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Abstractobjectives Interest in global health has increased greatly in the past two decades. Concomitantly, the number and complexity of research partnerships between high-income (HIC) and low-and middle-income countries (LMICs) has grown. We aimed to determine whether there is authorship parity (equitable representation and author order) or parasitism (no authors from study countries) in paediatric research conducted in LMICs.methods We reviewed all articles published from 2006 to 2015 in the four paediatric journals with the highest Eigenfactor scores. We limited our review to articles from LMICs and abstracted information on author affiliation and order, funding source and study design. We calculated Student's t-tests and chi-square using Fisher's exact test with Monte Carlo estimates.

IMPORTANCE Firearms caused more than 500 pediatric fatalities in 2017-a 50% increase from 2009. Laws regulating firearms are one approach to reducing pediatric firearm fatalities.OBJECTIVE To evaluate the association between state child access prevention (CAP) firearm laws and pediatric firearm fatalities. DESIGN, SETTING, AND PARTICIPANTSA state-level, cross-sectional study of CAP firearm laws throughout the United States, 1991-2016, was conducted using negative binomial regression to analyze differences in state fatality rates in children aged 0 to 14 years. Data analysis was performed from November 21, 2018, to October 18, 2019.EXPOSURES Implementation of 2 categories of state CAP firearm laws: recklessness laws, which pertain to providing a firearm to a child, and negligence laws, which pertain to accessibility of a firearm within the home. MAIN OUTCOMES AND MEASURESRates of firearm fatalities across all intents and by specific intent (homicide, suicide, and unintentional) per 100 000 children aged 0 to 14 years.RESULTS Twenty-five states passed CAP laws between 1989 and 2000. Between 1991 and 2016, 13 697 firearm fatalities occurred in children aged 0 to 14 years. Recklessness laws were not associated with changes in pediatric firearm fatality rates. Negligence laws overall were associated with significant reductions in firearm fatalities in children aged 0 to 14 years, with a 13% relative reduction in all firearm fatalities (95% CI, −18% to −7%), a 15% relative reduction in firearm homicides (95% CI, −22% to −7%), a 12% relative reduction in firearm suicides (95% CI, −20% to −2%), and a 13% relative reduction in unintentional firearm fatalities (95% CI, −24% to −1%). The most stringent negligence laws were associated with unintentional firearm fatality reductions of 59% (95% CI, −68% to −49%). A total of 3929 deaths (29% of all firearm deaths) were associated with states not having passed the most stringent form of negligence CAP laws.CONCLUSIONS AND RELEVANCE In this study, negligence laws were associated with relative reductions in firearm fatality rates in children aged 0 to 14 years. The most stringent negligence laws were associated with the largest reductions in unintentional firearm fatalities. Recklessness laws were not associated with reduced firearm fatality rates. The passage of negligence CAP laws may have the potential to reduce firearm fatalities in children.

Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. The role of arginine in COVID-19 is unknown, but could contribute to cellular damage if low. Our objective was to determine arginine bioavailability in adults and children with COVID-19 vs. healthy controls. We hypothesized that arginine bioavailability would be low in patients with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We conducted a prospective observational study of three patient cohorts; arginine bioavailability was determined in asymptomatic healthy controls, adults hospitalized with COVID-19, and hospitalized children/adolescents <21 y old with COVID-19, MIS-C, or asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified on admission screen. Mean patient plasma amino acids were compared to controls using the Student’s t test. Arginine-to-ornithine ratio, a biomarker of arginase activity, and global arginine bioavailability ratio (GABR, arginine/[ornithine+citrulline]) were assessed in all three groups. A total of 80 patients were included (28 controls, 32 adults with COVID-19, and 20 pediatric patients with COVID-19/MIS-C). Mean plasma arginine and arginine bioavailability ratios were lower among adult and pediatric patients with COVID-19/MIS-C compared to controls. There was no difference between arginine bioavailability in children with COVID-19 vs. MIS-C. Adults and children with COVID-19 and MIS-C in our cohort had low arginine bioavailability compared to healthy adult controls. This may contribute to immune dysregulation and endothelial dysfunction in COVID-19. Low arginine-to-ornithine ratio in patients with COVID-19 or MIS-C suggests an elevation of arginase activity. Further study is merited to explore the role of arginine dysregulation in COVID-19.

BackgroundRare diseases affect as many as 60 million people in the United States and Europe. However, most rare diseases lack effective therapies and are in critical need of clinical research. Our objective was to determine the frequency of noncompletion and nonpublication of trials studying rare diseases.Methods and findingsWe conducted a cross-sectional analysis of randomized clinical trials studying rare diseases as defined by the Genetic and Rare Disease Information Center database that were registered in ClinicalTrials.gov between January 1, 2010, and December 31, 2012, and completed or discontinued by December 31, 2014. Our main outcome measures were the frequency of trial noncompletion and, among completed studies, frequency of trial nonpublication at 2 and 4 years following trial completion. Reasons for discontinuation were extracted from the registry, and trial sponsors were contacted for additional information, as needed. Two independent investigators performed publication searches for each trial in PubMed, EMBASE, and GoogleScholar, allowing for a minimum of 45 months between trial completion and publication. When a publication could not be identified, trial sponsors were contacted to confirm publication status. The impact of funding source on trial noncompletion was assessed with multivariable logistic regression, and the effect on time to publication was examined with Cox proportional hazards regression. Control variables included intervention type, trial phase, masking, enrollment, and study population. We analyzed 659 rare disease trials accounting for 70,305 enrolled patients. Industry was the primary funder for 327 trials (49.6%) and academic institutions for 184 trials (27.9%). There were 79 trials (12.0%) focused on pediatric populations. A total of 199 trials (30.2%) were discontinued. Lack of patient accrual (n = 64, 32.1%) and informative termination (n = 41, 20.6%) were the most common reasons for trial noncompletion. Among completed trials, 306 (66.5%) remained unpublished at 2 years and 142 (31.5%) at 4 years. In multivariable analyses, industry-funded trials were less likely to be discontinued than trials funded by healthcare centers (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.34–4.39, P = 0.003). We found no significant association between funding source and time to publication. A total of 18,148 patients were enrolled in trials that were discontinued or unpublished 4 years after completion. A potential limitation of our study is that certain interventional trials for rare diseases may not have been registered in ClinicalTrials.gov, in particular Phase 0 and Phase I trials, which are not required to be registered.ConclusionsIn this study, over half of clinical trials initiated for rare diseases were either discontinued or not published 4 years after completion, resulting in large numbers of patients with rare diseases exposed to interventions that did not lead to informative findings. Concerted efforts are needed to ensure that participation of patients in rare disease trials a...

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

of participants who are members of racial and ethnic minority groups in clinical trials enhances inclusivity in the scientific process and generalizability of results.OBJECTIVE To assess participant race and ethnicity in pediatric clinical trials published from 2011 to 2020. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study examined articles reporting pediatric clinical trials conducted in the US published in 5 leading general pediatric and 5 leading general medical journals from January 1, 2011, to December 31, 2020. MAIN OUTCOMES AND MEASURESReporting of participant race and ethnicity and comparison of enrolled participants vs US census populations of pediatric racial and ethnic groups in published clinical trials. RESULTSThe study included 612 articles reporting pediatric clinical trials during the study period, with 565 618 total participants (median per trial, 200 participants [IQR, 90-571 participants]). Of the 612 articles, 486 (79.4%) reported participant race and 338 (55.2%) reported participant ethnicity. From 2011 to 2020, relative rates of reporting of participant race increased by 7.9% per year (95% CI, 0.2%-16.3% per year) and reporting of ethnicity increased by 11.4% per year (95% CI, 4.8%-18.4% per year). Among articles reporting race and ethnicity, the method of assignment was not reported in 261 of 511 articles (51.1%) and 207 of 359 articles (57.7%), respectively. Black/African American children were enrolled proportionally more than the US population of Black/African American children (odds ratio [OR], 1.88; 95% CI, 1.87-1.89). Hispanic/Latino children were enrolled commensurately with the US population of Hispanic/Latino children (OR, 1.02; 95% CI, 1.01-1.03). American Indian/Alaska Native (OR, 0.82; 95% CI, 0.79-0.85), Asian (OR, 0.56; 95% CI, 0.55-0.57), and Native Hawaiian/Pacific Islander (OR, 0.66; 95% CI, 0.61-0.72) children were enrolled significantly less compared with the respective US populations of these groups. White children were enrolled less than expected (OR, 0.84; 95% CI, 0.84-0.85) but represented 188 156 (46.0%) of participants in trials reporting race or ethnicity. CONCLUSIONS AND RELEVANCEThis cross-sectional study revealed that the proportion of published pediatric clinical trials that reported participant race and ethnicity increased from 2011 to 2020, but participant race and ethnicity were still underreported. Disparities existed in pediatric clinical trial enrollment of American Indian/Alaska Native, Asian, and Native Hawaiian/Pacific Islander children. The greater representation of Black/African American children compared with the US population suggests inclusive research practices that could be extended to other historically disenfranchised racial and ethnic groups.

IntroductionAuthorship parasitism (ie, no authors affiliated with the country in which the study took place) occurs frequently in research conducted in low-income and middle-income countries, despite published recommendations defining authorship criteria. The objective was to compare characteristics of articles exhibiting authorship parasitism in sub-Saharan Africa to articles with author representation from sub-Saharan African countries.MethodsA bibliometric review of articles indexed in PubMed published from January 2014 through December 2018 reporting research conducted in sub-Saharan Africa was performed. Author affiliations were assigned to countries based on regular expression algorithms. Choropleth maps and network diagrams were created to determine where authorship parasitism occurred, and multivariable logistic regression was used to determine associated factors.ResultsOf 32 061 articles, 14.8% (n=4754) demonstrated authorship parasitism, which was most common among studies from Somalia (n=175/233, 75.1%) and Sao Tome and Principe (n=20/28, 71.4%). Authors affiliated with USA and UK institutions were most commonly involved in articles exhibiting authorship parasitism. Authorship parasitism was more common in articles: published in North American journals (adjusted OR (aOR) 1.26, 95% CI 1.07 to 1.50) than in sub-Saharan African journals, reporting work from multiple sub-Saharan African countries (aOR 8.41, 95% CI 7.30 to 9.68) compared with work from upper-middle income sub-Saharan African countries, with <5 authors (aOR 14.46, 95% CI 12.81 to 16.35) than >10 authors, and was less common in articles published in French (aOR 0.60, 95% CI 0.41 to 0.85) than English.ConclusionsAuthorship parasitism was common in articles reporting research conducted in sub-Saharan Africa. There were reliable predictors of authorship parasitism. Investigators and institutions in high-income countries, as well as funding agencies and journals should promote research from sub-Saharan Africa, including its publication, in a collaborative and equitable manner.