A trial of mass isoniazid preventive therapy for tuberculosis control.

BACKGROUND: Tuberculosis is epidemic among workers in South African gold mines. We evaluated an intervention to interrupt tuberculosis transmission by means of mass screening that was linked to treatment for active disease or latent infection. METHODS: In a cluster-randomized study, we designated 15 clusters with 78,744 miners as either intervention clusters (40,981 miners in 8 clusters) or control clusters (37,763 miners in 7 clusters). In the intervention clusters, all miners were offered tuberculosis screening. If active tuberculosis was diagnosed, they were referred for treatment; if not, they were offered 9 months of isoniazid preventive therapy. The primary outcome was the cluster-level incidence of tuberculosis during the 12 months after the intervention ended. Secondary outcomes included tuberculosis prevalence at study completion. RESULTS: In the intervention clusters, 27,126 miners (66.2%) underwent screening. Of these miners, 23,659 (87.2%) started taking isoniazid, and isoniazid was dispensed for 6 months or more to 35 to 79% of miners, depending on the cluster. The intervention did not reduce the incidence of tuberculosis, with rates of 3.02 per 100 person-years in the intervention clusters and 2.95 per 100 person-years in the control clusters (rate ratio in the intervention clusters, 1.00; 95% confidence interval [CI], 0.75 to 1.34; P=0.98; adjusted rate ratio, 0.96; 95% CI, 0.76 to 1.21; P=0.71), or the prevalence of tuberculosis (2.35% vs. 2.14%; adjusted prevalence ratio, 0.98; 95% CI, 0.65 to 1.48; P=0.90). Analysis of the direct effect of isoniazid in 10,909 miners showed a reduced incidence of tuberculosis during treatment (1.10 cases per 100 person-years among miners receiving isoniazid vs. 2.91 cases per 100 person-years among controls; adjusted rate ratio, 0.42; 95% CI, 0.20 to 0.88; P=0.03), but there was a subsequent rapid loss of protection. CONCLUSIONS: Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control in South African gold mines, despite the successful use of isoniazid in preventing tuberculosis during treatment. (Funded by the Consortium to Respond Effectively to the AIDS TB Epidemic and others; Thibela TB Current Controlled Trials number, ISRCTN63327174.)

Teachers educators in South Africa: something amiss with their academic performance?

According to some observers, academics responsible for teacher education in South Africa and elsewhere traditionally have not enjoyed great esteem as academics from their colleagues in other disciplines and university structures. This is not only because of the nature of their subject, but also because they prepare students for one of the less esteemed professions, namely school teachers. Data from the South African part of the 22 country survey known as the Changing Academic Profession Research Project (CAP)(2007/8) confirm that their academic performance was not quite as high as that of their peers in other academic fields. The CAP data further suggest that their lower academic performance, operationally defined as research publication output, might among others be related to them feeling less in control of their professional environment than their peers in other disciplines, especially at departmental level. The discussion also reveals several shortcomings in the CAP survey and the data it provides

Eligibility for isoniazid preventive therapy in South African gold mines

Setting The “Thibela TB” cluster randomised trial of community-wide isoniazid preventive therapy (IPT) to reduce tuberculosis incidence in the South African gold mines. Objectives To determine the proportion of participants eligible for IPT and the reasons and risk factors for ineligibility, to inform the scale-up of IPT. Design Cross-sectional survey of participants in intervention clusters (mine shafts) consenting to tuberculosis screening and assessment for eligibility to start IPT. Results Among 27,126 consenting participants, 94.7% were male, the median age was 41 years, 12.2% reported previous tuberculosis, 0.6% reported ever taking IPT and 2.5% reported currently taking antiretroviral therapy. There were 24,430 (90.1%) assessed as eligible to start IPT, of whom 23,659 started IPT. The most common reasons for ineligibility were having suspected tuberculosis that was subsequently confirmed by a positive smear and/or culture (n=705), excessive alcohol consumption (n=427) and being on tuberculosis treatment at time of initial screen (n=241). Ineligibility was associated with factors including older age, female gender, prior history of tuberculosis and being in “HIV care”. However, at least 78% were eligible for IPT in all of these sub-groups. Conclusions The vast majority of participants in this community-wide intervention were eligible for IPT

Eligibility for isoniazid preventive therapy in South African gold mines.

SETTING: The "Thibela TB" cluster randomised trial of community-wide isoniazid preventive therapy (IPT) to reduce tuberculosis incidence in the South African gold mines. OBJECTIVES: To determine the proportion of participants eligible for IPT and the reasons and risk factors for ineligibility, to inform the scale-up of IPT. DESIGN: Cross-sectional survey of participants in intervention clusters (mine shafts) consenting to tuberculosis screening and assessment for eligibility to start IPT. RESULTS: Among 27,126 consenting participants, 94.7% were male, the median age was 41 years, 12.2% reported previous tuberculosis, 0.6% reported ever taking IPT and 2.5% reported currently taking antiretroviral therapy. There were 24,430 (90.1%) assessed as eligible to start IPT, of whom 23,659 started IPT. The most common reasons for ineligibility were having suspected tuberculosis that was subsequently confirmed by a positive smear and/or culture (n=705), excessive alcohol consumption (n=427) and being on tuberculosis treatment at time of initial screen (n=241). Ineligibility was associated with factors including older age, female gender, prior history of tuberculosis and being in "HIV care". However, at least 78% were eligible for IPT in all of these sub-groups. CONCLUSIONS: The vast majority of participants in this community-wide intervention were eligible for IPT

'Team up against TB': promoting involvement in Thibela TB, a trial of community-wide tuberculosis preventive therapy

Objective: To describe a programme of community education and mobilization to promote uptake in a cluster-randomized trial of tuberculosis preventive therapy offered to all members of intervention clusters. Setting and participants: Gold mines in South Africa, where tuberculosis incidence is extremely high, despite conventional control measures. All employees in intervention clusters (mine shaft and associated hostel) were invited to enrol. Main outcome measure: Cumulative enrolment in the study in intervention clusters. Results: Key steps in communicating information relevant to the study included extensive consultation with key stakeholders; working with a communication company to develop a project ‘brand’; developing a communication strategy tailored to each intervention site; and involving actors from a popular television comedy series to help inform communities about the study. One-to-one communications used peer educators along with study staff, and participant advisory groups facilitated two-way communication between study staff and participants. By contrast, treatment ‘buddies’ and text messaging to promote adherence proved less successful. Mean cumulative enrolment in the first four intervention clusters was 61.9%, increasing to 83.0% in the final four clusters. Conclusion: A tailored communication strategy can facilitate a high level of enrolment in a community health intervention

Proportion ineligible for isoniazid preventive therapy in sub-groups (n=26,912).

<p>CI = confidence interval</p>*<p>“HIV care” is a proxy from having ever taken IPT or currently being on ART</p>**<p>Weight less than or equal to 40kg was an exclusion criteria, but none of the participants in this table were excluded on this basis.</p>***<p>for women grouping is 0, 1-21, 22+. Excessive alcohol use, defined as 29+ units/week for men and 22+ units/week for women, was an exclusion criterion; hence, no confidence interval was given for the proportion.</p><p>Note: 214 participants had missing data on at least one of these variables and so were excluded from this analysis; they were more likely to be ineligible than those with no missing data (33.2% versus 9.8% respectively, p<0.001). </p

'Team up against TB': promoting involvement in Thibela TB, a trial of community-wide tuberculosis preventive therapy.

OBJECTIVE: To describe a programme of community education and mobilization to promote uptake in a cluster-randomized trial of tuberculosis preventive therapy offered to all members of intervention clusters. SETTING AND PARTICIPANTS: Gold mines in South Africa, where tuberculosis incidence is extremely high, despite conventional control measures. All employees in intervention clusters (mine shaft and associated hostel) were invited to enrol. MAIN OUTCOME MEASURE: Cumulative enrolment in the study in intervention clusters. RESULTS: Key steps in communicating information relevant to the study included extensive consultation with key stakeholders; working with a communication company to develop a project 'brand'; developing a communication strategy tailored to each intervention site; and involving actors from a popular television comedy series to help inform communities about the study. One-to-one communications used peer educators along with study staff, and participant advisory groups facilitated two-way communication between study staff and participants. By contrast, treatment 'buddies' and text messaging to promote adherence proved less successful. Mean cumulative enrolment in the first four intervention clusters was 61.9%, increasing to 83.0% in the final four clusters. CONCLUSION: A tailored communication strategy can facilitate a high level of enrolment in a community health intervention

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease