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This document reports a brief update to the previously published protocol of the MinDial study.Trial registration German Clinical Trials Register DRKS00029691. Registered on 12 Sept. 2022, https://drks.de/search/en/trial/DRKS00029691 ., (© 2024. The Author(s).)

Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)

Aim: As part of the 10-year evaluation of Gesundes Kinzigtal Integrated Care (IVGK, Innovation Fund Project 01VSF16002), a multidisciplinary group of experts agreed on 101 quality indicators (QI) to evaluate the quality of regionally integrated care with its focus on health and prevention programs. One criterion was that the selected QI should in principle be suitable for mapping using routine data. The aim of the study was to investigate how many and in what way the QI developed can actually be mapped in Germany with routine data and for what reasons operationalization was restricted or not possible., Material and Methods: The operationalization of the QIs was performed using pseudonymized billing data of the AOK Baden-Württemberg from 2006 to 2015, which the Scientific Institute of the AOK (WIdO) provided to the evaluation team. All operationalized indicators were binary coded (criterion fulfilled yes/no). The diagnoses, procedures, or drugs named in the numerator and denominator definitions were operationalized using ICD-10 codes (inclusion and exclusion diagnoses), EBM codes, OPS codes, ATC codes. Indicator prevalences were examined over time to check for abnormalities as an indication of possible misscoding., Results: Ninety of the 101 indicators were operationalizable with routine data. Fourteen of the 90 indicators could only be operationalized with restrictions, as corresponding service codes were only introduced or existing codes were changed during the observation period. Seventy-six of 90 indicators could be operationalized without restrictions. In this context, 15 of these 76 indicators required pre- and follow-up periods, which meant that they could not be presented for all years. Eleven of 101 QIs could not be operationalized because EBM codes were only introduced after 2015 or were not recorded as individual services for all physician groups (e. g., spirometry and long-term ECG). Striking trends in indicator prevalences could be explained., Conclusion: Routine data enable resource-saving quality monitoring. A change in the data basis during the observation period, for example through the introduction or deletion of billing codes, makes the longitudinal, routine data-based quality assessment more difficult, but enables further or new indicators to be operationalized for later periods., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: The population-based integrated health care system called "Gesundes Kinzigtal" (Integrierte Versorgung Gesundes Kinzigtal, IVGK) was initiated more than 10 years ago in the Kinzig River Valley region, which is located in the Black Forest in the German state of Baden-Württemberg. IVGK is intended to optimize health care while maximizing cost-effectiveness. It consists of programs for promoting health and for enabling cooperation among service providers, as well as of a shared-savings contract that has enabled resources to be saved every year. The goal of the present study was to investigate trends in the quality of care provided by IVGK over the past ten years in comparison to conventional care., Methods: This is a non-randomized observational study with a control-group design (Kinzig River Valley versus 13 structurally comparable control regions), employing data collected by AOK, a large statutory health-insurance provider in Germany, over the period 2006-2015. Quality assessment was conducted with the aid of a set of indicators, developed by the authors, that was based exclusively on claims data. The statistical analysis of the trends in these indicators over time was conducted with preset criteria for the relevance of any observed changes, as well as preset mechanisms of controlling for confounding factors., Results: For 88 of the 101 evaluable indicators, no relevant difference was seen between the trend over time in the region of the intervention and the average trend in the control regions. Relevant differences in favor of the IVGK were observed for six indicators, and negatively divergent trends compared to the controls were observed for seven indicators. In the main summarizing statistical analysis, no positive or negative difference was found between the Kinzig River Valley and the other regions with respect to trends in the health-care indicators over time., Conclusion: An evaluation based on 101 indicators derived from health-insurance data did not reveal any improvement of the quality of care by IVGK and the totality of the programs that were implemented under it. However, under the conditions of the shared-savings contract, no relevant diminution in the quality of care was observed over a period of 10 years either, compared with structurally similar control regions without an integrated care model.

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.

Background: Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB)., Methods: This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter., Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases., Trial Registration: The HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).

Introduction: The project "INTEGRAL-10-year evaluation of the population-based integrated health care model 'Gesundes Kinzigtal' (Healthy Kinzigtal)" (ICM-GK) is funded by the Innovation Committee of the Federal Joint Committee (G-BA) (grant no. 01VSF16002). The evaluation is to be based on a set of indicators that can be captured in routine data. On the one hand, they can be used to assess ICM-GK programs that are program-specific and geared towards prevention and disease management. On the other hand, possible negative side effects of the ICM-GK, which is designed as a "shared savings contract", are to be examined by also observing care needs not covered by the ICM-GK contract. Since an indicator set for the evaluation of regional integrated care (IC) programs in Germany is not yet available, a suitable indicator set should be developed., Methods: RESULTS: The methodological framework links the OECD concept for quality assessment of health systems with Kessner's tracer methodology. Disease groups with a high prevalence ("common diseases"), prevention potential and potential for improvement through IC were selected as tracers. The literature search resulted in 239 QIs and the QI database search in 293 QIs, which were supplemented by 21 QIs from the focus groups. Out of a total of 553 QIs, 251 QIs remained after removal of duplicates and comparison with the data basis. This preliminary QI set was reduced to 101 QIs by consensus. In addition, 48 health reporting indicators were supplemented which serve to classify regional quality results. The final QI set maps the following 19 disease categories/tracers: heart failure (16 QIs), myocardial infarction (4 QIs), CHD (10 QIs), stroke (6 QIs), metabolic syndrome (7 QIs of which 5 were diabetes-related), COPD (6 QIs), asthma (3 QIs), chronic pain (5 QIs), back pain (3 QIs), geriatrics (7 QIs), dementia (8 QIs), osteoporosis (3 QIs), rheumatism (3 QIs), multiple sclerosis (2 QIs), depression (4 QIs), antibiotic therapy (3 QIs), drug safety (1 QI), child care (5 QIs), early detection/prevention (5 QIs). 33 of these QIs are dedicated to five tracers that are not explicitly ICM-GK programs. Most QIs assess aspects of the effectiveness of care for the chronically ill and measure process quality., Discussion: The set of indicators initially enables the quality assessment of regional, cross-indication care quality in the population-based integrated health care model 'Gesundes Kinzigtal' on the basis of routine data. Although the QI set focuses on effectiveness and process quality, it also includes QIs for preventive and acute care, coordination of care, patient orientation and safety, and outcomes. In contrast to other QI sets, both primary care and specialist health care and integrated, cross-sectoral and cross-professional care aspects have been considered. The benefits of the QI set for comparisons of regional quality and the evaluation of different IC programs remain to be tested., Conclusion: On the basis of a broadly based research and participatory development process, a set of indicators has been developed that enables comprehensive evaluation of the regional quality of care of cross-indication, integrated care models focusing on common diseases. In order to be able to increasingly evaluate aspects of care coordination and patient orientation, health promotion as well as nursing, palliative and emergency care in the future, it would be helpful if routine data were collected or made accessible in these areas as well., (Copyright © 2020. Published by Elsevier GmbH.)

Aims: Several scoring systems have been introduced for prognostication after initiating venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy. However, static scores offer limited guidance once VA-ECMO is implanted, although continued allocation of healthcare resources is critical. Patients requiring continued VA-ECMO support are extremely unstable, with minimal heart function and multi-organ failure in most cases. The aim of the present study was to develop and validate a dynamic prognostic model for patients treated with VA-ECMO., Methods and Results: A derivation cohort included 205 all-comers undergoing VA-ECMO implantation at a tertiary referral hospital (51% received VA-ECMO during resuscitation and 43% had severe shock). Two prediction models based on point-of-care biomarkers were developed using penalised logistic regression in an elastic net approach. A validation cohort was recruited from an independent tertiary referral hospital. Comparators for the prediction of hospital survival were the SAVE score (area under the receiver operation characteristic curve (AUC) of 0.686), the SAPS score (AUC 0.679), the APACHE score (AUC 0.662) and the SOFA score (AUC 0.732) in 6-hour survivors. The 6-hour PREDICT VA-ECMO score (based on lactate, pH and standard bicarbonate concentration) outperformed the comparator scores with an AUC of 0.823. The 12-hour PREDICT VA-ECMO integrated lactate, pH and standard bicarbonate concentration at 1 hour, 6 hours and 12 hours after ECMO insertion allowed even better prognostication (AUC 0.839). Performance of the scores in the external validation cohort was good (AUCs 0.718 for the 6-hour score and 0.735 for the 12-hour score, respectively)., Conclusion: In patients requiring VA-ECMO therapy, a dynamic score using three point-of-care biomarkers predicts hospital mortality with high reliability. Furthermore, the PREDICT scores are the first scores for extracorporeal cardiopulmonary resuscitation patients.

Introduction: Patients often experience interface problems when treated by different specialists and in different healthcare sectors. Integrated care concepts aim to reduce these problems. While most integrated healthcare models focus on individual diseases, the integrated care model 'Gesundes Kinzigtal' applies a population-based approach and addresses the full spectrum of morbidities for a population defined by area of residence-the Kinzigtal. A special feature of the model is the joint savings contract between the regional management company and the statutory health insurers. The INTEGRAL study aims at assessing the effectiveness of 'Gesundes Kinzigtal' under routine conditions in comparison to conventional care over a period of 10 years in order to understand the benefits but also the potential for (unintended) harms. METHODS AND ANALYSIS: Database Claims data from statutory health insurance funds 2005-2015. The evaluation consists of a quasi-experimental study, with Kinzigtal as intervention region, at least 10 further regions with a similar population and healthcare infrastructure as primary controls and an additional random sample of insurees from the federal state of Baden-Württemberg as secondary controls. Model-specific and 'non-specific' indicators adopted from the literature and enriched by focus group interviews will be used to evaluate the model's effectiveness and potential unintended consequences by analysing healthcare utilisation in general. Temporal trends per indicator in the intervention region will be compared with those in each control region. The overall variation in trends for the indicators across all regions provides information about the potential to modify an indicator due to local differences in the healthcare system., Ethics and Dissemination: Ethic Commission of the Faculty of Medicine, Philipps-University Marburg (ek_mr_geraedts_131117). Results will be discussed in workshops, submitted for publication in peer-review journals and presented at conferences., Trial Registration Number: DRKS00012804., Competing Interests: Competing interests: AS declares involvement in former studies on Gesundes Kinzigtal GmbH (2006–2015) and an employment at Gesundes Kinzigtal GmbH (1 June 2015 until 31 December 2015). IS, IK and PI declare that they were involved in one former study evaluating the start-up phase (2006–2011) of the integrated care model ‘Gesundes Kinzigtal’. All authors report grants from the Innovation Committee of the Joint Federal Committee, during the conduct of the study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional six individuals from five families. Immunoblot analysis of mutant fibroblasts showed reduced protein levels of NBAS and its proposed interaction partner p31, both involved in retrograde transport between endoplasmic reticulum and Golgi. We recommend NBAS analysis in individuals with acute infantile liver failure, especially if triggered by fever., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Adult ADHD is a frequent psychiatric disorder affecting relevant aspects of an individual's life. The aim of our study group was to carry out the first randomized controlled multicenter study to evaluate the effects of psychotherapy compared to clinical management in combination with psychopharmacological treatment with methylphenidate (MPH) or placebo (Plac) in a factorial four-arm design. Here, we present the enrollment procedure and description of adult ADHD patients recruited for the trial. Four hundred and thirty-three adult patients with ADHD were randomized at seven study sites in Germany to four treatment conditions: manualized dialectical-behavioral-therapy-based group psychotherapy (GPT) plus MPH or Plac, or clinical management (CM) including supportive counseling plus MPH or Plac with weekly sessions in the first 12 weeks and monthly sessions thereafter. Assessment for eligibility included standardized scales and instruments. After prescreening of 1,480 patients, 518 were evaluated for trial participation and 433 were randomized. The main reasons for prescreening failure were lack of interest in participating (n = 205), difficulties in meeting the time and effort requirements for participation (n = 186), and contraindications for psychopharmacological treatment with MPH (n = 194). The full analysis set (FAS) comprised 419 adult ADHD patients (mean age 35.2 years, males/females 1:1). Fifty-seven percent of the patients suffered from the combined ADHD subtype. Prevalence of at least one current or lifetime axis-I comorbidity was 66 %. Axis-II comorbidity rates was 18 % (patients with comorbid borderline and antisocial personality disorders were excluded). Our network was able to recruit an adult ADHD sample essentially comparable to community samples. A selection bias was created by excluding patients unable or unwilling to participate, or who had somatic and psychiatric contraindications for stimulant treatment (Current Controlled Trials ISRCTN54096201, FUNDING: Federal Ministry of Education and Research 01GV0606).

Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow-up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.

Objective: The Conners Adult ADHD Rating Scales (CAARS) assess symptoms specific to adults that are frequently used and have been translated into German. The current study tests the factor structure of the CAARS in a large sample of German adults with ADHD and compares the means of the CAARS subscales with those of healthy German controls., Method: CAARS were completed by 466 participants with ADHD and 851 healthy control participants. Confirmatory factor analysis was used to establish model fit with the American original. Comparisons between participants with ADHD and healthy controls and influences of gender, age, and degree of education were analyzed., Results: Confirmatory factor analysis showed a very good fit with the model for the American original. Differences between ADHD participants and healthy controls on all Conners Adult ADHD Rating Scales-Self-Report (CAARS-S) subscales were substantial and significant., Conclusion: The factor structure of the original American model was successfully replicated in this sample of adult German ADHD participants.

Stratifying and matching by the propensity score are increasingly popular approaches to deal with confounding in medical studies investigating effects of a treatment or exposure. A more traditional alternative technique is the direct adjustment for confounding in regression models. This paper discusses fundamental differences between the two approaches, with a focus on linear regression and propensity score stratification, and identifies points to be considered for an adequate comparison. The treatment estimators are examined for unbiasedness and efficiency. This is illustrated in an application to real data and supplemented by an investigation on properties of the estimators for a range of underlying linear models. We demonstrate that in specific circumstances the propensity score estimator is identical to the effect estimated from a full linear model, even if it is built on coarser covariate strata than the linear model. As a consequence the coarsening property of the propensity score-adjustment for a one-dimensional confounder instead of a high-dimensional covariate-may be viewed as a way to implement a pre-specified, richly parametrized linear model. We conclude that the propensity score estimator inherits the potential for overfitting and that care should be taken to restrict covariates to those relevant for outcome., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Purpose: To investigate the effect of adjuvant sequential tamoxifen after chemotherapy in postmenopausal patients with hormone receptor-negative breast cancer., Methods: Patients were randomly assigned to oral tamoxifen (30 mg daily for 5 years; n = 421) or no additional treatment (n = 408) after risk-adapted polychemotherapy consisting of three 28-day cycles of CMF (cyclophosphamide, 500 mg/m(2), methotrexate, 40 mg/m(2), and fluorouracil, 600 mg/m(2)) in patients with negative or one to three positive lymph nodes and four 21-day cycles of epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2) followed by three cycles of CMF in patients with four to nine positive lymph nodes., Results: Thirty-six percent of the patients included were older than 60 years, 63% were node negative, 13% had four to nine positive nodes, 55% had tumor grade 3, and 41% received breast-preserving surgery. At 5.3 years' median follow-up, the first event of failure (recurrence, secondary tumor, or death) had occurred in 123 patients in the tamoxifen group and 107 patients of the control group. Event-free survival rates after 5 years were 70.3% (95% CI, 65.5% to 75.0%) and 72.8% (95% CI, 68.2% to 77.5%) for the tamoxifen and control groups, respectively. The estimated hazard ratio of tamoxifen versus control was 1.13 (95% CI, 0.87 to 1.48; P = .34), which gives no indication of an additional benefit of tamoxifen in these patients., Conclusion: This study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy.