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

Biochemical basis of resistance to pod borer ( Helicoverpa armigera ) in Australian wild relatives of pigeonpea

The domestication of pigeonpea has severely impacted the intrinsic host-plant resistance (HPR) to pest and diseases, particularly pod borer (Helicoverpa armigera hubner). This study with 41 Australian wild Cajanus genotypes and interspecific hybrids demonstrated a high level of resistance to H. armigera in the accessions of Cajanus acutifolius, C. latisepalus, C. lanceolatus, C. pubescens, and C. reticulatus var. reticulatus. Significant variation in herbivory development and mortality (P < 0.001) was observed in the wild accessions and their hybrids in response to feeding on leaves. A strong positive relationship (R2 = 0.69, P < 0.001) between total phenolic compounds (TPC) and the HPR was observed. Australian wild genotypes demonstrated the role of TPC and the absence of certain flavonoids such as rutin and quercetin in resistant genotypes. The detached leaf bioassay technique separated the wild and domesticated accessions into wild resistant, with herbivory weight difference (HWD) (Day 7–Day 1) ranging between −27 - 104 mg, wild susceptible, with HWD ranging between 124 - 207 mg and domesticated susceptible, with HWD ranging from 208 - 300 mg. Similarly, based on TPC, accessions were also categorised into wild high TPC, with TPC ranging between 32.3 - 42.5 GAE mg/g DW, and wild low TPC had only 17.2–24.8 GAE mg/g DW. Low TPC concentrations were found in domesticated pigeonpea, with 10.7–17.6 GAE mg/g DW. The presence of very high concentrations of the flavone isoorientin, an important antioxidant implicated in the intracellular defence mechanism of cancer therapy, was identified for the first time in wild species of pigeonpea