Background Since the start of the COVID-19 outbreak, a large number of COVID-19-related papers have been published. However, concerns about the risk of expedited science have been raised. We aimed at reviewing and categorizing COVID-19-related medical research and to critically appraise peer-reviewed original articles. Methods The data sources were Pubmed, Cochrane COVID-19 register study, arXiv, medRxiv and bioRxiv, from 01/11/2019 to 01/05/2020. Peer-reviewed and preprints publications related to COVID-19 were included, written in English or Chinese. No limitations were placed on study design. Reviewers screened and categorized studies according to i) publication type, ii) country of publication, and iii) topics covered. Original articles were critically appraised using validated quality assessment tools. Results Among the 11,452 publications identified, 10,516 met the inclusion criteria, among which 7468 (71.0%) were peer-reviewed articles. Among these, 4190 publications (56.1%) did not include any data or analytics (comprising expert opinion pieces). Overall, the most represented topics were infectious disease (n = 2326, 22.1%), epidemiology (n = 1802, 17.1%), and global health (n = 1602, 15.2%). The top five publishing countries were China (25.8%), United States (22.3%), United Kingdom (8.8%), Italy (8.1%) and India (3.4%). The dynamic of publication showed that the exponential growth of COVID-19 peer-reviewed articles was mainly driven by publications without original data (mean 261.5 articles ± 51.1 per week) as compared with original articles (mean of 69.3 ± 22.3 articles per week). Original articles including patient data accounted for 713 (9.5%) of peer-reviewed studies. A total of 576 original articles (80.8%) showed intermediate to high risk of bias. Last, except for simulation studies that mainly used large-scale open data, the median number of patients enrolled was of 102 (IQR = 37–337). Conclusions Since the beginning of the COVID-19 pandemic, the majority of research is composed by publications without original data. Peer-reviewed original articles with data showed a high risk of bias and included a limited number of patients. Together, these findings underscore the urgent need to strike a balance between the velocity and quality of research, and to cautiously consider medical information and clinical applicability in a pressing, pandemic context. Systematic review registration https://osf.io/5zjyx/

Background The COVID-19 pandemic has severely affected health systems and medical research worldwide but its impact on the global publication dynamics and non-COVID-19 research has not been measured. We hypothesized that the COVID-19 pandemic may have impacted the scientific production of non-COVID-19 research. Methods We conducted a comprehensive meta-research on studies (original articles, research letters and case reports) published between 01/01/2019 and 01/01/2021 in 10 high-impact medical and infectious disease journals (New England Journal of Medicine, Lancet, Journal of the American Medical Association, Nature Medicine, British Medical Journal, Annals of Internal Medicine, Lancet Global Health, Lancet Public Health, Lancet Infectious Disease and Clinical Infectious Disease). For each publication, we recorded publication date, publication type, number of authors, whether the publication was related to COVID-19, whether the publication was based on a case series, and the number of patients included in the study if the publication was based on a case report or a case series. We estimated the publication dynamics with a locally estimated scatterplot smoothing method. A Natural Language Processing algorithm was designed to calculate the number of authors for each publication. We simulated the number of non-COVID-19 studies that could have been published during the pandemic by extrapolating the publication dynamics of 2019 to 2020, and comparing the expected number to the observed number of studies. Results Among the 22,525 studies assessed, 6319 met the inclusion criteria, of which 1022 (16.2%) were related to COVID-19 research. A dramatic increase in the number of publications in general journals was observed from February to April 2020 from a weekly median number of publications of 4.0 (IQR: 2.8–5.5) to 19.5 (IQR: 15.8–24.8) (p < 0.001), followed afterwards by a pattern of stability with a weekly median number of publications of 10.0 (IQR: 6.0–14.0) until December 2020 (p = 0.045 in comparison with April). Two prototypical editorial strategies were found: 1) journals that maintained the volume of non-COVID-19 publications while integrating COVID-19 research and thus increased their overall scientific production, and 2) journals that decreased the volume of non-COVID-19 publications while integrating COVID-19 publications. We estimated using simulation models that the COVID pandemic was associated with a 18% decrease in the production of non-COVID-19 research. We also found a significant change of the publication type in COVID-19 research as compared with non-COVID-19 research illustrated by a decrease in the number of original articles, (47.9% in COVID-19 publications vs 71.3% in non-COVID-19 publications, p < 0.001). Last, COVID-19 publications showed a higher number of authors, especially for case reports with a median of 9.0 authors (IQR: 6.0–13.0) in COVID-19 publications, compared to a median of 4.0 authors (IQR: 3.0–6.0) in non-COVID-19 publications (p < 0.001). Conclusion In this meta-research gathering publications from high-impact medical journals, we have shown that the dramatic rise in COVID-19 publications was accompanied by a substantial decrease of non-COVID-19 research. Meta-research registration https://osf.io/9vtzp/.

Context: Acyclovir is an antiviral currently used for prevention and treatment of herpes simplex virus (HSV) and varicella-zona virus (VZV) infections. This study aimed to characterize pharmacokinetics of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Method: Children receiving acyclovir or valacyclovir were included in this study. Pharmacokinetics (PK) were described using the non-linear mixed-effect modelling. Dosing simulations were used to obtain trough concentrations above 50% inhibitory concentration for HSV or VZV (0.56mg/L and 1.125mg/L respectively) and maximal peak concentrations below 25 mg/L. Results: A total of 79 children (212 concentration-time observations) were included, 50 were taking IV acyclovir, 22 oral and 7 both IV and oral, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect and estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination Conclusion: To obtain target maximal and trough concentrations, the more suitable initial acyclovir IV dose was 10 mg/kg/6h for children with normal renal function (eGFR ≤ 250 mL/min/1.73m2) and 15 to 20 mg/kg/6h for children with ARC. (eGFR > 250 mL/min/1.73m2) The 20 mg/kg/8h for acyclovir and valacyclovir produced effective concentrations in more than 75% of children, however a 15 mg/kg/6h, if possible, should be preferred. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.

While the pathophysiology of chronic disorders varies there are three basic mechanisms-inflammation, oxidative stress and endothelial dysfunction-that are common in many chronic diseases. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases. We analyzed data of 178 patients from cohorts with selected chronic diseases in this quasi-experimental study. Endothelial dysfunction was determined by flow-mediated dilatation (FMD) and asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (anti-atherosclerotic liquid-AAL), omega-3 (anti-inflammatory capsules-AIC) and extract with Alaskan blueberry (anti-oxidant liquid-AOL). Stepwise multivariate regression analysis was used to evaluate the association of FMD with clinical and serologic parameters. Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. The FMD was negatively correlated with serum ADMA, MDA, PTX3, and hsCRP levels and positively correlated with CuZn-SOD and eGFR levels. ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies. Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. In addition, short-term AAL, AIC and AOL therapies significantly improves a number of parameters in our cohort and can normalize ADMA, PTX3, hsCRP and MDA levels. Chronic diseases are the leading causes of death in developed countries, with atherosclerosis and its complications at the top of the list. The commonest chronic diseases-cardiovascular disease, diabetes, obesity and Alzheimer's Disease-cannot be prevented by disease or cured by medication, are more common in older patients

Context: Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, in order to optimize dosing scheme.Method: All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using non-linear mixed-effect modelling. Monte Carlo simulations were used to optimize dosing regimen in order to maintain area under the concentration curve (AUC) in the preventive or therapeutic target.Results: Among the 105 children (374 concentration-time observations) included, 78 received intravenous (IV) ganciclovir, 19 oral valganciclovir and 6 both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and critically-ill children medical status were significantly associated with ganciclovir elimination.Conclusion: Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg/day oral or 15-20 mg/kg/day IV in children with normal eGFR and to 56 mg/kg/day oral or 20-25 mg/kg/day IV in children with augmented eGFR. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.

Infection is a serious concern in the short and long term after pediatric liver transplantation. Vaccination represents an easy and cheap opportunity to reduce morbidity and mortality due to vaccine-preventable infection. This retrospective, observational, multi-center study examines the immunization status in pediatric liver transplant candidates at the time of transplantation and compares it to a control group of children with acute liver disease. Findings show only 80% were vaccinated age-appropriately, defined as having received the recommended number of vaccination doses for their age prior to transplantation; for DTP-PV-Hib, less than 75% for Hepatitis B and two-thirds for pneumococcal conjugate vaccine in children with chronic liver disease. Vaccination coverage for live vaccines is better compared to the acute control group with 81% versus 62% for measles, mumps and rubella (p = 0.003) and 65% versus 55% for varicella (p = 0.171). Nevertheless, a country-specific comparison with national reference data suggests a lower vaccination coverage in children with chronic liver disease. Our study reveals an under-vaccination in this high-risk group prior to transplantation and underlines the need to improve vaccination.

No abstract

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a “Question Mark Ear” (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.