/IQWiG, maximizing weighted Cohen's Kappa approach was used. RESULTS: Our research depicts a high positive relationship between ASCO/IQWiG and a low positive relationship between ASCO/ESMO. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 corresponds to ESMO categories. Using ASCO values of 21 and 38 as cutoffs represents IQWiG categories. LIMITATIONS: We investigated the statistical aspects of the methods and hence implemented slightly reduced versions of all methods. CONCLUSIONS: IQWiG and ASCO are more conservative than ESMO, which often awards the maximal category independent of the true effect and is at risk of overcompensating with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and underpowered/overpowered studies influence all methods in some degree. Nevertheless, ESMO is the most liberal one. HIGHLIGHTS: For the additional benefit assessment, the American Society of Clinical Oncology (ASCO) uses the hazard ratio point estimate (HR-PE) for their continuous score. In contrast, the European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) use the lower and upper 95% HR confidence interval (HR-CI) to specific thresholds, respectively. ESMO generously assigns maximal scores, while IQWiG is more conservative.This research provides the first comparison between IQWiG and ASCO and describes all three frameworks for additional benefit assessment aiming for a fair comparison across different stakeholders. Furthermore, thresholds for ASCO consistent with ESMO and IQWiG categories are determined, enabling a comparison of the methods in practice in a fair manner.IQWiG and ASCO are the more conservative methods, while ESMO awards high percentages of maximal categories, especially with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and under/-overpowered studies influence all methods. Nevertheless, ESMO is the most liberal one. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 correspond to the categories of ESMO. Using ASCO values of 21 and 38 as cutoffs represents categories of IQWiG.

Robotic versus open partial pancreatoduodenectomy (EUROPA): a randomised controlled stage 2b trial.

Background: Open partial pancreatoduodenectomy (OPD) represents the current gold standard of surgical treatment of a wide range of diseases of the pancreatic head but is associated with morbidity in around 40% of cases. Robotic partial pancreatoduodenectomy (RPD) is being used increasingly, yet, no randomised controlled trials (RCTs) of RPD versus OPD have been published, leaving a low level of evidence to support this practice. Methods: This investigator-initiated, exploratory RCT with two parallel study arms was conducted at a high-volume pancreatic centre in line with IDEAL recommendations (stage 2b). Patients scheduled for elective partial pancreatoduodenectomy (PD) for any indication were randomised (1:1) to RPD or OPD with a centralised web-based tool. The primary endpoint was postoperative cumulative morbidity within 90 days, assessed via the Comprehensive Complication Index (CCI). Biometricians were blinded to the intervention, but patients and surgeons were not. The trial was registered prospectively (DRKS00020407). Findings: Between June 3, 2020 and February 14, 2022, 81 patients were randomly assigned to RPD (n = 41) or OPD (n = 40), of whom 62 patients (RPD: n = 29, OPD: n = 33) were analysed in the modified intention to treat analysis. Four patients in the OPD group were randomised, but did not undergo surgery in our department and one patient was excluded in the RPD group due to other reason. Nine patients in the RPD group and 3 patients in the OPD were excluded from the primary analysis because they did not undergo PD, but rather underwent other types of surgery. The CCI after 90 days was comparable between groups (RPD: 34.02 ± 23.48 versus OPD: 36.45 ± 27.65, difference in means [95% CI]: -2.42 [-15.55; 10.71], p = 0.713). The RPD group had a higher incidence of grade B/C pancreas-specific complications compared to the OPD group (17 (58.6%) versus 11 (33.3%); difference in rates [95% CI]: 25.3% [1.2%; 49.4%], p = 0.046). The only complication that occurred significantly more often in the RPD than in the OPD group was clinically relevant delayed gastric emptying. Procedure-related and overall hospital costs were significantly higher and duration of surgery was longer in the RPD group. Blood loss did not differ significantly between groups. The intraoperative conversion rate of RPD was 23%. Overall 90-day mortality was 4.8% without significant differences between RPD and OPD. Interpretation: In the setting of a very high-volume centre, both RPD and OPD can be considered safe techniques. Further confirmatory multicentre RCTs are warranted to uncover potential advantages of RPD in terms of perioperative and long-term outcomes. Funding: Federal Ministry of Education and Research (BMBF: 01KG2010).

Regional Variation in Hemoglobin Distribution Among Individuals With CKD: the ISN International Network of CKD Cohorts.

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin. Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model. Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%-44% across cohorts). Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.

Free-Flap Reconstruction in Early-Stage Squamous Cell Carcinoma of the Oral Cavity-A Prospective Monocentric Trial to Evaluate Oncological Outcome and Quality of Life.

Surgery is generally accepted as standard treatment in oral cancer, but the reconstructive procedures remain a matter of debate. The aim of this study was to evaluate oncological outcome and quality of life following surgical resection and free-flap reconstruction in patients with early oral squamous cell carcinoma. The presented trial was performed as a prospective, single-center observation study. Inclusion criteria were primary surgery in early-stage oral squamous cell carcinoma with free-flap reconstruction. Endpoints were overall and progression-free survival and quality of life up to 24 months after surgery. Twenty-six patients were included. Overall survival was 100% and progression-free survival was 92.3% in a maximum follow-up time of 21 months. Global quality of life showed no significant alteration after surgery. Patients reported a significant reduction in pain (p = 0.048) and a decreasing impairment of speech one year after surgery (p = 0.021). Free-flap reconstruction is a safe procedure that results in excellent oncological outcome and quality of life. Functional outcome is of high relevance in early-stage tumors of the head and neck and may mostly be affected by reconstructive procedures. Therefore, a prospective evaluation to explore success and the effects of surgical therapy is highly warranted.

Cerebellar Mutism Syndrome After Posterior Fossa Tumor Surgery in Children-A Retrospective Single-Center Study.

OBJECTIVE: Cerebellar mutism syndrome (CMS) is a well-known complication after posterior fossa tumor surgery in pediatric patients. We evaluated the incidence of CMS in our institute and analyzed its association with multiple risk factors, such as tumor entity, surgical approach, and hydrocephalus. METHODS: All pediatric patients who had undergone intra-axial tumor resection in the posterior fossa between January 2010 and March 2021 were included in the retrospective analysis. Various data points, including demographic, tumor-associated, clinical, radiological, surgery-associated, complications, and follow-up data, were collected and statistically evaluated for an association with CMS. RESULTS: A total of 63 surgeries in 60 patients were included. The median patient age was 8 years. Pilocytic astrocytoma was the most common tumor type (50%), followed by medulloblastoma (28%) and ependymomas (10%). Complete, subtotal, and partial resection was achieved in 67%, 23%, and 10%, respectively. A telovelar approach had been used the most often (43%) compared with a transvermian approach (8%). Of the 60 children, 10 (17%) had developed CMS and showed marked improvement but with residual deficits. The significant risk factors were a transvermian approach (P = 0.03), vermian splitting when added to another approach (P = 0.002), an initial presentation with acute hydrocephalus (P = 0.02), and hydrocephalus present after tumor surgery (P = 0.004). CONCLUSIONS: Our CMS rate is comparable to those described in the literature. Despite the limitations of the retrospective study design, we found that CMS was not only associated with a transvermian approach but was also associated with a telovelar approach, although to a lesser extent. Acute hydrocephalus at the initial presentation necessitating urgent management was significantly associated with a greater incidence of CMS.

Implementation of hyperspectral imaging in a trauma resuscitation room: a randomized controlled trial.

BACKGROUND: Hyperspectral imaging (HSI) is a novel imaging technology with the ability to assess microcirculatory impairment. We aimed to assess feasibility of performing HSI, a noninvasive, contactless method to assess microcirculatory alterations, during trauma resuscitation care. METHODS: This randomized controlled clinical trial was conducted in a dedicated trauma resuscitation room of a level one trauma center. We included adult patients who were admitted to the trauma resuscitation room. Patients were allocated in a 1:1 ratio to the HSI group (intervention) or control group. In addition to the standard of care, patients in the intervention group had two hyperspectral recordings (HSR) of their hand palm taken. Primary outcomes were the treatment duration of the primary survey (until end of ABCDE-evaluation, ultrasound and evaluation by the trauma team) and the total resuscitation room care (until transport to definitive care) as well as the ability to perform measurements from all HSR. Secondary outcomes were analyses from the intervention group compared to HSI measurements of 26 healthy volunteers including an analysis based on the ISS (Injury severity score) (< 16 vs. ≥ 16). Care givers, and those assessing the outcomes were blinded to group assignment. RESULTS: Our final analysis included 51 patients, with 25 and 26 allocated to the control and intervention group, respectively. There was a statistically significant shorter median duration of the primary survey in the control group (03:22 min [Q1-Q3 03:00-03:51]) compared to the intervention group (03:59 min [Q1-Q3 03:29-04:35]) with a difference of -37 s (95% CI -66 to -12). Total resuscitation room care was longer in the control group, but without significance: 60 s (95% CI -60 to 180). From 52 HSI, we were able to perform hyperspectral measurements on all images, with significant differences between injured patients and healthy volunteers. CONCLUSION: HSI proved to be feasible during resuscitation room care and can provide valuable information on the microcirculatory state. Trial registration DRKS DRKS00024047- www.drks.de . Registered on 13th April 2021.

Dorsal Root Ganglia Volume-Normative Values, Correlation with Demographic Determinants and Reliability of Three Different Methods of Volumetry.

Background: Dorsal root ganglia (DRG) volume assessment by MR-Neurography (MRN) has evolved to an important imaging marker in the diagnostic workup of various peripheral neuropathies and pain syndromes. The aim of this study was (1) to assess normal values of DRG volume and correlations with demographic determinants and (2) to quantify the inter-reader and inter-method reliability of three different methods of DRG volumetry. Methods: Sixty healthy subjects (mean age: 59.1, range 23-79) were examined using a 3D T2-weighted MRN of the lumbosacral plexus at 3 Tesla. Normal values of DRG L3 to S2 were obtained after exact volumetry based on manual 3D segmentation and correlations with demographic variables were assessed. For the assessment of inter-reader and inter-method reliability, DRG volumes in a subset of 25 participants were measured by two independent readers, each applying (1) exact volumetry based on 3D segmentation, (2) axis-corrected, and (3) non-axis-corrected volume estimation. Intraclass correlation coefficients were reported and the Bland-Altman analysis was conducted. Results: Mean DRG volumes ranged from 124.8 mm3 for L3 to 323.3 mm3 for S1 and did not differ between right and left DRG. DRG volume (mean of L3 to S1) correlated with body height (r = 0.42; p = 0.0008) and weight (r = 0.34; p = 0.0087). DRG of men were larger than of women (p = 0.0002); however, no difference remained after correction for body height. Inter-reader reliability was high for all three methods but best for exact volumetry (ICC = 0.99). While axis-corrected estimation was not associated with a relevant bias, non-axis-corrected estimation systematically overestimated DRG volume by on average of 15.55 mm3 (reader 1) or 18.00 mm3 (reader 2) when compared with exact volumetry. Conclusion: The here presented normal values of lumbosacral DRG volume and the correlations with height and weight may be considered in future disease specific studies and possible clinical applications. Exact volumetry was most reliable and should be considered the gold standard. However, the reliability of axis-corrected and non-axis-corrected volume estimation was also high and might still be sufficient, depending on the degree of the required measurement accuracy.

Incidences of Infectious Events in a Renal Transplant Cohort of the German Center of Infectious Diseases (DZIF).

Background: Infectious complications are a major cause of morbidity and mortality after kidney transplantation. Methods: In this transplant cohort study at the German Center of Infectious Diseases (DZIF), we evaluated all infections occurring during the first year after renal transplantation. We assessed microbial etiology, incidence rates, and temporal occurrence of these infections. Results: Of 804 renal transplant recipients (65.2% male, 51 ± 14 years), 439 (54.6%) had 972 infections within the first year after transplantation. Almost half of these infections (47.8%) occurred within the first 3 months. Bacteria were responsible for 66.4% (645/972) of all infections, followed by viral (28.9% [281/972]) and fungal (4.7% [46/972]) pathogens. The urinary tract was the most common site of infection (42.4%). Enterococcus was the most frequently isolated bacterium (20.9%), followed by E. coli (17.6%) and Klebsiella (12.5%). E. coli was the leading pathogen in recipients <50 years of age, whereas Enterococcus predominated in older recipients. Resistant bacteria were responsible for at least 1 infection in 9.5% (76/804) of all recipients. Viral infections occurred in 201 recipients (25.0%). Of these, herpes viruses predominated (140/281 [49.8%]), and cytomegalovirus had the highest incidence rate (12.3%). In the 46 fungal infections, Candida albicans (40.8%) was the most commonly isolated. Other fungal opportunistic pathogens, including Aspergillus fumigatus and Pneumocystis, were rare. Conclusions: Renal allograft recipients in Germany experience a high burden of infectious complications in the first year after transplantation. Bacteria were the predominating pathogen, followed by opportunistic infections such as cytomegalovirus. Microbial etiology varied between age groups, and resistant bacteria were identified in 10% of recipients.

Effect of scan-path length on the scanning accuracy of completely dentate and partially edentulous maxillae.

STATEMENT OF PROBLEM: The accuracy of fit of fixed partial dentures is directly dependent on the accuracy of a digital scan. However, the influence of scan-path length on scanning accuracy is unclear. PURPOSE: The purpose of this in vitro study was to evaluate how scan-path length influenced the scanning accuracy of a completely dentate or partially edentulous maxilla captured by 3 intraoral scanners: Omnicam AC (OC), TRIOS 4 (TR), and Primescan (PS). MATERIAL AND METHODS: Each intraoral scanner was used to make 30 scans each of the 2 clinical scenarios (completely dentate and partially edentulous) simulated with a reference model. The partially edentulous model simulated a maxilla with 6 prepared teeth to support a complete arch fixed partial denture. The missing teeth were then added to create a completely dentate model. The prepared teeth were later used to determine distance, angular, and tooth-axis deviations between the reference model (digitized with high precision before the tests) and the intraoral scans. Data were statistically analyzed by using a linear model or, if not applicable, a type II ANOVA (α=.05). RESULTS: Distance deviations increased linearly as the scan-path length increased. In contrast, angular and tooth-axis deviations did not increase linearly. All types of deviation differed depending on the scanning system used. Regarding the 90% quantile values, total distance deviations related to scan-path length amounted to 1.31 µm/mm (OC), 1.00 µm/mm (PS), and 1.45 µm/mm (TR) for the completely dentate maxilla and 1.10 µm/mm (OC), 1.46 µm/mm (PS), and 1.40 µm/mm (TR) for the partially edentulous maxilla. CONCLUSIONS: Distance deviations became larger as the scan-path length increased.

Quantitative MR-Neurography at 3.0T: Inter-Scanner Reproducibility.

BACKGROUND: Quantitative MR-neurography (MRN) is increasingly applied, however, the impact of the MR-scanner on the derived parameters is unknown. Here, we used different 3.0T MR scanners and applied comparable MR-sequences in order to quantify the inter-scanner reproducibility of various MRN parameters of the sciatic nerve. METHODS: Ten healthy volunteers were prospectively examined at three different 3.0T MR scanners and underwent MRN of their sciatic nerve using comparable imaging protocols including diffusion tensor imaging (DTI) and T2 relaxometry. Subsequently, inter-scanner agreement was assessed for seven different parameters by calculating the intraclass correlation coefficients (ICCs) and the standard error of measurement (SEM). RESULTS: Assessment of inter-scanner reliability revealed good to excellent agreement for T2 (ICC: 0.846) and the quantitative DTI parameters, such as fractional anisotropy (FA) (ICC: 0.876), whereas moderate agreement was observed for proton spin density (PD) (ICC: 0.51). Analysis of variance identified significant inter-scanner differences for several parameters, such as FA (p < 0.001; p = 0.02), T2 (p < 0.01) and PD (p = 0.02; p < 0.01; p = 0.02). Calculated SEM values were mostly within the range of one standard deviation of the absolute mean values, for example 0.033 for FA, 4.12 ms for T2 and 27.8 for PD. CONCLUSION: This study quantifies the measurement imprecision for peripheral nerve DTI and T2 relaxometry, which is associated with the use of different MR scanners. The here presented values may serve as an orientation of the possible scanner-associated fluctuations of MRN biomarkers, which can occur under similar conditions.

Validity of patient self-reports and clinical signs in the assessment of sleep bruxism based on home-recorded electromyographic/electrocardiographic data.

BACKGROUND: Reliable and suitable bruxism assessment would be desirable, but available studies presented heterogeneous results. OBJECTIVE: To determine the agreement of patient self-reports and clinical signs of sleep bruxism (SB) with electromyographic/electrocardiographic data. METHODS: Two hundred individuals from a German dental clinic population (120 women and 80 men) participated in the study. Participants completed different SB questionnaires, had a clinical examination to evaluate bruxism signs and used the Bruxoff® device to record electromyographic/electrocardiographic data for five nights. To investigate interrater reliability for clinical diagnosis of bruxism, 126 of the 200 participants were assessed for clinical signs of bruxism by two independent uncalibrated examiners. Statistical evaluation included calculation of sensitivity, specificity and accuracy and of Cohen's kappa. RESULTS: Based on the Bruxoff® data, 106 participants were identified as bruxers and 94 as non-bruxers. The 106 bruxers were further classified into 47 moderate and 59 intense bruxers. The highest accuracy and sensitivity values were recorded for the overall score for clinical bruxism signs (accuracy: 72.0% and sensitivity: 70.8%). The best specificity (96.8%) was seen for the question regarding tooth grinding in the last two weeks reported by others, but concurrent sensitivity was very low (3.8%). Analysis of interrater reliability revealed a substantial agreement (Cohen's kappa of 0.6). CONCLUSION: The study results indicate that self-report questionnaires and clinical signs have moderate sensitivity, specificity and accuracy for diagnosing bruxism comparing with an ambulatory device for current SB (Bruxoff®). Regarding interrater reliability for clinical signs of SB, substantial agreement was found between the two examiners. CLINICAL TRIAL NO: NCT03039985.

The 2018 classification of periodontal diseases: Its predictive value for tooth loss.

BACKGROUND: Predictive models and assessment tools for disease susceptibility and progression are necessary to enhance personalized medicine. The aim of this study is to assess the predictive accuracy of using the 2018 classification to predict likelihood of tooth loss. METHODS: A total of 134 patients were screened 10 years after periodontal therapy. Data were extracted from 82 patients' records and periodontal diagnoses were assigned according to the 1999 and 2018 classifications at baseline, whereas patient- and tooth-related parameters were documented at baseline and at reexamination. Statistical analysis included descriptive statistics, hurdle regression with a zero and count model as well as logistic regression. RESULTS: Significantly more teeth were lost during SPT in patients with Stage IV or Grade C (P < 0.05). Patients' adherence seems to have an impact on the predictability of the 2018 classification (P < 0.001). In comparison, neither classification system alone (1999 vs 2018) showed a high predictive value for tooth loss (area under the curve [AUC] = 59.2% vs 58.2%). CONCLUSION: Class III and IV/Grade C of the 2018 classification of periodontal diseases show similar predictive accuracy for tooth loss as severe cases in the former classification. Patients adherence seems to influence the prognostic value of the classification.

Five-year clinical performance of monolithic and partially veneered zirconia single crowns-a prospective observational study.

PURPOSE: The purpose of this study was to prospectively evaluate the medium-term clinical performance and esthetics of monolithic and partially (i.e., facially) veneered zirconia single crowns (MZ-SC and PZ-SC, respectively). METHODS: Between September 2011 and June 2013, 68 participants received 90 MZ-SC and 72 PZ-SC. Clinical study documentation was performed at crown cementation (baseline), at 6-month follow-up, and then yearly thereafter using standardized report forms. Three participants with four MZ-SC dropped out during clinical follow-up. Thus, 65 participants (n = 31, 47.7% men) fitted with 158 restorations (86 MZ-SC, 72 PZ-SC) were evaluated. The mean observation period of the restorations was 5.8 ±2.5 years; 6.3 ±2.2 for MZ-SC and 5.2 ±2.6 for PZ-SC. RESULTS: The 5-year rate of complication-free survival (success) was 87.0% for MZ-SC and 95.8% for PZ-SC (log-rank test, p = 0.026). The 5-year failure-free survival rate was 93.1% for MZ-SC and 96.2% for PZ-SC (log-rank test, p = 0.111), and the 5-year ceramic fracture-free survival rate was 100% for MZ-SC and 98.6% for PZ-SC (log-rank test, p = 0.274). Crowns of both designs were awarded excellent scores for esthetics by participants and dentists. CONCLUSION: Monolithic and partially veneered zirconia crowns can be used clinically with high medium-term survival and success and uncompromised esthetic results.

Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer.

BACKGROUND: Mutations in DNA damage repair genes, in particular genes involved in homology-directed repair, define a subgroup of men with prostate cancer with a more unfavorable prognosis but a therapeutic vulnerability to PARP inhibition. In current practice, mutational testing of prostate cancer patients is commonly done late i.e., when the tumor is castration resistant. In addition, most sequencing panels do not include TP53, one of the most crucial tumor suppressor genes in human cancer. In this proof-of-concept study, we sought to extend the clinical use of these molecular markers by exploring the early prognostic impact of mutations in TP53 and DNA damage repair genes in men with primary, nonmetastatic prostate cancer undergoing radical prostatectomy (RPX). METHODS: Tumor specimens from a cohort of 68 RPX patients with intermediate (n = 11, 16.2%) or high-risk (n = 57, 83.8%) disease were analyzed by targeted next generation sequencing using a 37 DNA damage repair and checkpoint gene panel including TP53. Sequencing results were correlated to clinicopathologic variables as well as PSA persistence or time to PSA failure. In addition, the distribution of TP53 and DNA damage repair gene mutations was analyzed in three large publicly available datasets (TCGA, MSKCC and SU2C). RESULTS: Of 68 primary prostate cancers analyzed, 23 (33.8%) were found to harbor a mutation in either TP53 (n = 12, 17.6%) or a DNA damage repair gene (n = 11, 16.2%). The vast majority of these mutations (22 of 23, 95.7%) were detected in primary tumors from patients with high-risk features. These mutations were mutually exclusive in our cohort and additional data mining suggests an enrichment of DNA damage repair gene mutations in TP53 wild-type tumors. Mutations in either TP53 or a DNA damage repair gene were associated with a significantly worse prognosis after RPX. Importantly, the presence of TP53/DNA damage repair gene mutations was an independent risk factor for PSA failure or PSA persistence in multivariate Cox regression models. CONCLUSION: TP53 or DNA damage repair gene mutations are frequently detected in primary prostate cancer with high-risk features and define a subgroup of patients with an increased risk for PSA failure or persistence after RPX. The significant adverse impact of these alterations on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.

In-vitro accuracy of complete arch scans of the fully dentate and the partially edentulous maxilla.

PURPOSE: This in-vitro study aimed to compare the accuracy of complete arch scans (CAS) of a fully dentate (FD) and a partially edentulous (PE) maxillary model. Three intraoral scanning systems were used: Omnicam AC (OC), TRIOS 4 (TR), and Primescan (PS). METHODS: Each intraoral scanner was used to take 30 scans each of two clinical scenarios (FD and PE) simulated by a reference model. The PE model simulated a maxilla with six prepared teeth to accommodate a jaw-spanning fixed partial denture (FPD). The missing teeth were then added to create an FD model. Five ceramic precision balls (ball centers P1-P5) mounted on metal pins were welded to the metal base on the buccal side of the dental arch. These were later used to determine dimensional (given by each 2 ball centers) and angular changes (given by each 3 or 4 ball centers) between the reference model (digitized with high precision before the tests) and the intraoral scans. Data were statistically analyzed using a type II ANOVA. RESULTS: The maximum mean absolute distance deviations were as follows. OC: 147 µm (FD) and 139 µm (PE). TR: 133 µm (FD) and 136 µm (PE). PS: 87 µm (FD) and 80 µm (PE). The scanning system used had a significant effect on distance deviations (p < 0.027) and CAS scanning time (p < 0.001). Dental status had no clear effect on distance deviations but did significantly affect angular changes (p < 0.001) and scanning time (p < 0.001). CONCLUSION: The manufacture of jaw-spanning FPDs based on a CAS cannot yet be recommended.

Variability of sleep bruxism-findings from consecutive nights of monitoring.

OBJECTIVES: To determine sleep bruxism (SB) behavior during five consecutive nights and to identify correlations between SB episodes per hour (SB index) and sleep-time masseter-muscle activity (sMMA). MATERIAL AND METHODS: Thirty-one participants were included in the study. Of these, 10 were classified as sleep bruxers (group SB-1) and nine as non-sleep bruxers (group non-SB). The bruxism status of these 19 patients was identified by means of questionnaires, an assessment of clinical symptoms, and electromyographic/electrocardiographic data (Bruxoff® device). The remaining 12 participants were also identified as bruxers, but based exclusively on data from the Bruxoff device (group SB-2). Data analysis included descriptive statistics and Spearman's correlation to assess the relationship between the SB index and sMMA. RESULTS: Participants in group SB-1 showed an overall mean SB index of 3.1 ± 1.6 and a mean total sMMA per night of 62.9 ± 38.3. Participants in group SB-2 had an overall mean SB index of 2.7 ± 1.5 and a mean total sMMA of 56.0 ± 29.3. In the non-SB group, participants showed an overall mean SB index of 0.8 ± 0.5 and a mean total sMMA of 56.8 ± 30.3. Spearman's correlation yielded values of - 0.27 to 0.71 for the correlation between sMMA and SB index. CONCLUSIONS: The data revealed variable SB activity and the absence of a reliable correlation between sMMA and the SB index. CLINICAL RELEVANCE: The high variation in SB activity and lack of correlation between sMMA and the SB index should be considered when diagnosing SB. TRIAL REGISTRATION: Clinical Trials [NIH], clinical trial no. NCT03039985.

Ceramic Crowns and Sleep Bruxism: First Results from a Randomized Trial.

Background: This randomized clinical trial was conducted to assess whether sleep bruxism (SB) is associated with an increased rate of technical complications (ceramic defects) in lithium disilicate (LiDi) or zirconia (Z) molar single crowns (SCs). Methods: Adult patients were classified as affected or unaffected by SB based on structured questionnaires, clinical signs, and overnight portable electromyography (BruxOff) and block randomized into four groups according to SB status and crown material (LiDi or Z): LiDi-SB (n = 29), LiDi-no SB (n = 24), Z-SB (n = 23), and Z-no SB (n = 27). Differences in technical complications (main outcome) and survival and success rates (secondary outcomes) one year after crown cementation were assessed using Fisher's exact test with significance level α = 0.05. Results: No technical complications occurred. Restoration survival rates were 100% in the LiDi-SB and LiDi-no SB groups, 95.7% in the Z-SB group, and 96.3% in the Z-no SB group (p > 0.999). Success rates were 96.6% in the LiDi-SB group, 95.8% in the LiDi-no SB group (p > 0.999), 91.3% in the Z-SB group, and 96.3% in the Z-no SB group (p ≥ 0.588). Conclusions: With a limited observation time and sample size, no effect of SB on technical complication, survival, and success rates of molar LiDi and Z SCs was detected.

Estimands-A Basic Element for Clinical Trials.

BACKGROUND: Clinical trials are of central importance for the evaluation and comparison of treatments. The transparency and intelligibility of the treatment effect under investigation is an essential matter for physicians, patients, and health-care authorities. The estimand framework has been introduced because many trials are deficient in this respect. METHODS: Introduction, definition, and application of the estimand framework on the basis of an example and a selective review of the literature. RESULTS: The estimand framework provides a systematic approach to the definition of the treatment effect under investigation in a clinical trial. An estimand consists of five attributes: treatment, population, variable, population-level summary, and handling of intercurrent events. Each of these attributes is defined in an interdisciplinary discussion during the trial planning phase, based on the clinical question being asked. Special attention is given to the handling of intercurrent events (ICEs): these are events-e.g., discontinuation or modification of treatment or the use of emergency medication-that can occur once the treatment has begun and might affect the possibility of observing the endpoints or their interpretability. There are various strategies for the handling of ICEs; these can, for example, also reflect the existing intention-to-treat (ITT) principle. Per-protocol analyses, in contrast, are prone to bias and cannot be represented in a sensible manner by an estimand, although they may be performed as a supplementary analysis. The discussion of potential intercurrent events and how they should appropriately be handled in view of the aim of the trial must already take place in the planning phase. CONCLUSION: Use of the estimand framework should make it easier for both physicians and patients to understand what trials reveal about the efficacy of treatment, and to compare the results of different trials.

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases: A Genome-wide Association Study Among Patients with Obstructive Uropathies.

BACKGROUND: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. OBJECTIVE: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. DESIGN SETTING AND PARTICIPANTS: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues. RESULTS AND LIMITATIONS: Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10-7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization. CONCLUSIONS: This study identified CDH12 as a candidate gene for kidney injury in PUV. PATIENT SUMMARY: We found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.

Development and Validation of a Novel Scoring System for Noninvasive Nonalcoholic Steatohepatitis Detection in Bariatric Patients.

INTRODUCTION: Nonalcoholic fatty liver disease covers a broad spectrum. Simple steatosis has usually a benign course while nonalcoholic steatohepatitis (NASH) can progress into hepatocellular carcinoma, and cirrhosis. Therefore, differentiating patients with benign steatosis and NASH is crucial. Liver biopsy, the usual gold standard for NASH diagnosis, cannot be used as a screening method due to its associated risks. This is especially problematic for obese patients with a prevalence of nonalcoholic fatty liver disease (NAFLD) in >80% of patients. The aim of this study was therefore to develop and validate a noninvasive NASH screening test in a cohort of high-risk, morbidly obese patients. METHODS: This prospective study examined diagnostic accuracy in accordance with STARD guidelines. 112 liver biopsies were consecutively assigned to either a training or validation cohort. Using the Bedossa histological scoring system, the cohorts were subdivided into NASH versus NAFLD/No NAFLD. Predictors of NASH were evaluated with receiver operating characteristic (ROC) curves. A model was then constructed using a backward stepwise logistic regression and evaluated in an independent validation cohort. RESULTS: 53.5% of the patients had NASH and 4 patients had cirrhosis. Mean body mass index (BMI) was 49.8 ± 7.5 kg/m2. Backward stepwise logistic regression identified 4 parameters associated with the presence of NASH: alanin-aminotransferase, albumin, BMI, and triglycerides. The noninvasive NASH detection score (NI-NASH-DS) had an ROC of 0.851 and 0.727 in the training and validation cohorts, respectively. Sensitivity and specificity were 77.1% and 88% in the training cohort and 88% and 48% in the validation cohort which was much better than the established noninvasive scores. DISCUSSION/CONCLUSION: The NI-NASH-DS is easy-to-use, inexpensive, and noninvasive and can reliably detect NASH in patients with morbid obesity. Due to its simplicity, it can be used frequently and repeatedly.