Publications by authors named "Harald Binder"

201 Publications

Automatic Classification Between COVID-19 and Non-COVID-19 Pneumonia Using Symptoms, Comorbidities, and Laboratory Findings: The Khorshid COVID Cohort Study.

Front Med (Lausanne) 2021 18;8:768467. Epub 2021 Nov 18.

Faculty of Medicine and Medical Center, Institute of Medical Biometry and Statistics, University of Freiburg, Freiburg, Germany.

Coronavirus disease-2019, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was a disaster in 2020. Accurate and early diagnosis of coronavirus disease-2019 (COVID-19) is still essential for health policymaking. Reverse transcriptase-polymerase chain reaction (RT-PCR) has been performed as the operational gold standard for COVID-19 diagnosis. We aimed to design and implement a reliable COVID-19 diagnosis method to provide the risk of infection using demographics, symptoms and signs, blood markers, and family history of diseases to have excellent agreement with the results obtained by the RT-PCR and CT-scan. Our study primarily used sample data from a 1-year hospital-based prospective COVID-19 open-cohort, the Khorshid COVID Cohort (KCC) study. A sample of 634 patients with COVID-19 and 118 patients with pneumonia with similar characteristics whose RT-PCR and chest CT scan were negative (as the control group) (dataset 1) was used to design the system and for internal validation. Two other online datasets, namely, some symptoms (dataset 2) and blood tests (dataset 3), were also analyzed. A combination of one-hot encoding, stability feature selection, over-sampling, and an ensemble classifier was used. Ten-fold stratified cross-validation was performed. In addition to gender and symptom duration, signs and symptoms, blood biomarkers, and comorbidities were selected. Performance indices of the cross-validated confusion matrix for dataset 1 were as follows: sensitivity of 96% [confidence interval, CI, 95%: 94-98], specificity of 95% [90-99], positive predictive value (PPV) of 99% [98-100], negative predictive value (NPV) of 82% [76-89], diagnostic odds ratio (DOR) of 496 [198-1,245], area under the ROC (AUC) of 0.96 [0.94-0.97], Matthews Correlation Coefficient (MCC) of 0.87 [0.85-0.88], accuracy of 96% [94-98], and Cohen's Kappa of 0.86 [0.81-0.91]. The proposed algorithm showed excellent diagnosis accuracy and class-labeling agreement, and fair discriminant power. The AUC on the datasets 2 and 3 was 0.97 [0.96-0.98] and 0.92 [0.91-0.94], respectively. The most important feature was white blood cell count, shortness of breath, and C-reactive protein for datasets 1, 2, and 3, respectively. The proposed algorithm is, thus, a promising COVID-19 diagnosis method, which could be an amendment to simple blood tests and screening of symptoms. However, the RT-PCR and chest CT-scan, performed as the gold standard, are not 100% accurate.
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http://dx.doi.org/10.3389/fmed.2021.768467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640954PMC
November 2021

Acquired Resistance to Antiangiogenic Therapies in Hepatocellular Carcinoma Is Mediated by Yes-Associated Protein 1 Activation and Transient Expansion of Stem-Like Cancer Cells.

Hepatol Commun 2021 Nov 24. Epub 2021 Nov 24.

Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center Schleswig Holstein, Luebeck, Germany.

Induction of neoangiogenesis is a hallmark feature during disease progression of hepatocellular carcinoma (HCC). Antiangiogenetic compounds represent a mainstay of therapeutic approaches; however, development of chemoresistance is observed in the majority of patients. Recent findings suggest that tumor-initiating cells (TICs) may play a key role in acquisition of resistance, but the exact relevance for HCC in this process remains to be defined. Primary and established hepatoma cell lines were exposed to long-term sorafenib treatment to model acquisition of resistance. Treatment effects on TICs were estimated by sphere-forming capacity in vitro, tumorigenicity in vivo, and flow cytometry. Adaptive molecular changes were assessed by whole transcriptome analyses. Compensatory mechanisms of resistance were identified and directly evaluated. Sustained antiproliferative effect following sorafenib treatment was observed in three of six HCC cell lines and was followed by rapid regrowth, thereby mimicking responses observed in patients. Resistant cells showed induction in sphere forming in vitro and tumor-initiating capacity in vivo as well as increased number of side population and epithelial cell adhesion molecule-positive cells. Conversely, sensitive cell lines showed consistent reduction of TIC properties. Gene sets associated with resistance and poor prognosis, including Hippo/yes-associated protein (YAP), were identified. Western blot and immunohistochemistry confirmed increased levels of YAP. Combined treatment of sorafenib and specific YAP inhibitor consistently revealed synergistic antioncogenic effects in resistant cell lines. Conclusion: Resistance to antiangiogenic therapy might be driven by transient expansion of TICs and activation of compensatory pro-oncogenic signaling pathways, including YAP. Specific targeting of TICs might be an effective therapeutic strategy to overcome resistance in HCC.
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http://dx.doi.org/10.1002/hep4.1869DOI Listing
November 2021

Identification of Genetic Predispositions Related to Ionizing Radiation in Primary Human Skin Fibroblasts From Survivors of Childhood and Second Primary Cancer as Well as Cancer-Free Controls: Protocol for the Nested Case-Control Study KiKme.

JMIR Res Protoc 2021 Nov 11;10(11):e32395. Epub 2021 Nov 11.

Department of Radiation Oncology and Radiation Therapy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Background: Therapy for a first primary neoplasm (FPN) in childhood with high doses of ionizing radiation is an established risk factor for second primary neoplasms (SPN). An association between exposure to low doses and childhood cancer is also suggested; however, results are inconsistent. As only subgroups of children with FPNs develop SPNs, an interaction between radiation, genetic, and other risk factors is presumed to influence cancer development.

Objective: Therefore, the population-based, nested case-control study KiKme aims to identify differences in genetic predisposition and radiation response between childhood cancer survivors with and without SPNs as well as cancer-free controls.

Methods: We conducted a population-based, nested case-control study KiKme. Besides questionnaire information, skin biopsies and saliva samples are available. By measuring individual reactions to different exposures to radiation (eg, 0.05 and 2 Gray) in normal somatic cells of the same person, our design enables us to create several exposure scenarios for the same person simultaneously and measure several different molecular markers (eg, DNA, messenger RNA, long noncoding RNA, copy number variation).

Results: Since 2013, 101 of 247 invited SPN patients, 340 of 1729 invited FPN patients, and 150 of 246 invited cancer-free controls were recruited and matched by age and sex. Childhood cancer patients were additionally matched by tumor morphology, year of diagnosis, and age at diagnosis. Participants reported on lifestyle, socioeconomical, and anthropometric factors, as well as on medical radiation history, health, and family history of diseases (n=556). Primary human fibroblasts from skin biopsies of the participants were cultivated (n=499) and cryopreserved (n=3886). DNA was extracted from fibroblasts (n=488) and saliva (n=510).

Conclusions: This molecular-epidemiological study is the first to combine observational epidemiological research with standardized experimental components in primary human skin fibroblasts to identify genetic predispositions related to ionizing radiation in childhood and SPNs. In the future, fibroblasts of the participants will be used for standardized irradiation experiments, which will inform analysis of the case-control study and vice versa. Differences between participants will be identified using several molecular markers. With its innovative combination of experimental and observational components, this new study will provide valuable data to forward research on radiation-related risk factors in childhood cancer and SPNs.

International Registered Report Identifier (irrid): DERR1-10.2196/32395.
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http://dx.doi.org/10.2196/32395DOI Listing
November 2021

[RECUR - Establishment of An Automated Digital Registry for Patients with Recurrent Stones in the Upper Urinary Tract].

Gesundheitswesen 2021 Nov 3;83(S 01):S27-S32. Epub 2021 Nov 3.

Urologie, Universitätsklinikum Freiburg, Freiburg, Deutschland.

Kidney stones, like cardiovascular diseases and diabetes mellitus, affect a large number of people. Patients suffer from acute pain, repeated hospitalizations and associated secondary diseases, such as arterial hypertension and renal insufficiency. This results in considerable costs for the society and its health care system. The recurrence rate is as high as 50%. The registry for RECurrent URolithiasis (RECUR) aims to fill existing evidence gaps. The prospective and longitudinal RECUR registry is funded by the German Ministry of Education and Science (BMBF). It is based on the digital infrastructure of the German Medical Informatics Initiative (MII). RECUR aims to include patients that have suffered from more than one stone occurrence and treated at any one of the ten participating university hospitals of the MIRACUM consortium. The intention is to obtain new information on risk factors and to evaluate different diagnosis and treatment algorithms. Along with the data form the patient's Electronic Health Records (EHR), the RECUR project will also collect Patient Reported Outcomes data from patients with recurrent kidney stones. These data will be collected at participating sites using digital questionnaires via a smartphone app. These data will be merged with medical data from the hospital information systems and saved in the MII research data repositories. The RECUR registry has a model character due to its fully federated, digital approach. This allows the recruitment of many patients, the collection of a wide range of data and their processing with low administrative and personnel costs.
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http://dx.doi.org/10.1055/a-1651-0311DOI Listing
November 2021

Management and Outcome of Traumatic Intracerebral Hemorrhage in 79 Infants and Children from a Single Level 1 Trauma Center.

Children (Basel) 2021 Sep 26;8(10). Epub 2021 Sep 26.

Department of Trauma Surgery, Medical University of Vienna, 1090 Vienna, Austria.

Objective: Traumatic brain injury is a leading form of pediatric trauma and a frequent cause of mortality and acquired neurological impairment in children. The aim of this study was to present the severity and outcomes of traumatic intracerebral bleeding in children and adolescence.

Methods: Seventy-nine infants and children with intracerebral bleedings were treated between 1992 and 2020 at a single level 1 trauma center. Data regarding accident, treatment and outcomes were collected retrospectively. The Glasgow Outcome Scale was used to classify the outcome at hospital discharge and at follow-up visits. CT scans of the brain were classified according to the Rotterdam score.

Results: In total, 41 (52%) patients with intracerebral bleedings were treated surgically, and 38 (48%) patients were treated conservatively; in 15% of the included patients, delayed surgery was necessary. Patients presenting multiple trauma ( < 0.04), higher ISS ( < 0.01), poor initial neurological status ( < 0.001) and a higher Rotterdamscore ( = 0.038) were significantly more often treated surgically. Eighty-three percent of patients were able to leave the hospital, and out of these patients, about 60% showed good recovery at the latest follow-up visit. Overall, 11 patients (14%) died.

Conclusion: The findings in this study verified intracerebral bleeding as a rare but serious condition. Patients presenting with multiple traumas, higher initial ISS, poor initial neurological status and a higher Rotterdamscore were more likely treated by surgery.

Trial Registration: (researchregistry 2686).
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http://dx.doi.org/10.3390/children8100854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534601PMC
September 2021

Stratified neural networks in a time-to-event setting.

Brief Bioinform 2021 Sep 28. Epub 2021 Sep 28.

Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Germany.

Deep neural networks are frequently employed to predict survival conditional on omics-type biomarkers, e.g., by employing the partial likelihood of Cox proportional hazards model as loss function. Due to the generally limited number of observations in clinical studies, combining different data sets has been proposed to improve learning of network parameters. However, if baseline hazards differ between the studies, the assumptions of Cox proportional hazards model are violated. Based on high dimensional transcriptome profiles from different tumor entities, we demonstrate how using a stratified partial likelihood as loss function allows for accounting for the different baseline hazards in a deep learning framework. Additionally, we compare the partial likelihood with the ranking loss, which is frequently employed as loss function in machine learning approaches due to its seemingly simplicity. Using RNA-seq data from the Cancer Genome Atlas (TCGA) we show that use of stratified loss functions leads to an overall better discriminatory power and lower prediction error compared to their non-stratified counterparts. We investigate which genes are identified to have the greatest marginal impact on prediction of survival when using different loss functions. We find that while similar genes are identified, in particular known prognostic genes receive higher importance from stratified loss functions. Taken together, pooling data from different sources for improved parameter learning of deep neural networks benefits largely from employing stratified loss functions that consider potentially varying baseline hazards. For easy application, we provide PyTorch code for stratified loss functions and an explanatory Jupyter notebook in a GitHub repository.
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http://dx.doi.org/10.1093/bib/bbab392DOI Listing
September 2021

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Thromb Haemost 2021 Sep 24. Epub 2021 Sep 24.

AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.
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http://dx.doi.org/10.1055/a-1653-4699DOI Listing
September 2021

The Frequent Stressor and Mental Health Monitoring-Paradigm: A Proposal for the Operationalization and Measurement of Resilience and the Identification of Resilience Processes in Longitudinal Observational Studies.

Front Psychol 2021 26;12:710493. Epub 2021 Aug 26.

Neuroimaging Center, Focus Program Translational Neuroscience, Johannes Gutenberg University Medical Center, Mainz, Germany.

Resilience has been defined as the maintenance or quick recovery of mental health during and after times of adversity. How to operationalize resilience and to determine the factors and processes that lead to good long-term mental health outcomes in stressor-exposed individuals is a matter of ongoing debate and of critical importance for the advancement of the field. One of the biggest challenges for implementing an outcome-based definition of resilience in longitudinal observational study designs lies in the fact that real-life adversity is usually unpredictable and that its substantial qualitative as well as temporal variability between subjects often precludes defining circumscribed time windows of inter-individually comparable stressor exposure relative to which the maintenance or recovery of mental health can be determined. To address this pertinent issue, we propose to frequently and regularly monitor stressor exposure (E) and mental health problems (P) throughout a study's observation period [Frequent Stressor and Mental Health Monitoring (FRESHMO)-paradigm]. On this basis, a subject's deviation at any single monitoring time point from the study sample's normative E-P relationship (the regression residual) can be used to calculate that subject's current mental health reactivity to stressor exposure ("stressor reactivity," SR). The SR score takes into account the individual extent of experienced adversity and is comparable between and within subjects. Individual SR time courses across monitoring time points reflect intra-individual temporal variability in SR, where periods of under-reactivity (negative SR score) are associated with accumulation of fewer mental health problems than is normal for the sample. If FRESHMO is accompanied by regular measurement of potential resilience factors, temporal changes in resilience factors can be used to predict SR time courses. An increase in a resilience factor measurement explaining a lagged decrease in SR can then be considered to index a process of adaptation to stressor exposure that promotes a resilient outcome (an allostatic resilience process). This design principle allows resilience research to move beyond merely determining baseline predictors of resilience outcomes, which cannot inform about how individuals successfully adjust and adapt when confronted with adversity. Hence, FRESHMO plus regular resilience factor monitoring incorporates a dynamic-systems perspective into resilience research.
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http://dx.doi.org/10.3389/fpsyg.2021.710493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444985PMC
August 2021

Chronic venous insufficiency, cardiovascular disease, and mortality: a population study.

Eur Heart J 2021 10;42(40):4157-4165

Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz 55131, Germany.

Aims: Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce.

Methods And Results: Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40-80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6-37.4%], 13.3% [12.6-13.9%], and 40.8% [39.9-41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19-1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11-2.05), P = 0.009].

Conclusion: Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.
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http://dx.doi.org/10.1093/eurheartj/ehab495DOI Listing
October 2021

Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Department of Medicine I, University Medical Center Mainz, Mainz, Germany.

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.
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http://dx.doi.org/10.1172/jci.insight.146196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492348PMC
September 2021

Domains of Physical Activity in Relation to Stiffness Index in the General Population.

J Am Heart Assoc 2021 08 5;10(16):e020930. Epub 2021 Aug 5.

Department of Cardiology Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz Mainz Germany.

Background Regular exercise training represents an important modifier of arterial stiffness (AS). Therefore, sex-specific relations between domains of physical activity (PA; commuting, domestic, and leisure-time PA, including active sport and occupational PA) with AS were investigated. Methods and Results Stiffness index by digital photoplethysmography was investigated in 12 650 subjects from the GHS (Gutenberg Health Study). Self-reported PA was evaluated by the "Short Questionnaire to Assess Health-Enhancing Physical Activity" and reported as activity score peer week, being a combined measure of duration, frequency, and intensity of PA. Multivariable linear regression analysis demonstrated strong beneficial effects of repetitive activities, such as active commuting or leisure-time PA-related walking on AS in men, but not in women. Lower AS associated with endurance training was also found among men and premenopausal women. In contrast, intense occupational PA was related to stiffer vessels in men (<0.0001) and women (=0.0021) in a fully adjusted model. Combination of both, performing endurance training and having stiffness index values below median, resulted in the best survival. In contrast, subjects with elevated stiffness index at baseline without any endurance activities demonstrated the worst survival. Conclusions In this population representative sample, a differential impact of domains of self-reported PA on AS was demonstrated. Our data strengthen the importance of regular endurance PA to induce a reduction of AS, which, in turn, may improve cardiovascular prognosis. We also report deleterious effects of intense occupational PA on stiffness index, a finding that needs further confirmation by larger prospective trials.
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http://dx.doi.org/10.1161/JAHA.121.020930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475023PMC
August 2021

Classification of psychiatric symptoms using deep interaction networks: the CASPIAN-IV study.

Sci Rep 2021 08 3;11(1):15706. Epub 2021 Aug 3.

Pediatrics Department, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.

Identifying the possible factors of psychiatric symptoms among children can reduce the risk of adverse psychosocial outcomes in adulthood. We designed a classification tool to examine the association between modifiable risk factors and psychiatric symptoms, defined based on the Persian version of the WHO-GSHS questionnaire in a developing country. Ten thousand three hundred fifty students, aged 6-18 years from all Iran provinces, participated in this study. We used feature discretization and encoding, stability selection, and regularized group method of data handling (GMDH) to classify the a priori specific factors (e.g., demographic, sleeping-time, life satisfaction, and birth-weight) to psychiatric symptoms. Self-rated health was the most critical feature. The selected modifiable factors were eating breakfast, screentime, salty snack for depression symptom, physical activity, salty snack for worriedness symptom, (abdominal) obesity, sweetened beverage, and sleep-hour for mild-to-moderate emotional symptoms. The area under the ROC curve of the GMDH was 0.75 (CI 95% 0.73-0.76) for the analyzed psychiatric symptoms using threefold cross-validation. It significantly outperformed the state-of-the-art (adjusted p < 0.05; McNemar's test). In this study, the association of psychiatric risk factors and the importance of modifiable nutrition and lifestyle factors were emphasized. However, as a cross-sectional study, no causality can be inferred.
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http://dx.doi.org/10.1038/s41598-021-95208-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333323PMC
August 2021

Impact of radiotherapy protocol adherence in NSCLC patients treated with concurrent chemoradiation: RTQA results of the PET-Plan trial.

Radiother Oncol 2021 Oct 24;163:32-38. Epub 2021 Jul 24.

Department of Radiation Oncology, Medical Center, University of Freiburg, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine, University of Freiburg, Germany; Department of Nuclear Medicine, Medical Center, University of Freiburg, Germany.

Introduction: The success of intensification and personalisation of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy. Here, we evaluate the impact of radiotherapy protocol adherence in a prospective multicentre trial.

Methods: In the open-label, randomised, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by F-FDG PET and CT plus elective nodal irradiation (arm A) or target volumes informed by PET alone (arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organised quality assurance program (RTQA) included individual case review by predefined criteria. For evaluation, protocol adherence was scored as per protocol (pP), with minor (miD), intermediate (inD) and major (maD) deviations. In order to exclude biases through patients who discontinued treatment, patients who received ≥60 Gy were additionally analysed.

Results: Between 05/2009-11/2016, 205 patients were randomized, 204 patients started treatment according to protocol of which 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, p < 0.0001) and a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, p < 0.0001). These results were significant also in the subgroup of patients receiving ≥ 60 Gy. Patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (p = 0.006) although no higher incidence of grade ≥ 3 toxicities.

Conclusions: Non-adherence to the radiotherapy protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA.
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http://dx.doi.org/10.1016/j.radonc.2021.07.017DOI Listing
October 2021

Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders.

PLoS One 2021 22;16(7):e0255192. Epub 2021 Jul 22.

Vitos Hochtaunus, Friedrichsdorf, Germany.

Introduction: The aim of this study was to describe the number and type of drugs used to treat depressive disorders in inpatient psychiatry and to analyse the determinants of potential drug-drug interactions (pDDI) and potentially inappropriate medication (PIM).

Methods: Our study was part of a larger pharmacovigilance project funded by the German Innovation Funds. It included all inpatients with a main diagnosis in the group of depressive episodes (F32, ICD-10) or recurrent depressive disorders (F33) discharged from eight psychiatric hospitals in Germany between 1 October 2017 and 30 September 2018 or between 1 January and 31 December 2019.

Results: The study included 14,418 inpatient cases. The mean number of drugs per day was 3.7 (psychotropic drugs = 1.7; others = 2.0). Thirty-one percent of cases received at least five drugs simultaneously (polypharmacy). Almost one half of all cases received a combination of multiple antidepressant drugs (24.8%, 95% CI 24.1%-25.5%) or a treatment with antidepressant drugs augmented by antipsychotic drugs (21.9%, 95% CI 21.3%-22.6%). The most frequently used antidepressants were selective serotonin reuptake inhibitors, followed by serotonin and norepinephrine reuptake inhibitors and tetracyclic antidepressants. In multivariate analyses, cases with recurrent depressive disorders and cases with severe depression were more likely to receive a combination of multiple antidepressant drugs (Odds ratio recurrent depressive disorder: 1.56, 95% CI 1.41-1.70, severe depression 1.33, 95% CI 1.18-1.48). The risk of any pDDI and PIM in elderly patients increased substantially with each additional drug (Odds Ratio: pDDI 1.32, 95% CI: 1.27-1.38, PIM 1.18, 95% CI: 1.14-1.22) and severity of disease (Odds Ratio per point on CGI-Scale: pDDI 1.29, 95% CI: 1.11-1.46, PIM 1.27, 95% CI: 1.11-1.44), respectively.

Conclusion: This study identified potential sources and determinants of safety risks in pharmacotherapy of depressive disorders and provided additional data which were previously unavailable. Most inpatients with depressive disorders receive multiple psychotropic and non-psychotropic drugs and pDDI and PIM are relatively frequent. Patients with a high number of different drugs must be intensively monitored in the management of their individual drug-related risk-benefit profiles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255192PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297778PMC
November 2021

Comments on "Identifying inconsistency in network meta-analysis: Is the net heat plot a reliable method?"

Stat Med 2021 08;40(18):4161-4163

Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center Johannes Gutenberg University, Mainz, Germany.

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http://dx.doi.org/10.1002/sim.9074DOI Listing
August 2021

Absolute mortality risk assessment of COVID-19 patients: the Khorshid COVID Cohort (KCC) study.

BMC Med Res Methodol 2021 07 14;21(1):146. Epub 2021 Jul 14.

Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.

Background: Already at hospital admission, clinicians require simple tools to identify hospitalized COVID-19 patients at high risk of mortality. Such tools can significantly improve resource allocation and patient management within hospitals. From the statistical point of view, extended time-to-event models are required to account for competing risks (discharge from hospital) and censoring so that active cases can also contribute to the analysis.

Methods: We used the hospital-based open Khorshid COVID Cohort (KCC) study with 630 COVID-19 patients from Isfahan, Iran. Competing risk methods are used to develop a death risk chart based on the following variables, which can simply be measured at hospital admission: sex, age, hypertension, oxygen saturation, and Charlson Comorbidity Index. The area under the receiver operator curve was used to assess accuracy concerning discrimination between patients discharged alive and dead.

Results: Cause-specific hazard regression models show that these baseline variables are associated with both death, and discharge hazards. The risk chart reflects the combined results of the two cause-specific hazard regression models. The proposed risk assessment method had a very good accuracy (AUC = 0.872 [CI 95%: 0.835-0.910]).

Conclusions: This study aims to improve and validate a personalized mortality risk calculator based on hospitalized COVID-19 patients. The risk assessment of patient mortality provides physicians with additional guidance for making tough decisions.
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http://dx.doi.org/10.1186/s12874-021-01340-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278186PMC
July 2021

The relation between childhood adversity and adult obesity in a population-based study in women and men.

Sci Rep 2021 07 7;11(1):14068. Epub 2021 Jul 7.

Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Semmelweisstrasse 10, 04103, Leipzig, Germany.

Childhood maltreatment has been shown to relate to adult obesity. In this epidemiological study, we investigate the association between childhood maltreatment and waist-to-height-ratio (WHtR) in a sample of the German adult population, comprising of N = 2936 participants. WHtR, an indicator for risk of obesity, was the primary outcome. Childhood maltreatment was assessed by the Childhood Trauma Screener (CTS), which assesses emotional and physical neglect, abuse as well as sexual abuse. Cohort-data were harmonized and analyzed within DataSHIELD. We used multivariable regression models to estimate the association of childhood maltreatment and WHtR at different levels of adjustments for potential confounders. Overall childhood maltreatment was associated with a higher WHtR in both sexes (women: p = 0.004, men: p < 0.001); associations were no longer significant in women after adding socioeconomic variables, but remained significant in men (p = 0.013). Additionally, we were able to identify sex specific patterns for childhood maltreatment predicting the WHtR. Emotional neglect and abuse had stronger impacts on the WHtR in women than in men, whereas physical neglect and abuse had stronger impacts in men. To our knowledge, this is the first comprehensive population-based study testing various types of childhood maltreatment with WHtR in sex-, region- and weight-stratified analyses. Future studies in clinical populations are warranted to examine U-shaped correlations between increased WHtR and childhood maltreatment.
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http://dx.doi.org/10.1038/s41598-021-93242-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263764PMC
July 2021

Clinical evaluation after matrix-associated autologous chondrocyte transplantation : a comparison of four different graft types.

Bone Joint Res 2021 Jul;10(7):370-379

Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria.

Aims: The aim of this retrospective study was to determine if there are differences in short-term clinical outcomes among four different types of matrix-associated autologous chondrocyte transplantation (MACT).

Methods: A total of 88 patients (mean age 34 years (SD 10.03), mean BMI 25 kg/m (SD 3.51)) with full-thickness chondral lesions of the tibiofemoral joint who underwent MACT were included in this study. Clinical examinations were performed preoperatively and 24 months after transplantation. Clinical outcomes were evaluated using the International Knee Documentation Committee (IKDC) Subjective Knee Form, the Brittberg score, the Tegner Activity Scale, and the visual analogue scale (VAS) for pain. The Kruskal-Wallis test by ranks was used to compare the clinical scores of the different transplant types.

Results: The mean defect size of the tibiofemoral joint compartment was 4.28 cm (SD 1.70). In total, 11 patients (12.6%) underwent transplantation with Chondro-Gide (matrix-associated autologous chondrocyte implantation (MACI)), 40 patients (46.0%) with Hyalograft C (HYAFF), 21 patients (24.1%) with Cartilage Regeneration System (CaReS), and 15 patients (17.2%) with NOVOCART 3D. The mean IKDC Subjective Knee Form score improved from 35.71 (SD 6.44) preoperatively to 75.26 (SD 18.36) after 24 months postoperatively in the Hyalograft group, from 35.94 (SD 10.29) to 71.57 (SD 16.31) in the Chondro-Gide (MACI) group, from 37.06 (SD 5.42) to 71.49 (SD 6.76) in the NOVOCART 3D group, and from 45.05 (SD 15.83) to 70.33 (SD 19.65) in the CaReS group. Similar improvements were observed in the VAS and Brittberg scores.

Conclusion: Two years postoperatively, there were no significant differences in terms of outcomes. Our data demonstrated that MACT, regardless of the implants used, resulted in good clinical improvement two years after transplantation for localized tibiofemoral defects. Cite this article:  2021;10(7):370-379.
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http://dx.doi.org/10.1302/2046-3758.107.BJR-2020-0370.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333036PMC
July 2021

Polypharmacy and the risk of drug-drug interactions and potentially inappropriate medications in hospital psychiatry.

Pharmacoepidemiol Drug Saf 2021 Sep 24;30(9):1258-1268. Epub 2021 Jun 24.

Vitos Hochtaunus gemeinnutzige GmbH, Friedrichsdorf, Germany.

Purpose: The aim of this study was to analyze the epidemiology of polypharmacy in hospital psychiatry. Another aim was to investigate predictors of the number of drugs taken and the associated risks of drug-drug interactions and potentially inappropriate medications in the elderly.

Methods: Daily prescription data were obtained from a pharmacovigilance project sponsored by the Innovations Funds of the German Federal Joint Committee.

Results: The study included 47 071 inpatient hospital cases from eight different study centers. The mean number of different drugs during the entire stay was 6.1 (psychotropic drugs = 2.7; others = 3.4). The mean number of drugs per day was 3.8 (psychotropic drugs = 1.6; others = 2.2). One third of cases received at least five different drugs per day on average during their hospital stay (polypharmacy). Fifty-one percent of patients received more than one psychotropic drug simultaneously. Hospital cases with polypharmacy were 18 years older (p < 0.001), more likely to be female (52% vs. 40%, p < 0.001) and had more comorbidities (5 vs. 2, p < 0.001) than hospital cases without polypharmacy. The risks of drug-drug interactions (OR = 3.7; 95% CI = 3.5-3.9) and potentially inappropriate medication use in the elderly (OR = 2.2; CI = 1.9-2.5) substantially increased in patients that received polypharmacy.

Conclusion: Polypharmacy is frequent in clinical care. The number of used drugs is a proven risk factor of adverse drug reactions due to drug-drug interactions and potentially inappropriate medication use in the elderly. The potential interactions and the specific pharmacokinetics and -dynamics of older patients should always be considered when multiple drugs are used.
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http://dx.doi.org/10.1002/pds.5310DOI Listing
September 2021

Assessing mediating effects of high-dimensional microbiome measurements in dietary intervention studies.

Biom J 2021 10 6;63(7):1366-1374. Epub 2021 May 6.

Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.

Habitual diet can influence health-related outcomes directly, but such effects may also be modulated indirectly by gut microbiota. We consider randomized trials and the question to what extent the effect of diet on an outcome of interest is mediated through the gut microbiome or whether there is a diet-microbiome interaction identifying subgroups of individuals who are more susceptible to specific dietary effects. The baseline microbiome by itself may be a modifier of the effects of diet on health. Yet, the high dimensionality of microbiome data requires innovative statistical approaches to identify potential mediating or moderating effects. To motivate our proposal for an appropriate analysis workflow, we consider a randomized trial that investigates the effect of a 4-week vegan diet on the diversity of gut microbiota and branched-chain amino acid metabolism in healthy omnivorous volunteers. To address the challenge of compositional microbiome data, we consider an adaptation of the lasso for penalized estimation of multivariable regression models with a large number of microbiotic taxa. This is plugged into a classical regression mediation effect analysis strategy. The interaction effects are obtained via an approach that can directly estimate them without having to deal with main effects. As a result we obtain signatures comprised of microbiotic taxa with potential mediating and moderating effects. Some taxa no longer show up as mediating, when taking moderating effects into account. Thus, the proposed analysis strategy allows to identify specific mediating effects, while avoiding potential erroneous conclusions, where moderating effects might have believed to be mediating effects.
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http://dx.doi.org/10.1002/bimj.201900373DOI Listing
October 2021

Assessing mediating effects of high-dimensional microbiome measurements in dietary intervention studies.

Biom J 2021 10 6;63(7):1366-1374. Epub 2021 May 6.

Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.

Habitual diet can influence health-related outcomes directly, but such effects may also be modulated indirectly by gut microbiota. We consider randomized trials and the question to what extent the effect of diet on an outcome of interest is mediated through the gut microbiome or whether there is a diet-microbiome interaction identifying subgroups of individuals who are more susceptible to specific dietary effects. The baseline microbiome by itself may be a modifier of the effects of diet on health. Yet, the high dimensionality of microbiome data requires innovative statistical approaches to identify potential mediating or moderating effects. To motivate our proposal for an appropriate analysis workflow, we consider a randomized trial that investigates the effect of a 4-week vegan diet on the diversity of gut microbiota and branched-chain amino acid metabolism in healthy omnivorous volunteers. To address the challenge of compositional microbiome data, we consider an adaptation of the lasso for penalized estimation of multivariable regression models with a large number of microbiotic taxa. This is plugged into a classical regression mediation effect analysis strategy. The interaction effects are obtained via an approach that can directly estimate them without having to deal with main effects. As a result we obtain signatures comprised of microbiotic taxa with potential mediating and moderating effects. Some taxa no longer show up as mediating, when taking moderating effects into account. Thus, the proposed analysis strategy allows to identify specific mediating effects, while avoiding potential erroneous conclusions, where moderating effects might have believed to be mediating effects.
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http://dx.doi.org/10.1002/bimj.201900373DOI Listing
October 2021

Synthetic single cell RNA sequencing data from small pilot studies using deep generative models.

Sci Rep 2021 04 30;11(1):9403. Epub 2021 Apr 30.

Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, 79104, Freiburg, Germany.

Deep generative models, such as variational autoencoders (VAEs) or deep Boltzmann machines (DBMs), can generate an arbitrary number of synthetic observations after being trained on an initial set of samples. This has mainly been investigated for imaging data but could also be useful for single-cell transcriptomics (scRNA-seq). A small pilot study could be used for planning a full-scale experiment by investigating planned analysis strategies on synthetic data with different sample sizes. It is unclear whether synthetic observations generated based on a small scRNA-seq dataset reflect the properties relevant for subsequent data analysis steps. We specifically investigated two deep generative modeling approaches, VAEs and DBMs. First, we considered single-cell variational inference (scVI) in two variants, generating samples from the posterior distribution, the standard approach, or the prior distribution. Second, we propose single-cell deep Boltzmann machines (scDBMs). When considering the similarity of clustering results on synthetic data to ground-truth clustering, we find that the [Formula: see text] variant resulted in high variability, most likely due to amplifying artifacts of small datasets. All approaches showed mixed results for cell types with different abundance by overrepresenting highly abundant cell types and missing less abundant cell types. With increasing pilot dataset sizes, the proportions of the cells in each cluster became more similar to that of ground-truth data. We also showed that all approaches learn the univariate distribution of most genes, but problems occurred with bimodality. Across all analyses, in comparing 10[Formula: see text] Genomics and Smart-seq2 technologies, we could show that for 10[Formula: see text] datasets, which have higher sparsity, it is more challenging to make inference from small to larger datasets. Overall, the results show that generative deep learning approaches might be valuable for supporting the design of scRNA-seq experiments.
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http://dx.doi.org/10.1038/s41598-021-88875-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087667PMC
April 2021

Predicting the risk of drug-drug interactions in psychiatric hospitals: a retrospective longitudinal pharmacovigilance study.

BMJ Open 2021 04 9;11(4):e045276. Epub 2021 Apr 9.

Waldkrankenhaus Köppern, Vitos Hospital Hochtaunus, Friedrichsdorf, Germany.

Objectives: The aim was to use routine data available at a patient's admission to the hospital to predict polypharmacy and drug-drug interactions (DDI) and to evaluate the prediction performance with regard to its usefulness to support the efficient management of benefits and risks of drug prescriptions.

Design: Retrospective, longitudinal study.

Setting: We used data from a large multicentred pharmacovigilance project carried out in eight psychiatric hospitals in Hesse, Germany.

Participants: Inpatient episodes consecutively discharged between 1 October 2017 and 30 September 2018 (year 1) or 1 January 2019 and 31 December 2019 (year 2).

Outcome Measures: The proportion of rightly classified hospital episodes.

Methods: We used gradient boosting to predict respective outcomes. We tested the performance of our final models in unseen patients from another calendar year and separated the study sites used for training from the study sites used for performance testing.

Results: A total of 53 909 episodes were included in the study. The models' performance, as measured by the area under the receiver operating characteristic, was 'excellent' (0.83) and 'acceptable' (0.72) compared with common benchmarks for the prediction of polypharmacy and DDI, respectively. Both models were substantially better than a naive prediction based solely on basic diagnostic grouping.

Conclusion: This study has shown that polypharmacy and DDI can be predicted from routine data at patient admission. These predictions could support an efficient management of benefits and risks of hospital prescriptions, for instance by including pharmaceutical supervision early after admission for patients at risk before pharmacological treatment is established.
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http://dx.doi.org/10.1136/bmjopen-2020-045276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043005PMC
April 2021

Deep generative models in DataSHIELD.

BMC Med Res Methodol 2021 04 3;21(1):64. Epub 2021 Apr 3.

Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.

Background: The best way to calculate statistics from medical data is to use the data of individual patients. In some settings, this data is difficult to obtain due to privacy restrictions. In Germany, for example, it is not possible to pool routine data from different hospitals for research purposes without the consent of the patients.

Methods: The DataSHIELD software provides an infrastructure and a set of statistical methods for joint, privacy-preserving analyses of distributed data. The contained algorithms are reformulated to work with aggregated data from the participating sites instead of the individual data. If a desired algorithm is not implemented in DataSHIELD or cannot be reformulated in such a way, using artificial data is an alternative. Generating artificial data is possible using so-called generative models, which are able to capture the distribution of given data. Here, we employ deep Boltzmann machines (DBMs) as generative models. For the implementation, we use the package "BoltzmannMachines" from the Julia programming language and wrap it for use with DataSHIELD, which is based on R.

Results: We present a methodology together with a software implementation that builds on DataSHIELD to create artificial data that preserve complex patterns from distributed individual patient data. Such data sets of artificial patients, which are not linked to real patients, can then be used for joint analyses. As an exemplary application, we conduct a distributed analysis with DBMs on a synthetic data set, which simulates genetic variant data. Patterns from the original data can be recovered in the artificial data using hierarchical clustering of the virtual patients, demonstrating the feasibility of the approach. Additionally, we compare DBMs, variational autoencoders, generative adversarial networks, and multivariate imputation as generative approaches by assessing the utility and disclosure of synthetic data generated from real genetic variant data in a distributed setting with data of a small sample size.

Conclusions: Our implementation adds to DataSHIELD the ability to generate artificial data that can be used for various analyses, e.g., for pattern recognition with deep learning. This also demonstrates more generally how DataSHIELD can be flexibly extended with advanced algorithms from languages other than R.
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http://dx.doi.org/10.1186/s12874-021-01237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019187PMC
April 2021

Primary dementia care based on the individual needs of the patient: study protocol of the cluster randomized controlled trial, DemStepCare.

BMC Geriatr 2021 04 1;21(1):222. Epub 2021 Apr 1.

Institute of Medical Biometry and Statistics, Section of Health Care Research and Rehabilitation Research, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.

Background: Most people with dementia (PwD) are cared for at home, with general practitioners (GPs) playing a key part in the treatment. However, primary dementia care suffers from a number of shortcomings: Often, diagnoses are made too late and therapies by GPs do not follow the guidelines. In cases of acute crises, PwD are too often admitted to hospital with adverse effects on the further course of the disease. The aim of this study is to implement and evaluate a new GP-based, complex dementia care model, DemStepCare. DemStepCare aims to ensure demand-oriented, stepped care for PwD and their caregivers.

Methods/design: In a cluster randomized controlled trial, the care of PwD receiving a complex intervention, where the GP is supported by a multi-professional team, is compared to (slightly expanded) usual care. GPs are clustered by GP practice, with 120 GP practices participating in total. GP practices are randomized to an intervention or a control group. 800 PwD are to be included per group. Recruitment takes place in Rhineland-Palatinate, Germany. In addition, a second control group with at least 800 PwD will be formed using aggregated routine data from German health insurance companies. The intervention comprises the training of GPs, case management including repeated risk assessment of the patients' care situation, the demand-oriented service of an outpatient clinic, an electronic case record, external medication analyses and a link to regional support services. The primary aims of the intervention are to positively influence the quality of life for PwD, to reduce the caregivers' burden, and to reduce the days spent in hospital. Secondary endpoints address medication adequacy and GPs' attitudes and sensitivity towards dementia, among others.

Discussion: The GP-based dementia care model DemStepCare is intended to combine a number of promising interventions to provide a complex, stepped intervention that follows the individual needs of PwD and their caregivers. Its effectiveness and feasibility will be assessed in a formative and a summative evaluation.

Trial Registration: German Register of Clinical Trials (Deutsches Register Klinischer Studien, DRKS), DRKS00023560 . Registered 13 November 2020 - Retrospectively registered. HTML&TRIAL_ID=DRKS00023560.
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http://dx.doi.org/10.1186/s12877-021-02114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012747PMC
April 2021

Mental burden and its risk and protective factors during the early phase of the SARS-CoV-2 pandemic: systematic review and meta-analyses.

Global Health 2021 03 29;17(1):34. Epub 2021 Mar 29.

Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background: Mental burden due to the SARS-CoV-2 pandemic has been widely reported for the general public and specific risk groups like healthcare workers and different patient populations. We aimed to assess its impact on mental health during the early phase by comparing pandemic with prepandemic data and to identify potential risk and protective factors.

Methods: For this systematic review and meta-analyses, we systematically searched PubMed, PsycINFO, and Web of Science from January 1, 2019 to May 29, 2020, and screened reference lists of included studies. In addition, we searched PubMed and PsycINFO for prepandemic comparative data. Survey studies assessing mental burden by the SARS-CoV-2 pandemic in the general population, healthcare workers, or any patients (eg, COVID-19 patients), with a broad range of eligible mental health outcomes, and matching studies evaluating prepandemic comparative data in the same population (if available) were included. We used multilevel meta-analyses for main, subgroup, and sensitivity analyses, focusing on (perceived) stress, symptoms of anxiety and depression, and sleep-related symptoms as primary outcomes.

Results: Of 2429 records retrieved, 104 were included in the review (n = 208,261 participants), 43 in the meta-analysis (n = 71,613 participants). While symptoms of anxiety (standardized mean difference [SMD] 0.40; 95% CI 0.15-0.65) and depression (SMD 0.67; 95% CI 0.07-1.27) were increased in the general population during the early phase of the pandemic compared with prepandemic conditions, mental burden was not increased in patients as well as healthcare workers, irrespective of COVID-19 patient contact. Specific outcome measures (eg, Patient Health Questionnaire) and older comparative data (published ≥5 years ago) were associated with increased mental burden. Across the three population groups, existing mental disorders, female sex, and concerns about getting infected were repeatedly reported as risk factors, while older age, a good economic situation, and education were protective.

Conclusions: This meta-analysis paints a more differentiated picture of the mental health consequences in pandemic situations than previous reviews. High-quality, representative surveys, high granular longitudinal studies, and more research on protective factors are required to better understand the psychological impacts of the SARS-CoV-2 pandemic and to help design effective preventive measures and interventions that are tailored to the needs of specific population groups.
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http://dx.doi.org/10.1186/s12992-021-00670-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006628PMC
March 2021

Dorsolateral Prefrontal Functional Connectivity Predicts Working Memory Training Gains.

Front Aging Neurosci 2021 1;13:592261. Epub 2021 Mar 1.

Department of Psychosomatic Medicine and Psychotherapy, Rostock University Medical Center, Rostock, Germany.

Normal aging is associated with working memory decline. A decrease in working memory performance is associated with age-related changes in functional activation patterns in the dorsolateral prefrontal cortex (DLPFC). Cognitive training can improve cognitive performance in healthy older adults. We implemented a cognitive training study to assess determinants of generalization of training gains to untrained tasks, a key indicator for the effectiveness of cognitive training. We aimed to investigate the association of resting-state functional connectivity (FC) of DLPFC with working memory performance improvement and cognitive gains after the training. A sample of 60 healthy older adults (mean age: 68 years) underwent a 4-week neuropsychological training, entailing a working memory task. Baseline resting-state functional MRI (rs-fMRI) images were acquired in order to investigate the FC of DLPFC. To evaluate training effects, participants underwent a neuropsychological assessment before and after the training. A second follow-up assessment was applied 12 weeks after the training. We used cognitive scores of digit span backward and visual block span backward tasks representing working memory function. The training group was divided into subjects who had and who did not have training gains, which was defined as a higher improvement in working memory tasks than the control group ( = 19). A high FC of DLPFC of the right hemisphere was significantly associated with training gains and performance improvement in the visuospatial task. The maintenance of cognitive gains was restricted to the time period directly after the training. The training group showed performance improvement in the digit span backward task. Functional activation patterns of the DLPFC were associated with the degree of working memory training gains and visuospatial performance improvement. Although improvement through cognitive training and acquisition of training gains are possible in aging, they remain limited.
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http://dx.doi.org/10.3389/fnagi.2021.592261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956962PMC
March 2021

Noninvasive peripheral vascular function, incident cardiovascular disease, and mortality in the general population.

Cardiovasc Res 2021 Mar 16. Epub 2021 Mar 16.

Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (PSW); Center for Cardiology-, Cardiology I (VHS, NA, AL, TG, TM).

Aims: Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of noninvasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality.

Methods And Results: In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N = 12,599) and fingertip peripheral arterial tonometry (N = 11,125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased event-free survival with higher mean brachial artery diameter and baseline pulse amplitude and better survival with higher mean flow-mediated dilatation and peripheral arterial tonometry ratio (all Plog rank<0.05). In multivariable-adjusted Cox regression analyses only baseline pulse amplitude was inversely related to mortality ((hazard ratio) per standard deviation increase, 0.86, 95% confidence interval, 0.79-0.94; P = 0.0009). After exclusion of individuals with prevalent cardiovascular disease the association was no longer statistically significant in multivariable-adjusted models (hazard ratio 0.91, 95% confidence interval 0.81-1.02; P = 0.11). None of the vascular variables substantially increased the C-index of a model comprising clinical risk factors.

Conclusions: In our cohort, noninvasive measures of peripheral vascular structure and function did not reveal clinically relevant associations with incident cardiovascular disease or mortality. Whether determination of pulse amplitude by peripheral arterial tonometry improves clinical decision-making in primary prevention needs to be demonstrated.

Translational Perspective: In our large middle-aged community cohort with more than 15,000 individuals, median age 55 years (25th/75th percentile 46/65), 49.5% women noninvasively measured peripheral vascular function using flow-mediated dilation after upper arm occlusion or fingertip peripheral arterial tonometry was not relevantly associated with incident cardiovascular disease or mortality in multivariable-adjusted analyses. An interaction of the association of peripheral arterial tonometry with mortality by prevalent cardiovascular disease was observed. Routine measurement of flow-mediated dilation or peripheral arterial tonometry in our community cohort to screen for high risk of cardiovascular disease or mortality was not effective.
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http://dx.doi.org/10.1093/cvr/cvab087DOI Listing
March 2021

Machine learning for identifying relevant publications in updates of systematic reviews of diagnostic test studies.

Res Synth Methods 2021 Jul 28;12(4):506-515. Epub 2021 Mar 28.

Faculty of Medicine and Medical Center, Institute of Medical Biometry and Statistics, University of Freiburg, Freiburg, Germany.

Updating systematic reviews is often a time-consuming process that involves a lot of human effort and is therefore not conducted as often as it should be. The aim of our research project was to explore the potential of machine learning methods to reduce human workload. Furthermore, we evaluated the performance of deep learning methods in comparison to more established machine learning methods. We used three available reviews of diagnostic test studies as the data set. In order to identify relevant publications, we used typical text pre-processing methods. The reference standard for the evaluation was the human-consensus based on binary classification (inclusion, exclusion). For the evaluation of the models, various scenarios were generated using a grid of combinations of data preprocessing steps. Moreover, we evaluated each machine learning approach with an approach-specific predefined grid of tuning parameters using the Brier score metric. The best performance was obtained with an ensemble method for two of the reviews, and by a deep learning approach for the other review. Yet, the final performance of approaches strongly depends on data preparation. Overall, machine learning methods provided reasonable classification. It seems possible to reduce human workload in updating systematic reviews by using machine learning methods. Yet, as the influence of data preprocessing on the final performance seems to be at least as important as choosing the specific machine learning approach, users should not blindly expect a good performance by solely using approaches from a popular class, such as deep learning.
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http://dx.doi.org/10.1002/jrsm.1486DOI Listing
July 2021

Similarities and Differences of Mental Health in Women and Men: A Systematic Review of Findings in Three Large German Cohorts.

Front Public Health 2021 5;9:553071. Epub 2021 Feb 5.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.

In Germany, large, population-based cohort studies have been implemented in order to identify risk and protective factors for maintaining health across the life span. The purpose of this systematic review is to analyse findings from three large ongoing cohorts and to identify sex-specific prevalence rates, risk and protective factors for mental health. Published studies from the Cooperative Health Research in the Region Augsburg (KORA), the Study of Health in Pomerania (SHIP) and the Gutenberg Health Study (GHS)), representing the southern, north-eastern and middle parts of Germany, were identified through searches of the databases PubMed and Web of Science. A total of 52 articles was identified from the start of each cohort until June 2019. Articles reporting prevalence rates of mental health [ = 22], explanatory factors for mental health [ = 25], or both [ = 5] were identified. Consistent across cohorts, higher prevalence rates of internalizing disorders were found for women and more externalizing disorders for men. Risk and protective factors for mental health included social factors, lifestyle, physical health, body mass index (BMI), diabetes, genetic and biological factors. In all areas, differences and similarities were found between women and men. The most evident were the sex-specific risk profiles for depression with mostly external risk factors for men and internal risk factors for women. Gender was not assessed directly, therefore we examined whether socioeconomic and family-related factors reflecting gender roles or institutionalized gender could be used as a proxy for gender. Overall, this systematic review shows differences and similarities in prevalence rates and determinants of mental health indicators between women and men. They underline the importance of focussing on sex specific approaches in mental health research and in the development of prevention measures. Current research on mental health still lacks focus on gender aspects. Therefore, an increased focus on sex and gender in mental health research is of great importance.
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http://dx.doi.org/10.3389/fpubh.2021.553071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892592PMC
May 2021
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