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Background: STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks., Methods: We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda). Participants were randomly assigned 1:2:2:2 (via permuted blocks and stratified by site and HIV status plus CD4 cell count) to the 2011 WHO long regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of an injectable antituberculous drug. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome, reported previously, was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable) at week 76. Here we report efficacy outcomes at week 132, analysed in the modified intention-to-treat (mITT) population. Safety assessments continued to 132 weeks and were in all participants who received at least one dose of the study regimen. All comparisons used concurrently randomised participants. This trial is registered on ISRCTN (ISRCTN18148631) and is now completed., Findings: Between March 28, 2016, and Jan 28, 2020, 588 participants were randomly assigned to the long (n=32), control (n=202), oral (n=211), or 6-month (n=143) treatment regimens; 352 (60%) were male and 236 (40%) were female. Of the 556 participants on the three shorter regimens, 517 were included in the mITT population (187 in control group, 196 in oral group, and 134 in 6-month group) and 465 in the per-protocol analyses. Six additional participants had an unfavourable outcome that occurred between week 76 and the end of efficacy follow-up (one in control group, four in oral group, one in 6-month group). In the mITT population, the proportion of patients with an unfavourable outcome at the end of follow-up was 19·6% (95% CI 14·3 to 24·9) in the oral group and 29·3% (23·3 to 36·5) in the control group (-9·7 percentage points difference [95% CI -18·7 to -1·8]; p superiority =0·024). An estimated 9·8% (95% CI 4·6 to 14·9) of participants on the 6-month regimen had an unfavourable outcome, which was significantly lower than for those concurrently on the control regimen (32·5% [23·7 to 40·2]; p superiority <0·0001) or the oral regimen (23·8% [16·9 to 31·1]; p superiority =0·013). Few serious or severe adverse events were reported after week 76, with no indication of a difference between the regimens. At week 132, treatment-emergent hearing loss was recorded in significantly fewer participants on the oral regimen (7/205; 3%) than the control regimen (16/198; 8%; p=0.041); there was no significant difference in severe hearing loss between the oral regimen (6/139; 4%) and the 6-month regimen (5/143; 4%; p=0·72). Death rates were low: 1·01 (95% CI 0·48 to 2·12) per 100 person-years in participants allocated to bedaquiline (ie, oral and 6-month regimen, n=287) compared with 1·52 (0·63 to 3·66) in participants on the control regimen (n=140; p=0·49)., Interpretation: Both of the bedaquiline-containing regimens maintained superiority to the control regimen, without evidence of increased mortality, providing two additional evidence-based treatment options for patients; previous mortality concerns for bedaquiline were not substantiated., Funding: US Agency for International Development and Janssen Research & Development., Competing Interests: Declaration of interests MR sat on the South African Bedaquiline, Pretomanid and Linezolid Clinical Access Program data monitoring committee and the BEAT Tuberculosis Trial data monitoring committee. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen., Methods: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631., Findings: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss., Interpretation: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss., Funding: USAID and Janssen Research & Development., Competing Interests: Declaration of interests SBS received a grant from the UK Foreign & Commonwealth Development Office for tuberculosis research through his institution. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Multi-arm, parallel-group clinical trials are an efficient way of testing several new treatments, treatment regimens or doses. However, guidance on the requirement for statistical adjustment to control for multiple comparisons (type I error) using a shared control group is unclear. We argue, based on current evidence, that adjustment is not always necessary in such situations. We propose that adjustment should not be a requirement in multi-arm, parallel-group trials testing distinct treatments and sharing a control group, and we call for clearer guidance from stakeholders, such as regulators and scientific journals, on the appropriate settings for adjustment of multiplicity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids., Methods: We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3-5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604., Findings: Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1-26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9-30·1), p=0·001., Interpretation: Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term., Funding: NIHR Health Technology Assessment Programme., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap., Methods: This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927., Findings: Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use., Interpretation: In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome., Funding: National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London., (Copyright © 2014 McMillan et al. Open Access article distributed under the terms of CC BY. Published by .. All rights reserved.)

Summary In children undergoing tonsillectomy, dexamethasone is recommended to reduce the risk of postoperative nausea and vomiting while non-steroidal anti-inflammatory drugs (NSAIDs) are used for pain relief. We aimed to determine whether children who receive dexamethasone or dexamethasone with NSAID are more likely to experience haemorrhage post-tonsillectomy. Randomized and non-randomized studies in which children undergoing tonsillectomy received dexamethasone or dexamethasone and NSAID were sought within bibliographic databases and selected tertiary sources. The risk of bias assessment and evaluation of haemorrhage rate data collection and reporting were assessed using the Cochrane Risk of Bias Tool and McHarm tool. Synthesis methods comprised pooled estimate of the effect of dexamethasone on the risk of haemorrhage rate using the Peto odds ratio (OR) method. The pooled estimate for haemorrhage rate in children who received dexamethasone was 6.2%, OR 1.41 (95% confidence interval 0.89-2.25, P=0.15). There was risk of bias and inconsistent data collection and reporting rates of haemorrhage in many of the included studies. Clinical heterogeneity was observed between studies. The pooled analysis did not demonstrate a statistically significant increase in the risk of post-tonsillectomy haemorrhage with dexamethasone with/without NSAID use in children. However, the majority of the included studies were not designed to investigate this endpoint, and thus large studies which are specifically designed to collect data on haemorrhage rate are needed., (© The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Pleural infection is associated with a high morbidity and mortality. Development of a validated clinical risk score at presentation to identify those at high risk of dying would enable patient triage and may help formulate early management strategies., Methods: A clinical risk score was derived based on data from patients entering the multicenter UK pleural infection trial (first Multicenter Intrapleural Sepsis Trial [MIST1], n=411). From 22 baseline clinical characteristics, model selection was undertaken to find variables predictive of poor clinical outcome. Outcomes were mortality at 3 months (primary), need for surgical intervention at 3 months, and time from randomization to discharge. The derived scoring system RAPID (renal, age, purulence, infection source, and dietary factors) was validated using patients enrolled in the subsequent MIST2 trial (n=191)., Results: Age, urea, albumin, hospital-acquired infection, and nonpurulence predicted poor outcome. Patients were stratified into low-risk (0-2), medium-risk (3-4), and high-risk (5-7) groups. Using the low-risk group as a reference, a RAPID score of 3 to 4 and >4 was associated with an OR of 24.4 (95% CI, 3.1-186.7; P=.002) and 192.4 (95% CI, 25.0-1480.4; P<.001), respectively, for death at 3 months. In the validation cohort (MIST2), a medium-risk RAPID score was nonsignificantly associated with mortality (OR, 3.2; 95% CI, 0.8-13.2; P=.11), and a high-risk score was associated with increased mortality (OR, 14.1; 95% CI, 3.5-56.8; P<.001). Hospitalization duration was associated with increasing RAPID score (score 0-2: median duration=7, interquartile range 6-13; score>5: median duration=15, interquartile range 9-28, P=.08)., Conclusions: The RAPID score may permit risk stratification of patients with pleural infection at presentation.

Background: Minimally symptomatic OSA is a highly prevalent disorder, and the effects of CPAP on vascular function in these patients are unknown. This trial aimed to investigate whether CPAP improves vascular function in minimally symptomatic OSA., Methods: In two centers taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial, 253 patients with minimally symptomatic OSA were randomized to 6 months of CPAP or standard care. Two hundred eight patients attended their follow-up visit within the predefined time window and had complete measurements of arterial stiffness (augmentation index [AIx]), and 64 patients had endothelial function measurements by brachial artery flow-mediated dilatation (FMD). Multivariable analyses adjusting for baseline measurements and minimization factors were performed to assess the effect of CPAP treatment on FMD (% dilatation) and AIx (% augmentation) compared with standard care., Results: The mean ± SD baseline oxygen desaturation index and Epworth Sleepiness Score (ESS) of the 208 patients (age 58 ± 7.3 years, 31 women) were 13.7 ± 12.8 events/h and 8.3 ± 4.2, respectively. There was no CPAP treatment effect on arterial stiffness (AIx, -1.4%; 95% CI, -3.6 to +0.9%; P = .23), but CPAP improved endothelial function (FMD, +2.1%; 95% CI, +1.0 to +3.2%; P &lt; .0001). CPAP reduced daytime sleepiness (ESS, -2.2; 95% CI, -3.0 to -1.5; P &lt; .0001) compared with standard care. There was a larger improvement in FMD in patients using CPAP for &gt; 4 h/night than those who used it less (P = .013)., Conclusions: CPAP improves endothelial function, but not arterial stiffness, in minimally symptomatic OSA. Thus, minimally symptomatic OSA may be a cardiovascular risk factor., Trial Registry: ISRCTN Register; No.: ISRCTN 34164388; URL: http://isrctn.org.

Microbicide trials aim to measure the effect of a microbicide in reducing the risk of acquiring human immunodeficiency virus. Such trials present a number of challenging issues from design and conduct through to analysis and reporting. This begins with the initial identification of the target trial population. Prevention trials need to identify those at risk of human immunodeficiency virus infection. This can be more difficult in the general population compared with treatment trials that can target specific patient groups who have a confirmed diagnosis of the disease of interest. Consequently, microbicide trial participants will inevitably be recruited who are never at risk of HIV infection. In this chapter we outline the main features of microbicide trial design, key issues during conduct and analysis, and discuss the challenges specific to these types of clinical trials., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Drugs for tuberculosis are inadequate to address the many inherent and emerging challenges of treatment. In the past decade, ten compounds have progressed into the clinical development pipeline, including six new compounds specifically developed for tuberculosis. Despite this progress, the global drug pipeline for tuberculosis is still insufficient to address the unmet needs of treatment. Additional and sustainable efforts, and funding are needed to further improve the pipeline. The key challenges in the development of new treatments are the needs for novel drug combinations, new trial designs, studies in paediatric populations, increased clinical trial capacity, clear regulatory guidelines, and biomarkers for prediction of long-term outcome. Despite substantial progress in efforts to control tuberculosis, the global burden of this disease remains high. To eliminate tuberculosis as a public health concern by 2050, all responsible parties need to work together to strengthen the global antituberculosis drug pipeline and support the development of new antituberculosis drug regimens., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: The optimal choice of chest tube size for the treatment of pleural infection is unknown, with only small cohort studies reported describing the efficacy and adverse events of different tube sizes., Methods: A total of 405 patients with pleural infection were prospectively enrolled into a multicenter study investigating the utility of fibrinolytic therapy. The combined frequency of death and surgery, and secondary outcomes (hospital stay, change in chest radiograph, and lung function at 3 months) were compared in patients receiving chest tubes of differing size (chi(2), t test, and logistic regression analyses as appropriate). Pain was studied in detail in 128 patients., Results: There was no significant difference in the frequency with which patients either died or required thoracic surgery in patients receiving chest tubes of varying sizes ( < 10F, number dying or needing surgery 21/58 [36%]; size 10-14F, 75/208 [36%]; size 15-20F, 28/70 [40%]; size > 20F, 30/69 [44%]; chi(2)trend, 1 degrees of freedom [df] = 1.21, P = .27), nor any difference in any secondary outcome. Pain scores were substantially higher in patients receiving (mainly blunt dissection inserted) larger tubes ( < 10F, median pain score 6 [range 4-7]; 10-14F, 5 [4-6]; 15-20F, 6 [5-7]; > 20F, 6 [6-8]; chi(2), 3 df = 10.80, P = .013, Kruskal-Wallis; chi(2)trend, 1 df = 6.3, P = .014)., Conclusions: Smaller, guide-wire-inserted chest tubes cause substantially less pain than blunt-dissection-inserted larger tubes, without any impairment in clinical outcome in the treatment of pleural infection. These results suggest that smaller size tubes may be the initial treatment of choice for pleural infection, and randomized studies are now required., Trial Registration: MIST1 trial ISRCTN number: 39138989.

Background: No trials of co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis for HIV-infected adults or children have been done in areas with high levels of bacterial resistance to this antibiotic. We aimed to assess the efficacy of daily co-trimoxazole in such an area., Methods: We did a double-blind randomised placebo-controlled trial in children aged 1-14 years with clinical features of HIV infection in Zambia. Primary outcomes were mortality and adverse events possibly related to treatment. Analysis was by intention to treat., Findings: In October, 2003, the data and safety monitoring committee recommended early stopping of the trial. 541 children had been randomly assigned; seven were subsequently identified as HIV negative and excluded. After median follow-up of 19 months, 74 (28%) children in the co-trimoxazole group and 112 (42%) in the placebo group had died (hazard ratio [HR] 0.57 [95% CI 0.43-0.77], p=0.0002). This benefit applied in children followed up beyond 12 months (n=320, HR 0.48 [0.27-0.84], test for heterogeneity p=0.60) and across all ages (test for heterogeneity p=0.82) and baseline CD4 counts (test for heterogeneity p=0.36). 16 (6%) children in the co-trimoxazole group had grade 3 or 4 adverse events compared with 18 (7%) in the placebo group. These events included rash (one placebo), and a neutrophil count on one occasion less than 0.5x10(9)/L (16 [6%] co-trimoxazole vs seven [3%] placebo, p=0.06). Pneumocystis carinii was identified by immunofluorescence in only one (placebo) of 73 nasopharyngeal aspirates from children with pneumonia., Interpretation: Our results suggest that children of all ages with clinical features of HIV infection should receive co-trimoxazole prophylaxis in resource-poor settings, irrespective of local resistance to this drug.

Background: A WHO-recommended 8-month regimen based on ethambutol and isoniazid was evaluated in a randomised clinical trial against a 6-month standard regimen., Methods: 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly assigned one of three regimens: daily ethambutol, isoniazid, rifampicin, and pyrazinamide for 2 months, followed by ethambutol and isoniazid for 6 months (2EHRZ/6HE); the same drugs but given three times weekly in the initial intensive phase (2[EHRZ]3/6HE); or the same initial intensive phase as the first regimen, followed by 4 months of daily rifampicin and isoniazid (2EHRZ/4HR). Follow-up was to 30 months after the start of chemotherapy. Sputum was regularly examined by microscopy and culture. Unfavourable outcome was defined as failure during treatment or relapse afterwards. Analyses were by intention to treat., Findings: At 2 months, a significantly higher proportion of patients assigned the daily intensive phase than of those assigned the three-times-weekly regimen were culture negative (700/828 [85%] vs 333/433 [77%], p=0.001). 12 months after the end of chemotherapy, the proportions of unfavourable outcomes were 36 of 346 (10%) with 2EHRZ/6HE, 48 of 351 (14%) with 2(EHRZ)3/6HE, and 17 of 347 (5%) with 2EHRZ/4HR. Both 8-month regimens were significantly inferior to the control 6-month standard regimen (difference between control and 2EHRZ/6HE 5.5% [95% CI 1.6 to 9.4]; between control and 2(EHRZ)3/6HE 8.8% [4.5 to 13.0]). Adverse effects leading to interruption of treatment for 7 days or longer occurred in 28 patients (12 2EHRZ/6HE, five 2[EHRZ]3/6HE, 11 2EHRZ/4HR)., Interpretation: The results of this study must be taken into account in recommendations on management of new cases of smear-positive tuberculosis.

The mortality in 15 villages in South-West Uganda was studied in relation to HIV infection. After a population census, serum samples were tested for antibodies to HIV-1. Deaths were ascertained over 2 years. Unequivocal HIV-1 serology results were available for 9389 individuals. The prevalence of infection was 4.8% for all ages and 8.2% for adults (aged 13 or more). 198 deaths were recorded during 15,725 person years of observation. Mortality among seronegative adults was 7.7 per 1000 and among seropositive adults 115.9 per 1000. The excess annual death rate associated with HIV-1 infection was 5.3 per 1000 and in adults 7.9 per 1000. Highest excess mortality was 16.9 per 1000 in the age group 25-34. Among adults, half of all deaths and among those aged 13-44 over 80% of deaths were attributable to HIV-1 infection. These results show the strong impact that HIV-1 infection is having on mortality in a rural area of Uganda where the overall HIV-1 adult prevalence rate is below 10%--a rate lower than in many other parts of East Africa.

The pattern of tuberculosis in Indian, Pakistani and Bangladeshi patients in Blackburn (1978-1987) was compared with that for England and Wales (MRC Survey), with particular reference to the proportion with parenchymal lung disease, by a generalized linear model allowing for age, ethnic group and time since first entry. In Blackburn, the proportion with lung disease was higher in Pakistani/Bangladeshi (46%) compared with 28% in Indians, although in both groups this increased with age. In the MRC Survey, the proportions with lung disease were similar (Pakistani/Bangladeshi 36.5%, Indians 34%) but there was an increase in lung disease with age and year since first entry in the Indian ethnic group only. The reasons for the differences, and their implications are discussed.

69 patients with steroid-dependent asthma (mean daily prednisolone dose 14.2 [SD 6.1] mg) took part in a randomised, double-blind, placebo-controlled study of 24 weeks' treatment with methotrexate 15 mg weekly. The patients were seen every 4 weeks by the same physician, who reduced the daily prednisolone dose by 2.5 mg if the daily diary card variables and measurements of lung function were unchanged or improved. All other treatment remained unchanged. After 24 weeks of treatment the prednisolone dose had been reduced by a significantly greater proportion in the methotrexate than in the placebo group (50% vs 14%) and the reduction was not sustained after the study treatment stopped. There were substantial abnormalities in liver function tests in 5 of the 38 patients taking methotrexate.

In Transkei, 143 patients with active tuberculous constrictive pericarditis without significant pericardial effusion all received the same daily 6-month antituberculosis regimen of streptomycin, isoniazid, rifampicin, and pyrazinamide for 14 weeks followed by isoniazid and rifampicin. They were randomly allocated to receive in addition either prednisolone or placebo for the first 11 weeks; the comparison was double-blind throughout treatment and follow-up. In the 114 patients assessable up to 24 months, improvement was significantly more rapid in the prednisolone group, as shown by the rate of fall in the mean pulse rate and the rate at which jugular venous pressure and level of physical activity became normal. During follow-up, 2 (4%) of the 53 prednisolone and 7 (11%) of the 61 placebo patients died from pericarditis, and 11 (21%) and 18 (30%), respectively, required pericardiectomy. By 24 months 50 (94%) prednisolone and 52 (85%) placebo patients had a favourable status. 3 patients (1 prednisolone, 2 placebo) were normally active but were classified as not having achieved a favourable status. It is recommended that, in the absence of a specific contraindication, antituberculosis chemotherapy should be initially supplemented by steroids.

In an inquiry into the matching quality of preparations employed in double-blind controlled clinical trials, a panel of 4 observers studied 22 pairs of agents used in a sample of such trials, examining features which might make one preparation distinguishable from the other. 5 pairs of substances were an excellent match, being virtually indistinguishable, but in 7 pairs ther were obvious differences, detected by all 4 observers. The preparations used in cross-over studies were not specially well matched. Colour differences were most readily detected, followed by taste. The observers differed in their ability to detect differences between pairs of preparations, and 1 panel member was approximately 3 times more successful in doing so than another.

240 patients with active tuberculous pericardial effusion received a 4-drug daily antituberculosis regimen for 6 months and have been studied for 24 months or longer. Those willing were randomly allocated to open pericardial biopsy and complete drainage of pericardial fluid on admission or percutaneous pericardiocentesis as required. All patients were randomly allocated to prednisolone or matching placebo for the first 11 weeks, on a double-blind basis. Complete open drainage on admission abolished the need for pericardiocentesis (p less than 0.01) but did not influence the need for pericardiectomy for subsequent constriction or the risk of death. Among patients who did not have open drainage on admission, 2 (3%) of 76 given prednisolone compared with 10 (14%) of 74 given placebo died of pericarditis (p less than 0.05), 6 (8%) and 9 (12%) respectively required pericardiectomy, 7 (9%) and 17 (23%) repeat pericardiocentesis (p less than 0.05), and 3 (4%) and 7 (9%) open surgical drainage. By 24 months, apart from the 16 who died from pericarditis, all but 3 patients (2%) had a favourable status.