Estimating time-varying exposure-outcome associations using case-control data: logistic and case-cohort analyses.

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

Small-area level socio-economic deprivation and tuberculosis rates in England: An ecological analysis of tuberculosis notifications between 2008 and 2012.

BACKGROUND: Tuberculosis (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. OBJECTIVES: To 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. METHODS: Ecological 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. RESULTS: There 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). CONCLUSIONS: Socio-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

Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study.

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

Loa loa Alben Trial data

Loiasis is a parasitic infection endemic in the African rain forest caused by the filarial nematode Loa loa. Loiasis can be co-endemic with onchocerciasis and/or lymphatic filariasis. Ivermectin, the drug used in the control of these diseases, can induce serious adverse reactions in patients with high L loa microfilaraemia (LLM). A drug is needed which can lower LLM below the level that represents a risk so that ivermectin mass treatment to support onchocerciasis and lymphatic filariasis elimination can be implemented safely. Sixty men and women from a loiasis endemic area in Cameroon were randomized after stratification by screening LLM (≤30000, 30001-50000, >50000) to three treatment arms: two doses albendazole followed by 4 doses matching placebo (n = 20), six doses albendazole (n = 20) albendazole or 6 doses matching placebo (n = 20) administered every two months. LLM was measured before each treatment and 14, 18, 21 and 24 months after the first treatment. Monitoring for adverse events occurred three and seven days as well as 2 months after each treatment. None of the adverse events recorded were considered treatment related. The percentages of participants with ≥ 50% decrease in LLM from pre-treatment for ≥ 4 months were 53%, 17% and 11% in the 6-dose, 2-dose and placebo treatment arms, respectively. The difference between the 6-dose and the placebo arm was significant (p = 0.01). The percentages of participants with LLM < 8100 mf/ml for ≥4 months were 21%, 11% and 0% in the 6-dose, 2-dose and placebo treatment arms, respectively. The 6-dose regimen reduced LLM significantly, but the reduction was insufficient to eliminate the risk of severe and/or serious adverse reactions during ivermectin mass drug administration in loiasis co-endemic areas

Effect of Two or Six Doses 800 mg of Albendazole Every Two Months on Loa loa Microfilaraemia: A Double Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Loiasis is a parasitic infection endemic in the African rain forest caused by the filarial nematode Loa loa. Loiasis can be co-endemic with onchocerciasis and/or lymphatic filariasis. Ivermectin, the drug used in the control of these diseases, can induce serious adverse reactions in patients with high L loa microfilaraemia (LLM). A drug is needed which can lower LLM below the level that represents a risk so that ivermectin mass treatment to support onchocerciasis and lymphatic filariasis elimination can be implemented safely. METHODOLOGY: Sixty men and women from a loiasis endemic area in Cameroon were randomized after stratification by screening LLM (≤ 30000, 30001-50000, >50000) to three treatment arms: two doses albendazole followed by 4 doses matching placebo (n = 20), six doses albendazole (n = 20) albendazole or 6 doses matching placebo (n = 20) administered every two months. LLM was measured before each treatment and 14, 18, 21 and 24 months after the first treatment. Monitoring for adverse events occurred three and seven days as well as 2 months after each treatment. PRINCIPAL FINDINGS: None of the adverse events recorded were considered treatment related. The percentages of participants with ≥ 50% decrease in LLM from pre-treatment for ≥ 4 months were 53%, 17% and 11% in the 6-dose, 2-dose and placebo treatment arms, respectively. The difference between the 6-dose and the placebo arm was significant (p = 0.01). The percentages of participants with LLM < 8100 mf/ml for ≥ 4 months were 21%, 11% and 0% in the 6-dose, 2-dose and placebo treatment arms, respectively. CONCLUSIONS/ SIGNIFICANCE: The 6-dose regimen reduced LLM significantly, but the reduction was insufficient to eliminate the risk of severe and/or serious adverse reactions during ivermectin mass drug administration in loiasis co-endemic areas

Drug misuse, tobacco smoking, alcohol and other social determinants of tuberculosis in UK-born adults in England: a community-based case-control study.

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

BCG vaccination for bovine tuberculosis; conclusions from the Jerusalem One Health workshop.

The global burden of bovine tuberculosis (bTB) remains poorly characterized, with spill-over impacts on multiple species. The "One Health" concept is especially relevant given the bidirectional risk of cattle infecting humans with Mycobacterium bovis and humans infecting cattle with Mycobacterium tuberculosis. "Test and cull" is the traditional bTB control method, but the strategy may not be economically feasible or culturally acceptable where cattle are highly prized or their killing is a religious taboo; it is also less effective when there are wildlife reservoirs of infection. Vaccination with M. bovis bacille Calmette-Guerin (BCG) provides protection against bTB, but its use in animals has been limited. The Jerusalem One Health workshop considered key bTB knowledge gaps and innovative solutions. Knowledge gaps identified included (a) the poorly quantified prevalence of M. bovis infection and disease in cattle, domestic camelids and human populations in developing countries, (b) the absence of alternatives to a "test and cull" strategy in settings where the killing of infected animals is culturally or economically unacceptable, or where affected species are protected and (c) an understanding of the induction of mucosal immunity against bTB. We summarize discussions on the use of BCG vaccination in domestic animals and wildlife and list potential projects to address the knowledge gaps identified

Effects of a social norm-based handwashing intervention including handwashing stations, and a handwashing station-only intervention on handwashing with soap in urban Côte d'Ivoire: a cluster randomised controlled trial.

BACKGROUND: Diarrhoeal diseases are an important cause of mortality in children younger than 5 years in sub-Saharan Africa. We aimed to evaluate the effect of three handwashing interventions on handwashing with soap (HWWS) after toilet use. METHODS: In this cluster randomised trial in Abidjan, Côte d'Ivoire, we randomly assigned communal housing compounds (1:1:1) to receive one of three interventions: a theory of normative social behaviour (TNSB) intervention, including provision of handwashing stations; handwashing stations only; and no intervention. The TNSB intervention was designed to shift the outcome expectation associated with HWWS from health to riddance of faeces-related disgust, and to increase the perceived descriptive norm and perceived handwashing publicness. Participants and fieldworkers were masked to the study objectives. The primary outcome was HWWS after toilet use, assessed at 1 month and 5 months follow-ups. Analysis was by intention to treat. This trial is registered at the Pan African Clinical Trial Registry, PACTR201501000892239. FINDINGS: Between April 10 and May 22, 2014, we identified 92 eligible compounds, of which 75 compounds were included. Follow-up data on HWWS were available for 23 compounds for the TNSB group, 25 compounds for the handwashing station-only group, and 25 compounds for the control group. The study ended in April, 2017. Compared with a frequency of 5% (29 of 604 occasions) in the control group, HWWS after toilet use increased to 9% (49 of 557 occasions; adjusted risk ratio 1·89, 95% CI 1·16-3·08) in the handwashing station-only group, and 24% (143 of 588 occasions; 4·82, 3·06-7·59) in the TNSB group, at the 1-month follow-up. The intervention effect was only sustained in the TNSB group (98 [22%] of 450 compounds; 2·68, 1·65-4·34). INTERPRETATION: A social norm-based handwashing intervention combined with disgust-inducing messages, with provision of handwashing stations, was effective at increasing HWWS after toilet use. The provision of handwashing stations alone had little effect. Future studies should investigate whether the same approach, when delivered via mass media, can have a similar effect to the face-to-face delivery used in this study

Measuring social norms related to handwashing : development and psychometric testing of measurement scales in a low-income urban setting in Abidjan, Côte d'Ivoire

OBJECTIVES: To design and test the psychometric properties of four context-specific norm-related scales around handwashing with soap after toilet use: (1) perceived handwashing descriptive norms (HWDN); (2) perceived handwashing injunctive norms (HWIN); (3) perceived handwashing behaviour publicness (HWP); and (4) perceived handwashing outcome expectations (HWOE). DESIGN: Scale items were developed based on previous work and pilot tested in an iterative process. Content experts and members of the study team assessed the face validity of the items. The psychometric properties of the scales were assessed in a cross-sectional study. SETTING: The study was conducted in communal housing compounds in Abidjan, Côte d'Ivoire. PARTICIPANTS: A convenience sample of 201 adult residents (≥16 years old) from 60 housing compounds completed the final questionnaire. OUTCOME MEASURE: Confirmatory factor analysis was used to assess the goodness of fit of the global model. We assessed the internal consistency of each scale using Cronbach's alpha (α) and the Spearman-Brown coefficient (ρ). RESULTS: The results of the psychometric tests supported the construct validity of three of the four scales, with no factor identified for the HWOE (α=0.15). The HWDN and HWP scales were internally consistent with correlations of ρ=0.74 and ρ=0.63, respectively. The HWIN scale appeared reliable (α=0.83). CONCLUSION: We were able to design three reliable context-specific handwashing norm-related scales, specific to economically disadvantaged community settings in Abidjan, Côte d'Ivoire, but failed to construct a reliable scale to measure outcome expectations around handwashing. The social desirability of handwashing and the narrow content area of social norms constructs relating to handwashing present significant challenges when designing items to measure such constructs. Future studies attempting to measure handwashing norm-related constructs will need to take this into account when developing such scales, and take care to adapt their scales to their study context

English headteacher perspectives on school responses to protect student and staff mental wellbeing in the later stages of the COVID-19 pandemic

Objective: The COVID-19 pandemic has had a significant impact on pupils and staff in English schools. This study aimed to provide an in-depth understanding of the challenges schools faced and the processes they implemented to protect the mental wellbeing of students and staff in the later stages of the pandemic, focusing on January–June 2022. Design: Qualitative study. Setting: Primary and secondary schools in England from April to September 2022. Method: Ten semi-structured interviews were conducted using Zoom with six primary and four secondary school headteachers (or other members of the senior leadership team) in England. Results: Mental wellbeing programming for students and staff was scaled up in both primary and secondary schools amid concerns that the COVID-19 pandemic would impact on mental health. Headteachers perceived changes in the behaviour of students, including increased dysregulation, and staff struggling with fatigue and a sense of being devalued as professionals. Schools scaled up the supports they offered to students and staff, but challenges remain in maintaining such increased support due to the perceived additional needs of staff and students within the context of funding constraints. Despite initial concerns that there would be tension between promoting mental wellbeing and academic catch-up among students, headteachers identified work addressing these two priorities as synergistic. Conclusion: Mental wellbeing impacts of the pandemic on pupils and staff required increased provision of support programmes. Ongoing efforts to monitor the wellbeing needs of students and staff is required. Formal and informal methods to enhance the mental health for pupils and staff should continue into the recovery period