In vitro biological control of Pyrrhoderma noxium using volatile compounds produced by termite gut-associated streptomycetes.

Introduction: Pyrrhoderma noxium is a plant pathogen that causes economic losses in agricultural and forestry industries, including significant destruction to amenity trees within the city of Brisbane in Australia. Use of chemical control agents are restricted in public areas, there is therefore an urgent need to investigate biological control approaches. Members of the phylum Actinomycetota, commonly known as actinomycetes, are known for their industrially important secondary metabolites including antifungal agents. They have proven to be ideal candidates to produce environmentally friendly compounds including the volatile organic compounds (VOCs) which can be used as biofumigants. Methods: Different Streptomyces species (n=15) previously isolated from the guts of termites and stored in the University of the Sunshine Coast'sMicrobial Library were tested for their antifungal VOCs against Pyrrhoderma noxium. Results: Fourteen of them were found to display inhibition (39.39-100%) to the mycelial development of the pathogen. Strongest antifungal activity displaying isolates USC-592, USC-595, USC-6910 and USC-6928 against the pathogen were selected for further investigations. Their VOCs were also found to have plant growth promotional activity observed for Arabidopsis thaliana with an increase of root length (22-36%) and shoot length (26-57%). The chlorophyll content of the test plant had a slight increase of 11.8% as well. Identified VOCs included geosmin, 2-methylisoborneol, 2-methylbutyrate, methylene cyclopentane, ß-pinene, dimethyl disulfide, ethyl isovalerate, methoxyphenyl-oxime and α-pinene. Additionally, all 15 Streptomyces isolates were found to produce siderophores and indole acetic acid as well as the enzyme chitinase which is known to break down the fungal cell wall. Discussion: Findings indicate that termite gut-associated streptomycetes might be used to control Pyrrhoderma noxium by utilizing their wide range of inhibitory mechanisms.

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Photochemically Aided Arteriovenous Fistula Creation to Accelerate Fistula Maturation.

Rates of arteriovenous fistula maturation failure are still high, especially when suboptimal size veins are used. During successful maturation, the vein undergoes lumen dilatation and medial thickening, adapting to the increased hemodynamic forces. The vascular extracellular matrix plays an important role in regulating these adaptive changes and may be a target for promoting fistula maturation. In this study, we tested whether a device-enabled photochemical treatment of the vein prior to fistula creation facilitates maturation. Sheep cephalic veins were treated using a balloon catheter coated by a photoactivatable molecule (10-8-10 Dimer) and carrying an internal light fiber. As a result of the photochemical reaction, new covalent bonds were created during light activation among oxidizable amino acids of the vein wall matrix proteins. The treated vein lumen diameter and media area became significantly larger than the contralateral control fistula vein at 1 week (p = 0.035 and p = 0.034, respectively). There was also a higher percentage of proliferating smooth muscle cells in the treated veins than in the control veins (p = 0.029), without noticeable intimal hyperplasia. To prepare for the clinical testing of this treatment, we performed balloon over-dilatation of isolated human veins and found that veins can tolerate up to 66% overstretch without notable histological damage.

Achieving the UNAIDS 90-90-90 targets: a comparative analysis of four large community randomised trials delivering universal testing and treatment to reduce HIV transmission in sub-Saharan Africa.

BACKGROUND: Four large community-randomized trials examining universal testing and treatment (UTT) to reduce HIV transmission were conducted between 2012-2018 in Botswana, Kenya, Uganda, Zambia and South Africa. In 2014, the UNAIDS 90-90-90 targets were adopted as a useful metric to monitor coverage. We systematically review the approaches used by the trials to measure intervention delivery, and estimate coverage against the 90-90-90 targets. We aim to provide in-depth understanding of the background contexts and complexities that affect estimation of population-level coverage related to the 90-90-90 targets. METHODS: Estimates were based predominantly on "process" data obtained during delivery of the interventions which included a combination of home-based and community-based services. Cascade coverage data included routine electronic health records, self-reported data, survey data, and active ascertainment of HIV viral load measurements in the field. RESULTS: The estimated total adult populations of trial intervention communities included in this study ranged from 4,290 (TasP) to 142,250 (Zambian PopART Arm-B). The estimated total numbers of PLHIV ranged from 1,283 (TasP) to 20,541 (Zambian PopART Arm-B). By the end of intervention delivery, the first-90 target (knowledge of HIV status among all PLHIV) was met by all the trials (89.2%-94.0%). Three of the four trials also achieved the second- and third-90 targets, and viral suppression in BCPP and SEARCH exceeded the UNAIDS target of 73%, while viral suppression in the Zambian PopART Arm-A and B communities was within a small margin (~ 3%) of the target. CONCLUSIONS: All four UTT trials aimed to implement wide-scale testing and treatment for HIV prevention at population level and showed substantial increases in testing and treatment for HIV in the intervention communities. This study has not uncovered any one estimation approach which is superior, rather that several approaches are available and researchers or policy makers seeking to measure coverage should reflect on background contexts and complexities that affect estimation of population-level coverage in their specific settings. All four trials surpassed UNAIDS targets for universal testing in their intervention communities ahead of the 2020 milestone. All but one of the trials also achieved the 90-90 targets for treatment and viral suppression. UTT is a realistic option to achieve 95-95-95 by 2030 and fast-track the end of the HIV epidemic.

Assessing the Various Antagonistic Mechanisms of Trichoderma Strains against the Brown Root Rot Pathogen Pyrrhoderma noxium Infecting Heritage Fig Trees.

A wide range of phytopathogenic fungi exist causing various plant diseases, which can lead to devastating economic, environmental, and social impacts on a global scale. One such fungus is Pyrrhoderma noxium, causing brown root rot disease in over 200 plant species of a variety of life forms mostly in the tropical and subtropical regions of the globe. The aim of this study was to discover the antagonistic abilities of two Trichoderma strains (#5001 and #5029) found to be closely related to Trichoderma reesei against P. noxium. The mycoparasitic mechanism of these Trichoderma strains against P. noxium involved coiling around the hyphae of the pathogen and producing appressorium like structures. Furthermore, a gene expression study identified an induced expression of the biological control activity associated genes in Trichoderma strains during the interaction with the pathogen. In addition, volatile and diffusible antifungal compounds produced by the Trichoderma strains were also effective in inhibiting the growth of the pathogen. The ability to produce Indole-3-acetic acid (IAA), siderophores and the volatile compounds related to plant growth promotion were also identified as added benefits to the performance of these Trichoderma strains as biological control agents. Overall, these results show promise for the possibility of using the Trichoderma strains as potential biological control agents to protect P. noxium infected trees as well as preventing new infections.

Ethnic inequities in multimorbidity among people with psychosis: a retrospective cohort study.

AIMS: Research shows persistent ethnic inequities in mental health experiences and outcomes, with a higher incidence of illnesses among minoritised ethnic groups. People with psychosis have an increased risk of multiple long-term conditions (MLTC; multimorbidity). However, there is limited research regarding ethnic inequities in multimorbidity in people with psychosis. This study investigates ethnic inequities in physical health multimorbidity in a cohort of people with psychosis. METHODS: In this retrospective cohort study, using the Clinical Records Interactive Search (CRIS) system, we identified service-users of the South London and Maudsley NHS Trust with a schizophrenia spectrum disorder, and then additional diagnoses of diabetes, hypertension, low blood pressure, overweight or obesity and rheumatoid arthritis. Logistic and multinomial logistic regressions were used to investigate ethnic inequities in odds of multimorbidity (psychosis plus one physical health condition), and multimorbidity severity (having one or two physical health conditions, or three or more conditions), compared with no additional health conditions (no multimorbidity), respectively. The regression models adjusted for age and duration of care and investigated the influence of gender and area-level deprivation. RESULTS: On a sample of 20 800 service-users with psychosis, aged 13-65, ethnic differences were observed in the odds for multimorbidity. Controlling for sociodemographic factors and duration of care, compared to White British people, higher odds of multimorbidity were found for people of Black African [adjusted Odds Ratio = 1.41, 95% Confidence Intervals (1.23-1.56)], Black Caribbean [aOR = 1.79, 95% CI (1.58-2.03)] and Black British [aOR = 1.64, 95% CI (1.49-1.81)] ethnicity. Reduced odds were observed among people of Chinese [aOR = 0.61, 95% CI (0.43-0.88)] and Other ethnic [aOR = 0.67, 95% CI (0.59-0.76)] backgrounds. Increased odds of severe multimorbidity (three or more physical health conditions) were also observed for people of any Black background. CONCLUSIONS: Ethnic inequities are observed for multimorbidity among people with psychosis. Further research is needed to understand the aetiology and impact of these inequities. These findings support the provision of integrated health care interventions and public health preventive policies and actions.

SARS-CoV-2 seroprevalence and associated risk factors in periurban Zambia: a population-based study.

BACKGROUND: We nested a seroprevalence survey within the TREATS (Tuberculosis Reduction through Expanded Antiretroviral Treatment and Screening) project. We aimed to measure the seroprevalence of SARS-CoV-2 infection and investigate associated risk factors in one community (population ∼27,000) with high prevalence of TB/HIV in Zambia. METHODS: The study design was cross-sectional. A random sample of 3592 individuals aged ≥15 years enrolled in the TREATS TB-prevalence survey were selected for antibody testing. Randomly selected blocks of residence were visited between October 2020 and March 2021. Antibodies against SARS-CoV-2 were detected using Abbott- ARCHITECT SARS-CoV-2 IgG assay. RESULTS: A total of 3035/3526 (86.1%) individuals had a blood sample taken. Antibody testing results were available for 2917/3035 (96.1%) participants. Overall, 401/2977 (13.5%) individuals tested positive for IgG antibodies. Seroprevalence was similar by sex (12.7% men vs 14.0% women) and was lowest in the youngest age group 15-19 years (9.7%) and similar in ages 20 years and older (∼15%). We found no evidence of an association between seroprevalence and HIV-status or TB. There was strong evidence (p <0.001) of variation by time of enrollment, with prevalence varying from 2.8% (95% CI 0.8-4.9) among those recruited in December 2020 to 33.7% (95% CI 27.7-39.7) among those recruited in mid-February 2021. CONCLUSION: Seroprevalence was 13.5% but there was substantial variation over time, with a sharp increase to approximately 35% toward the end of the second epidemic wave.

Intimate Partner Violence (IPV) and Associated Factors in HPTN 071 (PopART) Study Communities in Zambia and South Africa-A Comparison by HIV Status.

The HPTN 071(PopART) study was a community-randomised trial in Zambia and South Africa, examining the impact of combination-prevention including universal testing and treatment (UTT), on HIV-incidence. This sub-study evaluated factors associated with IPV (physical and/or sexual) to identify differences by HIV status. During 2015-16, a random subset of adults who participated in the first year of the PopART intervention were recruited and standardised questionnaires were administered. Logistic regression was performed to estimate odds ratios of factors associated with IPV. Among > 700 women studied (300 HIV-negative;400 HIV-positive), ~ 20% reported experiencing physical and/or sexual violence in the last 12-months. Sexual violence was similar by HIV status, but physical violence and reporting both physical/sexual violence was more common among HIV-positive women. Spending nights away from the community in the last 12-months was associated with higher odds of IPV among both HIV-negative (aOR 3.17, 95% CI 1.02-9.81) and HIV-positive women (aOR 1.79, 95% CI 0.99-3.24). Among HIV-positive women, financial autonomy was associated with reduced IPV (aOR:0.41,95%CI:0.23-0.75) while pregnancy in the last 12-months (aOR 2.25, 95% CI 1.07-4.74), risk of alcohol dependence (aOR 2.75, 95% CI 1.51-5.00) and risk of mental distress (aOR 2.62, 95% CI 1.33-5.16) were associated with increased IPV. Among HIV-negative women reporting sex in the last 12-months, transactional sex (aOR 3.97, 95% CI 1.02-15.37) and not knowing partner's HIV status (aOR 3.01, 95% CI 1.24-7.29) were associated with IPV. IPV was commonly reported in the study population and factors associated with IPV differed by HIV status. The association of mobility with IPV warrants further research. The high prevalence of harmful alcohol use and mental distress, and their association with IPV among HIV-positive women require urgent attention.

RESUMEN: El estudio HPTN 071 (PopART) fue un ensayo aleatorio-comunitario realizado en Zambia y Sudáfrica, que examinó el impacto de la prevención combinada, incluyendo las pruebas y tratamiento universal (UTT), en la incidencia del VIH. Este subestudio evaluó los factores asociados con la IPV (físicos y / o sexuales) para identificar diferencias en el estado del VIH. Durante 2015-16, un subconjunto aleatorio de adultos fueron reclutados para participar en el primer año de intervención de PopART, donde se administraron cuestionarios estandarizados. Se realizó una regresión logística para estimar las ratios de probabilidad de los factores asociados con la VPI. Entre las > 700 mujeres estudiadas (300 VIH negativas; 400 VIH positivas), ~ 20% informó haber experimentado violencia física y / o sexual en los últimos 12 meses. La violencia sexual fue similar en cuanto al estado del VIH. La denuncia de violencia física y sexual fue más común entre las mujeres VIH positivas. Pasar noches fuera de la comunidad en los últimos 12 meses, se asoció con mayores probabilidades de VPI entre las mujeres VIH negativas (ORa 3,17, 95% IC 1,02­9,81) y las mujeres VIH positivas (ORa 1,79, 95% IC 0,99­3,24). Entre las mujeres VIH positivas, la autonomía financiera se asoció con una reducción de la VPI (ORa 0,41; IC del 95% 0,23-0,75) mientras que en el embarazo en los últimos 12 meses (ORa 2,25; IC del 95% 1,07­4,74), riesgo a la dependencia del alcohol (ORa 2,75% IC 1,51­5,00) y el riesgo de angustia mental (ORa 2,62% IC del 95% 1,33­5,16) se asociaron con un aumento de la VPI. Entre las mujeres VIH negativas que informaron haber tenido relaciones sexuales en los últimos 12 meses, el sexo transaccional (ORa 3.97, 95% CI 1.02­15.37) y el desconocimiento del estado de VIH de la pareja (ORa 3.01, 95% CI 1.24­7.29) se asociaron con IPV. La IPV fue notificada mayoritariamente en la población de estudio y los factores asociados con la IPV diferían según el estado del VIH. La asociación de la movilidad con la IPV justifica una mayor investigación. La alta prevalencia de l consumo nocivo de alcohol y la angustia mental, y su asociación con la VPI entre las mujeres seropositivas, requieren atención urgente.

Creating a Natural Vascular Scaffold by Photochemical Treatment of the Extracellular Matrix for Vascular Applications.

The development of bioscaffolds for cardiovascular medical applications, such as peripheral artery disease (PAD), remains to be a challenge for tissue engineering. PAD is an increasingly common and serious cardiovascular illness characterized by progressive atherosclerotic stenosis, resulting in decreased blood perfusion to the lower extremities. Percutaneous transluminal angioplasty and stent placement are routinely performed on these patients with suboptimal outcomes. Natural Vascular Scaffolding (NVS) is a novel treatment in the development for PAD, which offers an alternative to stenting by building on the natural structural constituents in the extracellular matrix (ECM) of the blood vessel wall. During NVS treatment, blood vessels are exposed to a photoactivatable small molecule (10-8-10 Dimer) delivered locally to the vessel wall via an angioplasty balloon. When activated with 450 nm wavelength light, this therapy induces the formation of covalent protein-protein crosslinks of the ECM proteins by a photochemical mechanism, creating a natural scaffold. This therapy has the potential to reduce the need for stent placement by maintaining a larger diameter post-angioplasty and minimizing elastic recoil. Experiments were conducted to elucidate the mechanism of action of NVS, including the molecular mechanism of light activation and the impact of NVS on the ECM.

Uptake of HIV Testing Services Through Novel Community-Based Sexual and Reproductive Health Services: An Analysis of the Pilot Implementation Phase of the Yathu Yathu Intervention for Adolescents and Young People Aged 15-24 in Lusaka, Zambia.

Adolescents and young people aged 15-24 are underserved by available HIV-testing services (HTS). Delivering HTS through community-based, peer-led, hubs may prove acceptable and accessible to adolescents and young people, thus increasing HIV-testing coverage. We used data from the pilot phase of a cluster-randomised trial of community-based sexual and reproductive health services for adolescents and young people in Lusaka, Zambia, between September 2019 and January 2020, to explore factors associated with uptake of HTS through community-based hubs. 5,757 adolescents and young people attended the hubs (63% female), among whom 75% tested for HIV (76% of females, 75% of males). Community-based hubs provided HTS to 80% of adolescents and young people with no history of HIV-testing. Among females, uptake of HTS was lower among married/cohabiting females; among males, uptake was lower among unmarried males and among individuals at risk of hazardous alcohol use. The high number of adolescents and young people accessing hubs for HIV testing suggests they are acceptable. Enhanced targeting of HTS to groups who may not perceive their HIV risk needs to be implemented.

The effect of systematic screening of the general population on TB case notification rates.

BACKGROUND: Understanding how TB case notification rates (TB-CNR) change with TB screening and their association with underlying TB incidence/prevalence could inform how they are best used to monitor screening impact.METHODS: We undertook a systematic review to identify articles published between 1 January 1980 and 13 April 2020 on TB-CNR trends associated with TB screening in the general-population. Using a simple compartmental TB transmission model, we modelled TB-CNRs, incidence and prevalence dynamics during 5 years of screening.RESULTS: Of 27,282 articles, seven before/after studies were eligible. Two involved population-wide screening, while five used targeted screening. The data suggest screening was associated with initial increases in TB-CNRs. Increases were greatest with population-wide screening, where screening identified a large proportion of notified people with TB. Only one study reported on sustained screening; TB-CNR trends were compatible with model simulations. Model simulations always showed a peak in TB-CNRs with screening. Following the peak, TB-CNRs declined but were typically sustained above baseline during the intervention. Incidence and prevalence decreased during the intervention; the relative decline in incidence was smaller than the decline in prevalence.CONCLUSIONS: Published data on TB-CNR trends with TB screening are limited. These data are needed to identify generalisable patterns and enable method development for inferring underlying TB incidence/prevalence from TB-CNR trends.

Improving retention of community-recruited participants in HIV prevention research through Saturday household visits; findings from the HPTN 071 (PopART) study in South Africa.

BACKGROUND: Identifying successful strategies to improve participant retention in longitudinal studies remains a challenge. In this study we evaluated whether non-traditional fieldworker shifts (after hours during the week and weekends) enhanced participant retention when compared to retention during traditional weekday shifts in the HPTN 071 (PopART) population cohort (PC). METHODS: HPTN 071 (PopART) PC participants were recruited and followed up in their homes on an annual basis by research fieldworkers over a 3-4 year period. The average number of successful follow-up visits, where a PC participant was found and retained in the study, was calculated for each of 3 visit schedules (early weekday shift, late weekday shift, and Saturday shift), and standardized to account for variation in fieldwork shift duration. We used one-way univariate analysis of variance (ANOVA) to describe differences in mean-successful visits and 95% confidence intervals between the shift types. RESULTS: Data on 16 651 successful visits were included. Successful visit rates were higher when conducting Saturday visits (14.0; 95% CI: 11.3-16.6) compared to both regular (4.5; 95% CI: 3.7-5.3) and late weekday shifts (5.3; 95% CI: 4.7-5.8) overall and in all subgroup analyses (P<0.001). The successful visit rate was higher amongst women than men were during all shift types (3.2 vs. 1.3, p<0.001). Successful visit rates by shift type did not differ significantly by age, over time, by PC round or by community triplet. CONCLUSION: The number of people living with HIV continues to increase annually. High quality evidence from longitudinal studies remains critical for evaluating HIV prevention and treatment strategies. This study showed a significant benefit on participant retention through introduction of Saturday shifts for home visits and these data can make an important contribution to the emerging body of evidence for improving retention in longitudinal research. TRIAL REGISTRATION: PopART was approved by the Stellenbosch University Health Research Ethics Committees (N12/11/074), London School of Hygiene and Tropical Medicine (6326) ethics committee and the Division of AIDS (DAIDS) (Protocol ID 11865). PopART was registered with ClinicalTrials.gov (registration number NCT01900977 ).

Does tuberculosis screening improve individual outcomes? A systematic review.

BACKGROUND: To determine if tuberculosis (TB) screening improves patient outcomes, we conducted two systematic reviews to investigate the effect of TB screening on diagnosis, treatment outcomes, deaths (clinical review assessing 23 outcome indicators); and patient costs (economic review). METHODS: Pubmed, EMBASE, Scopus and the Cochrane Library were searched between 1/1/1980-13/4/2020 (clinical review) and 1/1/2010-14/8/2020 (economic review). As studies were heterogeneous, data synthesis was narrative. FINDINGS: Clinical review: of 27,270 articles, 18 (n=3 trials) were eligible. Nine involved general populations. Compared to passive case finding (PCF), studies showed lower smear grade (n=2/3) and time to diagnosis (n=2/3); higher pre-treatment losses to follow-up (screened 23% and 29% vs PCF 15% and 14%; n=2/2); and similar treatment success (range 68-81%; n=4) and case fatality (range 3-11%; n=5) in the screened group. Nine reported on risk groups. Compared to PCF, studies showed lower smear positivity among those culture-confirmed (n=3/4) and time to diagnosis (n=2/2); and similar (range 80-90%; n=2/2) treatment success in the screened group. Case fatality was lower in n=2/3 observational studies; both reported on established screening programmes. A neonatal trial and post-hoc analysis of a household contacts trial found screening was associated with lower all-cause mortality. Economic review: From 2841 articles, six observational studies were eligible. Total costs (n=6) and catastrophic cost prevalence (n=4; range screened 9-45% vs PCF 12-61%) was lower among those screened. INTERPRETATION: We found very limited patient outcome data. Collecting and reporting this data must be prioritised to inform policy and practice. FUNDING: WHO and EDCTP.

Yathu Yathu ("For us, by us"): Design of a cluster-randomised trial of the impact of community-based, peer-led comprehensive sexual and reproductive health services for adolescents and young people aged 15 to 24 in Lusaka, Zambia.

BACKGROUND: In sub-Saharan Africa, the growing population of adolescents and young people aged 15 to 24 face a high burden of HIV, and other preventable and treatable sexually transmitted infections. Despite this burden, adolescents and young people are the population least served by available sexual and reproductive (SRH) services. This trial aims to evaluate the impact of community-based peer-led SRH services, combined with a novel incentivised "loyalty card" system, on knowledge of HIV status and coverage of SRH services. METHODS: A cluster-randomised trial (CRT) with embedded process and economic evaluation. DISCUSSION: With little available evidence of the impact of community-based, peer-led services on coverage of SRH services, our study will provide evidence critical to expanding our knowledge of how to reach adolescents and young people. The "loyalty card" system is also a novel approach to providing SRH services. The delivery of community-based services supported by incentives in the form of loyalty cards is innovative, and may prove a simple strategy to improve access to SRH services. Adolescents and young people remain underserved by available SRH services; there remains a critical need to identify ways to provide adolescents and young people with access to SRH services. Rigorous evidence of whether this innovative strategy, with strong links to the local health facility, increases coverage of critical SRH services would add to the evidence-base of how to reach adolescents and young people.

Association between cervical dysplasia and female genital schistosomiasis diagnosed by genital PCR in Zambian women.

BACKGROUND: Female genital schistosomiasis (FGS) is a neglected tropical gynaecological disease that affects millions of women in sub-Saharan Africa (SSA). FGS is caused by Schistosoma haematobium, a parasitic carcinogen involved in the pathogenesis of squamous cell carcinoma of the bladder. Cervical cancer incidence and mortality are highest in SSA, where pre-cancerous cervical dysplasia is often detected on screening with visual inspection with acetic acid (VIA). There are no studies evaluating the association between VIA positivity and FGS diagnosed by genital PCR. METHODS: Women were recruited from the Bilharzia and HIV (BILHIV) study in Zambia a community-based study comparing genital self-sampling to provider obtained cervicovaginal-lavage for the diagnosis of FGS in women aged 18-31. FGS was defined as positive Schistosoma DNA from any genital PCR. Urogenital schistosomiasis diagnostics included urine circulating anodic antigen, urine microscopy and portable colposcopy. Participants were offered cervical cancer screening using VIA at Livingstone Central Hospital. Associations of PCR confirmed FGS and other diagnostics with VIA positivity were assessed using multivariable logistic regression. RESULTS: VIA results were available from 237 BILHIV participants. A positive Schistosoma PCR in any genital specimen was detected in 14 women (5.9%), 28.6% (4/14) of these women had positive VIA compared to 9.0% without PCR evidence of schistosome infection (20/223). Schistosoma PCR positivity in any genital specimen was strongly associated with VIA positivity (OR: 6.08, 95% CI: 1.58-23.37, P = 0.02). CONCLUSIONS: This is the first study to find an association between FGS and positive VIA, a relationship that may be causal. Further longitudinal studies are needed.

Does the number of doses matter? A qualitative study of HPV vaccination acceptability nested in a dose reduction trial in Tanzania.

BACKGROUND: The multi-dose regimen is a known barrier to successful human papillomavirus (HPV) vaccination. Emerging evidence suggests that one vaccine dose could protect against HPV. While there are clear advantages to a single dose schedule, beliefs about vaccine dosage in low and middle income countries (LMICs) are poorly understood. We investigated acceptability of dose-reduction among girls, and parents/guardians of girls, randomised to receive one, two or three doses in an HPV vaccine dose-reduction and immunobridging study (DoRIS trial) in Tanzania. METHODS: Semi-structured interviews with girls (n = 19), and parents/guardians of girls (n = 18), enrolled in the study and completing their vaccine course. RESULTS: Most participants said they entrusted decisions about the number of HPV vaccine doses to experts. Random allocation to the different dose groups did not feature highly in the decision to participate in the trial. Given a hypothetical choice, girls generally said they would prefer fewer doses in order to avoid the pain of injections. Parental views were mixed, with most wanting whichever dose was most efficacious. Nonetheless, a few parents equated a higher number of doses with greater protection. CONCLUSION: Vaccine trials and programmes will need to employ careful messaging to explain that one dose offers sufficient protection against HPV should emerging evidence from ongoing dose-reduction clinical trials support this.

The longitudinal relationship between child emotional disorder and parental mental health in the British Child and Adolescent Mental Health surveys 1999 and 2004.

BACKGROUND: Research suggests parental psychopathology has an adverse effect on child mental health. However, due to the interactional nature of parent-child relationships and with a high rate of emotional disorders reported in school-age children, it is important to know whether the effect is reciprocal. METHODS: We explored the longitudinal relationship between child and parent mental health in the British Child and Adolescent Mental Health Surveys (N=7,100 child-parent dyads) and their three-year follow-ups. The Development and Well-Being Assessment with DSM-IV diagnostic criteria was used to measure child psychiatric diagnoses, while parental mental health was assessed using the General Health Questionnaire. Multivariable logistic regression was used to explore the longitudinal association between child emotional disorder and parent mental health. RESULTS: Parents of children who had an emotional disorder at baseline were more likely to have poor mental health three years later compared with parents whose children had no psychiatric diagnosis (33.3% versus 16.7%; crude odds ratio=2.52; adjusted odds ratio=2.19, 95% CI=1.58 to 3.05, p<0.001). Children of parents with poor mental health at baseline were more likely to develop an emotional disorder three years later compared with children whose parents had good mental health (5.2% versus 2.5%; crude odds ratio=2.08; adjusted odds ratio=1.63, 95% CI=1.18 to 2.25, p=0.003). LIMITATIONS: The findings of this research are limited by the survey data collected, the measures used and survey dropout. CONCLUSIONS: We detected a bi-directional relationship between child and parent mental health, suggesting that effective intervention for one individual may benefit other family members.

Comparison of small-sample standard-error corrections for generalised estimating equations in stepped wedge cluster randomised trials with a binary outcome: A simulation study.

Generalised estimating equations with the sandwich standard-error estimator provide a promising method of analysis for stepped wedge cluster randomised trials. However, they have inflated type-one error when used with a small number of clusters, which is common for stepped wedge cluster randomised trials. We present a large simulation study of binary outcomes comparing bias-corrected standard errors from Fay and Graubard; Mancl and DeRouen; Kauermann and Carroll; Morel, Bokossa, and Neerchal; and Mackinnon and White with an independent and exchangeable working correlation matrix. We constructed 95% confidence intervals using a t-distribution with degrees of freedom including clusters minus parameters (DFC-P), cluster periods minus parameters, and estimators from Fay and Graubard (DFFG), and Pan and Wall. Fay and Graubard and an approximation to Kauermann and Carroll (with simpler matrix inversion) were unbiased in a wide range of scenarios with an independent working correlation matrix and more than 12 clusters. They gave confidence intervals with close to 95% coverage with DFFG with 12 or more clusters, and DFC-P with 18 or more clusters. Both standard errors were conservative with fewer clusters. With an exchangeable working correlation matrix, approximated Kauermann and Carroll and Fay and Graubard had a small degree of under-coverage.

Utility of CD4 count measurement in the era of universal antiretroviral therapy: an analysis of routine laboratory data in Botswana.

OBJECTIVES: National guidelines in Botswana recommend baseline CD4 count measurement and both CD4 and HIV viral load (VL) monitoring post-antiretroviral therapy (ART) initiation. We evaluated the utility of CD4 count measurement in Botswana in the era of universal ART. METHODS: CD4 and VL data were analysed for HIV-infected adults undergoing CD4 count measurement in 2015-2017 at the Botswana Harvard HIV-Reference Laboratory. We determined (1) the proportion of individuals with advanced HIV disease (CD4 count < 200 cells/µL) at initial CD4 assessment, (2) the proportion with an initial CD4 count ≥ 200 cells/µL experiencing a subsequent decline in CD4 count to < 200 cells/µL, and (3) the proportion of these immunologically failing individuals who had virological failure. Logistic regression modelling examined factors associated with advanced HIV disease. CD4 count trajectories were assessed using locally weighted scatterplot smoothing (LOWESS) regression. RESULTS: Twenty-five per cent (3571/14 423) of individuals with an initial CD4 assessment during the study period had advanced HIV disease at baseline. Older age [≥ 35 years; adjusted odds ratio (aOR) 1.9; 95% confidence interval (CI) 1.8-2.1] and male sex were associated with advanced HIV disease. Fifty per cent (7163/14 423) of individuals had at least two CD4 counts during the study period. Of those with an initial CD4 count ≥ 200 cells/µL, 4% (180/5061) experienced a decline in CD4 count to < 200 cells/µL; the majority of CD4 count declines were in virologically suppressed individuals and transient. CONCLUSIONS: One-quarter of HIV-positive individuals in Botswana still present with advanced HIV disease, highlighting the importance of baseline CD4 count measurement to identify this at-risk population. Few with a baseline CD4 count ≥ 200 cells/µL experienced a drop below 200 cells/µL, suggesting limited utility for ongoing CD4 monitoring.

Hospital admissions for non-communicable disease in the UK military and associations with alcohol use and mental health: a data linkage study.

BACKGROUND: Since the recent conflicts in Iraq and Afghanistan, the short-term focus of military healthcare research has been on the consequences of deployment for mental health and on those wounded or injured in combat. Now that these conflicts have ended for the UK Armed Forces, it is important to consider the longer term physical and mental health consequences, and just as importantly, the links between these. The aims of this study were to determine the most common physical conditions requiring a hospital admission in UK military personnel and whether they were more common in personnel with a mental health condition, smokers, and/or those misusing alcohol compared to those without. METHODS: Data linkage of a prospective UK military cohort study to electronic admitted patient care records for England, Wales and Scotland. Nine thousand nine hundred ninety military personnel completed phase 2 of a military cohort study (56% response rate, data collected from 2007 to 2009), with analyses restricted to 86% of whom provided consent for linkage to healthcare records (n = 8602). Ninety percent were male and the mean age at phase 2 was 36 years. The outcome was physical non communicable diseases (NCDs) requiring a hospital admission which occurred after phase 2 of the cohort when the mental health, smoking and alcohol use exposure variables had been assessed until the end of March 2014. RESULTS: The most common NCDs requiring a hospital admission were gastrointestinal disorders 5.62% (95% Confidence Intervals (CI) 5.04, 6.19) and joint disorders 5.60% (95% CI 5.02, 6.18). Number of NCDs requiring a hospital admission was significantly higher in those with a common mental disorder (Hazard ratio (HR) 1.40 (95% CI 1.16-1.68), post-traumatic stress disorder (HR 1.78 (95% CI 1.32-2.40)) and in current smokers (HR 1.35 (95% CI 1.12-1.64) compared to those without the disorder, and non-smokers, respectively. CONCLUSIONS: Military personnel with a mental health problem are more likely to have an inpatient hospital admission for NCDs compared to those without, evidencing the clear links between physical and mental health in this population.