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Background The integration of real-world evidence (RWE) from real-world data (RWD) in clinical research is crucial for bridging the gap between clinical trial results and real-world outcomes. Analyzing routinely collected data to generate clinical evidence faces methodological concerns like confounding and bias, similar to prospectively documented observational studies. This study focuses on additional limitations frequently reported in the literature, providing an overview of the challenges and biases inherent to analyzing routine clinical care data, including health claims data (hereafter: routine data). Methods We conducted a literature search on routine data studies in four high-impact journals based on the Journal Citation Reports (JCR) category “Medicine, General & Internal” as of 2022 and three oncology journals, covering articles published from January 2018 to October 2023. Articles were screened and categorized into three scenarios based on their potential to provide meaningful RWE: (1) Burden of Disease, (2) Safety and Risk Group Analysis, and (3) Treatment Comparison. Limitations of this type of data cited in the discussion sections were extracted and classified according to different bias types: main bias categories in non-randomized studies (information bias, reporting bias, selection bias, confounding) and additional routine data-specific challenges (i.e., operationalization, coding, follow-up, missing data, validation, and data quality). These classifications were then ranked by relevance in a focus group meeting of methodological experts. The search was pre-specified and registered in PROSPERO (CRD42023477616). Results In October 2023, 227 articles were identified, 69 were assessed for eligibility, and 39 were included in the review: 11 on the burden of disease, 17 on safety and risk group analysis, and 11 on treatment comparison. Besides typical biases in observational studies, we identified additional challenges specific to RWE frequently mentioned in the discussion sections. The focus group had varied opinions on the limitations of Safety and Risk Group Analysis and Treatment Comparison but agreed on the essential limitations for the Burden of Disease category. Conclusion This review provides a comprehensive overview of potential limitations and biases in analyzing routine data reported in recent high-impact journals. We highlighted key challenges that have high potential to impact analysis results, emphasizing the need for thorough consideration and discussion for meaningful inferences.

Background In patients with advanced or metastatic breast cancer (mBC), adherence to treatment, supportive therapy, and comorbidity medication is important for prolonging survival time, reducing symptom burden and side effects, and improving quality of life. The aim of the present study was to determine medication adherence and potential influencing factors in patients with advanced or mBC. Methods Adults with advanced or mBC treated at the University Hospital Würzburg living in Bavaria, were included in the BRE-BY-MED “Breast Cancer Care in Bavaria for Patients with Metastatic Disease” cohort study (DRKS00026601). Self-reported adherence was analysed using data from patients at baseline, and after 3-, 6-, and 12-months of follow-up, and using Bavarian cancer registry data. Results Between July 2022 and February 2024, 93 patients (median age 57 years; IQR = 48–64), were consecutively enrolled in the BRE-BY-MED study. At baseline, 75.3% ( n  = 70) and 86.0% ( n  = 80) of the patients reported being adherent and dosage adherent, respectively. During the follow-up period, no relevant changes in adherence levels were observed. Supportive therapy and medication for comorbidities were most affected by non-adherence. The most common reasons for non-adherence were medication beliefs, forgetfulness, and side effects. For 81.2% ( n  = 69) of the patients, complementary cancer registry data were available and complete, and therapy persistence was found in 78.3% ( n  = 54) of these patients. Conclusion The observed adherence rates indicate that tailored interventions to improve adherence to supportive therapy and medication for comorbidities in patients with advanced or mBC are needed, particularly considering the reasons for non-adherence.

ObjectivePrehospital notification by emergency medical services (EMS) can activate hospital resources before the patient arrives, which has been shown to improve in-hospital care for stroke patients. Optimising prehospital and handover processes in stroke care requires considering end-user perspectives to enhance acceptance and effectiveness of the developed solutions. The aim of this study was to identify current barriers in the preclinical-clinical phase of stroke care.Design and settingWithin the investigator-initiated CAEHR project (CArdiovascular diseases—Enhancing Healthcare through cross-sectoral Routine data integration), an interface for transferring data from the electronic prenotification system to the hospital information system is implemented. A mixed-methods approach with semi-structured interviews as well as a cross-sectional online survey was used to gather feedback from healthcare professionals at a single stroke centre in Germany as well as from the participating EMS personnel. Data collection for the interviews was conducted between January and August 2023 and for the online survey between May and September 2023.ParticipantsInterviews were conducted with 10 healthcare professionals, including seven from the neurological clinic and three from EMS. Additionally, 39 EMS employees took part in a cross-sectional online survey.ResultsChallenges identified were educational and training aspects affecting preclinical processes and patient handover procedures, along with the opportunity for establishing more uniform protocols. Participants emphasised the importance of detailed patient information. Electronic prenotification was seen as an important step regarding structured information transmission, reducing the risk of information loss in stroke care.ConclusionThe study highlights the importance of addressing organisational processes in addition to technical interfaces for implementing effective stroke care processes.Trial registration numberGerman Clinical Trials Register, DRKS00029103.

Background The treatment of metastatic breast cancer (mBC) focuses on prolonging patient survival, providing adequate symptom management, and maintaining quality of life (QoL). This includes supportive therapy to prevent or treat potential side effects and handle comorbidities. The combination of mBC therapy, supportive therapy, and treatment for comorbidities increases the risk for polypharmacy, potential drug-drug interactions (pDDI), potentially inappropriate medication (PIM), and potentially missing drugs (pMD). Therefore, the aim of this study was to assess medication patterns of mBC patients in routine care within a cohort study from South Germany. Methods Between July 2022 and February 2024 individuals with advanced or mBC, aged ≥ 18 years, living in Bavaria, and who gave written informed consent, were included in the BRE-BY-MED “Breast Cancer Care in Bavaria for Patients with Metastatic Disease” cohort study (DRKS00026601). BRE-BY-MED was carried out at the University Hospital Würzburg with the primary aim of estimating the prevalence of guideline-concordant treatment. For the present analysis cross-sectional data from the baseline assessment was used. Medication was extracted from routine medical records. PIM, pDDI and pMD were assessed using established criteria. Polypharmacy was defined as ≥ 5 concomitantly prescribed drugs. Results Ninety-three patients with a median age of 57 years (IQR = 48–64 years), were consecutively enrolled in the BRE-BY-MED study. One patient was male. At baseline, a total of 668 drugs were documented for all patients, including 131 unique substances, of which 44% were mBC therapy, 18% supportive therapy and 38% treatment for comorbidities or supplements. Patients took a median of 6 (IQR = 5–9) concomitant drugs. Polypharmacy (i.e. ≥ 5 concomitant drugs) was observed in 80.6% ( n  = 75) of the patients. PIM were documented in 9.7% ( n  = 9), pDDI in 12.9% ( n  = 12) and pMD in 64.5% ( n  = 60) of the patients. Conclusion We observed a high drug burden in mBC patients, largely due to treatment for comorbidities. These drugs might not only be associated with additional risk for side effects, pDDI, or PIM use, yet might also contribute to low medication adherence, higher medication costs and impaired QoL. Considering the burden of mBC and the predicted life expectancy, mBC patients might benefit from closer monitoring of their medication.

Background Digital health technologies (DHTs) are increasingly being used in healthcare, including breast cancer care and aftercare, to improve patient-related outcomes and efficiently organise care processes. This systematic review aims to synthesise existing evidence on perceived advantages and disadvantages of adopting DHTs from the perspective of healthcare professionals (HCPs). Methods A comprehensive literature search was conducted across PubMed, IEEE Xplore and PsycInfo using a peer-reviewed search strategy. Studies addressing advantages and disadvantages of DHTs in breast cancer care with a focus on HCPs’ perspectives were included. A thematic synthesis approach was employed to extract and categorise qualitative and quantitative findings. The quality assessment of the included studies was carried out using Mixed-Methods Appraisal Tool and Critical Appraisal Skills Programme Checklist. The protocol was registered on PROSPERO (CRD42024508808). Results The database search retrieved 657 records, of which 21 reports were included in the final analysis. HCPs mentioned several advantages of DHTs, including improved patient care as well as support for clinical decision-making. Disadvantages included concerns about clinical accuracy and increased complexity in clinical workflows. Factors that facilitated the adoption of DHTs involved user-centred design and the perception of improved care quality. As barriers a lack of technical infrastructure and doubts about clinical benefits were mentioned. Conclusion Although HCPs recognise the potential of DHTs to improve the quality of care, technical and organisational barriers can limit widespread adoption. Involving HCPs in the development and implementation of DHTs can support the sustainable integration of DHTs into breast cancer care.

If health impairments due to coronavirus disease 2019 (COVID-19) persist for 12 weeks or longer, patients are diagnosed with Post-COVID Syndrome (PCS), or Long-COVID. Although the COVID-19 pandemic has largely subsided in 2024, PCS is still a major health burden worldwide, and identifying potential genetic modifiers of PCS remains of great clinical and scientific interest. We therefore performed a case-control type genome-wide association study (GWAS) of three recently developed PCS (severity) scores in 2,247 participants of COVIDOM, a prospective, multi-centre, population-based cohort study of SARS-CoV-2-infected individuals in Germany. Each PCS score originally represented the weighted sum of the binary indicators of all, or a subset, of 12 PCS symptom complexes, assessed six months or later after the PCR test-confirmed SARS-CoV-2 infection of a participant. For various methodical reasons, however, the PCS scores were dichotomized along their respective median values in the present study, prior to the GWAS. Of the 6,383,167 single nucleotide polymorphisms included, various variants were found to be associated with at least one of the PCS scores, although not at the stringent genome-wide statistical significance level of 5 × 10 − 8 . With p  = 6.6 × 10 − 8 , however, the genotype-phenotype association of SNP rs9792535 at position chr9:127,166,653 narrowly missed this threshold. The SNP is located in a region including the NEK6 , PSMB7 and ADGRD2 genes which, however, does not immediately suggest an etiological connection to PCS. As regards functional plausibility, variants of a possible effect mapped to the olfactory receptor gene region (lead SNP rs10893121 at position chr11:123,854,744; p  = 2.5 × 10 − 6 ). Impairment of smell and taste is a pathognomonic feature of both, acute COVID-19 and PCS, and our results suggest that this connection may have a genetic basis. Three other genotype-phenotype associations pointed towards a possible etiological role in PCS of cellular virus repression ( CHD6 gene region), activation of macrophages ( SLC7A2 ) and the release of virus particles from infected cells ( ARHGAP44 ). All other gene regions highlighted by our GWAS did not relate to pathophysiological processes currently discussed for PCS. Therefore, and because the genotype-phenotype associations observed in our GWAS were generally not very strong, the complexity of the genetic background of PCS appears to be as high as that of most other multifactorial traits in humans.

Objective Our aim was to explore trends in price evolution and prescription volumes of anticonvulsants (AEDs, antiepileptic drugs) in Germany between 2000 and 2017. Method This study used data from annual reports on mean prescription frequency and prices of defined daily doses (DDD) of AEDs in Germany to analyze nationwide trends. Interrupted time series (ITS) analysis was employed to test for significant effects of several statutory healthcare reforms in Germany on AED price evolution. These data were compared to cohort-based prescription patterns of four German cohort studies from 2003, 2008, 2013, and 2016 that included a total of 1368 patients with focal and generalized epilepsies. Results Analysis of national prescription data between 2000 and 2017 showed that mean prices per DDD of third-generation AEDs decreased by 65% and mean prices of second-generation AEDs decreased by 36%, whereas mean prices of first-generation AEDs increased by 133%. Simultaneously, mean prescription frequency of third- generation AEDs increased by 2494%, while there was a substantial decrease in the use of first- (− 55%) and second- (− 16%) generation AEDs. ITS analysis revealed that in particular the introduction of mandatory rebates on drugs in 2003 affected prices of frequently used newer AEDs. These findings are consistent with data from cohort studies of epilepsy patients showing a general decrease of prices for frequently used AEDs in monotherapy by 62% and in combination therapies by 68%. The analysis suggests that overall expenses for AEDs remained stable despite an increase in the prescription of “newer” and “non-enzyme-inducing” AEDs for epilepsy patients. Conclusion Between 2000 and 2017, a distinct decline in AED prices can be observed that seems predominately caused by a governmentally obtained price decline of third- and second-generation drugs. These observations seem to be the result of a German statutory cost containment policy applied across all health-care sectors. The increasing use of third-generation AEDs to the disadvantage of “old” and “enzyme-inducing” AEDs reflects the preferences of physicians and patients with epilepsy and follows national treatment guidelines.

IntroductionSince a high proportion of refugees in Germany suffer from mental disorders, culturally adapted treatments are needed that target a broad range of symptoms. There is much evidence for the efficacy of culturally adapted cognitive behavioural therapy (CA-CBT). Given the promising results of CA-CBT, the combination with problem solving training (CA-CBT+) represents a novel approach that potentially improves the refugees’ ability to cope actively with psychosocial problems. This randomised controlled trial evaluates the efficacy of 12-session outpatient CA-CBT+ compared with to treatment as usual (TAU) in a sample of refugees suffering from at least one DSM-5 disorder.Methods and analysisThe present study will be carried out as two-group randomised trial with 1:1 individual allocation to either (1) culturally adapted cognitive behavioural therapy in a group setting (CA-CBT+) or (2) TAU. The study takes place at four sites in Germany, randomising in total 138 adult refugees with at least one primary DSM-5 diagnosis to the treatment conditions. In CA-CBT+ the patients receive 12 sessions of 120 min duration over the course of 12 weeks providing psychoeducation, meditation and other techniques of emotional regulation, stretching and problem solving training. The primary outcome is treatment response operationalised by a clinically significant change in General Health Questionnaire (GHQ-28) score. Follow-up visits will take place 3 and 9 months after the end of the intervention. Secondary outcomes include changes in psychopathological symptoms, somatic symptoms and quality of life. Intention-to-treat analysis will be performed. Adverse and serious adverse events will be analysed. Further, healthcare usage and economic outcomes will be assessed and analysed. Primary and secondary outcomes will be analysed using appropriate statistical methods.Ethics and disseminationThe study has been approved by the Ethics Commission of the German Psychological Society (ref: StangierUlrich2019-1018VA). Results will be disseminated via presentations, publication in international journals, and national outlets for clinicians. Furthermore, intervention materials will be available, and the existing network will be used to disseminate and implement the interventions into routine healthcare.Trial registration numberDRKS00021536.

While genome-wide association studies (GWAS) have linked common genetic variants to COVID-19 susceptibility and severity, rare high-impact variants may also contribute to phenotypic heterogeneity. Inborn errors of type I interferon immunity (IFN-I-IEIs), including X-linked TLR7 deficiency, account for ~ 2% of critical COVID-19 cases. In this study, we investigated rare potentially deleterious variants in IFN-I-IEI and GWAS-prioritized genes in young, severely affected COVID-19 patients from the German National Pandemic Cohort Network (NAPKON). Genome sequencing was performed on 110 hospitalized COVID-19 patients, including 82 males and 28 females, all under 60 years of age and without relevant pre-existing medical conditions. Rare potentially deleterious variants in TLR7 and 25 additional IFN-I-IEI genes, as well as 23 GWAS risk genes for COVID-19 severity, were analyzed based on allele frequency, predicted functional impact, and inheritance pattern models and subsequently classified based on the American College of Medical Genetics and Genomics (ACMG) criteria. Polygenic Risk Scores (PRS) were additionally calculated as an exploratory and case-only analysis to assess the contribution of common variant-derived genetic predisposition for severe COVID-19. Consistent with prior findings from other studies in German cohorts, no candidate variants or large deletions were identified in TLR7 . However, 7 variants of uncertain significance in IFN-I-IEI genes as well as 13 candidate variants of potential deleterious effect in GWAS risk genes were present in 19 individuals (17.3%). We observed nominally significant differences in PRS distributions, with younger individuals (< 40 years) having higher PRS (p = 0.045) compared to older individuals, and carriers of rare variants having lower PRS compared to non-carriers (p = 0.037). These patterns are consistent with an age-dependent contribution of polygenic risk to severe COVID-19 and a potentially lower polygenic burden among rare-variant carriers, although confirmation in larger well-controlled cohorts will be required. The candidate variants identified in IFN-I-IEI and GWAS risk genes represent targets for further functional studies to clarify their potential contribution to disease risk. These findings highlight the need for future integrative genomic approaches to better understand the joint contribution of common and rare variants to COVID-19 severity.

IntroductionDespite high levels of mental distress, accessing psychological treatment is difficult for asylum seekers in Western host countries due to a lack of knowledge about mental disorders, and the health system, as well as due to cultural and language barriers. This study aims to investigate whether brief culturally sensitive and transdiagnostic psychoeducation is effective in increasing mental health literacy.Methods and analysisThe study is a parallel two-group randomised controlled trial with 1:1 individual allocation to either culturally sensitive, low-threshold psychoeducation (‘Tea Garden’ (TG)) or a waitlist (WL) control group. It takes place at four study sites in Germany. A total of 166 adult asylum seekers who report at least mild mental distress will be randomly assigned. The TG consists of two 90 min group sessions and provides information about mental distress, resources and mental health services in a culturally sensitive manner. The primary outcome is the percentage of participants in the TG, as compared with the WL, achieving an increase in knowledge concerning symptoms of mental disorders, individual resources and mental healthcare from preintervention to postintervention. The further trajectory will be assessed 2 and 6 months after the end of the intervention. Secondary outcomes include changes in mental distress, openness towards psychotherapy and resilience. Furthermore, healthcare utilisation and economics will be assessed at all assessment points.Ethics and disseminationThe study has been approved by the Ethics Commission of the German Psychological Society (ref: WeiseCornelia2019-10-18VA). Results will be disseminated via presentations, publication in international journals and national outlets for clinicians. Furthermore, intervention materials will be available, and the existing network will be used to disseminate and implement the interventions into routine healthcare.Trial registration numberDRKS00020564; Pre-results.Protocol version2020-10-06, version number: VO2F.