Human papillomavirus (HPV) vaccine uptake among a community-recruited sample of gay, bisexual, and other men who have sex with men in the three largest cities in Canada from 2017 to 2019.

INTRODUCTION: In 2015/2016, Canada's largest provinces implemented publicly-funded human papillomavirus (HPV) vaccination programs for gay, bisexual, and other men who have sex with men (GBM) ≤ 26 years old. We sought to describe HPV vaccine uptake among GBM and determine barriers and facilitators to vaccine initiation with a focus on healthcare access and utilization. METHODS: Engage is a cohort study among GBM aged 16 + years in three Canadian cities recruited from 2017 to 2019 via respondent driven sampling (RDS). Men completed a comprehensive questionnaire at baseline. By publicly-funded vaccine eligibility (≤26 years old = eligible for vaccination, ≥27 years old = ineligible), we described HPV vaccine uptake (initiation = 1 + dose, completion = 3 doses) and explored factors associated with vaccine initiation using Poisson regression. All analyses were weighted with the RDS-II Volz-Heckathorn estimator. RESULTS: Across the three cities, 26-35% and 14-21% of men ≤ 26 years and 7-26% and 2-9% of men ≥ 27 years initiated and completed HPV vaccination, respectively. Vaccine initiation was significantly associated with STI/HIV testing or visiting a HIV care specialist in the past six months (≤26: prevalence ratio[PR] = 2.15, 95% confidence interval[CI] 1.06-4.36; ≥27: PR = 2.73, 95%CI 1.14-6.51) and past hepatitis A or B vaccination (≤26: PR = 2.88, 95%CI 1.64-5.05; ≥27: PR = 2.03, 95%CI 1.07-3.86). Among men ≥ 27 years old, vaccine initiation was also positively associated with accessing PrEP, living in Vancouver or Toronto, but negatively associated with identifying as Latin American and increasing age. Vaccine initiation was twice as likely among men ≥ 27 years with private insurance versus no insurance. CONCLUSIONS: Sixty-five to 74% of men eligible for publicly-funded vaccine across the three cities remained unvaccinated against HPV by 2019. High vaccine cost may partly explain even lower uptake among men ≥ 27 years old. Men seeking sexual health care were more likely to initiate vaccination; bundling vaccination with these services may help improve HPV vaccine uptake.

Results of a population screening intervention for tuberculosis in a Nunavik village, Quebec, 2015-2016.

BACKGROUND: A small village in Nunavik, Quebec experienced a tuberculosis (TB) outbreak in 2012-2013 and then a resurgence in 2015-2016. Cases were still occurring, despite the fact that contact tracing had already been conducted on one quarter of the population. A decision was taken to conduct large-scale screening of the population for TB. OBJECTIVE: To describe the results of a population-based TB screening intervention designed to identify individuals with latent TB infection (LTBI) or active TB requiring treatment. METHODOLOGY: The history of TB infection (either active TB or LTBI, defined as a positive tuberculin skin test result of at least five mm induration) and treatment (considered adequate if at least 80% of prescribed doses were taken) were determined. Those who were two years of age and older and had not been included in contact tracing after June 1, 2015 were included for TB screening (n=1,026 eligible individuals). Screening included a nurse assessment, tuberculin skin test (TST) for those with previous negative TST or of unknown status and chest X-ray for the others. RESULTS: Of the eligible individuals in the affected village, 1,004 (98%) participated in the screening. Of these, 30% had a history of previous TB infection. A TST screening was administered to 71% of the participants, 10% of whom had positive results. Assessments were performed on 425 participants and 385 underwent a chest X-ray. Fifty-two cases of previously diagnosed active TB and three cases of new active TB were documented. In addition, there were 247 individuals with LTBI who had been previously identified (191 were found to have had adequate LTBI treatment, 56 were found to have had inadequate LTBI treatment) and 69 were identified with de novo LTBI. In addition, 633 participants were found to have no TB infection. There were 125 participants who were referred for LTBI treatment. Follow-up information was available for 120 and 85 (71%) of these completed the treatment. CONCLUSION: Within this northern village, which had persistent TB transmission despite classic control measures, population-based screening had a high degree of coverage and was an effective way to detect additional cases of individuals with active TB and those with LTBI.

Modelling multi-site transmission of the human papillomavirus and its impact on vaccination effectiveness.

OBJECTIVE: Previous HPV models have only included genital transmission, when evidence suggests that transmission between several anatomical sites occurs. We compared model predictions of population-level HPV vaccination effectiveness against genital HPV16 infection in women, using a 1) uni-site (genital site), and a 2) multi-site model (genital and one extragenital site). METHODS: We developed a uni-site and a multi-site deterministic HPV transmission model, assuming natural immunity was either site-specific or systemic. Both models were calibrated to genital HPV16 prevalence (5%-7.5%), whilst the multi-site model was calibrated to HPV16 prevalence representative of oral (0%-1%) and anal (1%-7.5%) sites. For each model, we identified 2500 parameter sets that fit endemic genital and extragenital prevalences within pre-specified target ranges. In the Base-case analysis, vaccination was girls-only with 40% coverage. Vaccine efficacy was 100% for all sites with lifetime protection. The outcome was the relative reduction in genital HPV16 prevalence among women at post-vaccination equilibrium (RRprev). RRprev was stratified by extragenital prevalence pre-vaccination. RESULTS: Under assumptions of site-specific immunity, RRprev with the multi-site model was generally greater than with the uni-site model. Differences between the uni-site and multi-site models were greater when transmission from the extragenital site to the genital site was high. Under assumptions of systemic immunity, the multi-site and uni-site models yielded similar RRprev in the scenario without immunity after extragenital infection. In the scenario with systemic immunity after extragenital infection, the multi-site model yielded lower predictions of RRprev than the uni-site model. CONCLUSIONS: Modelling genital-site only transmission may overestimate vaccination impact if extragenital infections contribute to systemic natural immunity or underestimate vaccination impact if a high proportion of genital infections originate from extragenital infections. Under current understanding of heterosexual HPV transmission and immunity, a substantial bias from using uni-site models in predicting vaccination effectiveness against genital HPV infection is unlikely to occur.

Assortative mixing as a source of bias in epidemiological studies of sexually transmitted infections: the case of smoking and human papillomavirus.

For studies examining risk factors of sexually transmitted infections (STIs), confounding can stem from characteristics of partners of study subjects, and persist after adjustment for the subjects' individual-level characteristics. Two conditions that can result in confounding by the subjects' partners are: (C1) partner choice is assortative by the risk factor examined and, (C2) sexual activity is associated with the risk factor. The objective of this paper is to illustrate the potential impact of the assortativity bias in studies examining STI risk factors, using smoking and human papillomavirus (HPV) as an example. We developed an HPV transmission-dynamic mathematical model in which we nested a cross-sectional study assessing the smoking-HPV association. In our base case, we assumed (1) no effect of smoking on HPV, and (2) conditions C1-C2 hold for smoking (based on empirical data). The assortativity bias caused an overestimation of the odds ratio (OR) in the simulated study after perfect adjustment for the subjects' individual-level characteristics (adjusted OR 1·51 instead of 1·00). The bias was amplified by a lower basic reproductive number (R 0), greater mixing assortativity and stronger association of smoking with sexual activity. Adjustment for characteristics of partners is needed to mitigate assortativity bias.

Ki 67 is a major, but not the sole determinant of Oncotype Dx recurrence score.

BACKGROUND: Immunohistological assessment of Ki 67 expression is less expensive than Oncotype Dx, which is currently used to identify patients with lymph node-negative breast cancer, who will benefit from adjuvant chemotherapy. METHODS: The relationship of immunohistologically measured Ki 67 to Oncotype DX recurrence score (RS) was examined in 53 cases of T1-2 N0 M0 (oestrogen receptor-positive, HER2/neu negative) breast cancer. RESULTS: There was a strong linear correlation between Ki 67 value and the Oncotype Dx RS. All patients in the low Ki 67 group (Ki 67 of ≤ 10%) had Oncotype Dx RSs of low or intermediate risk. The vast majority of patients (93.8%) in the high-Ki 67 group (Ki 67 ≥ 25%) had oncotype RSs of high or intermediate risk. CONCLUSION: Ki 67 proliferation value is a major, but not the sole determinant of Oncotype Dx score.

Genetic factors determining the functional organization of neural circuits controlling rhythmic movements the murine embryonic parafacial rhythm generator.

In mammals, fetal movements governed by central pattern generators are essential for the development of adaptive behaviors such as breathing, walking, and chewing, which are vital after birth. Combining targeted mutations and genetic fate mapping can help to define the molecular determinants that control the development of these central pattern generators. In this chapter, recent results are presented on the embryonic parafacial (e-pF) rhythm generator, one of the two oscillators involved in controlling the breathing behavior and chemosensitive responsiveness.

Developmental basis of the rostro-caudal organization of the brainstem respiratory rhythm generator.

The Hox genetic network plays a key role in the anteroposterior patterning of the rhombencephalon at pre- and early-segmental stages of development of the neural tube. In the mouse, it controls development of the entire brainstem respiratory neuronal network, including the pons, the parafacial respiratory group (pFRG) and the pre-Bötzinger complex (preBötC). Inactivation of Krox20/Egr2 eliminates the pFRG activity, thereby causing life-threatening neonatal apnoeas alternating with respiration at low frequency. Another respiratory abnormality, the complete absence of breathing, is induced when neuronal synchronization fails to develop in the preBötC. The present paper summarizes data on a third type of respiratory deficits induced by altering Hox function at pontine levels. Inactivation of Hoxa2, the most rostrally expressed Hox gene in the hindbrain, disturbs embryonic development of the pons and alters neonatal inspiratory shaping without affecting respiratory frequency and apnoeas. The same result is obtained by the Phox2a(+/-) mutation modifying the number of petrosal chemoafferent neurons, by eliminating acetylcholinesterase and by altering Hox-dependent development of the pons with retinoic acid administration at embryonic day 7.5. In addition, embryos treated with retinoic acid provide a mouse model for hyperpnoeic episodic breathing, widely reported in pre-term neonates, young girls with Rett's syndrome, patients with Joubert syndrome and adults with Cheyne-Stokes respiration. We conclude that specific respiratory deficits in vivo are assignable to anteroposterior segments of the brainstem, suggesting that the adult respiratory neuronal network is functionally organized according to the rhombomeric, Hox-dependent segmentation of the brainstem in embryos.

Abnormal inspiratory depth in Phox2a haploinsufficient mice.

Mutations of genes encoding Phox2a or Phox2b transcription factors induce modifications of different brainstem neuronal networks. Such modifications are associated with defects in breathing behavior at birth. In particular, an abnormal breathing frequency is observed in Phox2a-/- mutant mice, resulting from abnormal development of the locus coeruleus (LC) nucleus. However, the role of Phox2a proteins in the establishment of respiratory neuronal pathways is unknown, largely because mutants die shortly after birth. In the present study, we examined the effects of a haploinsufficiency of the Phox2a gene. Phox2a heterozygotes survive and exhibit a significantly larger inspiratory volume both during normoxic breathing and in response to hypoxia and a delayed maturation of inspiratory duration compared to wild-type animals. This phenotype accompanied by an unaltered frequency is evident at birth and persists until at least postnatal day 10. Morphological analyses of Phox2a+/- animals revealed no anomaly in the LC region, but highlighted an increase in the number of cells expressing tyrosine hydroxylase enzyme, a marker of chemoafferent neurons, in the petrosal sensory ganglion. These data indicate that Phox2a plays a critical role in the ontogeny of the reflex control of inspiration.

Impact of model, methodological, and parameter uncertainty in the economic analysis of vaccination programs.

Guidelines for economic evaluations insist that the sensitivity of model results to alternative parameter values should be thoroughly explored. However, differences in model construction and analytical choices (such as the choice of a cost-effectiveness or cost-benefit framework) also introduce uncertainty in results, though these are rarely subjected to a thorough sensitivity analysis. In this article, the authors quantify the effect of model, methodological, and parameter uncertainty, taking varicella vaccination as an example. They used 3 different models (a static model, a dynamic model that only looks at the effect of vaccination on varicella, and a dynamic model that also assesses the implications of vaccination for zoster epidemiology) and 2 forms of analysis (cost-benefit and cost-utility). They also varied the discount rate and time frame of analysis. Probabilistic sensitivity analyses were performed to estimate the impact of parameter uncertainty. In their example, model and methodological choice had a profound effect on estimated cost-effectiveness, but parameter uncertainty played a relatively minor role. Under cost-utility analysis, the probabilistic sensitivity analysis suggested that there was a near certainty that vaccination dominates no vaccination, or the other way around, depending on model choice and perspective. Under cost-benefit analysis, vaccination always appeared to be attractive. Thus, the authors clearly show that model and methodological assumptions can have greater impact on results than parameter estimates, although sensitivity analyses are rarely performed on these sources of uncertainty.

Ontogeny of central rhythm generation in chicks and rodents.

Recent studies help in understanding how the basic organization of brainstem neuronal circuits along the anterior-posterior (AP) axis is set by the Hox-dependent segmentation of the neural tube in vertebrate embryos. Neonatal respiratory abnormalities in Krox20(-/-), Hoxa1(-/-) and kreisler mutant mice indicate the vital role of a para-facial (Krox20-dependent, rhombomere 4-derived) respiratory group, that is distinct from the more caudal rhythm generator called Pre-Bötzinger complex. Embryological studies in the chick suggest homology and conservation of this Krox20-dependent induction of parafacial rhythms in birds and mammals. Calcium imaging in embryo indicate that rhythm generators may derive from different cell lineages within rhombomeres. In mice, the Pre-Bötzinger complex is found to be distinct from oscillators producing the earliest neuronal activity, a primordial low-frequency rhythm. In contrast, in chicks, maturation of the parafacial generator is tightly linked to the evolution of this primordial rhythm. It seems therefore that ontogeny of brainstem rhythm generation involves conserved processes specifying distinct AP domains in the neural tube, followed by diverse, lineage-specific regulations allowing the emergence of organized rhythm generators at a given AP level.

The pre-Bötzinger oscillator in the mouse embryo.

Studies of the sites and mechanisms involved in mammalian respiratory rhythm generation point to two clusters of rhythmic neurons forming a coupled oscillator network within the brainstem. The location of these oscillators, the pre-Bötzinger complex (preBötC) at vagal level, and the para-facial respiratory group at facial level, probably result from regional patterning schemes specifying neural types in the hindbrain during embryogenesis. Here, we report evidence that the preBötC oscillator (i) is first active at embryonic stages, (ii) originates in the post-otic hindbrain neural tube and (iii) requires the glutamate vesicular transporter 2 for rhythm generation.

Neural tube patterning by Krox20 and emergence of a respiratory control.

Recent data begin to bridge the gap between developmental events controlling hindbrain neural tube regional patterning and the emergence of breathing behaviour in the fetus and its vital adaptive function after birth. In vertebrates, Hox paralogs and Hox-regulating genes orchestrate, in a conserved manner, the transient formation of developmental compartments in the hindbrain, the rhombomeres, in which rhythmic neuronal networks of the brainstem develop. Genetic inactivation of some of these genes in mice leads to pathological breathing at birth pointing to the vital importance of rhombomere 3 and 4 derived territories for maintenance of the breathing frequency. In chick embryo at E7, we investigated neuronal activities generated in neural tube islands deriving from combinations of rhombomeres isolated at embryonic day E1.5. Using a gain of function approach, we reveal a role of the transcription factor Krox20, specifying rhombomeres 3 and 5, in inducing a rhythm generator at the parafacial level of the hindbrain. The developmental genes selecting and regionally coordinating the fate of CNS progenitors may hold further clues to conserved aspects of neuronal network formation and function. However, the most immediate concern is to take advantage of early generated rhythmic activities in the hindbrain to pursue their downstream cellular and molecular targets, for it seems likely that it will be here that rhythmogenic properties will eventually take on a vital role at birth.

Persistence and discontinuation patterns of antihypertensive therapy among newly treated patients: a population-based study.

The objective was to assess persistence with antihypertensive therapy (AHT) and discontinuation patterns in patients newly dispensed different antihypertensive drug classes in a natural Canadian population-based setting. Hypertensive patients initiating AHT monotherapy were included in this 3-year retrospective cohort study (N=21 326) using the Saskatchewan health-care databases. Persistence was defined as consistently refilling a new prescription for AHT within 90 days of a previous dispensing. New courses of AHT were also documented in nonpersistent patients. Kaplan-Meier and Cox regression analyses were used to compare persistence and new courses of therapy across initial drugs. Compared to the newer angiotensin II antagonists (AIIAs), the likelihood of discontinuing therapy over the 39-month study period was significantly higher for angiotensin-converting enzymes inhibitors (HR=1.29; 95% CI=1.16-1.43), calcium channel blockers (HR=1.42; 95% CI=1.27-1.60), beta blockers (HR=1.62; 95% CI=1.45-1.80) and diuretics (HR=1.92; 95% CI=1.73-2.14). In the year following treatment discontinuation, between 54 and 75% of patients initiated a second course of treatment. Patients initiated on an AIIA had a significantly higher likelihood of starting a new course of therapy after a first treatment discontinuation, compared to all other agents. In conclusion, hypertensive patients initiated on an AIIA not only had greater persistence to AHT but were also more likely to initiate a new course of AHT after discontinuation than those initiating treatment with other agents. Further studies are required that relate intermittent treatment behaviours to health outcomes and costs in hypertension.

Varicella vaccination in England and Wales: cost-utility analysis.

AIMS: To assess the cost-effectiveness of varicella vaccination, taking into account its impact on zoster. METHODS: An age structured transmission dynamic model was used to predict the future incidence of varicella and zoster. Data from national and sentinel surveillance systems were used to estimate age specific physician consultation, hospitalisation, and mortality rates. Unit costs, taken from standard sources, were applied to the predicted health outcomes. RESULTS: In England and Wales, the annual burden of VZV related disease is substantial, with an estimated 651 000 cases of varicella and 189 000 cases of zoster, resulting in approximately 18 000 QALYs lost. The model predicts that although the overall burden of varicella will significantly be reduced following mass infant vaccination, these benefits will be offset by a significant rise in zoster morbidity. Under base case assumptions, infant vaccination is estimated to produce an overall loss of 54 000 discounted QALYs over 80 years and to result in a net cost from the health provider (NHS) and the societal perspectives. These results rest heavily on the impact of vaccination on zoster. Adolescent vaccination is estimated to cost approximately 18 000 pounds sterling per QALY gained from the NHS perspective. CONCLUSION: Routine infant varicella vaccination is unlikely to be cost-effective and may produce an increase in overall morbidity. Adolescent vaccination is the safest and most cost-effective strategy, but has the least overall impact on varicella.

Epidemiology of Varicella-Zoster Virus in England and Wales.

Many countries are studying currently the possibility of mass vaccination against varicella. The objective of this study was to provide a complete picture of the pre-vaccine epidemiology of the Varicella-Zoster Virus in England and Wales to aid in the design of immunisation programs. Population-based data including general practitioner sentinel surveillance, hospitalisation data, and death certificates from England and Wales were analysed. The average incidence rates for varicella and zoster between 1991 and 2000 were 1,291 and 373 per 100,000 years, respectively. Overall hospitalisation rates were equal for varicella and zoster (4.5 vs. 4.4 hospitalisation per 100,000 population) with 5 and 8%, respectively, having underlying immunosuppressive conditions. The age-specific proportion of cases hospitalised and length of stay were similar between the two diseases. However, the overall burden of disease is considerably higher for zoster. The number of inpatient days and case-fatality due to zoster are roughly 4 to 6 times greater than for varicella (11 vs. 3 days and 25 vs. 4 deaths per 100,000 case). These results provide base-line estimates should mass varicella vaccination be introduced in England and Wales.

Varicella vaccination: impact of vaccine efficacy on the epidemiology of VZV.

In 1995, varicella vaccination was introduced into the infant immunization schedule of the United States. Currently, many other countries are considering mass varicella vaccination. Mass vaccination has two dangers: it could increase the number of varicella cases in adults, where severity is greater, and increase cases of zoster. A deterministic, realistic, age-structured model (RAS) was built to study these concerns. Model parameter estimates were derived from a review of the literature and surveillance data from England and Wales. Different vaccine efficacy scenarios, vaccine coverages, and vaccination strategies were investigated. The model predicts that, although an upward shift in the age at infection occurs, the overall morbidity due to varicella is likely to decrease following mass infant vaccination. On the other hand, cases of zoster may significantly increase in the first 50 years following vaccination. The model predicts that, in a population similar to England and Wales (50 m people), varicella vaccination with 90% coverage would prevent 0.6 m inpatient days due to varicella but would generate an extra 1.1 m inpatient days due to zoster over the first 65 years. Thus, under base-case model assumptions, the gain in reduction of varicella morbidity from infant vaccination is offset in the short-term by the increases in zoster morbidity (using inpatient days as a proxy). Paradoxically, less effective vaccines or vaccine programmes can be more effective in reducing overall morbidity (varicella + zoster) by allowing the virus to circulate more, which produces a smaller shift in the age at infection and a smaller increase in zoster cases.

Economic evaluation of vaccination programs: the impact of herd-immunity.

The unique characteristic of vaccination is that it not only reduces the incidence of disease in those immunized but also indirectly protects nonvaccinated susceptibles against infection (produces herd-immunity). The bulk of economic evaluations of vaccination programs continue to use models that cannot take into account the indirect effects produced by herd-immunity. Here, the authors illustrate the importance of incorporating herd-immunity externalities when assessing the cost-effectiveness of vaccination progams. To do this, they compare 2 methods of estimating the benefits of routine mass vaccination: one that includes herd-immunity (dynamic approach) and one that does not (static approach). Finally, they use the results to clarify a number of misconceptions that are common in the literature concerning herd-immunity and dynamical effects produced by models.