Matthias Wjst

The integrity of evidence synthesis is threatened by problematic randomised controlled trials, where there are serious concerns about the trustworthiness of the data or findings. Such concerns could be due to research misconduct, including fraud, or due to honest critical errors. If these trials are not detected, they may be inadvertently included in systematic reviews and guidelines, potentially distorting their results. To resolve this problem, the INSPECT-SR (Investigating Problematic Clinical Trials in Systematic Reviews) tool has been developed to assess the trustworthiness of randomised controlled trials. This tool will help researchers to identify and exclude problematic trials from systematic reviews. This article describes the development of INSPECT-SR and presents the tool and an associated guidance document.

Background: A lower prevalence of allergy in children has been observed across numerous studies in the farming environment. However, establishing a causal relationship is contentious due to the typical farm versus non-farm study design, which may have introduced a stratification collider bias. Methods: We conducted a quantitative meta-analysis of published risks from farming studies, categorizing them into subgroups based on representative or stratified sampling. The two risk ratios are subjected to another fixed effects meta regression model and the difference is quantified. Additionally, we analyzed the correlation across generations to indicate if either exposure or disease changes among children. Finally we report synthesis of migration studies and simulate outcomes under various disease prevalences. Results: The results indicate that the lower prevalence of allergic diseases in farming environments depends on the sampling method used. The studies with random sampling (N=6) provided an OR of 1.2 which is significantly different from the OR of 0.6 in studies with stratified sampling (N=24, P=0.0001 for difference). Children of diseased farmers are not inherently 'protected' at farms as the association is found in their parents as well. Simulating a healthy worker effect in the farming communities shows that the observed ORs can already be observed if 1 in 100 children per generation moves out of the farming environment. Conclusion: The three analytical approaches presented here collectively suggest that the currently available observational evidence is insufficient to establish a protective effect of farming.

Background: Early-life vitamin D is a potentially modifiable risk factor for the development of eczema, but there is a lack of data on longitudinal associations. Method: We measured 25(OH)D3 levels from neonatal dried blood spots in 223 high-allergy-risk children. Latent class analysis was used to define longitudinal eczema phenotype up to 25 years (4 subclasses). Skin prick tests (SPTs) to 6 allergens and eczema outcomes at 6 time points were used to define eczema/sensitization phenotypes. Associations between 25(OH)D3 and prevalent eczema and eczema phenotypes were assessed using logistic regression models. Results: Median 25(OH)D3 level was 32.5 nmol/L (P25-P75 = 23.1 nmol/L). Each 10 nmol/L increase in neonatal 25(OH)D3 was associated with a 26% reduced odds of early-onset persistent eczema (adjusted multinomial odds ratio (aMOR) = 0.74, 95% CI = 0.56–0.98) and 30% increased odds of early-onset-resolving eczema (aMOR = 1.30, 95% CI = 1.05–1.62) when compared to minimal/no eczema up to 12 years. Similar associations were seen for eczema phenotype up to 25 years. We did not see any strong evidence for the association between neonatal 25(OH)D3 and prevalent eczema or eczema/sensitization phenotype. Conclusions: Higher neonatal 25(OH)D3 levels, a reflection of maternal vitamin D levels in pregnancy, may reduce the risk of early-onset persistent eczema.

Background: During the first wave of the COVID-19 pandemic a high case fatality rate (CFR) was noticed worldwide including also Germany where the first European cases have been observed. The WHO recommended immediate intubation for patients with dyspnoea which has since been revised after reviewing the initial clinical outcome. The objective of this study is to analyze CFR and assess if there is an advantage of a more conservative management of COVID-19 induced hypoxemia. Methods: PCR confirmed COVID-19 infections and death counts were obtained for all German districts from 27 Jan 2020 until 15 Feb 2021 using official reports of Robert Koch Institute Berlin, Germany. A moving average CFRt was constructed by dividing disease related deaths two weeks after a given index day by the number of infections two weeks prior to that date. In addition to a local comparison also mortality outcomes in other German speaking countries were compared. Results: The mean CFR is estimated to be 2.92% based on 71.965 fatalities and 2.465.407 cases. There was a large regional scattering of CFRs across the German districts. Differences of the mortality pattern were observed also at state level and preserved across different sex and age groups while being largely independent of case numbers. Although Munich city had higher infection rates, more patients died during the first wave in Hamburg (OR 1.6, 95% CI 1.3–1.9) which was mirrored also by higher death risk at Hamburg intensive care units (OR 2.0, 95% CI 1.3–3.1). While the majority of Munich hospitals favoured a conservative management of hypoxemia including high flow nasal cannula (HFNC), Hamburg hospitals followed a more aggressive scheme of early mechanical ventilation (MV). Austria and Switzerland experienced higher CFRs than Germany during the first wave but after changing their treatment guidelines, both countries experienced lower CFRs during the second wave. Conclusion: Using retrospective public health data, different case fatality rates have been observed across Germany. A more conservative management of COVID-19 induced Adult Respiratory Distress Syndrome (ARDS) is justified also by epidemiological data.

The mutational spectrum of asthma and allergy associated genes is not known although recent biobank based exome sequencing studies included these traits. We therefore conducted a secondary analysis of exome data from 281,104 UK Biobank samples for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier genome-wide SNP association studies (GWAS), whole genome sequencing, exome and bisulfit sequencing studies. 354 VOI were significantly associated with asthma, allergic rhinitis and atopic dermatitis. They cluster mainly in two large regions on chromosome 6 and 17. After exclusion of the variants associated with atopic dermatitis and redundant variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared among the 87 genes with increased and the 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common GWAS SNPs are not replicated here. Most identified genes are located in interferon ɣ and IL33 signaling pathway. These genes include already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, as well as TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population paving the way to individualized treatment.

Recent biobank based exon sequencing studies included thousands of traits while the mutational spectrum of asthma and allergy associated genes is still unknown. Methods Meta-analysis of exome data from 281,104 UK Biobank samples that were analyzed for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier GWAS, WGBS, WES and selected candidate gene studies. Results 354 VOI were significantly associated with the traits examined. They cluster mainly in two large regions on chromosome 6 and 17 while there is basically no overlap of atopic dermatitis with both other diseases. After exclusion of the two atopic dermatitis variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared by the group of 87 genes with increased and the group of 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common SNPs in GWAS can not be replicated. Discussion Most identified genes are involved in interferon γ and IL33 signaling pathway. They highlight already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population.

During the first wave of the COVID-19 pandemic high case fatality rates (CFR) were noticed. Due to the dire consequences WHO guidelines recommended immediate intubation for patients with dyspnoea which has since been questioned after reviewing the initial clinical outcome. Methods: PCR confirmed infection rates along with mortality data was obtained for all German districts from 27 Jan 2020 until 15 Feb 2021 using official data sources. A moving average CFRt was constructed by dividing disease related deaths two weeks after a given index days by the number of infections two weeks prior to that date. In addition to an international comparison, mortality data between the second and third largest German cities were also compared. Results: Mean CFR is estimated to be 2.92 based on 71.965 fatalities and 2.465.407 cases. There was a large regional scattering of CFRs across the regional districts. Differences of the mortality pattern were observed also at state level and preserved across different sex and age groups while being largely independent of case numbers. Although Munich city had higher infection rates, more patients died during the first wave in Hamburg (OR 1.6, 95% CI 1.3-1.9). While the majority of Munich hospitals favoured a conservative management of hypoxemia including high flow nasal cannula (HFNC), Hamburg hospitals followed a more aggressive scheme of mechanical ventilation (MV). Austria and Switzerland experienced higher CFRs than Germany during the first wave but after changing treatment guidelines, both countries experienced lower CFRs during the second wave. Conclusion: Different case fatality rates have been observed across Germany that are most likely caused by different treatment strategies.

Publication Date: 09 December 2020 (online) © 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Hintergrund Der Effekt von NPIs („nicht pharmakologische Interventionen“) beim Ausbruch von Epidemien ist unbestritten, sowohl bei historischen Ausbrüchen wie auch bei der aktuellen COVID-19-Pandemie. NPIs umfassen Maßnahmen wie Kontaktbeschränkungen oder Hygienevorschriften, die in abgestuften Schritten der aktuellen Lage angepasst werden. Die Auswirkung von NPIs wurde allerdings bisher kaum quantitativ untersucht. Methoden Aus den offiziellen Fallzahlen des Robert-Koch-Instituts in Berlin sowie Presse- und Twitter-Nachrichten wird eine Rekonstruktion der Frühphase der COVID-19-Pandemie 2020 in Bayern versucht. Ergebnisse Die ersten COVID-19-Fälle in Deutschland traten bereits Ende Januar in München auf. Während die Primärfälle erfolgreich durch Isolierung und Quarantäne eingegrenzt werden konnten, stellte sich die eigentliche Frühphase der COVID-19-Pandemie ab Ende Februar in 3 Phasen dar, bestehend aus den Winter-/Faschingsferien, den Starkbierfesten in der Folgewoche sowie den Wahlen am 15.03.2020. Der Notstand ab 16.03.2020 markiert das Ende der frühen Ausbreitung. Aus der Analyse der Fallzahlen ergibt sich ein weitgehend zusammenhängendes Bild, auch wenn viele epidemiologische Parameter noch fehlen. Die Ausbreitung begann in den Ferien und ging danach in ein exponentielles Wachstum über. Signifikant mehr Fälle wurden sowohl durch die Starkbierfeste, aber auch durch die bayerische Kommunalwahl registriert, jeweils im Vergleich zu Landkreisen mit der gleichen Prävalenz ohne Exposition. Bayern erreichte damit einen Spitzenplatz der Bundesländer, der sich auch durch restriktive Containment-Maßnahmen in den folgenden Wochen nicht mehr rückgängig machen lässt. Folgerung Um wirksam zu sein, müssen NPIs frühzeitig, möglichst vor Beginn der exponentiellen Ausbreitung, durchgeführt werden. Introduction The effect of non pharmacological interventions (NPIs) during an epidemic disease outbreak is well accepted dating back to historical events. NPIs involve numerous measurements like hygiene rules or contact restriction that are applied during given situations, while so far only limited quantitative data exist to rate the overall effectiveness. Methods Using the official counts of Robert Koch Institute in Berlin/Germany, press reports and Twitter messages, the early phase of the current COVID-19/Sars-CoV2 in Bavaria is being reconstructed. Results The first cases have been observed in Munich by the end of January 2020. While the initial outbreak could be sufficiently covered using isolation and quarantine measurements, the consecutive early spreading falls into three phases, starting with winter school holidays at the end of February, a number of beer festivals in the following week, and general elections on March, 15. The disaster plan on March, 16 indicates the end of the early phase. Using the official case counts, a rather coherent picture evolves although representative epidemiological studies are still missing. The epidemic started with a few cases during the winter holidays, increased exponentially afterwards including significant more cases by beer festivals and another significant excess of cases following the election that occurred in Bavaria only. Compared to other German countries, Bavaria reached the highest prevalence which could not be reversed by even the most restrictive containment measurements. Conclusion To be effective, NPIs need to applied early, if possible even before the beginning of the exponential phase. Publication Date: 27 November 2020 (online) © 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany