Near patient chlamydia and gonorrhoea screening and treatment in further education/technical colleges : a cost analysis of the 'Test n Treat' feasibility trial

Background Community-based screening may be one solution to increase testing and treatment of sexually transmitted infections in sexually active teenagers, but there are few data on the practicalities and cost of running such a service. We estimate the cost of running a ‘Test n Treat’ service providing rapid chlamydia (CT) and gonorrhoea (NG) testing and same day on-site CT treatment in technical colleges. Methods Process data from a 2016/17 cluster randomised feasibility trial were used to estimate total costs and service uptake. Pathway mapping was used to model different uptake scenarios. Participants, from six London colleges, provided self-taken genitourinary samples in the nearest toilet. Included in the study were 509 sexually active students (mean 85/college): median age 17.9 years, 49% male, 50% black ethnicity, with a baseline CT and NG prevalence of 6 and 0.5%, respectively. All participants received information about CT and NG infections at recruitment. When the Test n Treat team visited, participants were texted/emailed invitations to attend for confidential testing. Three colleges were randomly allocated the intervention, to host (non-incentivised) Test n Treat one and four months after baseline. All six colleges hosted follow-up Test n Treat seven months after baseline when students received a £10 incentive (to participate). Results The mean non-incentivised daily uptake per college was 5 students (range 1 to 17), which cost £237 (range £1082 to £88) per student screened, and £4657 (range £21,281 to £1723) per CT infection detected, or £13,970 (range £63,842 to £5169) per NG infection detected. The mean incentivised daily uptake was 19 students which cost £91 per student screened, and £1408/CT infection or £7042/NG infection detected. If daily capacity for screening were achieved (49 students/day), costs including incentives would be £47 per person screened and £925/CT infection or £2774/NG infection detected. Conclusions Delivering non-incentivised Test n Treat in technical colleges is more expensive per person screened than CT and NG screening in clinics. Targeting areas with high infection rates, combined with high, incentivised uptake could make costs comparable

The contribution of physical fitness to individual and ethnic differences in risk markers for type 2 diabetes in children: The Child Heart and Health Study in England (CHASE).

BACKGROUND: The relationship between physical fitness and risk markers for type 2 diabetes (T2D) in children and the contribution to ethnic differences in these risk markers have been little studied. We examined associations between physical fitness and early risk markers for T2D and cardiovascular disease in 9- to 10-year-old UK children. METHODS: Cross-sectional study of 1445 9- to 10-year-old UK children of South Asian, black African-Caribbean and white European origin. A fasting blood sample was used for measurement of insulin, glucose (from which homeostasis model assessment [HOMA]-insulin resistance [IR] was derived), glycated hemoglobin (HbA1c), urate, C-reactive protein (CRP), and lipids. Measurements of blood pressure (BP) and fat mass index (FMI) were made; physical activity was measured by accelerometry. Estimated VO2 max was derived from a submaximal fitness step test. Associations were estimated using multilevel linear regression. RESULTS: Higher VO2 max was associated with lower FMI, insulin, HOMA-IR, HbA1c, glucose, urate, CRP, triglycerides, LDL-cholesterol, BP and higher HDL-cholesterol. Associations were reduced by adjustment for FMI, but those for insulin, HOMA-IR, glucose, urate, CRP, triglycerides and BP remained statistically significant. Higher levels of insulin and HOMA-IR in South Asian children were partially explained by lower levels of VO2max compared to white Europeans, accounting for 11% of the difference. CONCLUSIONS: Physical fitness is associated with risk markers for T2D and CVD in children, which persist after adjustment for adiposity. Higher levels of IR in South Asians are partially explained by lower physical fitness levels compared to white Europeans. Improving physical fitness may provide scope for reducing risks of T2D

‘Test n Treat (TnT)’: a cluster-randomised feasibility trial of frequent, rapid-testing and same-day, on-site treatment to reduce rates of chlamydia in high-risk further education college students: statistical analysis plan

Background There are high rates of sexually transmitted infections (STIs) in ethnically diverse, sexually active students aged 16–24 years attending London further education (FE) colleges. However, uptake of chlamydia screening remains low. The TnT study aims to assess the feasibility of conducting a future trial in FE colleges to investigate if frequent, rapid, on-site testing and treatment (TnT) reduces chlamydia rates. This article presents the statistical analysis plan for the main study publication as approved and signed off by the Trial Management Group prior to the first data extraction for the final report. Methods/design TnT is a cluster-randomised feasibility trial conducted over 7 months with parallel qualitative and economic assessments. Colleges will be randomly allocated into the intervention (TnT) or the control group (no TnT). Six FE colleges in London will be included. At each college for 2 days, 80 consecutive sexually active students aged 16–24 years (total 480 students across all six colleges) will be recruited from public areas and asked to provide baseline samples. One and 4 months after recruitment intervention colleges will be visited on two consecutive days by the TnT team where participating students will be texted and invited to come for same-day, on-site, rapid chlamydia testing and, if positive, treatment. Participants in the control colleges will receive ‘thank you’ texts 1 and 4 months after recruitment. Seven months after recruitment, participants from both groups will be invited to complete questionnaires and provide samples for TnT. All samples will be tested, and same-day treatment offered to participants with positive results. Key feasibility outcomes include: recruitment rates, testing and treatment uptake rates (at 1 and 4 months) and follow-up rates (at 7 months). Trial registration ISRCTN 58038795. Registered on 31 August 2016

‘Test n Treat (TnT)’– Rapid testing and same-day, on-site treatment to reduce rates of chlamydia in sexually active further education college students: study protocol for a cluster randomised feasibility trial

Background Sexually active young people attending London further education (FE) colleges have high rates of chlamydia, but screening rates are low. We will conduct a cluster randomised feasibility trial of frequent, rapid, on-site chlamydia testing and same-day treatment (Test and Treat (TnT)) in six FE colleges (with parallel qualitative and economic assessments) to assess the feasibility of conducting a future trial to investigate if TnT reduces chlamydia rates. Methods We will recruit 80 sexually active students aged 16–24 years from public areas at each of six colleges. All participants (total n = 480) will be asked to provide samples (urine for males, self-taken vaginal swabs for females) and complete questionnaires on sexual lifestyle and healthcare use at baseline and after 7 months. Participants will be informed that baseline samples will not be tested for 7 months and be advised to get screened separately. Colleges will be randomly allocated to the intervention (TnT) or the control group (no TnT). One and 4 months after recruitment, participants at each intervention college (n = 3) will be texted and invited for on-site chlamydia tests using the 90-min Cepheid GeneXpert system. Students with positive results will be asked to see a visiting nurse health adviser for same-day treatment and partner notification, (backed by genitourinary medicine follow-up). Participants in control colleges (n = 3) will receive ‘thank you’ texts 1 and 4 months after recruitment. Seven months after recruitment, participants from both groups will be invited to complete questionnaires and provide samples for TnT. All samples will be tested, and same-day treatment offered to students with positive results. Acceptability of TnT will be assessed by qualitative interviews of purposively sampled students (n = 30) and college staff (n = 12). We will collect data on costs of TnT and usual healthcare. Discussion Findings will provide key values to inform feasibility, sample size and timescales of a future definitive trial of TnT in FE colleges, including: Recruitment rates TnT uptake rates Follow-up rates Prevalence of chlamydia in participants at baseline and 7 months Acceptability of TnT to students and college staff Estimate of the cost per person screened/treated in TnT versus usual care Trial registration International Standard Randomised Controlled Trials Registry, ID: ISRCTN58038795, Registered on 31 August 2016

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity

BACKGROUND: People with diabetes are more likely to develop tuberculosis (TB) and to have poor TB-treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at diagnosis. It is unknown whether this persists through treatment and contributes to the adverse outcomes.METHODS: Pulmonary TB patients recruited in South Africa, Indonesia and Romania were classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or TB-only, based on glycated haemoglobin concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood at diagnosis and intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification. Transcriptomic data were analysed by longitudinal mixed-model regression to identify whether genes were differentially expressed between clinical groups through time. Predictive models of TB-treatment response across groups were developed and cross-tested.RESULTS: Gene expression differed between TB and TB-DM patients at diagnosis and was modulated by TB treatment in all clinical groups but to different extents, such that differences remained in TB-DM relative to TB-only throughout. Expression of some genes increased through TB treatment, whereas others decreased: some were persistently more highly expressed in TB-DM and others in TB-only patients. Genes involved in innate immune responses, anti-microbial immunity and inflammation were significantly upregulated in people with TB-DM throughout treatment. The overall pattern of change was similar across clinical groups irrespective of diabetes status, permitting models predictive of TB treatment to be developed.CONCLUSIONS: Exacerbated transcriptome changes in TB-DM take longer to resolve during TB treatment, meaning they remain different from those in uncomplicated TB after treatment completion. This may indicate a prolonged inflammatory response in TB-DM, requiring prolonged treatment or host-directed therapy for complete cure. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes for use across populations.</p

Impact of intermediate hyperglycaemia as well as diabetes on immune dysfunction in tuberculosis

Background People living with diabetes have an increased risk of developing active tuberculosis and are more likely to have poor tuberculosis-treatment outcomes, which may impact on control of tuberculosis as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in active tuberculosis patients relative to healthy individuals. The effects of diabetes and intermediate hyperglycaemia on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-tuberculosis comorbidity. Methods Whole blood samples were collected from active tuberculosis patients with diabetes (HbA1c ≥6.5%) or intermediate hyperglycaemia (HbA1c 5.7-6.5%), tuberculosis-only patients and healthy controls in four countries: South Africa, Romania, Indonesia and Peru. Differential blood gene expression was determined by RNA-seq (n=249). Results Diabetes increased the magnitude of gene expression change in the host transcriptome in tuberculosis, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with intermediate hyperglycaemia and tuberculosis exhibited blood transcriptomes much more similar to diabetes-tuberculosis patients than to patients with only tuberculosis. Both diabetes-tuberculosis and intermediate hyperglycaemia-tuberculosis patients had a decreased type I interferon response relative to tuberculosis-only patients. Conclusions Co-morbidity in individuals with both tuberculosis and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type 1 interferon responses in co-morbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with intermediate hyperglycaemia, showing that altered immunity to tuberculosis may also be present in this group. The TB disease outcomes in individuals with intermediate hyperglycaemia diagnosed with TB should be investigated further

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment.

BACKGROUND: Globally, the tuberculosis (TB) treatment success rate is approximately 85%, with treatment failure, relapse and death occurring in a significant proportion of pulmonary TB patients. Treatment success is lower among people with diabetes mellitus (DM). Predicting treatment outcome early after diagnosis, especially in TB-DM patients, would allow early treatment adaptation for individuals and may improve global TB control. METHODS: Samples were collected in a longitudinal cohort study of adult TB patients from South Africa (n  =  94) and Indonesia (n  =  81), who had concomitant DM (n  =  59), intermediate hyperglycaemia (n  =  79) or normal glycaemia/no DM (n  =  37). Treatment outcome was monitored, and patients were categorized as having a good (cured) or poor (failed, recurrence, died) outcome during treatment and 12 months follow-up. Whole blood transcriptional profiles before, during and at the end of TB treatment were characterized using unbiased RNA-Seq and targeted gene dcRT-MLPA. FINDINGS: We report differences in whole blood transcriptome profiles, which were observed before initiation of treatment and throughout treatment, between patients with a good versus poor TB treatment outcome. An eight-gene and a 22-gene blood transcriptional signature distinguished patients with a good TB treatment outcome from patients with a poor TB treatment outcome at diagnosis (AUC = 0·815) or two weeks (AUC = 0·834) after initiation of TB treatment, respectively. High accuracy was obtained by cross-validating this signature in an external cohort (AUC = 0·749). INTERPRETATION: These findings suggest that transcriptional profiles can be used as a prognostic biomarker for treatment failure and success, even in patients with concomitant DM. FUNDING: The research leading to these results, as part of the TANDEM Consortium, received funding from the European Community's Seventh Framework Programme (FP7/2007-2013 Grant Agreement No. 305279) and the Netherlands Organization for Scientific Research (NWO-TOP Grant Agreement No. 91214038). The research leading to the results presented in the Indian validation cohort was supported by Research Council of Norway Global Health and Vaccination Research (GLOBVAC) projects: RCN 179342, 192534, and 248042, the University of Bergen (Norway)

A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the&nbsp;peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity