Analysis of the impact of the SARS-CoV-2 infection on the pediatric population hospitalized during the pandemic in the Greater Paris University Hospitals

BackgroundThe clinical characteristics, disease progression and outcome in children affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appear significantly milder compared to older individuals. Nevertheless, the trends in hospitalization and clinical characteristics in the pediatric population seem to be different over time across the different epidemic waves.ObjectiveOur aim was to understand the impact of the different COVID-19 variants in the pediatric population hospitalized in the Pediatric Departments of the Public Hospital in the Greater Paris area by the analysis performed with the Assistance Publique-Hopitaux de Paris (AP-HP) Health Data Warehouse.MethodsThis is a retrospective cohort study including 9,163 patients under 18 years of age, hospitalized from 1 March 2020 to 22 March 2022, in the Paris area, with confirmed infection by SARS-CoV-2. Three mutually exclusive groups with decreasing severity (Pediatric Inflammatory Multisystem Syndrome (PIMS), symptomatic infection, mild or asymptomatic infection) were defined and described regarding demography, medical history, complication of the SARS-CoV-2 infection, and treatment during admission. Temporal evolution was described by defining three successive waves (March–September 2020, October 2020–October 2021, and November 2021–March 2022) corresponding to the emergence of the successive variants.ResultsIn the study period, 9,163 pediatric patients with SARS-CoV-2 infection were hospitalized in 21 AP-HP hospitals. The number of patients with SARS-CoV-2 infection increased over time for each wave of the pandemic (the mean number of patients per month during the first wave was 332, 322 during the 2nd, and 595 during the third wave). In the medical history, the most associated concomitant disease was chronic respiratory disease. Patients hospitalized during the third wave presented a higher incidence of pulmonary involvement (10.2% compared to 7% and 6.5% during the first and second waves, respectively). The highest incidence of PIMS was observed during the first and second waves (4.2% in the first and second waves compared to 2.3% in the 3rd wave).DiscussionThis analysis highlighted the high incidence of hospitalized children in the Greater Paris Area during the third wave of SARS-CoV-2 pandemic corresponding to the Omicron Covid-19 variant, which is probably an expression of a concomitant SARS-CoV-2, while a decreased incidence of PIMS complication was observed during the same period

Ketogenic diet for super-refractory status epilepticus (SRSE) with NORSE and FIRES: Single tertiary center experience and literature data

Background and purposeKetogenic diet (KD) is an emerging treatment option for super-refractory status epilepticus (SRSE). We evaluated the effectiveness of KD in patients presenting SRSE including NORSE (and its subcategory FIRES).MethodsA retrospective review of the medical records was performed at the Necker Enfants Malades Hospital. All children with SRSE in whom KD was started during the last 10 years were included. A systematic search was carried out for all study designs, including at least one patient of any age with SRSE in whom KD was started. The primary outcome was the responder rate and Kaplan–Meier survival curves were generated for the time-to-KD response. As secondary outcomes, Cox proportional hazard models were created to assess the impact of NORSE-related factors on KD efficacy.ResultsSixteen children received KD for treatment of SRSE, and three had NORSE presentation (one infectious etiology, two FIRES). In medical literature, 1,613 records were initially identified, and 75 were selected for review. We selected 276 patients receiving KD during SRSE. The most common etiology of SRSE was acute symptomatic (21.3%), among these patients, 67.7% presented with NORSE of immune and infectious etiologies. Other etiologies were remote symptomatic (6.8%), progressive symptomatic (6.1%), and SE in defined electroclinical syndromes (14.8%), including two patients with genetic etiology and NORSE presentation. The etiology was unknown in 50.7% of the patients presenting with cryptogenic NORSE, of which 102 presented with FIRES. Overall, most patients with NORSE benefit from KD (p < 0.004), but they needed a longer time to achieve RSE resolution after starting KD compared with other non-NORSE SRSE (p = 0.001). The response to KD in the NORSE group with identified etiology compared to the cryptogenic NORSE was significantly higher (p = 0.01), and the time to achieve SE resolution after starting KD was shorter (p = 0.04).ConclusionsThe search for underlying etiology should help to a better-targeted therapy. KD can have good efficacy in NORSE; however, the time to achieve SE resolution seems to be longer in cryptogenic cases. These findings highlight the therapeutic role of KD in NORSE, even though this favorable response needs to be better confirmed in prospective controlled studies

Assessment of self-perceived knowledge of key clinical pharmacology concepts and educational needs among European Paediatric Intensive Care Units: an ESPNIC survey

Background: Knowledge of clinical pharmacology concepts is essential to improve patients’ outcomes. Scarce data is available on the utilisation of these concepts in the paediatric intensive care unit (PICU). We aimed to investigate the self-perceived knowledge of clinical pharmacology concepts, educational needs and identify priorities for pharmacological research across European PICUs. Methods: From July to November 2022 an online survey was distributed to evaluate i) the self-reported knowledge, and ii) application of key pharmacology concepts in clinical practice (using a likert scale from 1 = never apply to 10 = always apply); iii) need for additional education on them; and iv) key areas for future pharmacological research. The survey was distributed to European Society of Paediatric and Neonatal Intensive Care (ESPNIC) members and other European national PICUs societies members. Results: Two-hundred-thirty-seven responses from 149 PICUs were collected. 54% of PICUs reported to have a clinical pharmacologist available for consultation during drug prescription and 65% of them regularly contact them during the prescribing process. Among clinical pharmacology concepts the parameter with the highest self-reported knowledge was half-life (99%) and the lowest were pharmacodynamics and volume-of-distribution (92%). The reported median application of these concepts in clinical practice ranged between 5/10 and 7/10. Most of the respondents reported the need for additional education on specific pharmacology concepts. Reported priorities for drug research mostly involved analgesics/sedatives (87%), antimicrobials (86%), and cardiovascular medications (55%). Conclusions: Self-reported knowledge on clinical pharmacology concepts seems good, but self-perceived clinical application may improve and most of the respondents report a need for additional education. These findings call for concerted multidisciplinary efforts to streamline education and guidelines to fill this gap

recommendations by the Conect4Children expert advice group

Funding Information: Competing interests: A.V.R. has received Speaker fees/Consultant for Abbvie, Novartis, UCB, SOBI, Eli Lilly and Roche. N.M. reports grants outside the submitted work in the last five years from the Medical Research Council, National Institute of Health Research, March of Dimes, British Heart Foundation, HCA international, Health Data Research UK, Shire Pharmaceuticals, Chiesi Pharmaceuticals, Prolacta Life Sciences, and Westminster Children’s Research Fund; N.M. is a member of the Nestle Scientific Advisory Board and accepts no personal remuneration for this role. N.M. reports travel and accommodation reimbursements from Chiesi, Nestle and Shire. N.M. is a member of C4C, International Neonatal Collaboration (INC), UK National Research Ethics Advisory Service and MHRA advisory groups and/or working parties. S.W. has received compensation as a member of the scientific advisory board of AM Pharma, Novartis and Khondrion and receives research funding from IMI2 for the Conect4children project. B.A. has worked for GlaxoSmithKline between October 2006 and September 2009 and holds company shares. Between October 2009 and May 2015, she has worked for Novartis. M.S. has recieved research grant and honoraria for meetings and Advisory Boards from Alexion, Sanofi/Genzyme, Takeda, CHIESI, Ultragenix, Orchard, Orphazyme. P.I. is a permanent employee of Bayer AG, Germany. M.V. has received compensation for Advisory boards or Steering committes from Roche, Novartis, Achillion, Apellis, Retrophin/Travere, Alexion pharmaceuticals. C.M. has been a consultant to or has received honoraria from Janssen, Angelini, Servier, Nuvelution, Otsuka, Lundbeck, Pfizer, Neuraxpharm and Esteve outside the submitted work. She declares conflicts of interest unrelated to the present work. M.C. had advisory roles for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Lilly, and Roche in the last 2 years (outside the topic of the submitted work, for oncology drugs). M.J. has received research grants from Shire and has been engaged as a speaker or consultant by Shire, Ginsana, PCM Scientific Evolan, and New Nordic, all unrelated to the present work. P.S. has received speaker fees and participated at advisory boards for Biomarin, Zogenyx, GW Pharmaceuticals, and has received research funding by ENECTA BV, GW Pharmaceuticals, Kolfarma srl., Eisai. E.R. has received speaker fees and participated at advisory boards for Eisai and has received research funding by GW Pharmaceuticals, Pfizer, Italian Ministry of Health (MoH) and the Italian Medicine Agency (AIFA). This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). M.A.R. is a member of the c4c Ethics Expert Group and received compensation for ethical consulting activities from Bayer AG Wallace Crandall is employee of Eli Lilly and Co. P.C. is an employee of UCB, and owns stock in the company. She was previously an employee of GSK and owns stock in the company. N.R. has received honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB. The IRCCS Istituto Giannina Gaslini (IGG), where NR works as full-time public employee has received contributions from the following industries in the last 3 years: Bristol Myers and Squibb, Eli-Lilly, F Hoffmann-La Roche, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties. M.L. receives/has received consultation fees from CSL Behring, Novartis, Roche and Octopharma, travel grants from Merck Serono, and been awarded educational grants to organise meetings by Novartis, Biogen Idec, Merck Serono and Bayer. All other authors have no disclosures. Funding Information: Conect4children has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777389. The Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The views expressed in this article are the personal views of the author(s) and should not be interpreted as made on behalf of, or reflecting the position of, the regulatory agency/agencies or organisations with which the author(s) is/are employed/affiliated . Publisher Copyright: © 2021, The Author(s).Background: The COVID-19 pandemic has had a devastating impact on multiple aspects of healthcare, but has also triggered new ways of working, stimulated novel approaches in clinical research and reinforced the value of previous innovations. Conect4children (c4c, www.conect4children.org) is a large collaborative European network to facilitate the development of new medicines for paediatric populations, and is made up of 35 academic and 10 industry partners from 20 European countries, more than 50 third parties, and around 500 affiliated partners. Methods: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equity. Findings: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equityWe provide examples of research innovation, and follow this with recommendations to improve the efficiency of future trials, drawing on industry perspectives, regulatory considerations, infrastructure requirements and parent–patient–public involvement. We end with a comment on progress made towards greater international harmonisation of paediatric research and how lessons learned from COVID-19 studies might assist in further improvements in this important area.publishersversionepub_ahead_of_prin

Modélisation pharmacocinétique et pharmacodynamique de l'adrénaline et de la noradrénaline chez l'enfant

The effects of catecholamines are difficult to predict. The between-subject variability observed in clinical setting is multifactorial including constitutional and acquired characteristics of each individual. Epinephrine and norepinephrine dosages are usually extrapolated from adult data. Yet, age is a source of high variability due to development- related phenomena. A population model of epinephrine or norepinephrine was developed in haemodynamically critically ill children. This allowed to identify between-subject variability factors as well as to propose individualized dosage regimens of these two catecholamines according to the desired effect and child characteristics. Epinephrine pharmacokinetics in 39 children at high risk of postoperative low cardiac output syndrome followed a one-compartment model. Clearance increased with bodyweight according to the allometric rule. The resulting increases in heart rate and mean arterial pressure followed a direct Emax model. These were related to age and illness severity. A turn-over model described the increases in blood glucose and lactate. Norepinephrine pharmacokinetics in 38 hypotensive critically ill children followed a one compartment model. Clearance increased with bodyweight (allometry). The resulting increase in mean arterial pressure followed a direct Emax model. This was a function of age and illness severity. The dosage of epinephrine and norepinephrine in children should take into account the bodyweight, age and illness severity of the patient: the younger the child and the more serious the condition, the higher the dosage in order to meet the haemodynamic goals.Les effets des catécholamines en réanimation sont peu prédictibles. La variabilité interindividuelle des observations est d’origine multifactorielle dont des facteurs pharmacocinétiques et pharmacodynamiques, dépendant de caractéristiques constitutionnelles et acquises de chaque individu. Les posologies de l’adrénaline et de la noradrénaline chez l’enfant sont extrapolées des données adultes. Pourtant l’âge est une source de grande variabilité liée au développement. Un modèle pharmaco- statistique de l’adrénaline et de la noradrénaline a été établi chez l’enfant en insuffisance circulatoire aigüe. Il a permis d’identifier des facteurs de variabilité entre les individus ainsi que de proposer des schémas de prescription des deux molécules en fonction de l’effet souhaité et des caractéristiques de l’enfant. La pharmacocinétique de l’adrénaline chez 39 enfants en prévention du syndrome de bas débit cardiaque postopératoire suivait un modèle monocompartimental. La clairance augmentait avec le poids selon le principe de l’allométrie. Les augmentations résultantes de la fréquence cardiaque et de la pression artérielle moyenne suivaient un modèle d’effet direct Emax. Elles étaient influencées par l’âge et la gravité des patients. Les augmentations de glycémie et lactatémie suivaient un modèle d’effet indirect. Pour la noradrénaline, chez 38 enfants atteints d’hypotension artérielle systémique, la pharmacocinétique était mono-compartimentale. La clairance était influencée par le poids (allométrie). L’augmentation induite de la pression artérielle moyenne suivait un modèle direct Emax. Elle était fonction de l’âge et de la gravité des patients. Les posologies de l’adrénaline et de la noradrénaline chez l’enfant devraient tenir compte du poids, de l’âge et de la gravité du patient : plus jeune est l’enfant et plus grave est son état, plus la posologie doit être élevée pour satisfaire les objectifs hémodynamiques

Pharmacokinetics and pharmacodynamic modelling of epinephrine and norepinephrine in children

Les effets des catécholamines en réanimation sont peu prédictibles. La variabilité interindividuelle des observations est d’origine multifactorielle dont des facteurs pharmacocinétiques et pharmacodynamiques, dépendant de caractéristiques constitutionnelles et acquises de chaque individu. Les posologies de l’adrénaline et de la noradrénaline chez l’enfant sont extrapolées des données adultes. Pourtant l’âge est une source de grande variabilité liée au développement. Un modèle pharmaco- statistique de l’adrénaline et de la noradrénaline a été établi chez l’enfant en insuffisance circulatoire aigüe. Il a permis d’identifier des facteurs de variabilité entre les individus ainsi que de proposer des schémas de prescription des deux molécules en fonction de l’effet souhaité et des caractéristiques de l’enfant. La pharmacocinétique de l’adrénaline chez 39 enfants en prévention du syndrome de bas débit cardiaque postopératoire suivait un modèle monocompartimental. La clairance augmentait avec le poids selon le principe de l’allométrie. Les augmentations résultantes de la fréquence cardiaque et de la pression artérielle moyenne suivaient un modèle d’effet direct Emax. Elles étaient influencées par l’âge et la gravité des patients. Les augmentations de glycémie et lactatémie suivaient un modèle d’effet indirect. Pour la noradrénaline, chez 38 enfants atteints d’hypotension artérielle systémique, la pharmacocinétique était mono-compartimentale. La clairance était influencée par le poids (allométrie). L’augmentation induite de la pression artérielle moyenne suivait un modèle direct Emax. Elle était fonction de l’âge et de la gravité des patients. Les posologies de l’adrénaline et de la noradrénaline chez l’enfant devraient tenir compte du poids, de l’âge et de la gravité du patient : plus jeune est l’enfant et plus grave est son état, plus la posologie doit être élevée pour satisfaire les objectifs hémodynamiques.The effects of catecholamines are difficult to predict. The between-subject variability observed in clinical setting is multifactorial including constitutional and acquired characteristics of each individual. Epinephrine and norepinephrine dosages are usually extrapolated from adult data. Yet, age is a source of high variability due to development- related phenomena. A population model of epinephrine or norepinephrine was developed in haemodynamically critically ill children. This allowed to identify between-subject variability factors as well as to propose individualized dosage regimens of these two catecholamines according to the desired effect and child characteristics. Epinephrine pharmacokinetics in 39 children at high risk of postoperative low cardiac output syndrome followed a one-compartment model. Clearance increased with bodyweight according to the allometric rule. The resulting increases in heart rate and mean arterial pressure followed a direct Emax model. These were related to age and illness severity. A turn-over model described the increases in blood glucose and lactate. Norepinephrine pharmacokinetics in 38 hypotensive critically ill children followed a one compartment model. Clearance increased with bodyweight (allometry). The resulting increase in mean arterial pressure followed a direct Emax model. This was a function of age and illness severity. The dosage of epinephrine and norepinephrine in children should take into account the bodyweight, age and illness severity of the patient: the younger the child and the more serious the condition, the higher the dosage in order to meet the haemodynamic goals

Tolérance des apports glucidiques dans la prise en charge des maladies métaboliques d'intoxication protéique à révélation néonatale.

Le traitement des maladies métaboliques d intoxication comporte un arrêt de l apport protéique, une épuration du métabolite toxique et une stimulation de l anabolisme par un apport glucidique conséquent (8 mg/kg/min), afin de bloquer la production hépatique de glucose. Le risque d hyperglycémie est réel. L objectif de ce travail est d étudier la tolérance glucidique des nouveau-nés, de déterminer les facteurs de risque d hyperglycémie, d en apprécier la prise en charge thérapeutique ainsi que les complications.Cette étude rétrospective portait sur des nouveau-nés hospitalisés en réanimation à l hôpital Necker pour une maladie métabolique d intoxication entre 01.2000 et 11.2012. L hyperglycémie était définie par une glycémie capillaire > 12 mmol/L à deux reprises sur 24h.39 patients ont été étudiés avec un sexe ratio de 1,05. L âge moyen à l admission était de 9 jours et le taux de décès de 15%. Le nombre de patients hyperglycémiques était de 13 à J1, 8 à J2 et 4 à J3 pour des apports glucidiques moyens de 11,5 mg/kg/min. Les apports étaient à 83% sous forme parentérale à J1 et à 46% à J3. Aucun facteur de risque d hyperglycémie n était retrouvé, hormis un petit poids de naissance. Parmi les enfants hyperglycémiques, une abstention thérapeutique était décidée pour 4, une baisse des apports glucidiques pour 4, une insulinothérapie pour 1 et une baisse des apports associée à une insulinothérapie pour 4. Trois patients sous insuline ont présenté une hypoglycémie entre J1 et J3.L hyperglycémie est fréquente et sa prise en charge hétérogène. Les résultats suggèrent une baisse des apports glucidiques en cas d hyperglycémie, plus ou moins associée à une insulinothérapie quand celle-ci est réfractaire.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Modélisation pharmacocinétique et pharmacodynamique de l'adrénaline et de la noradrénaline chez l'enfant

Les effets des catécholamines en réanimation sont peu prédictibles. La variabilité interindividuelle des observations est d origine multifactorielle dont des facteurs pharmacocinétiques et pharmacodynamiques, dépendant de caractéristiques constitutionnelles et acquises de chaque individu. Les posologies de l adrénaline et de la noradrénaline chez l enfant sont extrapolées des données adultes. Pourtant l âge est une source de grande variabilité liée au développement. Un modèle pharmaco- statistique de l adrénaline et de la noradrénaline a été établi chez l enfant en insuffisance circulatoire aigüe. Il a permis d identifier des facteurs de variabilité entre les individus ainsi que de proposer des schémas de prescription des deux molécules en fonction de l effet souhaité et des caractéristiques de l enfant. La pharmacocinétique de l adrénaline chez 39 enfants en prévention du syndrome de bas débit cardiaque postopératoire suivait un modèle monocompartimental. La clairance augmentait avec le poids selon le principe de l allométrie. Les augmentations résultantes de la fréquence cardiaque et de la pression artérielle moyenne suivaient un modèle d effet direct Emax. Elles étaient influencées par l âge et la gravité des patients. Les augmentations de glycémie et lactatémie suivaient un modèle d effet indirect. Pour la noradrénaline, chez 38 enfants atteints d hypotension artérielle systémique, la pharmacocinétique était mono-compartimentale. La clairance était influencée par le poids (allométrie). L augmentation induite de la pression artérielle moyenne suivait un modèle direct Emax. Elle était fonction de l âge et de la gravité des patients. Les posologies de l adrénaline et de la noradrénaline chez l enfant devraient tenir compte du poids, de l âge et de la gravité du patient : plus jeune est l enfant et plus grave est son état, plus la posologie doit être élevée pour satisfaire les objectifs hémodynamiques.The effects of catecholamines are difficult to predict. The between-subject variability observed in clinical setting is multifactorial including constitutional and acquired characteristics of each individual. Epinephrine and norepinephrine dosages are usually extrapolated from adult data. Yet, age is a source of high variability due to development- related phenomena. A population model of epinephrine or norepinephrine was developed in haemodynamically critically ill children. This allowed to identify between-subject variability factors as well as to propose individualized dosage regimens of these two catecholamines according to the desired effect and child characteristics. Epinephrine pharmacokinetics in 39 children at high risk of postoperative low cardiac output syndrome followed a one-compartment model. Clearance increased with bodyweight according to the allometric rule. The resulting increases in heart rate and mean arterial pressure followed a direct Emax model. These were related to age and illness severity. A turn-over model described the increases in blood glucose and lactate. Norepinephrine pharmacokinetics in 38 hypotensive critically ill children followed a one compartment model. Clearance increased with bodyweight (allometry). The resulting increase in mean arterial pressure followed a direct Emax model. This was a function of age and illness severity. The dosage of epinephrine and norepinephrine in children should take into account the bodyweight, age and illness severity of the patient: the younger the child and the more serious the condition, the higher the dosage in order to meet the haemodynamic goals.PARIS5-Bibliotheque electronique (751069902) / SudocPARIS-BIUM-Bib. électronique (751069903) / SudocSudocFranceF

Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children.

International audienceINTRODUCTION: The response to exogenous epinephrine (Ep) is difficult to predict given the multitude of factors involved such as broad pharmacokinetic and pharmacodynamic between-subject variabilities, which may be more pronounced in children. We investigated the pharmacokinetics and pharmacodynamics of Ep, co-administered with milrinone, in children who underwent open heart surgical repair for congenital defects following cardiopulmonary bypass, including associated variability factors. METHODS: Thirty-nine children with a high risk of low cardiac output syndrome were prospectively enrolled. Ep pharmacokinetics, hemodynamic and metabolic effects were analyzed using the non-linear mixed effects modeling software MONOLIX. According to the final model, an Ep dosing simulation was suggested. RESULTS: Ep dosing infusions ranged from 0.01 to 0.23 mug.kg-1.min-1 in children whose weight ranged from 2.5 to 58 kg. A one-compartment open model with linear elimination adequately described the Ep concentration-time courses. Bodyweight (BW) was the main covariate influencing clearance (CL) and endogenous Ep production rate (q0) via an allometric relationship: CL(BWi) = thetaCL x (BWi)3/4 and q0(BWi) = thetaq0 x (BWi )3/4. The increase in heart rate (HR) and mean arterial pressure (MAP) as a function of Ep concentration were well described using an Emax model. The effect of age was significant on HR and MAP basal level parameters. Assuming that Ep stimulated the production rate of plasma glucose, the increases in plasma glucose and lactate levels were well described by turnover models without any significant effect of age, BW or exogenous glucose supply. CONCLUSIONS: According to this population analysis, the developmental effects of BW and age explained a part of the pharmacokinetic and pharmacodynamics between-subject variabilities of Ep administration in critically ill children. This approach ultimately leads to a valuable Ep dosing simulation which should help clinicians to determine an appropriate a priori dosing regimen

Pachymeningitis after meningococcal infection.

International audienc