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•A comparative efficacy meta-analysis of high and standard dose influenza vaccines in the elderly.•Two trials showed the high-dose vaccine was associated with lower rates of influenza infection.•No evidence for clinically-relevant outcomes (influenza-associated hospitalizations and deaths).•Pragmatic trials will be needed to determine if superiority persists in real-world settings. Older adults are prioritized for influenza vaccination but also have lowered antibody responses to the vaccine. Higher-doses of influenza antigen may increase immune response and thus be more effective. Our objectives were to compare the efficacy and safety of the high-dose influenza vaccine to the standard-dose influenza vaccine in the elderly (age>65). Data sources: Randomized trials (RCTs) from Medline (Ovid), EMBASE (Ovid), Cochrane Library (Wiley), ClinicalTrials.gov, reference lists of relevant articles, and gray literature. Study selection: Two reviewers independently identified RCTs comparing high-dose influenza vaccine (60μg of hemagglutinin per strain) to standard-dose influenza vaccine (15μg of hemagglutinin per strain) in adults over the age of 65years. Data extraction: Two reviewers independently extracted trial-level data including population characteristics, interventions, outcomes, and funding sources. Risk of bias was assessed using the Cochrane Risk of Bias tool. We included seven eligible trials; all were categorized as having a low (n=3) or unclear (n=4) risk of bias. Patients receiving the high-dose vaccine had significantly less risk of developing laboratory-confirmed influenza infections (Relative Risk 0.76, 95%CI 0.65 to 0.90; I2 0%, 2 trials, 41,141 patients). Post-vaccination geometric mean titres and seroprotection rates were also higher in high-dose vaccine recipients. There were no protocol-defined serious adverse events in the included trials in either group. In elderly adults, the high-dose influenza vaccine was well-tolerated, more immunogenic, and more efficacious in preventing influenza infections than the standard-dose vaccine. Further pragmatic trials are needed to determine if the higher efficacy translates into higher vaccine effectiveness in adults over the age of 65.

AbstractObjectiveTo estimate the effectiveness of mRNA covid-19 vaccines against symptomatic infection and severe outcomes (hospital admission or death).DesignTest negative design study.SettingOntario, Canada between 14 December 2020 and 19 April 2021.Participants324 033 community dwelling people aged ≥16 years who had symptoms of covid-19 and were tested for SARS-CoV-2.InterventionsBNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine.Main outcome measuresLaboratory confirmed SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) and hospital admissions and deaths associated with SARS-CoV-2 infection. Multivariable logistic regression was adjusted for personal and clinical characteristics associated with SARS-CoV-2 and vaccine receipt to estimate vaccine effectiveness against symptomatic infection and severe outcomes.ResultsOf 324 033 people with symptoms, 53 270 (16.4%) were positive for SARS-CoV-2 and 21 272 (6.6%) received at least one dose of vaccine. Among participants who tested positive, 2479 (4.7%) were admitted to hospital or died. Vaccine effectiveness against symptomatic infection observed ≥14 days after one dose was 60% (95% confidence interval 57% to 64%), increasing from 48% (41% to 54%) at 14-20 days after one dose to 71% (63% to 78%) at 35-41 days. Vaccine effectiveness observed ≥7 days after two doses was 91% (89% to 93%). Vaccine effectiveness against hospital admission or death observed ≥14 days after one dose was 70% (60% to 77%), increasing from 62% (44% to 75%) at 14-20 days to 91% (73% to 97%) at ≥35 days, whereas vaccine effectiveness observed ≥7 days after two doses was 98% (88% to 100%). For adults aged ≥70 years, vaccine effectiveness estimates were observed to be lower for intervals shortly after one dose but were comparable to those for younger people for all intervals after 28 days. After two doses, high vaccine effectiveness was observed against variants with the E484K mutation.ConclusionsTwo doses of mRNA covid-19 vaccines were observed to be highly effective against symptomatic infection and severe outcomes. Vaccine effectiveness of one dose was observed to be lower, particularly for older adults shortly after the first dose.

Prenatal antibiotic exposure induces changes in infants' gut microbiota composition and is suggested as a possible contributor in the development of autism spectrum disorders (ASD). In this study, we examined the association between prenatal antibiotic exposure and the risk of ASD. This was a population-based cohort study utilizing the Manitoba Population Research Data Repository. The cohort included 214 834 children born in Manitoba, Canada between April 1, 1998 and March 31, 2016. Exposure was defined as having filled one or more antibiotic prescription during pregnancy. The outcome was autism spectrum disorder diagnosis. Multivariable Cox proportional hazards regression was used to estimate the risk of developing ASD in the overall cohort and in a sibling cohort. Of all subjects, 80 750 (37.6%) were exposed to antibiotics prenatally. During follow-up, 2965 children received an ASD diagnosis. Compared to children who were not exposed to antibiotics prenatally, those who were exposed had a higher risk of ASD: (adjusted HR 1.10 [95% CI 1.01, 1.19]). The association was observed in those exposed to antibiotics in the second or third trimester (HR 1.11 [95% CI 1.01, 1.23] and 1.17 [95% CI 1.06, 1.30], respectively). In the siblings' cohort, ASD risk estimate remained unchanged (adjusted HR 1.08 [95% CI 0.90, 1.30], although it was not statistically significant. Prenatal antibiotic exposure is associated with a small increase in the risk of ASD. Given the potential of residual confounding beyond what it was controlled through our study design and because of possible confounding by indication, such a small risk increase in the population is not expected to be clinically significant.

Influenza vaccine effectiveness (VE) is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012-13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses. Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA) sequencing of established haemagglutinin (HA) antigenic sites and phenotypically through haemagglutination inhibition (HI) assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011) as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%). Nearly two-thirds of viruses typed/subtyped were A(H3N2) (394/626; 63%); the remainder were A(H1N1)pdm09 (79/626; 13%), B/Yamagata (98/626; 16%) or B/Victoria (54/626; 9%). Suboptimal VE of 50% (95%CI: 33-63%) overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17-59%). All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16-80%) against A(H1N1)pdm09, 67% (95%CI: 30-85%) against B/Yamagata (vaccine-lineage) and 75% (95%CI: 29-91%) against B/Victoria (non-vaccine-lineage) viruses. These findings underscore the need to monitor vaccine viruses as well as circulating strains to explain vaccine performance. Evolutionary drift in circulating viruses cannot be regulated, but influential mutations introduced as part of egg-based vaccine production may be amenable to improvements.

Despite influenza vaccination programs in various jurisdictions, seasonal influenza vaccine (SIV) uptake remains suboptimal among older people ([greater than or equal to]65years old), an important subpopulation for influenza vaccination. We sought to summarize determinants of SIV uptake (any vaccine receipt) and vaccination adherence (receipt of vaccine in two or more seasons in sequence) among older people. We searched for population-based studies conducted in community-dwelling older people (irrespective of their health status) from 2000-2019. Two reviewers independently selected publications for inclusion. One reviewer extracted data from the included studies; a second checked the extracted data for errors. Disagreements were resolved by discussion and consensus, or a third reviewer. We were interested in the determinants of SIV uptake and vaccination adherence. Where appropriate, we pooled adjusted results using the inverse variance, random-effects method and reported the odds ratios (OR) and their 95% confidence intervals (CI). Out of 11,570 citations screened, we included 34 cross-sectional studies. The following were associated with increased SIV uptake: being older (OR 1.52, 95%CI 1.38-1.67 [21 studies]), white (1.30, 1.14-1.49 [10 studies]), married (1.23, 1.17-1.28 [9 studies]), non-smoker (1.28, 1.11-1.47 [7 studies]), of a higher social class (1.20, 1.06-1.36 [2 studies]), having a higher education (1.12, 1.04-1.21 [14 studies]), having a higher household income (1.11, 1.05-1.18 [8 studies]), having a chronic illness (1.53, 1.44-1.63 [16 studies]), having poor self-assessed health (1.23, 1.02-1.40 [9 studies]), having a family doctor (2.94, 1.79-4.76 [2 studies]), and having health insurance (1.58, 1.13-2.21 [6 studies]). The influence of these factors varied across geographical regions. Being older (1.26, 1.11-1.44 [2 studies]) was also associated with increased vaccination adherence. Several factors may determine SIV uptake and vaccination adherence among older people. More studies are needed to provide a stronger evidence base for planning more effective influenza vaccination programs.

The incidence of anogenital warts (AGW) decreased after the introduction of the quadrivalent human papillomavirus (qHPV) vaccine in multiple jurisdictions. We studied how comparing AGW incidence rates with different outcomes affects the interpretation of the qHPV vaccination program. To do this, we replicated multiple study designs within a single jurisdiction (Manitoba). We measured the incidence rates of AGW, AGW-related prescriptions, chlamydia, and gonorrhea (the latter two as sham outcomes) between 2001 and 2017 using several clinical and administrative health databases from Manitoba. We then used incidence rate ratios (IRRs) to compare, for each outcome, the rate for the 1997-1998 birth cohort (the first cohorts eligible for the publicly funded qHPV vaccination program) and the older 1995-1996 birth cohort. AGW incidence in Manitoba dropped 72% (95% confidence interval 54-83%) among 16-18 year-old girls and 51% (14-72%) among boys after the introduction of the female-only qHPV vaccination program. Trends in AGW-related prescriptions were different from trends in AGW diagnoses as these prescriptions peaked shortly after the introduction of the publicly funded qHPV vaccine program. Chlamydia and gonorrhea incidence rates also decreased 12% (5-18%) and 16% (-1-30%), respectively, for 16-18 year-old girls. The publicly funded school-based qHPV vaccine program reduced AGW incidence in Manitoba by three-quarters in young females. AGW-related prescriptions are a poor proxy for medically attended AGW after the introduction of the publicly funded qHPV vaccination program. Different sexual habits in adolescents are, at most, responsible for a small portion of the reduction in AGW incidence.

Objective To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism.Design Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016.Setting Community based, using healthcare data from six jurisdictions in Canada and the United States.Participants 59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis.Main outcome measures Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites.Results Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients.Conclusions In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment.Trial registration Clinical trials NCT02833987.

ABSTRACT Background Influenza may contribute to coronary/cerebrovascular events and exacerbate underlying conditions. Methods We used self‐controlled case series (SCCS) design to analyze data from US Veterans ≥18 years with coronary/cerebrovascular or exacerbation event +/−1 year of lab‐confirmed influenza (LCI) during 2010–2018. We estimated the incidence ratio (IR) (95% CI) of the event for risk interval (Days 1–7 post‐LCI) versus control interval (all other times +/−1 year of LCI) with fixed‐effects conditional Poisson regression. We included biomarker data for mediation analysis. Results We identified 3439 episodes with coronary/cerebrovascular‐related hospitalizations. IRs (95% CI) for LCI risk versus control interval were STEMI 0.6 (0.1, 4.4), NSTEMI 7.3 (5.8, 9.2), ischemic stroke 4.0 (3.0, 5.4), hemorrhagic stroke 6.2 (3.4, 11.5), and coronary spasm 1.3 (0.5, 3.0). IR significantly increased for NSTEMI and ischemic stroke among those ≥ 65 years. IR for NSTEMI and ischemic stroke dropped 26% and 10%, respectively, when white blood cell (WBC) and platelet count were considered. LCI was significantly associated with exacerbation of preexisting asthma, chronic obstructive pulmonary disease, and congestive heart failure. Conclusions We found significant association between LCI and hospitalization for NSTEMI, ischemic stroke, and hemorrhagic stroke, the latter possibly due to unaccounted time‐varying confounding in SCCS design.

Previous studies established an association between laboratory-confirmed influenza infection (LCI) and hospitalization for acute myocardial infarction (AMI) but not causality. We aimed to explore the underlying mechanisms by adding biological mediators to an established study design used by earlier studies. With data on biomarkers, we used a self-controlled case-series design to evaluate the effect of LCI on hospitalization for AMI among Veterans Health Administration (VHA) patients. We included senior Veterans (age 65 years and older) with LCI between 2010 through 2015. Patient-level data from VHA electronic medical records were used to capture laboratory results, hospitalizations, and baseline patient characteristics. We defined the \"risk interval\" as the first 7 days after specimen collection and the \"control interval\" as 1 year before and 1 year after the risk interval. More importantly, using mediation analysis, we examined the role of abnormal white blood cell (WBC) and platelet count in the relationship between LCI and AMI to explore the thrombogenic nature of this association, thus potential causality. We identified 391 hospitalizations for AMI that occurred within +/-1 year of a positive influenza test, of which 31 (31.1 admissions/week) occurred during the risk interval and 360 (3.5/per week) during the control interval, resulting in an incidence ratio (IR) for AMI admission of 8.89 (95% confidence interval [CI]: 6.16-12.84). In stratified analyses, AMI risk was significantly elevated among patients with high WBC count (IR, 12.43; 95% CI: 6.99-22.10) and high platelet count (IR, 15.89; 95% CI: 3.59-70.41). We confirmed a significant association between LCI and AMI. The risk was elevated among those with high WBC or platelet count, suggesting a potential role for inflammation and platelet activation in the underlying mechanism.

A higher proportion of colorectal neoplasia among women occurs in the proximal colon, which might be more frequently missed by colonoscopy. There are no data on predictors of developing colorectal cancer (CRC) after a negative colonoscopy in usual clinical practice. We evaluated gender differences and predictors of CRC occurring after a negative colonoscopy. All individuals 40 years or older with negative colonoscopy were identified from Manitoba's provincial physicians' billing claims database. Individuals with less than 5 years of coverage by the provincial health plan, earlier CRC, inflammatory bowel disease, resective colorectal surgery, or lower gastrointestinal endoscopy were excluded. CRC risk after negative colonoscopy was compared to that in the general population by standardized incidence ratios. Cox regression analysis was performed to determine the independent predictors of CRC occurring after negative colonoscopy. A total of 45,985 individuals (18,606 men; 27,379 women) were followed up for 229,090 person-years. After a negative colonoscopy, men had a 40-50% lower risk of CRC diagnosis through most of the follow-up time. Risk among women was similar to that of women in the general population in the first 3 years and then was 40-50% lower. Older subject age and performance of index colonoscopy by non-gastroenterologists were independent predictors for early/missed CRC (cancers occurring within 3 years of negative colonoscopy). Women may have a higher rate of missed/early CRCs after negative colonoscopy. Predictors of missed/early CRCs after negative colonoscopy include older age and performance of index colonoscopy by a non-gastroenterologist.