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Background A major goal of coronavirus disease 2019 (COVID-19) vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of messenger RNA (mRNA) and ChAdOx1 COVID-19 vaccines against severe outcomes in 4 Canadian provinces between December 2020 and September 2021. Methods We conducted this multiprovincial, retrospective, test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random-effects models. Results We included 2 508 296 tested participants, with 31 776 COVID-19 hospitalizations and 5842 deaths. Vaccine effectiveness was 83% after a first dose and 98% after a second dose against both hospitalization and death (separately). Against severe outcomes, effectiveness was 87% (95% confidence interval [CI], 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95% CI, 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95% CI, 75%–94%) ≥56 days after a first dose, increasing to 97% (95% CI, 91%–99%) ≥56 days after a second dose. Lower 1-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules and against Alpha, Gamma, and Delta variants. Conclusions Two doses of mRNA or ChAdOx1 vaccine provide excellent protection against severe outcomes.

Background Changes to pertussis vaccination programmes can have impacts on disease burden that should be estimated independently from factors such as age- and period-related trends. We used age-period-cohort (APC) models to explore pertussis incidence in Manitoba over a 25-year period (1992–2017). Methods We identified all laboratory-confirmed cases of pertussis from Manitoba’s Communicable Diseases Database and calculated age-standardized incidence rates. We used APC models to investigate trends in pertussis incidence. Results During the study period, 2479 cases were reported. Age-standardized rates were highest during a large outbreak in 1994 (55 cases/100 000 person-years), with much lower peaks in 1998, 2012 and 2016. We saw strong age and cohort effects in the APC models, with a steady decrease in incidence with increasing age and increased risk in the cohort born between 1980 and 1995. Conclusions The highest risk for pertussis was consistently in young children, regardless of birth cohort or time period. The 1981 programme change to an adsorbed whole-cell pertussis vaccine with low effectiveness resulted in reduced protection in the 1981–95 birth cohort and contributed to the largest outbreak of disease during the 25-year study period.

Background We examined the influence of some factors on seasonal influenza vaccine effectiveness (VE) from test-negative design (TND) studies. Methods We systematically searched for full-text publications of VE against laboratory-confirmed influenza from TND studies in outpatient settings after the 2009/10 influenza pandemic. Two reviewers independently selected and extracted data from the included studies. We calculated pooled adjusted VE across geographical regions, age groups and levels of vaccine antigenic similarity with circulating virus strains, using an inverse variance, random-effects model. Results We included 76 full-text articles from 11,931 citations. VE estimates against A(H1N1)pdm09, A(H3N2), influenza B, and all influenza were homogenous and point pooled VE higher in the Southern hemisphere compared with the Northern hemisphere. The difference in pooled VE between the Southern and Northern hemispheres was statistically significant for A(H3N2), influenza B, and all influenza. A consistent pattern was observed in pooled VE across both hemispheres and continents, with the highest point pooled VE being against A(H1N1)pdm09, followed by influenza B, and lowest against A(H3N2). A nearly consistent pattern was observed in pooled VE across age groups in the Northern hemisphere, with pooled VE mostly decreasing with age. Point pooled VE against A(H3N2), influenza B, and all influenza were statistically significantly higher when vaccine was antigenically similar to circulating virus strains compared with when antigenically dissimilar. Similar pattern was observed in the Northern hemisphere, but there was a lack of data from the Southern hemisphere. Conclusion Consistent patterns appear to exist in seasonal influenza VE across regions, age groups, and levels of vaccine antigenic similarity with circulating virus strains, with best vaccine performance against A(H1N1)pdm09 and worst against A(H3N2). The evidence highlights the need to consider geographical location, age, and vaccine antigenic similarity with circulating virus strains when designing and evaluating influenza VE studies.

Background In children with epilepsy, fever and illness are known triggers for seizure; therefore, clinicians and parents could be concerned that immunization-induced inflammation and fever could also trigger seizures. We sought to estimate the risk of emergency department (ED) visit or hospitalization for epilepsy/seizure and all causes after immunization in children younger than 7 years of age with epilepsy. Methods We conducted a self-controlled case series of children diagnosed with epilepsy before their 7th birthday and immunized from 2005 to 2015 in Ontario (population 14.2 million) and Manitoba (population 1.3 million), Canada, using administrative healthcare data. We estimated the age- and season-adjusted relative incidence (aRI) of epilepsy/seizure-related and all-cause ED visits/hospitalizations during various risk periods 0-28 days after inactivated and live immunizations versus a control period 35-83 days postimmunization. Estimates from each province were analyzed separately and then combined in a random-effects meta-analysis. Results The combined risk of epilepsy/seizure-related hospitalization/ED visit was increased 0-2 days after inactivated vaccines (aRI = 1.5, 95% confidence interval: 1.1-1.9) and 7-10 days after live vaccines (aRI = 1.9, 1.4-2.7). For all-cause ED visit/hospitalization, the combined aRI estimate was 0.9 (0.8-1.2) 0-2 days after inactivated vaccines and 1.3 (1.1-1.5) 7-10 days after live vaccines. Conclusions The risk of epilepsy/seizure-related ED visit/hospitalization was modestly increased among children with epilepsy during peak periods of fever and inflammation following inactivated and live vaccines. These risks must be balanced against the risk of complications from vaccine-preventable diseases.

BackgroundA major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021.MethodsWe conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models.ResultsWe included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%–94%) ≥56 days after a first dose, increasing to 97% (95%CI: 91%–99%) ≥56 days after a second dose. Lower one-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants.ConclusionsTwo doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.

We investigated the role of individual, community and vaccinator characteristics in mediating racial/ethnic disparities in the uptake of differentiated influenza vaccines (DIVs; including high-dose, adjuvanted, recombinant and cell-based vaccines). We included privately-insured (commercial and Medicare Advantage) ≥65 years-old community-dwelling health plan beneficiaries in the US with1 year of continuous coverage and who received ≥1 influenza vaccine during the study period (July 2014-June 2018). Of 2.8 million distinct vaccination claims, 60% were for DIVs; lower if received in physician offices (49%) compared to pharmacies/facilities (74%). Among those vaccinated in physician offices, non-whites had lower odds of receiving a DIV if they lived in a non-minority county (0.77;95%CI 0.75-0.80) and even lower odds if they lived in a minority county (0.62;0.60-0.63). Differences in education, household income, medical history, community and vaccinator characteristics did not fully explain the disparities. Similar patterns emerged for vaccinations in pharmacies/facilities, although disparities disappeared altogether after controlling for socio-economic and vaccinator characteristics. When vaccinated in physician offices, minority county residents were less likely to receive a DIV, especially for non-whites (0.72;0.67-0.78). These disparities disappeared for whites, but not for non-whites, after controlling for community and vaccinator characteristics. We found an alarming level of inequity in DIV vaccine uptake among fully insured older adults that could not be fully explained by differences in sociodemographic, medical, community, and vaccinator characteristics. New strategies are urgently needed to address these inequities.

Better CLL patient survival has been reported for specialized CLL clinics/hematologists (compared to other CLL patients). It is possible that improved survival is driven by a better prognosis of referred patients.We used logistic regression to calculate the odds ratios (ORs) and 95 % confidence intervals 95 %CIs) of the association between patient characteristics and CLL referral of all persons diagnosed in 2005-2016 with a pathologically-confirmed CLL or SLL.Two-thirds of 1293 patients were referred to the CLL clinic. Referred patients were younger (16 % vs 44 % were 80 +) and in better health (47 % vs 56 % with a chronic diseases) than non-referred patients. Referral increased over time: in 2005-2010, about 60 % of patients were referred; in 2011-2016, this increased to 76 %. Gender did not affect referral (the OR for females is 1.0, 95 %CI 0.8-1.2), but age played a major role; CLL patients diagnosed at age 80 + were less likely to be referred than patients diagnosed 60, 0.2 (0.1-0.3).Because referral to Manitoba's specialized CLL clinic is associated with age and the patient's overall health before referral, one should be careful in interpreting differences in outcomes between CLL patients based on referral status alone.

Objective To estimate the effectiveness of mRNA covid-19 vaccines against symptomatic infection and severe outcomes (hospital admission or death). Design Test negative design study. Setting Ontario, Canada between 14 December 2020 and 19 April 2021. Participants 324 033 community dwelling people aged ≥16 years who had symptoms of covid-19 and were tested for SARS-CoV-2. Interventions BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. Main outcome measures Laboratory 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. Results Of 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. Conclusions Two 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.

Background Pertussis persists in Manitoba despite the universal availability of pertussis vaccines. Recent cases have included previously vaccinated individuals, raising concerns about declining vaccine effectiveness (VE). We measured pertussis VE and duration of protection using Manitoba’s provincial immunization and communicable disease registries. Methods Using a nested case-control design, individuals with laboratory-confirmed pertussis in Manitoba diagnosed between April 1, 1992, and March 31, 2015, were matched to up to five population-based controls on age, gender, geography, and case physician or number of physician visits. Conditional logistic regression was used to estimate VE against pertussis for both the whole-cell (wP) and acellular (aP) pertussis vaccines. Duration of protection was assessed using time since last dose. Results Data on 534 eligible cases and 2614 controls were available for analysis. The adjusted VE estimate for aP-containing vaccines was 85% (95%CI: 74–91%); VE was 89% (66–96%) one to three years after the last vaccination. The adjusted VE of wP-containing vaccines was –15% (–91–31%) during a large outbreak in 1994 and 1995 compared to 35% (–26–66%) during non-outbreak years. Conclusions Our estimates suggest that the aP vaccine was effective in preventing pertussis since its introduction in Manitoba. VE was lower during a large outbreak, highlighting the importance of separately analyzing outbreak periods when estimating pertussis VE over time.

Several epidemiological studies have found an association between maternal antibiotics use during pregnancy and increased risk of certain cancer types, although conclusions differ between studies. We examined this association in a cohort study including 262 116 mother‐child pairs of Manitoba births between 1996 and 2013. Maternal antibiotics use during prepregnancy (6 months prior to pregnancy) and pregnancy periods was assessed. Children's cancer incidence was tracked up to the end of the follow‐up period (December 2015). We calculated incidence rate and used Cox regression to estimate adjusted hazard ratios (HRs). Antibiotics use during pregnancy was not associated with overall cancer (HR = 1.1, 95% confidence interval 0.9‐1.4), leukemias (1.3, 0.9‐1.8), or acute lymphocytic leukemia (1.1, 0.7‐1.6). The association between antibiotics use and overall cancer risk differed by trimester: 1.5 (1.1‐1.9) in the first, 0.8 (0.6‐1.0) in the second, and 1.1 (0.8‐1.5) in the third trimester. Further research is necessary to confirm the association between first‐trimester exposure and cancer risk after a better controlling of confounding factors.

Background: Recent studies have reported reduced risk of chronic lymphocytic leukemia (CLL) among statin users. However, the possibility that the effect of statins may differ by their chemical or pharmacodynamic properties has not been investigated. Methods: In this nested case-control study, all Manitobans aged ≥ 40 years when diagnosed with CLL (as a first cancer) from 1999 to 2014 (n=1,385) were matched (on gender, age, residence, and duration of insurance coverage) to cancer-free controls (n=6,841). Using conditional logistic regression, statin use was analyzed by individual statins and groups: hydrophilic, low-potency lipophilic (fluvastatin and lovastatin) and high-potency lipophilic statins. Results: Statin users constituted 27% and 28% of the CLL cases and controls. After adjusting for potential confounding by indication, patterns of healthcare utilization and use of other drugs, CLL incidence was not associated with use of hydrophilic (odds ratio: 1.08; 95% confidence interval: 0.86-1.34) or high-potency lipophilic statins (0.94; 0.79-1.11). Low-potency lipophilic statins were associated with a lower risk of CLL (0.64; 0.45-0.92), with stronger association (0.44; 0.22-0.88) observed with more regular use (half to full standard dose on average). Conclusions: We found an association between low-potency lipophilic statin use and reduced CLL risk, with a possible dose-response effect. Impact: While requiring replication in future studies, our findings suggest that the effect of statins on CLL risk may depend on their specific chemical or pharmacodynamic properties.

The effectiveness of a vaccination program is influenced by its design and implementation details and by the target population characteristics. Using routinely collected population-based individual-level data, we assessed the effectiveness (against cervical dysplasia) of Manitoba's quadrivalent human papillomavirus (qHPV) routine school-based vaccination program and a short-lived campaign that targeted women at high-risk of developing cervical cancer. Females ≥9 years old who received the qHPV vaccine in Manitoba (Canada) between September 1, 2006, and March 31, 2013 (N = 31,442) were matched on age and area of residence to up to three unvaccinated females. Cox proportional hazards models were used to estimate qHPV VE against high-grade (HSILs) and low-grade squamous intraepithelial lesions (LSILs) and atypical squamous cells of undetermined significance (ASCUS). Among 14-17-year-old participants who had Pap cytology after enrollment, the adjusted qHPV VE estimates were 30% (17-58%) and 36% (21-48%) against the detection of HSILs and LSILs, respectively. There was, however, no evidence of program effectiveness among females vaccinated at ≥18 years of age and among those with a history of abnormal cytology, who were mostly vaccinated as part of the high-risk program. Estimates of VE for females vaccinated in the school-based program are consistent with the expected benefits from qHPV vaccination. No similar benefits were detected among women vaccinated at an older age, and those with abnormal cytology, who were targeted by the high-risk program. Further efforts should be targeted at achieving higher vaccine coverage among preadolescents, prior to the initiation of sexual activity.

ObjectivesTo estimate the effectiveness of mRNA COVID-19 vaccines against symptomatic infection and severe outcomes.DesignWe applied a test-negative design study to linked laboratory, vaccination, and health administrative databases, and used multivariable logistic regression adjusting for demographic and clinical characteristics associated with SARS-CoV-2 and vaccine receipt to estimate vaccine effectiveness (VE) against symptomatic infection and severe outcomes.SettingOntario, Canada between 14 December 2020 and 19 April 2021.ParticipantsCommunity-dwelling adults aged ≥16 years who had COVID-19 symptoms and were tested for SARS-CoV-2.InterventionsPfizer-BioNTech’s BNT162b2 or Moderna’s mRNA-1273 vaccine.Main outcome measuresLaboratory-confirmed SARS-CoV-2 by RT-PCR; hospitalization/death associated with SARS-CoV-2 infection.ResultsAmong 324,033 symptomatic individuals, 53,270 (16.4%) were positive for SARS-CoV-2 and 21,272 (6.6%) received ≥1 vaccine dose. Among test-positive cases, 2,479 (4.7%) had a severe outcome. VE against symptomatic infection ≥14 days after receiving only 1 dose was 60% (95%CI, 57 to 64%), increasing from 48% (95%CI, 41 to 54%) at 14–20 days after the first dose to 71% (95%CI, 63 to 78%) at 35–41 days. VE ≥7 days after 2 doses was 91% (95%CI, 89 to 93%). Against severe outcomes, VE ≥14 days after 1 dose was 70% (95%CI, 60 to 77%), increasing from 62% (95%CI, 44 to 75%) at 14–20 days to 91% (95%CI, 73 to 97%) at ≥35 days, whereas VE ≥7 days after 2 doses was 98% (95%CI, 88 to 100%). For adults aged ≥70 years, VE estimates were lower for intervals shortly after receiving 1 dose, but were comparable to younger adults for all intervals after 28 days. After 2 doses, we observed high VE against E484K-positive variants.ConclusionsTwo doses of mRNA COVID-19 vaccines are highly effective against symptomatic infection and severe outcomes. Single-dose effectiveness is lower, particularly for older adults shortly after the first dose.

ObjectiveThe objective of this study was to estimate background rates of selected thromboembolic and coagulation disorders in Ontario, Canada.DesignPopulation-based retrospective observational study using linked health administrative databases. Records of hospitalizations and emergency department visits were searched to identify cases using diagnostic codes from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Canada (ICD-10-CA).ParticipantsAll Ontario residents.Primary outcome measuresIncidence rates of stroke, deep vein thrombosis, pulmonary embolism, idiopathic thrombocytopenia, disseminated intravascular coagulation, and cerebral venous thrombosis during five pre-pandemic years (2015–2019, annually, averaged, and monthly average) and 2020.ResultsThe average annual population was 14 million with 51% female. The mean annual rates during 2015–2019 were 127.1/100,000 population (95% confidence interval [CI], 126.2, 127.9) for ischemic stroke, 22.0/100,000 (95%CI, 21.6, 22.3) for intracerebral haemorrhage, 9.4 (95%CI, 9.2, 9.7) for subarachnoid haemorrhage, 86.8/100,000 (95%CI, 86.1, 87.5) for deep vein thrombosis, 63.7/100,000 (95%CI, 63.1, 64.3) for pulmonary embolism, 6.1/100,000 (95%CI, 5.9, 6.3) for idiopathic thrombocytopenia, 1.6/100,000 (95%CI, 1.5, 1.7) for disseminated intravascular coagulation, and 1.5/100,000 (95%CI, 1.4, 1.6) for cerebral venous thrombosis. Rates were lower in 2020 than during the pre-pandemic years for ischemic stroke, deep vein thrombosis, and idiopathic thrombocytopenia. Rates were generally consistent over time, except for pulmonary embolism, which increased from 57.1 to 68.5 per 100,000 between 2015 and 2019. Rates were higher for females than males for subarachnoid haemorrhage, pulmonary embolism, and cerebral venous thrombosis, and vice versa for ischemic stroke and intracerebral haemorrhage. Rates increased with age for most of these conditions, but idiopathic thrombocytopenia demonstrated a bimodal distribution with incidence peaks at 0–19 years and ≥60 years.ConclusionsOur estimated background rates help to contextualize observed events of these potential adverse events of special interest and to detect potential safety signals related to COVID-19 vaccines.Strengths and limitations of this study➢Recent background rates of selected thromboembolic and coagulation disorders that are potential adverse events special interest related to COVID-19 vaccine are estimated.➢Background rates during five pre-pandemic (2015–2019) years and 2020 will provide context for these events to identify vaccine safety signals.➢We used recorded diagnostic codes in administrative data without information on clinical and/or diagnostic confirmation, and the validity of these data are imperfect, which may result in under or overestimation.

BackgroundEvidence suggests that repeated influenza vaccination may reduce vaccine effectiveness (VE). Using influenza vaccination program maturation (PM; number of years since program inception) as a proxy for population-level repeated vaccination, we assessed the impact on pooled adjusted end-season VE estimates from outpatient test-negative design studies.MethodsWe systematically searched and selected full-text publications from January 2011 to February 2020 (PROSPERO: CRD42017064595). We obtained influenza vaccination program inception year for each country and calculated PM as the difference between the year of deployment and year of program inception. We categorized PM into halves (cut at the median), tertiles, and quartiles and calculated pooled VE using an inverse-variance random-effects model. The primary outcome was pooled VE against all influenza.ResultsWe included 72 articles from 11 931 citations. Across the 3 categorizations of PM, a lower pooled VE against all influenza for all patients was observed with PM. Substantially higher reductions were observed in older adults (≥65 years). We observed similar results for A(H1N1)pdm09, A(H3N2), and influenza B.ConclusionsThe evidence suggests that influenza VE declines with vaccination PM. This study forms the basis for further discussions and examinations of the potential impact of vaccination PM on seasonal VE.

A comprehensive review of observational pertussis vaccine effectiveness (VE) studies is needed to update gaps from previous reviews. We conducted a systematic review of VE and duration of protection studies for the whole-cell (wP) and acellular (aP) pertussis vaccines and conducted a formal meta-analysis using random effects models. Evidence continues to suggest that receipt of any pertussis vaccine confers protection in the short-term against disease although this protection wanes rapidly for aP vaccine. We detected significant heterogeneity in pooled estimates due, in part, to factors such as bias and confounding which may be mitigated by study design. Our review of possible sources of heterogeneity may help interpretation of other VE studies and aid design decisions in future pertussis VE research.

Limited time for seasonal influenza vaccine development means that the World Health Organization has to consider interim (early) rather than final vaccine effectiveness (VE) estimates in deciding influenza vaccine composition. We assessed agreement between interim and final VE estimates, and factors that may determine a substantial difference (≥10%) between point estimates. This was a mixed methods study. We systematically searched, identified, and matched interim/final VE studies of test-negative design (TND) type in outpatient settings after the 2009/10 influenza pandemic. The chi-square statistic (χ2) was used to assess the statistical significance of the difference between paired interim/final VE estimates. We calculated the difference between point estimates and used multivariable logistic regression to assess factors that may determine a substantial difference. We identified 68 interim/final VE pairs. There was no statistically significant difference between almost all compared pairs. An inconsistent statistical model for interim/final VE estimation and interim VE estimation before the epidemic peak increased the odds of having a substantial difference between estimates. : Interim influenza VE appears to be sufficient for vaccine composition decision-making. Consistency in interim/final VE estimation, and interim VE estimation during/after epidemic peak may increase agreement between the VE estimates.

Background: We estimated the effectiveness of BNT162b2 and mRNA-1273 vaccines among residents of Ontario, Canada, where a policy to use an up to 16-week interval between doses was adopted in March 2021. Methods: We conducted a test-negative design study using linked province-wide laboratory, vaccination, and health administrative datasets. We included symptomatic individuals tested for SARS-CoV-2 by RT-PCR between 14 December 2020 and 19 April 2021. Study outcomes included symptomatic infection and associated severe outcomes (hospitalization or death). We estimated adjusted vaccine effectiveness (aVE) using multivariable logistic regression. Findings: Among 324,033 symptomatic tested individuals, 53,270 (16·4%) were positive for SARS-CoV-2 and 21,272 (6·6%) had received ≥1 dose of mRNA vaccine. Among test-positive cases, 2,479 (4·7%) had a severe outcome. aVE against symptomatic infection ≥14 days after receiving only 1 dose was 60% (95%CI, 57–64%), increasing from 48% (95%CI, 41–54%) at 14–20 days after the first dose to 71% (95%CI, 63–78%) at 35–41 days. aVE ≥7 days after receiving 2 doses was 91% (95%CI, 89–93%). Against severe outcomes, aVE ≥14 days after receiving 1 dose was 70% (95%CI, 60–77%) and aVE ≥7 days after receiving 2 doses was 98% (95%CI, 88–100%). We observed lower aVE against both outcomes after receiving 1 dose for adults aged ≥70 years, but aVE estimates for older adults were comparable to younger adults after 28 days. After 2 doses, we observed high aVE against E484K-positive variants. Interpretation: Our findings suggest that 2 doses of BNT162b2 and mRNA-1273 vaccines are highly effective against both symptomatic infection and associated severe outcomes for all circulating variants, with effectiveness lower after only a single dose, particularly for older adults shortly after the first dose. Funding Information: Canadian Institutes of Health Research, Public Health Agency of Canada, Ontario Ministries of Health and Long-Term Care. Declaration of Interests: KW is CEO of CANImmunize and serves on the data safety board for the Medicago COVID-19 vaccine trial. SMM has received unrestricted research grants from Merck, GlaxoSmithKline, Sanofi Pasteur, Pfizer, and Roche-Assurex for unrelated studies. SMM has received fees as an advisory board member for GlaxoSmithKline, Merck, Pfizer, Sanofi Pasteur, and Seqirus. CHR has received an unrestricted research grant from Pfizer for an unrelated study. The other authors declare no conflicts of interest. Ethics Approval Statement: ICES is a prescribed entity under Ontario’s Personal Health Information Protection Act (PHIPA). Section 45 of PHIPA authorizes ICES to collect personal health information, without consent, for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, the allocation of resources to or planning for all or part of the health system. Projects that use data collected by ICES under section 45 of PHIPA, and use no other data, are exempt from REB review. The use of the data in this project is authorized under section 45 and approved by ICES’ Privacy and Legal Office.

BACKGROUND Pertussis remains poorly controlled relative to other diseases targeted by childhood vaccination programs. We combined estimates from four population-based studies of pertussis vaccine effectiveness (VE) in three Canadian provinces using a meta-analytic approach to improve precision and explore regional variation in VE and durability of protection. METHODS Studies were conducted in Alberta, Manitoba, and Ontario over periods ranging from 1996 to 2015. Adjusted log odds ratios (OR; VE = 100*[1-OR]) of the effect of vaccination on pertussis risk were estimated by time since last vaccination in each study and pooled using DerSimonian and Laird random-effects models. We used the I2 statistic to estimate between-study heterogeneity and assessed methodological and clinical heterogeneity through subgroup analyses of study design and age. RESULTS Data on 3,270 pertussis cases and 23,863 controls were available. Pertussis VE declined from 86% (95% CI 79%-90%, I2 = 81.5%) at

BackgroundThere is little information on the economic burden of human papillomavirus-related diseases (HPV-RDs) among men. We used province-wide clinical, administrative and accounting databases to measure the direct medical costs of HPV infections in men in Manitoba (Canada).MethodsWe included all males aged 9 years and older with health insurance coverage in Manitoba between January 1997 and December 2016. We identified HPV-RD patient cohorts and matched each patient to HPV-RD-free men. We estimated the net direct medical cost (excess cost of hospitalizations, outpatient visits, and prescription drugs) of patients compared to their matches for anogenital warts (AGWs) and HPV-caused cancers. We adjusted costs to 2017 Canadian dollars. For each condition, we attributed costs to HPV based on the etiological fraction caused by HPV infection.ResultsWe found that the median net direct medical cost was about $250 for AGW patients and $16,000 for invasive cancer patients. The total cost was about $49 million or $2.6 million per year. Overall, 54%-67% ($26-$33 million) was attributable to HPV infection according different estimates of the attributable fraction. The net annual attributable cost was $2.37-$2.95 per male resident and $161-$200 per male newborn. The estimated potential savings was 30% for the bivalent vaccine and 56%-60% for the quadrivalent and nonavalent vaccines.ConclusionsOverall, HPV’s economic burden on males remains significant, the average cost of treating all conditions attributable to HPV was about $180 per male newborn. Invasive cancer accounted for the majority of these costs.

Objectives Children with epilepsy are at increased risk of complications from vaccine-preventable infections, yet information on vaccine coverage in these children is scarce. We aimed to compare vaccine coverage among children with epilepsy to children without epilepsy. Study design We conducted a retrospective cohort study including all 2005–2013 births in Manitoba and Ontario, Canada, creating two cohorts: 2-year-olds and 7-year-olds (followed to age 2 and 7 years). We split each cohort into epilepsy and non-epilepsy subcohorts. We assessed vaccination coverage based on provincial schedules and determined timeliness of MMR (measles, mumps, rubella) dose 1 (recommended at 12 months) and DTaP (diphtheria, tetanus, pertussis) dose 4 (recommended at 18 months). We used logistic regression to calculate adjusted odds ratios (aORs) of the association between epilepsy and vaccination, combining both provincial estimates using random effects meta-analysis. Results We included 16,558 2-year-olds (Manitoba, 653; Ontario, 15,905) and 13,004 7-year-olds (Manitoba, 483; Ontario, 12,521) with epilepsy. At age 2 years, the aOR for up-to-date vaccination among children with versus without epilepsy was 0.9 (95% confidence interval 0.8–1.1); at age 7 years it was 1.0 (0.9–1.1). Infants diagnosed with epilepsy before age 6 months were less likely to be up-to-date at age 2 years (0.9; 0.8–0.9), although this difference disappeared by age 7 years. Vaccine timeliness was similar between children with and without epilepsy for MMR dose 1 and DTaP dose 4. Conclusions Overall, this study suggests that children with epilepsy are not significantly under-vaccinated compared to their peers without epilepsy. As children with epilepsy are at a higher risk of complications from vaccine-preventable diseases, vaccination in children with epilepsy should be optimized, especially early in life, as these children may not be able to rely on herd protection.

Background Study characteristics influence vaccine effectiveness (VE) estimation. We examined the influence of some of these on seasonal influenza VE estimates from test-negative design (TND) studies. Methods We systematically searched bibliographic databases and websites for full-text publications of TND studies on VE against laboratory-confirmed seasonal influenza in outpatients after the 2009 pandemic influenza. We followed the Cochrane Handbook for Systematic Reviews of Interventions guidelines. We examined influence of source of vaccination information, respiratory specimen swab time, and covariate adjustment on VE. We calculated pooled adjusted VE against H1N1 and H3N2 influenza subtypes, influenza B, and all influenza using an inverse-variance random-effects model. Results We included 70 full-text articles. Pooled VE against H1N1 and H3N2 influenza subtypes, influenza B, and all influenza was higher for studies that used self-reported vaccination than for those that used medical records. Pooled VE was higher with respiratory specimen collection within ≤7 days vs ≤4 days of symptom onset, but the opposite was observed for H1N1. Pooled VE was higher for studies that adjusted for age but not for medical conditions compared with those that adjusted for both. There was, however, a lack of statistical significance in almost all differences in pooled VE between compared groups. Conclusions The available evidence is not strong enough to conclude that influenza VE from TND studies varies by source of vaccination information, respiratory specimen swab time, or adjustment for age/medical conditions. The evidence is, however, indicative that these factors ought to be considered while designing or evaluating TND studies of influenza VE.

In this article, we present attrition, a suite of commands to simplify the maintenance and documentation of implemented exclusion criteria and attrition conditions using standard Stata facilities and to generate an attrition diagram. attrition can be used, both from the command line and in do-files, to keep the diagram up to date with the analysis it documents. Six subcommands (set, exclude, count, tab, list, graph) allow the diagram to be constructed in a versatile way.

BACKGROUND We assessed the effectiveness of the quadrivalent human papillomavirus vaccine (qHPV) vaccination program in Manitoba, Canada, in reducing incident anogenital warts (AGWs) and to what extent effectiveness depends on age at vaccination and number of doses. METHODS Female participants 9 years or older who received the qHPV in Manitoba between September 2006 and March 2013 (n = 31,464) through the publicly funded school-based program and a high-risk catch-up program were included. They were matched on age and area of residence to unvaccinated female participants. Information on incident AGWs was obtained from provincial administrative databases using validated algorithms. Using stratified Cox regression models, we estimate hazard ratios (HRs) for the association between qHPV and AGWs. RESULTS For female participants vaccinated at age 18 years or younger, receipt of qHPV was associated with a 40% reduction in AGW risk (HR, 0.6; 95% confidence interval [CI], 0.4-0.8). Further adjustment for socioeconomic and medical history did not alter this estimate. For women vaccinated at age 19 years or older, we saw an increase in AGW incidence, especially among those who were sexually active (HR, 2.8; 95% CI, 2.1-3.7). Among female participants vaccinated at age 18 years or younger, risk of AGWs was lowest among those who received 3 doses, corresponding to a vaccine effectiveness of 56% (95% CI, 30%-70%). For women vaccinated at older age, risk of AGWs remained increased regardless of the number of doses. CONCLUSIONS Women vaccinated at an older (≥19 years) age may be less protected against AGWs, particularly if sexually active before vaccine administration. Further efforts should be targeted at increasing vaccine uptake among preadolescents before the initiation of sexual activity.

Non-Hodgkin lymphomas (NHL) are a group of cancers with highly heterogeneous biology and clinical features. Statins are increasingly prescribed to prevent cardiovascular diseases. Early evidence shows a preventive effect of statins for some cancers, but their effect on NHL risk is unclear. We conducted a population-based nested case-control study involving 5,541 NHL cases and 27,315 controls matched for gender, age, place of residence and length of period of available prescription drug data. We assessed the use of statins prior to diagnosis (excluding the 12 months prior to the index date). We used conditional logistic regression models to estimate odds ratio (OR) and 95% confidence interval (CI) for use of any statin, adjusting for medical conditions, number of family physician visits for 5 years prior to index date, healthcare utilization, income and use of other medications. Over one-quarter of cases and controls were prescribed statins. Ever-use of any statin was associated with lower risk of Total NHL (OR = 0.82, 95% CI 0.76-0.89) and of certain subtypes including diffuse large B-cell lymphomas (DLBCL, OR = 0.77, 95% CI 0.65-0.92), plasma cell neoplasms (PCN, OR = 0.76, 95% CI 0.63-0.91) and other B-cell NHL (0.75, 0.59-0.95). Analysis by statin type suggested that the association was limited to high potency statin and lipophilic statin users. No clear duration or dose-response relationships were observed. Our findings provide evidence that statin use can reduce the risk of DLBCL and plasma cell lymphomas, but not other NHL types. Further studies are warranted to verify these associations and to examine the biological mechanisms.

ObjectiveThe objective of this study was to estimate background rates of selected thromboembolic and coagulation disorders in Ontario, Canada.DesignPopulation-based retrospective observational study using linked health administrative databases. Records of hospitalisations and emergency department visits were searched to identify cases using International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada diagnostic codes.ParticipantsAll Ontario residents.Primary outcome measuresIncidence rates of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, deep vein thrombosis, pulmonary embolism, idiopathic thrombocytopaenia, disseminated intravascular coagulation and cerebral venous thrombosis during five prepandemic years (2015–2019) and 2020.ResultsThe average annual population was 14 million with 51% female. The mean annual rates per 100 000 population during 2015–2019 were 127.1 (95% CI 126.2 to 127.9) for ischaemic stroke, 22.0 (95% CI 21.6 to 22.3) for intracerebral haemorrhage, 9.4 (95% CI 9.2 to 9.7) for subarachnoid haemorrhage, 86.8 (95% CI 86.1 to 87.5) for deep vein thrombosis, 63.7 (95% CI 63.1 to 64.3) for pulmonary embolism, 6.1 (95% CI 5.9 to 6.3) for idiopathic thrombocytopaenia, 1.6 (95% CI 1.5 to 1.7) for disseminated intravascular coagulation, and 1.5 (95% CI 1.4 to 1.6) for cerebral venous thrombosis. Rates were lower in 2020 than during the prepandemic years for ischaemic stroke, deep vein thrombosis and idiopathic thrombocytopaenia. Rates were generally consistent over time, except for pulmonary embolism, which increased from 57.1 to 68.5 per 100 000 between 2015 and 2019. Rates were higher for females than males for subarachnoid haemorrhage, pulmonary embolism and cerebral venous thrombosis, and vice versa for ischaemic stroke and intracerebral haemorrhage. Rates increased with age for most of these conditions, but idiopathic thrombocytopaenia demonstrated a bimodal distribution with incidence peaks at 0–19 years and ≥60 years.ConclusionsOur estimated background rates help contextualise observed events of these potential adverse events of special interest and to detect potential safety signals related to COVID-19 vaccines.

The advent of super‐resolution microscopy allowed for new insights into cellular and physiological processes of normal and diseased cells. In this study, we report for the first time on the super‐resolved DNA structure of buccal cells from patients with Alzheimer's disease (AD) versus age‐ and gender‐matched healthy, non‐caregiver controls. In this super‐resolution study cohort of 74 participants, buccal cells were collected and their spatial DNA organization in the nucleus examined by 3D Structured Illumination Microscopy (3D‐SIM). Quantitation of the super‐resolution DNA structure revealed that the nuclear super‐resolution DNA structure of individuals with AD significantly differs from that of their controls (p

Background Vaccine effectiveness (VE) studies provide essential evidence on waning vaccine-derived immunity, a major threat to pertussis control. We evaluated how study design affects estimates by comparing 2 case-control studies conducted in Ontario, Canada. Methods We compared results from a test-negative design (TND) with a frequency-matched design (FMD) case-control study using pertussis cases from 2005–2015. In the first study, we identified test-negative controls from the public health laboratory that diagnosed cases and, in the second, randomly selected controls from patients attending the same physicians that reported cases, frequency matched on age and year. We compared characteristics of cases and controls using standardized differences. Results In both designs, VE estimates for the early years postimmunization were consistent with clinical trials (TND, 84%; FMD, 89% at 1–3 years postvaccination) but diverged as time since last vaccination increased (TND, 41%; FMD, 74% by 8 years postvaccination). Overall, we observed lower VE and faster waning in the TND than the FMD. In the TND but not FMD, controls differed from cases in important confounders, being younger, having more comorbidities, and higher healthcare use. Differences between the controls of each design were greater than differences between cases. TND controls were more likely to be unvaccinated or incompletely vaccinated than FMD controls (P Conclusions The FMD adjusted better for healthcare-seeking behavior than the TND. Duration of protection from pertussis vaccines is unclear because estimates vary by study design. Caution should be exercised by experts, researchers, and decision makers when evaluating evidence on optimal timing of boosters.

Background: A link between statin use and prostate cancer risk has been proposed. Epidemiologic evidence is, however, inconclusive, and data for specific statin types as well as for period, duration, and dose of use are lacking. Methods: We conducted a population-based nested case– control study using administrative data in Manitoba, Canada. Prostate cancer cases were matched to cancer-free controls, and their statin use (including period, duration, and dose of use) was assessed (with adjustment for prostate cancer screening) for statins as a class and for each specific statin. Results: We matched 9,384 prostate cancer cases to 46,749 cancer-free controls. Ever use of any statin was not associated with prostate cancer risk, odds ratio (OR) 0.96 (95% confidence interval, 0.90–1.03). Except for pravastatin, 0.82 (0.71–0.96), individual statins were not associated with prostate cancer risk. There was no dose or duration response for pravastatin (or any other statin). Conclusions: We found limited evidence of an association between statin use and prostate cancer risk. The association between pravastatin and prostate cancer risk may be due to chance. Impact: We show that statin use is not associated with prostate cancer risk after adjustment for screening for a large population with data going back to the mid-1990s.

The consistent appearance of specific chromosomal translocations in multiple myeloma has suggested that the positioning of chromosomes in the interphase nucleus might play a role in the occurrence of particular chromosomal rearrangements associated with malignant transformation. Using fluorescence in situ hybridization, we have determined the positions of selected chromosome pairs (18 and 19, 9 and 22, 4 and 14, 14 and 16, 11 and 14) in interphase nuclei of myeloma cells compared to normal lymphocytes of treatment‐naïve patients. All chromosome pairs were arranged in a nonrandom pattern. Chromosomes commonly involved in myeloma‐associated translocations (4 and 14, 14 and 16, 11 and 14) were found in close spatial proximity, and this is correlated with the occurrence of overlapping chromosome territories. The spatial distribution of chromosomes may increase the possibility of chromosomal translocations in multiple myeloma., What's new? The positioning of chromosomes in the interphase nucleus might play a role in the occurrence of chromosomal rearrangements associated with malignant transformation. Here, the authors examined the nuclei of myeloma cells and control lymphocytes from treatment‐naïve patients using conventional 3D imaging and super‐resolution microscopy. Common and distinct chromosome positions were found in lymphocytes and myeloma cells with respect to neighborhood relationships and tendency to overlap. Chromosomes commonly involved in myeloma‐associated translocations were found in close spatial proximity, which correlated with the occurrence of overlapping chromosome territories. The spatial distribution of chromosomes may increase the possibility of translocations in multiple myeloma.

Background: Surgical removal of solid tumors is a frequent treatment for cancer patients. Immunosuppression after surgery, which suppresses natural killer (NK) cells, increases the risk of metastasis (mets). Preclinical and animal studies have shown that perioperative vaccination can prevent postoperative NK cell dysfunction and may reduce the risk of mets. In the first epidemiologic study of its kind, we investigated this intriguing hypothesis in the Canadian province of Manitoba (MB). Methods: We linked the MB Cancer Registry, containing all cancer diagnoses and cancer-specific therapy in MB, with the MB Immunization Monitoring System and other administrative health databases covering >99% of the population. We identified all first cancer surgeries conducted during 1994-2014 in MB for an invasive, nonmetastatic, primary, solid cancer. We followed patients from their date of surgery to the earliest date of metastasis, 2nd primary cancer, 2nd cancer surgery, death, loss of coverage, or study end. We used competing-risk Cox models adjusted for age at surgery, gender, comorbidities, and cancer stage at diagnosis. Results: Out of 29,120 persons with a cancer surgery, 0.2% and 0.4% received a vaccine, mostly seasonal flu vaccines, 2-4 and 0-5 days before surgery respectively, and 21.8% developed metastasis during follow-up. Compared to those vaccinated 30 days before to 14 days after surgery outside of the specific time window, the hazard ratio of the association between vaccination 0-5 days before surgery and metastasis was 0.72 (0.32-1.61) for a 15-year follow-up, and the association was 0.44 (0.11-1.78) for vaccination 2-4 days before surgery. Conclusion: In this relatively small study, we found evidence for a strong association between vaccination just before cancer surgery and long-term occurrence of mets. Further studies of this associations in humans are warranted; they must be sufficiently large to investigate potentially narrow windows of vaccine effectiveness, and they could use biomarkers of mets as intermediate endpoints. Citation Format: Christiaan H. Righolt, Geng Zhang, Salaheddin M. Mahmud. Linking cancer and vaccine registries in a retrospective cohort study: Risk of metastasis following perioperative vaccine use among cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A13.

Background/objectivesDespite influenza vaccination programs in various jurisdictions, seasonal influenza vaccine (SIV) uptake remains suboptimal among older people (≥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.MethodsWe 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).ResultsOut 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.ConclusionsSeveral 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.

Objectives The uptake of the seasonal influenza vaccine (SIV) is thought to be poor among pregnant women. Our objective was to identify drivers of vaccine uptake among pregnant women in Manitoba, Canada from 2000–2015. Methods All women pregnant during influenza season and who delivered an infant >20 weeks gestation in Manitoba, Canada between 2000–2015 were eligible for inclusion in our retrospective cohort study. Informed by a priori causal diagrams, we used logistic regression to estimate the adjusted odds ratio (OR) of the association between individual and provider characteristics and the receipt of the SIV during pregnancy. Results We included 144,790 eligible deliveries. Uptake of the SIV increased over time with 1.3%, 7.7% and 14.2% of pregnant women receiving the SIV in 2000–2004, 2005–2009 and 2010–2015, respectively. Uptake was lower among rural women (OR 0.80, 0.77–0.84), women with lower incomes (OR 0.89, 0.84–0.94) and limited prenatal care (0.57, 0.51–0.64). Prenatal care from a family physician compared to an obstetrician was associated with higher uptake of the SIV during pregnancy (OR 1.21, 95% 1.16–1.26). Women with history of prior influenza immunization and those who engaged in regular cervical cancer screening were 5-fold and 4-fold more likely to receive the SIV during pregnancy, respectively. Conclusions Uptake of the SIV during pregnancy remains low in Manitoba. A number of individual and provider factors are associated with uptake of the SIV and these may help target strategies to improve uptake of the SIV among pregnant women.

The effectiveness of a vaccination program is influenced by its design and implementation details and by the target population characteristics. Using routinely collected population-based individual-level data, we assessed the effectiveness (against cervical dysplasia) of Manitoba's quadrivalent human papillomavirus (qHPV) routine school-based vaccination program and a short-lived campaign that targeted women at high-risk of developing cervical cancer. Females ≥9 years old who received the qHPV vaccine in Manitoba (Canada) between September 1, 2006, and March 31, 2013 (N = 31,442) were matched on age and area of residence to up to three unvaccinated females. Cox proportional hazards models were used to estimate qHPV VE against high-grade (HSILs) and low-grade squamous intraepithelial lesions (LSILs) and atypical squamous cells of undetermined significance (ASCUS). Among 14-17-year-old participants who had Pap cytology after enrollment, the adjusted qHPV VE estimates were 30% (17-58%) and 36% (21-48%) against the detection of HSILs and LSILs, respectively. There was, however, no evidence of program effectiveness among females vaccinated at ≥18 years of age and among those with a history of abnormal cytology, who were mostly vaccinated as part of the high-risk program. Estimates of VE for females vaccinated in the school-based program are consistent with the expected benefits from qHPV vaccination. No similar benefits were detected among women vaccinated at an older age, and those with abnormal cytology, who were targeted by the high-risk program. Further efforts should be targeted at achieving higher vaccine coverage among preadolescents, prior to the initiation of sexual activity.

Recent developments in microscopy have led to superresolution microscopy images of cells. Structured illumination microscopy was used before to reveal new details in the DNA structure and the structure of the DNA-free space in the DAPI-stained cell nuclei of the Hodgkin's lymphoma HDLM-2 cell line. This study extends this technology to primary pre-treatment classical Hodgkin's lymphoma samples of ten patients. Significant differences in both the DNA structure and the structure of the DNA-free space were detected between lymphocytes and malignant cells. Both types of structures were similar for lymphocytes of different patients. When the patients were un-blinded and grouped based on their clinical outcome, either non-relapsed or relapsed, a significant difference in the DNA structure of their Reed-Sternberg (RS) cells was found. Since, RS cells develop from mono-nucleated Hodgkin (H) cells, these data suggest distinct architectural restructuring of nuclei during RS cell formation in patients going to long-lasting remission versus relapse. J. Cell. Biochem. 117: 1633-1637, 2016. © 2015 Wiley Periodicals, Inc.

MYCN amplification and MYCN overexpression are poor prognostic factors in neuroblastoma. Tumors with unbalanced chromosome arm 17q gain are often associated with MYCN amplification; however, the relationship between chromosome 17 copy number status and MYCN expression is not known. We investigated the relationship between MYCN expression and chromosome 17 copy number, nuclear location, and gene expression. By performing dual-colored fluorescence in situ hybridization on 16 primary neuroblastomas, we found that those with unbalanced gain of 17q have high MYCN expression, those with no gain have medium expression, and those with numerical gain have low expression (P

The nuclear architecture of a cell may change as a result of various diseases, including cancer. A variety of nuclear features are, therefore, of interest to cell biologists. Recently, several studies have investigated the orientation of chromosomes in the interphase nucleus either visually or semi-automatically. In this article an automated method to measure this orientation is presented. The theoretical difference between performing these measurements in two and three dimensions is discussed and experimentally verified. The results computed from measurements of murine nuclei correspond with results from visual inspection. We found significant differences in the orientation of chromosome 11 between nuclei from a PreB cell line of BALB/c origin and primary B nuclei from congenic [T38HxBALB/c]N wild-type mice. Since our new automatic method concurs with both the visual and semi-automatic methods, we conclude that the automatic method can replace these methods in assessing chromosome orientation.

Background: Several epidemiological studies have shown a positive association between diabetes and increased risk of non-Hodgkin lymphoma (NHL), but the effect of diabetic treatment drugs such as metformin on the risk is unknown. Methods: We conducted a population-based nested case–control study involving 878 NHL cases and 4,364 controls diagnosed with diabetes. Use of metformin and other medications before diagnosis and medical condition histories were assessed using administrative databases. We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for use of metformin, adjusting for confounders. Results: Risk of total NHLs is not associated with ever use of metformin (OR, 0.93; 95% CI, 0.79–1.10) among diabetic patients. NHL subtypes were also not associated with metformin use. Conclusions: Metformin use is not associated with overall or subtype NHL risk among diabetic patients. Impact: NHLs are etiologically heterogeneous and larger scale studies are warranted to test the potential effect of metformin by NHL subtype. Cancer Epidemiol Biomarkers Prev; 27(5); 610–2. ©2018 AACR.

The total direct cost of screening and treating all human papillomavirus-related diseases (HPV-RD) has not been measured in a single study. Accurate cost estimates are needed to inform decisions on intervention priorities and evaluate the cost-effectiveness of existing programs. We used province-wide clinical, administrative, and accounting databases to measure direct medical costs of HPV infection in Manitoba (Canada). All persons 9 years or older with health insurance coverage in Manitoba between April 2000 and March 2015 were eligible. We identified all persons with an incident HPV-RD and aggregated all medical costs (in 2014 Canadian dollars) related to that condition, including prescription drugs, diagnostic procedures, in-hospital and outpatient treatment, and physician visits. We found that the median cost of treating a case of anogenital warts was $130. An episode of cervical dysplasia had a median cost of $220, compared to $1300 for an episode of cervical carcinoma in situ. The cost of treating HPV-related invasive cancer varied from $15,000 for cervical cancer to $33,000 for oral cavity cancer. Overall, 80% ($145 million) of the total cost was attributable to HPV infection. Cervical screening and follow-up accounted for $96 million (66%) of all costs and this cost component has declined following the introduction of new screening guidelines. Overall, the average direct medical cost of HPV infection was $720 per newborn. The economic burden of HPV remains significant, although changes in cervical screening guidelines, prompted by the introduction of a public HPV vaccine program, appear to have promoted a promising trend towards lower costs.

Information on inappropriate empiric antimicrobial therapy (ET) in Canadian hospitals is scarce. All Manitobans 18 years of age and over who were admitted to a hospital in Winnipeg with a complicated urinary tract infection (cUTI) or complicated intra-abdominal infection (cIAI) from January 2006 to December 2014 were eligible for inclusion in this cohort study. The prevalence of inappropriate ET was 11% for cUTI patients and 9% for cIAI patients. The risk of receiving inappropriate ET was higher for older patients (cUTI patients 65 or older had 2-fold increased risk compared to younger patients; odds ratio 2.1, 95% confidence interval 1.3–3.6; this was 1.6 [0.7–3.5] for cIAI patients) and those hospitalized in the previous year: 1.5 (1.0–2.4) in cUTIs and 1.5 (0.6–3.4) in cIAIs. The risk for a hospital stay over 3 weeks was increased for inappropriate ET in cUTI patients, 2.3 (1.4–3.7), but not in cIAI patients, 0.9 (0.4–2.1).