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BackgroundStatus asthmaticus respiratory failure is associated with thickened mucus secretions necessitating aggressive pulmonary clearance. The role of bronchoscopy in pediatric mechanically ventilated asthmatic patients has not been published.MethodsA chart review was performed on all pediatric intensive care unit (PICU) asthmatics with respiratory failure over 13 years. Forty-four patients were identified. Patients were managed per standardized guidelines for status asthmaticus with mechanical ventilation. Ventilator management prioritized spontaneous breathing with pressure support. Extubation criteria included spontaneous tidal volumes of 5-7 cm(3) /kg on low-pressure support. Standard endotracheal tube pulmonary toilet were implemented. Twenty-nine patients underwent bronchoscopy as an adjunctive therapy. Indications for bronchoscopy included: Pathogen identification via bronchoalveolar ravage, atelectasis, mucus obstruction resulting in severe air trapping, suspected aspiration, and poor response to standard therapy. Clinical outcomes of this intervention were compared to the fifteen patient cohort who did not undergo bronchoscopy.ResultsBronchoscopies revealed thick mucus plugs, secretions, and bronchial casts. The large airways were lavaged for clearance of obstructive secretions with normal saline. All patients tolerated the procedure without any complications. Demonstrable improvement in pulmonary compliance was noted. The median time of intubation for the bronchoscopy group was 10 hr compared to 20.5 hr for the control group (P < 0.0005). The mean intensive care unit length of stay was 3.06 days for the bronchoscopy group versus 3.4 days for the non-bronchoscopy group (P < 0.05).ConclusionFlexible bronchoscopy with bronchial lavage is a safe adjunctive therapy in pediatric asthmatics with respiratory failure resulting in reduced mechanical ventilation and intensive care length of stay. Restoring lung volume in certain asthmatics during respiratory failure may be deemed beneficial. Further validated studies are necessary to recommend bronchoscopy to the present, accepted treatment regimen in pediatric asthmatic respiratory failure.

Background: The role of aminophylline in the management of patients with severe asthma remains controversial. Children with severe asthma are treated initially with continuous BETA-2 agonists, inhaled anticholinergics and intravenous steroids. When expected improvement does not occur, aminophylline is considered as an adjunctive therapy, but there is no scientifically proven benefit in this addition. It is hoped that this study will provide objective data to answer this question. Methods: A prospective, randomized, double blind, placebo controlled trial in patients [is greater than] 30 days and up to 18 years of age, with status asthmaticus and admitted to the PICU. The clinical severity of the event was assessed before and during therapeutic interventions by using the Woods-Downes-Lecks clinical asthma score. Patients were randomized to treatment and placebo groups. The patients in the treatment group receive a loading dose of aminophylline followed by a continuous infusion of this drug. Patients in the control group receive a bolus of Normal Saline followed by a continuous infusion of this solution. A clinical pharmacist adjusted the infusion of aminophylline in the treatment group patients to achieve a level between 13-18 mcg/ml. Similar adjustments were made in the Normal Saline infusions in the control group to ensure the blinding. Results: A total of 21 patients have been included in the study. Eleven of the 21 patients received aminophylline and 10 received placebo. Variables from both groups were statistically compared. 1. There was a significant difference in the number of PICU days, with the aminophylline treated group requiring less days in the PICU (log rank and Wilcox test). (P [is greater than or equal to] 0.04 [is greater than or equal to] 0.04). 2. No significant difference in initial asthma score and adverse effects during infusion of aminophylline or placebo. (P [is greater than or equal to] 0.28 and [is greater than or equal to] 0.30). 3. There was no significant difference in the time of continuous albuterol required to achieve a clinical asthma score equal or less than 4 (significant clinical improvement), using log rank and Wilcox tests. (P [is greater than or equal to] 0.32 [is greater than or equal to] 0.22). 4. No difference in complications (respiratory failure) or use of other medications such as intravenous Terbutaline or Magnesium Sulphate. Conclusions: Our study suggests that aminophylline use may shorten the length of stay in the PICU, may not decrease the interval between admission and significant clinical improvement, and may not decrease the incidence of complications. The cost of hospitalization may be decreased by using aminophylline in this patient population. The final analysis will be performed when a total of 25 patients are included in each group., Luis Torero, MD, FAAP AND J. Carlos Maggi, MD, FAAP, FCCP. Department of Pediatric Critical Care and Pulmonary Medicine, Miller Children's at Long Beach Memorial Medical Center, Long Beach, [...]

Abstract Increasing evidence suggests the microbiome plays an important role in bee ecology and health. However, the relationship between bees and their bacterial symbionts has only been explored in a handful of species. We characterized the microbiome across the life cycle of solitary, ground-nesting alkali bees (Nomia melanderi). We find that feeding status is a major determinant of microbiome composition. The microbiome of feeding larvae was similar to that of pollen provisions, but the microbiome of post-feeding larvae (pre-pupae) was similar to that of the brood cell walls and newly-emerged females. Feeding larvae and pollen provisions had the lowest beta diversity, suggesting the composition of larval diet is highly uniform. Comparisons between lab-reared, newly-emerged, and nesting adult females suggest that the hindgut bacterial community is largely shaped by the external environment. However, we also identified taxa that are likely acquired in the nest or which increase or decrease in relative abundance with age. Although Lactobacillus micheneri was highly prevalent in pollen provisions, it was only detected in one lab-reared female, suggesting it is primarily acquired from environmental sources. These results provide the foundation for future research on metagenomic function and development of probiotics for these native pollinators.

Objective: In vitro studies report that valproic acid causes an increase in HIV-1 replication. This retrospective study examines a sample of patients with HIV disease and behavioural disturbances, for which the treatment of choice is divalproex sodium (DVP), to determine whether DVP causes an increase in HIV-1 replication.Method: A chart and database review identified 15 patients with HIV disease presenting with either 1) mania or hypomania or 2) dementia with mania or with hypomania or behavioural disturbances. HIV-1 viral load was compared before and after mood stabilizer initiation.Results: Eleven patients started therapy with DVP, and 4 patients declined treatment with a mood stabilizer. Nine of the 11 patients taking DVP were also receiving antiretroviral therapy. HIV-1 viral load did not increase in 6 of the 9 patients who had measurements between 1 week and 3.5 months after DVP initiation. No follow-up was available for the other 3 patients. Of the 2 patients receiving DVP but not antiretroviral medication, 1 had an increase of 0.17 log in HIV-1 viral load at 4 months. No follow-up record was available for the second patient. The 4 patients not taking DVP were all on antiretroviral therapy; viral loads in 2 of them remained nondetectable over 3 to 4 months, and 1 had an increase of 0.32 log in HIV-1 viral load at 3 months. No follow-up record was available for the fourth patient.Conclusions: These preliminary data suggest that, in the presence of effective antiretroviral therapy, HIV-1 viral load appears not to be adversely affected by the administration of DVP. The results for the patients receiving DVP in the absence of antiretroviral medication remain indeterminate. Further prospective study is required. [ABSTRACT FROM AUTHOR]

The effect of pentobarbital therapy was studied prospectively in 31 nearly drowned children in a flaccid state of coma. Each child was assigned to one of two sequential treatment groups. Group A: 16 children were treated with hypothermia and IV pentobarbital, achieving serum levels >25 micro/mL within 48 hours of admission. Group B: 15 children were treated with hypothermia but no pentobarbital. All patients received "conventional therapy" (ie, PaCO[sub 2] 20 to 25 mm Hg, PaO[sub 2] 90 to 100 mm Hg, fluid restriction, pancuronium bromide, and furosemide or mannitol). Analysis of variance failed to detect differences for age, estimated time of submersion, arterial pH, core temperature, and mean intracranial pressure between the patients prior to treatment with pentobarbital. In Group A, six patients (37%) recovered completely and were neurologically intact, six patients (37%) had severe brain damage and four patients (26%) died. In Group B, six patients (40%) recovered completely, six patients (40%) survived with brain damage, and three patients (20%) died. There were no statistical differences between the two groups (P >.05, chi[sup 2] analysis) for the mortality rate, survival with brain damage, and complete recovery. The results suggest that: (1) pentobarbital therapy does not improve neurologic outcome for nearly drowned, flaccid-comatose children; (2) previous claims implying better outcome with hypothermia combined with pentobarbital therapy may be attributed to the effect of hypothermia alone; and (3) pentobarbital therapy may not be justified in nearly drowned, flaccid-comatose victims. [ABSTRACT FROM AUTHOR]

The article cites that clonidine (catapres) is used extensively in the management of adult hypertension. Major toxic effects of clonidine include respiratory depression, hypotension, hypothermia, bradycardia, and decreased cardiac output. The article reports two toddlers (twin sisters) who accidentally ingested massive doses of clonidine, sustained respiratory and hemodynamic failures, and required critical care support. They presented comatose, in respiratory failure, hypotensive, hypothermic, and bradycardic. A trial of Naloxone failed to reverse respiratory depression in both.

Background: Despite widespread consensus that additional training in administration is needed to prepare physicians for practice, little is known about how best to teach managerial competencies and how to integrate teaching into existing postgraduate curricula. Aim: This study aimed to elicit resident perspectives on administrative curriculum development following exposure to a pilot physician manager curriculum at the University of Toronto. Methods: The authors held five focus groups of psychiatry residents at the University of Toronto during 2008, engaging 40 trainees. Resident perspectives on barriers to teaching and learning administrative skills, preferred curriculum content and format and suggestions for integration of administrative training into the residency programme were elicited. Results: Identified barriers to learning include lack of physician manager role clarity, dearth of learning opportunities and multiple competing demands on residents' time. Residents value a formal administrative curriculum and propose additional opportunities for experiential learning such as elective rotations and mentorship opportunities. Suggested strategies for integrating administrative teaching into residency include faculty development, rotation-specific administrative objectives and end of rotation resident evaluations. Conclusion: Our findings provide valuable learner input into an emerging educational framework aiming to address barriers to teaching administrative skills during residency and facilitate longitudinal reinforcement of learning. [ABSTRACT FROM AUTHOR]

The contribution of splicing variants to molecular diagnostics of inherited diseases is reported to be less than 10%. This figure is likely an underestimation due to several factors including difficulty in predicting the effect of such variants, the need for functional assays, and the inability to detect them (depending on their locations and the sequencing technology used). The aim of this study was to assess the utility of Nanopore sequencing in characterizing and quantifying aberrant splicing events. For this purpose, we selected 19 candidate splicing variants that were identified in patients affected by inherited retinal dystrophies. Several in silico tools were deployed to predict the nature and estimate the magnitude of variant-induced aberrant splicing events. Minigene assay or whole blood-derived cDNA was used to functionally characterize the variants. PCR amplification of minigene-specific cDNA or the target gene in blood cDNA, combined with Nanopore sequencing, was used to identify the resulting transcripts. Thirteen out of nineteen variants caused aberrant splicing events, including cryptic splice site activation, exon skipping, pseudoexon inclusion, or a combination of these. Nanopore sequencing allowed for the identification of full-length transcripts and their precise quantification, which were often in accord with in silico predictions. The method detected reliably low-abundant transcripts, which would not be detected by conventional strategies, such as RT-PCR followed by Sanger sequencing.

Background: The literature on gun violence is broad and variable, describing multiple legislation types and outcomes in observational studies. Our objective was to document the extent and nature of evidence on the impact of firearm legislation on mortality from firearm violence., Methods: A scoping review was conducted under PRISMA-ScR guidance. A comprehensive peer-reviewed search strategy was executed in several electronic databases from inception to March 2024. Grey literature was searched for unpublished sources. Data were extracted on study design, country, population, type of legislation, and overall study conclusions on legislation impact on mortality from suicide, homicide, femicide, and domestic violence. Critical appraisal for a sample of articles with the same study design (ecological studies) was conducted for quality assessment., Findings: 5057 titles and abstracts and 651 full-text articles were reviewed. Following full-text review and grey literature search, 202 articles satisfied our eligibility criteria. Federal legislation was identified from all included countries, while state-specific laws were only reported in studies from the U.S. Numerous legislative approaches were identified including preventative, prohibitive, and more tailored strategies focused on identifying high risk individuals. Law types had various effects on rates of firearm homicide, suicide, and femicide. Lack of robust design, uneven implementation, and poor evaluation of legislation may contribute to these differences., Interpretation: We found that national, restrictive laws reduce population-level firearm mortality. These findings can inform policy makers, public health researchers, and governments when designing and implementing legislation to reduce injury and death from firearms., Funding: Funding is provided by the Strategy for Patient-Oriented Research (SPOR) Evidence Alliance and in part by St. Michael's Hospital, University of Toronto., Scoping Review Registration: Open Science Framework (OSF): https://osf.io/sf38n., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

The proneural transcription factor atonal basic helix-loop-helix transcription factor 7 ( ATOH7 ) is expressed in early progenitors in the developing neuroretina. In vertebrates, this is crucial for the development of retinal ganglion cells (RGCs), as mutant animals show an almost complete absence of RGCs, underdeveloped optic nerves, and aberrations in retinal vessel development. Human mutations are rare and result in autosomal recessive optic nerve hypoplasia (ONH) or severe vascular changes, diagnosed as autosomal recessive persistent hyperplasia of the primary vitreous (PHPVAR). To better understand the role of ATOH7 in neuroretinal development, we created ATOH7 knockout and eGFP-expressing ATOH7 reporter human induced pluripotent stem cells (hiPSCs), which were differentiated into early-stage retinal organoids. Target loci regulated by ATOH7 were identified by Cleavage Under Targets and Release Using Nuclease with sequencing (CUT&RUN-seq) and differential expression by RNA sequencing (RNA-seq) of wildtype and mutant organoid-derived reporter cells. Additionally, single-cell RNA sequencing (scRNA-seq) was performed on whole organoids to identify cell type-specific genes. Mutant organoids displayed substantial deficiency in axon sprouting, reduction in RGCs, and an increase in other cell types. We identified 469 differentially expressed target genes, with an overrepresentation of genes belonging to axon development/guidance and Notch signaling. Taken together, we consolidate the function of human ATOH7 in guiding progenitor competence by inducing RGC-specific genes while inhibiting other cell fates. Furthermore, we highlight candidate genes responsible for ATOH7 -associated optic nerve and retinovascular anomalies, which sheds light to potential future therapy targets for related disorders.