Target regimen profiles for tuberculosis treatment.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles.

Candidate anti-tuberculosis medicines and regimens under clinical evaluation.

Background: Tuberculosis (TB) is the leading cause of mortality by an infectious disease worldwide. Despite national and international efforts, the world is not on track to end TB by 2030. Antibiotic treatment of TB is longer than for most infectious diseases and is complicated by frequent adverse events.

Kilo-Scale GMP Synthesis of Renewable Semisynthetic Vaccine-Grade Squalene.

Emulsions of the triterpene squalene ((6,10,14,18)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene, CAS 111-02-4) have been used as adjuvants in influenza vaccines since the 1990s. Traditionally sourced from shark liver oil, the overfishing of sharks and concomitant reduction in the oceanic shark population raises sustainability issues for vaccine adjuvant grade squalene. We report a semisynthetic route to squalene meeting current pharmacopeial specifications for use in vaccines that leverages the ready availability of -β-farnesene ((6)-7,11-dimethyl-3-methylene-1,6,10-dodecatriene, CAS 18794-84-8), manufactured from sustainable sugarcane via a yeast fermentation process.

Moving the needle: Employing deep reinforcement learning to push the boundaries of coarse-grained vaccine models.

Highly mutable infectious disease pathogens (hm-IDPs) such as HIV and influenza evolve faster than the human immune system can contain them, allowing them to circumvent traditional vaccination approaches and causing over one million deaths annually. Agent-based models can be used to simulate the complex interactions that occur between immune cells and hm-IDP-like proteins (antigens) during affinity maturation-the process by which antibodies evolve. Compared to existing experimental approaches, agent-based models offer a safe, low-cost, and rapid route to study the immune response to vaccines spanning a wide range of design variables.

Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial.

Background: Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment.

Methods: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia, Lithuania, Moldova, Peru, the Philippines, and South Africa).

Longitudinal study of narcolepsy symptoms in first, second, and third-degree relatives of simplex and multiplex narcolepsy families.

Objective: To assess the evolution of narcolepsy symptoms in first-, second, and third-degree relatives and to compare multiplex and simplex families.

Methods: A total of 4045 family members and 362 narcoleptic individuals were entered in the study; with 3255 family members interviewed twice, five to seven years apart. A control group (n = 178) composed of spouses or housemates was also interviewed twice.

A Randomized Crossover Trial of a Pressure Relief Technology (SensAwake™) in Continuous Positive Airway Pressure to Treat Obstructive Sleep Apnea.

Objectives/background: Improving adherence to CPAP devices is crucial to reduce the long-term morbidity associated with OSA. SensAwake is a unique pressure relief technology that aims to promptly reduce the pressure upon sensing irregular respiration indicative of wakefulness. The purpose of this study was to compare adherence and sleep-quality outcomes in patients treated by CPAP with and without SensAwake technology.

Exposure to the Dietary Supplement N-Acetyl-L-Cysteine during Pregnancy Reduces Cyclophosphamide Teratogenesis in ICR Mice.

Cyclophosphamide (CP) is a complex multifaceted developmental toxicant, with mechanisms of teratogenesis thought to include production of excessive reactive oxygen species (ROS). N-acetyl-L-cysteine (NAC) is a powerful antioxidant that may decrease the toxicity of certain anticancer drugs, such as doxorubicin and CP. The current study explored the potential of NAC to attenuate CP-induced damage to the conceptus.

Rigorous Clinical Trial Design in Public Health Emergencies Is Essential.

Randomized clinical trials are the most reliable approaches to evaluating the effects of new treatments and vaccines. During the 2014-2015 West African Ebola epidemic, many argued that such trials were neither ethical nor feasible in an environment of limited health infrastructure and severe disease with a high fatality rate. Consensus among the numerous organizations providing help to the affected areas was never achieved, resulting in fragmented collaboration, delayed study initiation, and ultimately failure to provide definitive evidence on the efficacy of treatments and vaccines.

Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects.

Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects.

Building clinical trial capacity to develop a new treatment for multidrug-resistant tuberculosis.

Problem: New drugs for infectious diseases often need to be evaluated in low-resource settings. While people working in such settings often provide high-quality care and perform operational research activities, they generally have less experience in conducting clinical trials designed for drug approval by stringent regulatory authorities.

Approach: We carried out a capacity-building programme during a multi-centre randomized controlled trial of delamanid, a new drug for the treatment of multidrug-resistant tuberculosis.

Evaluation of multisystemic therapy pilot services in Services for Teens Engaging in Problem Sexual Behaviour (STEPS-B): study protocol for a randomized controlled trial.

Background: Clinically effective and cost-effective methods for managing problematic sexual behaviour in adolescents are urgently needed. Adolescents who show problematic sexual behaviour have a range of negative psychosocial outcomes, and they and their parents can experience stigma, hostility and rejection from their community. Multisystemic therapy (MST) shows some evidence for helping to reduce adolescent sexual reoffending and is one of the few promising interventions available to young people who show problematic sexual behaviour.

Long-term mortality assessment of multidrug-resistant tuberculosis patients treated with delamanid.

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Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis.

Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are associated with worse treatment outcomes for patients, including higher mortality, than for drug-sensitive tuberculosis. Delamanid (OPC-67683) is a novel anti-TB medication with demonstrated activity against multidrug-resistant disease. Patients who participated in the previously reported randomised, placebo-controlled trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes.

Delamanid for multidrug-resistant pulmonary tuberculosis.

Background: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis.

Methods: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M.

Moving toward tuberculosis elimination: implementation of statewide targeted tuberculin testing in Tennessee.

Rationale: From 1993 to 2010, annual U.S. tuberculosis (TB) rates declined by 58%.

6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial.

Background: In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy.

Methods: In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana.

Global Impact of Multidrug-Resistant Pulmonary Tuberculosis Among HIV-Infected and Other Immunocompromised Hosts: Epidemiology, Diagnosis, and Strategies for Management.

Multidrug-resistant (MDR) tuberculosis (TB), or TB caused by strains of Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, represents a major threat to global TB control. Comprising more than 5% of all TB cases annually worldwide, these cases require treatment duration of 2 years on average with expensive and toxic second-line anti-TB drugs. Cure rates are far lower and mortality far higher than for drug-susceptible TB, particularly if patients are coinfected with HIV.

Outcome Findings from a Parent Training Programme for Young People with Conduct Problems.

Background:   Group-based parent training programmes are a common intervention for tackling conduct problems in young people. The objective of this study was to evaluate the impact of a parent training programme on young people presenting with conduct problems.

Method:   123 parents of young people aged 10 to 17 with conduct problems participated in the study.