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Background Chronic kidney disease (CKD) is a risk factor for severe coronavirus disease 2019 (COVID-19). We aimed to evaluate the real-life effectiveness of the BNT162b2 messenger RNA vaccine for a range of outcomes in patients with CKD compared with matched controls. Methods Data from Israel's largest healthcare organization were retrospectively used. Vaccinated CKD [estimated glomerular filtration rate (eGFR) Results There were 67 861 CKD patients not treated with dialysis, 2606 hemodialysis (HD) patients and 70 467 matched controls. The risk of severe disease {RR 1.84 [95% confidence interval (CI) 0.95–2.67]} and death [RR 2.00 (95% CI 0.99–5.20)] was increased in nondialysis CKD patients compared with controls without CKD following vaccination. For the subgroup of patients with eGFR Conclusion Two doses of the BNT162b2 vaccine were found to be less efficient for patients with eGFR

To quantify the healthcare costs associated with opioid use disorder among members in a public healthcare system and compare them with healthcare costs in the general population.Retrospective cohort study.Inpatient and outpatient care settings of Israel's largest public healthcare provider (that covers 4.7 million members).Participants included 1173 members who had a diagnosis of opioid use disorder in the years between 2013 and 2018. Each patient was matched with 10 controls based on age and sex.The main outcome was monthly healthcare costs.The mean monthly healthcare cost of members with opioid use disorder was $1102 compared with $211 among controls (5.2-fold difference; 95% CI, 4.6-6.0). After excluding members with heroin related diagnoses before the index date (to focus on prescription opioids), this healthcare cost ratio did not substantially change (4.6-fold; 95% CI, 3.9-5.4). Members with opioid use disorder under the age of 65 years had a cost difference of 6.1-fold (95% CI, 5.2-7.1), whereas those 65 years and older experienced cost difference of 3.4-fold (95% CI, 2.6-4.5), compared with controls. The category with the highest cost for members with opioid use disorder was inpatient services, which was 8.7-fold (95%CI, 7.2-10.4) greater than among controls.Healthcare costs among individuals with opioid use disorder in Israel's public health system are substantially higher than among controls, at least partially attributable to prescription opioid use disorder. Differences are greater among individuals under 65 years.

Heart failure prevalence is increasing worldwide and is associated with significant morbidity and mortality. Guidelines emphasize prevention in those at risk, but HF-specific risk prediction equations developed in US population-based cohorts lack external validation in large, real-world datasets outside of the US. The purpose of this study was to assess the model performance of the Pooled Cohort Equations to Prevent Heart Failure (PCP-HF) within a contemporary electronic health record for 5-year and 10-year risk. Utilizing a retrospective cohort study design of Israeli residents between 2008 and 2018 with continuous membership until end of follow-up, HF or death, we quantified 5-year and 10-year estimated risk of HF using the PCP-HF equations, which integrate demographics (age, sex, race) and risk factors (body mass index, systolic blood pressure, glucose, medication use for hypertension or diabetes, and smoking status). Of 1,394,411 patients included, 56% were women with mean age of 49.6 (standard deviation 13.2) years. Incident HF occurred in 1.2% and 4.5% of participants over 5- and 10-years of follow-up. The PCP-HF model had excellent discrimination for 5-year and 10-year prediction of incident HF (C statistic 0.82 [0.82, 0.82] and 0.84 [0.84, 0.84]), respectively. In conclusion, HF-specific risk equations (PCP-HF) accurately predict the risk of incident HF in ambulatory and hospitalized patients using routinely available clinical data.

BACKGROUND Emerging data suggest increased arterial thrombosis risk in the months preceding a cancer diagnosis. OBJECTIVES Assess whether patients without documented vascular risk factors or pre-existent cardiovascular disease have a higher relative risk of cancer 12 months after arterial thrombotic events (ATE), compared to unselected patients. PATIENTS/METHODS A population-based cohort study of Clalit Health Services (CHS) database included CHS members ≥25 years without prior cancer or ATE (n=2804584). An iterative matching process selected 10 potential controls chronologically for each consecutive exposed, age- and sex-matched (actual controls drawn 1:1 from a lot). Study exposure, ATE, was defined as ischemic stroke, transient ischemic attack, myocardial infarction or systemic arterial thromboembolism during hospitalization. The outcome was newly-diagnosed cancer within 12 months, based on Israeli national cancer registry. Cox proportional hazards multivariate regression calculated hazard ratio (HR) for outcomes, adjusted for cancer risk factors. Analysis also performed for 3 subgroups: age≤50 years; no cardiovascular risk factors; no prior cardiovascular disease. RESULTS The full ATE and matched control cohorts included 43108 patients. The 12-month cumulative incidence of cancer (95% confidence interval) was 0.020 (0.019-0.022) in the ATE cohort and 0.012 (0.011-0.013) in controls, corresponding to an adjusted HR of 1.665 (1.489-1.862). The relative risk of cancer was high in all subgroups up to a HR of 3.754 (1.912-7.372) in patients without cardiovascular risk factors. CONCLUSION There is an increased risk of previously undiagnosed cancer at 12 months after ATE, especially in patients without documented vascular risk factors or pre-existent cardiovascular disease.

Background Methodologically rigorous studies on Covid-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection are critically needed to inform national and global policy on Covid-19 vaccine use. In Israel, healthcare personnel (HCP) were initially prioritized for Covid-19 vaccination, creating an ideal setting to evaluate early real-world VE in a closely monitored population. Methods We conducted a prospective study among HCP in 6 hospitals to estimate the effectiveness of the BNT162b2 mRNA Covid-19 vaccine in preventing SARS-CoV-2 infection. Participants filled out weekly symptom questionnaires, provided weekly nasal specimens, and three serology samples – at enrollment, 30 days and 90 days. We estimated VE against PCR-confirmed SARS-CoV-2 infection using the Cox Proportional Hazards model and against a combined PCR/serology endpoint using Fisher’s exact test. Results Of the 1567 HCP enrolled between December 27, 2020 and February 15, 2021, 1250 previously uninfected participants were included in the primary analysis; 998 (79.8%) were vaccinated with their first dose prior to or at enrollment, all with Pfizer BNT162b2 mRNA vaccine. There were four PCR-positive events among vaccinated participants, and nine among unvaccinated participants. Adjusted two-dose VE against any PCR-confirmed infection was 94.5% (95% CI: 82.6%-98.2%); adjusted two-dose VE against a combined endpoint of PCR and seroconversion for a 60-day follow-up period was 94.5% (95% CI: 63.0%-99.0%). Five PCR-positive samples from study participants were sequenced; all were alpha variant. Conclusions Our prospective VE study of HCP in Israel with rigorous weekly surveillance found very high VE for two doses of Pfizer BNT162b2 mRNA vaccine against SARS-CoV-2 infection in recently vaccinated HCP during a period of predominant alpha variant circulation. Funding Clalit Health Services.

Background Reports have suggested an association between the development of myocarditis and the receipt of messenger RNA (mRNA) vaccines against coronavirus disease 2019 (Covid-19), but the frequency and severity of myocarditis after vaccination have not been extensively explored. Methods We searched the database of Clalit Health Services, the largest health care organization (HCO) in Israel, for diagnoses of myocarditis in patients who had received at least one dose of the BNT162b2 mRNA vaccine (Pfizer–BioNTech). The diagnosis of myocarditis was adjudicated by cardiologists using the case definition used by the Centers for Disease Control and Prevention. We abstracted the presentation, clinical course, and outcome from the patient’s electronic health record. We performed a Kaplan–Meier analysis of the incidence of myocarditis up to 42 days after the first vaccine dose. Results Among more than 2.5 million vaccinated HCO members who were 16 years of age or older, 54 cases met the criteria for myocarditis. The estimated incidence per 100,000 persons who had received at least one dose of vaccine was 2.13 cases (95% confidence interval [CI], 1.56 to 2.70). The highest incidence of myocarditis (10.69 cases per 100,000 persons; 95% CI, 6.93 to 14.46) was reported in male patients between the ages of 16 and 29 years. A total of 76% of cases of myocarditis were described as mild and 22% as intermediate; 1 case was associated with cardiogenic shock. After a median follow-up of 83 days after the onset of myocarditis, 1 patient had been readmitted to the hospital, and 1 had died of an unknown cause after discharge. Of 14 patients who had left ventricular dysfunction on echocardiography during admission, 10 still had such dysfunction at the time of hospital discharge. Of these patients, 5 underwent subsequent testing that revealed normal heart function. Conclusions Among patients in a large Israeli health care system who had received at least one dose of the BNT162b2 mRNA vaccine, the estimated incidence of myocarditis was 2.13 cases per 100,000 persons; the highest incidence was among male patients between the ages of 16 and 29 years. Most cases of myocarditis were mild or moderate in severity. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.)

We assess the immunogenicity and efficacy of Spikevax and Comirnaty as fourth dose COVID-19 vaccines. Six months post-fourth-dose, IgG levels were higher than pre-fourth dose at 1.58-fold (95% CI: 1.27–1.97) in Spikevax and 1.16-fold (95% CI: 0.98–1.37) in Comirnaty vaccinees. Nearly 60% (159/274) of vaccinees contracted SARS-CoV-2. Infection hazard ratios (HRs) for Spikevax (0.82; 95% CI: 0.62–1.09) and Comirnaty (0.86; 95% CI: 0.65–1.13) vaccinees were similar, as were substantial-disease HRs, i.e. 0.28 (95% CI: 0.13–0.62) and 0.51 (95% CI: 0.27–0.96), respectively.

Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose study, comparing BNT162b2 and mRNA1273, administered four months after a third BNT162b2 dose. Waning of the immune response was evident during follow-up, with an 11% (ß=0.89, 95% CI, 0.88–0.9) and 21% (ß=0.79, 95% CI, 0.76–0.82) multiplicative decay per week of IgG and neutralizing antibodies, respectively, in the mRNA1273 group, and of 14% (ß=0.86, 95% CI, 0.86–0.87) and 26% (ß=0.74, 95% CI, 0.72–0.76), respectively, in the BNT162b2 group. Direct neutralization of Omicron variants was low relative to ancestral strains. Cumulatively over the study period, both vaccines showed little efficacy against infection but were highly efficacious against substantial disease [89% [(IRR 0.11, 95% CI, 0.02–0.37) and 71% (IRR 0.29, 95% CI, 0.13–0.57) for mRNA1273 and BNT162b2, respectively]. These results are informative for further boosting policy-making.

This work evaluated neutralising antibody titres against wild type (WT) SARS-CoV-2 and four Omicron variants (BA.1, BA.2, BA.4 and BA.5) in healthcare workers who had breakthrough BA.1 infection. Omicron breakthrough infection in individuals vaccinated three or four times before infection resulted in increased neutralising antibodies against the WT virus. The fourth vaccine dose did not further improve the neutralising efficiency over the third dose against all Omicron variants, especially BA.4 and BA.5. An Omicron-specific vaccine may be indicated.

ImportanceA correlation between antibody levels and risk of infection has been demonstrated for the wild-type, Alpha, and Delta SARS-COV-2 variants. High rates of breakthrough infections by the Omicron variant emphasized the need to investigate whether the humoral response elicited by mRNA vaccines is also associated with reduced risk of Omicron infection and disease.ObjectiveTo investigate whether the high antibody levels in individuals who have received at least 3 doses of an mRNA vaccine are associated with reduced risk of Omicron infection and disease.Design, Setting, and ParticipantsThis prospective cohort study used serial real time–polymerase chain reaction (RT-PCR) and serological test data from January and May 2022 to assess the association of preinfection immunoglobin G (IgG) and neutralizing antibody titers with incidence of Omicron variant infection, incidence of symptomatic disease, and infectivity. Participants included health care workers who had received 3 or 4 doses of an mRNA COVID-19 vaccine. Data were analyzed from May to August 2022.ExposuresLevels of SARS-CoV-2 anti–receptor binding domain IgG and neutralizing antibodies.Main Outcomes and MeasuresThe main outcomes were incidence of Omicron infection, incidence of symptomatic disease, and infectivity. Outcomes were measured using SARS-COV-2 PCR and antigen testing and daily online surveys regarding symptomatic disease.ResultsThis study included 3 cohorts for 3 different analyses: 2310 participants were included in the protection from infection analysis (4689 exposure events; median [IQR] age, 50 [40-60] years; 3590 [76.6%] among female health care workers), 667 participants (median [IQR] age, 46.28 (37.44,54.8); 516 [77.4%] female) in the symptomatic disease analysis, and 532 participants (median [IQR] age, 48 [39-56] years; 403 [75.8%] female) in the infectivity analysis. Lower odds of infection were observed for each 10-fold increase in preinfection IgG (odds ratio [OR], 0.71; 95% CI, 0.56-0.90) and for each 2-fold increase in neutralizing antibody titers (OR, 0.89; 95% CI, 0.83-0.95). The odds of substantial symptomatic disease were reduced for each 10-fold increase in IgG levels (OR, 0.48; 95% CI, 0.29-0.78) and for each 2-fold increase in neutralizing antibodies levels (OR, 0.86; 95% CI, 0.76-0.96). Infectivity, assessed by mean cycle threshold value, was not significantly decreased with increasing IgG or neutralizing antibodies titers.Conclusions and RelevanceIn this cohort study of vaccinated health care workers, IgG and neutralizing antibody titer levels were associated with protection against infection with the Omicron variant and against symptomatic disease.

BNT162b2 Effectiveness against Delta Variant in Adolescents A study involving more than 94,000 vaccinated and unvaccinated adolescents between the ages of 12 and 18 years in Israel showed increasin...

To evaluate the effectiveness of the BNT162b2 messenger RNA vaccine in pregnant women, we conducted an observational cohort study of pregnant women aged 16 years or older, with no history of SARS-CoV-2, who were vaccinated between 20 December 2020 and 3 June 2021. A total of 10,861 vaccinated pregnant women were matched to 10,861 unvaccinated pregnant controls using demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. Estimated vaccine effectiveness from 7 through to 56 d after the second dose was 96% (95% confidence interval 89-100%) for any documented infection, 97% (91-100%) for infections with documented symptoms and 89% (43-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group and no deaths were observed in either group. In summary, the BNT162b2 mRNA vaccine was estimated to have high vaccine effectiveness in pregnant women, which is similar to the effectiveness estimated in the general population.

Summary Background Pneumonia is more common in smokers compared with non-smokers. A high 1-year prevalence of lung cancer following hospitalization for pneumonia was demonstrated in heavy smokers. Aim To assess the association between hospitalization for pneumonia among ever-smokers and subsequent lung cancer risk. Design Retrospective analysis. Methods The study cohort included all ever-smokers aged 55–80 hospitalized for pneumonia between the years 2010–15 covered by a large medical insurer in Israel. Controls were matched to cases by age in a 4:1 ratio. The primary outcome was the association between hospitalization for pneumonia and subsequent 1-year incidence of lung cancer, adjusted for gender, smoking status (past/current) and pack years. Pre-specified sensitivity analyses excluded heavy smokers (smoking history of more than 30 pack years) and patients diagnosed with lung cancer within 30 days of hospitalization, as they probably had clinical or radiological findings suggestive of lung cancer, making them ineligible for screening. Results Lung cancer was identified in 275 of 12 807 (2.1%) patients following hospitalization for pneumonia and in 44 of 51 228 (0.1%) controls (adjusted odds ratio 22.46, 95% CI 16.29–30.96, P Conclusions Hospitalization for pneumonia is associated with high 1-year incidence of lung cancer in ever-smokers, supporting the important role of the widely used practice of performing follow up imaging post-pneumonia to exclude occult malignancy.

The association between use of renin-angiotensin-aldosterone (RAAS) inhibitors and both SARS-CoV-2 infection and the development of severe COVID-19 has been presented in the recent medical literature with inconsistent results.To assess the association between RAAS inhibitor use and two outcomes: infection with SARS-CoV-2 (Model 1) and severe COVID-19 among those infected (Model 2).We accessed used electronic health records of individuals from Israel who were receiving anti-hypertensive medications for this retrospective study. For Model 1 we used a case-control design. For Model 2 we used a cohort design. In both models, inverse probability weighting adjusted for identified confounders as part of doubly robust outcome regression.We tested 38,554 individuals for SARS-CoV-2 who had hypertension and were being treated with medication; 691 had a positive test result. Among those with a positive test, 119 developed severe illness. There was no association between RAAS inhibitor use and a positive test. Use of RAAS inhibitors was associated with a decreased risk for severe COVID-19 (adjusted odds ratio [OR] 0.47, 95% confidence interval [95%CI] 0.29-0.77) compared with users of non-RAAS anti-hypertensive medication. The association remained significant when use of angiotensin-converting-enzyme inhibitors (adjusted OR 0.46, 95%CI 0.27-0.77) and angiotensin II receptor blockers (adjusted OR 0.39, 95%CI 0.16-0.95) were analyzed separately.Among individuals with hypertension using RAAS inhibitors, we found a lower risk of severe disease compared to those using non-RAAS anti-hypertensive medications. This finding suggests that RAAS inhibitors may have a protective effect on COVID-19 severity among individuals with medically treated hypertension.

Objective To illustrate the problem of subpopulation miscalibration, to adapt an algorithm for recalibration of the predictions, and to validate its performance. Materials and Methods In this retrospective cohort study, we evaluated the calibration of predictions based on the Pooled Cohort Equations (PCE) and the fracture risk assessment tool (FRAX) in the overall population and in subpopulations defined by the intersection of age, sex, ethnicity, socioeconomic status, and immigration history. We next applied the recalibration algorithm and assessed the change in calibration metrics, including calibration-in-the-large. Results 1 021 041 patients were included in the PCE population, and 1 116 324 patients were included in the FRAX population. Baseline overall model calibration of the 2 tested models was good, but calibration in a substantial portion of the subpopulations was poor. After applying the algorithm, subpopulation calibration statistics were greatly improved, with the variance of the calibration-in-the-large values across all subpopulations reduced by 98.8% and 94.3% in the PCE and FRAX models, respectively. Discussion Prediction models in medicine are increasingly common. Calibration, the agreement between predicted and observed risks, is commonly poor for subpopulations that were underrepresented in the development set of the models, resulting in bias and reduced performance for these subpopulations. In this work, we empirically evaluated an adapted version of the fairness algorithm designed by Hebert-Johnson et al. (2017) and demonstrated its use in improving subpopulation miscalibration. Conclusion A postprocessing and model-independent fairness algorithm for recalibration of predictive models greatly decreases the bias of subpopulation miscalibration and thus increases fairness and equality.

Methods for identifying patients at high risk for osteoporotic fractures, including dual-energy X-ray absorptiometry (DXA)1,2 and risk predictors like the Fracture Risk Assessment Tool (FRAX)3-6, are underutilized. We assessed the feasibility of automatic, opportunistic fracture risk evaluation based on routine abdomen or chest computed tomography (CT) scans. A CT-based predictor was created using three automatically generated bone imaging biomarkers (vertebral compression fractures (VCFs), simulated DXA T-scores and lumbar trabecular density) and CT metadata of age and sex. A cohort of 48,227 individuals (51.8% women) aged 50-90 with available CTs before 2012 (index date) were assessed for 5-year fracture risk using FRAX with no bone mineral density (BMD) input (FRAXnb) and the CT-based predictor. Predictions were compared to outcomes of major osteoporotic fractures and hip fractures during 2012-2017 (follow-up period). Compared with FRAXnb, the major osteoporotic fracture CT-based predictor presented better receiver operating characteristic area under curve (AUC), sensitivity and positive predictive value (PPV) (+1.9%, +2.4% and +0.7%, respectively). The AUC, sensitivity and PPV measures of the hip fracture CT-based predictor were noninferior to FRAXnb at a noninferiority margin of 1%. When FRAXnb inputs are not available, the initial evaluation of fracture risk can be done completely automatically based on a single abdomen or chest CT, which is often available for screening candidates7,8.

Introduction: With the COVID-19 pandemic ongoing, accurate assessment of population immunity and the effectiveness of booster and enhancer vaccines is critical. Methods We compare COVID-19-related hospitalization incidence rate ratios, adjusted for potential demographic, clinical and health-seeking-behavior confounders, in 2,412,755 individuals (235,552,274 person-days), across four exposures: 2 BNT162b2 doses, 5 or more months prior ("non-recent vaccine immunity"); 3 BNT162b2 doses (“boosted vaccine immunity”); previous COVID-19, with or without a subsequent BNT162b2 dose (“natural immunity” and “enhanced natural immunity” respectively). Results Compared with non-recent vaccine immunity, COVID-19-related hospitalization incidence rate ratios are 11% (9%-13%) for boosted vaccine immunity, 34% (23%-50%) for natural immunity and 25% (17%-39%) for enhanced natural immunity. Conclusion We demonstrate that natural immunity (enhanced or not) provides better protection against COVID-19-related hospitalization than non-recent vaccine immunity, but less protection than that attained from booster vaccination. Additionally, our results suggest that vaccinating individuals with natural immunity further enhances their protection.

Evidence regarding the effectiveness of COVID-19 vaccine in patients with impaired immunity is limited. Initial observations suggest a lower humoral response in these patients. We evaluated the relative effectiveness of the mRNA BNT162b2 vaccine in patients with hematological neoplasms compared with matched controls. Data on patients with hematological neoplasms after 2 vaccine doses were extracted and matched 1:1 with vaccinated controls. Subpopulation analyses focused on patients receiving therapy for hematological neoplasm, patients without treatment who were only followed, and recipients of specific treatments. The analysis focused on COVID-19 outcomes from days 7 through 43 after the second vaccine dose in these areas: documented COVID-19 infection by polymerase chain reaction; symptomatic infection; hospitalizations; severe COVID-19 disease; and COVID-19–related death. In a population of 4.7 million insured people, 32 516 patients with hematological neoplasms were identified, of whom 5017 were receiving therapy for an active disease. Vaccinated patients with hematological neoplasms, compared with vaccinated matched controls, had an increased risk of documented infections (relative risk [RR] 1.60, 95% CI 1.12-2.37); symptomatic COVID-19 (RR 1.72, 95% CI 1.05-2.85); COVID-19–related hospitalizations (RR 3.13, 95% CI 1.68-7.08); severe COVID-19 (RR 2.27, 95% CI 1.18-5.19); and COVID-19–related death (RR 1.66, 95% CI 0.72-4.47). Limiting the analysis to patients on hematological treatments showed a higher increased risk. This analysis shows that vaccinated patients with hematological neoplasms, in particular patients receiving treatment, suffer from COVID-19 outcomes more than vaccinated individuals with intact immune system. Ways to enhance COVID-19 immunity in this patient population, such as additional doses, should be explored.

BackgroundMethodologically rigorous studies on Covid-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection are critically needed to inform national and global policy on Covid-19 vaccine use. In Israel, healthcare personnel (HCP) were initially prioritized for Covid-19 vaccination, creating an ideal setting to evaluate real-world VE in a closely monitored population.MethodsWe conducted a prospective study among HCP in 6 hospitals to estimate the effectiveness of the BNT162b2 mRNA Covid-19 vaccine in preventing SARS-CoV-2 infection. Participants filled out weekly symptom questionnaires, provided weekly nasal specimens, and three serology samples – at enrollment, 30 days and 90 days. We estimated VE against PCR-confirmed SARS-CoV-2 infection using the Cox Proportional Hazards model and against a combined PCR/serology endpoint using Fisher’s exact test.FindingsOf the 1,567 HCP enrolled between December 27, 2020 and February 15, 2021, 1,250 previously uninfected participants were included in the primary analysis; 998 (79.8%) were vaccinated with their first dose prior to or at enrollment, all with Pfizer BNT162b2 mRNA vaccine. There were four PCR-positive events among vaccinated participants, and nine among unvaccinated participants. Adjusted two-dose VE against any PCR- confirmed infection was 94.5% (95% CI: 82.6%-98.2%); adjusted two-dose VE against a combined endpoint of PCR and seroconversion for a 60-day follow-up period was 94.5% (95% CI: 63.0%-99.0%). Five PCR-positive samples from study participants were sequenced; all were alpha variant.InterpretationOur prospective VE study of HCP in Israel with rigorous weekly surveillance found very high VE for two doses of Pfizer BNT162b2 mRNA vaccine against SARS-CoV-2 during a period of predominant alpha variant circulation.FundingClalit Health Services

Early risk stratification is essential for determining the appropriate therapeutic management approach of pulmonary embolism (PE). This study aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in patients hospitalized with acute pulmonary embolism by investigating its association with mortality in a large-scale population diagnosed and hospitalized with acute PE. We retrieved all consecutive patients hospitalized in an internal medicine department or an intensive care unit in a tertiary medical center from December 2007 to April 2021 with a discharge diagnosis of pulmonary embolism. A total of 2068 patients were included. Patients with above-median NLR (i.e., 5.12) had a higher 30-day mortality risk (adjusted odds ratio (aOR), 2.82, 95% confidence interval (CI) 2.14–3.70) and higher one-year mortality risk (aOR, 2.51, 95% CI 2.04–3.08). Similar trends were demonstrated in a sub-analysis of patients without cancer and hemodynamically stable (i.e., systolic blood pressure over 90 mmHg). Furthermore, the median hospital length of stay in patients with an elevated NLR was higher, and so was the in-hospital mortality rate. Elevated NLR in acute PE is associated with a worse short-term and long-term prognosis and with a longer duration of hospitalization.

The Hungarian vaccination campaign was conducted with five different vaccines during the third wave of the coronavirus disease 2019 (COVID-19) pandemic in 2021. This observational study (HUN-VE: Hungarian Vaccine Effectiveness) estimated vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related mortality in 3.7 million vaccinated individuals.Incidence rates of SARS-CoV-2 infection and COVID-19-related mortality were calculated using data from the National Public Health Centre surveillance database. Estimated vaccine effectiveness was calculated as 1 - incidence rate ratio ≥7 days after the second dose for each available vaccine versus an unvaccinated control group using mixed-effect negative binomial regression controlling for age, sex and calendar day.Between 22 January 2021 and 10 June 2021, 3 740 066 Hungarian individuals received two doses of the BNT162b2 (Pfizer-BioNTech), HB02 (Sinopharm), Gam-COVID-Vac (Sputnik-V), AZD1222 (AstraZeneca), or mRNA-1273 (Moderna) vaccines. Incidence rates of SARS-CoV-2 infection and COVID-19-related death were 1.73-9.3/100 000 person-days and 0.04-0.65/100 000 person-days in the fully vaccinated population, respectively. Estimated adjusted effectiveness varied between 68.7% (95% CI 67.2%-70.1%) and 88.7% (95% CI 86.6%-90.4%) against SARS-CoV-2 infection, and between 87.8% (95% CI 86.1%-89.4%) and 97.5% (95% CI 95.6%-98.6%) against COVID-19-related death, with 100% effectiveness in individuals aged 16-44 years for all vaccines.Our observational study demonstrated the high or very high effectiveness of five different vaccines in the prevention SARS-CoV-2 infection and COVID-19-related death.

Background Preapproval trials showed that messenger RNA (mRNA)–based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed. Methods We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan–Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2–infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses. Results In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. Conclusions In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.)

Background: As mass vaccination campaigns against COVID-19 accelerate worldwide, there remains only limited evidence regarding vaccine effectiveness (VE) among pregnant women. Pregnant women have been shown to be at risk for severe COVID-19, resulting in adverse obstetrics outcomes, and their immune system is known to undergo alterations during pregnancy. Phase III clinical trials of the approved mRNA COVID-19 vaccines excluded pregnant women, yet current guidelines encourage offering the vaccine to pregnant women. In this study, we examine data from Israel’s largest healthcare organization to evaluate the effectiveness of the BNT162b2 mRNA vaccine among pregnant women. Methods: We conducted an observational cohort study of pregnant women 16 years or older, with no history of SARS-CoV-2, who were vaccinated between December 20, 2020 and June 3, 2021. Vaccinated subjects were matched to unvaccinated controls according to a set of demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. For each outcome, VE was estimated at several periods following vaccination as one minus the risk ratio using the Kaplan–Meier estimator. Results: 10,861 vaccinated women were matched to an identical number of unvaccinated controls. Estimated VE from 7 through 28 days after the second dose was 97% (95% CI 91%-100%) for any documented infection, 96% (86-100%) for infections with documented symptoms, and 85% (32%-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group, and no deaths were observed in either group -- insufficient incidence for estimating VE for these outcomes. Discussion: The BNT162b2 mRNA vaccine was found to have high VE among pregnant women. Since high VE has been reported as one of the strongest predictors of COVID-19 vaccine acceptance among pregnant women, the high VE estimates found in this study have the potential to increase vaccine acceptance in this group. In addition, the present VE estimates are similar to those reported in the general population for the same variants, suggesting that it may be possible to infer the VE for pregnant women from studies in the general population for both current and future variants.

Background and objectivesTo quantify the healthcare costs associated with opioid use disorder among members in a public healthcare system, and compare them to healthcare costs in the general population.MethodsRetrospective cohort study in inpatient and outpatient care settings of Israel’s largest public healthcare provider (that covers 4.7 million members).Participants included 1,173 members who had a diagnosis of opioid use disorder in the years between 2013 and 2018. Each patient was matched with 10 controls based on age and sex. The main outcome was monthly healthcare costs.ResultsThe mean monthly healthcare cost of members with opioid use disorder was $1,102 compared to $211 among controls (5.2-fold difference; 95% confidence interval [CI]: 4.6-6.0). After excluding members with heroin related diagnoses before the index date (in order to focus on prescription opioids), this healthcare cost ratio did not substantially change (4.6-fold; 95%-CI: 3.9-5.4). Members with opioid use disorder under the age of 65 years had a cost difference of 6.1-fold (95%-CI: 5.2-7.1), while those 65 years and older experienced cost difference of 3.4-fold (95%-CI: 2.6-4.5). The category with the highest cost for members with opioid use disorder was inpatient services, which was 8.7-fold (95%-CI 7.2-10.4) greater than among controls.ConclusionsHealthcare costs among individuals with opioid use disorder in a public health system were substantially higher than among controls, at least partially attributed to prescription opioid use disorder. Differences were greater among individuals younger than 65 years, highlighting the importance of preventing and treating opioid use disorder among younger adult populations.

Bacillus Calmette–Guerin (BCG) is a live attenuated form of Mycobacterium bovis that was developed 100 years ago as a vaccine against tuberculosis (TB) and has been used ever since to vaccinate children globally. It has also been used as the first-line treatment in patients with nonmuscle invasive bladder cancer (NMIBC), through repeated intravesical applications. Numerous studies have shown that BCG induces off-target immune effects in various pathologies. Accumulating data argue for the critical role of the immune system in the course of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we tested whether repeated exposure to BCG during the treatment of NMIBC is associated with the risk of developing AD and PD. We presented a multi-center retrospective cohort study with patient data collected between 2000 and 2019 that included 12,185 bladder cancer (BC) patients, of which 2301 BCG-treated patients met all inclusion criteria, with a follow-up of 3.5 to 7 years. We considered the diagnosis date of AD and nonvascular dementia cases for BC patients. The BC patients were partitioned into those who underwent a transurethral resection of the bladder tumor followed by BCG therapy, and a disjoint group that had not received such treatment. By applying Cox proportional hazards (PH) regression and competing for risk analyses, we found that BCG treatment was associated with a significantly reduced risk of developing AD, especially in the population aged 75 years or older. The older population (≥75 years, 1578 BCG treated, and 5147 controls) showed a hazard ratio (HR) of 0.726 (95% CI: 0.529–0.996, p-value = 0.0473). While in a hospital-based cohort, BCG treatment resulted in an HR of 0.416 (95% CI: 0.203–0.853, p-value = 0.017), indicating a 58% lower risk of developing AD. The risk of developing PD showed the same trend with a 28% reduction in BCG-treated patients, while no BCG beneficial effect was observed for other age-related events such as Type 2 diabetes (T2D) and stroke. We attributed BCG’s beneficial effect on neurodegenerative diseases to a possible activation of long-term nonspecific immune effects. We proposed a prospective study in elderly people for testing intradermic BCG inoculation as a potential protective agent against AD and PD.

HLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with COVID-19 severity. Studies have proposed associations, based on a very small sample and a large number of tested HLA alleles, but no clear association between HLA and COVID-19 incidence or severity has been reported. We conducted a large-scale HLA analysis of Israeli individuals who tested positive for SARS-CoV-2 infection by PCR. Overall, 72,912 individuals with known HLA haplotypes were included in the study, of whom 6413 (8.8%) were found to have SARS-CoV-2 by PCR. A total of 20,937 subjects were of Ashkenazi origin (at least 2/4 grandparents). One hundred eighty-one patients (2.8% of the infected) were hospitalized due to the disease. None of the 66 most common HLA loci (within the five HLA subgroups: A, B, C, DQB1, DRB1) was found to be associated with SARS-CoV-2 infection or hospitalization in the general Israeli population. Similarly, no association was detected in the Ashkenazi Jewish subset. Moreover, no association was found between heterozygosity in any of the HLA loci and either infection or hospitalization. We conclude that HLA haplotypes are not a major risk/protecting factor among the Israeli population for SARS-CoV-2 infection or severity. Our results suggest that if any HLA association exists with the disease it is very weak, and of limited effect on the pandemic. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01071-x.

IMPORTANCEDespite years of investigation and billions of dollars, there is no cure or even a disease-slowing remedy for Alzheimer’s disease (AD). Most studies thus far have focused on amyloid beta plaques (Aβ) and neurofibrillary tangles as therapeutic targets, and only a few on modulating the associated inflammatory process.OBJECTIVETo determine if exposure to Bacillus Calmette–Guérin (BCG) during treatment of non-muscle-invasive bladder cancer (NMIBC) is associated with a lower risk of developing AD.DESIGN, SETTING AND PARTICIPANTSMulticenter retrospective study of 12,185 bladder cancer patients including 2301 BCG-treated patients between 2000 and 2019 meeting all inclusion criteria. Data was retrieved from two tertiary hospital systems in Israel and the United States, and the largest Israeli health provider database, with a median follow up of 3.5 to 7 years.MAIN OUTCOMES AND MEASURESThe primary outcome was time to the first occurrence of AD/Dementia events following a diagnosis of bladder cancer by trans-urethral resection (TURBT) in BCG treated patients, and in bladder cancer patients not receiving BCG (control group).RESULTSBCG treatment was associated with a significantly reduced risk of developing AD in bladder cancer patients of ≥75 years following BCG treatment. A competing risk model using Cox Proportional-Hazard (PH) analysis applied to the largest medical records data showed a Hazard Ratio (HR) of 0.726 (95% CI: 0.529 – 0.996, P = 0.0473). The results were duplicated in analyzing NMIBC patients from a tertiary hospital with a HR of 0.416 (95% CI: 0.203 – 0.853, P = 0.017). A reduction in the risk (by 28%) for developing Parkinson’s disease (PD) was also shown in bladder cancer patients subjected to BCG immunotherapy.CONCLUSIONS AND RELEVANCEBCG treatment for bladder cancer patients was associated with a significantly reduced risk for developing AD and PD in the elderly population (>75 years), and in NMIBC patients from a tertiary hospital. Prospective studies in elderly inoculated with intradermic BCG should be initiated to evaluate the potential protective effect of BCG against AD and PD.KEY POINTSQuestionWhether bladder cancer patients treated with BCG immunotherapy have a lower risk to develop AD than bladder cancer patients that do not receive such treatment.FindingsIn a multicenter retrospective study composed of three cohorts covering >12,000 bladder cancer patients, those receiving intravesical BCG immunotherapy had a significantly lower risk of developing AD.MeaningIntradermal inoculation of BCG to elderly people should be tested as a potential preventive approach against AD.

Background As mass vaccination campaigns against coronavirus disease 2019 (Covid-19) commence worldwide, vaccine effectiveness needs to be assessed for a range of outcomes across diverse populations in a noncontrolled setting. In this study, data from Israel’s largest health care organization were used to evaluate the effectiveness of the BNT162b2 mRNA vaccine. Methods All persons who were newly vaccinated during the period from December 20, 2020, to February 1, 2021, were matched to unvaccinated controls in a 1:1 ratio according to demographic and clinical characteristics. Study outcomes included documented infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), symptomatic Covid-19, Covid-19–related hospitalization, severe illness, and death. We estimated vaccine effectiveness for each outcome as one minus the risk ratio, using the Kaplan–Meier estimator. Results Each study group included 596,618 persons. Estimated vaccine effectiveness for the study outcomes at days 14 through 20 after the first dose and at 7 or more days after the second dose was as follows: for documented infection, 46% (95% confidence interval [CI], 40 to 51) and 92% (95% CI, 88 to 95); for symptomatic Covid-19, 57% (95% CI, 50 to 63) and 94% (95% CI, 87 to 98); for hospitalization, 74% (95% CI, 56 to 86) and 87% (95% CI, 55 to 100); and for severe disease, 62% (95% CI, 39 to 80) and 92% (95% CI, 75 to 100), respectively. Estimated effectiveness in preventing death from Covid-19 was 72% (95% CI, 19 to 100) for days 14 through 20 after the first dose. Estimated effectiveness in specific subpopulations assessed for documented infection and symptomatic Covid-19 was consistent across age groups, with potentially slightly lower effectiveness in persons with multiple coexisting conditions. Conclusions This study in a nationwide mass vaccination setting suggests that the BNT162b2 mRNA vaccine is effective for a wide range of Covid-19–related outcomes, a finding consistent with that of the randomized trial.

Myocardial injury in hospitalized patients is associated with poor prognosis. This study aimed to evaluate risk factors for myocardial injury in hospitalized patients with coronavirus disease 2019 (COVID-19) and its prognostic value. We retrieved all consecutive patients who were hospitalized in internal medicine departments in a tertiary medical center from February 9th, 2020 to August 28thwith a diagnosis of COVID-19. A total of 559 adult patients were hospitalized in the Sheba Medical Center with a diagnosis of COVID-19, 320 (57.24%) of whom were tested for troponin levels within 24-hours of admission, and 91 (28.44%) had elevated levels. Predictors for elevated troponin levels were age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01–1.06), female sex (OR, 3.03; 95% CI 1.54–6.25), low systolic blood pressure (OR, 5.91; 95% CI 2.42–14.44) and increased creatinine level (OR, 2.88; 95% CI 1.44–5.73). The risk for death (hazard ratio [HR] 4.32, 95% CI 2.08–8.99) and a composite outcome of invasive ventilation support and death (HR 1.96, 95% CI 1.15–3.37) was significantly higher among patients who had elevated troponin levels. In conclusion, in hospitalized patients with COVID-19, elevated troponin levels are associated with poor prognosis. Hence, troponin levels may be used as an additional tool for risk stratification and a decision guide in patients hospitalized with COVID-19.