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Ki‐67, a nuclear protein expressed in all stages of cellular proliferation, is a valuable tool to assess tumor proliferation and has been linked to more aggressive tumor behavior. However, interlaboratory staining heterogeneity and inter‐observer variability challenge its reproducibility. Round Robin tests are a suitable tool to standardize and harmonize immunohistochemical and molecular analyses in histopathology. The study investigates the interrater and interlaboratory reproducibility of Ki‐67‐scoring using both manual and automated approaches. Unstained TMA slides comprising diverse tumor types (breast cancer, neuroendocrine tumors, lymphomas, and head and neck squamous cell carcinoma) were distributed to six pathology laboratories, each employing their routine staining protocols. Manual and automated scoring methods were applied, and interrater and interlaboratory agreement assessed using intraclass correlation coefficients (ICC). The results highlight good‐to‐excellent reliability overall, with automated scoring demonstrating higher consistency (ICC 0.955) than manual scoring (ICC 0.871). Results were more variable when looking at the individual entities. Reliability remained good for lymphomas (ICC 0.878) and breast cancer (ICC 0.784) and was poor in well‐differentiated neuroendocrine tumors (ICC 0.354). This study clearly advocates standardized practices and training to ensure consistency in Ki‐67‐assessment, and it demonstrates that this can be achieved in a peer‐to‐peer approach in local quality‐circles. [ABSTRACT FROM AUTHOR]

Purpose: Iodine deficiency increases the risk of cognitive impairment and delayed physical development in children. It is also associated with cognitive impairment in adults. Cognitive abilities are among the most inheritable behavioural traits. However, little is known about the consequences of insufficient postnatal iodine intake and whether the individual genetic disposition modifies the association between iodine intake and fluid intelligence in children and young adults. Methods: The cultural fair intelligence test was used to assess fluid intelligence in the participants of the DONALD study (n = 238; mean age, 16.5 [SD = 7.7] years). Urinary iodine excretion, a surrogate iodine intake marker, was measured in 24-h urine. Individual genetic disposition (n = 162) was assessed using a polygenic score, associated with general cognitive function. Linear regression analyses were conducted to determine whether Urinary iodine excretion was associated with fluid intelligence and whether this association was modified by individual genetic disposition. Results: Urinary iodine excretion above the age-specific estimated average requirement was associated with a five-point higher fluid intelligence score than that below the estimated average requirement (P = 0.02). The polygenic score was positively associated with the fluid intelligence score (β = 2.3; P = 0.03). Participants with a higher polygenic score had a higher fluid intelligence score. Conclusion: Urinary iodine excretion above the estimated average requirement in childhood and adolescence is beneficial for fluid intelligence. In adults, fluid intelligence was positively associated with a polygenic score for general cognitive function. No evidence showed that the individual genetic disposition modifies the association between Urinary iodine excretion and fluid intelligence. [ABSTRACT FROM AUTHOR]

Metabolomics-derived metabolites (henceforth metabolites) may mediate the relationship between modifiable risk factors and clinical biomarkers of metabolic health (henceforth clinical biomarkers). We set out to study the associations of metabolites with clinical biomarkers and a potential mediation effect in a population of young adults. First, we conducted a systematic literature review searching for metabolites associated with 11 clinical biomarkers (inflammation markers, glucose, blood pressure or blood lipids). Second, we replicated the identified associations in a study population of n = 218 (88 males and 130 females, average age of 18 years) participants of the DONALD Study. Sex-stratified linear regression models adjusted for age and BMI and corrected for multiple testing were calculated. Third, we investigated our previously reported metabolites associated with anthropometric and dietary factors mediators in sex-stratified causal mediation analysis. For all steps, both urine and blood metabolites were considered. We found 41 metabolites in the literature associated with clinical biomarkers meeting our inclusion criteria. We were able to replicate an inverse association of betaine with CRP in women, between body mass index and C-reactive protein (CRP) and between body fat and leptin. There was no evidence of mediation by lifestyle-related metabolites after correction for multiple testing. We were only able to partially replicate previous findings in our age group and did not find evidence of mediation. The complex interactions between lifestyle factors, the metabolome, and clinical biomarkers warrant further investigation. [ABSTRACT FROM AUTHOR]

Purpose: Research suggests that diet influences cognitive function and the risk for neurodegenerative disease. The present study aimed to determine whether a recently developed diet score, based on recommendations for dietary priorities for cardio metabolic health, was associated with fluid intelligence, and whether these associations were modified by individual genetic disposition. Methods: This research has been conducted using the UK Biobank Resource. Analyses were performed using self-report data on diet and the results for the verbal-numerical reasoning test of fluid intelligence of 104,895 individuals (46% male: mean age at recruitment 57.1 years (range 40–70)). For each participant, a diet score and a polygenic score (PGS) were constructed, which evaluated predefined cut-offs for the intake of fruit, vegetables, fish, processed meat, unprocessed meat, whole grain, and refined grain, and ranged from 0 (unfavorable) to 7 (favorable). To investigate whether the diet score was associated with fluid intelligence, and whether the association was modified by PGS, linear regression analyses were performed. Results: The average diet score was 3.9 (SD 1.4). After adjustment for selected confounders, a positive association was found between baseline fluid intelligence and PGS (P < 0.001). No association was found between baseline fluid intelligence and diet score (P = 0.601), even after stratification for PGS, or in participants with longitudinal data available (n = 9,482). Conclusion: In this middle-aged cohort, no evidence was found for an association between the investigated diet score and either baseline or longitudinal fluid intelligence. However, as in previous reports, fluid intelligence was strongly associated with a PGS for general cognitive function. [ABSTRACT FROM AUTHOR]

Objective: Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis. Methods: In this retrospective observation, we analyzed two independent hospital‐based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (nd = 298; nv = 49), serum neurofilament light chain (nd = 117; nv = 17), and respiratory tests (nd = 93; nv = 49). Results: Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = −0.45, p = 0.001) and slow vital capacity % (r = −0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62–0.84) and <50% (AUC 0.80, 95% CI 0.68–0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61–0.83) and <50% (AUC 0.79, 95% CI 0.67–0.91). Interpretation: Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function. [ABSTRACT FROM AUTHOR]

Random forests have become an established tool for classification and regression, in particular in high-dimensional settings and in the presence of nonadditive predictor-response relationships. For bounded outcome variables restricted to the unit interval, however, classical modeling approaches based on mean squared error loss may severely suffer as they do not account for heteroscedasticity in the data. To address this issue, we propose a random forest approach for relating a beta distributed outcome to a set of explanatory variables. Our approach explicitly makes use of the likelihood function of the beta distribution for the selection of splits during the tree-building procedure. In each iteration of the tree-building algorithm it chooses one explanatory variable in combination with a split point that maximizes the log-likelihood function of the beta distribution with the parameter estimates derived from the nodes of the currently built tree. Results of several simulation studies and an application using data from the U.S.A. National Lakes Assessment Survey demonstrate the properties and usefulness of the method, in particular when compared to random forest approaches based on mean squared error loss and parametric regression models. for this article are available online. [ABSTRACT FROM AUTHOR]

Background: Germany's high density of under-equipped hospitals and anticipated surge in orthopedic and trauma surgery-related diseases by 2030, combined with personnel shortages, are expected to increase patient transfers between hospitals, an issue that urgently needs standardized protocols. Despite some existing cooperative agreements, such as between joint-replacement centers or within the Trauma Network DGU®, these measures do not adequately address the full range of patient-transfer cases, including those due to a lack of specialization or staff shortages, resulting in delayed treatment and potential health risks. This study aims to dissect the intricacies of interhospital transfers in orthopedics and trauma surgery across Germany, focusing on understanding the underlying reasons for transfers, comparing the operational structures of small and large hospitals, and laying the groundwork for future standardized protocols to enhance patient care. Material and Methods: A cross-sectional study was conducted in the form of an online survey via SoSci Survey, which was directed at orthopedic surgeons and trauma surgeons working in hospitals in Germany. The 22-question survey gathered information on participants' clinic roles, departmental details, transfer processes, frequent diagnoses, perceptions of transfer quality, and improvement areas. The survey was sent to orthopedic and trauma surgeons in Germany by the specialist society. The data were analyzed using descriptive and inferential statistics to ensure a comprehensive insight into interhospital transfer practices. Results: The study involved 152 participants from various hospital ranks and located in different hospital sizes and types across rural and urban areas. A significant difference was observed between the care structures of basic/regular care and central/maximum care hospitals, especially regarding the available facilities and specialties. These findings suggest improvements such as better patient documentation, increased digital communication, optimized patient distribution, and standardization of transfer requests, among others. Conclusions: This study highlights the urgent need for improved protocols and resource allocation to eliminate inequalities in transfers between hospitals in orthopedics and trauma surgery in Germany. [ABSTRACT FROM AUTHOR]

Motivation To provide an integrated software environment for model fitting and variable selection in regression models with a bounded outcome variable. Implementation The proposed modelling framework is implemented in the add-on package betaboost of the statistical software environment R. General features The betaboost methodology is based on beta-regression, which is a state-of-the-art method for modelling bounded outcome variables. By combining traditional model fitting techniques with recent advances in statistical learning and distributional regression, betaboost allows users to carry out data-driven variable and/or confounder selection in potentially high-dimensional epidemiological data. The software package implements a flexible routine to incorporate linear and non-linear predictor effects in both the mean and the precision parameter (relating inversely to the variance) of a beta-regression model. Availability The software is hosted publicly at [ http://github.com/boost-R/betaboost ] and has been published under General Public License (GPL) version 3 or newer. [ABSTRACT FROM AUTHOR]

Motivation: To provide an integrated software environment for model fitting and variable selection in regression models with a bounded outcome variable.Implementation: The proposed modelling framework is implemented in the add-on package betaboost of the statistical software environment R.General features: The betaboost methodology is based on beta-regression, which is a state-of-the-art method for modelling bounded outcome variables. By combining traditional model fitting techniques with recent advances in statistical learning and distributional regression, betaboost allows users to carry out data-driven variable and/or confounder selection in potentially high-dimensional epidemiological data. The software package implements a flexible routine to incorporate linear and non-linear predictor effects in both the mean and the precision parameter (relating inversely to the variance) of a beta-regression model.Availability: The software is hosted publicly at [http://github.com/boost-R/betaboost] and has been published under General Public License (GPL) version 3 or newer. [ABSTRACT FROM AUTHOR]

Background: The analysis of DNA methylation is a key component in the development of personalized treatment approaches. A common way to measure DNA methylation is the calculation of beta values, which are bounded variables of the form M/(M + U) that are generated by Illumina's 450k BeadChip array. The statistical analysis of beta values is considered to be challenging, as traditional methods for the analysis of bounded variables, such as M-value regression and beta regression, are based on regularity assumptions that are often too strong to adequately describe the distribution of beta values. Results: We develop a statistical model for the analysis of beta values that is derived from a bivariate gamma distribution for the signal intensities M and U. By allowing for possible correlations between M and U, the proposed model explicitly takes into account the data-generating process underlying the calculation of beta values. Using simulated data and a real sample of DNA methylation data from the Heinz Nixdorf Recall cohort study, we demonstrate that the proposed model fits our data significantly better than beta regression and M-value regression. Conclusion: The proposed model contributes to an improved identification of associations between beta values and covariates such as clinical variables and lifestyle factors in epigenome-wide association studies. It is as easy to apply to a sample of beta values as beta regression and M-value regression. [ABSTRACT FROM AUTHOR]

B Background: b Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder with a substantial genetic contribution. B Results: b OCD polygenic risk scores significantly predicted OCD status (max R² = 0.026, p < 0.001 at pT = 0.3), with patients having the highest scores and relatives having intermediate scores. [Extracted from the article]

Simple Summary: Locally adapted chicken strains are frequently discussed as a favorable alternative in poultry production. They might serve as dual-purpose and robust strains that have advantageous behaviors, such as exploration and reduced fear reactions, which might support animal welfare in general. Therefore, it is important to characterize welfare-related behaviors, such as fear and exploration, and to identify these behavioral traits among the diversity of chicken strains. The aim of this study was to characterize fear reactions and exploration based on the avoidance of a novel object and the avoidance of a human in three different chicken strains. To identify interesting alternatives for future poultry production, a layer hybrid (Lohmann Brown), a dual-purpose hybrid (Lohmann Dual) and a locally adapted strain (Rhinelander) were tested for their fear and exploration behavior towards unknown objects and humans. Results showed clear differences in fear and exploration between all three strains, regarding fear of objects and humans. The strain-specific results illustrate the high diversity of behavioral traits. The understanding of behavioral diversity, including fear and exploration, might contribute substantially to future breeding programs, including of commercial strains, and the preservation of local strains in general, which can improve animal welfare on a genetic and individual basis. Fear and exploration are crucial traits determining how animals behave in novel situations, and thus, they influence animal welfare. The aim of this study was the characterization of these behavioral traits among different strains to identify interesting alternatives for future poultry production. Whereas the Novel Object Test (NOT) focuses on fear and exploration of novel objects, the Avoidance Distance Test (ADT) addresses this in the context of humans. Here, a commercial hybrid line, a dual-purpose hybrid and a local adapted strain were tested. For the differences between strains and development of fear, Lohmann Brown (n = 714), Lohmann Dual (n = 844) and Rhinelander (n = 458) were observed weekly until maturity. Results show that fear and exploration towards unknown objects and humans are breed-specific (all p < 0.01). Additionally, development of fear in NOT and ADT differed between all three strains (both p < 0.01). The expressions of fear of humans or objects should be regarded as characteristics adapted for different husbandry systems and breeding goals, e.g., high exploratory behavior in aviary or high avoidance of predators in free-ranging husbandry or at least a balanced ratio between fear and exploration. Characterization of behavioral traits among different strains, understanding diversity and integrating these behaviors into future breeding and husbandry systems might reflect the need to preserve local strains and the potential to improve animal welfare. [ABSTRACT FROM AUTHOR]

Simple Summary: Meningiomas are most commonly benign intracranial tumors, and surgical resection represents the treatment modality of choice. However, especially for patients of higher age and with increasing comorbidities, brain surgery might be accompanied by the need for postoperative prolonged intensive care, which might impair intended operative benefit. In the present study, we therefore analyzed prolonged mechanical ventilation (PMV) as an indicator variable for such intensive care treatment with regard to potential effects on mortality after meningioma resection in patients aged 70 years and older. We found that patients with postoperative PMV exhibited a profoundly increased probability to die within 1 year after surgery. Based on these findings, we identified risk factors for postoperative PMV occurrence and developed an easy-to-use score which allows us to estimate the risk of PMV occurrence preliminary to the surgical resection. We believe that this score might help to more sufficiently guide patients in the course of risk–benefit assessment and preoperative counseling. Indication for surgical treatment in patients with intracranial meningioma must include both clinical aspects and an individual risk–benefit stratification, especially in geriatric patients. Prolonged mechanical ventilation (PMV) has not been investigated for its potential effects in patients with meningioma. We therefore analyzed the impact of PMV on mortality in geriatric patients who had undergone meningioma resection. Between 2009 and 2019, 261 patients aged ≥ 70 years were surgically treated for intracranial meningioma at our institution. PMV was defined as postoperative invasive ventilation of >7 days. Postoperative PMV was present in 17 of 261 geriatric meningioma patients (7%). Twenty-five geriatric patients (10%) died within 1 year after surgery. A scoring system ("ACKT") based on the variables of age, preoperative C-reactive protein (CRP) value, Karnofsky performance scale and tumor size supports prediction of postoperative PMV (sensitivity 73%, specificity 84%). PMV is significantly associated with increased mortality after surgical treatment of meningiomas in geriatric patients. Furthermore, we suggest a novel score ("ACKT") to preoperatively estimate the risk of PMV occurrence, which might help to guide future risk–benefit assessment and patient counseling in the geriatric meningioma population. [ABSTRACT FROM AUTHOR]

Background: Head and neck cancer (HNC) patients are particularly vulnerable to drug-related problems (DRPs) given the toxicity of concomitant chemoradiotherapy (CCRT). Objective: To investigate the number and type of potential DRPs (pDRPs) in HNC outpatients undergoing five consecutive cycles of CCRT. Methods: A single-centre, non-randomized, non-interventional, observational study was conducted at the Oncological Outpatient Clinic of the Center for Integrated Oncology at the University Hospital Bonn, Germany. Clinical pharmacists took a comprehensive medication history, documented laboratory data, assessed patients' symptom burden, and retrospectively performed medication reviews at study entry and on the first day of each therapy cycle without any clinical intervention. Results: In 26 patients, the mean number of pDRPs continuously increased during therapy course, from 4.8 (SD 2.7, range 2–12) at cycle 1 to 6.9 (SD 2.6, range 2–12) at cycle 5, with drug-drug interactions, adverse drug reactions, inappropriate durations of use, and inappropriate dosage intervals being the most common. Considering only new and recurrent pDRPs, the mean number was 4.3 (SD 2.3, range 2–9) at cycle 1 and lower in the further therapy course with an average of 1.3 (SD 1.7, range 0–7) at cycle 2 and 1.9 (SD 1.5, range 0–5) at cycle 5. The number of pDRPs was found to be associated with medication regimen complexity and health-related quality of life assessed in the first therapy cycle. Conclusion: pDRPs frequently occurred in HNC outpatients demonstrating the need for pharmaceutical care. A methodological framework for repeated medication reviews was established, facilitating implementation into routine healthcare practice. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) comprises a wide variety of pulmonary parenchymal disorders within which progressive fibrosing ILD (PF-ILD) constitutes a phenotypic subset. By use of speckle tracking-based strain analysis we aimed to evaluate the degree of left ventricular (LV) dysfunction in progressive vs. non-progressive fibrosing ILD (non-PF-ILD). Methods: A total of 99 ILD patients (mean age 63.7 ± 13.5 years, 37.4% female), composed of 50 PF-ILD and 49 non-PF-ILD patients, and 33 controls were prospectively enrolled and underwent conventional and speckle tracking echocardiography. Additional laboratory and pulmonary function testing, as well as six-minute walk test were performed. Results: As compared to the non-PF-ILD cohort, PF-ILD patients exhibited a significantly impaired forced vital capacity (2.4 ± 1.0l vs. 3.1 ± 0.9l, p = 0.002), diffusion capacity for carbon monoxide (DLCO, 25.6 ± 16.3% predicted vs. 43.6 ± 16.67% predicted, p <0.001) and exercise capacity response as measured by the six-minute walk test distance (268.1 ± 178.2m vs. 432.6 ± 94.2m, p <0.001). Contrary to conventional echocardiographic LV parameters, both regional and global longitudinal LV strain measurements were significantly altered in ILD patients as compared to controls. No differences in LV strain were found between both patient groups. Significant correlations were observed between global longitudinal strain, on the one hand, and systemic inflammation markers, total lung capacity (TLC) and DLCO, on the other hand (high-sensitivity C-reactive protein: Pearson´s r = -0.30, p< 0.001; interleukin-6: Pearson´s r = -0.26, p = 0.007; TLC % predicted: Pearson´s r = 0.22, p = 0.02; DLCO % predicted: Pearson´s r = 0.21, p = 0.02). Conclusions: ILD is accompanied by LV dysfunction. LV functionality inversely correlates with the severity of the restrictive ventilatory defect and inflammation marker levels. These observations support the assumption of persistent low-grade systemic inflammation that may link systemic cardiovascular function to ILD status. [ABSTRACT FROM AUTHOR]

Recent years have seen the development of many novel scoring tools for disease prognosis and prediction. To become accepted for use in clinical applications, these tools have to be validated on external data. In practice, validation is often hampered by logistical issues, resulting in multiple small‐sized validation studies. It is therefore necessary to synthesize the results of these studies using techniques for meta‐analysis. Here we consider strategies for meta analyzing the concordance probability for time‐to‐event data ("C‐index"), which has become a popular tool to evaluate the discriminatory power of prediction models with a right‐censored outcome. We show that standard meta‐analysis of the C‐index may lead to biased results, as the magnitude of the concordance probability depends on the length of the time interval used for evaluation (defined e.g., by the follow‐up time, which might differ considerably between studies). To address this issue, we propose a set of methods for random‐effects meta‐regression that incorporate time directly as covariate in the model equation. In addition to analyzing nonlinear time trends via fractional polynomial, spline, and exponential decay models, we provide recommendations on suitable transformations of the C‐index before meta‐regression. Our results suggest that the C‐index is best meta‐analyzed using fractional polynomial meta‐regression with logit‐transformed C‐index values. Classical random‐effects meta‐analysis (not considering time as covariate) is demonstrated to be a suitable alternative when follow‐up times are small. Our findings have implications for the reporting of C‐index values in future studies, which should include information on the length of the time interval underlying the calculations. [ABSTRACT FROM AUTHOR]

Objectives: To find simple imaging-based features on cardiac magnetic resonance (CMR) that are associated with major adverse cardiovascular events (MACE) in takotsubo syndrome (TTS). Methods: Patients with TTS referred for CMR between 2007 and 2021 were retrospectively evaluated. Besides standard CMR analysis, commonly known complications of TTS based on expert knowledge were assessed and summarised via a newly developed PE2RT score (one point each for pleural effusion, pericardial effusion, right ventricular involvement, and ventricular thrombus). Clinical follow-up data was reviewed up to three years after discharge. The relationship between PE2RT features and the occurrence of MACE (cardiovascular death or new hospitalisation due to acute myocardial injury, arrhythmia, or chronic heart failure) was examined using Cox regression analysis and Kaplan–Meier estimator. Results: Seventy-nine patients (mean age, 68 ± 14 years; 72 women) with TTS were included. CMR was performed in a median of 4 days (IQR, 2–6) after symptom onset. Over a median follow-up of 13.3 months (IQR, 0.4–36.0), MACE occurred in 14/79 (18%) patients: re-hospitalisation due to acute symptoms (9/79, 11%) or chronic heart failure symptoms (4/79, 5%), and cardiac death (1/79, 1%). Patients with MACE had a higher PE2RT score (median [IQR], 2 [2–3] vs 1 [0–1]; p < 0.001). PE2RT score was associated with MACE on Cox regression analysis (hazard ratio per PE2RT feature, 2.44; 95%CI: 1.62–3.68; p < 0.001). Two or more PE2RT complications were strongly associated with the occurrence of MACE (log-rank p < 0.001). Conclusions: The introduced PE2RT complication score might enable an easy-to-assess outcome evaluation of TTS patients by CMR. Key Points: • Complications like pericardial effusion, pleural effusion, right ventricular involvement, and ventricular thrombus (summarised as PE2RT features) are relatively common in takotsubo syndrome. • The proposed PE2RT score (one point per complication) was associated with the occurrence of major adverse cardiac events on follow-up. • Complications easily detected by cardiac magnetic resonance imaging can help clinicians derive long-term prognostic information on patients with takotsubo syndrome. [ABSTRACT FROM AUTHOR]

Simple Summary: There are many studies that discuss pineal tumors (not specifically germinoma). Some advocate for biopsy over resection due to the fact that germinoma is radio- and chemosensitive; others advocate for primary resection due to multiple differential diagnoses that require resection in the pineal region, such as pineocytoma, teratoma, meningioma, epidermoid, etc. However, with respect to solitary pineal germinoma, there is still no study that analyzes and compares both surgical options regarding peri- and postoperative courses and complications. We evaluated the perioperative course and postoperative complications of patients with isolated pineal germinoma who underwent a primary biopsy or resection, treated according to the European SIOP CNS GCT 96 trial. The key finding of our study was that postoperative complications, including hydrocephalus, Parinaud syndrome, double vision, etc., were significantly higher in patients who underwent primary resection (p < 0.008). Background: CNS germinoma, being marker-negative, are mainly diagnosed by histological examination. These tumors predominantly appear in the suprasellar and/or pineal region. In contrast to the suprasellar region, where biopsy is the standard procedure in case of a suspected germ-cell tumor to avoid mutilation to the endocrine structures, pineal tumors are more accessible to primary resection. We evaluated the perioperative course of patients with pineal germinoma who were diagnosed by primary biopsy or resection in the SIOP CNS GCT 96 trial. Methods: Overall, 235 patients had germinoma, with pineal localization in 113. The relationship between initial symptoms, tumor size, and postoperative complications was analyzed. Results: Of 111 evaluable patients, initial symptoms were headache (n = 98), hydrocephalus (n = 93), double vision (n = 62), Parinaud syndrome (n = 57), and papilledema (n = 44). There was no significant relationship between tumor size and primary symptoms. A total of 57 patients underwent primary resection and 54 underwent biopsy. Postoperative complications were reported in 43.2% of patients after resection and in 11.4% after biopsy (p < 0.008). Biopsy was significantly more commonly performed on larger tumors (p= 0.002). Conclusions: These results support the practice of biopsy over resection for histological confirmation of pineal germinoma. [ABSTRACT FROM AUTHOR]

Background: The validity of current tools for intraoperative objective assessment of nociception/antinociception balance during anesthesia in young and very young surgery children is unknown. Aim: Primary aim of the study was to test the hypothesis that the Newborn Infant Parasympathetic Evaluation (NIPE) index performs better in indicating nociception in anesthetized children below 2 years than changes in heart rate. Secondary aims were to evaluate associations between intraoperative changes in NIPE index values and postoperative pain and emergence delirium. Methods: Fifty‐one children aged <2 years who underwent surgery were included in this prospective observational study. Patients were assigned to either group 1 (healthy children, n = 31) or group 2 (critically ill, ventilated premature infants and neonates, n = 20). The NIPE index and heart rate in response to three defined nociceptive stimuli were continuously recorded. Two different scales, Kindliche Unbehagens‐ und Schmerzskala (KUS) and Pediatric Anesthesia Emergence Delirium (PAED) as well as a Pain Questionnaire were used to assess postoperative pain levels and emergence delirium. Results: In total, 110 nociceptive events were evaluated. The analysis revealed a statistically significant association between a decrease in the NIPE index and all nociceptive stimuli, with a sensitivity of 92% and a specificity of 96%. The mean percentage decrease ranged from approx. 15%–30% and was highly statistically significant in both groups and for each of the nociceptive events except for venous puncture (p =.004). In contrast, no consistent change in heart rate was demonstrated. The KUS and PAED scale scores were significantly associated with the duration of anesthesia (p =.04), but not with intraoperative NIPE depression. Conclusion: The NIPE index was reliable for assessing intraoperative nociception in children aged <2 years and was more reproducible for detecting specific nociceptive stimuli during general anesthesia than heart rate. An effect on postoperative outcome is still elusive. [ABSTRACT FROM AUTHOR]

The influence of perioperative red blood cell (RBC) transfusion on prognosis of glioblastoma patients continues to be inconclusive. The aim of the present study was to evaluate the association between perioperative blood transfusion (PBT) and overall survival (OS) in patients with newly diagnosed glioblastoma. Between 2013 and 2018, 240 patients with newly diagnosed glioblastoma underwent surgical resection of intracerebral mass lesion at the authors' institution. PBT was defined as the transfusion of RBC within 5 days from the day of surgery. The impact of PBT on overall survival was assessed using Kaplan–Meier analysis and multivariate regression analysis. Seventeen out of 240 patients (7%) with newly diagnosed glioblastoma received PBT. The overall median number of blood units transfused was 2 (95% CI 1–6). Patients who received PBT achieved a poorer median OS compared to patients without PBT (7 versus 18 months; p < 0.0001). Multivariate analysis identified "age > 65 years" (p < 0.0001, OR 6.4, 95% CI 3.3–12.3), "STR" (p = 0.001, OR 3.2, 95% CI 1.6–6.1), "unmethylated MGMT status" (p < 0.001, OR 3.3, 95% CI 1.7–6.4), and "perioperative RBC transfusion" (p = 0.01, OR 6.0, 95% CI 1.5–23.4) as significantly and independently associated with 1-year mortality. Perioperative RBC transfusion compromises survival in patients with glioblastoma indicating the need to minimize the use of transfusions at the time of surgery. Obeying evidence-based transfusion guidelines provides an opportunity to reduce transfusion rates in this population with a potentially positive effect on survival. [ABSTRACT FROM AUTHOR]

We present a new procedure for enhanced variable selection for component-wise gradient boosting. Statistical boosting is a computational approach that emerged from machine learning, which allows to fit regression models in the presence of high-dimensional data. Furthermore, the algorithm can lead to data-driven variable selection. In practice, however, the final models typically tend to include too many variables in some situations. This occurs particularly for low-dimensional data (p < n), where we observe a slow overfitting behavior of boosting. As a result, more variables get included into the final model without altering the prediction accuracy. Many of these false positives are incorporated with a small coefficient and therefore have a small impact, but lead to a larger model. We try to overcome this issue by giving the algorithm the chance to deselect base-learners with minor importance. We analyze the impact of the new approach on variable selection and prediction performance in comparison to alternative methods including boosting with earlier stopping as well as twin boosting. We illustrate our approach with data of an ongoing cohort study for chronic kidney disease patients, where the most influential predictors for the health-related quality of life measure are selected in a distributional regression approach based on beta regression. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to validate myfood24-Germany, a web-based 24-h dietary recall (24HDR), by comparing its performance with a weighed dietary record (WDR) and biomarkers. Methods: 97 adults (77% female) completed a 3-day WDR with a 24-h urine collection on day 3, followed by at least one 24HDR with myfood24-Germany (corresponding to day 3 of the WDR). Intake of energy and 32 nutrients assessed by myfood24-Germany and the WDR for the same day were compared (method comparison). Intakes of protein and potassium assessed by myfood24-Germany/WDR were compared with intake estimated from urinary biomarkers for protein and potassium (biomarker comparison). Results: In the method comparison, significant correlations were found for energy and all tested nutrients (range 0.45–0.87). There was no significant difference between both methods in the assessed mean energy and macronutrient intake. However, myfood24-Germany underestimated mean intake of 15 nutrients. In the biomarker comparison, protein intake reported by myfood24-Germany/WDR was on average 10%/8% lower than estimated by biomarker. There was no significant difference in mean potassium intake assessed by myfood24-Germany/WDR and biomarker. However, a shared bias in the assessment of potassium intake was observed for both instruments. Concordance correlation coefficients (pc) and weighted Kappa coefficients (κ) confirmed good agreement with the biomarker estimates for myfood24-Germany/WDR in case of protein (pc = 0.58/0.66, κ = 0.51/0.53) and moderate agreement in case of potassium (pc = 0.44/0.51; κ = 0.30/0.33). Conclusion: Our results suggest that myfood24-Germany is of comparable validity to traditional dietary assessment methods. [ABSTRACT FROM AUTHOR]

Alterations in frontal and parietal neural activations during working memory task performance have been suggested as a candidate endophenotype of obsessive-compulsive disorder (OCD) in studies involving first-degree relatives. However, the direct link between genetic risk for OCD and neuro-functional alterations during working memory performance has not been investigated to date. Thus, the aim of the current functional magnetic resonance imaging (fMRI) study was to test the direct association between polygenic risk for OCD and neural activity during the performance of a numeric n-back task with four working memory load conditions in 128 participants, including patients with OCD, unaffected first-degree relatives of OCD patients, and healthy controls. Behavioral results show a significant performance deficit at high working memory load in both patients with OCD and first-degree relatives (p < 0.05). A whole-brain analysis of the fMRI data indicated decreased neural activity in bilateral inferior parietal lobule and dorsolateral prefrontal cortex in both patients and relatives. Most importantly, OCD polygenic risk scores predicted neural activity in orbitofrontal cortex. Results indicate that genetic risk for OCD can partly explain alterations in brain response during working memory performance, supporting the notion of a neuro-functional endophenotype for OCD. [ABSTRACT FROM AUTHOR]

Background: Oro‐facial dysfunctions (OFDs; oro‐facial myofunctional disorders) in children and childhood apraxia of speech (CAS) often cause severe problems in articulation, chewing, swallowing and oral posture. Objectives: Pathognomonic symptoms could yet not be identified, but central problems in planning, programming, timing and automating oro‐facial, as well as other fine motor skills, are assumed to be affected. Methods: To investigate the nature of motor and coordinative deficits in OFD and CAS, digitomotography was applied. The testing focused on recording frequency, force, rhythm and regularity of the index finger including speeded and metronome tapping tasks. 25 children with OFD (7 girls and 18 boys, age 7.9 ± 2.3) and 5 children with CAS (0 girls and 5 boys, age 7.6 ± 2.3), and 31 healthy controls (12 girls and 19 boys, age 9.3 ± 2.2) were tested. Statistical significance was accepted at α = 0.05. ANOVA test, non‐parametric Mann‐Whitney U test, Kruskal‐Wallis test and Spearman's rank correlation coefficient were used. Results: Cross‐sectional data revealed consistent significant differences between children with OFD and healthy controls concerning frequency, force, rhythm and regularity of index finger tapping. Individuals with CAS showed particularly low results. Tapping results correlated with disease burden. Conclusion: These findings support that underlying superordinated sensorimotor deficits exist. This may help phenotyping and influence diagnostical and therapeutical approaches. [ABSTRACT FROM AUTHOR]

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD. [ABSTRACT FROM AUTHOR]

Background: Failed total knee arthroplasty (TKA) with significant bone loss and compromised soft-tissues is challenging and the final results are often inferior to patient's expectation. The objective of this study was to present a comparison of outcomes in patients with failed infected TKA treated with two-stage revision TKA or knee arthrodesis and to assess clinical and functional results, implant survival and infection recurrence. The hypothesis was that an arthrodesis may result in beneficial effects on patients' outcome.Methods: Clinical data of 81 patients with periprosthetic joint infection (PJI) of the knee joint were collected and analyzed retrospectively. Between 2008 and 2014, a total of 36 patients had been treated within a two-stage exchange procedure and reimplantation of a modular intramedullary arthodesis nail and 45 patients with revision TKA. Patients were treated according to the same structured treatment algorithm. Clinical and functional evaluation was performed using the Oxford knee score (OKS) and the visual analogue scale (VAS).Results: The mean follow-up was 32.9 ± 14.0 months. The rate of definitely free of infection at last follow-up in the arthrodesis group was 32 of 36 (88.9%) and 36 of 45 (80.0%) in the revision TKA group (p = 0.272). Mean VAS for pain in the arthrodesis group was 3.1 ± 1.4 compared to 3.2 ± 1.6 in the revision TKA group (p = 0.636). The OKS in the arthrodesis group was 38.7 ± 8.9 and 36.5 ± 8.9 (p = 0.246) in patients with revision TKA. Rate of revisions in the revision-TKA group was 2.8 ± 3.7 compared to 1.2 ± 2.4 in the arthrodesis group (p = 0.021).Conclusion: Treatment of PJI needs a distinct therapy with possible fallback strategies in case of failure. A knee arthrodesis is a limb salvage procedure that showed no significant benefits on the considered outcome factors compared to revision TKA but is associated with significantly lower revision rate. After exhausted treatment modalities, a knee arthrodesis should be considered as an option in selected patients.Level Of Evidence: Level III, retrospective cohort study. [ABSTRACT FROM AUTHOR]

Background: Recent epidemiological studies indicate that the so-called 'Nordic' diet (rich in berries, fish and nuts) as well as a vegetarian diet improve serum glucose kinetics and, thus, reduce the risk of diabetes development compared to the 'Western' diet. Evidence for these effects from controlled human intervention studies is limited. Methods: One hundred and twenty overweight adults with at least 1 metabolic syndrome trait (60±7 y, BMI 31.1±3.5 kg/m2, WC men 109±9 cm, women 104±9 cm) were randomized into 3 groups, adhering to Nordic diet [ND], lacto-ovo vegetarian diet [VD], or habitual control diet [HD] for 6 weeks, based on a recipe list, which was adapted to individual energy expenditure (RMR measured by QuarkRMR device, multiplied by a factor of 1.5 for physical activity). At baseline and after 6 weeks, OGTT and mixed meal tolerance test [MMTT] (180 min; postprandial measurements at 7 time points [tp]) were performed. Statistical data analysis was conducted using linear mixed-effect models (group-specific comparison: visit*diet*tp interaction). Results: As expected no changes in body weight (p=0.083) and body composition (p=0.354) were detected. Within groups, fasting glucose (p=0.760) and insulin levels (p=0.066), HbA1c (p=0.979) and HOMA index (p=0.150) did not change after 6 weeks compared to baseline. Insulin sensitivity (Matsuda index p=0.498, OGIS p=0.478, insulinogenic index p=0.203) and ß-cell function (disposition index p=0.997) showed no intergroup variations. In the group comparison, no effect was found after OGTT and MMTT on AUC of glucose (p=0.869/p=0.824) and insulin (p=0.850/p=0.999). However, compared to controls, VD improved kidney values and ND improved blood lipids, liver and kidney values. Conclusion: Our medium-term isoenergetic intervention study did not confirm earlier results. Improvements in glucose kinetics as observed in epidemiologic studies are possibly due to a loss of body weight (hypoenergetic nutrition) independent of diet composition. Disclosure: H. Huber: None. B. Stoffel-wagner: None. M. Coenen: None. L. Weinhold: None. M. Schmid: None. P. Stehle: None. M. Simon: None. Funding: German Federal Ministry of Education and Research (01EA1809A) [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with brain metastasis must face advanced cancer diseases, and neurosurgical resection is often considered an inevitable part of treatment. However, peri- and postoperative complications might further worsen the prognosis for these vulnerable patients. It is therefore important to investigate risk factors for such unfavorable events in order to recognize high-risk patients at the earliest possible stage of disease. For this purpose, we aimed to identify risk factors for early postoperative complications following surgical resection of brain metastases. Our results showed that the presence of multiple brain metastases in a single patient and a high rate of additional comorbidities were associated with elevated levels of postoperative complications. Furthermore, patients who suffered from such unfavorable postoperative events were significantly more likely to die during the initial hospital stay. The present study therefore might help to preoperatively select for critically ill patients who are in mandatory need of advanced treatment and care. Surgical resection is a key treatment modality for brain metastasis (BM). However, peri- and postoperative adverse events (PAEs) might be associated with a detrimental impact on postoperative outcome. We retrospectively analyzed our institutional database with regard to patient safety indicators (PSIs), hospital-acquired conditions (HACs) and specific cranial surgery-related complications (CSCs) as high-quality metric profiles for PAEs in patients who had undergone surgery for BM in our department between 2013 and 2018. The comorbidity burden was assessed by means of the Charlson comorbidity index (CCI). A multivariate analysis was performed to identify independent predictors for the development of PAEs after surgical resection of BM. In total, 33 patients (8.5%) suffered from PAEs after surgery for BM. Of those, 17 PSI, 5 HAC and 11 CSC events were identified. Multiple brain metastases (p = 0.02) and a higher comorbidity burden (CCI > 10; p = 0.003) were associated with PAEs. In-hospital mortality of patients suffering from a PAE was significantly higher than that of patients without a PAE (24% vs. 0.6%; p < 0.0001). Awareness of risk factors for postoperative complications enables future prevention and optimal response, particularly in vulnerable oncological patients. The present study identified the presence of multiple brain metastases and increased comorbidity burden associated with PAEs in patients suffering from BM. [ABSTRACT FROM AUTHOR]