Background rates of 41 adverse events of special interest for COVID-19 vaccines in 10 European healthcare databases - an ACCESS cohort study.

BACKGROUND: In May 2020, the ACCESS (The vACCine covid-19 monitoring readinESS) project was launched to prepare real-world monitoring of COVID-19 vaccines. Within this project, this study aimed to generate background incidence rates of 41 adverse events of special interest (AESI) to contextualize potential safety signals detected following administration of COVID-19 vaccines. METHODS: A dynamic cohort study was conducted using a distributed data network of 10 healthcare databases from 7 European countries (Italy, Spain, Denmark, The Netherlands, Germany, France and United Kingdom) over the period 2017 to 2020. A common protocol (EUPAS37273), common data model, and common analytics programs were applied for syntactic, semantic and analytical harmonization. Incidence rates (IR) for each AESI and each database were calculated by age and sex by dividing the number of incident cases by the total person-time at risk. Age-standardized rates were pooled using random effect models according to the provenance of the events. FINDINGS: A total number of 63,456,074 individuals were included in the study, contributing to 211.7 million person-years. A clear age pattern was observed for most AESIs, rates also varied by provenance of disease diagnosis (primary care, specialist care). Thrombosis with thrombocytopenia rates were extremely low ranging from 0.06 to 4.53/100,000 person-years for cerebral venous sinus thrombosis (CVST) with thrombocytopenia (TP) and mixed venous and arterial thrombosis with TP, respectively. INTERPRETATION: Given the nature of the AESIs and the setting (general practitioners or hospital-based databases or both), background rates from databases that show the highest level of completeness (primary care and specialist care) should be preferred, others can be used for sensitivity. The study was designed to ensure representativeness to the European population and generalizability of the background incidence rates. FUNDING: The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE.

Are prescribers not aware of cardiovascular contraindications for diclofenac? A claims data analysis.

OBJECTIVES: To compare diclofenac use before and after implementation of European risk minimization measures in 2013, focusing on diclofenac initiators and prevalence of congestive heart failure (NYHA class II-IV), ischaemic heart disease, peripheral arterial disease and cerebrovascular disease (new contraindications) in these patients in Germany. METHODS: We included adults with health insurance coverage on 1 January 2011 (cohort 2011) or 1 January 2014 (cohort 2014) and during a 1-year pre-observation period. We defined diclofenac initiators as persons filling a prescription of systemic diclofenac in 2011 (cohort 2011) or 2014 (cohort 2014) and without such a prescription during the respective pre-observation period. RESULTS: Each cohort comprised >10 million persons. Between 2011 and 2014, the age-standardized proportion of persons initiating diclofenac decreased by 29% (from 8.2% to 5.8%) amongst female patients and by 26% (from 8.5% to 6.3%) amongst male patients; in the subgroup of persons with new contraindications, this proportion decreased by 33% (from 9.8% to 6.6%) amongst female patients and by 31% (from 10.0% to 6.7%) amongst male patients. Amongst diclofenac initiators, the proportion of those with new contraindications did not change between 2011 (12.0%) and 2014 (11.8%). CONCLUSION: The overall decline of about 30% in diclofenac initiation between 2011 and 2014 was largely independent of the presence or absence of new contraindications. The proportion of diclofenac initiators with a new contraindication remained at a high level (more than one in ten patients), demonstrating the need for research at the prescriber level (e.g. interventional studies) and further measures to improve patient safety.

[Implementing an Organised Colorectal Cancer Screening Programme in Germany: Opportunities and Challenges]. / Einführung eines organisierten Darmkrebs-Screenings in Deutschland: Chancen und Herausforderungen.

BACKGROUND: Each year in Germany, about 65,000 people are diagnosed with colorectal cancer (CRC) and more than 25,000 people die of the disease. The majority of these cases could be avoided by a more effective screening programme. Recently, a law came into force that offers a great opportunity in this regard. It calls for introducing an organised CRC screening programme in Germany, which includes an invitation system as well as further measures for quality assurance and programme evaluation. To realise this opportunity, challenges of implementation need to be considered. The aim of this review article is to elaborate the challenges of an organised CRC screening in Germany in order to derive the need for action regarding successful implementation. METHODS: This review article is based on a selective literature search, including current guidelines and recommendations. RESULTS AND CONCLUSION: In the context of CRC screening, but also by colonoscopies performed for other indications (e.g., due to symptoms), precancerous lesions (adenomas) are detected and removed in a relevant proportion of the target population, which requires a surveillance examination after 3 or 5 years according to current recommendations. Therefore, an efficient invitation system for CRC screening should be designed to allow for a flexible interval depending on previous findings, which differs from mammography screening with its fixed interval. A prerequisite would be the standardised documentation of all colonoscopies irrespective of the indication, given that a substantial proportion of colonoscopies in Germany are performed outside of the screening program. Still, the work load regarding documentation could be less than for mammography screening. Another challenge in terms of organisation results from the parallel offer of 2 different screening tools (colonoscopy and faecal occult blood test). To realise the potential of an organised CRC screening, it seems important to devote sufficient time and resources for developing an efficient and feasible concept, while there might be interim options to avoid further delay regarding the initial invitation of the target population. Given that expertise from, amongst others, gastroenterology, epidemiology, clinical chemistry and health communication is required, an interdisciplinary approach appears essential.

Comparison and combination of blood-based inflammatory markers with faecal occult blood tests for non-invasive colorectal cancer screening.

BACKGROUND: Faecal occult blood tests (FOBTs) are widely used for colorectal cancer (CRC) screening. Blood-based inflammatory markers have been suggested as alternative or supplementary non-invasive CRC screening tests. METHODS: Among 179 CRC patients, 193 people with advanced adenoma and 225 people free of neoplasm, C-reactive protein (CRP), serum CD26 (sCD26), complement C3a anaphylatoxin and tissue inhibitor of metalloproteinases 1 (TIMP-1) levels in blood were measured by ELISA tests, and an immunochemical FOBT (iFOBT) and a guaiac-based FOBT were performed. Receiver operating characteristic curves were constructed and the areas under the curves (AUCs) were compared. RESULTS: The blood levels of CRP, sCD26 and TIMP-1 showed statistically significant differences between CRC patients and neoplasm-free participants, and levels of TIMP-1 were furthermore significantly elevated in advanced adenoma patients. For the four inflammatory markers, AUCs ranged from 0.52 to 0.62 for CRC detection and from 0.50 to 0.58 for advanced adenomas detection, compared with AUCs of 0.90 and 0.68 for the iFOBT. At 97% specificity, blood markers showed much lower sensitivities than FOBTs. Combining inflammatory markers with the iFOBT increased the AUC for advanced adenomas. CONCLUSION: These blood-based markers do not seem to be an alternative to FOBT-based CRC screening. The potential use of these and other blood-based tests in combination with iFOBT might deserve further attention.

Sensitivity of immunochemical faecal occult blood testing for detecting left- vs right-sided colorectal neoplasia.

BACKGROUND: Faecal occult blood tests (FOBTs) are used for colorectal cancer (CRC) screening. We aimed to assess the sensitivity of an immunochemical FOBT for detecting advanced colorectal neoplasia in the left vs the right colon and to explore reasons for potential differences in site-specific test performance. METHODS: We prospectively measured faecal occult blood levels by a quantitative immunochemical FOBT (RIDASCREEN) in 2310 average-risk subjects undergoing screening colonoscopy. We compared diagnostic performance for subjects with left- vs right-sided advanced neoplasia, as well as patient characteristics and adenoma characteristics that have been suggested to impact faecal haemoglobin levels. RESULTS: Sensitivities for subjects with left- vs right-sided advanced neoplasia were 33% (95% confidence interval (CI), 26-41%) and 20% (CI, 11-31%) (P=0.04) at a specificity of 95% (overall sensitivity: 29%) and the areas under the receiver-operating characteristics curve were 0.71 (CI, 0.69-0.72) and 0.60 (CI, 0.58-0.63), respectively. Pedunculated shape was strikingly more common in participants with left- vs right-sided advanced neoplasia (47% vs 14%). In logistic regression analyses adjusted for site, pedunculated shape was statistically significantly associated with test sensitivity (P=0.04). CONCLUSIONS: The immunochemical FOBT in our study was more sensitive for detecting subjects with left- vs right-sided advanced colorectal neoplasia. Our findings may stimulate further diagnostic research in the field as well as modelling analyses to estimate the potential effect of site-specific test performance on the effectiveness of annual or biennial FOBT-based screening programmes, in particular with respect to protection from right-sided CRC.

Colonoscopy use in a country with a long-standing colorectal cancer screening programme: evidence from a large German survey.

BACKGROUND: Given the potential colonoscopy has in prevention and early detection of colorectal cancer (CRC), its overall use within a population is a meaningful parameter to estimate the future CRC burden. We aimed to examine overall prevalence and correlates of colonoscopy use in Germany, a country with a long-standing, opportunistic CRC screening programme. METHODS: The data were collected in 2004 through the Health Care Access Panel, a nationally generalisable survey of German households. The sample comprised 15,810 men and women aged 50 to 70 years without a personal history of cancer. RESULTS: Overall, 36 % of respondents reported to have had at least one colonoscopy in the past (25 % once and 11 % more than once). Prevalence of colonoscopy use strongly increased by age (from 25 % to 43 % in age groups 50 - 54 and 65 - 70, respectively), but hardly differed by sex. Previous faecal occult blood testing (FOBT) was the most important correlate of colonoscopy use in either sex. CONCLUSIONS: Our survey from 2004, when FOBT was still the most important screening tool in Germany, suggests that more than one third of the German population underwent colonoscopy at least once up to age 70. While introduction of screening colonoscopy is expected to impact on overall colonoscopy use in the long run, these data can serve as point of reference to assess the extent and the patterns of such changes.

Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk.

BACKGROUND: In 1980, Garland hypothesized that lower levels of vitamin D resulting from much weaker UV-B radiation at higher latitudes may account for the striking geographical pattern of cancer mortality. Further research has been conducted over the past 20 years. AIM: To perform a systematic review and meta-analysis of longitudinal studies on the association between serum 25 hydroxyvitamin D (25(OH)D) and the risk of colorectal cancer (CRC). METHODS: Relevant studies published until September 2008 were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. Due to the heterogeneity of studies in categorizing serum vitamin D levels, all results were recalculated for an increase of serum 25(OH)D by 20 ng/mL. Summary odds ratios (ORs) were calculated using meta-analysis methods. RESULTS: Overall, eight original articles reporting on the association between serum 25(OH) D and CRC risk were included. In meta-analyses, summary ORs (95% confidence intervals) for the incidence of CRC, colon cancer and rectal cancer associated with an increase of 25(OH)D by 20 ng/mL were 0.57 (0.43-0.76), 0.78 (0.54-1.13) and 0.41 (0.11-1.49). No indication for publication bias was found. CONCLUSIONS: Our results support suggestions that serum 25(OH)D is inversely related to CRC risk.

Should colorectal cancer screening start at the same age in European countries? Contributions from descriptive epidemiology.

We assessed incidence and mortality of colorectal cancer (CRC) at various ages among women and men in 38 European countries. The ages at which defined levels of incidence and mortality were reached varied between 9 and 17 years between countries. This variation requires consideration in the definition of screening guidelines.

Sensitivity and specificity of faecal tumour M2 pyruvate kinase for detection of colorectal adenomas in a large screening study.

The measurement of faecal tumour M2 pyruvate kinase (tumour M2 PK) has been proposed as a novel approach for early detection of colorectal cancer (CRC). However, as regards the potential of the test to detect precursors to CRC, an issue that is highly relevant to estimate its use in reducing CRC incidence and mortality, the available evidence is scant and controversial. The aim of our study was to determine the performance characteristics of the tumour M2 PK test with respect to colorectal adenomas in the target population of screening. Among 1082 participants of screening colonoscopy in Germany, of whom 30% had any adenoma and 10% had an advanced adenoma, the median (interquartile range) tumour M2 PK level in the whole study population was 1.3 U ml(-1) (0.3-3.3). At a cutoff value of 4 U ml(-1), sensitivity was 22 and 23% for detection of advanced and other adenomas, respectively, whereas specificity was 82%. The area under the receiver-operating characteristics curve (95% confidence interval) was 0.54 (0.51-0.58) and 0.56 (0.52-0.59) for advanced and other adenomas, respectively. In conclusion, the tumour M2 PK test has only very limited potential to distinguish between people bearing precursors to CRC and people with no finding at colonoscopy.

[Screening: prerequisites]. / Welche Voraussetzungen sind für ein Screening notwendig?

Screening can be a very powerful tool for prevention or more effective treatment of diseases. However, a number of prerequisites have to be met. Only diseases with a preclinical phase, during which the disease or its precursors can be detected by a suited test, are amenable to screening. Early detection of the disease must enable either prevention or more effective management of the disease and not just prolong the "patient career". The benefits of screening must encompass potential harms, which may include, for example, complications, false positive diagnoses or over-diagnoses (i.e. the diagnosis of clinically irrelevant disease). Benefits from screening must be achieved at acceptable costs. Implementation of screening has to be based on scientific evidence and accompanied by scientific evaluation.

Tumour M2-PK as a stool marker for colorectal cancer: comparative analysis in a large sample of unselected older adults vs colorectal cancer patients.

Stool testing based on tumour-derived markers might offer a promising approach for non-invasive colorectal cancer (CRC) screening. The aim of this study was to estimate the potential of a new test for faecal tumour M2-PK to discriminate patients with CRC from a large sample of unselected older adults. Faecal tumour M2-PK concentrations were determined in 65 CRC patients and in a population-based sample of 917 older adults (median age: 65 and 62 years, respectively). Sensitivity and specificity of the test were calculated at different cutoff values, and receiver-operating characteristic curves (ROC) were constructed to visualise the discriminatory power of the test. The median (interquartile range) faecal tumour M2-PK concentration was 8.6 U ml(-1) (2.8-18.0) among CRC patients and <2 U ml(-1) (<2-3.2; P<0.0001) in the population sample. At a cutoff value of 4 U ml(-1), sensitivity (95% confidence interval) was 85% (65-96%) for colon cancer and 56% (41-74%) for rectum cancer. Specificity (95% confidence interval) was estimated to be 79% (76-81%). Given the comparatively high sensitivity of the tumour M2-PK stool test (especially for colon cancer) and its simple analysis, the potential use of the test for early detection of CRC merits further investigation. Possibilities to enhance specificity of the test should be explored.

Gender differences in colorectal cancer: implications for age at initiation of screening.

There is some variation regarding age at initiation of screening for colorectal cancer (CRC) between countries, but the same age of initiation is generally recommended for women and men within countries, despite important gender differences in the epidemiology of CRC. We have explored whether, and to what extent, these differences would be relevant regarding age at initiation of CRC screening. Using population-based cancer registry data from the US and national mortality statistics from different countries, we looked at cumulative 10-year incidence and mortality of CRC reached among men at ages 50, 55, and 60, and found that women mainly reached equivalent levels when 4 to 8 years older. The gender differences were remarkably constant across populations and over time. These patterns suggest that gender differentiation of age at initiation may be worthwhile to utilise CRC-screening resources more efficiently.

Alveolar liver echinococcosis: a comparative study of three imaging techniques.

BACKGROUND: We compared the imaging findings in patients with alveolar liver echinococcosis using ultrasound (US), computerized tomography (CT) and magnetic resonance imaging (MRI) in a prospective study. PATIENTS AND METHODS: 30 patients with alveolar echinococcosis (AE) were examined with the above imaging techniques. RESULTS: 30 lesions were detected with all three methods and most lesions (n = 55) were detected with CT. Calcifications were seen in 15 lesions with US, in 21 with CT and in 16 with MRI. MRI best detected necrotic areas and multivesicuLar structures. CONCLUSION: US is the screening method of choice and should primarily be complemented by CT due to its ability to detect the greatest number of lesions and clear demarcation of the characteristic calcifications. MRI may facilitate the diagnosis in uncertain cases with noncalcified or partially calcified lesions by showing the characteristic multivesicular structure, necrotic areas and proximity to vascular structures.

[Not Available]. / Gruppentherapie in der Tavistock-Tradition.

The authors are describing a particular style of group psychotherapy as it is taught and practiced at the Tavistock Clinic in London. The main empahsis on group transference interpretations is explained by stating the explicit and implicit theoretical backgrounds of this paradigm and discussing the tacit conventions of this particular model of group psychotherapy. The authors then focus on clinical material, partly in order to illustrate the theoretical points discussed, but mainly in order to bring to life the practice of group psychotherapy. The emphasis on practice is an essential feature of the Tavistock approach.

Role of proteinase/antiproteinase inhibitor disequilibrium in the bioincompatibility induced by artificial surfaces.

As one aspect of bioincompatibility, the importance of activation of proteolytic systems as a result of an imbalance between protease and antiprotease activity has been increasingly recognized. This principle is illustrated by selected studies in our laboratory. These concern (i) generation of kinins on membranes with negative surface charge, (ii) activation of the complement system as a function of binding to the membrane of the regulatory protein H, (iii) generation of thrombin-antithrombin complexes (TAT), and (iv) generation of plasmin/antiplasmin complexes with an interesting discrepancy between in vivo and in vitro.

Idiopathic myelofibrosis: a retrospective study of 103 patients.

The clinical course of 103 patients (50 males, 53 females; median age 59 years) with idiopathic myelofibrosis (IMF) seen at our hospital between 1967 and 1986 was analyzed retrospectively. Common symptoms and signs at the time of diagnosis were: myelofibrosis (96%), splenomegaly (84%), anemia (81%), osteosclerosis (45%), malaise (41%) and leukocytosis (41%). It was possible to follow the majority of patients without treatment or with transfusion therapy only for prolonged periods of time. The use of cytostatic drugs and radiotherapy was restricted as much as possible. Probably due to this treatment strategy the incidence of acute leukemia was low (5%). Major thromboembolic complications were seen in 19% of the patients. Median survival of the patients was 4.3 years. The prognostic influence of several disease parameters determined at the time of diagnosis was tested: age, sex, leukocytes, platelets, hemoglobin, reticulocytes, LDH, ANP-score, spleen size and percentage of peripheral blood blasts + promyelocytes had no significant influence on the length of survival. Osteosclerosis, a presumed sign of advanced disease, was not correlated with survival either.

Polycythemia vera. A clinical study of 141 patients.

The clinical course of 141 unselected patients (64 m, 77 f, median age 59) with polycythemia vera (PV), treated during the period 1967 to 1986 was analyzed to study prognostic factors and the correlation between treatment strategies and complication rates. Therapy was performed according to a prospectively defined treatment protocol. Primary control of the disease was achieved by phlebotomy. Marrow suppression by radioactive phosphorus or low dose busulphan was used only as a second-line therapy or to lower high platelet counts. The clinical course of the patients was characterized by a low rate of acute leukemia (4%) and a high rate of thromboembolic complications (40%). Myelofibrosis developed in 17 patients (12%). Median survival of the patents was 9.4 years. The prognostic influence of several parameters at the time of diagnosis was tested: age, sex, spleen size, percentage of blood blasts + promyelocytes, leucocyte count, platelet count, hemoglobin, hematocrit, reticulocyte count and the values of the lactate-dehydrogenase (LDH) and the alkaline neutrophil phosphatase (ANP) all had no significant influence on the length of survival. The prognosis of PV patients with atypical disease presentation at diagnosis was not different from patients with typical disease.