Search

Background: Isolation precautions used in methicillin-resistant (MRSA) infection control are effective in inhibiting pathogen transmission, but may cause unintended consequences in medical care. In addition, while costs attributed to MRSA are known to be substantial, little is known about their reimbursement in the German Diagnosis Related Groups (G-DRG) payment system. The aim of our study was to examine the effect of isolation precautions used in MRSA infection control on care processes, patient outcomes and deliver reliable data on MRSA-attributed reimbursement.Methods: A retrospective, matched cohort study of inpatients admitted to a general care teaching hospital in Bad Neuenahr, Germany, between January 1, 2016, and December 31, 2017 was performed. Patients isolated for MRSA colonization were matched to non-isolated controls based on age, gender, MRSA-adjusted Patient Clinical Complexity Level (Ma-PCCL) and Major Diagnostic Category (MDC). Main outcome measures on care processes and patient outcomes included adverse events, patient complaints, 30-day readmission rates, length of stay, type of discharge, and performance of instrument-based diagnostics. MRSA-attributed reimbursement was measured by conducting two separate G-DRG groupings, one with inclusion of MRSA-related codes and one without. Results: A total of 26,059 patients were admitted to Maria Hilf Hospital in Bad Neuenahr, Germany, during the study period. We identified 304 patients isolated for MRSA colonization. Compared to non-isolated matched controls, those on isolation precautions for MRSA colonization acquired about 45% more pressure ulcers and experienced significant delays in the performance of radiological diagnostics and echocardiographs. Patients isolated for MRSA colonization received about 49% fewer echocardiographs and had about 38% fewer abdominal ultrasound exams performed compared to non-isolated matched controls. A non-significant tendency towards fewer discharges to rehabilitation clinics and higher mortality rates were observed in patients isolated for MRSA colonization. Reimbursements were negligibly affected when MRSA-related codes were integrated by the grouper.Conclusion: Isolation precautions are associated with adverse consequences for care processes. These consequences need to be mitigated in order to justify placing patients at risk.

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.

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]

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]

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]

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]

INTRODUCTION: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD‐related biomarkers in cognitively healthy, obese adults at high metabolic risk. METHODS: One‐hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid‐beta (Aβ) 42/40, phosphorylated tau (p‐tau) 181 and 231, and total‐tau were measured via single molecule array assays. RESULTS: Significant differences were found for NfL, GFAP, Aβ42/40, p‐tau181, and p‐tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p‐tau181 (120 min postprandially, p < 0.0001). CONCLUSION: Our data suggest that AD‐related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. Highlights: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults.We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations.Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy. [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]

Background and Objectives: Early postoperative mobilization is central for postoperative outcomes after lower extremity joint replacement surgery. By providing adequate pain control, regional anaesthesia plays an important role for postoperative mobilization. It was the objective of this study to investigate the use of the nociception level index (NOL) to determine the effect of regional anaesthesia in hip or knee arthroplasty patients undergoing general anaesthesia with additional peripheral nerve block. Materials and Methods: Patients received general anaesthesia, and continuous NOL monitoring was established before anaesthesia induction. Depending on the type of surgery, regional anaesthesia was performed with a Fascia Iliaca Block or an Adductor Canal Block. Results: For the final analysis, 35 patients remained, 18 with hip and 17 with knee arthroplasty. We found no significant difference in postoperative pain between hip or knee arthroplasty groups. NOL increase at the time of skin incision was the only parameter associated with postoperative pain measured using a numerical rating scale (NRS > 3) after 24 h in movement (−12.3 vs. +119%, p = 0.005). There was no association with intraoperative NOL values and postoperative opioid consumption, nor was there an association between secondary parameters (bispectral index, heart rate) and postoperative pain levels. Conclusions: Intraoperative NOL changes may indicate regional anaesthesia effectiveness and could be associated with postoperative pain levels. This remains to be confirmed in a larger study. [ABSTRACT FROM AUTHOR]

Background. Vitamins A, D and E and beta-carotene may have a protective function for cognitive health, due to their antioxidant capacities. Methods. We analyzed data from 1334 non-demented participants (mean age 84 years) from the AgeCoDe study, a prospective multicenter-cohort of elderly general-practitioner patients in Germany, of whom n = 250 developed all-cause dementia and n = 209 developed Alzheimer's dementia (AD) during 7 years of follow-up. We examined whether concentrations of vitamins A (retinol), D (25-hydroxycholecalciferol) and E (alpha-tocopherol) and beta-carotene, would be associated with incident (AD) dementia. Results. In our sample, 33.7% had optimum vitamin D concentrations (≥50 nmol/L). Higher concentrations of vitamin D were associated with lower incidence of all-cause dementia and AD (HR 0.99 (95%CI 0.98; 0.99); HR0.99 (95%CI 0.98; 0.99), respectively). In particular, subjects with vitamin D deficiency (25.3%, <25 nmol/L) were at increased risk for all-cause dementia and AD (HR1.91 (95%CI 1.30; 2.81); HR2.28 (95%CI 1.47; 3.53), respectively). Vitamins A and E and beta-carotene were unrelated to (AD) dementia. Conclusions. Vitamin D deficiency increased the risk to develop (AD) dementia. Our study supports the advice for monitoring vitamin D status in the elderly and vitamin D supplementation in those with vitamin D deficiency. We observed no relationships between the other vitamins with incident (AD) dementia, which is in line with previous observational studies. [ABSTRACT FROM AUTHOR]

We sought to assess the anti‐seizure efficacy of carbamazepine (CBZ) and retention rate (RR) in randomized, controlled trials (RCTs) in epilepsy. Our analysis was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. Inclusion criteria were monotherapy of CBZ in adequate dosage for epilepsy treatment and RCT duration of ≥3 months. Outcome measures were seizure freedom rate (SFR) and RR. Random‐effects meta‐analyses were performed to allow for comparison with other anti‐seizure medications (ASMs). Thirty RCTs of 734 were included. SFR at last follow‐up ranged from 11% at 36 months to 85% at 3 months. The aggregated SFR at 6 months was 58% (CI 49–66%) and 48% (CI 40–57%) at 12 months. The 6‐month SFR among blinded studies was 55% (CI 43–66%), compared with 61% (CI 50–71%) in unblinded studies. The 12‐month SFR was not significantly linked to the age of study participants. RR varied from 36% at 24 months to 81% at 6 months. When adjusting for blinding, the aggregated 6‐month RR in blinded studies was 59% (CI 52–66%) vs 76% (CI 71–81%) in unblinded studies. The point estimates of SFR of all RCTs showed an upward time trend, with an increase of approximately 15% between the years 1981 and 2018. In conclusion, the SFR and RR of CBZ were highly variable in RCTs and especially affected by study duration and blinding. These results underscore the impact of the design of RCTs investigating ASM and may challenge the wide use of CBZ as a comparator. [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]

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]

Background: Blood‐based biomarkers of Alzheimer's disease (AD) may provide an avenue for early identification of individuals at risk for AD dementia, which is a crucial task for implementing upcoming disease‐modifying therapies in clinical practice. Among blood‐based biomarkers, P‐tau217 has shown a particular sensitivity to amyloid pathology and utility for differential diagnosis of AD. However, less is known about the association of P‐tau217 with dementia risk in older primary care patients. Method: To address this question in an extreme phenotype design, we measured plasma P‐tau217 using the validated ALZPath pTau217 assay developed on the Single molecule array (Simoa) technology in 184 patients (median age = 83 years) free of dementia at blood draw who converted to clinically diagnosed dementia of the Alzheimer's type (DAT) during up to eight years of follow‐up. Furthermore, P‐tau217 was measured in 184 age‐ and sex‐matched cognitively normal controls that stayed free of any cognitive impairment during follow‐up. All participants were derived from the primary care‐based AgeCoDe‐cohort. In addition, Aβ42/Aβ40, P‐tau181, NfL, and GFAP were quantified using Simoa technology. Associations between P‐tau217 and conversion to DAT were assessed using conditional logistic regression and compared to associations of conversion to DAT with Aβ42/Aβ40, P‐tau181, NfL, and GFAP. The influence of time to DAT diagnosis on the associations was assessed by generalized additive models. Result: P‐tau217 was strongly associated with conversion to DAT (ORper‐1SD‐increase [95%‐CI] = 10.29 [5.16‐20.41], p = 2.0*10−11, N = 368). This association was present irrespective of whether DAT‐converter showed MCI (ORper‐1SD‐increase [95%‐CI] = 3.49 [1.34‐9.12], p = 1.1*10−2) or no MCI (ORper‐1SD‐increase[95%‐CI] = 16.07[6.54‐39.71], p = 1.3*10−9) at blood draw. No other marker showed a similarly strong association with conversion (second‐best performance: GFAP; ORper‐1SD‐increase [95%‐CI] = 1.36 [1.19‐1.54], p = 2.15*10−2). Patients converting to DAT eight years after blood draw already presented with elevated P‐tau217 levels compared to their matched controls. Other markers (GFAP, P‐tau181) started to show differences in individuals converting to DAT four years after blood draw. Conclusion: P‐tau217 is the most sensitive plasma marker for risk of conversion to DAT in older patients from primary care patients in comparison to plasma P‐tau181, Aβ42/Aβ40, NfL, and GFAP. [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: 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]

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]

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]