Self-controlled Case Series Study Research Articles

Risk benefit analysis to evaluate risk of thromboembolic events after mRNA COVID-19 vaccination and COVID-19

We compared the risks and benefits of COVID-19 vaccines using a causal pathway analysis to weigh up possible risk factors of thromboembolic events post-vaccination. The self-controlled case series (SCCS) method examined the association between thromboembolic events and vaccination while a case-control study assessed the association between thromboembolic events and COVID-19, addressing under-reported infection data issues. The net vaccine effect was estimated using results from SCCS and case-control studies. We used electronic health record data from Corewell Health (16,640 subjects in SCCS and 106,143 in case-control). We found increased risks of thromboembolic events post-vaccination (incidence rate ratio: 1.19, 95% CI: [1.08, 1.31] after the first dose; 1.22, 95% CI: [1.11, 1.34] after the second dose). Vaccination attenuated infection-associated thromboembolic risks (odds ratio: 4.65, 95% CI: [4.18, 5.17] in unvaccinated vs 2.77, 95% CI: [2.40, 3.24] in vaccinated). After accounting for vaccine efficacy and protection against infection-associated thromboembolic events, vaccination decreases thromboembolic event risk, especially during high infection rate periods.

Drug-drug interaction between diltiazem and tacrolimus in relation to CYP3A5 genotype status in Chinese pediatric patients with nephrotic range proteinuria: a retrospective study.

Tacrolimus is widely used to treat pediatric nephrotic range proteinuria (NRP). Diltiazem, a CYP3A4/5 inhibitor, is often administered with tacrolimus, affecting its pharmacokinetic profile. The impact of this combination on tacrolimus exposure, particularly in CYP3A5*3 genetic polymorphism, remains unclear in pediatric NRP patients. This study aimed to evaluate the effects of diltiazem on tacrolimus pharmacokinetics, focusing on the CYP3A5*3 polymorphism. We conducted a retrospective clinical study involving pediatric NRP patients, divided into two groups: those receiving tacrolimus with diltiazem and those receiving tacrolimus alone. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups. We compared daily dose-adjusted trough concentrations (C0/D) of tacrolimus in both the original and PSM cohorts. The influence of diltiazem on tacrolimus C0/D, stratified by CYP3A5*3 genetic polymorphism, was assessed in a self-controlled case series study. Before PSM, the tacrolimus C0/D in patients taking diltiazem was significantly higher compared to those with tacrolimus alone (75.84 vs. 56.86ng/mL per mg/kg, P = 0.034). This finding persisted after PSM (75.84 vs. 46.93ng/mL per mg/kg, P= 0.028). In the self-controlled case study, tacrolimus C0/D elevated about twofold (75.84 vs. 34.76ng/mL per mg/kg, P < 0.001) after diltiazem administration. CYP3A5 expressers (CYP3A5*1/*1 and *1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3) experienced a 1.8-fold and 1.3-fold increase in tacrolimus C0/D when combined with diltiazem, respectively. Diltiazem significantly increased tacrolimus C0/D, with CYP3A5*3 expressers showing higher elevations than non-expressers among pediatric NRP patients. These findings highlight the importance of personalized tacrolimus therapy based on CYP3A5*3 genotypes in pediatric patients taking diltiazem.

Ocular Adverse Events After Influenza Vaccination in Older Adults: Self-Controlled Case Series Using a Large Database in Japan

ABSTRACT Background To clarify the risk of adverse ocular events following influenza vaccination. Methods This self-controlled case series study used a claims database linked to vaccination records of a large city in Japan between April 2014 and September 2021. Individuals aged ≥ 65 years who developed adverse ocular events during the follow-up period were included. The exposure was influenza vaccination. The primary outcome was defined as the occurrence of at least one of the following five eye diseases: uveitis, scleritis, retinal vein occlusion, retinal artery occlusion, or optic neuritis. Conditional Poisson regression was used to estimate the within-subject incidence rate ratio of ocular adverse events during the risk period (0–56 days after vaccination) compared to the control period. Results A total of 4,527 cases were eligible for the study (median age, 74 years; male, 42%). The incidence rate ratio for the outcome during the risk period was 0.99 (95% confidence interval, 0.87 to 1.14). No increased risk was observed for individual components of the outcome either; the incidence rate ratio was 0.94 (0.78 to 1.13) for uveitis, 1.17 (0.86 to 1.59) for scleritis, 0.98 (0.76 to 1.27) for retinal vein occlusion, 0.89 (0.42 to 1.87) for retinal artery occlusion, and 0.87 (0.44 to 1.70) for optic neuritis. Conclusions This self-controlled case series showed no apparent increase in the risk of adverse ocular events after influenza vaccination among older adults. These results mitigate the concerns of older adults who may hesitate to receive influenza vaccination for fear of adverse ocular events. Abbreviation HR = hazard ratio; CI = confidence interval; RVO = retinal vein occlusion; SCCS = self-controlled case series

Cholinesterase Inhibitor Initiation Does Not Increase the Risk of Fall-Related Injury in Older Adults Treated with Beta-blockers: a self-controlled case series design.

Prescribing cholinesterase inhibitors (ChEIs) concurrently with beta-blockers might cause syncope that increases the risk of fall-related injuries (FRIs). This self-controlled case series study assesses the risk of FRIs associated with initiating ChEIs while receiving beta-blockers among Medicare fee-for-service-insured nursing home (NH) residents in the United States. We identified individuals at their first dispensing of a beta-blocker between 2016 and 2019 after at least 45 days of long-stay NH residency. Individuals were followed from the first day of beta-blocker use until beta-blocker discontinuation, Medicare disenrollment, death, or study end. ChEI initiation was classified as the first 60 days of new ChEI dispensing after 45 days of no ChEI exposure. FRIs were assessed during beta-blocker use periods and age-adjusted incidence rate ratios (IRR) for ChEI-initiation days versus other days were calculated using conditional Poisson regression models. Analyses were weighted for event-dependent observation periods due to the high risk of mortality after an FRI in this population. Subgroup analyses were conducted for several key time-fixed variables, including sex, age, ChEI type, ChEI dose, beta-blocker selectivity and beta-blocker dose. The FRI risk after ChEI initiation was not elevated among 837 residents who experienced an FRI while using beta-blockers (IRR=0.90 [95%CLs 0.71, 1.15]). Analyses of ChEI initiation in several subgroups yielded similar results. There was no substantial difference in FRI risk when initiating ChEIs among older NH residents receiving beta-blocker therapy versus periods without ChEI initiation, suggesting that there is no clinically significant pharmacodynamic drug-drug interaction between beta-blockers and ChEIs.

Risk of falls or fall-related injuries associated with potentially inappropriate medication use among older adults with dementia.

Potentially inappropriate medications (PIMs) are prevalent in older adults with dementia and subsequent falls or fall-related injuries. The present study determined the risk of falls or fall-related injuries associated with PIM use in older adults with dementia. The National Health Insurance Service-Elderly Cohort Database 2.0 (NHIS-ECDB2.0) was used for this self-controlled case series (SCCS) study. This study included 1430 participants who went through exposure and non-exposure periods of PIM application among patients with dementia and experienced outcome events of falls or fall-related injuries between January 2016 and December 2019. The incidence of falls or fall-related injuries during the exposure and post-exposure periods was compared with that during the non-exposure period. Beers Criteria were used to define PIMs in patients with dementia. Negative binomial regression was conducted. The incidence rate ratio (IRR) was used to determine the risk of falls or fall-related injuries. During the exposure periods in which falls or fall-related injuries occurred, the mean number of PIMs among patients with dementia was 3.76 (SD = 2.99), and the most commonly used PIMs among patients with dementia were first-generation antihistamines (n = 283; 59.1%). Compared to the non-exposure period, the adjusted IRR during the exposure period was 1.57 (95% CI = 1.39-1.76). The risk of falls or fall-related injuries was increased when PIM use in patients with dementia was initiated (1-14days: IRR = 2.76, 95% CI = 2.31-3.28; 15-28days: IRR = 1.95, 95% CI = 1.48-2.56; ≥ 29days: IRR = 1.17, 95% CI = 1.01-1.35). Especially, an increased risk of falls or fall-related injuries was associated with greater PIM use among patients with dementia. Among older adults with dementia, PIMs significantly increase the risk of falls and fall-related injuries. Therefore, strategies should be developed to manage PIM prescriptions in patients with dementia to prevent falls.

COVID-19 Vaccination and Ocular Adverse Events: A Self-Controlled Case Series Study From the Entire South Korean Population

This study aimed to assess the risk of ocular adverse events, including retinal artery occlusion (RAO), retinal vein occlusion (RVO), noninfectious uveitis (NIU), noninfectious scleritis (NIS), optic neuritis (ON), ischemic optic neuropathy (ION), and ocular motor cranial nerve palsy (OMCNP), following Coronavirus Disease 2019 (COVID-19) vaccination. Population-based self-controlled case series METHODS: This study utilized nationwide claims and vaccination data provided by the Korea National Health Insurance Service and Korea Disease Control and Prevention Agency. From the entire South Korean population of 52 million individuals, patients with incident RAO, RVO, anterior NIU, nonanterior NIU, NIS, ON, ION, or OMCNP between January 2021 and March 2022 were included. The postvaccination risk period was defined as up to 56 days after COVID-19 vaccination. The relative incidence rate ratios (IRRs) for RAO, RVO, anterior NIU, nonanterior NIU, NIS, ON, ION, and OMCNP during the risk periods were measured using conditional Poisson regression. The study included 6,590, 70,120, 137,958, 17,921, 15,492, 2,039, 49,089, and 11,312 cases of incident RAO, RVO, anterior NIU, nonanterior NIU, NIS, ON, ION, and OMCNP, respectively. The IRRs (95% confidence interval) during the early risk period (0-28 days) were 0.95 (0.88-1.01), 0.96 (0.94-0.98), 0.93 (0.91-0.94), 0.93 (0.89-0.96), 0.96 (0.92-1.01), 1.04 (0.92-1.18), 0.98 (0.95-1.00), and 0.91 (0.86-0.96), respectively. In the late risk period (29-56 days), the IRRs were 0.96 (0.89-1.03), 0.93 (0.91-0.96), 0.96 (0.95-0.98), 1.00 (0.95-1.04), 0.96 (0.91-1.01), 1.00 (0.87-1.15), 1.01 (0.98-1.04), and 0.95 (0.90-1.01), respectively. COVID-19 vaccination did not increase the risk of incident RAO, RVO, anterior NIU, nonanterior NIU, NIS, ON, ION, or OMCNP during the postvaccination period.

Acute Appendicitis After COVID-19 Vaccines in Italy: A Self-Controlled Case Series Study.

Cases of appendicitis were identified in the pivotal randomized clinical trial on BNT162b2 mRNA vaccine and reported from coronavirus disease 2019 (COVID-19) vaccine pharmacovigilance systems. Three cohort studies and two self-controlled case series (SCCS) studies evaluating the association between mRNA vaccines and appendicitis reported discordant results. To address this uncertainty, the present study examines in a large population, with a SCCS design, the association between mRNA (BNT162b2 and mRNA-1273) and, for the first time, viral vector (ChAdOx1-S and Ad26.COV2-S) COVID-19 vaccines and acute appendicitis. The SCCS study design was used to evaluate the association between COVID-19 vaccination and subsequent onset of acute appendicitis. The study was based on record linkage of health archives through TheShinISS application, a statistical tool that locally processes data from regional health care databases according to ad hoc, study-tailored and common data model. The study population included all vaccinated subjects ≥ 12 years old between 27 December 2020 and 30 September 2021. The acute appendicitis was identified through discharge diagnoses of hospital admissions or emergency department visits. Incident cases were defined as those who experienced a first event of acute appendicitis in the study period, excluding subjects with a diagnosis of appendicitis in the previous 5 years. Exposure was defined as the first or second dose of BNT162b2, mRNA-1273 and ChAdOx1-S and the single dose of Ad26.COV2-S. The risk interval was defined as 42 days from the first or second vaccination dose and divided into pre-specified risk subperiods; the reference period was the observation time outside the risk interval. Relative incidences (RI) and 95% confidence intervals (95% CI) were estimated with the SCCS method 'modified for event-dependent exposures', through unbiased estimating equations. The seasonal component was considered as a time-dependent covariate. In the 42-day risk interval 1285 incident cases of acute appendicitis occurred: 727 cases after the first dose and 558 cases after the second dose. In the main analysis, no increased risks of acute appendicitis were observed in subjects vaccinated with BNT162b, mRNA-1273, ChAdOx1-S and Ad26.COV2-S. The subgroup analyses by sex showed an increased risk in the 14-27 day risk interval, in males after the first dose of mRNA-1273 (RI of 1.71; 95% CI 1.08-2.70, p = 0.02) and in females after the single dose of Ad26.COV2-S (RI of 4.40; 95% CI 1.29-15.01, p = 0.02). There was no evidence of association of BNT162b, ChAdOx1-S, mRNA-1273 and Ad26.COV2-S with acute appendicitis in the general population. The results of the subgroup analyses by sex needs to be considered with caution. The multiplicity issue cannot be excluded being these hypotheses two of several hypotheses tested. In addition, relevant literature on the biological mechanism of the disease and evidence of similar effects with other vaccines or with the same vaccines are still lacking to provide strong support for a conclusion that there is an harmful effect in males and females with mRNA-1273 and Ad26.COV2-S.

Thromboembolism after coronavirus disease 2019 vaccination in atrial fibrillation/flutter: a self-controlled case series study.

Concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines in patients with atrial fibrillation/flutter (AF/AFL) have arisen due to reports of thrombo-embolic events following COVID-19 vaccination in the general population. This study aimed to evaluate the risk of thrombo-embolic events after COVID-19 vaccination in patients with AF/AFL. This was a modified self-controlled case-series study using a comprehensive nationwide-linked database provided by the National Health Insurance Service in South Korea to calculate incidence rate ratios (IRRs) of thrombo-embolic events. The study population included individuals aged ≥12 years who were either vaccinated (e.g. one or two doses) or unvaccinated during the period from February to December 2021. The primary outcome was a composite of thrombo-embolic events, including ischaemic stroke, transient ischaemic attack, and systemic thromboembolism. The risk period was defined as 0-21 days following COVID-19 vaccination. The final analysis included 124 127 individuals with AF/AFL. The IRR of thrombo-embolic events within 21 days after COVID-19 vaccination, compared with that during the unexposed control period, was 0.93 [95% confidence interval (CI) 0.77-1.12]. No significant risk variations were noted by sex, age, or vaccine type. However, patients without anticoagulant therapy had an IRR of 1.88 (95% CI 1.39-2.54) following vaccination. In patients with AF/AFL, COVID-19 vaccination was generally not associated with an increased risk of thrombo-embolic events. However, careful individual risk assessment is required when advising vaccination for those not on oral anticoagulant, as these patients exhibited an increased risk of thrombo-embolic events post-vaccination.

Ischemic Stroke After Bivalent COVID-19 Vaccination: Self-Controlled Case Series Study.

The potential association between bivalent COVID-19 vaccination and ischemic stroke remains uncertain, despite several studies conducted thus far. This study aimed to evaluate the risk of ischemic stroke following bivalent COVID-19 vaccination during the 2022-2023 season. A self-controlled case series study was conducted among members aged 12 years and older who experienced ischemic stroke between September 1, 2022, and March 31, 2023, in a large health care system. Ischemic strokes were identified using International Classification of Diseases, Tenth Revision codes in emergency departments and inpatient settings. Exposures were Pfizer-BioNTech or Moderna bivalent COVID-19 vaccination. Risk intervals were prespecified as 1-21 days and 1-42 days after bivalent vaccination; all non-risk-interval person-time served as the control interval. The incidence of ischemic stroke was compared in the risk interval and control interval using conditional Poisson regression. We conducted overall and subgroup analyses by age, history of SARS-CoV-2 infection, and coadministration of influenza vaccine. When an elevated risk was detected, we performed a chart review of ischemic strokes and analyzed the risk of chart-confirmed ischemic stroke. With 4933 ischemic stroke events, we found no increased risk within the 21-day risk interval for the 2 vaccines and by subgroups. However, risk of ischemic stroke was elevated within the 42-day risk interval among individuals aged younger than 65 years with coadministration of Pfizer-BioNTech bivalent and influenza vaccines on the same day; the relative incidence (RI) was 2.13 (95% CI 1.01-4.46). Among those who also had a history of SARS-CoV-2 infection, the RI was 3.94 (95% CI 1.10-14.16). After chart review, the RIs were 2.34 (95% CI 0.97-5.65) and 4.27 (95% CI 0.97-18.85), respectively. Among individuals aged younger than 65 years who received Moderna bivalent vaccine and had a history of SARS-CoV-2 infection, the RI was 2.62 (95% CI 1.13-6.03) before chart review and 2.24 (95% CI 0.78-6.47) after chart review. Stratified analyses by sex did not show a significantly increased risk of ischemic stroke after bivalent vaccination. While the point estimate for the risk of chart-confirmed ischemic stroke was elevated in a risk interval of 1-42 days among individuals younger than 65 years with coadministration of Pfizer-BioNTech bivalent and influenza vaccines on the same day and among individuals younger than 65 years who received Moderna bivalent vaccine and had a history of SARS-CoV-2 infection, the risk was not statistically significant. The potential association between bivalent vaccination and ischemic stroke in the 1-42-day analysis warrants further investigation among individuals younger than 65 years with influenza vaccine coadministration and prior SARS-CoV-2 infection. Furthermore, the findings on ischemic stroke risk after bivalent COVID-19 vaccination underscore the need to evaluate monovalent COVID-19 vaccine safety during the 2023-2024 season.

Influenza Infection and Acute Myocardial Infarction

BackgroundAcute respiratory infections can trigger acute myocardial infarction. We aimed to quantify the association between laboratory-confirmed influenza infection and acute myocardial infarction, particularly in patients with and without known coronary artery disease.MethodsThis observational, registry-based, self-controlled case series study evaluated the association between laboratory-confirmed influenza infection and occurrence of acute myocardial infarction. Laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories across the Netherlands were linked to national mortality, hospitalization, medication, and administrative registries. Influenza infection was defined as a positive PCR test result. Acute myocardial infarction was defined as a registered diagnostic code for either acute myocardial infarction hospitalization or death. Using a self-controlled case series method, we then compared the incidence of acute myocardial infarction during the risk period (days 1 to 7 after influenza infection) versus the control period (1 year before and 51 weeks after the risk period).ResultsBetween 2008 and 2019, we identified 158,777 PCR tests for influenza in the study population; 26,221 were positive for influenza, constituting 23,405 unique influenza illness episodes. A total of 406 episodes were identified with acute myocardial infarction occurring within 1 year before and 1 year after confirmed influenza infection and were included in analysis. Twenty-five cases of acute myocardial infarction occurred during the risk period versus 394 during the control period. The adjusted relative incidence of acute myocardial infarction during the risk period compared with the control period was 6.16 (95% confidence interval [CI], 4.11 to 9.24). The relative incidence of acute myocardial infarction in individuals without prior hospitalization for coronary artery disease was 16.60 (95% CI, 10.45 to 26.37) compared with 1.43 (95% CI, 0.53 to 3.84) for those with prior admission for coronary artery disease.ConclusionsInfluenza infection was associated with an increased risk of acute myocardial infarction, especially in individuals without a prior hospitalization for coronary artery disease. (Funded by the Dutch Research Council [NWO].)

Relationship between proton pump inhibitor prescription and asthma exacerbation among adult patients: a self-controlled case series study.

Proton-pump inhibitors (PPI) are empirically used to treat asthma symptoms such as cough; however, the effectiveness of PPI on asthma exacerbation has not been well studied. We aimed to evaluate the relationship between PPI use and asthma exacerbation using a large administrative claims database in Japan. We conducted a self-controlled case series using the JMDC Claims Database (JMDC, Inc., Tokyo, Japan). The cases included adult patients with asthma who were prescribed PPI and experienced at least one outcome event between January 2015 and December 2019. The primary outcome was the composite outcome of hospital admissions and unscheduled outpatient clinic visits due to asthma exacerbation. We also conducted stratified analyses based on PPI generation, the presence of gastroesophageal reflux disease (GERD), asthma severity, and the number of allergic comorbidities. A total of 7379 eligible patients were included in the study. PPI prescription was associated with a decrease in the composite outcomes (incidence rate ratio, 0.90; 95% confidence interval, 0.87-0.93). However, PPI prescriptions did not affect the outcomes of hospital admissions (incidence rate ratio, 1.34; 95% confidence interval, 0.86-2.10). Stratified analyses based on PPI generation, the presence of GERD, asthma severity (except for severe asthma), and the number of allergic comorbidities yielded consistent results. PPI use was associated with a moderate decrease in asthma exacerbation, regardless of the patient profile. However, this effect was not as strong as the prevention of hospital admissions, and outcome events were not prevented in patients with severe asthma.

Self-controlled risk interval study of rotavirus vaccine safety: Findings and implications.

The self-controlled case series (SCCS) is often used to monitor vaccine safety. The evaluation of intussusception after the rotavirus vaccine is complicated because the baseline rate varies with age. Time-varying baseline risk adjustments with data from unexposed cohorts are utilised. Self-controlled risk interval (SCRI), with a shorter observation period, can also mitigate the problem by studying a control period close to the risk period. An Indian rotavirus vaccine has previously been studied using SCCS. The risk of intussusception in the high-risk windows (21 days after vaccination) was comparable to the background risk. The aim was to re-analyse data of an existing SCCS study using alternate statistical methods to examine vaccine safety. We examined the mean age of intussusception in the vaccinated and the unvaccinated. We performed an SCRI analysis of the surveillance data from the SCCS study, limiting the observation period to 180 days. We analysed the time-to-intussusception from the last vaccination. Finally, we performed an SCCS analysis, excluding unvaccinated cases from the analysis. We found that the mean age of intussusception was significantly lower in the vaccinated (205 days) compared to the unvaccinated (223 days) (p-value 0.0026). The Incident Risk Ratio (IRR) on SCRI analysis was 1.62 (95% CI 1.07-2.44). There were significantly more intussusceptions in the first 30 days after vaccination compared to the next 30-day window. (92 vs 63 p-value = 0.009). We found that excluding unvaccinated infants from the SCCS analysis demonstrated significantly increased risk for the risk period 1-21 days after the 3rd dose (IRR 2.47, 95% CI 1.70-3.59). The risks of intussusception were missed in traditional SCCS analysis using unvaccinated infants as controls. Traditional risk adjustments using data from unexposed cohorts in SCCS may not be appropriate for investigating the risk of intussusception where vaccination lowers the mean age of intussusception.

Association between influenza vaccination and one-year all-cause and cardiovascular mortality risk: A self-controlled case series and matched case-control study.

Debates surrounding the efficacy of influenza vaccination for survival benefits persist, and there is a lack of data regarding its duration of protection. A self-controlled case series (SCCS) and a 1:4 matched case-control study were conducted using the National Health Interview Survey (NHIS) and public-use mortality data from 2005 to 2018 in the United States. The SCCS study identified participants who received influenza vaccination within 12 months before the survey and subsequently died within 1 year of postvaccination. The matched case-control study paired participants who died during the influenza season at the time of survey with four survivors. Among 1167 participants in the SCCS study, there was a 46% reduction in all-cause mortality and a 43% reduction in cardiovascular mortality within 29-196 days of postvaccination. The greatest protection was observed during days 29-56 (all-cause mortality: RI: 0.19; 95% CI: 0.12-0.29; cardiovascular mortality: RI: 0.28; 95% CI: 0.14-0.56). Among 626 cases and 2504 controls included in the matched case-control study, influenza vaccination was associated with a reduction in all-cause mortality (OR: 0.74, 95% CI: 0.60-0.92) and cardiovascular mortality (OR: 0.64, 95% CI: 0.44-0.93) during the influenza season. This study highlights the importance of influenza vaccination in reducing the risks of all-cause and cardiovascular mortality, with effects lasting for approximately 6 months.

Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England

The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1–42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0–23) hospitalisations with epilepsy and 4 (95%CI 0–6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.

Autologous PRP therapy for thin endometrium: A self-controlled case series study across menstrual cycles

ObjectivesThin endometrium (TE) compromises endometrial receptivity, often leading to implantation failure and lower clinical pregnancy rates. As autologous platelet-rich plasma (PRP) emerges as a potential remedy, the present study focused on its therapeutic effects on TE in infertile women who underwent frozen embryo transfer. Study designPatients with TE who underwent frozen embryo transfer treatment in our hospital were included. To diminish individual variability, a self-controlled series approach was used. Two menstrual study cycles were arranged for each participant before the actual embryo transfer cycle; PRP treatment was conducted in the second cycle. Key metrics analyzed included endometrial thickness and the expression of specific endometrial biomarkers including HOXA-10, Ki67, and αvβ3 integrin. Transvaginal ultrasound was employed to measure endometrial thickness on Days 11 and 14, and an endometrial biopsy was conducted on progesterone Day 5 of the first two cycles. Pregnancy outcomes were observed after the embryo transfer cycle. ResultsPRP treatment significantly increased the median endometrial thickness, from 5.8 mm to 6.5 mm (P = 0.0066). Additionally, PRP treatment resulted in a statistically significant increase in the H-score for all endometrial markers. Importantly, during the subsequent embryo transfer cycle with PRP treatment, two patients successfully achieved pregnancies, both culminating in live births. ConclusionsThese findings emphasize the potential of PRP in improving endometrial conditions, especially for individuals grappling with thin endometrium issues, as underscored by this self-comparison methodology.

Pfizer COVID19 vaccine is not associated with acute cardiovascular events excluding myocarditis– a national self-controlled case series study

BackgroundDespite publications assuring no increased risk for acute cardiovascular events (excluding myocarditis) and sudden death following administration of COVID19 vaccines, these issues still stir much public ado. We assessed the risk for acute cardiovascular events that require hospitalization (excluding myocarditis) and for mortality in the short-term following administration of the second dose of the Pfizer COVID19 vaccine in Israel.MethodsUsing a self-controlled case series (SCCS) study design and national databases, all second-dose vaccinees, who had not been diagnosed with COVID19 and who had an acute cardiovascular event (acute myocardial infarction/acute stroke/acute thromboembolic event) that required hospitalization in the 60 days following vaccine administration between Jan 11th, 2021 and Oct 31st 2021, were included. A similar analysis was carried out for mortality. The first 30 days following vaccination were defined as risk period while the next 30 days were defined as control period. The probability for an event between these periods was compared using a conditional logistic regression model, accounting for sex, age group, background morbidity and seasonal risk.ResultsOut of 5,700,112 second dose vaccinees, 4,163 had an acute cardiovascular event in the 60 days following vaccine administration. Following exclusion of 106 due to technical considerations, 1,979 events occurred during the risk period and 2,078 during the control period: Odds ratio, OR = 0.95, 95% confidence interval, CI 0.90–1.01, p = 0.12. Adjusted OR was similar (OR = 0.88, 95%CI 0.72–1.08). Stratifying by age showed no increased risk in any age group. Mortality assessment indicated low number of events in both periods. These results were consistent in sensitivity analyses.ConclusionsThere was no increased risk for acute cardiovascular events (excluding myocarditis) in the risk period compared to the control period following administration of the second dose of Pfizer COVID19 vaccine. Mortality data raised no concerns either, but may have been biased.

Antibiotic Prophylaxis and Infective Endocarditis Incidence Following Invasive Dental Procedures

The association between antibiotic prophylaxis and infective endocarditis after invasive dental procedures is still unclear. Indications for antibiotic prophylaxis were restricted by guidelines beginning in 2007. To systematically review and analyze existing evidence on the association between antibiotic prophylaxis and infective endocarditis following invasive dental procedures. PubMed, Cochrane-CENTRAL, Scopus, Web of Science, Proquest, Embase, Dentistry and Oral Sciences Source, and ClinicalTrials.gov were systematically searched from inception to May 2023. Studies on the association between antibiotic prophylaxis and infective endocarditis following invasive dental procedures or time-trend analyses of infective endocarditis incidence before and after current antibiotic prophylaxis guidelines were included. Study quality was evaluated using structured tools. Data were extracted by independent observers. A pooled relative risk (RR) of developing infective endocarditis following invasive dental procedures in individuals who were receiving antibiotic prophylaxis vs those who were not was computed by random-effects meta-analysis. The outcome of interest was the incidence of infective endocarditis following invasive dental procedures in relation to antibiotic prophylaxis. Of 11 217 records identified, 30 were included (1 152 345 infective endocarditis cases). Of them, 8 (including 12 substudies) were either case-control/crossover or cohort studies or self-controlled case series, while 22 were time-trend studies; all were of good quality. Eight of the 12 substudies with case-control/crossover, cohort, or self-controlled case series designs performed a formal statistical analysis; 5 supported a protective role of antibiotic prophylaxis, especially among individuals at high risk, while 3 did not. By meta-analysis, antibiotic prophylaxis was associated with a significantly lower risk of infective endocarditis after invasive dental procedures in individuals at high risk (pooled RR, 0.41; 95% CI, 0.29-0.57; P for heterogeneity = .51; I2, 0%). Nineteen of the 22 time-trend studies performed a formal pre-post statistical analysis; 9 found no significant changes in infective endocarditis incidence, 7 demonstrated a significant increase for the overall population or subpopulations (individuals at high and moderate risk, streptococcus-infective endocarditis, and viridans group streptococci-infective endocarditis), whereas 3 found a significant decrease for the overall population and among oral streptococcus-infective endocarditis. While results from time-trend studies were inconsistent, data from case-control/crossover, cohort, and self-controlled case series studies showed that use of antibiotic prophylaxis is associated with reduced risk of infective endocarditis following invasive dental procedures in individuals at high risk, while no association was proven for those at low/unknown risk, thereby supporting current American Heart Association and European Society of Cardiology recommendations. Currently, there is insufficient data to support any benefit of antibiotic prophylaxis in individuals at moderate risk.

A self-controlled case series study to measure the risk of SARS-CoV-2 infection associated with attendance at sporting and cultural events: the UK Events Research Programme events

BackgroundIn 2021, whilst societies were emerging from major social restrictions during the SARS-CoV-2 pandemic, the UK government instigated an Events Research Programme to examine the risk of COVID-19 transmission from attendance at cultural events and explore ways to enable people to attend a range of events whilst minimising risk of transmission. We aimed to measure any impact on risk of COVID-19 transmission from attendance at events held at or close to commercially viable capacity using routinely collected data.MethodsData were obtained on attendees at Phase 3 Events Research Programme events, for which some infection risk mitigation measures were in place (i.e. evidence of vaccination or a negative lateral flow test). Attendance data were linked with COVID-19 test result data from the UK Test and Trace system. Using a self-controlled case series design, we measured the within person incidence rate ratio for testing positive for COVID-19, comparing the rate in days 3 to 9 following event attendance (high risk period) with days 1 and 2 and 10–16 (baseline period). Rate ratios were adjusted for estimates of underlying regional COVID-19 prevalence to account for population level fluctuations in infection risk, and events were grouped into broadly similar types.ResultsFrom attendance data available for 188,851 attendees, 3357 people tested positive for COVID-19 during the observation period. After accounting for total testing trends over the period, incidence rate ratios and 95% confidence intervals for positive tests were 1.16 (0.53–2.57) for indoor seated events, 1.12 (0.95–1.30) for mainly outdoor seated events, 0.65 (0.51–0.83) for mainly outdoor partially seated events, and 1.70 (1.52–1.89) for mainly outdoor unseated multi-day events.ConclusionsFor the majority of event types studied in the third phase of the UK Events Research Programme, we found no evidence of an increased risk of COVID-19 transmission associated with event attendance. However, we found a 70% increased risk of infection associated with attendance at mainly outdoor unseated multi-day events. We have also demonstrated a novel use for self-controlled case series methodology in monitoring infection risk associated with event attendance.

Tigecycline-associated hypofibrinogenemia: A single center, retrospective, controlled study

BackgroundTigecycline-associated hypofibrinogenemia has been reported as an important adverse effect in recent years, but controlled studies minimizing confounding factors are needed. The objective of our study was to assess changes in fibrinogen levels in patients for hospitalization, comparing two antibiotic episodes (tigecycline and other) within the same patients. MethodsThe retrospective, self-controlled case series study was conducted at our University Hospitals. The study compared the change in fibrinogen levels during the patient's hospitalization for tigecycline (TigePer) and another antibiotic period (OtherPer). In addition, bleeding events, bleeding risk (determined by the IMPROVE bleeding risk score), as well as 15- and 30-day mortality rates between TigePer and OtherPer were compared. ResultsThe study enrolled 50 patients with 100 episodes of antibiotic treatment. The median age (interquartile range) of the patients was 68.5 (21.5) years, and 38 % were female. As compared to OtherPer, TigePer had a statistically significant reduction in fibrinogen levels (p < 0.001), with a hypofibrinogenemia rate of 40 % in TigePer as compared to 2 % in OtherPer (p < 0.001). TigePer demonstrated a significantly higher 15-day mortality rate (p = 0.006). No significant differences were observed between the two periods in terms of bleeding risk, rate of bleeding events, and 30-day mortality rate (p > 0.05). ConclusionHypofibrinogenemia and other coagulopathies, without associated bleeding events, are more frequently observed in patients receiving tigecycline. Therefore, it is crucial for clinicians to monitor fibrinogen levels during tigecycline use.

Estimation and reduction of bias in self-controlled case series with non-rare event dependent outcomes and heterogeneous populations.

The self-controlled case series (SCCS) is a commonly adopted study design in the assessment of vaccine and drug safety. Recurrent event data collected from SCCS studies are typically analyzed using the conditional Poisson model which assumes event times are independent within-cases. This assumption is violated in the presence of event dependence, where the occurrence of an event influences the probability and timing of subsequent events. When event dependence is suspected in an SCCS study, the standard recommendation is to include only the first event from each case in the analysis. However, first event analysis can still yield biased estimates of the exposure relative incidence if the outcome event is not rare. We first demonstrate that the bias in first event analysis can be even higher than previously assumed when subpopulations with different baseline incidence rates are present and describe an improved method for estimating this bias. Subsequently, we propose a novel partitioned analysis method and demonstrate how it can reduce this bias. We provide a recommendation to guide the number of partitions to use with the partitioned analysis, illustrate this recommendation with an example SCCS study of the association between beta-blockers and acute myocardial infarction, and compare the partitioned analysis against other SCCS analysis methods by simulation.