Disruption of gene HI0894 or HI0895 in Haemophilus influenzaeRd, homologs of Escherichia coli acrAB multidrug efflux genes, caused hypersusceptibility to erythromycin, rifampin, novobiocin, and dyes such as ethidium bromide and crystal violet and increased accumulation of radioactive erythromycin, showing that these genes are expressed and contribute to the baseline level resistance of this organism through active drug efflux. The gene disruption did not produce detectable changes in susceptibility to several other antibiotics, possibly because rapid influx of small antibiotic molecules through the large H. influenzae porin channels counterbalances their efflux.Haemophilus influenzae is a well-known pathogen that colonizes the upper respiratory tract and invades the respiratory mucous membranes. H. influenzae strains frequently exhibit multiple antibiotic resistance, usually attributed to the presence of large R plasmids containing several resistance genes, each directed toward a specific antibiotic (23). However, a more general mechanism for baseline and increased levels of resistance, such as that conferred by the synergistic interaction of the outer membrane barrier and the multidrug efflux pumps (19), should also be considered.H. influenzae has only one porin, Omp2, which produces large, highly permeable channels. The large size of the channel is evident from the observations that it allowed the penetration of a 1,845-Da oligosaccharide (25) (in contrast to Escherichia coli porins, which were impermeable to 666-Da stachyose [17]) and that the intact cells showed outer membrane permeability for ␤-lactams that was much higher than that observed in E. coli (3,22). Planar lipid membrane experiments gave a singlechannel conductance of 1.1 nS in 1 M KCl (24), and the apparently low level of this conductance, in comparison with the 2.0-nS conductance obtained in the same study with E. coli OmpF porin, was a puzzle. However, it has since become clear that the 1.2-to 2.0-nS "single-channel" conductance of E. coli porin is caused by the insertion of three channels of porin trimer (18). (Furthermore, a more recent study showed that the single-channel conductance steps of H. influenzae porin had a population centered at 2.3 nS [2], although this could have resulted from the insertion of oligomers.) Thus, all assays, including the planar lipid bilayer assay, show that the H. influenzae Omp2 porin produces a much wider channel than those of E. coli porins.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

Introduction:The results of studies of tocilizumab (TCZ) in COVID-19 are contradictory. Our study aims to update medical evidence from controlled observational studies and randomized clinical trials (RCTs) on the use of TCZ in hospitalized patients with COVID-19. Methods:We searched the following databases from January 1, 2020 to April 13, 2021 (date of the last search): MEDLINE database through the PubMed search engine and Scopus, using the terms ("COVID-19" [Supplementary Concept]) AND "tocilizumab" [Supplementary Concept]).Results: Sixty four studies were included in the present study: 54 were controlled observational studies (50 retrospective and 4 prospective) and 10 were RCTs. The overall results provided data from 20,616 hospitalized patients with COVID-19: 7668 patients received TCZ in addition to standard of care (SOC) (including 1915 patients admitted to intensive care units (ICU) with reported mortality) and 12,948 patients only receiving SOC (including 4410 patients admitted to the ICU with reported mortality). After applying the random-effects model, the hospital-wide (including ICU) pooled mortality odds ratio (OR) of patients with COVID-19 treated with TCZ was 0.73 (95% confidence interval (CI) = 0.56-0.93). The pooled hospital-wide mortality OR was 1.25 (95% CI = 0.74-2.18) in patients admitted at conventional wards versus 0.66 (95% CI = 0.59-0.76) in patients admitted to the ICU. The pooled OR of hospitalwide mortality (including ICU) of COVID-19 patients treated with TCZ plus corticosteroids (CS) was 0.67 (95% CI = 0.54-0.84). The pooled in-hospital mortality OR was 0.71 (95% CI = 0.35-1.42) when TCZ was early administered (≤10 days from symptom onset) versus 0.83 (95% CI 0.48-1.45) for late administration (>10 days from symptom onset). The meta-analysis did not find significantly higher risk for secondary infections in COVID-19 patients treated with TCZ.Conclusions: TCZ prevented mortality in patients hospitalized for COVID-19. This benefit was seen to a greater extent in patients receiving concomitant CS and when TCZ administration occurred within the first 10 days after symptom onset.