GiANT: gene set uncertainty in enrichment analysis.

UNLABELLED: Over the past years growing knowledge about biological processes and pathways revealed complex interaction networks involving many genes. In order to understand these networks, analysis of differential expression has continuously moved from single genes towards the study of gene sets. Various approaches for the assessment of gene sets have been developed in the context of gene set analysis (GSA). These approaches are bridging the gap between raw measurements and semantically meaningful terms.We present a novel approach for assessing uncertainty in the definition of gene sets. This is an essential step when new gene sets are constructed from domain knowledge or given gene sets are suspected to be affected by uncertainty. Quantification of uncertainty is implemented in the R-package GiANT. We also included widely used GSA methods, embedded in a generic framework that can readily be extended by custom methods. The package provides an easy to use front end and allows for fast parallelization. AVAILABILITY AND IMPLEMENTATION: The package GiANT is available on CRAN. CONTACTS: hans.kestler@leibniz-fli.de or hans.kestler@uni-ulm.de.

Methadone and buprenorphine-related deaths among people prescribed and not prescribed Opioid Agonist Therapy during the COVID-19 pandemic in England.

BACKGROUND: The coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine), including changes in the prescribing and dispensing of OAT and patterns of drug availability and use. We aimed to assess the impact of the first lockdown (initiated March 23rd 2020) on methadone- and buprenorphine-related deaths in England in people both prescribed and not prescribed OAT using data from the National Programme on Substance Abuse Deaths. METHODS: This was a retrospective post-mortem toxicology study of OAT-related deaths which occurred in the 3-month period March 23rd to June 22nd in the years 2016-2020. Provisional data regarding numbers accessing treatment for opioid use disorder was provided by the National Drug Treatment Monitoring System. RESULTS: We found a 64% increase in methadone-related deaths in March to June 2020 compared to March to June 2019 (2019 n = 96; 2020 projected n = 157). There were increases in the mortality rate of both in-treatment decedents (22% increase; 2019 n = 45; an exponential smoothing model of the 2016-19 trend [α=0.5] predicted 44 deaths in 2020, 55 were reported) and decedents not prescribed methadone (74% increase; 2019 n = 46; 2016-19 trend predicted 43 deaths in 2020, 80 were reported). There was no increase in buprenorphine-related deaths (2019 n = 9/529; 2020 n = 11/566). There were no changes in the numbers of deaths where other opioids or multiple substances were detected, or in methadone levels detected. Numbers of people accessing treatment for opioid use disorder in 2020 did not decrease relative to previous years (p >0.05). CONCLUSIONS: Methadone-related deaths in non-prescribed individuals, but not prescribed individuals, increased considerably above the annual trend forecast for 2020 during the first COVID-19 lockdown in England. Further studies are thus needed to understand this difference.

Undetected Respiratory Depression in People with Opioid Use Disorder.

BACKGROUND: Opioid-related deaths are increasing globally. Respiratory complications of opioid use and underlying respiratory disease in people with Opioid Use Disorder (OUD) are potential contributory factors. Individual variation in susceptibility to overdose is, however, incompletely understood. This study investigated the prevalence of respiratory depression (RD) in OUD treatment and compared this to patients with chronic obstructive pulmonary disease (COPD) of equivalent severity. We also explored the contribution of opioid agonist treatment (OAT) dosage, and type, to the prevalence of RD. METHODS: There were four groups of participants: 1) OUD plus COPD ('OUD-COPD', n = 13); 2) OUD without COPD ('OUD', n = 7); 3) opioid-naïve COPD patients ('COPD'n = 13); 4) healthy controls ('HC'n = 7). Physiological indices, including pulse oximetry (SpO2%), end-tidal CO2 (ETCO2), transcutaneous CO2 (TcCO2), respiratory airflow and second intercostal space parasternal muscle electromyography (EMGpara), were recorded continuously over 40 min whilst awake at rest. Significant RD was defined as: SpO2%< 90% for > 10 s, ETCO2 per breath > 6.6 kPa, TcCO2 overall mean > 6 kPa, respiratory pauses > 10 s RESULTS: At least one indicator was observed in every participant with OUD (n = 20). This compared to RD episode occurrence in only 2/7 HC and 2/13 COPD participants (p < 0.05,Fisher's exact test). The occurrence of RD was similar in OUD participants prescribed methadone (n = 6) compared to those prescribed buprenorphine (n = 12). CONCLUSIONS: Undetected RD is common in OUD cohorts receiving OAT and is significantly more severe than in opioid-naïve controls. RD can be assessed using simple objective measures. Further studies are required to determine the association between RD and overdose risk.

Mobile telephone delivered contingency management for encouraging adherence to supervised methadone consumption: feasibility study for an RCT of clinical and cost-effectiveness (TIES).

BACKGROUND: Prescription methadone or buprenorphine enables people with opioid use disorder to stop heroin use safely while avoiding withdrawal. To ensure methadone is taken as prescribed and to prevent diversion onto the illicit market, people starting methadone take their daily dose under a pharmacist's supervision. Many patients miss their daily methadone dose risking withdrawal, craving for heroin and overdose due to loss of heroin tolerance. Contingency management (CM) can improve medication adherence, but remote delivery using technology may be resource-light and cost-effective. We developed an innovative way to deliver CM by mobile telephone. Software monitors patients' attendance and supervised methadone consumption through an internet self-login at the pharmacy and sends reinforcing text messages to patients' mobile telephones. A linked system sends medication adherence reports to prescribers and provides early warning alerts of missed doses. A pre-paid debit card system provides financial incentives. METHODS: A cluster randomised controlled trial design was used to test the feasibility of conducting a future trial of mobile telephone CM to encourage adherence to supervised methadone in community pharmacies. Each cluster (drug service/3 allied pharmacies) was randomly allocated to provide patient's presenting for a new episode of opiate agonist treatment (OAT) with either (a) mobile telephone text message CM, (b) mobile telephone text message reminders, or (c) no text messages. We assessed acceptability of the interventions, recruitment, and follow-up procedures. RESULTS: Four drug clinics were approached and three recruited. Thirty-three pharmacists were approached and 9 recruited. Over 3 months, 173 individuals were screened and 10 enrolled. Few patients presented for OAT and high numbers were excluded due to receiving buprenorphine or not attending participating pharmacies. There was 96% consistency in recording medication adherence by self-login vs. pharmacy records. In focus groups, CM participants were positive about using self-login, the text messages, and debit card. Prescribers found weekly reporting, time saving, and allowed closer monitoring of patients. Pharmacists reported that the tablet device was easy to host. CONCLUSION: Mobile telephone CM worked well, but a planned future trial will use modified eligibility criteria (existing OAT patients who regularly miss their methadone/buprenorphine doses) and increase the number of participating pharmacies. TRIAL REGISTRATION: The trial is retrospectively registered, ISRCTN 58958179 .

Changes in neuropsychological functioning during alcohol detoxification.

This study investigates changes in neuropsychological functioning during early abstinence from alcohol. 30 alcohol-dependent inpatients were tested at intake (day 4 of admission) and post detoxification (day 26), using a test-retest design. The neuropsychological battery included measures of pre-morbid IQ, full-scale IQ, verbal and non-verbal measures of memory and executive function. IQ was within the normal range at intake and comparable with age-adjusted normative values and there were some impairments in memory and executive function. There were significant increases in performance scores post detoxification in working memory, verbal fluency and verbal inhibition but not in non-verbal executive function tasks (mental flexibility and planning ability). Despite increased scores on tests of verbal and memory skills after 3 weeks of abstinence, complex executive abilities showed little change. These may have a negative impact on engagement and response to treatment and compromise clinical outcomes, heightening the risk of relapse.

Positive reinforcement targeting abstinence in substance misuse (PRAISe): Study protocol for a Cluster RCT & process evaluation of contingency management.

There are approximately 256,000 heroin and other opiate users in England of whom 155,000 are in treatment for heroin (or opiate) addiction. The majority of people in treatment receive opiate substitution treatment (OST) (methadone and buprenorphine). However, OST suffers from high attrition and persistent heroin use even whilst in treatment. Contingency management (CM) is a psychological intervention based on the principles of operant conditioning. It is delivered as an adjunct to existing evidence based treatments to amplify patient benefit and involves the systematic application of positive reinforcement (financial or material incentives) to promote behaviours consistent with treatment goals. With an international evidence base for CM, NICE recommended that CM be implemented in UK drug treatment settings alongside OST to target attendance and the reduction of illicit drug use. While there was a growing evidence base for CM, there had been no examination of its delivery in UK NHS addiction services. The PRAISe trial evaluates the feasibility, acceptability, clinical and cost effectiveness of CM in UK addiction services. It is a cluster randomised controlled effectiveness trial of CM (praise and financial incentives) targeted at either abstinence from opiates or attendance at treatment sessions versus no CM among individuals receiving OST. The trial includes an economic evaluation which explores the relative costs and cost effectiveness of the two CM intervention strategies compared to TAU and an embedded process evaluation to identify contextual factors and causal mechanisms associated with variations in outcome. This study will inform UK drug treatment policy and practice. Trial registration ISRCTN 01591254.

In-patient detoxification procedures, treatment retention, and post-treatment opiate use: comparison of lofexidine + naloxone, lofexidine + placebo, and methadone.

OBJECTIVE: In-treatment and post-treatment outcomes were compared for three detoxification procedures (lofexidine+naloxone, lofexidine+placebo naloxone, and methadone). SAMPLE AND DESIGN: The sample was 137 opiate dependent in-patients. Detoxification treatments were 6-day lofexidine+naloxone (n=45), lofexidine+placebo naloxone (n=46), or 10-day methadone reduction (n=46). A cohort study design was used with double-blind random allocation to lofexidine+naloxone versus lofexidine+placebo. Patients who did not consent to, or who were excluded from randomisation received methadone. RESULTS: Outcome differences between treatment groups at follow-up were generally associated with length of stay post-detoxification rather than detoxification procedure. Among patients who were not opiate abstinent throughout follow-up (n=85), those who received lofexidine+naloxone detoxification reported a longer interval to first heroin use, with an interaction between detoxification medication and subsequent retention in treatment also identified. CONCLUSIONS: Detoxification medication may influence medium-term opiate use outcomes via its effect upon retention in treatment.

Alcohol: a missed opportunity. A survey of all accident and emergency departments in England.

AIM: To determine the extent to which the recommendations of the alcohol harm reduction strategy for England and the Choosing Health white paper for the provision of screening and brief interventions for hazardous and harmful drinkers have been adopted by accident and emergency departments. METHOD: Telephone/postal survey of all 191 Type 1 departments in England. The survey was part of a larger study investigating the impact of the changes in the licensing act (2004) on alcohol-related attendances. RESULTS: 4 departments use formal screening tools and 24 ask general questions about consumption (98.9% response rate). Blood alcohol levels were measured as required by 100 departments. No departments routinely measure blood alcohol, and 84 departments never assess blood alcohol levels. Alcohol-related attendances were formally recorded by 131 departments. Access to an alcohol health worker or a clinical nurse specialist was reported by 32 departments. DISCUSSION: Although departments may be willing to address hazardous alcohol consumption, the low numbers of departments utilising formal screening tools suggests that patients who may benefit from help or advice remain undetected.

Robotic system for prostate brachytherapy.

In contemporary brachytherapy procedures, needle placement at the desired target is challenging for a variety of reasons. A robot-assisted brachytherapy system can potentially improve needle placement and seed delivery, resulting in enhanced therapeutic outcome. In this paper we present a robotic system with 16 degrees of freedom (DOF) (9 DOF for the positioning module and 7 DOF for the surgery module) that has been developed and fabricated for prostate brachytherapy. Strategies to reduce needle deflection and target movement were incorporated after extensive experimental validation. Provision for needle motion and force feedback was included in the system to improve robot control and seed delivery. Preliminary experimental results reveal that the prototype system is sufficiently accurate in placing brachytherapy needles.

Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence.

BACKGROUND: The clinical implementation and evaluation of heroin substitution programmes have been confounded by the lack of objective and validated biomarkers for illicit heroin use in patients prescribed pharmaceutical heroin. This study examined the capacity to detect illicit heroin use by gas chromatography-mass spectrometry (GC-MS) analysis of urine samples for the presence of opium impurities common to illicit, but not pharmaceutical heroin. AIMS: To characterize the diagnostic properties of the metabolites of noscapine and papaverine in comparison to morphine as a gold-standard marker of illicit heroin use; and to examine the relationships between the self-reported time since most recent heroin use and the detection of these opioids in urine. DESIGN: A cross-sectional study of 52 opioid-dependent patients in treatment (not prescribed heroin), who self-reported illicit heroin use within the preceding 2 weeks. Self-report data regarding recent drug use and a urine sample were collected. GC-MS analyses of urines were conducted and reported by laboratory staff blinded to self-report data. FINDINGS: The metabolites of papaverine (hydroxypapaverine and dihydroxypapeverine) were found to have high sensitivity, specificity and negative predictive values as markers for illicit heroin use compared to the 'gold-standard' morphine. Other opioids, including 6-mono-acetylmorphine (6-MAM), codeine and noscapine metabolites (e.g. meconine) were less adequate in detecting heroin use. CONCLUSIONS: GC-MS detection of papaverine metabolites in urine appears to be suitable method of identifying illicit heroin use for clinical and research purposes.

Inpatient versus other settings for detoxification for opioid dependence.

BACKGROUND: There are a complex range of variables that can influence the course and subjective severity of opioid withdrawal. There is a growing evidence for the effectiveness of a range of medically-supported detoxification strategies, but little attention has been paid to the influence of the setting in which the process takes place. OBJECTIVES: To evaluate the effectiveness of any inpatient opioid detoxification programme when compared with all other time-limited detoxification programmes on the level of completion of detoxification, the intensity and duration of withdrawal symptoms, the nature and incidence of adverse effects, the level of engagement in further treatment post-detoxification, and the rates of relapse post-detoxification. SEARCH STRATEGY: Electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library Issue 3, 2004); MEDLINE (January 1966-March 2004); EMBASE (January 1988-March 2004); PsycInfo (January 1967-March 2004); CINAHL (January 1982-March 2004). In addition the Current Contents, Biological Abstracts, Science Citation Index and Social Sciences Index were searched. SELECTION CRITERIA: Randomised controlled clinical trials comparing inpatient opioid detoxification (any drug or psychosocial therapy) with other time-limited detoxification programmes (including residential units that are not staffed 24 hours per day, day-care facilities where the patient is not resident for 24 hours per day, and outpatient or ambulatory programmes, and using any drug or psychosocial therapy). DATA COLLECTION AND ANALYSIS: All abstracts were independently inspected by two reviewers (ED & JI) and relevant papers were retrieved and assessed for methodological quality using Cochrane Reviewers' Handbook criteria. MAIN RESULTS: Only one study met the inclusion criteria. This did not explicitly report the number of participants in each group that successfully completed the detoxification process, but the published data allowed us to deduce that 7 out of 10 (70%) in the inpatient detoxification group were opioid-free on discharge, compared with 11 out of 30 (37%) in the outpatient group. There was very limited data about the other outcomes of interest. AUTHORS' CONCLUSIONS: This review demonstrates that there is no good available research to guide the clinician about the outcomes or cost-effectiveness of inpatient or outpatient approaches to opioid detoxification.

Predicting Variabilities in Cardiac Gene Expression with a Boolean Network Incorporating Uncertainty.

Gene interactions in cells can be represented by gene regulatory networks. A Boolean network models gene interactions according to rules where gene expression is represented by binary values (on / off or {1, 0}). In reality, however, the gene's state can have multiple values due to biological properties. Furthermore, the noisy nature of the experimental design results in uncertainty about a state of the gene. Here we present a new Boolean network paradigm to allow intermediate values on the interval [0, 1]. As in the Boolean network, fixed points or attractors of such a model correspond to biological phenotypes or states. We use our new extension of the Boolean network paradigm to model gene expression in first and second heart field lineages which are cardiac progenitor cell populations involved in early vertebrate heart development. By this we are able to predict additional biological phenotypes that the Boolean model alone is not able to identify without utilizing additional biological knowledge. The additional phenotypes predicted by the model were confirmed by published biological experiments. Furthermore, the new method predicts gene expression propensities for modelled but yet to be analyzed genes.

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response.

Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and protein turnover. Deregulation of Notch signaling and stabilizing mutations of Notch1 have been linked to leukemia development. We found that the methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1; also known as PRMT4) methylated NICD at five conserved arginine residues within the C-terminal transactivation domain. CARM1 physically and functionally interacted with the NICD-coactivator complex and was found at gene enhancers in a Notch-dependent manner. Although a methylation-defective NICD mutant was biochemically more stable, this mutant was biologically less active as measured with Notch assays in embryos of Xenopus laevis and Danio rerio. Mathematical modeling indicated that full but short and transient Notch signaling required methylation of NICD.

Intraoperative optimized inverse planning for prostate brachytherapy: early experience.

PURPOSE: To demonstrate the feasibility of an intraoperative inverse planning technique with advanced optimization for prostate seed implantation. METHODS AND MATERIALS: We have implemented a method for optimized inverse planning of prostate seed implantation in the operating room (OR), based on the genetic algorithm (GA) driven Prostate Implant Planning Engine for Radiotherapy (PIPER). An integrated treatment planning system was deployed, which includes real-time ultrasound image acquisition, treatment volume segmentation, GA optimization, real-time decision making and sensitivity analysis, isodose and DVH evaluation, and virtual reality navigation and surgical guidance. Ten consecutive patients previously scheduled for implantation were included in the series. RESULTS: The feasibility of the technique was established by careful monitoring of each step in the OR and comparison with conventional preplanned implants. The median elapsed time for complete image capture, segmentation, GA optimization, and plan evaluation was 4, 10, 2.2, and 2 min, respectively. The dosimetric quality of the OR-based plan was shown to be equivalent to the corresponding preplan. CONCLUSION: An intraoperative optimized inverse planning technique was developed for prostate brachytherapy. The feasibility of the method was demonstrated through an early clinical experience.

Automated treatment planning engine for prostate seed implant brachytherapy.

PURPOSE: To develop a computer-intelligent planning engine for automated treatment planning and optimization of ultrasound- and template-guided prostate seed implants. METHODS AND MATERIALS: The genetic algorithm was modified to reflect the 2D nature of the implantation template. A multi-objective decision scheme was used to rank competing solutions, taking into account dose uniformity and conformity to the planning target volume (PTV), dose-sparing of the urethra and the rectum, and the sensitivity of the resulting dosimetry to seed misplacement. Optimized treatment plans were evaluated using selected dosimetric quantifiers, dose-volume histogram (DVH), and sensitivity analysis based on simulated seed placement errors. These dosimetric planning components were integrated into the Prostate Implant Planning Engine for Radiotherapy (PIPER). RESULTS: PIPER has been used to produce a variety of plans for prostate seed implants. In general, maximization of the minimum peripheral dose (mPD) for given implanted total source strength tended to produce peripherally weighted seed patterns. Minimization of the urethral dose further reduced the loading in the central region of the PTV. Isodose conformity to the PTV was achieved when the set of objectives did not reflect seed positioning uncertainties; the corresponding optimal plan generally required fewer seeds and higher source strength per seed compared to the manual planning experience. When seed placement uncertainties were introduced into the set of treatment planning objectives, the optimal plan tended to reach a compromise between the preplanned outcome and the likelihood of retaining the preferred outcome after implantation. The reduction in the volatility of such seed configurations optimized under uncertainty was verified by sensitivity studies. CONCLUSION: An automated treatment planning engine incorporating real-time sensitivity analysis was found to be a useful tool in dosimetric planning for prostate brachytherapy.

Screening a living kidney donor for polycystic kidney disease using heavily T2-weighted MRI.

Autosomal dominant polycystic kidney disease (ADPKD) accounts for approximately 8% of those awaiting renal transplantation. Living related kidney donors for these patients require screening for ADPKD, most commonly by ultrasonography. Ultrasound has a negative predictive value (NPV) of 100% in patients aged older than 30 years, but only 96% for donors aged 20 to 30 years. This case shows that heavily T2-weighted magnetic resonance imaging (HT2MRI) may be a more sensitive screening method for ADPKD in younger kidney donors. Despite a normal screening ultrasound result, a kidney donor with a family history of ADPKD was found to have renal cysts intraoperatively, and the transplantation was canceled. Afterward, the donor was imaged with HT2MRI. In addition, the mathematical relationship between sensitivity, specificity, and NPV for ADPKD screening tests was derived. After the canceled transplantation, a second ultrasound still could not identify renal cysts. However, HT2MRI showed multiple small ( approximately 3-mm) cysts in both kidneys and a 2.5-cm cyst on the right kidney. Mathematical analysis showed that the NPV of a screening test for ADPKD was most closely related to sensitivity and that only tests with 100% sensitivity would have a 100% NPV. We conclude that ultrasound is not a sufficiently sensitive screening test for ADPKD in younger living related renal donors. HT2MRI has improved sensitivity and may be the best screening test for ADPKD in this population.

Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: a dose-response study.

RATIONALE: Methadone is the most widespread pharmacological treatment for opiate dependency but relatively little is known of its effects on cognitive and psychomotor functioning, drug craving and mood. OBJECTIVE: The present study aimed to assess the acute effects of methadone in patients admitted to an opiate detoxification programme. METHODS: Patients were randomly allocated to one of two groups who received either 50% or 100% of their daily stabilisation dose, and a placebo, in a double-blind, cross-over design. Twenty patients completed the study, all were assessed pre- and post-drug on 2 separate testing days. RESULTS: Performance on a task tapping episodic memory (delayed recall of a prose passage) was significantly impaired following the 100% daily dose of methadone. Methadone treatment had no effect on craving or mood. Patients were unable to distinguish between methadone and placebo treatments. CONCLUSIONS: A single dose of methadone can induce episodic memory impairment in patients who have a history of heroin use averaging more than 10 years. Such impairment can be avoided by giving methadone in divided doses.

Serodiagnosis of pericardial tuberculosis.

The AIDS epidemic has led to the resurgence of tuberculosis. Extrapulmonary manifestations may appear in over half of the patients who are dually infected. This has resulted in a rising incidence of tuberculous pericarditis in several parts of Africa such as Tanzania. We tested a solid-phase antibody competition sandwich ELISA (SACT-SE) as a potential means of diagnosing tuberculous pericarditis. Fifty-one African patients with clinically diagnosed tuberculous pericardial effusion (of whom 25 had confirmation by pericardial fluid culture) were tested using a monoclonal antibody (CDC/WHO ref. no. IT39) which was raised against a specific epitope on the Mycobacterium tuberculosis 30 kDa antigen. All but one patient had negative sputum microscopy for acid-fast bacilli. A sensitivity of 61% (at 96% specificity) was achieved. Sera from 25 African patients with smear-positive tuberculosis were also examined; of which 20 tested positive (sensitivity 80%). This is the largest study to date on the potential application of serology in diagnosing pericardial tuberculosis.

Management of tuberculous constrictive pericarditis and tuberculous pericardial effusion in Transkei: results at 10 years follow-up.

BACKGROUND: Tuberculous pericarditis is common in Transkei (Eastern Cape). Two randomized trials showed benefits at two years for prednisolone in patients with constrictive pericarditis, and open drainage plus prednisolone in patients with pericardial effusion. AIM: To see whether the advantages of prednisolone and open drainage were maintained up to 10 years. DESIGN: Follow-up of randomized, double-blind, placebo-controlled trials. METHODS: All 383 patients (143 constriction, 240 effusion) received the same anti-tuberculosis chemotherapy. They were randomized to prednisolone or placebo for the first 11 weeks, and were followed-up over 10 years. Among the 240 with effusion, 122 were also randomized to immediate open surgical drainage of pericardial fluid versus pericardiocentesis as required. Adverse outcomes were: death from pericarditis, pericardiectomy, repeat pericardiocentesis, and subsequent open drainage. RESULTS: The 10-year follow-up rate was 96%. In constriction patients, adverse outcomes occurred in 19/70 (27%) prednisolone vs. 28/73 (38%) placebo (p = 0.15), deaths from pericarditis being 2 (3%) vs. 8 (11%), respectively (p = 0.098, Fisher's exact test). In effusion patients, adverse outcomes occurred in 14/27 (52%) with neither drainage nor prednisolone, vs. 4/29 (14%) drainage and prednisolone, 4/35 (11%) drainage and placebo, and 6/31 (19%) prednisolone and no drainage (p = 0.08 for interaction). Drainage eliminated the need for repeat pericardiocentesis. In the 176 with effusion and no drainage, adverse outcomes occurred in 17/88 (19%) prednisolone vs. 35/88 (40%) placebo patients (p = 0.003), with repeat pericardiocentesis 20 (23%) placebo vs. 9 (10%) prednisolone (p = 0.025). In a multivariate survival analysis (stratified by type of pericarditis), prednisolone reduced the overall death rate after adjusting for age and sex (p = 0.044), and substantially reduced the risk of death from pericarditis (p = 0.004). At 10 years, the great majority of surviving patients in all treatment groups were either fully active or out and about, even if activity was restricted. DISCUSSION: In the absence of a clear contraindication, a corticosteroid should be used in addition to antituberculosis chemotherapy in the management of patients with tuberculous pericarditis.