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 frst tuberculosis episode, and randomly selected age and sex frequencymatched 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 fndings suggest that socio-economic deprivation remains a driver of tuberculosis in England, including through drugs misuse, tobacco smoking, and homelessness. These fndings further support the integration of health and social services in high-risk young adults to improve TB control eforts

Serological Cross-Reactivity in Zoonotic Flaviviral Infections of Medical Importance

Flaviviruses are enveloped RNA viruses from the family Flaviviridae that comprise many important human pathogenic arboviruses such as Yellow Fever, Dengue, and Zika viruses. Because they belong to the same genus, these viruses show sequence and structural homology among them, which results in serological cross-reactivity. Upon infection, the immune system produces both species-specific and cross-reactive antibodies, and depending on the virus, in a successive flavivirus infection, cross-reactive antibodies either enhance protection or exacerbate the disease-the latter usually due to antibody-dependent enhancement. These antigenic relationships between different flaviviruses that lead to serological cross-reactivity make them difficult to be identified through serological methods, especially when it comes to successive flavivirus infections. We present here an overview of the main structural, epidemiological, and immunological aspects of flaviviruses, highlighting the role of neutralizing antibodies in fighting viral infections and in the original antigenic sin problem. Finally, we draw attention to the importance of developing a rapid serological diagnostic test for flaviviruses with high sensitivity and specificity, especially when considering that cross-reactive immunity can influence the outcome of these infections

Susceptibility of Candida glabrata biofilms to echinocandins: alterations in the matrix composition

Candidiases are the most recurrent fungal infections, especially among immunosuppressed patients. Although Candida albicans is still the most widespread isolated species, non-Candida albicans Candida species have been increasing. The goal of this work was to determine the susceptibility of C. glabrata biofilms to echinocandins and to evaluate their effect on the biofilm matrix composition, comparing the results with other Candida species. Drug susceptibilities were assessed through the determination of minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC) and minimum biofilm eradication concentration (MBEC) of caspofungin (Csf) and micafugin (Mcf). The -1,3 glucans content of the matrices was assessed after contact with the drugs. The data suggest that, generally, after contact with echinocandins, the concentration of -1,3 glucans increased. These adjustments in the matrix composition of C. glabrata biofilms and the chemical differences between Csf and Mcf, seem responsible and may determine the effectivity of the drug responses.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 [POCI-01–0145-FEDER-006684] and BioTecNorte operation [NORTE-01–0145-FEDER-000004] funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte, Célia F. Rodrigues’ [SFRH/BD/93078/2013] PhD grant and M. Elisa Rodrigues [SFRH/BPD/95401/2013] post-doctoral grant.info:eu-repo/semantics/publishedVersio

Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guérin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK.

Until 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. To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. Two 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. In 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 [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5-10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10-15 years after vaccination (VE 36%, 95% CI negative to 77%; 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. The 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. Infant 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. The 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

Effect of reminders on mitigating participation bias in a case-control study

BACKGROUND: Researchers commonly employ strategies to increase participation in health studies. These include use of incentives and intensive reminders. There is, however, little evidence regarding the quantitative effect that such strategies have on study results. We present an analysis of data from a case-control study of Campylobacter enteritis in England to assess the usefulness of a two-reminder strategy for control recruitment. METHODS: We compared sociodemographic characteristics of participants and non-participants, and calculated odds ratio estimates for a wide range of risk factors by mailing wave. RESULTS: Non-participants were more often male, younger and from more deprived areas. Among participants, early responders were more likely to be female, older and live in less deprived areas, but despite these differences, we found little evidence of a systematic bias in the results when using data from early reponders only. CONCLUSIONS: We conclude that the main benefit of using reminders in our study was the gain in statistical power from a larger sample size

A commonly occurring genetic variant within the NPLOC4–TSPAN10–PDE6G gene cluster is associated with the risk of strabismus

Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×1020 protons on target in which neutrinos of energies between ~500¿¿MeV and 120 GeV are produced predominantly as ¿µ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ¿µ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles ¿24 and ¿34 are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime t3/m3>2.1×10-12¿¿s/eV at 90% C.L