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.

Use of antihistamines and risk of ventricular tachyarrhythmia: a nested case-control study in five European countries from the ARITMO project.

PURPOSE: After regulatory restrictions for terfenadine and astemizole in '90s, only scarce evidence on proarrhythmic potential of antihistamines has been published. We evaluate the risk of ventricular tachyarrhythmia (VA) related to the use of individual antihistamines. METHODS: A matched case-control study nested in a cohort of new users of antihistamines was conducted within the EU-funded ARITMO project. Data on 1997-2010 were retrieved from seven healthcare databases: AARHUS (Denmark), GEPARD (Germany), HSD and ERD (Italy), PHARMO and IPCI (Netherlands) and THIN (UK). Cases of VA were selected and up to 100 controls were matched to each case. The odds ratio (OR) of current use for individual antihistamines (AHs) was estimated using conditional logistic regression. RESULTS: For agents largely used to prevent allergic symptoms, such as cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine, we found no VA risk. A statistically significant, increased risk of VA was found only for current use of cyclizine in the pooled analysis (ORadj, 5.3; 3.6-7.6) and in THIN (ORadj, 5.3; 95% CI, 3.7-7.6), for dimetindene in GEPARD (ORadj, 3.9; 1.1-14.7) and for ebastine in GEPARD (ORadj, 3.3; 1.1-10.8) and PHARMO (ORadj, 4.6; 1.3-16.2). CONCLUSIONS: The risk of VA associated with a few specific antihistamines could be ascribable to heterogeneity in pattern of use or in receptor binding profile.

A Consensus German Reporting Standard for Secondary Data Analyses, Version 2 (STROSA-STandardisierte BerichtsROutine für SekundärdatenAnalysen).

Although secondary data analyses have been established in recent years in health research, explicit recommendations for standardized, transparent and complete reporting of secondary data analyses do not exist as yet. Therefore, between 2009 and 2014, a first proposal for a specific reporting standard for secondary data analysis was developed (STROSA 1). Parallel to this national process in Germany, an international reporting standard for routine data analysis was initiated in 2013 (RECORD). Nevertheless, because of the specific characteristics of the German health care system as well as specific data protection requirements, the need for a specific German reporting standard for secondary data analyses became evident. Therefore, STROSA was revised and tested by a task force of 15 experts from the working group Collection and Use of Secondary Data (AGENS) of the German Society for Social Medicine and Prevention (DGSMP) and the German Society for Epidemiology (DGEpi) as well as from the working group Validation and Linkage of Secondary Data of the German Network for Health Services Research (DNVF). The consensus STROSA-2 checklist includes 27 criteria, which should be met in the reporting of secondary data analysis from Germany. The criteria have been illustrated and clarified with specific explanations and examples of good practice. The STROSA reporting standard aims at stimulating a wider scientific discussion on the practicability and completeness of the checklist. After further discussions and possibly resulting modifications, STROSA shall be implemented as a reporting standard for secondary data analyses from Germany. This will guarantee standardized and complete information on secondary data analyses enabling assessment of their internal and external validity.

The Risk of Opioid Intoxications or Related Events and the Effect of Alcohol-Related Disorders: A Retrospective Cohort Study in German Patients Treated with High-Potency Opioid Analgesics.

INTRODUCTION: Intoxications involving prescription opioids are a major public health problem in many countries. When taken with opioids, alcohol can enhance the effects of opioids, particularly in the central nervous system. However, data quantifying the impact of alcohol involvement in opioid-related intoxications are limited. METHODS: Using claims data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a retrospective cohort study based on users of high-potency opioid (HPO) analgesics during the years 2005-2009. HPO use was classified as extended-release, immediate-release or both. We calculated incidence rates (IRs) for opioid intoxications or related events as well as adjusted IR ratios (aIRR) comparing HPO-treated patients with alcohol-related disorders (ARDs) to those without ARDs overall and within each HPO category. RESULTS: During the study period, 308,268 HPO users were identified with an overall IR of 340.4 per 100,000 person-years [95 % confidence interval (CI) 325.5-355.7]. The risk was highest when patients received concomitant treatment with extended- and immediate-release HPOs (IR 1093.8; 95 % CI 904.6-1310.9). ARDs increased the risk during HPO use by a factor of 1.7 and the highest aIRR was seen when comparing patients simultaneously exposed to extended- and immediate-release HPOs with ARDs to those without ARD also after excluding patients with potential improper/non-medical HPO use. CONCLUSIONS: Physicians should be aware of these elevated risks in HPO patients with ARDs. Active patient education by healthcare providers regarding the risk of opioid intoxications or related events due to alcohol in conjunction with HPOs is warranted.

Influence of bathing or washing on skin barrier function in newborns during the first four weeks of life.

BACKGROUND AND OBJECTIVES: After birth, skin barrier function is in state of flux and at risk of dysfunction. In a prospective clinical study, we compared the effects of 2 standard cleansing procedures on skin barrier function in newborns. METHODS: Fifty-seven healthy full-term neonates aged < or = 48 h were randomly assigned to either a bathing group (group B; n = 29), who were bathed with clear water twice weekly, or to a washing group (group W; n = 28), who were washed with a washcloth moistened with clear water twice weekly. Transepidermal water loss (TEWL), skin pH, stratum corneum hydration (SCH) and sebum production were measured at days 2, 7 and 28 of life on the forehead, abdomen, upper leg and buttock. RESULTS: Group B showed significantly lower TEWL on the buttock and higher SCH on the abdomen and forehead compared to group W at day 28. CONCLUSIONS: Both skin care regimens do not harm the adaptation of the skin barrier in healthy neonates within the first 4 weeks of life. Skin barrier function differentiates after birth in a regionally specific fashion.

[Can the frequency of color-coded duplex sonography in urgent examination of deep vein thrombosis be reduced by application of a clinical probability assessment?]. / Kann die Frequenz duplexsonografischer Notfalluntersuchungen der tiefen Beinvenenthrombose durch Anwendung einer klinischen Wahrscheinlichkeitsbewertung reduziert werden?

PURPOSE: Application and verification of the Wells score for pre-test probability of deep vein thrombosis in the lower limbs in clinical routine. The goal was to reduce the number of immediate diagnostic measures for excluding vein thrombosis during acute investigation. New parameters for upgrading or modification the existing score were checked. MATERIALS AND METHODS: In a period from March through November 2007, 333 patients were assigned to the department of radiology in order to exclude deep vein thrombosis. A standardized questionnaire was used to identify the probability of deep vein thrombosis. The patients were categorized as low, moderate, and high risk. The examination was conducted with colored-coded duplex sonography. RESULTS: In the patient population of 333, 41 (12 %) had deep vein thrombosis of the lower limb. The prevalence was approximately 3 % in the low risk group, 34 % in the moderate risk group, and 63 % in the high risk group. Categorization with the Wells score is an instrument with high sensitivity (99.6 %) and specificity (100 %). CONCLUSION: The pre-test probability with the Wells score represents a useful and established instrument in the clinical routine. Acute examinations, especially during stand-by, can be reduced without neglecting patient safety. Patients with a Wells score of 0 don't require an acute examination. An elective investigation should be targeted. Patients with a score between 1 and 8 needed to be treated (within the next 24 hours) with KS and FKDS. According to on our data records, therapy should be started immediately for patients with a high risk of deep vein thrombosis.

[Treatment of the femoropopliteal arteries with a novel rotational atherectomy system: early single-center experience with the Pathway PVTM Atherectomy System]. / Behandlung von Läsionen der femoropoplitealen Arterien mittels eines neuartigen Rotationsatherektomiesystems: Erste single-center Erfahrungen mit dem Pathway PVTM Atherectomy System.

PURPOSE: The main problem when treating the superficial femoral and popliteal artery with PTA or stent implantation is the relatively high restenosis rate. Several ablative systems are available as an alternative. The purpose of this prospective study was to evaluate the safety and performance of a novel rotational and aspirating atherectomy system. MATERIALS AND METHODS: From June to December 2006, we treated 23 patients, median age 70.3 years (58-91), with the rotational atherectomy system. All patients had de-novo lesions of the SFA or PA with a minimum stenosis of 70%. According to the Rutherford classification, 39% of the patients were in category 2 and 61% in category 3. The median lesion length was 26.3 mm (5-100 mm). 26% of the patients had occlusions. RESULTS: The technical success rate was 100%. In 14 cases (61%) additional balloon dilatation was applied, in two cases stent implantation were performed. The median treatment duration with the device was 187.7 +/- 106.1 s (59-391 s). The aspirated volume was 116.5 +/- 72.0 ml. The ankle brachial index improved from preinterventional 0.60 +/- 0.16 to postinterventional 0.85 +/- 0.13 and after 6 month 0.80 +/- 0.13. During follow-up, two (8%) restenosis occurred. There were two complications, one dissection and one distal embolization. Follow-up could not be performed for two patients (8%). CONCLUSION: Atherectomy of femoropopliteal lesions with the Pathway PV Atherectomy System is very safe and effective. The low restenosis rate of 8% is promising, but there is still a lack of long-term results.

[Treatment of acute femoropopliteal bypass graft occlusion: comparison of mechanical rotational thrombectomy with ultrasound-enhanced lysis]. / Behandlung akuter Okklusionen von femoropoplitealen Bypässen: Vergleich der mechanischen Rotationsthrombektomie mit der ultraschallgestützten Lyse.

PURPOSE: Mechanical thrombectomy has become a viable alternative to intra-arterial thrombolysis for the treatment of acute infrainguinal occlusion. The aim of this prospective study was to evaluate the safety and effectiveness of a mechanical thrombectomy system in comparison with ultrasound-enhanced thrombolysis. MATERIALS AND METHODS: From April 2005 to March 2007, 20 patients, mean age 67.4+/-13.6, with acute occlusions of the femoropopliteal bypass graft were treated with either a rotational thrombectomy system (Straub Rotarex, n=10) or with 1.0 mg/h Actilyse using an ultrasound-enhanced lysis system (EKOS Lysus Peripheral Catheter System, n=10). The mean occlusion length was 33.1 cm (range 28-40 cm) in the thrombectomy group and 33.7 cm (11-50 cm) in the lysis group. RESULTS: The technical success rate was 100% in the thrombectomy group and 90 % in the lysis group. The mean treatment time was significantly lower with 64.5 min (45-90 min) in the thrombectomy group in comparison with 904.0 min (120-1350 min) in the lysis group. The ankle brachial index (ABI) improved in the thrombectomy group from 0.41+/-0.09 to 0.86+/-0.10 at discharge and 0.85+/-0.07 after 1 month (p<0.05) and in the lysis group from preinterventional 0.37+/-0.15 to 0.82+/-0.16 at discharge and 0.80+/-0.24 after 1 month (p<0.05). In one case lysis had to be stopped after two hours because of dislocation of the introducer sheath which was then treated by open surgery. CONCLUSION: Mechanical-rotational thrombectomy with the Rotarex system and lysis with the ultrasound-enhanced catheter from Ekos were very safe and effective treatment options for acute occlusion. Blood flow is restored much faster with mechanical thrombectomy.

[Peripartum changes of the pelvic ring: usefulness of magnetic resonance imaging]. / Peripartale Veränderungen des Beckenringes: Wie sinnvoll ist die Magnetresonanztomografie?

PURPOSE: Postpartum pelvic pain beyond the normal level poses a problem to obstetricians. Beyond normal physiologic loosening of the pubic symphysis and sacroiliac joints (SIJs) during pregnancy, symphyseal separation and rupture must be excluded. The aim of this prospective study was to determine whether magnetic resonance imaging (MRI) allows for reliable differentiation of normal postpartum findings and pathologic lesions. MATERIAL AND METHODS: The study included a total of 77 women (mean age 30), among them 21 healthy subjects (group A), 21 asymptomatic postpartum women (group B), and 35 patients with postpartum pelvic pain (group C). The analyzed parameters comprised symphyseal and iliosacral tenderness, subjective pain assessed on a visual analog scale, and data pertaining to obstetric history. All 77 women underwent 1.5T MRI of the pelvic ring using oblique angulated coronal T 1-weighted and STIR sequences for imaging of the symphysis and SIJs in one slice package. Analysis of the MR images comprised signal intensities of pelvic bone marrow, width of the symphyseal cleft, and the symphyseal capsule. RESULTS: Subjects in group A in general had a normal bone marrow signal. The STIR sequence showed increased signal intensity of the pubic bone near the symphysis in 16 women (76 %) of group B and 31 patients of group C (86 %) (not significant). An increased periarticular bone marrow signal of the SIJs on the STIR images was seen in 13 women (62 %) of group B and 23 patients (63 %) of group C. The mean width of the symphyseal cleft differed significantly among the three groups (3.4 mm vs. 5.4 mm vs. 6.7 mm). A width >10 mm was observed in only 4 cases (11 %). Moreover, associated findings such as interpubic hematoma (n=23) or tears of the symphyseal capsule (n=7) were detected in patients of group C. CONCLUSION: The wide overlap of findings between symptomatic and asymptomatic postpartum patients does not allow reliable differentiation by MRI of normal and abnormal findings. MRI contributes to the differentiation of symphyseal contusion and rupture and provides information on severe associated changes.

Low-field MRI for assessing synovitis in patients with rheumatoid arthritis. Impact of Gd-DTPA dose on synovitis scoring.

OBJECTIVE: To investigate the impact of a double dose compared to a single dose of contrast material in low-field magnetic resonance imaging (MRI) on semi-quantitative scoring of synovitis in patients with rheumatoid arthritis (RA). METHODS: This prospective study included 38 RA patients (23 women and 15 men, mean age 51 years). All patients underwent low-field MRI of the hand before administration of contrast medium, after intravenous injection of 0.1 mmol/kg gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA), and after another dose of 0.1 mmol/kg Gd-DTPA. Two readers (A and B) blinded to dosage independently scored the single dose and double dose image sets for synovitis according to outcome measures in rheumatology (OMERACT) recommendations. Contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) were also calculated for each set. RESULTS: 149 metacarpophalangeal (MCP) joints were evaluated. There was good inter-reader agreement for each of the two sets (intra-class correlation coefficient of 0.75 for the single dose set and 0.83 for the double dose). Median CNR and SNR values were 5.4 and 15.9, respectively, for the single dose set and 8.5 and 16.6, respectively, for the double dose set (p<0.0001). Single dose set mean synovitis scores were 1.7 and 1.6 for readers A and B, respectively. Double dose set scores were 1.9 and 2.0, respectively. Thus, higher synovitis scores were recorded for the double dose sets than the single dose sets (p<0.005). CONCLUSION: In low-field MRI, when evaluating RA, the dose of the contrast material influences synovitis scoring. Therefore, dosage of contrast material should be taken into consideration when using extremity dedicated low-field MRI.

A randomized trial of botulinum toxin A for treatment of drooling.

The authors compared the efficacy of three different doses (18.75, 37.5, and 75 MU per parotid gland) of botulinum toxin A (BTX-A; Dysport, Ipsen Pharma, Germany) injections vs vehicle in patients with sialorrhea (n = 32) using a single-center, prospective, double-blind, placebo-controlled dose-finding study. The primary endpoint was achieved with 75 MU BTX-A without treatment-related adverse events, suggesting BTX-A is a safe and effective treatment for patients with sialorrhea.

Cellular profiles of induced sputum in children with stable cystic fibrosis: comparison with BAL.

Neutrophil-dominated endobronchial inflammation is a major characteristic of cystic fibrosis (CF) and there is increasing demand for easy-to-perform noninvasive monitoring for prediction and intervention. Fourteen stable paediatric CF patients (8-17 yrs; mean forced expiratory volume in one second 86.7% of the predicted value) were investigated once by fractional bronchoalveolar lavage (BAL) and by sputum induction on three occasions, 2-6 weeks apart. Sputum was induced by consecutive 10-min inhalations of 3, 4 and 5% saline. CF sputum cellular profiles were compared with BAL fluid cell counts and samples from age-matched healthy children, and between different time points to assess reproducibility. Adequate sputum was recovered on >95% of occasions. In all sputum fractions, CF patients showed higher neutrophil counts than healthy children. Neutrophil percentages were highest in the first BAL fraction (median 92%), followed by sputum, in which the percentages decreased in consecutive fractions (72, 66 and 64%), whereas counts were lowest in the pooled BAL fraction (53%). Increasing percentages of macrophages mirrored the decreases in neutrophil percentage. Results of sputum induction at different time points in the CF patients showed good reproducibility and nonoverlap with counts from healthy children. In conclusion, the results of sputum induction in children with mild stable cystic fibrosis adequately describe airway inflammation by providing cellular profiles with lower relative neutrophil counts than in the first ("bronchial") bronchoalveolar lavage fraction and higher relative neutrophil counts than in subsequent pooled ("more peripheral") bronchoalveolar lavage fractions.