Risk for Myocardial Infarction, Stroke, and Pulmonary Embolism Following COVID-19 Vaccines in Adults Younger Than 75 Years in France.

BACKGROUND: The BNT162b2 (Pfizer-BioNTech) vaccine has been shown to be safe with regard to risk for severe cardiovascular events (such as myocardial infarction [MI], pulmonary embolism [PE], and stroke) in persons aged 75 years or older. Less is known about the safety of other COVID-19 vaccines or outcomes in younger populations. OBJECTIVE: To assess short-term risk for severe cardiovascular events (excluding myocarditis and pericarditis) after COVID-19 vaccination in France's 46.5 million adults younger than 75 years. DESIGN: Self-controlled case series method adapted to event-dependent exposure and high event-related mortality. SETTING: France, 27 December 2020 to 20 July 2021. PATIENTS: All adults younger than 75 years hospitalized for PE, acute MI, hemorrhagic stroke, or ischemic stroke (n = 73 325 total events). MEASUREMENTS: Linkage between the French National Health Data System and COVID-19 vaccine databases enabled identification of hospitalizations for cardiovascular events (MI, PE, or stroke) and receipt of a first or second dose of the Pfizer-BioNTech, mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine. The relative incidence (RI) of each cardiovascular event was estimated in the 3 weeks after vaccination compared with other periods, with adjustment for temporality (7-day periods). RESULTS: No association was found between the Pfizer-BioNTech or Moderna vaccine and severe cardiovascular events. The first dose of the Oxford-AstraZeneca vaccine was associated with acute MI and PE in the second week after vaccination (RI, 1.29 [95% CI, 1.11 to 1.51] and 1.41 [CI, 1.13 to 1.75], respectively). An association with MI in the second week after a single dose of the Janssen vaccine could not be ruled out (RI, 1.75 [CI, 1.16 to 2.62]). LIMITATIONS: It was not possible to ascertain the relative timing of injection and cardiovascular events on the day of vaccination. Outpatient deaths related to cardiovascular events were not included. CONCLUSION: In persons aged 18 to 74 years, adenoviral-based vaccines may be associated with increased incidence of MI and PE. No association between mRNA-based vaccines and the cardiovascular events studied was observed. PRIMARY FUNDING SOURCE: None.

Nanocatalyzed Hydrogen Isotope Exchange.

Recently, hydrogen isotope exchange (HIE) reactions have experienced impressive development due to the growing importance of isotope containing compounds in various fields including materials and life sciences, in addition to their classical use for mechanistic studies in chemistry and biology. Tritium-labeled compounds are also of crucial interest to study the in vivo fate of a bioactive substance or in radioligand binding assays. Over the past few years, deuterium-labeled drugs have been extensively studied for the improvement of ADME (absorption, distribution, metabolism, excretion) properties of existing bioactive molecules as a consequence of the primary kinetic isotope effect. Furthermore, in the emergent "omic" fields, the need for new stable isotopically labeled internal standards (SILS) for quantitative GC- or LC-MS analyses is increasing. Because of their numerous applications, the development of powerful synthetic methods to access deuterated and tritiated molecules with either high isotope incorporation and/or selectivities is of paramount importance.HIE reactions allow a late-stage incorporation of hydrogen isotopes in a single synthetic step, thus representing an advantageous alternative to conventional multistep synthesis approaches which are time- and resource-consuming. Moreover, HIE reactions can be considered as the most fundamental C-H functionalization processes and are therefore of great interest for the chemists' community. Depending on the purpose, HIE reactions must either be highly regioselective or allow a maximal incorporation of hydrogen isotopes, sometimes both. In this context, metal-catalyzed HIE reactions are generally performed using either homogeneous or heterogeneous catalysis which may have considerable drawbacks including an insufficient isotope incorporation and a lack of chemo- and/or regioselectivity, respectively.Over the past 6 years, we have shown that nanocatalysis can be considered as a powerful tool to access complex labeled molecules (e.g., pharmaceuticals, peptides and oligonucleotides) via regio- and chemoselective or even enantiospecific labeling processes occurring at the surface of metallic nanoclusters (Ru or Ir). Numerous heterocyclic (both saturated and unsaturated) and acyclic scaffolds have been labeled with an impressive functional group tolerance, and highly deuterated compounds or high molar activity tritiated drugs have been obtained. An insight into mechanisms has also been provided by theoretical calculations to explain the regioselectivities of the isotope incorporation. Our studies have suggested that undisclosed key intermediates, including 4- and 5-membered dimetallacycles, account for the particular regioselectivities observed during the process, in contrast to the 5- or 6-membered metallacycle key intermediates usually encountered in homogeneous catalysis. These findings together with the important number of available coordination sites explain the compelling reactivity of metal nanoparticles, in between homogeneous and heterogeneous catalysis. They represent innovative tools combining the advantages of both methods for the isotopic labeling and activation of C-H bonds of complex molecules.

A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.

We propose a modified self-controlled case series (SCCS) method to handle both event-dependent exposures and high event-related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID-19 vaccines. Event-dependence of vaccinations, and high event-related mortality, are likely to arise in other SCCS studies of COVID-19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death.

Tuning the Reactivity of a Heterogeneous Catalyst using N-Heterocyclic Carbene Ligands for C-H Activation Reactions.

We report the dramatic impact of the addition of N-heterocyclic carbenes (NHCs) on the reactivity and selectivity of heterogeneous Ru catalysts in the context of C-H activation reactions. Using a simple and robust method, we prepared a series of new air-stable catalysts starting from commercially available Ru on carbon (Ru/C) and differently substituted NHCs. Associated with C-H deuteration processes, depending on Ru/C-NHC ratios, the chemical outcome can be controlled to a large extent. Indeed, tuning the reactivity of the Ru catalyst with NHC enabled: 1) increased chemoselectivity and the regioselectivity for the deuteration of alcohols in organic media; 2) the synthesis of fragile pharmaceutically relevant deuterated heterocycles (azine, purine) that are otherwise completely reduced using unmodified commercial catalysts; 3) the discovery of a novel reactivity for such heterogeneous Ru catalysts, namely the selective C-1 deuteration of aldehydes.

Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals.

Radiolabelling is fundamental in drug discovery and development as it is mandatory for preclinical ADME studies and late-stage human clinical trials. Herein, a general, effective, and easy to implement method for the multiple site incorporation of deuterium and tritium atoms using the commercially available and air-stable iridium precatalyst [Ir(COD)(OMe)]2 is described. A large scope of pharmaceutically relevant substructures can be labelled using this method including pyridine, pyrazine, indole, carbazole, aniline, oxa-/thia-zoles, thiophene, but also electron-rich phenyl groups. The high functional group tolerance of the reaction is highlighted by the labelling of a wide range of complex pharmaceuticals, containing notably halogen or sulfur atoms and nitrile groups. The multiple site hydrogen isotope incorporation has been explained by the in situ formation of complementary catalytically active species: monometallic iridium complexes and iridium nanoparticles.

Association of Hysteroscopic vs Laparoscopic Sterilization With Procedural, Gynecological, and Medical Outcomes.

Importance: Safety of hysteroscopic sterilization has been recently questioned following reports of general symptoms such as allergy, tiredness, and depression in addition to associated gynecological results such as pelvic pain, perforation of fallopian tubes or uterus, and unwanted pregnancy. Objective: To compare the risk of reported adverse events between hysteroscopic and laparoscopic sterilization. Design, Setting, and Participants: French nationwide cohort study using the national hospital discharge database linked to the health insurance claims database. Women aged 30 to 54 years receiving a first hysteroscopic or laparoscopic sterilization between 2010 and 2014 were included and were followed up through December 2015. Exposures: Hysteroscopic sterilization vs laparoscopic sterilization. Main Outcomes and Measures: Risks of procedural complications (surgical and medical) and of gynecological (sterilization failure that includes salpingectomy, second sterilization procedure, or pregnancy; pregnancy; reoperation) and medical outcomes (all types of allergy; autoimmune diseases; thyroid disorder; use of analgesics, antimigraines, antidepressants, benzodiazepines; outpatient visits; sickness absence; suicide attempts; death) that occurred within 1 and 3 years after sterilization were compared using inverse probability of treatment-weighted Cox models. Results: Of the 105 357 women included (95.5% of eligible participants; mean age, 41.3 years [SD, 3.7 years]), 71 303 (67.7% ) underwent hysteroscopic sterilization, and 34 054 (32.3%) underwent laparoscopic sterilization. During the hospitalization for sterilization, risk of surgical complications for hysteroscopic sterilization was lower: 0.13% for hysteroscopic sterilization vs 0.78% for laparoscopic sterilization (adjusted risk difference [RD], -0.64; 95% CI, -0.67 to -0.60) and was lower for medical complications: 0.06% vs 0.11% (adjusted RD, -0.05; 95% CI, -0.08 to -0.01). During the first year after sterilization, 4.83% of women who underwent hysteroscopic sterilization had a higher risk of sterilization failure than the 0.69% who underwent laparoscopic sterilization (adjusted hazard ratio [HR], 7.11; 95% CI, 5.92 to 8.54; adjusted RD, 4.23 per 100 person-years; 95% CI, 3.40 to 5.22). Additionally, 5.65% of women who underwent hysteroscopic sterilization required gynecological reoperation vs 1.76% of women who underwent laparoscopic sterilization (adjusted HR, 3.26; 95% CI, 2.90 to 3.67; adjusted RD, 4.63 per 100 person-years; 95% CI, 3.38 to 4.75); these differences persisted after 3 years, although attenuated. Hysteroscopic sterilization was associated with a lower risk of pregnancy within the first year of the procedure but was not significantly associated with a difference in risk of pregnancy by the third year (adjusted HR, 1.04; 95% CI, 0.83-1.30; adjusted RD, 0.01 per 100 person-years; 95% CI, -0.04 to 0.07). Risks of medical outcomes were not significantly increased with hysteroscopic sterilization compared with laparoscopic sterilization. Conclusions and Relevance: Among women undergoing first sterilization, the use of hysteroscopic sterilization was significantly associated with higher risk of gynecological complications over 1 year and over 3 years than was laparoscopic sterilization. Risk of medical outcomes was not significantly increased over 1 year or over 3 years. These findings do not support increased medical risks associated with hysteroscopic sterilization.

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Benzodiazepine, psychotropic medication, and dementia: A population-based cohort study.

INTRODUCTION: Benzodiazepine use has been associated with increased risk of dementia. However, it remains unclear whether the risk relates to short or long half-life benzodiazepines and whether it extends to other psychotropic drugs. METHODS: Prospective cohort study among 8240 individuals ≥65, interviewed on medication use. Incident dementia confirmed by an end point committee after a multistep procedure. RESULTS: During a mean of 8 years of follow-up, 830 incident dementia cases were observed. Users of benzodiazepines at baseline had a 10% increased risk of dementia (adjusted hazard ratio [HR], 1.10; 95% confidence interval, 0.90-1.34). However, long half-life (>20 hours) benzodiazepine users had a marked increased risk of dementia (HR = 1.62; 1.11-2.37) compared with short half-life users (HR = 1.05; 0.85-1.30). Users of psychotropics had an increased risk of dementia (HR = 1.47; 1.16-1.86). DISCUSSION: Results of this large, prospective study show increased risk of dementia for long half-life benzodiazepine and psychotropic use.

Sleep complaints and metabolic syndrome in an elderly population: the Three-City Study.

OBJECTIVES: To assess whether sleep complaints (rather than clinically defined sleep disturbances) were associated with the metabolic syndrome (MetS) and each of its components in an elderly population. METHODS: Cross-sectional analyses of data from the French Three City Study, a large multicenter cohort of elderly community-dwellers. PARTICIPANTS: 6,354 participants (56.4% women, median age 73; range: 65-97 years). MEASUREMENTS: Frequency of insomnia complaints (difficulty in initiating sleep, difficulty in maintaining sleep [DMS], and early morning awakening) and excessive daytime sleepiness (EDS) were self-reported. MetS was assessed using National Cholesterol Education program Adult Treatment Panel III criteria. RESULTS: A total of 977 participants had MetS. After adjustment for a large range of potential confounders, we report an association between the number of insomnia complaints and MetS. Among insomnia complaints only DMS was consistently associated with MetS (OR: 1.23, 95% CI: 1.06 to 1.43). Our results showed that EDS independently increased the risk of MetS (OR: 1.46, 95% CI: 1.18 to 1.81 for "frequently"; OR: 1.99, 95% CI: 1.49 to 1.67 for "often"). The EDS-MetS association was independent of past-history of cardiovascular disease, insomnia complaints, and obesity and loud snoring. CONCLUSION: We report significant independent associations between frequent sleep complaints (EDS and to a lesser extent DMS) and MetS in the elderly with potential implications in terms of management and cardiovascular prevention in general geriatric practice. Prospective studies are required to clarify the direction of the association between sleep complaints and MetS.

Risk factors for COVID-19 hospitalisation after booster vaccination during the Omicron period: A French nationwide cohort study.

BACKGROUND: In spite of major effectiveness, a residual risk after COVID-19 primary vaccination was identified, in particular, for vulnerable individuals of advanced age or with comorbidities. Less is known about the Omicron period in people protected by a booster dose. We aimed to identify the characteristics associated with severe COVID-19 during the Omicron period in a population that had received a booster dose in France and to compare differences with the previous periods of the pandemic. METHODS: This study was carried out using the French national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS). Individuals aged 12 years or over who received at least one booster dose were identified. Associations between socio-demographic and clinical characteristics and the risk of COVID-19 hospitalisation occurring at least 14 days after receiving a third dose of vaccine during the period of Omicron predominance, i.e., from 1 January 2022 to 10 November 2022, were assessed using Cox proportional hazard models adjusted for age, sex, time since booster dose and vaccination schedule. Analyses were performed overall and by sub-period of circulation of the strains BA.1, BA.2, and BA.4/BA.5, defined as periods where the main sub-variant accounted for more than 80 % of genotyped samples. FINDINGS: In total, 35,640,387 individuals received a booster dose (mean follow-up of 291 days) and 73,989 were hospitalised for COVID-19 during the total period. Older age (aHR 20.5 95 % CI [19.6-21.5] for 90 years of age or older versus 45-54 years of age), being male (aHR 1.52 [1.50-1.55]), and social deprivation (aHR 1.33 [1.30-1.37] for the most deprived areas versus the least deprived) were associated with an increased risk of hospitalisation for COVID-19. Most of the chronic diseases considered were also positively associated with a residual risk, in particular, cystic fibrosis (aHR 9.83 [7.68-12.56]), active lung cancer (aHR 3.26 [3.06-3.47]), chronic dialysis (aHR 3.79 [3.49-4.11]), psychological and neurodegenerative diseases (more markedly than during the periods of circulation of the alpha and delta variants), and organ transplantation. The use of immunosuppressants was also associated with an increased risk (aHR 2.24 [2.14-2.35], including oral corticosteroids aHR (2.58 [2.50-2.67]). CONCLUSION: Despite an effective booster and a generally less virulent circulating variant, a residual risk of severe COVID-19 still exists in vulnerable populations, especially those with neurological disorders.

A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis.

BACKGROUND: Venous Thrombosis (VT) is a common multifactorial disease with an estimated heritability between 35% and 60%. Known genetic polymorphisms identified so far only explain ~5% of the genetic variance of the disease. This study was aimed to investigate whether pair-wise interactions between common single nucleotide polymorphisms (SNPs) could exist and modulate the risk of VT. METHODS: A genome-wide SNP x SNP interaction analysis on VT risk was conducted in a French case-control study and the most significant findings were tested for replication in a second independent French case-control sample. The results obtained in the two studies totaling 1,953 cases and 2,338 healthy subjects were combined into a meta-analysis. RESULTS: The smallest observed p-value for interaction was p = 6.00 10(-11) but it did not pass the Bonferroni significance threshold of 1.69 10(-12) correcting for the number of investigated interactions that was 2.96 10(10). Among the 37 suggestive pair-wise interactions with p-value less than 10(-8), one was further shown to involve two SNPs, rs9804128 (IGFS21 locus) and rs4784379 (IRX3 locus) that demonstrated significant interactive effects (p = 4.83 10(-5)) on the variability of plasma Factor VIII levels, a quantitative biomarker of VT risk, in a sample of 1,091 VT patients. CONCLUSION: This study, the first genome-wide SNP interaction analysis conducted so far on VT risk, suggests that common SNPs are unlikely exerting strong interactive effects on the risk of disease.

KNG1 Ile581Thr and susceptibility to venous thrombosis.

Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P = .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P = .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT.

Trends in recognition and treatment of dementia in france analysis of the 2004 to 2010 database of the national health insurance plan.

Dementia is considered as underdiagnosed. We examined whether the proportion of persons aged 65 years and older who had been diagnosed as demented has changed over a 7-year period. The study population was constituted by a cohort of about 70,000 persons who were representative of the French elderly covered by the national health care insurance plan. Data about all health care consumptions were extracted from the national insurance database. Patients using an antidementia drug, having a special dementia-related coverage status, or both were identified. Annual age-standardized and sex-standardized proportions of recognized dementia cases were estimated. Between 2004 and 2010, the overall standardized proportion of persons recognized as having dementia increased slightly but significantly (P<0.004) from 3.68% to 4.20%. The proportion of persons recognized as demented increased strongly with age. In 2010, it increased from 1.44% at age 70-74 to 10% at age more than 90 in men and from 1.30% to 17.0% in women. The proportion of cholinesterase inhibitor users decreased after the age of 85 years, whereas memantine use continued to increase. Our study suggested that, in 2010, >75% of the demented persons had been recognized and received pharmacological or/and nonpharmacological therapies for dementia.

Risk of Guillain-Barré Syndrome Following COVID-19 Vaccines: A Nationwide Self-Controlled Case Series Study.

BACKGROUND AND OBJECTIVES: Guillain-Barré syndrome (GBS) has been inconsistently associated with some coronavirus disease 2019 (COVID-19) vaccines. We aimed to quantify the risk of GBS according to the type of COVID-19 vaccine in a large population. METHODS: Using the French National Health Data System linked to the COVID-19 vaccine database, we analyzed all individuals aged 12 years or older admitted for GBS from December 27, 2020, to May 20, 2022. We estimated the relative incidence (RI) of GBS within 1-42 days after vaccination up to the first booster dose compared with baseline periods using a self-controlled case series design. We then derived the number of cases attributable to the vaccination. Analyses were adjusted for the period and stratified by age group, sex, and for the presence of severe acute respiratory syndrome coronavirus 2 or common acute infections. RESULTS: Of 58,530,770 people aged 12 years or older, 88.8% received at least 1 COVID-19 vaccine dose and 2,229 were hospitalized for GBS during the study period. Patients had a median age of 57 years, and 60% were male patients. The RI of GBS between 1-42 days was 2.5 (95% CI 1.8-3.6) for the first dose of ChAdOx1-S and 2.4 (95% CI 1.2-5.0) for the unique dose of Ad26.COV2.S vaccine. We estimated 6.5 attributable GBS cases per million persons having received a first dose of ChAdOx1-S and 5.7 cases per million for the Ad26.COV2.S vaccine. Except for the age group of 12-49 years after the second dose of the messenger RNA (mRNA)-1273 vaccine (RI 2.6, 95% CI 1.2-5.5), none of the RI estimates were found significantly increased for the mRNA vaccines. DISCUSSION: In summary, we found increased risks of GBS after the first administration of ChAdOx1-S and Ad26.COV2.S vaccines. In this comprehensive assessment at the French population level, there was no statistically significant increase in the risk of GBS after the administration of mRNA vaccines. This is reassuring in the context of the ongoing and future use of mRNA-based booster vaccination.

Intravitreal anti-VEGF use in France: a cross-sectional and longitudinal Nationwide observational study.

PURPOSE: To describe the sociodemographic, medical and management characteristics of patients using intravitreal (IVT) anti-vascular endothelial growth factors (VEGF) in France. METHODS: An observational study was conducted in patients treated with IVT ranibizumab or aflibercept, aged 18 years or older using the French National Health Insurance Databases covering 99% of the French population. Patients currently treated in 2018 were included in a cross-sectional approach to describe treatment history over the previous 6 years. Patients newly treated between 2014 and 2018 were included in a longitudinal approach to describe treatment management during up to 6 years of follow-up. Sociodemographic characteristics and medical history were described in both populations. The analyses were performed at the patient level, as no distinction between the eyes could be made. RESULTS: A total of 224 775 current users of IVT anti-VEGF in 2018 (mean age 78.1 ± 11.3 years, 60% female) and 330 969 new users between 2014 and 2018 (mean age 75.9 ± 12.0 years, 59% female) were included. In both populations cardiovascular comorbidities or risk factors were frequent and the main treatment indications were age-related macular degeneration and diabetic macular oedema. Among current users of IVT anti-VEGF in 2018, the mean number of years receiving a treatment was 2.9 ± 2.0 years, with a mean of 13.7 ± 11.8 dispensations. In the longitudinal approach, a 26% increase in IVT anti-VEGF initiation was observed between 2014 and 2018. For new users, the mean number of years receiving a treatment was 1.6 ± 1.6 and 67% had at least three dispensations within the first three months. A treatment interruption was observed for 83% of new users and occurred on average of 6.1 ± 8.1 months after initiation. The mean number of dispensations was 4.8 ± 2.8 in the first year and 2.2 ± 2.9 in the second year. The mean number of eye monitoring examinations was 6.5 ± 4.7 in the first year and 4.6 ± 4.4 in the second year. CONCLUSION: This study described the real-world conditions of IVT anti-VEGF dispensing at the entire French population scale. Less frequent dispensations and surveillance examinations were observed than in monthly schemes applied in registration trials for IVT anti-VEGF. These results may indicate a lack of systematic monitoring associated with fewer injections and/or clinicians' preference for more flexible and personalized injection schemes than those originally recommended.

Risk of Myocardial Infarction, Stroke, or Death in New Users of Intravitreal Aflibercept Versus Ranibizumab: A Nationwide Cohort Study.

INTRODUCTION: The risk of thromboembolic events or death in patients treated with intravitreal anti-vascular endothelial growth factor (IVT anti-VEGF) is poorly described on a large scale and by molecule. This study aimed to assess the risk of myocardial infarction (MI), stroke, or death in new users of IVT aflibercept versus ranibizumab in real-world practice. METHODS: A nationwide cohort study using the French National Health Insurance databases covering 99% of the French population was conducted in patients aged 18 years or older who initiated IVT therapy with ranibizumab or aflibercept between 2014 and 2018. Patients were followed for up to 6 years until December 31, 2019. The risks of MI, stroke, and death were compared in new aflibercept versus ranibizumab users using Kaplan-Meier and multivariate Cox proportional hazards models adjusted on sociodemographic characteristics and cardiovascular disease or risk factors. Subgroup analyses were performed according to history of ischemic heart disease or stroke, diabetes, indication for treatment, sex, age, and number of IVT anti-VEGF injections. RESULTS: When compared to new users of ranibizumab (n = 174,794, mean age 76.0 ± 11.9 years, 59.2% female), new users of aflibercept (n = 76,242, mean age 76.6 ± 11.2 years, 59.2% female) did not have an increased risk of MI (n = 1523 incident MI, adjusted hazard ratio [aHR] 1.00; 95% CI 0.89-1.11), stroke (n = 2306 incident strokes, aHR 1.03; 95% CI 0.95-1.13), or death (n = 4135 deaths, aHR 0.98; 95% CI 0.92-1.05). However, a small but non-statistically significant increase in the risk of stroke was observed in new users of aflibercept versus ranibizumab among patients with diabetes (aHR 1.15; 95% CI 0.98-1.35), particularly those with diabetic macular edema (aHR 1.20; 95% CI 1.00-1.44). The remaining subgroup analyses did not change the results. CONCLUSION: Aflibercept and ranibizumab appear to have similar safety profiles with respect to the risk of MI, stroke, or death under real-world conditions of use.

Age and sex-specific risks of myocarditis and pericarditis following Covid-19 messenger RNA vaccines.

Cases of myocarditis and pericarditis have been reported following the receipt of Covid-19 mRNA vaccines. As vaccination campaigns are still to be extended, we aimed to provide a comprehensive assessment of the association, by vaccine and across sex and age groups. Using nationwide hospital discharge and vaccine data, we analysed all 1612 cases of myocarditis and 1613 cases of pericarditis that occurred in France in the period from May 12, 2021 to October 31, 2021. We perform matched case-control studies and find increased risks of myocarditis and pericarditis during the first week following vaccination, and particularly after the second dose, with adjusted odds ratios of myocarditis of 8.1 (95% confidence interval [CI], 6.7 to 9.9) for the BNT162b2 and 30 (95% CI, 21 to 43) for the mRNA-1273 vaccine. The largest associations are observed for myocarditis following mRNA-1273 vaccination in persons aged 18 to 24 years. Estimates of excess cases attributable to vaccination also reveal a substantial burden of both myocarditis and pericarditis across other age groups and in both males and females.

Association of Statins for Primary Prevention of Cardiovascular Diseases With Hospitalization for COVID-19: A Nationwide Matched Population-Based Cohort Study.

Background There is little evidence on the relationship between statin use and the risk of hospitalization attributable to COVID-19. Methods and Results The French National Healthcare Data System database was used to conduct a matched-cohort study. For each adult aged ≥40 years receiving statins for the primary prevention of cardiovascular diseases, one nonuser was randomly selected and matched for year of birth, sex, residence area, and comorbidities. The association between statin use and hospitalization for COVID-19 was examined using conditional Cox proportional hazards models, adjusted for baseline characteristics, comorbidities, and long-term medications. Its association with in-hospital death from COVID-19 was also explored. All participants were followed up from February 15, 2020, to June 15, 2020. The matching procedure generated 2 058 249 adults in the statin group and 2 058 249 in the control group, composed of 46.6% of men with a mean age of 68.7 years. Statin users had a 16% lower risk of hospitalization for COVID-19 than nonusers (adjusted hazard ratio [HR], 0.84; 95% CI, 0.81-0.88). All types of statins were significantly associated with a lower risk of hospitalization, with the adjusted HR ranging from 0.75 for fluvastatin to 0.89 for atorvastatin. Low- and moderate-intensity statins also showed a lower risk compared with nonusers (HR, 0.78 [95% CI, 0.71-0.86] and HR, 0.84 [95% CI, 0.80-0.89], respectively), whereas high-intensity statins did not (HR, 1.01; 95% CI, 0.86-1.18). We found similar results with in-hospital death from COVID-19. Conclusions Our findings support that the use of statins for primary prevention is associated with lower risks of hospitalization for COVID-19 and of in-hospital death from COVID-19.