Comparing the Efficacy of Drug Regimens for Pulmonary Tuberculosis: Meta-analysis of Endpoints in Early-Phase Clinical Trials

Background A systematic review of early clinical outcomes in tuberculosis was undertaken to determine ranking of efficacy of drugs and combinations, define variability of these measures on different endpoints, and to establish the relationships between them. Methods Studies were identified by searching PubMed, Medline, Embase, LILACS (Latin American and Caribbean Health Sciences Literature), and reference lists of included studies. Outcomes were early bactericidal activity results over 2, 7, and 14 days, and the proportion of patients with negative culture at 8 weeks. Results One hundred thirty-three trials reporting phase 2A (early bactericidal activity) and phase 2B (culture conversion at 2 months) outcomes were identified. Only 9 drug combinations were assessed on >1 phase 2A endpoint and only 3 were assessed in both phase 2A and 2B trials. Conclusions The existing evidence base supporting phase 2 methodology in tuberculosis is highly incomplete. In future, a broader range of drugs and combinations should be more consistently studied across a greater range of phase 2 endpoints

Breakthrough Seizures - Further analysis of the Standard versus New Antiepileptic Drugs (SANAD) study

Objectives To develop prognostic models for risk of a breakthrough seizure, risk of seizure recurrence after a breakthrough seizure, and likelihood of achieving 12-month remission following a breakthrough seizure. A breakthrough seizure is one that occurs following at least 12 months remission whilst on treatment. Methods We analysed data from the SANAD study. This long-term randomised trial compared treatments for participants with newly diagnosed epilepsy. Multivariable Cox models investigated how clinical factors affect the probability of each outcome. Best fitting multivariable models were produced with variable reduction by Akaike’s Information Criterion. Risks associated with combinations of risk factors were calculated from each multivariable model. Results Significant factors in the multivariable model for risk of a breakthrough seizure following 12-month remission were number of tonic-clonic seizures by achievement of 12-month remission, time taken to achieve 12-month remission, and neurological insult. Significant factors in the model for risk of seizure recurrence following a breakthrough seizure were total number of drugs attempted to achieve 12-month remission, time to achieve 12-month remission prior to breakthrough seizure, and breakthrough seizure treatment decision. Significant factors in the model for likelihood of achieving 12-month remission after a breakthrough seizure were gender, age at breakthrough seizure, time to achieve 12-month remission prior to breakthrough, and breakthrough seizure treatment decision. Conclusions This is the first analysis to consider risk of a breakthrough seizure and subsequent outcomes. The described models can be used to identify people most likely to have a breakthrough seizure, a seizure recurrence following a breakthrough seizure, and to achieve 12-month remission following a breakthrough seizure. The results suggest that focussing on achieving 12-month remission swiftly represents the best therapeutic aim to reduce the risk of a breakthrough seizure and subsequent negative outcomes. This will aid individual patient risk stratification and the design of future epilepsy trials

Predictors of severe asthma attack re-attendance in Ecuadorian children: a cohort study.

Asthma is a common cause of emergency care attendance in low- and middle-income countries (LMICs). While few prospective studies of predictors for emergency care attendance have been undertaken in high-income countries, none have been performed in a LMIC.We followed a cohort of 5-15-year-old children treated for asthma attacks in emergency rooms of public health facilities in Esmeraldas City, Ecuador. We collected blood and nasal wash samples, and performed spirometry and exhaled nitric oxide fraction measurements. We explored potential predictors for recurrence of severe asthma attacks requiring emergency care over 6 months' follow-up.We recruited 283 children of whom 264 (93%) were followed-up for ≥6 months or until their next asthma attack. Almost half (46%) had a subsequent severe asthma attack requiring emergency care. Predictors of recurrence in adjusted analyses were (adjusted OR, 95% CI) younger age (0.87, 0.79-0.96 per year), previous asthma diagnosis (2.2, 1.2-3.9), number of parenteral corticosteroid courses in previous year (1.3, 1.1-1.5), food triggers (2.0, 1.1-3.6) and eczema diagnosis (4.2, 1.02-17.6). A parsimonious Cox regression model included the first three predictors plus urban residence as a protective factor (adjusted hazard ratio 0.69, 95% CI 0.50-0.95). Laboratory and lung function tests did not predict recurrence.Factors independently associated with recurrent emergency attendance for asthma attacks were identified in a low-resource LMIC setting. This study suggests that a simple risk-assessment tool could potentially be created for emergency rooms in similar settings to identify higher-risk children on whom limited resources might be better focused

RISK OF A SEIZURE RECURRENCE AFTER A BREAKTHROUGH SEIZURE AND THE IMPLICATIONS FOR DRIVING - FURTHER ANALYSIS OF THE STANDARD VERSUS NEW ANTIEPILEPTIC DRUGS (SANAD) RANDOMISED CONTROLLED TRIAL

Objectives A breakthrough seizure is one occurring after at least 12 months seizure freedom while on treatment. The Driver and Vehicle Licensing Agency (DVLA) allows an individual to return to driving once they have been seizure free for 12 months following a breakthrough seizure. This is based on the assumption that the risk of a further seizure in the next 12 months has dropped <20%. This analysis considers whether the prescribed 1 year off driving following a breakthrough seizure is sufficient for this and stratifies risk according to clinical characteristics. Design, setting, participants, interventions and main outcome measures The multicentre UK-based Standard versus New Antiepileptic Drugs (SANAD) study was a randomised controlled trial assessing standard and new antiepileptic drugs for patients with newly diagnosed epilepsy. For participants aged at least 16 with a breakthrough seizure, data have been analysed to estimate the annual seizure recurrence risk following a period of 6, 9 and 12 months seizure freedom. Regression modelling was used to investigate how antiepileptic drug treatment and a number of clinical factors influence the risk of seizure recurrence. Results At 12 months following a breakthrough seizure, the overall unadjusted risk of a recurrence over the next 12 months is lower than 20%, risk 17% (95% CI 15% to 19%). However, some patient subgroups have been identified which have an annual recurrence risk significantly greater than 20% after an initial 12-month seizure-free period following a breakthrough seizure. Conclusions This reanalysis of SANAD provides estimates of seizure recurrence risks following a breakthrough seizure that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be used

Risk of seizure recurrence in people with single seizures and early epilepsy - Model development and external validation

PURPOSE: Following a single seizure, or recent epilepsy diagnosis, it is difficult to balance risk of medication side effects with the potential to prevent seizure recurrence. A prediction model was developed and validated enabling risk stratification which in turn informs treatment decisions and individualises counselling. METHODS: Data from a randomised controlled trial was used to develop a prediction model for risk of seizure recurrence following a first seizure or diagnosis of epilepsy. Time-to-event data was modelled via Cox's proportional hazards regression. Model validity was assessed via discrimination and calibration using the original dataset and also using three external datasets - National General Practice Survey of Epilepsy (NGPSE), Western Australian first seizure database (WA) and FIRST (Italian dataset of people with first tonic-clonic seizures). RESULTS: People with neurological deficit, focal seizures, abnormal EEG, not indicated for CT/MRI scan, or not immediately treated have a significantly higher risk of seizure recurrence. Discrimination was fair and consistent across the datasets (c-statistics: 0.555 (NGPSE); 0.558 (WA); 0.597 (FIRST)). Calibration plots showed good agreement between observed and predicted probabilities in NGPSE at one and three years. Plots for WA and FIRST showed poorer agreement with the model underpredicting risk in WA, and over-predicting in FIRST. This was resolved following model recalibration. CONCLUSION: The model performs well in independent data especially when recalibrated. It should now be used in clinical practice as it can improve the lives of people with single seizures and early epilepsy by enabling targeted treatment choices and more informed patient counselling

Liver stiffness and virologic outcomes after introducing tenofovir as part of antiretroviral therapy in lamivudine-experienced adults with HIV and hepatitis B virus (HBV) co-infection in Ghana: four-year follow up of the prospective HEPIK cohort

Introduction Until recently lamivudine was the only available agent to treat hepatitis B in the context of HIV infection in sub‐Saharan Africa. Tenofovir is gradually becoming available although access remains far from universal. Long‐term outcomes of introducing tenofovir as part of antiretroviral therapy (ART) in subjects previously extensively exposed to lamivudine as the sole HBV‐active agent in the region are unknown. Methods We report from a prospective cohort of HIV/HBV co‐infected adults attending for HIV care in Kumasi, Ghana, where HBsAg prevalence is 14%. HBsAg‐positive subjects were invited to attend for transient elastography (TE) and blood sampling before the introduction of tenofovir (TO) as part of ART, and within 1 year (T1) and 4 years (T2) of starting tenofovir. Adherence and alcohol consumption were determined by a questionnaire‐based interview. Results Overall 178 patients underwent evaluation at T0/T1, of whom 98 (55%) also attended for assessment at T2. Remaining patients were lost to follow up (50; 28%); had died (10; 6%); declined to attend (17; 10%); or were excluded due to pregnancy (2; 1 %) or invalid TE (1; 1 %). Of the 98 subjects, 94 had started tenofovir‐based ART and had received tenofovir for median 4 years (IQR 3.8, 4.1), while continuing previous lamivudine (Table 1). By multivariable linear regression, female gender, no history of alcohol excess, and higher HBV DNA level, higher liver stiffness, and lower platelet count at T0/T1 were significant predictors of decreasing liver stiffness between TO/1 and T2. No treatment‐emergent resistance mutations in HBV polymerase were observed by Sanger sequencing among subjects with HBV DNA>100 lU/ml at T2; one subject showed M204V+V173L+L180M at both TO and T2. Conclusions This is the first report of the long‐term impact on liver stiffness and virologic parameters of introducing tenofovir as part of ART in extensively lamivudine exposed HIV/HBV co‐infected patients in sub‐Saharan Africa. Significant reductions in liver stiffness and improved HBV control were observed at four years

Identification of patients who will not achieve seizure remission within 5 years on AEDs

Objective: To identify people with epilepsy who will not achieve a 12-month seizure remission within 5 vyears of starting treatment. Methods: The Standard and New Antiepileptic Drug (SANAD) study is the largest prospective study in patients with epilepsy to date. We applied a recently developed multivariable approach to the SANAD dataset that takes into account not only baseline covariates describing a patient’s history before diagnosis but also follow-up data as predictor variables. Results: Changes in number of seizures and treatment history were the most informative timedependent predictors and were associated with history of neurologic insult, epilepsy type, age at start of treatment, sex, and having a first-degree relative with epilepsy. Our model classified 95% of patients. Of those classified, 95% of patients observed not to achieve remission at 5 years were correctly classified (95% confidence interval [CI] 89.5%–100%), with 51% identified by 3 years and 90% within 4 years of follow-up. Ninety-seven percent (95% CI 93.3%–98.8%) of patients observed to achieve a remission within 5 years were correctly classified. Of those predicted not to achieve remission, 76% (95% CI 58.5%–88.2%) truly did not achieve remission (positive predictive value). The predictive model achieved similar accuracy levels via external validation in 2 independent United Kingdom–based datasets. Conclusion: Our approach generates up-to-date predictions of the patient’s risk of not achieving seizure remission whenever new clinical information becomes available that could influence patient counseling and management decisions

Can acoustic radiation force imaging of the liver and spleen predict the presence of gastroesophageal varices?

Aim To determine whether acoustic radiation force imaging (ARFI) of the liver/spleen could be used in patients with cirrhosis to predict the presence of gastroesophageal varices (GOVs). Materials and methods Fifty-eight patients with cirrhosis who were undergoing 6-monthly ultrasound examinations for hepatoma surveillance and who were due to have oesophagogastroduodenoscopy (OGD) within 6 months of their ultrasound were recruited. During routine ultrasound, the patient's liver and spleen were also assessed using ARFI. Other clinical parameters (platelet count, spleen size, and transient elastography measurements) were also collected. Logistic regression was used to determine which variables were significantly associated with presence or absence of varices univariably and multivariably Results Fourteen patients (24%) had GOVs. Patients with GOVs had higher ARFI measurements in the liver and spleen than patients without GOVs (liver: 2.39 versus 2.13, spleen: 2.89 versus 2.82), but these results were not statistically significant (odds ratio=1.75, 95% confidence interval [CI]=0.82, 3.91 and odds ratio=1.12, 95% CI=0.33, 3.97, respectively). The platelet/splenic ratio, in comparison, was associated with the presence or absence of GOVs in multivariate analysis (odds ratio=0.32, 95% CI=0.008, 0.91). Conclusion Although patients with GOVs had overall higher ARFI liver and spleen results, this was not statistically significant. As such, ARFI cannot yet replace OGD in predicting GOVs in this patient group

A systematic review of interventions to increase physical activity and reduce sedentary behaviour following bariatric surgery.

BACKGROUND: Bariatric surgery promotes weight loss and improves co-morbid conditions, with patients who are more physically active having better outcomes. However, levels of physical activity and sedentary behaviour often remain unchanged following surgery. OBJECTIVES: To identify interventions and components thereof that are able to facilitate changes in physical activity and sedentary behaviour. ELIGIBILITY: Physical activity and/or sedentary behaviour must have been measured, pre and post intervention, in patients who have undergone bariatric surgery. STUDY APPRAISAL AND SYNTHESIS METHODS: Four databases were searched with key-words. Two researchers conducted paper screening, data extraction and risk-of-bias assessment. RESULTS: Twelve studies were included; eleven were randomised. Two were delivered presurgery and ten postsurgery; five found positive effect. Moderate to vigorous physical activity increased in three studies, two of which also found a significant increase in step count. The fourth found a significant increase in strenuous activity and the fifth a significant increase in metabolic equivalent of task/day and reduced time spent watching television. LIMITATIONS: Meta-analysis could not be conducted due to heterogeneity of outcomes and the tools used. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: This review has identified interventions and components thereof that were able to provoke positive effect. However, intervention and control conditions were not always well described particularly in terms of behaviour change techniques and the rationale for their use. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO (CRD42019121372)