Analysing Interrupted Time Series with a Control

Abstract Interrupted time series are increasingly being used to evaluate the population-wide implementation of public health interventions. However, the resulting estimates of intervention impact can be severely biased if underlying disease trends are not adequately accounted for. Control series offer a potential solution to this problem, but there is little guidance on how to use them to produce trend-adjusted estimates. To address this lack of guidance, we show how interrupted time series can be analysed when the control and intervention series share confounders, i. e. when they share a common trend. We show that the intervention effect can be estimated by subtracting the control series from the intervention series and analysing the difference using linear regression or, if a log-linear model is assumed, by including the control series as an offset in a Poisson regression with robust standard errors. The methods are illustrated with two examples.</jats:p

The effect of distance on observed mortality, childhood pneumonia and vaccine efficacy in rural Gambia.

We investigated whether straight-line distance from residential compounds to healthcare facilities influenced mortality, the incidence of pneumonia and vaccine efficacy against pneumonia in rural Gambia. Clinical surveillance for pneumonia was conducted on 6938 children living in the catchment areas of the two largest healthcare facilities. Deaths were monitored by three-monthly home visits. Children living >5 km from the two largest healthcare facilities had a 2·78 [95% confidence interval (CI) 1·74-4·43] times higher risk of all-cause mortality compared to children living within 2 km of these facilities. The observed rate of clinical and radiological pneumonia was lower in children living >5 km from these facilities compared to those living within 2 km [rate ratios 0·65 (95% CI 0·57-0·73) and 0·74 (95% CI 0·55-0·98), respectively]. There was no association between distance and estimated pneumococcal vaccine efficacy. Geographical access to healthcare services is an important determinant of survival and pneumonia in children in rural Gambia

Pneumococcal conjugate vaccine dose-ranging studies in humans: A systematic review

Background: Streptococcus pneumoniae is one of the most common bacterial pathogens of infants and young children. Antibody responses against the pneumococcal polysaccharide capsule are the basis of vaccine-mediated protection. We examined the relationship between the dose of polysaccharide in pneumococcal conjugate vaccines (PCVs) and immunogenicity. Methods: A systematic search of English publications that evaluated the immunogenicity of varying doses of pneumococcal conjugate vaccines was performed in Medline and Embase (Ovid Sp) databases in August 2019. We included only articles that involved administration of pneumococcal conjugate vaccine in humans and assessed the immunogenicity of more than one serotype-specific saccharide dose. Results were synthesised descriptively due to the heterogeneity of product valency, product content and vaccine schedule. Results: We identified 1691 articles after de-duplication; 9 studies met our inclusion criteria; 2 in adults, 6 in children and 1 in both. Doses of polysaccharide evaluated ranged from 0.44 mcg to 17.6 mcg. In infants, all doses tested elicited IgG geometric mean concentrations (GMCs) above the established correlate of protection (COP; 0.35 mcg/ml). A month after completion of the administered vaccine schedule, 95% confidence intervals of only three out of all the doses evaluated had GMCs that crossed below the COP. In the adult studies, all adults achieved GMCs that would be considered protective in children who have received 3 standard vaccine doses. Conclusion: For some products, the mean antibody concentrations induced against some pneumococcal serotypes increased with increasing doses of the polysaccharide conjugate, but for other serotypes, there were no clear dose–response relationships or the dose response curves were negative. Fractional doses of polysaccharide which contain less than is included in currently distributed formulations may be useful in the development of higher valency vaccines, or dose-sparing delivery for paediatric use

Measuring socioeconomic inequalities in relation to malaria risk: a comparison of metrics in rural Uganda

ocioeconomic position (SEP) is an important risk factor for malaria, but there is no consensus on how to measure SEP in malaria studies. We evaluated the relative strength of four indicators of SEP in predicting malaria risk in Nagongera, Uganda. 318 children resident in 100 households were followed for 36 months to measure parasite prevalence routinely every three months and malaria incidence by passive case detection. Household SEP was determined using: (1) two wealth indices, (2) income, (3) occupation and (4) education. Wealth Index I (reference) included only asset ownership variables. Wealth Index II additionally included food security and house construction variables, which may directly affect malaria. In multivariate analysis, only Wealth Index II and income were associated with the human biting rate, only Wealth Indices I and II were associated with parasite prevalence and only caregiver’s education was associated with malaria incidence. This is the first evaluation of metrics beyond wealth and consumption indices for measuring the association between SEP and malaria. The wealth index still predicted malaria risk after excluding variables directly associated with malaria, but the strength of association was lower. In this setting, wealth indices, income and education were stronger predictors of socioeconomic differences in malaria risk than occupation

Effect of strikes by health workers on mortality between 2010 and 2016 in Kilifi, Kenya: a population-based cohort analysis

BACKGROUND: Health workers' strikes are a global occurrence. Kenya has had several strikes by health workers in recent years but their effect on mortality is unknown. We assessed the effect on mortality of six strikes by health workers that occurred from 2010 to 2016 in Kilifi, Kenya. METHODS: Using daily mortality data obtained from the Kilifi Health and Demographic Surveillance System, we fitted a negative binomial regression model to estimate the change in mortality during strike periods and in the 2 weeks immediately after strikes. We did subgroup analyses by age, cause of death, and strike week. FINDINGS: Between Jan 1, 2010, and Nov 30, 2016, we recorded 1 829 929 person-years of observation, 6396 deaths, and 128 strike days (median duration of strikes, 18·5 days [range 9-42]). In the primary analysis, no change in all-cause mortality was noted during strike periods (adjusted rate ratio [RR] 0·93, 95% CI 0·81-1·08; p=0·34). Weak evidence was recorded of variation in mortality rates by age group, with an apparent decrease among infants aged 1-11 months (adjusted RR 0·58, 95% CI 0·33-1·03; p=0·064) and an increase among children aged 12-59 months (1·75, 1·11-2·76; p=0·016). No change was noted in mortality rates in post-strike periods and for any category of cause of death. INTERPRETATION: The brief strikes by health workers during the period 2010-16 were not associated with obvious changes in overall mortality in Kilifi. The combined effects of private (and some public) health care during strike periods, a high proportion of out-of-hospital deaths, and a low number of events might have led us to underestimate the effect. FUNDING: Wellcome Trust and MRC Tropical Epidemiology Group

Why is malaria associated with poverty? Findings from a cohort study in rural Uganda

Background Malaria control and sustainable development are linked, but implementation of ‘multisectoral’ intervention is restricted by a limited understanding of the causal pathways between poverty and malaria. We investigated the relationships between socioeconomic position (SEP), potential determinants of SEP, and malaria in Nagongera, rural Uganda. Methods Socioeconomic information was collected for 318 children aged six months to 10 years living in 100 households, who were followed for up to 36 months. Mosquito density was recorded using monthly light trap collections. Parasite prevalence was measured routinely every three months and malaria incidence determined by passive case detection. First, we evaluated the association between success in smallholder agriculture (the primary livelihood source) and SEP. Second, we explored socioeconomic risk factors for human biting rate (HBR), parasite prevalence and incidence of clinical malaria, and spatial clustering of socioeconomic variables. Third, we investigated the role of selected factors in mediating the association between SEP and malaria. Results Relative agricultural success was associated with higher SEP. In turn, high SEP was associated with lower HBR (highest versus lowest wealth index tertile: Incidence Rate Ratio 0.71, 95 % confidence intervals (CI) 0.54–0.93, P = 0.01) and lower odds of malaria infection in children (highest versus lowest wealth index tertile: adjusted Odds Ratio 0.52, 95 % CI 0.35–0.78, P = 0.001), but SEP was not associated with clinical malaria incidence. Mediation analysis suggested that part of the total effect of SEP on malaria infection risk was explained by house type (24.9 %, 95 % CI 15.8–58.6 %) and food security (18.6 %, 95 % CI 11.6–48.3 %); however, the assumptions of the mediation analysis may not have been fully met. Conclusion Housing improvements and agricultural development interventions to reduce poverty merit further investigation as multisectoral interventions against malaria. Further interdisplinary research is needed to understand fully the complex pathways between poverty and malaria and to develop strategies for sustainable malaria control

Formation and stability of self-assembled coherent islands in highly mismatched heteroepitaxy

We study the energetics of island formation in Stranski-Krastanow growth within a parameter-free approach. It is shown that an optimum island size exists for a given coverage and island density if changes in the wetting layer morphology after the 3D transition are properly taken into account. Our approach reproduces well the experimental island size dependence on coverage, and indicates that the critical layer thickness depends on growth conditions. The present study provides a new explanation for the (frequently found) rather narrow size distribution of self-assembled coherent islands.Comment: 4 pages, 5 figures, In print, Phys. Rev. Lett. Other related publications can be found at http://www.fhi-berlin.mpg.de/th/paper.htm

Incidence, remission and mortality of convulsive epilepsy in rural northeast South Africa

Background: Epilepsy is one of the most common neurological conditions globally, estimated to constitute 0.75% of the global burden of disease, with the majority of this burden found in low- and middle- income countries (LMICs). Few studies from LMICs, including much of sub-Saharan Africa, have described the incidence, remission or mortality rates due to epilepsy, which are needed to quantify the burden and inform policy. This study investigates the epidemiological parameters of convulsive epilepsy within a context of high HIV prevalence and an emerging burden of cardiovascular disease. Methods: A cross-sectional population survey of 82,818 individuals, in the Agincourt Health and Socio-demographic Surveillance Site (HDSS) in rural northeast South Africa was conducted in 2008, from which 296 people were identified with active convulsive epilepsy. A follow-up survey was conducted in 2012. Incidence and mortality rates were estimated, with duration and remission rates calculated using the DISMOD II software package. Results: The crude incidence for convulsive epilepsy was 17.4/100,000 per year (95%CI: 13.1-23.0). Remission was 4.6% and 3.9% per year for males and females, respectively. The standardized mortality ratio was 2.6 (95%CI: 1.7-3.5), with 33.3% of deaths directly related to epilepsy. Mortality was higher in men than women (adjusted rate ratio (aRR) 2.6 (95%CI: 1.2-5.4)), and was significantly associated with older ages (50+ years versus those 0-5 years old (RR 4.8 (95%CI: 0.6-36.4)). Conclusions: The crude incidence was lower whilst mortality rates were similar to other African studies; however, this study found higher mortality amongst older males. Efforts aimed at further understanding what causes epilepsy in older people and developing interventions to reduce prolonged seizures are likely to reduce the overall burden of ACE in rural South Africa

SosA inhibits cell division in Staphylococcus aureus in response to DNA damage.

Inhibition of cell division is critical for viability under DNA-damaging conditions. DNA damage induces the SOS response that in bacteria inhibits cell division while repairs are being made. In coccoids, such as the human pathogen, Staphylococcus aureus, this process remains poorly studied. Here, we identify SosA as the staphylococcal SOS-induced cell division inhibitor. Overproduction of SosA inhibits cell division, while sosA inactivation sensitizes cells to genotoxic stress. SosA is a small, predicted membrane protein with an extracellular C-terminal domain in which point mutation of residues that are conserved in staphylococci and major truncations abolished the inhibitory activity. In contrast, a minor truncation led to SosA accumulation and a strong cell division inhibitory activity, phenotypically similar to expression of wild-type SosA in a CtpA membrane protease mutant. This suggests that the extracellular C-terminus of SosA is required both for cell division inhibition and for turnover of the protein. Microscopy analysis revealed that SosA halts cell division and synchronizes the cell population at a point where division proteins such as FtsZ and EzrA are localized at midcell, and the septum formation is initiated but unable to progress to closure. Thus, our findings show that SosA is central in cell division regulation in staphylococci