Associations between age of menarche, early sexual debut and high-risk sexual behaviour among urban Tanzanian schoolgirls: A cross-sectional study.

OBJECTIVES: This cross-sectional survey aimed to explore associations between age of menarche, early sexual debut and high-risk sexual behaviour among urban Tanzanian schoolgirls. METHODS: Secondary schoolgirls aged 17-18 years from Mwanza, Tanzania, participated in structured face-to-face questionnaire-based interviews, conducted by nurses and clinicians. Age of menarche was evaluated in categories of 11-12, 13-14, 15-16 or ≥17 years. Primary outcome measures were self-reported early sexual debut (first vaginal sex at <16 years) and high-risk sexual behaviour, including non-use of condoms, having sex for gifts/money, having older sexual partners and/or other risky behaviours. RESULTS: Of 401 girls enrolled, 174 (43.4%) reported prior vaginal sex. Prevalence of early sexual debut was 14.2% but pressured/forced sex and risky sexual behaviours were common. Adjusted for potential confounding, younger age at menarche was associated with early sexual debut (adjusted odds ratio for linear trend: 1.88 per category, 95% confidence interval: 1.21-2.92, p = 0.005). This association remained after excluding girls with first sex at <8 years or experiencing pressure or force at first sex. Further, adjusted for potential confounding (including ever experiencing forced sex), early sexual debut was associated with high-risk sexual behaviour (adjusted odds ratio: 2.85, 95% confidence interval: 1.38-5.88, p = 0.004). CONCLUSIONS: Among urban Tanzanian school girls, younger age of menarche was associated with early sexual debut, and early sexual debut was associated with high-risk sexual behaviour. Researchers and public health professionals developing and delivering interventions aimed at preventing adverse sexual health outcomes should consider the impact of these early biological and sexual exposures.

IGRAs--the gateway to T cell based TB diagnosis.

Development of Interferon-Gamma Release Assays (IGRAs) and implementation of their use in clinical practice almost 10 years ago has revolutionised diagnosis of latent tuberculosis (TB) infection (LTBI). The commercially available IGRAs, TSPOT.TB (Oxford Immunotech, Oxford, UK) and QuantiFERON Gold In-Tube (Cellestis, Victoria, Australia), allow detection of TB infection with greater specificity and sensitivity than the tuberculin skin test (TST) and are now recommended for diagnosis of LTBI. The TSPOT.TB assay is a simplified enzyme-linked immunospot assay (ELISpot) that enumerates TB-specific T lymphocytes (T cells) secreting interferon-gamma (IFNγ). In comparison, the QuantiFERON Gold In-Tube assay constitutes an enzyme-linked immunosorbent assay (ELISA) to quantify IFNγ released into blood plasma after incubation of whole blood with TB antigens. Release of IFNγ, as a result of antigen stimulation of TB-specific T cells within blood, is indicative of TB infection. Although IGRAs have significant advantages over the TST in diagnosis of latent TB, they have significant limitations. Discovery of new antigens and advances in methodology for measuring cellular immunity have recently paved the way for novel tests that overcome these limitations. By establishing for the first time technological platforms for T cell based diagnosis in diagnostic service laboratories, IGRAs provide a bridgehead to clinical application of T cell based diagnosis in routine practice.

T-cell immunophenotyping distinguishes active from latent tuberculosis.

BACKGROUND: Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection. METHODS: A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α). RESULTS: Frequencies of CD4+ and CD8+ cells secreting IFN-γ-only, TNF-α-only and dual IFN-γ/TNF-α were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor α (CD127) expression. The frequency of PPDspecific CD4+ TNF-α-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone. CONCLUSIONS: Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies.

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to multidose vaccination regimens or no vaccination: An updated systematic review of evidence from clinical trials.

Objectives: This study systematically reviewed the published literature from clinical trials on the efficacy and immunogenicity of single-dose HPV vaccination compared to multidose schedules or no HPV vaccination. Methods: Four databases were searched for relevant articles published from Jan-1999 to Feb-2023. Articles were assessed for eligibility for inclusion using pre-defined criteria. Relevant data were extracted from eligible articles and a descriptive quality assessment was performed for each study. A narrative data synthesis was conducted, examining HPV infection, other clinical outcomes and immunogenicity responses by dose schedule. Results: Fifteen articles reporting data from six studies (all in healthy young females) were included. One article was included from each of three studies that prospectively randomised participants to receive a single HPV vaccine dose versus one or more comparator schedule(s). The other 12 articles reported data from three studies that randomised participants to receive multidose HPV vaccine (or control vaccine) schedules; in those studies, some participants failed to complete their allocated schedule, and evaluations were conducted to compare participants who actually received one, two or three doses. Across all efficacy studies, the incidence or prevalence of HPV16/18 infection was very low among HPV-vaccinated participants, regardless of the number of doses received; with no evidence for a difference between dose groups. In immunogenicity studies, HPV16/18 antibody seropositivity rates were high among all HPV-vaccinated participants. Antibody levels were significantly lower with one dose compared to two or three doses, but levels with one dose were stable and sustained to 11 years post-vaccination. Conclusions: Results from this review support recent World Health Organization recommendations allowing either one- or two-dose HPV vaccination in healthy young females. Longer-term efficacy and immunogenicity data from ongoing studies are awaited. Randomised trials of single-dose HPV-vaccination are urgently needed in other populations, e.g. boys, older females and people with HIV.

COVID-19 Vaccine Acceptability Among Healthcare Facility Workers in Sierra Leone, the Democratic Republic of Congo and Uganda: A Multi-Centre Cross-Sectional Survey.

Objectives: This cross-sectional survey explored COVID-19 vaccine acceptability among public healthcare facility workers in Kambia (Sierra Leone), Goma (Democratic Republic of Congo) and Masaka (Uganda). Methods: Questionnaire-based interviews conducted between April-October 2021 explored participants' knowledge and perceptions of, and attitudes towards, the COVID-19 pandemic and COVID-19 vaccines, as well as COVID-19 vaccine acceptability (defined as uptake of ≥1 dose or intent to get vaccinated). Results: Whilst most (n = 444; 81.8%) of the 543 participants had one or more concerns about COVID-19 vaccines, 487 (89.7%) nonetheless perceived that they were important for pandemic control. Most participants from Kambia or Masaka either were vaccinated (n = 137/355; 38.6%) or intended to get vaccinated (n = 211/355; 59.4%) against COVID-19. In Goma, all 188 participants were unvaccinated; only 81 (43.1%) participants intended to get vaccinated, and this was associated with positive perceptions about COVID-19 vaccines. In Goma, the most common reasons for not wanting a COVID-19 vaccine were concerns that the vaccines were new (n = 75/107; 70.1%) and fear of side effects (n = 74/107; 69.2%). Conclusion: Reported COVID-19 vaccine acceptability was high among healthcare facility workers in Kambia and Masaka. The lower vaccine acceptability in Goma may highlight the importance of social mobilisation and accurate, accessible information that addresses specific concerns.

A dose-reduction HPV vaccine immunobridging trial of two HPV vaccines among adolescent girls in Tanzania (the DoRIS trial) - Study protocol for a randomised controlled trial.

BACKGROUND: Human papillomavirus (HPV) infection is the primary cause of cervical cancer. In 2018, the World Health Organization (WHO) Director General announced his commitment to eliminate cervical cancer, with HPV vaccination as a priority. However, the costs of setting up a multi-dose HPV vaccination programme remain a barrier to its introduction. METHODS/DESIGN: We are conducting a randomised-controlled trial of reduced dose schedules of HPV vaccine in Tanzania to establish whether a single dose produces immune responses that will be effective in preventing cervical cancer. 930 girls aged 9-14 years in Mwanza, Tanzania, were randomised to one of 6 arms, comprising 3 different dose schedules of the 2-valent (Cervarix) and 9-valent (Gardasil-9) HPV vaccines: 3 doses; 2 doses given 6 months apart; or a single dose. All participants will be followed for 36 months; those in the 1 and 2 dose arms will be followed for 60 months. Trial outcomes focus on vaccine immune responses including HPV 16/18-specific antibody levels, antibody avidity, and memory B cell responses. Results will be immunobridged to historical cohorts of girls and young women in whom efficacy has been demonstrated. DISCUSSION: This is the first randomised trial of the single dose HPV vaccine schedule in the target age group. The trial will allow us to examine the quality and durability of immune responses of reduced dose schedules in a population with high burden of malaria and other infections that may affect vaccine immune responses. Initial results (24 months) are expected to be published in early 2021.

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to no vaccination or standard three and two-dose vaccination regimens: A systematic review of evidence from clinical trials.

OBJECTIVES: This study aimed to systematically review the literature on the efficacy and immunogenicity of single-dose HPV vaccination compared to no vaccination or multi-dose schedules among vaccine trial participants. METHODS: Medline, EMBASE, Global Health Database and Cochrane Central Register of Controlled Trials were searched for publications and conference abstracts (dated January 1999-August 2018) using MeSH and non-MeSH terms for human papillomavirus AND vaccines AND (immunogenicity OR efficacy/effectiveness) AND dosage. Search results were screened against pre-specified eligibility criteria. Data were extracted from included articles, and a narrative synthesis conducted on efficacy against HPV16/18 infection and humoral immunogenicity. RESULTS: Seven of 6,523 unique records identified were included in the review. Six were nested observational studies of participants randomised to receive two or three doses in three large HPV vaccine trials, in which some participants did not complete their allocated schedules. One small pilot study prospectively allocated participants to receive one or no vaccine dose. Frequency of HPV16/18 infection was low (e.g. <1% for 12-month-persistent infection) in all vaccinated participants up to seven years post vaccination and did not significantly differ by number of doses (p > 0.05 in all cases). Frequency of infection was significantly lower in one-dose recipients compared to unvaccinated controls (p < 0.01 for all infection endpoints in each study). HPV16/18 seropositivity rates were high in all HPV vaccine recipients (100% in three of four studies reporting this endpoint), though antibody levels were lower with one compared to two or three doses. CONCLUSIONS: This review supports the premise that one HPV vaccine dose may be as effective in preventing HPV infection as multi-dose schedules in healthy young women. However, it also highlights the paucity of available evidence from purpose-designed, prospectively-randomised trials. Results from ongoing clinical trials assessing the efficacy and immunogenicity of single-dose HPV vaccination compared to currently-recommended schedules are awaited.

Drowning among fishing communities on the Tanzanian shore of lake Victoria: a mixed-methods study to examine incidence, risk factors and socioeconomic impact.

OBJECTIVES: To estimate the incidence of unintentional fatal drowning and describe associated risk factors among Lake Victoria fishing communities, and to assess perceived social, financial and other impacts among families and colleagues of persons who drowned. DESIGN: A retrospective, observational mixed-methods study, conducted between September 2017 and February 2018. SETTING: Eight Tanzanian fishing communities on Lake Victoria. PARTICIPANTS: Persons who drowned in the preceding 24 months were identified using an extensive community networking approach. Adult family members, colleagues or community members familiar with the habits and behaviours of people who drowned and/or circumstances of drowning incidents participated in surveys (n=44) and in-depth interviews (n=22). MAIN OUTCOME MEASURES: Pooled drowning incidence, with sensitivity analyses allowing for uncertainties in population estimates. Risk factors were identified through the evaluation of behavioural characteristics of persons who drowned and circumstances of drowning incidents. Perceived socioeconomic impacts were assessed through semi-structured interviews with their family members and colleagues. RESULTS: The estimated drowning incidence was 217/100 000 person-years (95% CI 118 to 425/100 000). Of 86 victims identified, 70 (81%) were fishermen (79% aged 18-40 years; all men) and 9 were children (all ≤10 years). All deaths occurred in the lake. Most adults (65/77; 84%) were fishing from a boat when they drowned; 57/77 (74%) died in the evening (from ~5 pm) or at night. Six children (67%) drowned while swimming/playing at the lakeshore unsupervised. Few victims (2/86; 2%) were wearing a life jacket at the time of death. Reported socioeconomic impacts of these deaths ranged from income loss to family break-up. CONCLUSIONS: Drowning is a significant risk in Tanzanian lakeside fishing communities, with estimated mortality exceeding national incidence rates of fatal malaria, tuberculosis or HIV, but preventative strategies appear uncommon. Socioeconomic impact at the family level may be substantial. Intervention strategies are required to reduce the drowning burden among this neglected at-risk population.

Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study.

BACKGROUND: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. METHODS: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. FINDINGS: Of the 1060 adults enrolled in the study, 845 were included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs. INTERPRETATION: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis. FUNDING: National Institute for Health Research.

Biomarkers of tuberculosis: a research roadmap.

Tuberculosis (TB) continues to represent a major public health problem worldwide. Prompt and accurate diagnosis and effective treatment are fundamental to reducing morbidity and mortality and curtailing spread of infection. Furthermore, tackling the large reservoir of latent infection is the cornerstone to TB control in many high income low TB incidence countries. However, our existing toolkit for prevention, diagnosis and treatment remains outdated and inadequate. Here, we discuss the key targets for biomarker research and discovery in TB and recent developments in the field. We focus on host biomarkers, in particular: correlates of vaccine efficacy and sterilizing immunity; biomarkers of latent TB infection, including diagnosis, risk of progression to active TB and response to treatment; and markers of active TB, including diagnosis, response to treatment and risk of relapse. Recent scientific and technological advances have contributed to significant recent progression in biomarker discovery. Although there are clear remaining paucities, continued efforts within scientific, translational and clinical studies are likely to yield a number of clinically useful biomarkers of TB in the foreseeable future.

Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention.

Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested the hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by GH secretagogue receptor (GHS-R(1a))-mediated lipolysis. Chronic iv infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial sc fat, food intake, or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export (ATP-binding cassette transporter G1 mRNA expression and circulating free fatty acids were halved by ghrelin infusion). In contrast, ghrelin treatment did not up-regulate biomarkers of adipogenesis (peroxisome proliferator-activated receptor-gamma2 or CCAAT/enhancer binding protein-alpha) or substrate uptake (glucose transporter 4, lipoprotein lipase, or CD36) and although ghrelin elevated sterol-regulatory element-binding protein 1c expression, WAT-specific mediators of lipogenesis (liver X receptor-alpha and fatty acid synthase) were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R(1a), but GHS-R(1a) mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine tuning of signal transduction and/or lipid-handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R(1a)-dependent mechanism. Our data imply that, during periods of energy insufficiency, exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R(1a)-dependent lipid retention.