Background and Purpose-Type 2 diabetes mellitus is a strong predictor of cerebrovascular disease, yet few studies have assessed the incidence of stroke and the role of other risk factors in unselected type 2 diabetes mellitus populations. Methods-We prospectively followed-up 14 432 type 2 diabetes mellitus patients, aged 40 to 97 years, with and without a history of cardiovascular disease at enrollment, and we estimated the incidence of stroke and the hazards ratios with respect to clinical variables. Results-During a 4-year follow-up, 296 incident stroke events were recorded. In persons with no history of cardiovascular disease, the age-standardized incidence of stroke (per 1000 person-years) was 5.5 (95% confidence interval, 4.2 to 6.8) in men and 6.3 (95% confidence interval, 4.5 to 8.2) in women. In persons with a history of cardiovascular disease, it was 13.7 (95% confidence interval, 7.5 to 19.8) in men and 10.8 (95% confidence interval, 7.3 to 14.4) in women. The hazards ratios of stroke incidence varied according to age, sex, and history of cardiovascular disease. Among men with no history, HbA1c and smoking were predictors of stroke. Among patients with a history, the risk factors were, in men, therapy with insulin plus oral agents, treated high total cholesterol and low HDL cholesterol, whereas in women microvascular complications were a risk factor. Previous stroke was a strong predictor of stroke in both sexes. Conclusions-Age and previous stroke are the main predictors of stroke in diabetes. The combined role of Hba1c, microvascular complications, low HDL cholesterol, and treatment with insulin plus oral agents highlights the importance of diabetic history and clinical background in the development of stroke.

Objectives To estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different time after vaccination. Design Retrospective cohort study. Setting Italy, 27 December 2020 to 7 November 2021. Participants 33 250 344 people aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. Main outcome measures SARS-CoV-2 infection and severe covid-19 (admission to hospital or death). Data were divided by weekly time intervals after vaccination. Incidence rate ratios at different time intervals were estimated by multilevel negative binomial models with robust variance estimator. Sex, age group, brand of vaccine, priority risk category, and regional weekly incidence in the general population were included as covariates. Geographic region was included as a random effect. Adjusted vaccine effectiveness was calculated as (1−IRR)×100, where IRR=incidence rate ratio, with the time interval 0-14 days after the first dose of vaccine as the reference. Results During the epidemic phase when the delta variant was the predominant strain of the SARS-CoV-2 virus, vaccine effectiveness against SARS-CoV-2 infection significantly decreased (P<0.001) from 82% (95% confidence interval 80% to 84%) at 3-4 weeks after the second dose of vaccine to 33% (27% to 39%) at 27-30 weeks after the second dose. In the same time intervals, vaccine effectiveness against severe covid-19 also decreased (P<0.001), although to a lesser extent, from 96% (95% to 97%) to 80% (76% to 83%). High risk people (vaccine effectiveness −6%, −28% to 12%), those aged ≥80 years (11%, −15% to 31%), and those aged 60-79 years (2%, −11% to 14%) did not seem to be protected against infection at 27-30 weeks after the second dose of vaccine. Conclusions The results support the vaccination campaigns targeting high risk people, those aged ≥60 years, and healthcare workers to receive a booster dose of vaccine six months after the primary vaccination cycle. The results also suggest that timing the booster dose earlier than six months after the primary vaccination cycle and extending the offer of the booster dose to the wider eligible population might be warranted.

IMPORTANCEConvalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. OBJECTIVE To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg were eligible. INTERVENTIONS Patients in the experimental group received intravenous high-titer CP (Ն1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. MAIN OUTCOMES AND MEASURESThe primary outcome was a composite of worsening respiratory failure (PaO 2 /FiO 2 ratio <150 mm Hg) or death within 30 days from randomization. RESULTSOf the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P = .54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P = .04). CONCLUSIONS AND RELEVANCEIn patients with moderate to severe COVID-19 pneumonia, hightiter anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. (continued) Key Points Question Is convalescent plasma useful in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia? Findings In this randomized clinical trial of 487 patients with COVID-19 pneumonia and a partial pressure of arterial oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg at enrollment, the rate of the primary clinical end point (need for mechanical ventilation, defined as PaO 2 /FiO 2 ratio <150 mm Hg, or death) was not significantly different between the convalescent plasma group and the control group. Meaning In this trial, convalescent plasma did not reduce the progression to severe respiratory failure or death within 30 days.

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Introduction The epidemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. There are several controversial hypotheses on the potentially harmful or beneficial effects of antihypertensive drugs acting on the renin-angiotensin-aldosterone system (RAAS) in coronavirus disease 2019 (COVID-19). Furthermore, there is accumulating evidence, based on several observational studies, that angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) do not increase the risk of contracting SARS-CoV-2 infection. On the other hand, conflicting findings regarding the role of ACEIs/ARBs as prognosis modifiers in COVID-19 hospitalised patients have been reported. Objective The aim of this large-scale, retrospective cohort study was to investigate whether prior exposure to ACEIs and/or ARBs was associated with all-cause mortality among over 40,000 hospitalised COVID-19 patients compared with calcium channel blockers (CCBs), a potential therapeutic alternative. Methods This study was conducted using COVID-19 registries linked to claims databases from Lombardy, Veneto and Reggio Emilia (overall, 25% of Italian population). Overall, 42,926 patients hospitalised between 21 February and 21 April 2020 with a diagnosis of COVID-19 confirmed by real-time polymerase chain reaction tests were included in this study. All-cause mortality occurring in or out of hospital, as reported in the COVID-19 registry, was estimated. Using Cox models, adjusted hazard ratios (HRs) of all-cause mortality (along with 95% confidence intervals [CIs]) were estimated separately for ACEIs/ARBs and other antihypertensives versus CCBs and non-use. Results Overall, 11,205 in-and out-of-hospital deaths occurred over a median of 24 days of follow-up after hospital admission due to COVID-19. Compared with CCBs, adjusted analyses showed no difference in the risk of death among ACEI (HR 0.97, 95% CI 0.89-1.06) or ARB (HR 0.98, 95% CI 0.89-1.06) users. When non-use of antihypertensives was considered as a comparator, a modest statistically significant increase in mortality risk was observed for any antihypertensive use. However, when restricting to drugs with antihypertensive indications only, these marginal increases disappeared. Sensitivity and subgroup analyses confirmed our main findings. Conclusions ACEI/ARB use is not associated with either an increased or decreased risk of all-cause mortality, compared with CCB use, in the largest cohort of hospitalised COVID-19 patients exposed to these drugs studied to date. The use of Gianluca Trifirò and Marco Massari contributed equally to this article. The members of ITA-COVID-19: RAAS inhibitor group are listed in acknowledgements.

Introduction COVID-19 case fatality rate in hospitalized patients varies across countries and studies. Reliable estimates, specific for age, sex, and comorbidities, are needed to monitor the epidemic, to compare the outcome in different settings, and to correctly design trials for COVID-19 interventions. The aim of this study was to provide population-based survival curves of hospitalized COVID-19 patients. Materials and Methods A cohort study was conducted in three areas of Northern Italy, heavily affected by SARS-CoV-2 infection (Lombardy and Veneto Regions, and Reggio Emilia province), using a loco-regional COVID-19 surveillance system, linked to hospital discharge databases. We included all patients testing positive for SARS-CoV-2 RNA by RT-PCR on nasopharyngeal/throat swab samples who were hospitalized from 21 February to 21 April 2020. Kaplan–Meier survival estimates were calculated at 14 and 30 days for death in any setting, stratifying by age, sex, and the Charlson Index. Results Overall, 42,926 hospitalized COVID-19 patients were identified. Patients’ median age was 69 years (IQR: 57–79), 62.6% were males, and 6.0% had a Charlson Index ≥3. Survival curves showed that 22.0% (95% CI 21.6–22.4) of patients died within 14 days and 27.6% (95% CI 27.2–28.1) within 30 days from hospitalization. Survival was higher in younger patients and in females. The negative impact of comorbidities on survival was more pronounced in younger age groups. Conclusion The high fatality rate observed in the study (28% at 30 days) suggests that studies should focus on death as primary endpoint during a follow-up of at least one month.

OBJECTIVE -The purpose of this study was to assess incidence of and risk factors for recurrent cardiovascular disease (CVD) in type 2 diabetes.RESEARCH DESIGN AND METHODS -We estimated the incidence of recurrent cardiovascular events in type 2 diabetic patients, aged 40 -97 years, followed by a network of diabetes clinics. The analysis was conducted separately for 2,788 patients with CVD at enrollment (cohort A) and for 844 patients developing the first episode during the observation period (cohort B).RESULTS -During 4 years of follow-up, in cohort A the age-adjusted incidence of a recurrent event (per 1,000 person-years) was 72.7 (95% CI 58.3-87.1) in men and 32.5 (21.2-43.7) in women, whereas in cohort B it was 40.1 (17.4 -62.9) in men and 22.4 (12.9 -32.0) in women. After controls were included for potential predictors (familial CVD, obesity, smoking, diabetes duration, glycemic control, microvascular complications, geographic area, and antihypertensive and lipid-lowering treatment), male sex, older age, and insulin use were significant independent risk predictors (cohort A) and serum triglyceride levels Ն1.69 mmol/l emerged as the only metabolic (negative) prognostic factor (cohort B). In both cohorts, a prior CVD episode, especially myocardial infarction, was by far the strongest predictor of recurrent CVD.CONCLUSIONS -Approximately 6% of unselected diabetic patients in secondary prevention develop recurrent major CVD every year. Those with long-standing previous CVD show a higher incidence of recurrence. Male sex, age, high triglyceride levels, and insulin use are additional predictors of recurrence.

Objective To assess the risk of maternal, fetal, and neonatal outcomes associated with the administration of an MF59 adjuvanted A/H1N1 vaccine during pregnancy.Design Historical cohort study.Setting Singleton pregnancies of the resident population of the Lombardy region of Italy.Participants All deliveries between 1 October 2009 and 30 September 2010. Data on exposure to A/H1N1 pandemic vaccine, pregnancy, and birth outcomes were retrieved from regional databases. Vaccinated and non-vaccinated women were compared in a propensity score matched analysis to estimate risks of adverse outcomes.Main outcome measures Main maternal outcomes included type of delivery, admission to intensive care unit, eclampsia, and gestational diabetes; fetal and neonatal outcomes included perinatal deaths, small for gestational age births, and congenital malformations.Results Among the 86 171 eligible pregnancies, 6246 women were vaccinated (3615 (57.9%) in the third trimester and 2557 (40.9%) in the second trimester). No difference was observed in terms of spontaneous deliveries (adjusted odds ratio 1.02, 95% confidence interval 0.96 to 1.08) or admissions to intensive care units (0.95, 0.47 to 1.88), whereas a limited increase in the prevalence of gestational diabetes (1.26, 1.04 to 1.53) and eclampsia (1.19, 1.04 to 1.39) was seen in vaccinated women. Rates of fetal and neonatal outcomes were similar in vaccinated and non-vaccinated women. A slight increase in congenital malformations, although not statistically significant, was present in the exposed cohort (1.14, 0.99 to 1.31).Conclusions Our findings add relevant information about the safety of the MF59 adjuvanted A/H1N1 vaccine in pregnancy. Residual confounding may partly explain the increased risk of some maternal outcomes. Meta-analysis of published studies should be conducted to further clarify the risk of infrequent outcomes, such as specific congenital malformations.