Vibrio effector protein VopQ inhibits fusion of V-ATPase-containing membranes.

Vesicle fusion governs many important biological processes, and imbalances in the regulation of membrane fusion can lead to a variety of diseases such as diabetes and neurological disorders. Here we show that the Vibrio parahaemolyticus effector protein VopQ is a potent inhibitor of membrane fusion based on an in vitro yeast vacuole fusion model. Previously, we demonstrated that VopQ binds to the V(o) domain of the conserved V-type H(+)-ATPase (V-ATPase) found on acidic compartments such as the yeast vacuole. VopQ forms a nonspecific, voltage-gated membrane channel of 18 Å resulting in neutralization of these compartments. We now present data showing that VopQ inhibits yeast vacuole fusion. Furthermore, we identified a unique mutation in VopQ that delineates its two functions, deacidification and inhibition of membrane fusion. The use of VopQ as a membrane fusion inhibitor in this manner now provides convincing evidence that vacuole fusion occurs independently of luminal acidification in vitro.

Managing cystic fibrosis in children aged 6-11yrs: a critical review of elexacaftor/tezacaftor/ivacaftor combination therapy.

INTRODUCTION: Cystic fibrosis is a life-limiting, autosomal recessive genetic disorder resulting in multi-organ disease due to CF transmembrane conductance regulator (CFTR) protein dysfunction. CF treatment previously focused on mitigation of disease signs and symptoms. The recent introduction of highly effective CFTR modulators, for which ~90% of people with CF are CFTR variant-eligible, has resulted in substantial health improvements. AREAS COVERED: In this review, we will describe the clinical trials leading to approval of the highly effective CFTR modulator, elexacaftor-tezacaftor-ivacaftor (ETI), with a focus on the safety and efficacy of this treatment in children aged 6-11 years. EXPERT OPINION: The use of ETI in variant-eligible children aged 6-11 is associated with marked clinical improvements with a favorable safety profile. We anticipate that introduction of ETI in early childhood may result in the prevention of pulmonary, gastrointestinal, and endocrine complications from CF, consequently leading to previously unimaginable gains in the quality and quantity of life. However, there is an urgent need to develop effective treatments for the remaining 10% of people with CF who are not eligible or unable to tolerate ETI treatment, and to increase access of ETI to more pwCF across the world.

Diversity, Equity, and Inclusion in the Pediatric Pulmonary Workforce: An Official American Thoracic Society Workshop Report.

Despite growing recognition of the need for increased diversity among students, trainees, and faculty in health care, the medical workforce still lacks adequate representation from groups historically underrepresented in medicine (URiM). The subspecialty field of pediatric pulmonology is no exception. Although there have been efforts to address issues of diversity, equity, and inclusion (DEI) in our own field, gaps persist. To address these gaps, the members of the Diversity, Equity, and Inclusion Advisory Group (DEI-AG) of the American Thoracic Society Pediatrics Assembly created and distributed a Needs Assessment Survey in the United States and Canada to better understand the racial and ethnic demographics of the pediatric pulmonary workforce and to learn more about successes, gaps, and opportunities to enhance how we recruit, train, and retain a diverse workforce. The DEI-AG leadership cochairs convened a workshop to review the findings of the DEI Needs Assessment Survey and to develop strategies to improve the recruitment and retention of URiM fellows and faculty. This Official ATS Workshop Report aims to identify barriers and opportunities for recruitment, training, and career development within the field of pediatric pulmonology. Additionally, we offer useful strategies and resources to improve the recruitment of URiM residents, the mentorship of trainees and junior faculty, and the career development of URiM faculty in academic centers. This Workshop Report is an important first deliverable by the DEI-AG. We hope that this work, originating from within the Pediatrics Assembly, will serve as a model for other Assemblies, disciplines across the ATS, and other fields in Pediatrics.

School Asthma Care During COVID-19: What We Have Learned and What We Are Learning.

The focus of this article is to review school asthma care during coronavirus disease 2019 (COVID-19). Asthma is listed as a risk factor in some guidelines, although children with asthma appear to not be at increased risk of severe respiratory outcomes compared with children without asthma during the pandemic. Differentiating COVID-19 from allergic disease is very difficult in the school-aged children. For school management, there is firm evidence that masks do not exacerbate underlying lung conditions including asthma, and evidence to date supports that children with asthma can learn in-person at school because they do not appear to be at increased risk of COVID-19 morbidity or mortality. For children and adolescents, the COVID-19 vaccine has been demonstrated to be safe and well tolerated. School asthma management includes remaining on prescribed asthma medications. Asthma management, as with management of all pediatric conditions, must also factor in the impact of adverse social determinants and health disparities. Broadly, the pandemic has also served as a call to resource stewardship and innovation and allowed practitioners to consider how this may impact asthma care moving forward.

The Effect of COVID-19 on United States Pediatric Emergency Departments and Its Impact on Trainees.

INTRODUCTION: The purpose of this study was to quantify the effects of the coronavirus disease 2019 (COVID-19) pandemic on pediatric emergency departments (PED) across the United States (US), specifically its impact on trainee clinical education as well as patient volume, admission rates, and staffing models. METHODS: We conducted a cross-sectional study of US PEDs, targeting PED clinical leaders via a web-based questionnaire. The survey was sent via three national pediatric emergency medicine distribution lists, with several follow-up reminders. RESULTS: There were 46 questionnaires included, completed by PED directors from 25 states. Forty-two sites provided PED volume and admission data for the early pandemic (March-July 2020) and a pre-pandemic comparison period (March-July 2019). Mean PED volume decreased >32% for each studied month, with a maximum mean reduction of 63.6% (April 2020). Mean percentage of pediatric admissions over baseline also peaked in April 2020 at 38.5% and remained 16.4% above baseline by July 2020. During the study period, 33 (71.1%) sites had decreased clinician staffing at some point. Only three sites (6.7%) reported decreased faculty protected time. All PEDs reported staffing changes, including decreased mid-level use, increased on-call staff, movement of staff between the PED and other units, and added tele-visit shifts. Twenty-six sites (56.5%) raised their patient age cutoff; median was 25 years (interquartile ratio 25-28). Of 44 sites hosting medical trainees, 37 (84.1%) reported a decrease in number of trainees or elimination altogether. Thirty (68.2%) sites had restrictions on patient care provision by trainees: 28 (63.6%) affected medical students, 12 (27.3%) affected residents, and two (4.5%) impacted fellows. Fifteen sites (34.1%) had restrictions on procedures performed by medical students (29.5%), residents (20.5%), or fellows (4.5%). CONCLUSION: This study highlights the marked impact of the COVID-19 pandemic on US PEDs, noting decreased patient volumes, increased admission rates, and alterations in staffing models. During the early pandemic, educational restrictions for trainees in the PED setting disproportionately affected medical students over residents, with fellows' experience largely preserved. Our findings quantify the magnitude of these impacts on trainee pediatric clinical exposure during this period.