Three-weekly doses of azithromycin for Indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial

Background: Bronchiolitis is a major health burden in infants globally, particularly among Indigenous populations. It is unknown if 3 weeks of azithromycin improve clinical outcomes beyond the hospitalization period. In an international, double-blind randomized controlled trial, we determined if 3 weeks of azithromycin improved clinical outcomes in Indigenous infants hospitalized with bronchiolitis.Methods: Infants aged ≤24 months were enrolled from three centers and randomized to receive three once-weekly doses of either azithromycin (30 mg/kg) or placebo. Nasopharyngeal swabs were collected at baseline and 48 h later. Primary endpoints were hospital length of stay (LOS) and duration of oxygen supplementation monitored every 12 h until judged ready for discharge. Secondary outcomes were: day-21 symptom/signs, respiratory rehospitalizations within 6 months post-discharge and impact upon nasopharyngeal bacteria and virus shedding at 48 h.Results: Two hundred nineteen infants were randomized (n = 106 azithromycin, n = 113 placebo). No significant between-group differences were found for LOS (median 54 h for each group, difference = 0 h, 95% CI: −6, 8; p = 0.8), time receiving oxygen (azithromycin = 40 h, placebo = 35 h, group difference = 5 h, 95% CI: −8, 11; p = 0.7), day-21 symptom/signs, or rehospitalization within 6 months (azithromycin n = 31, placebo n = 25 infants, p = 0.2). Azithromycin reduced nasopharyngeal bacterial carriage (between-group difference 0.4 bacteria/child, 95% CI: 0.2, 0.6; p < 0.001), but had no significant effect upon virus detection rates.Conclusion: Despite reducing nasopharyngeal bacterial carriage, three large once-weekly doses of azithromycin did not confer any benefit over placebo during the bronchiolitis illness or 6 months post hospitalization. Azithromycin should not be used routinely to treat infants hospitalized with bronchiolitis.Clinical trial registration: The trial was registered with the Australian and New Zealand Clinical Trials Register: Clinical trials number: ACTRN1261000036099

NANOG is required to establish the competence for germ-layer differentiation in the basal tetrapod axolotl

Pluripotency defines the unlimited potential of individual cells of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programming of pluripotency evolved has been obscured in part by a lack of data from lower vertebrates; in model systems such as frogs and zebrafish, the function of the pluripotency genes NANOG and POU5F1 have diverged. Here, we investigated how the axolotl ortholog of NANOG programs pluripotency during development. Axolotl NANOG is absolutely required for gastrulation and germ-layer commitment. We show that in axolotl primitive ectoderm (animal caps; ACs) NANOG and NODAL activity, as well as the epigenetic modifying enzyme DPY30, are required for the mass deposition of H3K4me3 in pluripotent chromatin. We also demonstrate that all 3 protein activities are required for ACs to establish the competency to differentiate toward mesoderm. Our results suggest the ancient function of NANOG may be establishing the competence for lineage differentiation in early cells. These observations provide insights into embryonic development in the tetrapod ancestor from which terrestrial vertebrates evolved. [Abstract copyright: Copyright: © 2023 Simpson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms

Background: Hyperekplexia mutations have provided much information about glycine receptor structure and function. Results: Weidentified and characterized nine new mutations. Dominant mutations resulted in spontaneous activation, whereas recessive mutations precluded surface expression. Conclusion: These data provide insight into glycine receptor activation mechanisms and surface expression determinants. Significance: The results enhance our understanding of hyperekplexia pathology and glycine receptor structure-function. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Population Pharmacokinetic and Pharmacodynamic Modeling of High-Dose Intermittent Ticarcillin-Clavulanate Administration in Pediatric Cystic Fibrosis Patients

Background The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)–approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen. Objectives The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF). Methods This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses. Results A total of 127 patients (age, 0–19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/mL. Conclusions The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs \u3c16 μg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs \u3e32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen

Population Pharmacokinetic and Pharmacodynamic Modeling of High-Dose Intermittent Ticarcillin-Clavulanate Administration in Pediatric Cystic Fibrosis Patients

Background The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)–approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen. Objectives The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF). Methods This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses. Results A total of 127 patients (age, 0–19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/mL. Conclusions The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs \u3c16 μg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs \u3e32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen