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.

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.

Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps [see comment].

Are different forms of breathing derived from one or multiple neural networks? We demonstrate that brainstem slices containing the pre-Bötzinger complex generated two rhythms when normally oxygenated, with striking similarities to eupneic ('normal') respiration and sighs. Sighs were triggered by eupneic bursts under control conditions, but not in the presence of strychnine (1 microM). Although all neurons received synaptic inputs during both activities, the calcium channel blocker cadmium (4 microM) selectively abolished sighs. In anoxia, sighs ceased, and eupneic activity was reconfigured into gasping, which like eupnea was insensitive to 4 microM cadmium. This reconfiguration was accompanied by suppression of synaptic inhibition. We conclude that a single medullary network underlies multiple breathing patterns.

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.

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.

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.

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.

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.

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.

The role of the hyperpolarization-activated current in modulating rhythmic activity in the isolated respiratory network of mice.

We examined the role of the hyperpolarization-activated current (I(h)) in the generation of the respiratory rhythm using a spontaneously active brainstem slice of mice. This preparation contains the hypoglossus (XII) nucleus, which is activated in-phase with inspiration and the pre-Bötzinger complex (PBC), the presumed site for respiratory rhythm generation. Voltage-clamp recordings (n = 90) indicate that cesium (Cs) (5 mM) blocked 77.2% of the I(h) current, and ZD 7288 (100 microM) blocked 85.8% of the I(h) current. This blockade increased the respiratory frequency by 161% in Cs and by 150% in ZD 7288 and increased the amplitude of integrated population activity in the XII by 97% in Cs and by 162% in ZD 7288, but not in the PBC (Cs, by 19%; ZD 7288, by -4.56%). All inspiratory PBC neurons (n = 44) recorded in current clamp within the active network revealed a significantly decreased frequency of action potentials during the interburst interval and an earlier onset of inspiratory bursts after I(h) current blockade. However, hyperpolarizing current pulses evoked only in a small proportion of inspiratory neurons (0% of type I; 29% of type II neurons) a depolarizing sag. Most of the neurons expressing an I(h) current (86%) were pacemaker neurons, which continued to generate rhythmic bursts after inactivating the respiratory network pharmacologically with CNQX alone or with CNQX, AP-5, strychnine, bicuculline, and carbenoxolone. Cs and ZD 7288 increased the frequency of pacemaker bursts and decreased the frequency of action potentials between pacemaker bursts. Our findings suggest that the I(h) current plays an important role in modulating respiratory frequency, which is presumably mediated by pacemaker neurons.

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.

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.

Acute pulmonary edema as the initial hospital presentation of systemic lupus erythematosus.

Acute pulmonary edema is an unusual initial presentation for systemic lupus erythematosus. A 46-year-old woman required intensive care for life-threatening pulmonary edema of unknown etiology, which was unresponsive to conventional treatment. Her condition improved only when pulse corticosteroid therapy was initiated, with clinical and echocardiographic improvement in cardiac function. The diagnosis of systemic lupus erythematosus was then made, based on immunologic tests and renal biopsy. The patient's condition remained stable only with continuation of appropriate therapy for systemic lupus erythematosus.

Subcellular trafficking of the cytoplasmic expression system.

Cationic liposomes have provided many advantages over viral vector formulations; however, the problem of inefficient gene expression remains. This is due in part to the nuclear membrane, which limits DNA entry into the nucleus. Cytoplasmic expression systems using T7 RNA polymerase have been developed to express genes in the cytoplasm and avoid the need for nuclear import of DNA. Although these systems show improved transgene expression, little is known about how they function in transfected cells. Direct comparisons between a cytoplasmic and nuclear expression system were carried out with a 293 cell line stably expressing T7 RNA polymerase. A formulation for optimal reporter gene expression was developed and used in conjunction with a variety of subcellular trafficking inhibitors to study the process of DNA endocytosis. Transfected cells were also studied at different stages of the cell cycle to determine the dependence of each system on mitosis. These results showed that cytoplasmic and nuclear expression systems utilize similar endocytosis pathways to the point of endosomal release. Once DNA is released into the cytoplasm, the cytoplasmic expression system shows immediate expression that is proportional to the amount of DNA released. In contrast, DNA targeted for nuclear expression requires additional time for nuclear entry. The level of nuclear expression is also restricted by the limited amount of DNA that is imported into the nucleus. Finally, mitosis is required for effective nuclear expression but not for cytoplasmic expression. Therefore, the cytoplasmic expression system has considerable advantages over traditional nuclear expression systems and may be an effective method for transfecting nondividing cells. Efficient expression of genes delivered by nonviral vectors is hindered owing to poor nuclear transport of plasmid DNA. A potential solution to this problem would be to use a cytoplasmic expression system. Previous studies have shown that this method produces enhanced gene expression when compared with traditional nuclear expression systems; however, the actual mechanisms by which the cytoplasmic expression system works remains unknown. This article focuses on a direct comparison between cytoplasmic and nuclear expression in terms of optimal DNA delivery formulations, intracellular trafficking of DNA, and cell cycle dependence. These results indicate that the cytoplasmic expression system has two primary advantages over nuclear expression in that it does not rely on nuclear DNA transport or mitosis for efficient expression.

Analysis of neuroendocrine markers, HER2 and CEA before and after chemotherapy in patients with stage IIIA non-small cell lung cancer: a Cancer and Leukemia Group B study.

Several studies have suggested that biochemical or molecular markers examined in non-small cell lung cancer carry prognostic or treatment response information. Non-small cell lung cancer patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of HER2 (c-erbB-2), a membrane-bound receptor with tyrosine kinase activity, has been associated with shortened survival. The Cancer and Leukemia Group B (CALGB) performed a study of patients with stage IIIA (N2 nodes positive) non-small cell lung cancer in which patients received initial chemotherapy followed by surgery, then post-operative therapy consisting of sequential chemotherapy and radiation therapy. Since all patients underwent mediastinoscopy, this provided an opportunity to compare pre- and post-chemotherapy tumor specimens to test the hypothesis that these proteins would predict treatment response. In particular, we hypothesized that the post-chemotherapy specimens would be enriched for NE marker negative cells because of the increased sensitivity of NE positive cells to chemotherapy. We performed immunohistochemical analysis for a panel of NE markers [neuron-specific enolase (NSE), Leu-7, chromogranin A (ChrA), synaptophysin (Syn)], HER2 and CEA to determine if there was an effect of therapy on the percentage of cells expressing these markers. Secondary endpoints were a correlation with chemotherapy response and survival. Slides were scored for intensity (0-4) and percentage of cells positive (0-4). Of 61 eligible patients, there were 38 with both pre- and post-chemotherapy specimens. When both intensity of staining and percentage of positive cells were considered, post-chemotherapy specimens had a higher percentage of positive NE markers compared with pre-chemotherapy. In addition, there was no correlation between NE marker, HER2 or CEA expression (prior to or post treatment) and response to chemotherapy or survival. These data do not support the hypothesis that NE positive tumor cells are preferentially killed by chemotherapy in patients with stage IIIA non-small cell lung cancer.

Liposomes: conquering the nuclear barrier.

The field of non-viral vector gene therapy has become increasingly successful due to the production of improved liposomes, polymers and other formulations. These novel vectors have increased the amount of DNA delivered to cells both in vitro and in vivo, and in turn, have increased gene expression. However, DNA transport to the nucleus still remains one of the largest problems in obtaining efficient, high levels of gene expression. This review addresses the reasons why the nucleus is a major barrier to transfected DNA and introduces the cytoplasmic expression system as a possible alternative to nuclear expression.

Metastatic carcinoma resulting in hepar lobatum.

Hepar lobatum is an acquired liver deformity mostly known as the end-stage of tertiary syphilis. The authors report two cases of hepar lobatum resulting from metastatic mammary ductal carcinoma in the liver and reassess the clinicopathologic features of seven previously reported cases (two in the German language). A liver of near-normal weight with an irregularly lobulated contour, capsular indentations/crevices from which intersecting (carcinoma-bearing) fibrous septa extended deep into the parenchyma, a predominant centrifugal distribution of lesional areas, and many septa abutting on the degenerated center of tumor nodules were the salient gross features. No significant tumor/fibrous occlusion of intrahepatic branches of portal or hepatic veins, nor cirrhotic type nodular hepatocellular regeneration was observed. Both of these patients experienced a drastic decrease in CEA serum levels during multiagent palliative chemotherapy. In one patient, abundant macrophages in conjunction with minimal residual tumor were present within intrahepatic septa. The pathogenesis of this condition appears largely related to an active phase of chemo-induced tumor regression with subsequent tissue collapse, followed by an organizing phase of healing and scar contraction.

The effect of vaccination on the epidemiology of varicella zoster virus.

Varicella zoster virus (VZV) causes chickenpox (varicella) on primary exposure and can reactivate later in life to cause shingles (zoster). As primary infection is more serious in adults than children, and exposure to the virus might boost the immune response to both chickenpox and shingles, there are two main concerns regarding infant VZV vaccination: that it could lead to an increase in adult disease; and/or that it could lead to a temporary increase in the incidence of shingles. This paper reviews the evidence for such outcomes. The consensus view of mathematical modelling studies is that the overall varicella associated burden is likely to decrease in the long term, regardless of the level of vaccine coverage. On the other hand, recent evidence suggests that an increase in zoster incidence appears likely, and the more effective vaccination is at preventing varicella, the larger the increase in zoster incidence. Targeted vaccination of susceptible adolescents and/or the contacts of high-risk individuals can be effective at preventing disease in these individuals with minimal risk to the community. However, targeted strategies would not prevent most disease (including most severe disease), and will not lead to a long-term reduction in the incidence of zoster. Understanding the mechanisms for maintaining immunity against varicella and zoster is critical for predicting the long-term effects of vaccination. Meanwhile sensitive surveillance of both chickenpox and shingles is essential in countries that have implemented, or are about to implement, varicella vaccination.