Challenges in conducting trials for pediatric tuberculous meningitis: lessons from the field

SETTING: TBM-KIDS is a phase I/II trial enrolling children with tuberculous meningitis (TBM) in three tertiary referral centers in India and Malawi. OBJECTIVE: To describe the challenges encountered in conducting the first randomized clinical trial of antimicrobial agents in pediatric TBM. DESIGN: The sources of the data were primarily monthly trial reports, non-enrollment case report forms, study diaries and registers maintained for recruitment, experiences shared by key team members during regular study calls and comments from site review visits. We reviewed, broadly categorized, and describe in detail the challenges encountered by study teams in trial implementation. RESULTS: Over 17 months, 3371 children with clinical presentations consistent with meningoencephalitis or undergoing lumbar puncture were assessed for eligibility; 21 (<1%) met enrollment criteria. We encountered challenges related to diagnosis, management of sick children, large catchment areas, adverse event attribution, concomitant medications, infrastructure requirements, expensive pediatric formulations with short expiry, and detection of treatment response in a highly variable disease across the age continuum. Training and adaptation of tools for neurocognitive and neurologic function assessment were necessary. Special care was undertaken to explain study participation to distraught caregivers and manage children longitudinally. CONCLUSION: Interventional trials in pediatric TBM are challenging but are critically important for improving the treatment of a disease that disables children physically, cognitively and emotionally. Sharing these challenges may help to address them more effectively as a TB research community and to advance treatments for this at-risk population

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

Background. Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). Conclusions. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. Clinical Trials Registration. NCT02958709

Numerical and Experimental Study on Jet Trajectories and Mixing Behavior of Venturi-Jet Mixer

An investigation of the jet trajectories and mixing behavior of venturi-jet mixer

The effects of arbitrary injection angle and flow conditions on venturi-jet mixer

This paper describes the effect of jet injection angle, cross flow Reynolds number and velocity ratio on entrainment and mixing of jet with incompressible cross flow in venturi-jet mixer. Five different jet injection angles 45o, 60o, 90o, 125o, 135o are tested to evaluate the entrainment of jet and mixing performances of the mixer. Tracer concentration along the downstream of the jet injection, cross flow velocity, jet velocity and pressure drop across the mixer are determined experimentally to characterize the mixing performance of the mixer. The experiments show that the performance of a venturi-jet-mixer substantially improves at high injection angle and can be augmented still by increasing velocity ratio. The jet deflects much and penetrates less in the cross flow as the cross flow Reynolds number is increased. The effect could contribute substantially to the better mixing index with moderate pressure drop. Normalized jet profile, concentration decay, jet velocity profile are computed from equations of conservation of mass, momentum and concentration written in natural co-ordinate systems. The comparison between the experimental and numerical results confirms the accuracy of the simulations. Correlations for jet trajectory and entrainment ratio of the mixer are obtained by multivariate-linear regression analysis using power law

Optimization of Liquid Desiccant Dehumidifier Performance Using Taguchi Method

An attempt has been made to improve the performance of dehumidifier using liquid desiccant in this study. Experiments have been conducted based on L 16 orthogonal array in order to experimentally investigate the influence of dehumidification process parameters like desiccant temperature, desiccant concentration, desiccant flow rate, air flow rate, and relative humidity on the effectiveness of dehumidifier. The optimum dehumidification condition has been found through Taguchi method. It has been confirmed that the optimum condition exhibited better effectiveness for the dehumidification process