Comparison of tools for assessing the methodological quality of primary and secondary studies in health technology assessment reports in Germany

Health care policy background: Findings from scientific studies form the basis for evidence-based health policy decisions. Scientific background: Quality assessments to evaluate the credibility of study results are an essential part of health technology assessment reports and systematic reviews. Quality assessment tools (QAT) for assessing the study quality examine to what extent study results are systematically distorted by confounding or bias (internal validity). The tools can be divided into checklists, scales and component ratings. Research questions: What QAT are available to assess the quality of interventional studies or studies in the field of health economics, how do they differ from each other and what conclusions can be drawn from these results for quality assessments? Methods: A systematic search of relevant databases from 1988 onwards is done, supplemented by screening of the references, of the HTA reports of the German Agency for Health Technology Assessment (DAHTA) and an internet search. The selection of relevant literature, the data extraction and the quality assessment are carried out by two independent reviewers. The substantive elements of the QAT are extracted using a modified criteria list consisting of items and domains specific to randomized trials, observational studies, diagnostic studies, systematic reviews and health economic studies. Based on the number of covered items and domains, more and less comprehensive QAT are distinguished. In order to exchange experiences regarding problems in the practical application of tools, a workshop is hosted. Results: A total of eight systematic methodological reviews is identified as well as 147 QAT: 15 for systematic reviews, 80 for randomized trials, 30 for observational studies, 17 for diagnostic studies and 22 for health economic studies. The tools vary considerably with regard to the content, the performance and quality of operationalisation. Some tools do not only include the items of internal validity but also the items of quality of reporting and external validity. No tool covers all elements or domains. Design-specific generic tools are presented, which cover most of the content criteria. Discussion: The evaluation of QAT by using content criteria is difficult, because there is no scientific consensus on the necessary elements of internal validity, and not all of the generally accepted elements are based on empirical evidence. Comparing QAT with regard to contents neglects the operationalisation of the respective parameters, for which the quality and precision are important for transparency, replicability, the correct assessment and interrater reliability. QAT, which mix items on the quality of reporting and internal validity, should be avoided. Conclusions: There are different, design-specific tools available which can be preferred for quality assessment, because of its wider coverage of substantive elements of internal validity. To minimise the subjectivity of the assessment, tools with a detailed and precise operationalisation of the individual elements should be applied. For health economic studies, tools should be developed and complemented with instructions, which define the appropriateness of the criteria. Further research is needed to identify study characteristics that influence the internal validity of studies

Interventions for increasing uptake in screening programmes

Introduction: Opportunities for the early detection of disease are not sufficiently being taken advantage of. Specific interventions could increase the uptake of prevention programmes. A comprehensive analysis of effectiveness and cost-effectiveness of these interventions with reference to Germany is still needed. Objectives: This report aimed to describe and assess interventions to increase uptake in primary and secondary prevention and to explore the assessment of their cost-effectiveness. Methods: 29 scientific databases were systematically searched in a wide strategy. Additional references were located from bibliographies. All published systematic reviews and primary studies were assessed for inclusion without language restrictions. Teams of two reviewers identified the literature, extracted data and assessed the quality of the publications independently. Results: Four HTA reports and 22 systematic reviews were identified for the medical evaluation covering a variety of interventions. The economic evaluation was based on two HTA-reports, one meta-analysis and 15 studies. The evidence was consistent for the effectiveness of invitations and reminders aimed at users, and for prompts aimed at health care professionals. These interventions were the most commonly analysed. (Financial) Incentives for users and professionals were identified in a small number of studies. Limited evidence was available for cost-effectiveness showing incremental costs for follow-up reminders and invitations by telephone. Evidence for ethical, social and legal aspects pointed to needs in vulnerable populations. Discussion: The material was heterogeneous regarding interventions used, study populations and settings. The majority of references originated from the United States and focused on secondary prevention. Approaching all target groups by invitations and reminders was recommended to increase uptake in prevention programmes in general. Conclusions: Further research should aim to focus on primary prevention. Future research should also focus on specific interventions aiming to include vulnerable target groups and individuals, who have not previously made use of opportunities for prevention

Terminal spreading depolarization and electrical silence in death of human cerebral cortex

Objective: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury. Methods: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate–Comfort Care order followed by terminal extubation. Results: Withdrawal of life‐sustaining therapies produced a decline in brain tissue partial pressure of oxygen (ptiO2) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed “nonspreading depression,” developed during the steep falling phase of ptiO2 (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7–14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6–6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter. Interpretation: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295–31

Correlation of velocity and susceptibility in patients with aneurysmal subarachnoid hemorrhage

In many cerebral grey matter structures including the neocortex, spreading depolarization (SD) is the principal mechanism of the near-complete breakdown of the transcellular ion gradients with abrupt water influx into neurons. Accordingly, SDs are abundantly recorded in patients with traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH) and malignant hemispheric stroke using subdural electrode strips. SD is observed as a large slow potential change, spreading in the cortex at velocities between 2 and 9 mm/min. Velocity and SD susceptibility typically correlate positively in various animal models. In patients monitored in neurocritical care, the Co-Operative Studies on Brain Injury Depolarizations (COSBID) recommends several variables to quantify SD occurrence and susceptibility, although accurate measures of SD velocity have not been possible. Therefore, we developed an algorithm to estimate SD velocities based on reconstructing SD trajectories of the wave-front's curvature center from magnetic resonance imaging scans and time-of-SD-arrival- differences between subdural electrode pairs. We then correlated variables indicating SD susceptibility with algorithm-estimated SD velocities in twelve aSAH patients. Highly significant correlations supported the algorithm's validity. The trajectory search failed significantly more often for SDs recorded directly over emerging focal brain lesions suggesting in humans similar to animals that the complexity of SD propagation paths increase in tissue undergoing injury

Study protocol for a randomised controlled trial of an e-health stepped care approach for the treatment of internet use disorders versus a placebo condition: the SCAPIT study

Introduction Excessive internet use can lead to problems for some individuals. The WHO has introduced Gaming Disorder in the International Classification of Diseases-11 (ICD-11). Previous research has shown that other internet applications can cause serious mental health problems as well. It is important to provide measures of prevention, early intervention and therapy for internet use disorders (IUDs). Methods and analysis The study ‘Stepped Care Approach for Problematic Internet use Treatment’ is a randomised, two-arm, parallel-group, observer-blind trial. The aim of the study is to investigate if a stepped care approach is effective to reduce symptom severity for IUD. The sample is primarily recruited online with a focus on employees in companies with support of health insurances. After screening, the stepped care approach depends on the success of the previous step—that is, the successful reduction of criteria—and comprise: (1) app-intervention with questionnaires and feedback, (2) two telephone counsellings (duration: 50 min) based on motivational interviewing, (3) online therapy over 17 weeks (15 weekly group sessions, eight individual sessions) based on cognitive–behavioural therapy. A follow-up is conducted after 6 months. A total of 860 participants will be randomised. Hierarchical testing procedure is used to test the coprimary endpoints number of Diagnostic and Statistical Manual of Mental Disorders, fifth edition and ICD-11 criteria. Primary analysis will be performed with a sequential logit model. Ethics and dissemination The study has been approved by the Ethics Committees of the Universities of Lübeck (file number: 21-068), Mainz (file number: 2021-15907) and Berlin (file number: 015.2021). Results will be reported in accordance to the CONSORT statement. If the approach is superior to the control condition, it may serve as part of treatment for IUD. Trial registration number DRKS00025994

Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts

In DISCHARGE-1, a recent Phase III diagnostic trial in aneurysmal subarachnoid haemorrhage patients, spreading depolarization variables were found to be an independent real-time biomarker of delayed cerebral ischaemia. We here investigated based on prospectively collected data from DISCHARGE-1 whether delayed infarcts in the anterior, middle, or posterior cerebral artery territories correlate with (i) extravascular blood volumes; (ii) predefined spreading depolarization variables, or proximal vasospasm assessed by either (iii) digital subtraction angiography or (iv) transcranial Doppler-sonography; and whether spreading depolarizations and/or vasospasm are mediators between extravascular blood and delayed infarcts. Relationships between variable groups were analysed using Spearman correlations in 136 patients. Thereafter, principal component analyses were performed for each variable group. Obtained components were included in path models with a priori defined structure. In the first path model, we only included spreading depolarization variables, as our primary interest was to investigate spreading depolarizations. Standardised path coefficients were 0.22 for the path from extravascular bloodcomponent to depolarizationcomponent (P = 0.010); and 0.44 for the path from depolarizationcomponent to the first principal component of delayed infarct volume (P < 0.001); but only 0.07 for the direct path from bloodcomponent to delayed infarctcomponent (P = 0.36). Thus, the role of spreading depolarizations as a mediator between blood and delayed infarcts was confirmed. In the principal component analysis of extravascular blood volume, intraventricular haemorrhage was not represented in the first component. Therefore, based on the correlation analyses, we also constructed another path model with bloodcomponent without intraventricular haemorrhage as first and intraventricular haemorrhage as second extrinsic variable. We found two paths, one from (subarachnoid) bloodcomponent to delayed infarctcomponent with depolarizationcomponent as mediator (path coefficients from bloodcomponent to depolarizationcomponent = 0.23, P = 0.03; path coefficients from depolarizationcomponent to delayed infarctcomponent = 0.29, P = 0.002), and one from intraventricular haemorrhage to delayed infarctcomponent with angiographic vasospasmcomponent as mediator variable (path coefficients from intraventricular haemorrhage to vasospasmcomponent = 0.24, P = 0.03; path coefficients from vasospasmcomponent to delayed infarctcomponent = 0.35, P < 0.001). Human autopsy studies shaped the hypothesis that blood clots on the cortex surface suffice to cause delayed infarcts beneath the clots. Experimentally, clot-released factors induce cortical spreading depolarizations that trigger (i) neuronal cytotoxic oedema and (ii) spreading ischaemia. The statistical mediator role of spreading depolarization variables between subarachnoid blood volume and delayed infarct volume supports this pathogenetic concept. We did not find that angiographic vasospasm triggers spreading depolarizations, but angiographic vasospasm contributed to delayed infarct volume. This could possibly result from enhancement of spreading depolarization-induced spreading ischaemia by reduced upstream blood supply.Peer Reviewe

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Long-Term Effects of Integrated Strategies of Community Health Promotion on Diabetes Mellitus Mortality: a Natural Policy Experiment Based on Aggregated Longitudinal Secondary Data

Integrated strategies of community health promotion (ISCHP) are based on intersectoral collaborations using the Health in All Policies approach to address determinants of health. While effects on health determinants have been shown, evidence on the effectiveness of ISCHP on health outcomes is scarce. The aim of this study is to assess the long-term effects of ISCHP on diabetes mellitus mortality (DMM) in German communities. A nonrandomized evaluation based on secondary county-level official data (1998-2016) was performed. In April 2019, 149 communities in Germany with ISCHP out of 401 were identified. Communities with &amp;lt; 5 measurements of DMM, starting before 1999 or after 2015, were excluded. Analyses included 65 communities with ISCHP (IG) and 124 without ISCHP (CG). ISCHP ran for a mean of 5.6 years. Fixed effects (FE) models were used to estimate effects of ISCHP and duration on DMM taking into account the time-varying average age. The FE estimator for DMM is b =  - 2.48 (95% CI - 3.45 to - 1.51) for IG vs. CG and b =  - 0.30 (95% CI - 0.46 to - 0.14) for ISCHP duration (0-16 years). In the first year of an ISCHP, a reduction of the annual DMM of 0.3 per 100,000 population (1%), and in the 16th year of 4.8 (14%) was achieved. This study provides preliminary evidence of the effectiveness of ISCHP in Germany. Limitations include inaccuracies to classify IG and CG and possible selection bias. Longitudinal county-level data may be an efficient data source to evaluate complex interventions, thereby contributing to further strengthen evidence-based integrated health promotion

Demystifying a buzzword: Use of the term “human-animal-interface” in One Health oriented research based on a literature review and expert interviews

As of today, 75% of infectious human diseases are caused by zoonotic pathogens, which use the interface between humans and animal species to cross. Due to this ability, zoonoses affect more than just one health sector and the effective control is a matter of the One Health concept. One defining feature of this concept is the “human-animal-interface”. However, even though the term is ubiquitously used in the field of infectious disease research, a clear definition of the term is lacking, leading to a rather nebulous understanding of what this interface really encompasses. Based on this observation, this study aimed to analyze the use of the term “human-animal-interface” in scientific literature to identify patterns and categories facilitating a scientific categorization.A systematic literature search of two electronic databases was performed complemented by interviews with health experts in the field of zoonoses/One Health conducted between March 2019 and May 2021. From identified publications, keywords and interface descriptions were extracted and categorized. Interviews followed a questioning route, were audio recorded, transcribed, and qualitative content was inductively categorized.Findings are based on 208 publications and 27 expert interviews. “Transmission” and “zoonosis” were the most frequent literature-based keywords, while the interviewees clearly favored “interface” followed by “contact”. Seven categories of contact interfaces were inductively derived: direct contact (physical contact), consumption of animal products, use of animal products (blood transfusion, skin), contact with animal products (blood, secretion, meat), indirect contact (dust, inhalation, droplets), environmental contact (same surface or food), vector contact). Precise descriptions of the interfaces varied greatly depending on the pathogen domain (bacterial, viral, fungal). Specific patterns could be identified that were consistent between the literature and experts.The study results showed a general concordance in defining and describing the human-animal-interface indicating a general understanding of the term. However, studies on a larger scale are recommended (e.g. systematic review) to allow a more thorough view of the understanding and definition of the human-animal-interface

Comparing different data sources by examining the associations between surrounding greenspace and children's weight status

Background: Studies on the association between surrounding greenspace and being overweight in childhood show inconsistent results, possibly because they differ widely in their definition and measurement of surrounding greenspace. Our aim was to evaluate whether the association of greenspace with being overweight depends on the measurement of greenspace in different data sources. Methods: Based on data from the school entry examinations of 22,678 children in the city of Hannover, Germany, from 2010 to 14, the association between greenspace availability and overweight was examined. Three different sources of greenspace availability were derived for a set of 51 areas of the city: The Normalized Difference Vegetation Index (NDVI), the OpenStreetMap (OSM) dataset, and the European Urban Atlas (UA) dataset. Agreement between the indicators on the quantity of greenspace coverage was compared. The association with children's BMI z-score, including potential interaction terms, was assessed using multilevel regression analysis. Results: Greenspace availability per district area derived by NDVI was on average 42%, by OSM 29% and UA 22%, with OSM and UA being strongly correlated. Only the greenspace availability derived by NDVI showed an association with children's BMI z-score: The higher the greenspace availability was, the lower the BMI. The trend of association was higher for boys and migrant children than for girls and non-migrants and was restricted to the highest levels of greenspace availability. Conclusions: Associations of greenspace with children's weight status depend on the greenspace measurement chosen. Surrounding greenspace was measured more comprehensively by NDVI. Data sources based on land use categories such as UA and OSM may be less suitable to reflect surrounding greenspace relevant for health outcomes. Potential mechanisms warrant further analysis and investigation