BACKGROUND:Growing evidence supports the existence of a sex difference in immunity to tuberculosis (TB). This is most often to the detriment of males. This study aimed to assess the association between scar size from bacillus Calmette-Guérin (BCG) and mortality risk stratified by sex.METHODS:Kaplan-Meier survivor functions and Cox proportional hazard models were used to assess mortality risk by sex and scar size. Groups were further compared by clinical and epidemiological characteristics.RESULTS:Between 2003 and 2019, 2944 eligible patients were identified, of whom 1003 were included in the final analysis. Males with BCG scars, particularly large scars, were less likely to die within 1 y of diagnosis than males with no scar (adjusted hazard ratio 0.36 [95% confidence interval 0.15 to 0.88]). In contrast, females with small scars trended towards higher mortality than females with no scars or females with large scars.CONCLUSIONS:BCG protects against death in male but not female patients with TB. More research is needed to determine the mechanisms underpinning these sex differences and whether they are generalizable beyond this setting.

BACKGROUND:Few studies have assessed life expectancy of patients with tuberculosis (TB) against a comparable background population, particularly in low-income, high-incidence settings. This study aimed to estimate the life expectancy (LE) of patients with TB in the West African country of Guinea-Bissau and compare it with the LE of the background population.METHODS:This study used data from the Bandim TB cohort from 2004-20 as well as census data from the capital of Guinea-Bissau. LE was estimated using a bootstrapped Kaplan-Meier survival analysis for patients with TB and the background population, stratifying by age of entry and various patient subgroups. The analysis was further stratified by diagnosis period and length of schooling (an indicator of socioeconomic status), to assess their influence on LE. A sensitivity analysis was performed assuming death at loss to follow-up.RESULTS:The analysis included 2278 patients and a background population of 169 760 individuals. Overall median LE among 30-year-old patients with TB was 10.7 years (95% CI: 8.7-12.6), compared with 35.8 (95% CI: 35.1-36.5) in the background population. LE was shorter in HIV-infected patients and those who had unsuccessful treatment outcome; however, even among those who were both uninfected with HIV and experienced successful treatment outcome, LE was 20% shorter than in the background population. Longer schooling appeared to decrease mortality.CONCLUSIONS:TB substantially shortens LE. This effect is present even in patients who are uninfected with HIV and who have successful treatment outcome.

OBJECTIVES:Previous studies have found declining incidence of tuberculosis (TB) in Bissau, Guinea-Bissau. This study aimed to report incidence rates of TB for the period 2004-2020, stratifying by sex, smear-status, and HIV-status, as well as describe developments in TB case fatality rate and diagnostic delay.DESIGN AND METHODS:Data from the Bandim Health Project HDSS and the TB registry from Jan 1st, 2004 to Dec 31st, 2020 were used. Incidence rates were calculated for each year and for smear-positive, smear-negative, HIV-positive, HIV-negative, and unknown HIV-status. Incidence rate ratio and test for trend were done using a one-step Newton approximation to the log-linear Poisson regression coefficient.RESULTS:Overall TB incidence declined only slightly over the period from 294 per 100,000 in 2004 to 273 in 2020. TB/HIV coinfection declined from 108 in 2004 to 14 in 2020, as did incidence among females and smear-negative cases.CONCLUSIONS:Incidence of PTB in Bissau, Guinea-Bissau is declining slowly, if at all. TB incidence among females, smear-negative TB, TB case fatality rate, and TB/HIV coinfection and diagnostic delay are declining.

BACKGROUND: Health-related quality of life (HRQoL) in patients with pulmonary TB may be predictive of disease outcome; however, HRQoL instruments are often complicated and unsuitable for use in low-resource settings. A single-item self-rated health (SRH) score may represent a simpler alternative which could be used in clinical decision-making.AIMS: To evaluate internal and external validity of SRH and its correlation with TBscore/TBscoreII in a low-resource setting.METHODS: We used data from our ongoing prospective TB cohort study in Guinea-Bissau. Cohen´s d was used to assess internal validity, and receiver-operating characteristics and mortality statistics to assess external validity. Correlation between SRH and TBscore/TBscoreII was estimated using linear regression.RESULTS: SRH showed satisfactory internal validity and ability to discriminate between fatal cases at high and low scores, although not at middling scores. SRH and TBscore/TBscoreII correlated well at each examination but changes in scores did not, which may be due to ceiling/floor effects and a lag between disease severity and HRQoL.CONCLUSION: SRH shows potential as a quick and simple method to identify patients in need of intensified follow-up during treatment provision. More research is needed to assess its generalisability beyond our setting and to develop models for clinical use of SRH.

BACKGROUNDGlobally, more males than females are diagnosed with pulmonary TB (PTB); however, the cause of this gender disparity remains unknown. We aimed to assess gender differences in an observational cohort of patients with presumed PTB (prePTB) at the Bandim Health Project, Guinea-Bissau.METHODSAdult patients with signs and symptoms suggestive of PTB seeking medical care were invited to participate and were referred to comprehensive diagnostic work-up.RESULTSWe included 2020 patients with prePTB; 54.6% were female. Females were younger than males and more often infected with HIV. More male patients with prePTB were diagnosed with PTB and the proportion of smear-positive cases was greater among males. There was no gender difference in loss to follow-up during the diagnostic process. Of 219 patients with PTB, 205 started treatment, with no difference between genders regarding pretreatment loss to follow-up or treatment outcome.CONCLUSIONSMore women sought help for symptoms indicative of PTB, yet more men were diagnosed. Women did not have more clinically severe disease at presentation, did not drop out of diagnostic procedures more frequently and did not experience a worse outcome than men. This suggests that the gender gap in PTB is unlikely to be due solely to differences in care-seeking behaviour or diagnostic procedures in our setting.

Background The World Health Organization (WHO) recommends active case-finding (ACF) of tuberculosis (TB) in certain high-risk groups; however, more evidence is needed to elucidate the scope of ACF beyond the current recommendations. In this study we aimed to systematically review yields (the prevalence of active TB) of studies on ACF in general populations and at-risk groups. Methods A literature search in PubMed, Embase and the Cochrane Central Library (CENTRAL) was performed for studies concluded after 31 December 1999 and published before 1 September 2020. Screening yields were estimated and yield/prevalence ratios (ratio between yield of study and WHO estimated prevalence of TB) were calculated to assess which groups might especially benefit from ACF. Finally, risk of bias was assessed and heterogeneity was investigated using meta-regression and sensitivity analyses. Results We included 197 studies, with a total of 12 372 530 screened and 53158 cases found. Yields were high among drug users, close contacts, the poor and marginalised, people living with HIV, and prison inmates across incidence strata, and estimated yield/prevalence ratios in screenings of general populations tended to be >1 with an overall ratio of 1.4 and ranging between 1.0 and 1.5. Sensitivity analyses suggested that inclusion of studies at high risk of bias contributed to underestimation of yields. Conclusion Despite many studies using insensitive screening methods, these results suggest that more at risk groups should be considered for inclusion in future screening recommendations and that screening of general populations may outperform current case-finding practices, providing evidence for extending ACF beyond the current recommendations.

Tuberculosis (TB) is the leading cause of death from a single infectious agent. According to the WHO, 85% of cases in 2018 were pulmonary tuberculosis (PTB), making it the most prevalent form of the disease. Although the bacillus responsible for disease, Mycobacterium tuberculosis (MTB), is estimated to infect 1.7 billion people worldwide, only a small portion of those infected (5-10%) will transition into active TB. Because such a small fraction of infected people develop active disease, we hypothesized that underlying host genetic variation associates with developing active pulmonary disease. Variation in CLEC4E has been of interest in previous association studies showing either no effect or protection from PTB. For our study we assessed 60 SNPs in 11 immune genes, including CLEC4E, using a case-control study from Guinea-Bissau. The 289 cases and 322 controls differed in age, sex, and ethnicity all of which were included in adjusted models. Initial association analysis with unadjusted logistic regression revealed putative association with seven SNPs (p < 0.05). All SNPs were then assessed in an adjusted model. Of the six SNPs that remained significant, three of them were assigned to the CLEC4E gene (rs12302046, rs10841847, and rs11046143). Of these, only rs10841847 passed FDR adjustment for multiple testing. Adjusted regression analyses showed that the minor allele at rs10841847 associated with higher risk of developing PTB (OR = 1.55, CI = 1.22-1.96, p-value = 0.00036). Based on these initial association tests, CLEC4E seemed to be the predictor of interest for PTB risk in this population. Haplotype analysis (2-SNP and 3-SNP windows) showed that minor alleles in segments including rs10841847 were the only ones to pass the threshold of global significance, compared to other haplotypes (p-value< 0.05). Linkage disequilibrium patterns showed that rs12302046 is in high LD with rs10841847 (r(2) = 0.67), and all other SNPs lost significance when adjusted for rs10841847 effects. These findings indicate that rs10841847 in CLEC4E is the single best predictor of pulmonary tuberculosis risk in our study population. These results provide evidence for the hypothesis that genetic variation of CLEC4E influences risk to TB in Guinea-Bissau.

BACKGROUND:Genetic disruption of slc4a10, which encodes the sodium-dependent chloride/bicarbonate exchanger Ncbe, leads to a major decrease in Na+-dependent HCO3- import into choroid plexus epithelial cells in mice and to a marked reduction in brain intraventricular fluid volume. This suggests that Ncbe functionally is a key element in vectorial Na+ transport and thereby for cerebrospinal fluid secretion in the choroid plexus. However, slc4a10 disruption results in severe changes in expression of Na+,K+-ATPase complexes and other major transport proteins, indicating that profound cellular changes accompany the genetic manipulation.METHODS:A tandem mass tag labeling strategy was chosen for quantitative mass spectrometry. Alterations in the broader patterns of protein expression in the choroid plexus in response to genetic disruption of Ncbe was validated by semi-quantitative immunoblotting, immunohistochemistry and morphometry.RESULTS:The abundance of 601 proteins were found significantly altered in the choroid plexus from Ncbe ko mice relative to Ncbe wt. In addition to a variety of transport proteins, particularly large changes in the abundance of proteins involved in cellular energy metabolism were detected in the Ncbe ko mice. In general, the abundance of rate limiting glycolytic enzymes and several mitochondrial enzymes were reduced following slc4a10 disruption. Surprisingly, this was accompanied by increased ATP levels in choroid plexus cells, indicating that the reduction in capacity for energy metabolism was adaptive to high ATP rather than causal for a decreased capacity for ion and water transport. Ncbe-deficient cells also had a reduced cell area and decreased K+ content.CONCLUSION:Our findings suggest that the lack of effective Na+-entry into the epithelial cells of the choroid plexus leads to a profound change in the cellular phenotype, shifting from a high-rate secretory function towards a more dormant state; similar to what is observed during ageing or Alzheimer's disease.