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Background Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization–recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. Methods Children weighing 4.0–7.9, 8.0–11.9, 12.0–15.9, or 16.0–24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0–36.9 kg received doses recommended for adults <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. Results In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4–6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1–45.1), 16.7 (9.2–25.9), 317 (263–399), and 9.5 (7.5–11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0–7.9-, 8–11.9-, and ≥25-kg weight bands, isoniazid in the 4.0–7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. Conclusions Recommended weight band–based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization–recommended doses requires further evaluation. [ABSTRACT FROM AUTHOR]

Background: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level., Methods: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC 0-24 ) and peak plasma concentration ( C max ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC 0-24 and C max were assessed with linear mixed-effects models., Results: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC 0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L -1 ), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L -1 ), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L -1 ) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L -1 ). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC 0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC 0-24 for isoniazid and pyrazinamide. N -acetyltransferase 2 rapid acetylators had lower isoniazid AUC 0-24 and slow acetylators had higher isoniazid AUC 0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC 0-24 ., Conclusions: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring., Competing Interests: Conflict of interest: H.S. Schaaf reports grants from the NIH/IMPAACT; and honoraria from Ann Lake publications (sponsored by Johnson & Johnson) for an educational publication on the management of MDR-TB in children. A. Bekker reports grants from IMPAACT, UNITAID; lecture honoraria from Sandoz; support for attending PENTA PIM meeting; and received generic LPV/r, 3TC and ABC for the PETITE study. D.J. Bell reports support for attending a meeting from ViiV pharmaceuticals; and attendance fees for an advisory board meeting from ViiV pharmaceuticals. L. Choo reports grants from the UKRI MRC DFID Wellcome NIHR Joint Global Health Trials, TB Alliance Support for trial drug purchase and UKRI COVID-19 Grant Extension Allocation Award. P. Denti reports a grant for WHO expert review for TB drugs in children. S.M. Graham reports participation on a data safety monitoring board for the TB CHAMP trial; and leadership roles as a co-chair for the Guidelines Development Committee of the WHO updated recommendations and consolidated guidelines on child and adolescent TB, and as a core member for the WHO Child and Adolescent TB Working Group. S.K. Heysell reports grants from the NIH, DANIDA and EDTCP; royalties or licences from UpToDate; and honoraria for lectures from Henry Stewart Talks. A. Kwara reports a grant from the NIH/NICHD. V. Mave reports grants from the NIH and CDC. C.A. Peloquin reports a grant from the NIH. V. Roy reports a grant from the Delhi State TB Association; and leadership roles as a member of the Delhi State TB Association and the MAMC TB Committee. E.M. Svensson reports grants from the NWO personal Veni, IMI UNITE4TB consortium, TB Alliance, UNITAID BenefitKids consortium, WHO expert review, NIH support for IMPAACT studies, Blueprint, Probex, ACTG study Clo-FAST, Janssen Pharmaceuticals, EDCTP support PanTB-HM and Legochem; and leadership or fiduciary roles in the ISOP DI&E committee and BenNeLux PMX organising committee. U. Thatte reports participation on a data safety monitoring board for an ICMR TB trial. T.A. Thomas reports grants from the NIH and the University of Virginia. D.J. Touw reports a grant from Chiesi; consulting fees from Pure IMS and Sanguin; and participation on a data safety monitoring board for the FORMAT trial. A. Turkova reports grants from the UKRI MRC DFID Wellcome NIHR Joint Global Health Trials and MRC Grants for core funding of the Medical Research Council Clinical Trials Unit at the UCL; and TB Alliance Support for SHINE trial drug purchase. All of this work was declared by the authors to be outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Background: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen., Methods: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment., Results: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups)., Conclusions: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction and Aims: Naloxone is an opioid antagonist used for emergency resuscitation following opioid overdose. Prisoners with a history of heroin use by injection have a high risk of drug-related death in the first weeks after prison-release. The N-ALIVE trial was planned as a large prison-based randomised controlled trial (RCT) to test the effectiveness of naloxone-on-release in the prevention of fatal opiate overdoses soon after release. The N-ALIVE pilot trial was conducted to test the main trial's assumptions on recruitment of prisons and prisoners, and the logistics for ensuring that participants received their N-ALIVE pack on release., Design and Methods: Adult prisoners who had ever injected heroin, were incarcerated for ≥7 days and were expected to be released within 3 months were eligible. Participants were randomised to receive, on liberation, a pack containing a single 'rescue' injection of naloxone or a control pack with no naloxone syringe. The trial was double-blind prior to prison-release., Results: We randomised 1685 prisoners (842 naloxone; 843 control) across 16 prisons in England. We stopped randomisation on 8 December 2014 because only one-third of administrations of naloxone-on-release were to the randomised ex-prisoner; two-thirds were to others whom we were not tracing., Discussion and Conclusions: Prevention RCTs are seldom conducted within prisons; we demonstrated the feasibility of conducting a multi-prison RCT to prevent fatality from opioid overdose in the outside community. We terminated the N-ALIVE trial due to the infeasibility of individualised randomisation to naloxone-on-release. Large RCTs are feasible within prisons., (© 2017 The Authors Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Objective: To investigate the prevalence, predictors, and management of anaemia in pregnancy., Study Design: A multi centre study across 11 maternity units in the UK. Data were collected over a two week study period in 2008 on maternal history, haemoglobin (Hb) and ferritin concentrations, iron therapy during pregnancy and in the postpartum period. Logistic regression models were used to explore factors associated with anaemia during pregnancy. Main outcomes included anaemia, defined as Hb<11 g/dl at booking, Hb<10.5 g/dl in subsequent antenatal visits, and Hb<10 g/dl postnatally., Results: Completed data were received on 2103 of 2155 women (97% completion rate). Of these, 24.4% (502) (95% CI 22.5-26.2%) were anaemic at some stage during the antenatal period. Predictors for having anaemia by 32 weeks gestation included young maternal age (odds ratio 1.96, 95% CI 1.38-2.79), non-white ethnic origin (odds ratios varied 1.37-2.89 depending on ethnic origin) and increasing parity (odds ratio 1.24, 95% CI 1.08-1.41). Of women who had postnatal Hb levels checked, 30% (309/1031) were anaemic and, depending on centre, 16% to 86% of these received iron therapy., Conclusion: Anaemia was reported in nearly one in four women in the antenatal period, and nearly one in three of the women who had a postpartum Hb checked. Despite national guidelines, there was considerable variation in administration of iron including low utilisation of parenteral iron therapy. Future research needs to focus on the consequences of iron deficiency anaemia for maternal and infant health outcomes and effectiveness of implementation strategies to reduce anaemia., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: A cross-sectional, observational study of outcomes for neonates with severe neonatal thrombocytopenia (SNT; platelet count of <60 x 10(9) platelets per L) was performed to examine hemorrhage and use of platelet transfusions., Methods: Neonates who were admitted to 7 NICUs and developed SNT were enrolled for daily data collection., Results: Among 3652 neonatal admissions, 194 neonates (5%) developed SNT. The median gestational age of 169 enrolled neonates was 27 weeks (interquartile range [IQR]: 24-32 weeks), and the median birth weight was 822 g (IQR: 670-1300 g). Platelet count nadirs were <20 x 10(9), 20 to 39 x 10(9), and 40 to 59 x 10(9) platelets per L for 58 (34%), 64 (39%), and 47 (28%) of all enrolled infants, respectively. During the study, 31 infants (18%) had no recorded hemorrhage, 123 (73%) developed minor hemorrhage, and 15 (9%) developed major hemorrhage. Thirteen (87%) of 15 episodes of major hemorrhage occurred in neonates with gestational ages of <28 weeks. Platelet transfusions (n = 415) were administered to 116 infants (69%); for 338 (81%) transfusions, the main recorded reason was low platelet count. Transfusions increased the platelet count from a median of 27 x 10(9) platelets per L (IQR: 19-36 x 10(9) platelets per L) to 79 x 10(9) platelets per L (IQR: 47.5-127 x 10(9) platelets per L)., Conclusions: Although one third of neonates enrolled in this study developed thrombocytopenia of <20 x 10(9) platelets per L, 91% did not develop major hemorrhage. Most platelet transfusions were given to neonates with thrombocytopenia with no bleeding or minor bleeding only.