Exploring the effects of BCG vaccination in patients diagnosed with tuberculosis: Observational study using the Enhanced Tuberculosis Surveillance system.

BACKGROUND: Bacillus Calmette-Guérin (BCG) is one of the most widely-used vaccines worldwide. BCG primarily reduces the progression from infection to disease, however there is evidence that BCG may provide additional benefits. We aimed to investigate whether there is evidence in routinely-collected surveillance data that BCG vaccination impacts outcomes for tuberculosis (TB) cases in England. METHODS: We obtained all TB notifications for 2009-2015 in England from the Enhanced Tuberculosis surveillance system. We considered five outcomes: All-cause mortality, death due to TB (in those who died), recurrent TB, pulmonary disease, and sputum smear status. We used logistic regression, with complete case analysis, to investigate each outcome with BCG vaccination, years since vaccination and age at vaccination, adjusting for potential confounders. All analyses were repeated using multiply imputed data. RESULTS: We found evidence of an association between BCG vaccination and reduced all-cause mortality (aOR:0.76 (95%CI 0.64-0.89), P:0.001) and weak evidence of an association with reduced recurrent TB (aOR:0.90 (95%CI 0.81-1.00), P:0.056). Analyses using multiple imputation suggested that the benefits of vaccination for all-cause mortality were reduced after 10 years. CONCLUSIONS: We found that BCG vaccination was associated with reduced all-cause mortality in people with TB although this benefit was less pronounced more than 10 years after vaccination. There was weak evidence of an association with reduced recurrent TB

Open-resorcinarenes, a new family of multivalent scaffolds

A new family of multivalent ligand platforms, the open-resorcinarenes, has been prepared in a straightforward two-step reaction. Modification of the core gives a range of topologically diverse scaffolds; functionalisation confirms the versatility of this approach, as shown through the formation of an octacalixarene array

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Persistence of the immune response induced by BCG vaccination.

BACKGROUND: Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. METHODS: A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-gamma) response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD) in a whole blood assay before, 3 months, 12 months (n = 148) and 3 years (n = 19) after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16). RESULTS: A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13%) failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13%) or 3 (3/19; 16%) years. IFN-gamma response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81%) made a detectable IFN-gamma response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38%) matched unvaccinated controls (p = 0.012); teenagers vaccinated in infancy were 19 times more likely to make an IFN-gamma response of > 500 pg/ml than unvaccinated teenagers. CONCLUSION: BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the majority of vaccinees, although the magnitude of the peripheral blood response wanes from 3 months to 12 months and from 12 months to 3 years post vaccination. The data presented here suggest that because of such waning in the response there may be scope for boosting anti-tuberculous immunity in BCG vaccinated children anytime from 3 months post-vaccination. This supports the prime boost strategies being employed for some new TB vaccines currently under development

Decoding the auditory brain with canonical component analysis

The relation between a stimulus and the evoked brain response can shed light on perceptual processes within the brain. Signals derived from this relation can also be harnessed to control external devices for Brain Computer Interface (BCI) applications. While the classic event-related potential (ERP) is appropriate for isolated stimuli, more sophisticated “decoding” strategies are needed to address continuous stimuli such as speech, music or environmental sounds. Here we describe an approach based on Canonical Correlation Analysis (CCA) that finds the optimal transform to apply to both the stimulus and the response to reveal correlations between the two. Compared to prior methods based on forward or backward models for stimulus-response mapping, CCA finds significantly higher correlation scores, thus providing increased sensitivity to relatively small effects, and supports classifier schemes that yield higher classification scores. CCA strips the brain response of variance unrelated to the stimulus, and the stimulus representation of variance that does not affect the response, and thus improves observations of the relation between stimulus and response

Childbirth-related posttraumatic stress disorder: definition, risk factors, pathophysiology, diagnosis, prevention, and treatment

Psychological birth trauma and childbirth-related posttraumatic stress disorder represent a substantial burden of disease with 6.6 million mothers and 1.7 million fathers or co-parents affected by childbirth-related posttraumatic stress disorder worldwide each year. There is mounting evidence to indicate that parents who develop childbirth-related posttraumatic stress disorder do so as a direct consequence of a traumatic childbirth experience. High-risk groups, such as those who experience preterm birth, stillbirth, or preeclampsia, have higher prevalence rates. The main risks include antenatal factors (eg, depression in pregnancy, fear of childbirth, poor health or complications in pregnancy, history of trauma or sexual abuse, or mental health problems), perinatal factors (eg, negative subjective birth experience, operative birth, obstetrical complications, and severe maternal morbidity, as well as maternal near misses, lack of support, dissociation), and postpartum factors (eg, depression, postpartum physical complications, and poor coping and stress). The link between birth events and childbirth-related posttraumatic stress disorder provides a valuable opportunity to prevent traumatic childbirths and childbirth-related posttraumatic stress disorder from occurring in the first place. Childbirth-related posttraumatic stress disorder is an extremely distressing mental disorder and has a substantial negative impact on those who give birth, fathers or co-parents, and, potentially, the whole family. Still, a traumatic childbirth experience and childbirth-related posttraumatic stress disorder remain largely unrecognized in maternity services and are not routinely screened for during pregnancy and the postpartum period. In fact, there are gaps in the evidence on how, when, and who to screen. Similarly, there is a lack of evidence on how best to treat those affected. Primary prevention efforts (eg, screening for antenatal risk factors, use of trauma-informed care) are aimed at preventing a traumatic childbirth experience and childbirth-related posttraumatic stress disorder in the first place by eliminating or reducing risk factors for childbirth-related posttraumatic stress disorder. Secondary prevention approaches (eg, trauma-focused psychological therapies, early psychological interventions) aim to identify those who have had a traumatic childbirth experience and to intervene to prevent the development of childbirth-related posttraumatic stress disorder. Tertiary prevention (eg, trauma-focused cognitive behavioural therapy and eye movement desensitization and reprocessing) seeks to ensure that people with childbirth-related posttraumatic stress disorder are identified and treated to recovery so that childbirth-related posttraumatic stress disorder does not become chronic. Adequate prevention, screening, and intervention could alleviate a considerable amount of suffering in affected families. In light of the available research on the impact of childbirth-related posttraumatic stress disorder on families, it is important to develop and evaluate assessment, prevention, and treatment interventions that target the birthing person, the couple dyad, the parent-infant dyad, and the family as a whole. Further research should focus on the inclusion of couples in different constellations and, more generally, on the inclusion of more diverse populations in diverse settings. The paucity of national and international policy guidance on the prevention, care, and treatment of psychological birth trauma and the lack of formal psychological birth trauma services and training, highlight the need to engage with service managers and policy makers

Decoding the auditory brain with canonical component analysis

The relation between a stimulus and the evoked brain response can shed light on perceptual processes within the brain. Signals derived from this relation can also be harnessed to control external devices for Brain Computer Interface (BCI) applications. While the classic event-related potential (ERP) is appropriate for isolated stimuli, more sophisticated “decoding” strategies are needed to address continuous stimuli such as speech, music or environmental sounds. Here we describe an approach based on Canonical Correlation Analysis (CCA) that finds the optimal transform to apply to both the stimulus and the response to reveal correlations between the two. Compared to prior methods based on forward or backward models for stimulus-response mapping, CCA finds significantly higher correlation scores, thus providing increased sensitivity to relatively small effects, and supports classifier schemes that yield higher classification scores. CCA strips the brain response of variance unrelated to the stimulus, and the stimulus representation of variance that does not affect the response, and thus improves observations of the relation between stimulus and response

Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa.

BACKGROUND: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas. METHODS: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens. RESULTS: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen. CONCLUSIONS: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials

Total immersion : Designing for affective symbiosis in a virtual reality game with haptics, biosensors, and emotive agents

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