Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- ("Triple") wild type melanomas.

BACKGROUND: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. METHODS: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. RESULTS: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2). CONCLUSIONS: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.

On the gap between objective and perceived risks of COVID-19.

A survey conducted by the German Socio-Economic Panel during the early phase of the SARS-CoV­2 pandemic in spring 2020 showed that the perceived risks of SARS-CoV­2 infection were a massive overestimation of the actual risks. A total of 5783 people (2.3% missing data) stated how likely they thought it was that SARS-CoV­2 would cause a life-threatening illness in them in the next 12 months. The average subjective probability was 26%. We consider how such an overestimation could have occurred and how a more realistic risk assessment could be achieved in the population in a future pandemic. We show that qualitative attributes of the pandemic, the reporting of the media, and psychological features may have contributed to the overestimation of SARS-CoV­2 risks. In its early stages, the SARS-CoV­2 pandemic had qualitative characteristics known to lead to an overestimation of risks: The risks associated with the pandemic were new, unfamiliar, perceived as poorly controllable, and were taken involuntarily. Phenomena known from cognitive psychology such as the availability and anchor heuristics can also explain the overestimation of pandemic risks. Characteristics of media coverage such as the focus on individual fates and the associated neglect of the denominator also contributed to the gap between perceived and objective risk. In a potential future pandemic, people need to be vigilant but not in a panic. Better risk communication-for example, with better prepared figures and graphically presented percentages while avoiding the denominator neglect-could help the population to perceive risks of future pandemics more realistically.

A twenty-first century perspective on concepts of modern epidemiology in Ignaz Philipp Semmelweis' work on puerperal sepsis.

We aimed to review Semmelweis's complete work on puerperal sepsis mortality in maternity wards in relation to exposure to cadavers and chlorine handwashing and other factors from the perspective of modern epidemiological methods. We reviewed Semmelweis' complete work and data as published by von Györy 1905 according to current standards. We paid particular attention to Semmelweis's definition of mortality in and of itself, to concepts of modern epidemiology that were already recognizable in Semmelweis's work, and to bias sources. We did several quantitative bias analyses to address selection bias and information bias from outcome measurement error. Semmelweis addressed biases that have become known to modern epidemiology, such as confounding, selection bias and bias from outcome misclassification. Our bias analysis shows that differential loss to follow-up is an unlikely explanation for his results. Bias due to outcome misclassification would only be relevant if misclassification differed between time periods. Confounding by health status was likely but could not be quantitatively addressed. Semmelweis was aware that cause-specific mortality is a function of incidence and prognosis. He reasoned in potential outcome terms to estimate the reduced number of deaths from an intervention. He advanced a hypothesis of clinic overcrowding as a risk factor for puerperal sepsis mortality that turns out to be wrong. Semmelweis' data provide a great pool for illustrating the logic of scientific discovery by use of the numerical method. The explanatory power of his work was strong and Semmelweis was able to refute several previous causal explanations.

COVID-19: Vaccination Side Effects and Sick Leave in Frontline Healthcare-Workers-A Web-Based Survey in Germany.

(1) Background: The COVID-19 vaccination has caused uncertainty among employees and employers regarding vaccination reactions and incapacitation. At the time of our study, three vaccines are licensed in Germany to combat the COVID-19 pandemic (BioNTech/Pfizer (Comirnaty), AstraZeneca (Vaxzevria), and Moderna (Spikevax). We aim to assess how often and to what extent frontline healthcare workers had vaccination reactions after the first and second vaccination. The main focus is on the amount of sick leave after the vaccinations. (2) Methods: We create a web-based online questionnaire and deliver it to 270 medical directors in emergency medical services all over Germany. They are asked to make the questionnaire public to employees in their area of responsibility. To assess the association between independent variables and adverse effects of vaccination, we use log-binomial regression to estimate prevalence ratios (PR) with 95% confidence intervals (95%CI) for dichotomous outcomes (sick leave). (3) Results: A total of 3909 individuals participate in the survey for the first vaccination, of whom 3657 (94%) also provide data on the second vaccination. Compared to the first vaccination, mRNA-related vaccine reactions are more intense after the second vaccination, while vaccination reactions are less intense for vector vaccines. (4) Conclusion: Most vaccination reactions are physiological (local or systemic). Our results can help to anticipate the extent to which personnel will be unable to work after vaccination. Even among vaccinated HCWs, there seems to be some skepticism about future vaccinations. Therefore, continuous education and training should be provided to all professionals, especially regarding vaccination boosters. Our results contribute to a better understanding and can therefore support the control of the pandemic.

[SARS-CoV-2 IgG seroprevalence in personnel of the extraclinical fight against the COVID-19 pandemic]. / SARS-CoV-2-IgG-Antikörperseroprävalenz bei Personal in der außerklinischen Bekämpfung der COVID-19-Pandemie.

BACKGROUND AND OBJECTIVES: The SARS-CoV­2 pandemic and the different manifestations of the coronavirus disease 2019 (COVID-19) are a major challenge for health systems worldwide. Medical personnel have a special role in containing the pandemic. The aim of the study was to investigate the SARS-CoV­2 IgG antibody prevalence in extraclinical personnel depending on their operational area in the fight against the COVID-19 pandemic. METHODS: On May 28 and 29, 2020, serum samples were taken from 732 of 1183 employees (61.9%) of the professional fire brigade and aid organizations in the city area and tested for SARS-CoV­2 IgG antibodies. The employees were divided into four categories according to their type of participation. category 1: decentralized PCR sampling teams, category 2: rescue service, category 3: fire protection, category 4: situation center. Some employees participated in more than one operational area. RESULTS: SARS-CoV­2 IgG antibodies were detected in 8 of 732 serum samples. This corresponds to a prevalence of 1.1%. A previous COVID-19 infection was known in 3 employees. In order to make a separate assessment of the other employees possible and to diagnose unknown infections, a corrected collective of 729 employees with 6 SARS-CoV­2 antibody detection was considered separately. The prevalence in the corrected collective is 0.82%. After subdividing the collective into areas of activity, the prevalence was low (1: 0.77%, 2: 0.9%, 3: 1.00%, 4: 1.58%). CONCLUSIONS: The seroprevalence of SARS-CoV­2 in the study collective is low at 1.1% and 0.82%, respectively. There is an increased seroprevalence in operational areas with a lower risk of virus exposure in comparison to operational areas with a higher risk.

Excess mortality due to Covid-19? A comparison of total mortality in 2020 with total mortality in 2016 to 2019 in Germany, Sweden and Spain.

INTRODUCTION: Excess mortality is a suitable indicator of health consequences of COVID-19 because death from any cause is clearly defined contrary to death from Covid-19. We compared the overall mortality in 2020 with the overall mortality in 2016 to 2019 in Germany, Sweden and Spain. Contrary to other studies, we also took the demographic development between 2016 and 2020 and increasing life expectancy into account. METHODS: Using death and population figures from the EUROSTAT database, we estimated weekly and cumulative Standardized Mortality Ratios (SMR) with 95% confidence intervals (CI) for the year 2020. We applied two approaches to calculate weekly numbers of death expected in 2020: first, we used mean weekly mortality rates from 2016 to 2019 as expected mortality rates for 2020, and, second, to consider increasing life expectancy, we calculated expected mortality rates for 2020 by extrapolation from mortality rates from 2016 to 2019. RESULTS: In the first approach, the cumulative SMRs show that in Germany and Sweden there was no or little excess mortality in 2020 (SMR = 0.976 (95% CI: 0.974-0.978), and 1.030 (1.023-1.036), respectively), while in Spain the excess mortality was 14.8% (1.148 (1.144-1.151)). In the second approach, the corresponding SMRs for Germany and Sweden increased to 1.009 (1.007-1.011) and 1.083 (1.076-1.090), respectively, whereas results for Spain were virtually unchanged. CONCLUSION: In 2020, there was barely any excess mortality in Germany for both approaches. In Sweden, excess mortality was 3% without, and 8% with consideration of increasing life expectancy.

GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.

Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi's sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi's sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in GNA genes, including GNA14 Q205, GNA11 and GNAQ Q209 were identified in 16 of 64 benign vascular tumors (25%). GNA gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating RAS mutations (HRAS and NRAS) were identified in three samples (16%). No activating GNA or RAS gene mutations were identified in Kaposi's sarcomas. Our study identifies GNA14 Q205, GNA11 and GNAQ Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.

Calculating the number of undetected active SARS-CoV-2 infections from results of population-wide antigen tests.

Current European research estimates the number of undetected active SARS-CoV-2 infections (dark figure) to be two- to 130-fold the number of detected cases. We revisited the population-wide antigen tests in Slovakia and South Tyrol and calculated the dark figure of active cases in the vulnerable populations and the number of undetected active cases per detected active case at the time of the population-wide tests. Our analysis follows three steps: using the sensitivities and specificities of the used antigen tests, we first calculated the number of test-positive individuals and the proportion of actual positives in those who participated in the antigen tests. We then calculated the dark figure in the total population of Slovakia and South Tyrol, respectively. Finally, we calculated the ratio of the dark figure in the vulnerable population to the number of newly detected infections through PCR tests. Per one positive PCR result, another 0.15 to 0.71 cases must be added in South Tyrol and 0.01 to 1.25 cases in Slovakia. The dark figure was in both countries lower than assumed by earlier studies.

Excess mortality due to COVID-19 in Germany.

OBJECTIVES: The first wave of the SARS-CoV-2 pandemic in Germany lasted from week 10 to 23 in 2020. The aim is to provide estimates of excess mortality in Germany during this time. METHODS: We analyzed age-specific numbers of deaths per week from 2016 to week 26 in 2020. We used weekly mean numbers of deaths of 2016-2019 to estimate expected weekly numbers for 2020. We estimated standardized mortality ratios (SMR) and 95% confidence intervals. RESULTS: During the first wave observed numbers of deaths were higher than expected for age groups 60-69, 80-89, and 90+. The age group 70-79 years did not show excess mortality. The net excess number of deaths for weeks 10-23 was +8,071. The overall SMR was 1•03 (95%CI 1•03-1•04). The largest increase occurred among people aged 80-89 and 90+ (SMR=1•08 and SMR=1•09). A sensitivity analysis that accounts for demographic changes revealed an overall SMR of 0•98 (95%CI 0•98-0•99) and a deficit of 4,926 deaths for week 10-23, 2020. CONCLUSIONS: The excess mortality existed for two months. The favorable course of the first wave may be explained by a younger age at infection at the beginning of the pandemic, lower contact rates, and a more efficient pandemic management.