Conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU): a UK multicentre, open, parallel-group, randomised clinical trial.

BACKGROUND: The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practiced, but has been associated with harm in paediatric patients. We aimed to evaluate whether conservative oxygenation would reduce duration of organ support or incidence of death compared to standard care. METHODS: Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in 15 UK paediatric intensive care units (PICUs). Children admitted as an emergency, who were older than 38 weeks corrected gestational age and younger than 16 years receiving invasive ventilation and supplemental oxygen were randomly allocated in a 1:1 ratio via a concealed, central, web-based randomisation system to conservative peripheral oxygen saturations ([SpO2] 88-92%) or liberal (SpO2 >94%) targets. The primary outcome was the duration of organ support at 30 days following random allocation, a rank-based endpoint with death either on or before day 30 as the worst outcome (a score equating to 31 days of organ support), with survivors assigned a score between 1 and 30 depending on the number of calendar days of organ support received. The primary effect estimate was the probabilistic index, a value greater than 0·5 indicating more than 50% probability that conservative oxygenation is superior to liberal oxygenation for a randomly selected patient. All participants in whom consent was available were included in the intention-to-treat analysis. The completed study was registered with the ISRCTN registry (ISRCTN92103439). FINDINGS: Between Sept 1, 2020, and May 15, 2022, 2040 children were randomly allocated to conservative or liberal oxygenation groups. Consent was available for 1872 (92%) of 2040 children. The conservative oxygenation group comprised 939 children (528 [57%] of 927 were female and 399 [43%] of 927 were male) and the liberal oxygenation group included 933 children (511 [56%] of 920 were female and 409 [45%] of 920 were male). Duration of organ support or death in the first 30 days was significantly lower in the conservative oxygenation group (probabilistic index 0·53, 95% CI 0·50-0·55; p=0·04 Wilcoxon rank-sum test, adjusted odds ratio 0·84 [95% CI 0·72-0·99]). Prespecified adverse events were reported in 24 (3%) of 939 patients in the conservative oxygenation group and 36 (4%) of 933 patients in the liberal oxygenation group. INTERPRETATION: Among invasively ventilated children who were admitted as an emergency to a PICU receiving supplemental oxygen, a conservative oxygenation target resulted in a small, but significant, greater probability of a better outcome in terms of duration of organ support at 30 days or death when compared with a liberal oxygenation target. Widespread adoption of a conservative oxygenation saturation target (SpO2 88-92%) could help improve outcomes and reduce costs for the sickest children admitted to PICUs. FUNDING: UK National Institute for Health and Care Research Health Technology Assessment Programme.

Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans.

Invasive fungal infections are a leading global cause of human mortality. Only three major classes of antifungal drugs are widely used, and resistance to all three classes can arise rapidly. The most widely prescribed antifungal drug, fluconazole, disseminates rapidly and reaches a wide range of concentrations throughout the body. The impact of drug concentration on the spectrum and effect of mutations acquired during adaptation is not known for any fungal pathogen, and how the specific level of a given stress influences the distribution of beneficial mutations has been poorly explored in general. We evolved 144 lineages from three genetically distinct clinical isolates of Candida albicans to four concentrations of fluconazole (0, 1, 8, and 64 µg/ml) and performed comprehensive phenotypic and genomic comparisons of ancestral and evolved populations. Adaptation to different fluconazole concentrations resulted in distinct adaptive trajectories. In general, lineages evolved to drug concentrations close to their MIC50 (the level of drug that reduces growth by 50% in the ancestor) tended to rapidly evolve an increased MIC50 and acquired distinct segmental aneuploidies and copy number variations. By contrast, lineages evolved to drug concentrations above their ancestral MIC50 tended to acquire a different suite of mutational changes and increased in drug tolerance (the ability of a subpopulation of cells to grow slowly above their MIC50). This is the first evidence that different concentrations of drug can select for different genotypic and phenotypic outcomes in vitro and may explain observed in vivo drug response variation.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Protocol for a Randomized Multiple Center Trial of Conservative Versus Liberal Oxygenation Targets in Critically Ill Children (Oxy-PICU): Oxygen in Pediatric Intensive Care.

OBJECTIVES: Oxygen administration is a fundamental part of pediatric critical care, with supplemental oxygen offered to nearly every acutely unwell child. However, optimal targets for systemic oxygenation are unknown. Oxy-PICU aims to evaluate the clinical effectiveness and cost-effectiveness of a conservative peripheral oxygen saturation (Sp o2 ) target of 88-92% compared with a liberal target of more than 94%. DESIGN: Pragmatic, open, multiple-center, parallel group randomized control trial with integrated economic evaluation. SETTING: Fifteen PICUs across England, Wales, and Scotland. PATIENTS: Infants and children age more than 38 week-corrected gestational age to 16 years who are accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. INTERVENTION: Adjustment of ventilation and inspired oxygen settings to achieve an Sp o2 target of 88-92% during invasive mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Randomization is 1:1 to a liberal Sp o2 target of more than 94% or a conservative Sp o2 target of 88-92% (inclusive), using minimization with a random component. Minimization will be performed on: age, site, primary reason for admission, and severity of abnormality of gas exchange. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred to after randomization. The primary clinical outcome is a composite of death and days of organ support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support, and discharge outcomes. This trial received Health Research Authority approval on December 23, 2019 (reference: 272768), including a favorable ethical opinion from the East of England-Cambridge South Research Ethics Committee (reference number: 19/EE/0362). Trial findings will be disseminated in national and international conferences and peer-reviewed journals.

Correlates and determinants of Early Infant Diagnosis outcomes in North-Central Nigeria.

BACKGROUND: A negative status following confirmatory Early Infant Diagnosis (EID) is the desired pediatric outcome of prevention of Mother to Child Transmission (PMTCT) programs. EID impacts epidemic control by confirming non-infected HIV-exposed infants (HEIs) and prompting timely initiation of ART in HIV-infected babies which improves treatment outcomes. OBJECTIVES: We explored factors associated with EID outcomes among HEI in North-Central Nigeria. METHOD: This is a cross-sectional study using EID data of PMTCT-enrollees matched with results of HEI's dried blood samples (DBS), processed for DNA-PCR from January 2015 through July 2017. Statistical analyses were done using SPSS version 20.0 to generate frequencies and examine associations, including binomial logistic regression with p < 0.05 being statistically significant. RESULTS: Of 14,448 HEI in this analysis, 51.8% were female and 95% (n = 12,801) were breastfed. The median age of the infants at sample collection was 8 weeks (IQR 6-20), compared to HEI tested after 20 weeks of age, those tested earlier had significantly greater odds of a negative HIV result (≤ 6 weeks: OR = 3.8; 6-8 weeks: OR = 2.1; 8-20 weeks: OR = 1.5) with evidence of a significant linear trend (p < 0.001). Similarly, HEI whose mothers received combination antiretroviral therapy (cART) before (OR = 11.8) or during the index pregnancy (OR = 8.4) had significantly higher odds as compared to those whose mothers did not receive cART. In addition, HEI not breastfed had greater odds of negative HIV result as compared to those breastfed (OR = 1.9). CONCLUSIONS: cART prior to and during pregnancy, earlier age of HEI at EID testing and alternative feeding other than breastfeeding were associated with an increased likelihood of being HIV-negative on EID. Therefore, strategies to scale-up PMTCT services are needed to mitigate the burden of HIV among children.

Blueprint for building a biorepository in a resource-limited setting that follows international best practices.

BACKGROUND: Genetic diversity is abundant on the African continent. However, genomic research has been hampered by a lack of high quality and extensively annotated biospecimens and the necessary infrastructure to support such a technology-intensive effort. OBJECTIVE: The Institute of Human Virology Nigeria (IHVN) partnered with the H3Africa Consortium and the Coriell Institute for Medical Research to build an internationally recognised biorepository for the receipt, processing, storage and distribution of biospecimens for biomedical research. Here, the authors describe the procedures, challenges and results encountered. RESULTS: Key requirements for a high-quality biorepository were identified: (1) institutional support of infrastructure and services, (2) on-site trained staff with primary commitment to the biorepository, (3) reliance on best practices from globally recognised biorepository groups, (4) early implementation of a quality management system, (5) adoption of a laboratory information management system with demonstrated versatility in functions, (6) collaboration with external experts and sharing of experience through abstracts, newsletters, published manuscripts, and attendance at meetings and workshops, (7) strict adherence to local and national ethical standards and (8) a sustainability plan that is reviewed and updated annually. CONCLUSION: Utilising published best practices of globally recognised experts in the biorepository field as a benchmark, IHVN expanded and reorganised its existing laboratory facility and staff to take on this new purpose.

Diagnostic system strengthening for drug resistant tuberculosis in Nigeria: impact and challenges.

BACKGROUND: The increasing prevalence of drug-resistant tuberculosis and the threat of extensively-drug-resistant tuberculosis in HIV hotspots have made the detection and treatment of drug-resistant tuberculosis in the sub-Saharan Africa setting a global public health priority. OBJECTIVE: We sought to examine the impact and challenges of tuberculosis diagnostic capacity development for the detection of drug-resistant tuberculosis and bio-surveillance using a modular biosafety level 3 (BSL-3) laboratory in Nigeria. METHOD: In 2010, the United States President's Emergency Plan for AIDS Relief (PEPFAR) programme, through the Institute of Human Virology at the University of Maryland in Baltimore, Maryland, United States, deployed a modular, BSL-3 laboratory to support the national tuberculosis programme in drug-resistant tuberculosis detection and bio-surveillance for effective tuberculosis prevention and control. RESULTS: From 2010 until present, sputum samples from 11 606 suspected cases in 33 states were screened for drug-resistant tuberculosis. Of those, 1500 (12.9%) had mono-resistant tuberculosis strains, and 459 (4.0%) cases had multidrug-resistant tuberculosis. Over the last four years, 133 scientists were trained in a train-the-trainer programme on advanced tuberculosis culture, drug susceptibility testing, line-probe assays and Xpert® MTB/RIF, in addition to safety operations for biosafety facilities. Power instability, running cost and seasonal dust are notable challenges to optimal performance and scale up. CONCLUSION: Movable BSL-3 containment laboratories can be deployed to improve diagnostic capacity for drug-resistant tuberculosis and bio-surveillance in settings with limited resources.

Impairment in the mesohippocampal dopamine circuit following exposure to the brominated flame retardant, HBCDD.

Many chemicals have been used to increase the safety of consumer products by reducing their flammability and risk for ignition. Recent focus on brominated flame retardants, such as polybrominated diphenyl ethers (PBDEs) has shown them to contribute to neurobehavioral deficits in children, including learning and memory. As the manufacture and use of PBDEs have been reduced, replacement chemicals, such as hexabromocyclododecane (HBCDD) have been substituted. Our current study evaluated the neurotoxicity of HBCDD, concentrating on dopaminergic innervation to the hippocampus. Using an in vivo model, we exposed male mice to HBCDD and then assessed alterations to the dopamine synapse 6 weeks later. These exposures elicited significant reductions in presynaptic dopaminergic proteins, including TH, COMT, MAO-B, DAT, VMAT2, and alpha-synuclein. In contrast, postsynaptic dopamine receptors were not impaired. These findings suggest that the mesohippocampal dopamine circuit is vulnerable to HBCDD and the dopamine terminal may be a selective target for alteration.

Improved Performance of COBAS AmpliPrep/COBAS TaqMan Version 2.0 Assay Over Amplicor Monitor Version 1.5 in the Quantification of HIV-1 RNA Viral Load in Abuja, Nigeria.

BACKGROUND: Improved viral detections by the real time PCR over the manual assays have been reported by various manufacturers. However, discrepancies and discordance between different platforms targeting the same pathogen have also been observed at different settings. METHODS: We used an analytical study design to compare the performance of the Cobas Taqman /Cobas Ampliprep version 2.0 against the standard Amplicor Monitor 1.5 using 200 routine clinical samples, in Abuja- Nigeria. RESULTS: Taqman and Amplicor detected 118/200 (59%) and 83/200 (41.5%) samples respectively. Two of 83 samples (2.4%) undetectable by Cobas Taqman, were detectable by Roche Amplicor, while 5 of 37 samples (13.5%) which were undetectable by Amplicor using Taqman. Among the 81 detectable samples by both assays 4 samples (4.9%) had a log10 difference > 0.5 log copies, while 9 samples (11.1%) showed a wider discrepancy of >1 log10. Bland and Altman's comparison shows no significant difference between the two methods (p=0.2825) and CI-0.06171 to 0.2087. CONCLUSION: We observed a remarkable improvement in the performance of COBAS AmpliPrep/COBAS TaqMan version 2.0 Assay over Amplicor Monitor version 1.5 in the quantification of HIV1 RNA viral load. Discrepancies of clinical significance, in the viral load between the two platforms were also recorded. The implications of the inability of the automated Taqman 2.0 to detect 2.4% of samples detectable by the Amplicor need to be considered by programs, clinicians and the manufacturers. Periodic evaluation of platforms to detect new circulating HIV subtypes within each locality is also recommended.

Experiences in establishing a PEPFAR-supported laboratory quality system in Nigeria.

The need to accurately diagnose HIV-infected persons and monitor their immune status and sequelae from increased access to antiretroviral therapy dictated the establishment of a quality assurance (QA) system supported by dedicated personnel, financial resources, and a close monitoring system. Assessment of laboratories and personnel in Nigeria revealed the need for improved laboratory infrastructure and training, including on-site didactic and wet workshops and the institution of a tiered QA unit of laboratory regional officers, focal persons, and site monitors who provided guidance and continuous monitoring. Quarterly assessments and generated reports guided corrective actions. A sustainable quality laboratory system was developed for the first time in Nigeria with funding from the US President's Emergency Plan for AIDS Relief. With expansion from 7 to 34 comprehensive treatment sites, a tiered laboratory organizational structure with regional and site-based Nigerian quality control officers was developed. Measured improvements included reduction in deficiencies from 13% to 2%.