Emergency department visits for pediatric traumatic injuries during general confinement: A single-center study in an urban setting.

BACKGROUND: The first case of SARS-CoV-2 was detected in France in January 2020 and the government decided on national confinement from March 17 to May 11, 2020. Our aim was to analyze the incidence of pediatric emergency department (ED) visits and hospitalizations for traumatic injuries during this period. METHODS: Any visit with an ICD-10 discharge diagnosis code of burn, fracture, traumatic wound, or sprain/bruise contusion was recorded within the 2 weeks before (weeks 10 and 11) and during the confinement (weeks 12 and 19). The visits with the same ICD-10 discharge diagnosis code during similar weeks of the previous 2 years were also included. For each of those visits, the number of hospitalizations was counted. RESULTS: The number of recorded visits between week 10 and 19 in 2018, 2019, and 2020 was, respectively, 2657, 2625, and 1106 children. The average number of visits per day during the confinement (13±5) was significantly different from the average number of visits per day during the same weeks in 2018 and 2019 (38±8 vs. 39±9, P<0.0001). The average number of visits per day was significantly lower during confinement compared with 2018/2019 for three categories of diagnoses (P<0.0001) but not for burns (1.7 vs. 1.8, P=0.23). The average number of hospitalizations per day was significantly lower during the confinement than during 2018/2019 (1.6±1.3 vs. 2.6±1.8, P<0.0001). CONCLUSION: Confining children in an urban setting appears to decrease the incidence of injuries, except for burns. These data may be useful in reorganizing caregiver supervision and hospital units. These results will need to be consolidated in a multicenter study.

Acute gingivostomatitis in children: Epidemiology in the emergency department, pain, and use of codeine before its restriction.

Acute gingivostomatitis is relatively frequent in children; of viral origin, its diagnosis is usually straightforward. Acute gingivostomatitis is very painful and for many years, codeine, whose use was restricted in 2013, was widely employed in this context. The aim of this study was to ascertain the prevalence of acute stomatitis in pediatric emergency care, to evaluate the pain caused by stomatitis, and to determine the analgesic resources deployed both in the emergency department and at discharge, over the 5-year period preceding restriction of the use of codeine. METHODS: This was a retrospective study conducted in a pediatric emergency department (PED) of a university hospital between August 2008 and June 2013. RESULTS: A total of 702 children (372 herpetic gingivostomatitis [HGS], 149 herpangina [H], 181 hand, foot, and mouth disease [HFMD]) were included. Over the 5 years, one case of gingivostomatitis was identified for 303 visits to the PED. A total of 548 (78.1%) children were aged less than 36 months and the median age was 22 months. For 501 of 702 (71.4%) children, parents reported pain and/or feeding difficulties; in the HGS group, 314 of 372 (84.4%) patients had these symptoms. Of the 702 children, 48 (6.8%) were admitted to hospital. Overall, 457 (65.1%) of 702 children were given codeine before the PED visit, during the PED visit, or as a medication to take after discharge. The corresponding figures were 314 of 372 (84.4%) for the HGS group, 67 of 149 (45.0%) for the H group, and 76 of 181 (42.0%) for the HFMD group, P<0.001. CONCLUSIONS: Acute gingivostomatitis is a relative frequent reason for PED visits, and the pain and feeding difficulties that it elicits are a real challenge. Before codeine restriction, this medication played a major role in the analgesic strategy for this disease. It is essential that analgesic regimens at least as effective as codeine replace it. Morphine combined with paracetamol or the association of ibuprofen with paracetamol are options that are recommended by the French National Health Authority (HAS).

[AIDS: ethics and scientific investigation on human beings]. / Sida: éthique et investigation scientifique sur l'être humain.

The experimentation on human beings of one or several therapeutic molecules discovered in laboratory is necessary and important because it helps to find new treatments or new diagnostic methods. But, it presents serious ethical problems. In this article we are analysing the example of the HIV infection. We are succinctly describing the research methods in laboratory for therapeutic molecules, first the experimentation on animals and then on human being in clinical trials. We will then try to show, with several examples, how during these last 25 years of HIV infection, the research of new molecules has not always respected the ethical rules set out in Helsinki declaration, "Code de la santé publique" or "Guide de bonnes pratiques cliniques-ICH" etc. We are discussing here the way to avoid these irregularities.

[Newly formed French residents in pediatrics are not well prepared for conducting pediatric resuscitation after medical school]. / Le deuxième cycle des études médicales prépare-t-il les étudiants hospitaliers à leurs fonctions d'internes ? Exemple de l'arrêt cardiaque de l'enfant.

BACKGROUND: Medical schools aim to prepare medical students for their residency responsibilities. However, in France, there is no assessment of medical students' skills when they start their residency. GOAL: The objective of this study was to assess the quality of basic life support delivered by first-year residents in pediatrics during a simulated pediatric cardiopulmonary arrest. MATERIALS AND METHODS: First-year residents in pediatrics were assessed during a simulated pediatric cardiopulmonary arrest. Their performance score (based on adherence to international guidelines) and no-flow and no-blow fractions were recorded. RESULTS: Forty-two first-year residents were evaluated. Their median performance score was 4 out of 13. No-blow and no-flow fractions were 55 and 81 %, respectively. There was no correlation between their skills and their knowledge assessed during the national ranking exam at the end of the 6th year of medical school. CONCLUSION: At the beginning of their residency, pediatric residents are not able to properly provide basic life support. The introduction of simulation in French medical schools may be an effective way to improve their skills.

[Intracellular pharmacodynamic-pharmacokinetic of antiretroviral drugs]. / Pharmacodynamie plasmatique et intracellulaire des antirétroviraux anti-VIH.

Therapeutic Drug Monitoring (TDM) became these last years very attractive in clinical and fundamental researches for several reasons. In one hand, 21 antiretroviral drugs are currently used and pharmacological studies to understand drugs interactions and to choose the best drug combinations are needed. On the other hand, we observe treatment failure and numerous side effects such as lipodystropy in HIV treated patients. An inadequate intracellular concentration of the drug might be one of the main raisons of the ineffectiveness of therapy. Moreover, beside interindividual metabolism variations, unique posologies are still prescribed. Clinical trial uses a necessary statistic method, but it leads to one dose which should fit all subjects.We discuss here the importance ofTDM using both plasmatic and intracellular analyses to improve our antiretroviral drug understanding and try to lead to the personalization of treatment.

[Pain in neonatology. Non-pharmacological treatment]. / Douleur en néonatologie. Traitements non médicamenteux.

Diagnostic and therapeutic skin-breaking procedures have become ubiquitous in current medical practice and neonatology does not constitute an exception. One of the main sources of neonatal pain is procedure-induced pain. It has recently become clear that pain prevention must be a health care priority. Non-pharmacological approaches constitute a first option for the analgesia of common procedures performed in neonatology. This article reviews the non-pharmacological treatments most frequently used in this context: swaddling, tucking, containment, sweet solutions, non-nutritive sucking (NNS), breastfeeding analgesia, breast milk and music. In practice, the dose of 1 to 2mL of 24% or 30% sucrose solution or 30% glucose solution immediately followed by NNS can be given for minor painful procedures in term neonates or those weighing more than 2500g. In the preterm, 0.3mL of a sweet solution (sucrose or glucose) can be given for infants weighing less than 1500g and 0.5mL for those weighing between 1500 and 2500g. The synergistic effect of sweet solutions and NNS has been clearly shown and thus their association is largely justified in practice. For breast-fed term neonates, breastfeeding can be given to sooth procedure-induced pain. All these non-pharmacological options can be effective to relieve pain from minor or moderate procedures. However, when more painful procedures are performed, stronger analgesics must be used.

[Unscheduled pediatrician office visits: A national survey]. / Enquête nationale sur les consultations non programmées en pédiatrie de ville.

INTRODUCTION: Unscheduled visits (UV) are defined as visits to the family pediatrician (FP) without an appointment or when the appointment was made less than 24h before. Because the number of FPs has decreased since the 2000s, the FP might be less available for UVs and that might be one of the reasons for the increase in emergency department visits. OBJECTIVES: The main objective of the study was to evaluate the proportion of UVs among visits with a FP. The secondary objective was to describe the daily activity of FPs. METHODS: In February 2012, e-mail requests were sent to 1022 FPs, asking them to complete an anonymous questionnaire online at the website of the French Association of Pediatricians in Outpatient Practice (AFPA). The questionnaire was about 1 day of activity. RESULTS: A total of 434 FPs participated in the study (42.5%). Among the 10,263 visits a day conducted by these FPs, 4574 were UVs (44.6% [95% CI: 43.6-45.5]). Two hundred and fifty FPs (59.5%) could not conduct one or more UVs because of a lack of availability. The number of children who were not treated on the same day because of a lack of availability was 959, i.e., 2.2 children per day and pediatrician. An absence of off-hour pediatricians in outpatient practice during weekends and during the night was reported by 61% (266) and 90% (391) of the FPs, respectively. CONCLUSION: FPs' activity includes a considerable number of UVs. However, a large number of UVs could not be made because of a lack of pediatricians' availability.

Measurement of the anti-HIV agent 2',3'-didehydro-2',3'-dideoxythymidine (D4T) by competitive ELISA.

2',3'-didehydro-2',3'-dideoxythymidine (D4T) is a thymidine analogue with potent anti-HIV activity in vitro and is currently being investigated therapeutically in patients with advanced HIV infection. We describe a first one-step competitive ELISA method developed for D4T measurement. Anti-D4T rabbit antibodies were raised against a D4T hemisuccinate-bovine serum albumin immunogen. A D4T-hemisuccinate-horseradish peroxidase conjugate and a monoclonal anti-rabbit IgG antibody insolubilized onto a microtiter plate were used as a tracer and capture system, respectively. The method was capable of detecting 2 ng/ml of D4T in cell cultures and 20 ng/ml of D4T in plasma samples previously separated in microconcentrator devices. Cross-reactivity analysis showed that thymidine, D4T monophosphate, or azidothymidine, were weakly recognized by the ELISA and that thymine or other nucleosides were unreactive. The test was successfully used for the quantification of D4T in cell extracts from CEM or Molt 4 cell lines cultured with D4T and in the plasma of patients with advanced HIV infection, receiving D4T therapy. Moreover this ELISA could be used for the indirect quantification of D4T phosphorylated intracellular metabolites previously separated by reverse phase HPLC and hydrolyzed with alkaline phosphatase.

Synthesis and antiviral activity of ethidium-arginine conjugates directed against the TAR RNA of HIV-1.

The regulatory protein Tat is essential for viral gene expression and replication of the human immunodeficiency virus type 1 (HIV-1). Tat transactivates the HIV-1 long terminal repeat (LTR) via its binding to the transactivation responsive element (TAR) and increases the viral transcription. Studies have shown that the binding of arginine and arginine derivatives induces a conformational change of the TAR RNA at the Tat-binding site. The unpaired A17 residue delimits a small cavity which constitutes a receptor site for small molecules, especially for ethidium bromide. These binding characteristics have prompted us to design a series of ethidium-arginine conjugates capable of interacting with the TAR RNA. Here we report the synthesis of six ethidium derivatives equipped with arginine side chains. These molecules were biologically evaluated, and two compounds (17 and 20) exhibited in vitro anti-HIV-1 activity at micromolar concentration, without toxicity (up to 100 microM concentration). Melting temperature studies indicated that the most active molecule (20) bound strongly to TAR in vitro. RNase protection experiments agreed with the molecular modeling studies which suggested that the ethidium moiety of 20 was inserted next to the A17 residue while the arginine side chain occupied the pyrimidine bulge.

Synthesis and anti-HIV activity of some novel arylphosphate and H-phosphonate derivatives of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine.

Phosphate and H-phosphonate derivatives of anti-HIV nucleoside analogues (AZT and d4T) were prepared as potential prodrugs of the bio-active free nucleotide and they were evaluated for their inhibitory effects on the replication of HIV-1 in several cell culture systems. One compound exhibited an important anti-HIV-1 activity and proved to be significantly more efficient than the parent nucleoside.

Synthesis and anti-HIV activity of prodrugs derived from saquinavir and indinavir.

With a view to improving the pharmacological properties, safety and pharmacokinetic profiles of current protease inhibitors, the synthesis of various acyl-substituted saquinavir and indinavir prodrugs, their in vitro stability with respect to hydrolysis and their anti-HIV (LAI and HTLV IIIB) activity and cytotoxicity in CEM-SS and MT4 cells have been investigated. Hydrolysis of the ester bond and liberation of the active free drug was found to be crucial for HIV inhibition: the faster the hydrolysis, the closer the anti-HIV activity was to that of the respective parent drug. This is the case for most of the C-14-substituted indinavir and saquinavir derivatives (IC50 from 10 to 360 nM for ester half-lives of 90 min to 40 h). Concomitantly, the level of HIV inhibition is very low for the prodrugs for which hydrolysis is very slow. This is the case with the myristoyl or oleyl saquinavir esters, owing to the stable masking of the hydroxyl that is part of the peptidomimetic non-cleavable transition state isostere responsible for the inhibitory potency of saquinavir (and indinavir). In contrast, the anti-HIV activity of the monosubstituted C-8 indinavir prodrugs seems not to be correlated with their resistance to hydrolysis, as expected (the C-8 hydroxyl of indinavir is not involved in the transition state isostere). No cytotoxicity was detected for the indinavir and saquinavir prodrugs for concentrations as high as 10 or even 100 microM, thus indicating promising therapeutic potential.

Four steroidal alkaloids from the leaves of Buxus sempervirens.

Four new steroidal alkaloids, N20-formylbuxaminol E [(20S)-16alpha-hydroxy-20-(formylamino)-3beta-(dimethylamino)-9,10 -seco-buxa-9(11),10(19)-diene] (1), O16-syringylbuxaminol E [(20S)-16alpha-syringoyl-3beta-(dimethylamino)-20-(amino)-9, 10-seco-buxa-9(11),10(19)-diene] (2), N20-acetylbuxamine G [(20S)-20-(acetylamino)-3beta-(methylamino)-9,10-seco-buxa-9(11),1 0(19)-diene] (3) and N20-acetylbuxamine E [(20S)-20-(acetylamino)-3beta-(dimethylamino)-9,10-seco-buxa-9(11) ,10(19)-diene] (4) were isolated from the leaves of Buxus sempervirens. Their structures were determined mainly on the basis of 2D NMR studies.

Synthesis and anti-HIV activity of glucose-containing prodrugs derived from saquinavir, indinavir and nelfinavir.

With the aim at improving the transport of the current HIV protease inhibitors across the intestinal and blood brain barriers and their penetration into the central nervous system, the synthesis of various acyl and carbamatoyl glucose-containing prodrugs derived from saquinavir, indinavir and nelfinavir, their in vitro stability with respect to hydrolysis, and their anti-HIV activity have been investigated. D-Glucose, which is actively transported across these barriers, was connected through its 3-hydroxyl to these antiproteases via a linker. The liberation of the active free drug during the incubation time of the prodrugs with the cells was found to be crucial for HIV inhibition. The labile ester linking of the glucose-containing moiety to the peptidomimetic hydroxyl of saquinavir or to the indinavir C-8 hydroxyl, which is not part of the transition state isostere, is not an obstacle for anti-HIV activity. This is not the case for its stable carbamate linking to the peptidomimetic hydroxyl of saquinavir, indinavir and nelfinavir. The chemical stability with respect to hydrolysis of some of the saquinavir and indinavir prodrugs reported here, the liberation rate of the active free drug and the HIV inhibitory potency are acceptable for an in vivo use of these prodrugs. These glucose-linked ester and carbamate prodrugs display a promising therapeutic potential provided that their bioavailability, penetration into the HIV sanctuaries, and/or the liberation of the active free drug from the carbamate prodrugs are improved. Furthermore, no cytotoxicity was detected for the prodrugs for concentrations as high as 10 or even 100 microM, thus indicating an encouraging therapeutic index.

The production and evaluation of antibodies for enzyme immunoassay of AZTTP.

We describe the development of the first enzyme immunoassay for quantifying AZTTP that does not use of radioactive labeling. Anti-AZTTP antibodies were raised in rabbits by immunizing with an AZTTP-kelhoyle limpet hemocyanin (KLH) conjugate. Competitive immunoassays indicated a nanomolar sensitivity to AZTTP. One of the antisera produced was specific for AZTTP.

Impact of 2011 French guidelines on antibiotic prescription for acute otitis media in infants.

OBJECTIVE: In 2011, new guidelines on antibiotic prescription for acute otitis media (AOM) were published in France to decrease the use of third generation cephalosporins that promote the carriage of extended-spectrum beta-lactamase producing Escherichia coli. Our objective was to assess the impact of the 2011 French recommendations on the type of antibiotics prescribed for AOM. METHODS: Fourteen thousand six hundred and sixty-one children, 6 to 24 months of age, presenting with AOM were included in 2 studies, between November 1, 2009 and October 31, 2012. The first one was conducted with the support of 62 private practice pediatricians; the second one was conducted in 7 pediatric emergency departments. Three periods of 1 year each were defined. RESULTS: Antibiotics were prescribed in 12,471 (85.1%) of cases of AOM during the study period. Amoxicillin prescriptions was multiplied by 25, between the first year (2.6%) and the last year (66.1%). Conversely, prescriptions of cefpodoxime proxetil and amoxicillin-clavulanic acid decreased from 33.6% and 62.0% in the first year to 5.2% and 27.7% in the last year, respectively. This trend was observed in both private practices and in the pediatric emergency departments. CONCLUSION: Amoxicillin became the most frequently prescribed antibiotic for AOM in 2012, complying with the 2011 French guidelines, while the proportion of prescribed broad-spectrum antibiotics decreased. Our study highlights the importance of guidelines to decrease the prescription of broad-spectrum antibiotics, a crucial factor in the prevention of antibiotic resistance.

[Treatment of acute gastroenteritis in private practice: a survey of 641 pediatricians]. / Pratiques de prise en charge des gastro-entérites aiguës : enquête auprès de 641 pédiatres libéraux.

UNLABELLED: Acute gastroenteritis (AGE) is a very common reason for pediatric consultations. Various expert committees have issued guidelines for its management, based on systematic use of an oral rehydration solution (ORS), early appropriate nutrition (most recent previous diet), and avoiding routine treatment with medication. The aim of the study was to assess the application of these guidelines by pediatricians in outpatient practice for mild to moderate AGE. A secondary objective was to question pediatricians about their practices for vaccination against rotavirus. METHODS: In June 2012, e-mail requests were sent to 1187 pediatricians in private practice, asking them to complete an anonymous questionnaire online at the website of the French Association of Pediatricians in Outpatient Practice. RESULTS: A total of 641 (54%) responses could be analyzed. Nearly all the pediatricians recommended early resumption of nutrition after administration of ORS. Depending on the child's age, 16 to 23% reported they would recommend resuming feeding with lactose-free milk, and 80% would advise an antidiarrhea diet for children older than 6 months. The drugs prescribed most often were, in decreasing order, racecadotril (acetorphan), diosmectite, and probiotics. Although 90% of the pediatricians prescribed vaccination against rotavirus, 65% estimated that it was performed in more than half of all children. CONCLUSION: This study of the management of moderate acute gastroenteritis shows variable adhesion to guidelines by pediatricians treating outpatients. Although ORS, maintenance of breastfeeding, and early nutrition after ORS are now widely applied, the type of nutrition recommended often failed to meet guidelines. Drug prescription is still too frequent. Anti-rotavirus vaccine is prescribed often but is administered much less frequently.

Radioimmunoassay for quantitation of 2',3'-didehydro-3'-deoxythymidine (D4T) in human plasma.

2',3'-Didehydro-3'-deoxythymidine (D4T, or stavudine) has been recently approved for the treatment of AIDS. In the present study, a specific and sensitive radioimmunoassay (RIA) was developed for the quantitation of D4T in human plasma. The RIA is a double-antibody competitive binding assay which uses anti-D4T antiserum raised in rabbits as the primary antibody, a tritiated derivative of D4T as the radioactive tracer, and goat anti-rabbit immunoglobulin G as the secondary antibody. No cross-reaction between D4T and various nucleoside analogs was detected. The limit of quantitation of the method approximated 20 ng/ml. Replicate analyses of quality control samples (40 to 3,500 ng/ml) had satisfactory intra- and interassay precision (coefficient of variation, 1.7 to 16.7%) and accuracy (deviation, -9.5 to +21.0). This newly developed RIA was successfully used in the monitoring of plasma drug levels in healthy volunteers receiving an oral dose of D4T.

Quantification of lamivudine (3TC) by competitive immunoassay.

Lamivudine or 3TC, the (-) eniantiomer of 2'-deoxy-3'-thiacytidine, is a prototype of a novel class of levogyre dideoxynucleosides analogues used in treatment of HIV and HBV infection. We describe a method corresponding to the first enzyme immunoassay for quantifying this antiviral drug. This technique use an enzyme conjugate that not require the use of radioactive labelling. In this study, anti-3TC antibodies were raised in rabbits by immunising with 3TC-HS-kelhoyle limpet hemocyanin (KLH) conjugate.

Modeling of the interaction between new ethidium derivatives and TAR RNA of HIV-1.

During the HIV-1 replication process, interactions between the first sequence of RNA synthesized named TAR RNA and a viral protein named Tat permit a fast and efficient transcription of viral DNA in RNA. Based on the NMR structure of TAR RNA found on the PDB, new derivatives of ethidium were designed by molecular modeling to inhibit this interaction. The studied molecules are composed of three domains: an arginine, a linker, and an ethidium. Three linkers of different lengths were considered in the first step, with the TAR RNA-arginine interaction and the intercalation of the ethidium simulated by docking methods. In a second step, the structure of the TAR RNA was completed to obtain a whole ethidium interaction site and docking of the whole studied molecules was investigated. Molecules were synthesized and tested on infected cells. The predicted models and activity are in good agreement with the reported experimental results.