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After the first detection of Middle East respiratory syndrome coronavirus (MERS-CoV) in camels in Jordan in 2013, we conducted 2 consecutive surveys in 2014–2015 and 2017–2018 investigating risk factors for MERS-CoV infection among camel populations in southern Jordan. Multivariate analysis to control for confounding demonstrated that borrowing of camels, particularly males, for breeding purposes was associated with increased MERS-CoV seroprevalence among receiving herds, suggesting a potential route of viral transmission between herds. Increasing age, herd size, and use of water troughs within herds were also associated with increased seroprevalence. Closed herd management practices were found to be protective. Future vaccination strategies among camel populations in Jordan could potentially prioritize breeding males, which are likely to be shared between herds. In addition, targeted management interventions with the potential to reduce transmission between herds should be considered; voluntary closed herd schemes offer a possible route to achieving disease-free herds.

Background During the first wave of the influenza A(H1N1)pdm09 pandemic in England in 2009, morbidity and mortality were higher in patients of South Asian (Indian, Pakistani or Bangladeshi) ethnic minority groups. Objectives This study aims to provide insights in the representation of this group among reported cases, indicating susceptibility and exposure. Methods All laboratory‐confirmed cases including basic demographic and limited clinical information that were reported to the FluZone surveillance system between April and October 2009 were retrieved. Missing ethnicity data were imputed using the previously developed and validated South Asian Names and Group Recognition Algorithm (SANGRA). Differences between ethnic groups were calculated using chi‐square, log‐rank and t tests and rate ratios. Geographic clustering was compared using Ripley's K functions. Results SANGRA identified 2447 (28%) of the total of 8748 reported cases as South Asian. South Asian cases were younger (P < .001), more often male (P = .002) and more often from deprived areas (P < .001) than cases of other ethnic groups. Time between onset of symptoms and laboratory sampling was longer in this group (P < .001), and they were less often advised antiviral treatment (P < .001), however, declined treatment less. The highest cumulative incidence was seen in the West Midlands region (32.7/10 000), London (7.0/10 000) and East of England region (5.7/10 000). Conclusions People of South Asian ethnic groups were disproportionally affected by the first wave of the influenza pandemic in England in 2009. The findings presented contribute to further understanding of demographic, socioeconomic and ethnic factors of the outbreak and inform future influenza preparedness to ensure appropriate prevention and care.

Background Available evidence indicates that seasonal inactivated influenza vaccination during pregnancy protects both the mother and her newborn and is safe. Nevertheless, ongoing safety assessments are important in sustaining vaccine uptake. Few studies have explored safety in relation to major congenital malformations (MCMs), particularly in the first trimester when most organogenesis occurs. Methods Anonymized UK primary care data (the Clinical Practice Research Datalink), including a recently developed Pregnancy Register, were used to identify live-born singletons delivered between 2010 and 2016. Maternal influenza vaccination was determined using primary care records and stratified by trimester. Ascertainment of MCMs from infant primary care records was maximized by linkage to hospitalization data and death certificates. The relationship between vaccination and MCMs recorded in the year after delivery and in early childhood was then assessed using multivariable Cox regression. Results A total of 78 150 live-birth pregnancies were identified: 6872 (8.8%) were vaccinated in the first trimester, 11 678 (14.9%) in the second, and 12 931 (16.5%) in the third. Overall, 5707 live births resulted in an infant with an MCM recorded in the year after delivery and the adjusted hazard ratio when comparing first-trimester vaccination to no vaccination was 1.06 (99% CI, .94–1.19; P = .2). Results were similar for second- and third-trimester vaccination and for analyses considering MCMs recorded beyond the first birthday. Conclusions In this large, population-based historical cohort study there was no evidence to suggest that seasonal influenza vaccine was associated with MCMs when given in the first trimester or subsequently in pregnancy., In this UK-based historical cohort study, there was no evidence to suggest that seasonal influenza vaccine was associated with major malformations when given in the first trimester or subsequently in pregnancy.

Background Brucellosis is an important neglected zoonosis. Effective cattle vaccines are available but are infrequently used in India, where rural households commonly own one or two cattle as sources of protein and income. We assessed the prevalence of infection and risk factors in humans. Methods We conducted a cross-sectional sero-survey in randomly selected individuals in 60 villages in Punjab. Infection prevalence was assessed by positive Rose Bengal testing or immunoglobulin G enzyme-linked immunosorbent assay. Risk factors were adjusted for potential confounding using multivariable analyses. Results Of the 1927 subjects who were approached, 93% agreed to participate. Age-standardised prevalence for Brucella infection was 2.24% (95% confidence interval [CI] 1.61 to 3.11). More than 60% of households kept cattle and 10% assisted with calving or abortions. Nearly all individuals consumed boiled cow/buffalo milk from their own or neighbours' cattle and 3.3% consumed goat’s milk. There was a 2.18 times increased odds (95% CI 0.96 to 4.95) of infection with calving/abortions and a 4.26 times increased odds (95% CI 1.33 to 13.6) with goat’s milk but not bovine milk consumption. Conclusions An association with calving/abortions and goat’s milk consumption was seen. Brucella vaccination of household livestock would reduce the risk to humans in such settings. Additional measures include biosecurity training around calving/abortions, education to boil all milk and for healthcare workers to test for brucellosis.

In response to unusual crow die‐offs from avian influenza A(H5N1) virus infection during January‐February 2017 in Dhaka, Bangladesh, a One Health team assessed potential infection risks in live bird markets (LBMs). Evidence of aerosolized avian influenza A viruses was detected in LBMs and in the respiratory tracts of market workers, indicating exposure and potential for infection. This study highlighted the importance of surveillance platforms with a coordinated One Health strategy to investigate and mitigate zoonotic risk.

Highlights • Applicability of GAIA definitions were assessed using medical records in LMICs. • LBW, preterm birth and neonatal death definitions were applicable in the field. • SGA, stillbirth, neonatal infection, congenital microcephaly definitions were less applicable. • Suggestions to the improvement in GAIA definitions were made. • Better documentation of maternal immunization is suggested for vaccine-safety studies., Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1–3 of BC diagnostic certainty). Over a one-year period (2019–2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies.

Live animal markets are known hotspots of zoonotic disease emergence. To mitigate those risks, we need to understand how networks shaped by trading practices influence disease spread. Yet, those practices are rarely recorded in high-risk settings. Through a large cross-sectional study, we assessed the potential impact of live poultry trading networks’ structures on avian influenza transmission dynamics in Bangladesh. Networks promoted mixing between chickens sourced from different farming systems and geographical locations, fostering co-circulation of viral strains of diverse origins in markets. Viral transmission models suggested that the observed rise in viral prevalence from farms to markets was unlikely explained by intra-market transmission alone, but substantially influenced by transmission occurring in upstream network nodes. Disease control interventions should therefore alter the entire network structures. However, as networks differed between chicken types and city supplied, standardised interventions are unlikely to be effective, and should be tailored to local structural characteristics.

Brucellosis is a zoonotic disease imposing significant impacts on livestock production and public health worldwide. India is the world’s leading milk producer and Punjab is the state which produces the most cattle and buffalo milk per capita. The aim of this study was to investigate the epidemiology of bovine brucellosis to provide evidence for control of the disease in Punjab State, India. A cross-sectional study of dairy farms was conducted in humans and livestock in rural Ludhiana district using a multi-stage sampling strategy. The study suggests that brucellosis is endemic at high levels in cattle and buffalo in the study area with 15.1% of large ruminants testing seropositive and approximately a third of dairy farms having at least one animal test seropositive. In total, 9.7% of those in direct contact with livestock tested seropositive for Brucella spp. Persons that assisted with calving and/or abortion within the last year on a farm with seronegative livestock and people which did not assist with calving/abortion had 0.35 (95% CI: 0.17 to 7.1) and 0.21 (0.09 to 0.46) times the odds of testing seropositive compared to persons assisting with calving/abortion in a seropositive farm, respectively. The study demonstrated that persons in direct contact with cattle and buffalo in the study area have high risk of exposure to Brucella spp. Control of the disease in livestock is likely to result in benefits to both animal and public health sectors., Author summary Brucellosis is a bacterial disease that causes production losses in livestock due to abortions, increased calving intervals and reduced milk production. The disease can also be transmitted to humans via direct contact with livestock when they give birth or abort or via consumption of unpasteurised dairy products. This study aimed to estimate the frequency of exposure to the bacteria (Brucella spp.) in cattle and buffalo in Ludhiana district, Punjab State, India. In addition, persons in contact with these livestock, either through their occupation or household, were also tested for Brucella spp. antibodies and the data used to identify factors increasing their risk of exposure. The study found high levels of exposure in cattle and buffalo in the study area with 15.1% of large ruminants testing positive for antibodies to Brucella spp. (seropositive) and approximately a third of dairy farms having at least one animal test seropositive. Around 10% of people tested seropositive for the bacteria and those that assisted with calving and/or abortion on a farm where at least one animal tested seropositive had a high risk of infection. Control of brucellosis could reduce production losses in livestock and protect humans in contact with livestock from becoming infected.

This systematic review assesses the literature for estimates of influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalization in children. Studies of any design to June 8, 2020, were included if the outcome was hospitalization, participants were 17 years or younger and influenza infection was laboratory-confirmed. A random-effects meta-analysis of 37 studies that used a test-negative design gave a pooled seasonal IVE against hospitalization of 53.3% (47.2–58.8) for any influenza. IVE was higher against influenza A/H1N1pdm09 (68.7%, 56.9–77.2) and lowest against influenza A/H3N2 (35.8%, 23.4–46.3). Estimates by vaccine type ranged from 44.3% (30.1–55.7) for live-attenuated influenza vaccines to 68.9% (53.6–79.2) for inactivated vaccines. IVE estimates were higher in seasons when the circulating influenza strains were antigenically matched to vaccine strains (59.3%, 48.3–68.0). Influenza vaccination gives moderate overall protection against influenza-associated hospitalization in children supporting annual vaccination. IVE varies by influenza subtype and vaccine type.

International audience; BackgroundInfluenza surveillance helps time prevention and control interventions especially where complex seasonal patterns exist. We assessed influenza surveillance sustainability in Africa where influenza activity varies and external funds for surveillance have decreased.MethodsWe surveyed African Network for Influenza Surveillance and Epidemiology (ANISE) countries about 2011-2017 surveillance system characteristics. Data were summarized with descriptive statistics and analyzed with univariate and multivariable analyses to quantify sustained or expanded influenza surveillance capacity in Africa.ResultsEighteen (75%) of 24 ANISE members participated in the survey; their cumulative population of 710 751 471 represent 56% of Africa's total population. All 18 countries scored a mean 95% on WHO laboratory quality assurance panels. The number of samples collected from severe acute respiratory infection case-patients remained consistent between 2011 and 2017 (13 823 vs 13 674 respectively) but decreased by 12% for influenza-like illness case-patients (16 210 vs 14 477). Nine (50%) gained capacity to lineage-type influenza B. The number of countries reporting each week to WHO FluNet increased from 15 (83%) in 2011 to 17 (94%) in 2017.ConclusionsDespite declines in external surveillance funding, ANISE countries gained additional laboratory testing capacity and continued influenza testing and reporting to WHO. These gains represent important achievements toward sustainable surveillance and epidemic/pandemic preparedness.

BackgroundTuberculosis (TB) rates in England are among the highest in high-income countries. Poverty and historic and current immigration from high TB incidence parts of the world are two major drivers of tuberculosis in England. However, little has been done in recent years to examine socio-economic trends in TB rates in England, and to disentangle the role of deprivation from that of place of birth in the current TB epidemiology.ObjectivesTo assess the association between England's 2008-2012 TB notification rates and small area-level deprivation, together and separately in the UK-born and foreign-born populations.MethodsEcological analysis of the association between quintiles of England's 2010 Index of Multiple Deprivation (IMD) and TB rates at the Lower-layer Super Output Area (LSOA; average population ~1500) level, using negative binomial and zero-inflated negative binomial regression models, adjusting for age, sex, urban/rural area classification, and area-level percentage of non-White residents.ResultsThere was a log-linear gradient between area-deprivation levels and TB rates, with overall TB rates in the most deprived quintile areas three times higher than the least deprived quintile after adjustment for age and sex (IRR = 3.35; 95%CI: 3.16 to 3.55). The association and gradient were stronger in the UK-born than the foreign-born population, with UK-born TB rates in the most deprived quintiles about two-and-a-half times higher than the least deprived quintile (IRR = 2.39; 95%CI: 2.19 to 2.61) after controlling for age, sex, urban/rural classification and percentage of non-White residents; whereas the comparable figure for foreign-born persons was 80% higher (IRR = 1.78; 95%CI: 1.66 to 1.91).ConclusionsSocio-economic deprivation continues to play a substantial role in sustaining the TB epidemic in England, especially in the UK-born population. This supports the case for further investigations of the underlying social- determinants of TB.

Background People with end-stage kidney disease have an increased risk of active tuberculosis (TB). Previous systematic reviews have demonstrated that patients with chronic kidney disease (CKD) have increased risk of severe community-acquired infections. We investigated the association between CKD (prior to renal replacement therapy) and incidence of TB in UK General Practice. Methods Using the UK Clinical Practice Research Datalink, 242,349 patients with CKD (stages 3-5) (estimated glomerular filtration rate 2 for ≥3 months) between April 2004 and March 2014 were identified and individually matched (by age, gender, general practice and calendar time) to a control from the general population without known CKD. The association between CKD (overall and by stage) and incident TB was investigated using a Poisson regression analysis adjusted for age, gender, ethnicity, socio-economic status, chronic obstructive pulmonary disease (COPD) and diabetes. Results The incidence of TB was higher amongst patients with CKD compared to those without CKD: 14.63 and 9.89 cases per 100,000 person-years. After adjusting for age, gender, ethnicity, socio-economic status, diabetes and COPD, the association between CKD and TB remained (adjusted rate ratio [RR] 1.42, 95% confidence interval [CI] 1.01–1.85). The association may be stronger amongst those from non-white ethnic minorities (adjusted RR 2.83, 95%CI 1.32–6.03, p-value for interaction with ethnicity = 0.061). Amongst those with CKD stages 3–5, there was no evidence of a trend with CKD severity. Conclusions CKD is associated with an increased risk of TB diagnosis in a UK General Practice cohort. This group of patients should be considered for testing and treating for latent TB.

PURPOSE: To describe the methods used to identify and validate congenital malformation diagnoses recorded in UK electronic health records, and the results of validation studies. METHODS: Medline and Embase were searched for publications between 1987 and 2019 that involved identifying congenital malformations from UK electronic health records using diagnostic codes. The methods and code-lists used to identify congenital malformations, and the methods and results of validations, were examined. RESULTS: We retrieved 54 eligible studies; 36 identified congenital malformations from primary care data and 18 from secondary care data alone or in combination with birth and/or death records. Identification in secondary care data relied on codes from the 'Q' chapter for congenital malformations in ICD-10. In contrast, studies using primary care data frequently used additional codes outside of the 'P' chapter for congenital malformation diagnoses in Read, although the exact codes used were not always clear. Eight studies validated diagnoses identified in primary care data. The positive predictive value was highest (80%-100%) for congenital malformations overall, major malformations, and heart defects although the validity of the reference standard used was often uncertain. It was lowest for neural tube defects (71%) and developmental hip dysplasia (56%). CONCLUSIONS: Studies identifying congenital malformations from primary care data provided limited details about the methods used. The few validation studies were limited to diagnoses recorded in primary care. Further assessments of all measures of validity in both data sources and of other malformation subgroups are needed, using robust reference standards and adhering to reporting guidelines.

Addressing social determinants of tuberculosis (TB) is essential to achieve elimination, including in low-incidence settings. We measured the association between socio-economic status and intermediate social determinants of health (SDHs, including drug misuse, tobacco smoking and alcohol), and TB, taking into account their clustering in individuals. We conducted a case-control study in 23–38 years old UK-born White adults with first tuberculosis episode, and randomly selected age and sex frequency-matched community controls. Data was collected on education, household overcrowding, tobacco smoking, alcohol and drugs use, and history of homelessness and prison. Analyses were done using logistic regression models, informed by a formal theoretical causal framework (Directed Acyclic Graph). 681 TB cases and 1183 controls were recruited. Tuberculosis odds were four times higher in subjects with education below GCSE O-levels, compared to higher education (OR = 3.94; 95%CI: 2.74, 5.67), after adjusting for other TB risk factors (age, sex, BCG-vaccination and stays ≥3 months in Africa/Asia). When simultaneously accounting for respective SDHs, higher tuberculosis risk was independently associated with tobacco smoking, drugs use (especially injectable drugs OR = 5.67; 95%CI: 2.68, 11.98), homelessness and area-level deprivation. Population Attributable Fraction estimates suggested that tobacco and class-A drug use were, respectively, responsible for 18% and 15% of TB cases in this group. Our findings suggest that socio-economic deprivation remains a driver of tuberculosis in England, including through drugs misuse, tobacco smoking, and homelessness. These findings further support the integration of health and social services in high-risk young adults to improve TB control efforts.

Background Global efforts to adequately monitor safety of new vaccines for pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) project recently published case definitions based on levels of diagnostic certainty for pregnancy- and neonatal outcomes and maternal vaccination. As a preliminary step to assessing the applicability of these definitions in LMICs, WHO selected sites and conducted a feasibility assessment to evaluate their ability to identify and classify selected outcomes (preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth) and maternal vaccination. Methods Candidate sites were initially screened using a questionnaire. For each outcome, eligible sites were asked to retrospectively identify and collect information for three individuals born in 2016. Subsequently, outcomes were classified by level of diagnostic certainty. Results Fifty-one sites (15 countries) were screened; 32 of them (9 countries) participated in the assessment and identified 315 subjects with the outcomes of interest. Twenty-four sites (8 countries) identified at least one subject per outcome and agreed to continue participating. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for not classifying stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%); or that not all data for one subject fit into a single level of diagnostic certainty (35%). Forty-nine percent of mothers were considered vaccinated, 6% not-vaccinated, and vaccination status could not be assessed in 44% of them. Discussion GAIA case definitions for four neonatal outcomes and maternal vaccination were successfully piloted in 24 sentinel sites across four WHO regions. Our assessment found that modification of the stillbirth definition could help avoid potential misclassification. Vaccine safety monitoring in LMICs will benefit from systematic recording of all vaccinations during pregnancy.

Background Tuberculosis (TB) remains a public health problem in the UK-born population of England, including among young adults. Ecological studies indicate that deprivation is an important risk factor for TB, but there are few recent individual-level studies in high income countries that have investigated the association between poverty-related social determinants of health inequality (SDH) and TB. Our objective was to measure the association between individual socio-economic status and social determinants of health, and TB, taking into account the clustering of social risk factors in individuals, and to estimate the potential population impact on TB rates. Methods Secondary analyses of a nationwide case-control study conducted among UK-born White adults aged 23 to 38 years at diagnosis of their first TB episode, and randomly selected age and sex frequency-matched community controls. Data on some SDH (education, household overcrowding, tobacco smoking, alcohol use, drugs use, and history of homelessness and prison) were collected in face-to-face interviews. Statistical analyses, using logistic regression models, was informed by a theoretical causal framework (Directed Acyclic Graph) of plausible inter-relationships between the measured social factors. Results Overall, 681 TB cases and 1183 controls were recruited. The risk of TB was about four times higher in subjects whose formal education was up to GCSE O-levels or less compared to those with at least a university degree (OR=3.94; 95%CI: 2.74; 5.67), after controlling for other TB risk factors (age, sex, BCG vaccination and stays in Africa or Asia for 33 months). After simultaneously adjusting for these risk factors and all measured social determinants, higher TB risk was also independently associated with tobacco smoking, use of drugs (especially injectable drugs - OR=5.67; 95%CI: 2.68; 11.98), history of homelessness and deprivation in the area of residence. Population Attributable Fraction (PAF) estimates suggested that tobacco use and class-A drug use were, respectively, responsible for 18% and 15% of TB cases in the target population. Conclusion The results provide insight into some of the mechanisms through which deprivation increases the risk of TB in the general population in England and support the argument for improved approaches to TB control efforts, such as integrated health and social services in high-risk young adult populations.

Background The roll-out of anti-retroviral therapy (ART) has changed contexts of human immunodeficiency virus (HIV) risk. Here, we summarise direct estimates of HIV incidence among adolescent girls and young women (AGYW) since ART and before large investments in targeted prevention for AGYW in sub-Saharan Africa. Methods Database searches identified studies reporting HIV incident data from serological samples collected among 15-24 year-old females in 10 countries selected for PEPFAR investment in 2015. Estimates collected between 2005-2015, published or received from authors, were summarised by age and sex, and pooled by region. Findings Fifty-one analyses were identified from nine of the eligible countries (save Lesotho). Directly-observed incidence rates were lowest among AGYW in Kumi, Uganda (0.38%) and highest in KwaZulu-Natal, South Africa (7.8% among 15-19y; 8.6% in 20-24y); fishing communities in Uganda (12.4% and 4.7% among 15-19y and 20-24y females); and among sex workers aged 18-24y in South Africa (13.2%) and Zimbabwe (10.8%). In pooled rates from general population studies, the greatest sex differentials were in the youngest age groups, i.e., 15-19y females compared to males in both Southern African (relative risk=5.94; 95% CI:3.39-10.44) and Eastern African countries (3.22; 95% CI:1.51-6.87), and not significantly different among the oldest (25-29y) in either region. Incidence often peaked earlier (during teenage years) among high-risk compared to general populations. Since 2005, AGYW incidence declined in Rakai (Uganda), Manicaland (Zimbabwe), and among sex workers in Kenya, but not in the highest-risk communities in South Africa. Interpretation Few sources of direct estimates of HIV incidence exist in high-burden countries and trend analyses with age/sex disaggregated data are rare but indicate recent declines among AGYW. In some of the highest-risk settings, however, little evidence exists to suggest ART availability and other efforts slowed transmission by 2016. Despite wide geographic diversity in absolute levels of AGYW incidence, risk relative to males persisted in all settings, with the greatest sex differentials in the youngest age groups. To end new infections among the growing population of adolescents in sub-Saharan Africa, prevention programs must address gender inequalities driving excessive risk among adolescent girls.

Background Traditional analyses of standard case-control studies using logistic regression do not allow estimation of time-varying associations between exposures and the outcome. We present two approaches which allow this. The motivation is a study of vaccine efficacy as a function of time since vaccination. Methods Our first approach is to estimate time-varying exposure-outcome associations by fitting a series of logistic regressions within successive time periods, reusing controls across periods. Our second approach treats the case-control sample as a case-cohort study, with the controls forming the subcohort. In the case-cohort analysis, controls contribute information at all times they are at risk. Extensions allow left truncation, frequency matching and, using the case-cohort analysis, time-varying exposures. Simulations are used to investigate the methods. Results The simulation results show that both methods give correct estimates of time-varying effects of exposures using standard case-control data. Using the logistic approach there are efficiency gains by reusing controls over time and care should be taken over the definition of controls within time periods. However, using the case-cohort analysis there is no ambiguity over the definition of controls. The performance of the two analyses is very similar when controls are used most efficiently under the logistic approach. Conclusions Using our methods, case-control studies can be used to estimate time-varying exposure-outcome associations where they may not previously have been considered. The case-cohort analysis has several advantages, including that it allows estimation of time-varying associations as a continuous function of time, while the logistic regression approach is restricted to assuming a step function form for the time-varying association.

BackgroundEvidence of protection from childhood BCG against tuberculosis (TB) in adulthood, when most transmission occurs, is important for TB control and resource allocation.MethodsWe conducted a population-based case-control study of protection by BCG given to children aged 12 to 13 years against tuberculosis occurring 10 to 29 years later. We recruited UK-born white subjects with tuberculosis and randomly sampled white community controls. Hazard ratios and 95% confidence intervals were estimated using case-cohort Cox regression, adjusting for potential confounding factors, including socio-economic status, smoking, drug use, prison and homelessness. Vaccine effectiveness (VE=1-hazard ratio) was assessed at successive intervals more than 10 years following vaccinationResultsWe obtained 677 cases and 1170 controls after a 65% response rate in both groups. Confounding by deprivation, education and lifestyle factors was slight 10-20 years after vaccination, more evident after 20 years. VE 10 -15 years after vaccination was 51% (95% CI 21, 69%) and 57% (CI 33, 72%) at 15-20 years. Subsequently BCG protection appeared to wane; 20-25 years VE=25% (CI -14%, 51%) and 25-29 years VE= 1% (CI -84%, 47%). Based on multiple imputation of missing data (in 17% subjects) VE estimated in the same intervals after vaccination were similar (56% (CI 33, 72%), 57% (CI 36, 71%), 25% (-10, 48%), 21% (-39, 55%).ConclusionsSchool-age BCG vaccination offered moderate protection against tuberculosis for at least 20 years which is longer than previously thought. This has implications for assessing the costeffectiveness of BCG vaccination and when evaluating new TB vaccines.

In 2017, WHO convened a working group of global experts to develop the Preferred Product Characteristics (PPC) for Next-Generation Influenza Vaccines. PPCs are intended to encourage innovation in vaccine development. They describe WHO preferences for parameters of vaccines, in particular their indications, target groups, implementation strategies, and clinical data needed for assessment of safety and efficacy. PPCs are shaped by the global unmet public health need in a priority disease area for which WHO encourages vaccine development. These preferences reflect WHO's mandate to promote the development of vaccines with high public health impact and suitability in Low- and Middle-Income Countries (LMIC). The target audience is all entities intending to develop or to achieve widespread adoption of a specific influenza vaccine product in these settings. The working group determined that existing influenza vaccines are not well suited for LMIC use. While many developed country manufactures and research funders prioritize influenza vaccine products for use in adults and the elderly, most LMICs do not have sufficiently strong health systems to deliver vaccines to these groups. Policy makers from LMICs are expected to place higher value on vaccines indicated for prevention of severe illness, however the clinical development of influenza vaccines focuses on demonstrating prevention of any influenza illness. Many influenza vaccine products do not meet WHO standards for programmatic suitability of vaccines, which introduces challenges when vaccines are used in low-resource settings. And finally, current vaccines do not integrate well with routine immunization programs in LMICs, given age of vaccine licensure, arbitrary expiration dates timed for temperate country markets, and the need for year-round immunization in countries with prolonged influenza seasonality. While all interested parties should refer to the full PPC document for details, in this article we highlight data needs for new influenza vaccines to better demonstrate the value proposition in LMICs.

BackgroundUntil recently, evidence that protection from the bacillus Calmette–Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK’s universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced.ObjectivesTo assess the duration of protection of infant and school-age BCG vaccination against TB in the UK.MethodsTwo case–control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0–19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10–29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case–cohort analysis based on Cox regression.ResultsIn the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10–15 years after vaccination and 57% (95% CI 33% to 72%) 15–20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading.LimitationsThe difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination.ConclusionsInfant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading.FundingThe National Institute for Health Research Health Technology Assessment programme. During the conduct of the study, Jonathan Sterne, Ibrahim Abubakar and Laura C Rodrigues received other funding from NIHR; Ibrahim Abubakar and Laura C Rodrigues have also received funding from the Medical Research Council. Punam Mangtani received funding from the Biotechnology and Biological Sciences Research Council.

Almost all human infections by avian influenza viruses (AIVs) are transmitted from poultry. A systematic review was conducted to identify practices associated with human infections, their prevalence, and rationale. Observational studies were identified through database searches. Meta-analysis produced combined odds ratio estimates. The prevalence of practices and rationales for their adoptions were reported. Of the 48,217 records initially identified, 65 articles were included. Direct and indirect exposures to poultry were associated with infection for all investigated viral subtypes and settings. For the most frequently reported practices, association with infection seemed stronger in markets than households, for sick and dead than healthy poultry, and for H7N9 than H5N1. Practices were often described in general terms and their frequency and intensity of contact were not provided. The prevalence of practices was highly variable across studies, and no studies comprehensively explored reasons behind the adoption of practices. Combining epidemiological and targeted anthropological studies would increase the spectrum and detail of practices that could be investigated and should aim to provide insights into the rationale(s) for their existence. A better understanding of these rationales may help to design more realistic and acceptable preventive public health measures and messages.

Conjugate vaccines against Haemophilus influenzae type b (Hib) are widely used. The full implications of Hib vaccination schedule for vaccine effectiveness (VE) are unclear.We searched the literature for observational studies reporting the effectiveness of conjugate Hib vaccines administered according to different schedules. We summarized dose-specific VE estimates, where appropriate, using random effects meta-analysis.Thirty-one eligible articles (reporting 30 studies conducted in 17 countries) were identified. Meta-analysis of case-control studies using community controls produced VE estimates against Hib meningitis of 55% (95% confidence interval: 2-80%, based on 3 studies), 96% (86-99%, 3 studies) and 96% (86-99%, 4 studies) after 1, 2 and 3 doses of vaccines other than the polyribosyl ribitol phosphate outer membrane protein vaccine. Estimates were similar using hospital controls. VE against invasive Hib disease in case-control studies was estimated as 59% (30-76%, 3 studies) and 97% (87-99%, 3 studies) for 1 and 3 doses (insufficient data were identified to estimate 2-dose VE). Point estimates from 2 studies suggested VE90% after 1 dose of the polyribosyl ribitol phosphate outer membrane protein vaccine, but meta-analysis was not possible. Using data from 4 cohort studies, 3-dose VE was estimated as 94% (88-97%). There was some evidence that Hib vaccine was less effective when administered with acellular (rather than whole cell) pertussis vaccine. Weak evidence from 2 studies suggested that a booster confers some additional protection following full primary vaccination and may compensate for an incomplete primary series.Observational data suggest that ≥2 doses of Hib vaccine are required for high effectiveness, but do not strongly favor any particular schedule.

Highly pathogenic avian influenza virus subtype H5N1 is endemic in Asia, with live bird trade as a major disease transmission pathway. A cross-sectional survey was undertaken in northern Vietnam to investigate the structure of the live bird market (LBM) contact network and the implications for virus spread. Based on the movements of traders between LBMs, weighted and directed networks were constructed and used for social network analysis and individual-based modeling. Most LBMs were connected to one another, suggesting that the LBM network may support large-scale disease spread. Because of cross-border trade, it also may promote transboundary virus circulation. However, opportunities for disease control do exist. The implementation of thorough, daily disinfection of the market environment as well as of traders’ vehicles and equipment in only a small number of hubs can disconnect the network dramatically, preventing disease spread. These targeted interventions would be an effective alternative to the current policy of a complete ban of LBMs in some areas. Some LBMs that have been banned still are very active, and they likely have a substantial impact on disease dynamics, exhibiting the highest levels of susceptibility and infectiousness. The number of trader visits to markets, information that can be collected quickly and easily, may be used to identify LBMs suitable for implementing interventions. This would not require prior knowledge of the force of infection, for which laboratory-confirmed surveillance would be necessary. These findings are of particular relevance for policy development in resource-scarce settings.

School closure is often considered as an influenza control measure, but its effects on transmission are poorly understood. We used 2 approaches to estimate how school holidays affect the contact parameter (the per capita rate of contact sufficient for infection transmission) for influenza using primary care data from England and Wales (1967–2000). Firstly, we fitted an age-structured susceptible-infectious-recovered model to each year's data to estimate the proportional change in the contact parameter during school holidays as compared with termtime. Secondly, we calculated the percentage difference in the contact parameter between holidays and termtime from weekly values of the contact parameter, estimated directly from simple mass-action models. Estimates were combined using random-effects meta-analysis, where appropriate. From fitting to the data, the difference in the contact parameter among children aged 5–14 years during holidays as compared with termtime ranged from a 36% reduction to a 17% increase; estimates were too heterogeneous for meta-analysis. Based on the simple mass-action model, the contact parameter was 17% (95% confidence interval: 10, 25) lower during holidays than during termtime. Results were robust to the assumed proportions of infections that were reported and individuals who were susceptible when the influenza season started. We conclude that school closure may reduce transmission during influenza outbreaks.

Studies on cancer in migrants are informative about the relative influence of environmental and genetic factors on cancer risk. This study investigates trends in incidence from colorectal, lung, breast and prostate cancer in England among South Asians and examines the influence of deprivation, a key environmental exposure. South Asian ethnicity was assigned to patients recorded in the population-based National Cancer Registry of England during 1986-2004, using the computerized algorithm SANGRA: South Asian Names and Groups Recognition Algorithm. Population denominators were derived from population censuses. Multivariable flexible (splines) Poisson models were used to estimate trends and socioeconomic differentials in incidence in South Asians compared to non-South Asians. Overall, age-adjusted cancer incidence in South Asians was half that in non-South Asians but rose over time. Cancer-specific incidence trends and patterns by age and deprivation differed widely between the two ethnic groups. In contrast to non-South Asians, lung cancer incidence in South Asians did not fall. Colorectal and breast cancer incidence rose in both groups, more steeply in South Asians though remaining less common than in non-South Asians. The deprivation gaps in cancer-specific incidence were much less marked among South Asians, explaining some of the ethnic differences in overall incidence. Although still lower than in non-South Asians, cancer incidence is rising in South Asians, supporting the concept of transition in cancer incidence among South Asians living in England. Although these trends vary by cancer, they have important implications for both prevention and anticipating health-care demand.

To describe Ontario Telehealth usage for respiratory complaints during normal (i.e., interpandemic) circumstances.Descriptive analyses were conducted on symptom calls of a respiratory nature made to Ontario (Canada) Telehealth during a 25-month period.Approximately 300,000 calls were made during the period under study, peaking annually in January/February. Calls were above average during the weekend and Mondays (p0.0001). All-ages consultation rate was 0.21/1,000 (range, 0.11-0.43). Standardized call rates suggested an inverse relationship between age and call rate (except for65 years of age). During peak activity, weekly telehealth call rates were up to more than twice the weekly mean and up to four times as high as the lowest weekly rate. Highest call rate was for under 5 years old (158.4/1,000). Male rates exceed female call rates in younger age groups; the pattern reversed in older age groups. The relationship between income and call pattern showed that income and call patterns were (1) directly related for under 5 years old, (2) inversely related for callers aged 45 years and above, and (3) bimodal (higher call rates in both the highest and lowest income groups) for callers 5-44 years old.The advent of annual respiratory illness seasons under study here resulted in surge capacity. Data such as these can and should be used for exercises such as seasonal and pandemic forecasting. Also, recent pandemic experience has showed us monitoring both overall exceedances in usage and deviances from established demographic patterns could enhance existing routine surveillance.

Estimation of influenza vaccine effectiveness (VE) is complicated by various degrees of mismatch between circulating and vaccine strains each season. We carried out a cohort study to estimate VE of trivalent (TIV) and pandemic influenza vaccines (PIV) in preventing various respiratory outcomes among general practice (GP) patients in England and Wales between 2008 and 2010. Dates of consultations for influenza-like illness (ILI), acute respiratory tract infection (ARTI), lower respiratory tract infection (LRTI) and nasopharyngeal swabs were obtained from the patient-level electronic records of the 100 practices enrolled in a national GP network. Dates of vaccination with TIV and PIV were also extracted. Confounders including age, time period and consultation frequency were adjusted for through Poisson regression models. In the winter of 2008/9, adjusted VE of TIV in preventing ILI was 22.3% (95% CI 13.5%, 30.2%). During the 2009/10 winter VE for PIV in preventing ILI was 21.0% (5.3%, 34.0%). The VE for PIV in preventing PCR-confirmed influenza A/H1N1 (2009) was 63.7% (-6.1%, 87.6%). TIV during the period of influenza circulation of 2008/9 and PIV in the winter of 2009/10 were effective in preventing GP consultations for ILI. The cohort study design could be used each season to estimate VE; however, residual confounding by indication could still present issues, despite adjustment for propensity to consult.

Setting The state of Sabah contributes one third of the tuberculosis (TB) cases in Malaysia. Objective To collect information on factors that affect the time period from the onset of symptoms to first contact with health care providers, whether private or government. Design A cross-sectional study using a pre-tested questionnaire was conducted among 296 newly registered smear-positive TB patients in 10 districts in Sabah. Univariable and multivariable analyses were used to determine which risk factors were associated with patient delay (>30 days) and 'extreme' patient delay (>90 days). Results The percentage of patients who sought treatment after 30 and 90 days was respectively 51.8% (95%CI 45.7-57.9) and 23.5% (95%CI 18.6-29.0). The strongest factors associated with patient delay and 'extreme' patient delay was when the first choice for treatment was a non-government health facility and in 30-39-year-olds. 'Extreme' patient delay was also weakly associated, among other factors, with comorbidity and livestock ownership. Conclusion Delay and extreme delay in seeking treatment were more common when the usual first treatment choice was a non-government health facility. Continuous health education on TB aimed at raising awareness and correcting misconceptions is needed, particularly among those who use non-government facilities.

Live bird markets (LBMs) act as a network ‘hub’ and potential reservoir of infection for domestic poultry. They may therefore be responsible for sustaining H5N1 highly pathogenic avian influenza (HPAI) virus circulation within the poultry sector, and thus a suitable target for implementing control strategies. We developed a stochastic transmission model to understand how market functioning impacts on the transmission dynamics. We then investigated the potential for rest days—periods during which markets are emptied and disinfected—to modulate the dynamics of H5N1 HPAI within the poultry sector using a stochastic meta-population model. Our results suggest that under plausible parameter scenarios, HPAI H5N1 could be sustained silently within LBMs with the time spent by poultry in markets and the frequency of introduction of new susceptible birds' dominant factors determining sustained silent spread. Compared with interventions applied in farms (i.e. stamping out, vaccination), our model shows that frequent rest days are an effective means to reduce HPAI transmission. Furthermore, our model predicts that full market closure would be only slightly more effective than rest days to reduce transmission. Strategies applied within markets could thus help to control transmission of the disease.

Background: Cancer mortality has been examined among ethnic South Asian migrants in England and Wales, but not by generation of migration. Methods: Using South Asian mortality records, identified by a name-recognition algorithm, and census information, age-standardised rates among South Asians, and South Asian vs non-South Asian rate ratios, were calculated. Results and conclusions: All-cancer rates in ethnic South Asians were half of those in non-South Asians in first-generation (all-cancer-standardised mortality ratio (SMR) in males 0.51 and in females 0.56) and subsequent-generation South Asians (SMR in males 0.43 and in females 0.36). The higher mortality in first-generation South Asians for liver (both sexes), oral cavity and gallbladder cancer (females), particularly marked among Bangladeshis, was reduced in subsequent generations.

Movement of poultry through markets is potentially important in the circulation and spread of highly pathogenic avian influenza. However little is understood about poultry market chains in Cambodia. We conducted a cross-sectional survey of 715 rural villagers, 123 rural, peri-urban and urban market sellers and 139 middlemen from six provinces and Phnom Penh, to evaluate live poultry movement and trading practices. Direct trade links with Thailand and Vietnam were identified via middlemen and market sellers. Most poultry movement occurs via middlemen into Phnom Penh making live bird wet markets in Phnom Penh a potential hub for the spread of H5N1 and ideal for surveillance and control.

In several countries, pregnant women are recommended seasonal influenza vaccination and identified as a priority group for vaccination in the event of a pandemic. We review the evidence for the risks of influenza and the risks and benefits of seasonal influenza vaccination in pregnancy. Data on influenza vaccine safety in pregnancy are inadequate, but the few published studies report no serious side-effects in women or their infants, including no indication of harm from vaccination in the first trimester. National policies differ widely, mainly because of the limited data available, particularly on vaccination in the first trimester. The evidence of excess morbidity during seasonal influenza supports vaccinating healthy pregnant women in the second or third trimester and those with comorbidities in any trimester. The evidence of excess mortality in two previous influenza pandemics supports vaccinating in any trimester during a pandemic.

Data are limited regarding cancer incidence among Indians residing in different geographic regions around the world. Examining such rates may provide us with insights into future aetiological research possibilities as well as screening and prevention.Incidence rates for all cancers combined and 19 specific cancers were obtained for India from Globocan 2002, for Indians in Singapore from Cancer Incidence in Five Continents (VIII), and from national data sources for South Asians (SA) in the United Kingdom (UK) and for Asian Indians/Pakistanis (AIP) and whites in the United States (US).We observed the lowest total cancer incidence rates in India (111 and 116 per 100,000 among males and females, respectively, age-standardized to the 1960 world population) and the highest among US whites (362 and 296). Cancer incidence rates among Indians residing outside of India were: intermediate Singapore (102 and 132), UK (173 and 179) and US ranges 152-176 and 142-164. A similar pattern was observed for cancers of the colorectum, prostate, thyroid, pancreas, lung, breast and non-Hodgkin lymphoma. In contrast, rates for cancers of the oral cavity, oesophagus, larynx and cervix uteri were highest in India. Although little geographic variability was apparent for stomach cancer incidence, Indians in Singapore had the highest rates compared with any other region. The UK SA and the US AIP appear with adopt the cancer patterns of their host country.Variations in environmental exposures such as tobacco use, diet and infection, as well as better health care access and knowledge may explain some of the observed incidence differences.

Summary Background Little is known about how long the BCG vaccine protects against tuberculosis. We assessed the long-term vaccine effectiveness (VE) in Norwegian-born individuals. Methods In this retrospective population-based cohort study, we studied Norwegian-born individuals aged 12–50 years who were tuberculin skin test (TST) negative and eligible for BCG vaccination as part of the last round of Norway's mandatory mass tuberculosis screening and BCG vaccination programme between 1962 and 1975. We excluded individuals who had tuberculosis before or in the year of screening and those with unknown TST and BCG status. We obtained TST and BCG information and linked it to the National Tuberculosis Register, population and housing censuses, and the population register for emigrations and deaths. We followed individuals up to their first tuberculosis episode, emigration, death, or Dec 31, 2011. We used Cox regressions to estimate VE against all tuberculosis and just pulmonary tuberculosis by time since vaccination, adjusted for age, time, county-level tuberculosis rates, and demographic and socioeconomic indicators. Findings Median follow-up was 41 years (IQR 32–49) for 83 421 BCG-unvaccinated and 44 years (41–46) for 297 905 vaccinated individuals, with 260 tuberculosis episodes. Tuberculosis rates were 3·3 per 100 000 person-years in unvaccinated and 1·3 per 100 000 person-years in vaccinated individuals. The adjusted average VE during 40 year follow-up was 49% (95% CI 26–65), although after 20 years, the VE was not significant (up to 9 years VE [excluding tuberculosis episodes in the first 2 years] 61% [95% CI 24–80]; 10–19 years 58% [27–76]; 20–29 years 38% [–32 to 71]; 30–40 years 42% [–24 to 73]). VE against pulmonary tuberculosis up to 9 years (excluding tuberculosis episodes in the first 2 years) was 67% (95% CI 27–85), 10–19 years was 63% (32–80), 20–29 years was 50% (−19 to 79), and 30–40 years was 40% (−46 to 76). Interpretation Findings are consistent with long-lasting BCG protection, but waning of VE with time. The vaccine could be more cost effective than has been previously estimated Funding Norwegian Institute of Public Health and London School of Hygiene & Tropical Medicine.

Background: South Asian migrants show lower cancer incidence than their host population in England for most major cancers. We seek to study the ethnic differences in survival from cancer. Methods: We described and modelled the effect of ethnicity, time, age and deprivation on survival for the five most incident cancers in each sex in South Asians in England between 1986 and 2004 using national cancer registry data. South Asian ethnicity was flagged using the validated name-recognition algorithm SANGRA (South Asian Names and Group Recognition Algorithm). Results: We observed survival advantage in South Asians in earlier periods. This ethnic gap either remained constant or narrowed over time. By 2004, age-standardised net survival was comparable for all cancers except three in men, where South Asians had higher survival 5 years after diagnosis: colorectal (58.9% vs 53.6%), liver (15.0% vs 9.4%) and lung (15.9% vs 9.3%). Compared with non-South Asians, South Asians experienced a slower increase in breast and prostate cancer survival, both cancers associated with either a screening programme or an early diagnosis test. We did not find differential patterns in survival by deprivation between both ethnicities. Conclusions: Considering recent survival trends, appropriate action is required to avoid deficits in cancer survival among South Asians in the near future.