Respiratory Paradoxical Adverse Drug Reactions Associated with Acetylcysteine and Carbocysteine Systemic Use in Paediatric Patients: A National Survey

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence

Empirical analysis of PGA-MAP-Elites for neuroevolution in uncertain domains

Quality-Diversity algorithms, among which MAP-Elites, have emerged as powerful alternatives to performance-only optimisation approaches as they enable generating collections of diverse and high-performing solutions to an optimisation problem. However, they are often limited to low-dimensional search spaces and deterministic environments. The recently introduced Policy Gradient Assisted MAP-Elites (PGA-MAP-Elites) algorithm overcomes this limitation by pairing the traditional Genetic operator of MAP-Elites with a gradient-based operator inspired by Deep Reinforcement Learning. This new operator guides mutations toward high-performing solutions using policy-gradients. In this work, we propose an in-depth study of PGA-MAP-Elites. We demonstrate the benefits of policy-gradients on the performance of the algorithm and the reproducibility of the generated solutions when considering uncertain domains. We first prove that PGA-MAP-Elites is highly performant in both deterministic and uncertain high-dimensional environments, decorrelating the two challenges it tackles. Secondly, we show that in addition to outperforming all the considered baselines, the collections of solutions generated by PGA-MAP-Elites are highly reproducible in uncertain environments, approaching the reproducibility of solutions found by Quality-Diversity approaches built specifically for uncertain applications. Finally, we propose an ablation and in-depth analysis of the dynamic of the policy-gradients-based variation. We demonstrate that the policy-gradient variation operator is determinant to guarantee the performance of PGA-MAP-Elites but is only essential during the early stage of the process, where it finds high-performing regions of the search space

Analysis of travelling waves associated with the modelling of aerosolised skin grafts

A previous model developed by the authors investigates the growth patterns of keratinocyte cell colonies after they have been applied to a burn site using a spray technique. In this paper, we investigate a simplified one-dimensional version of the model. This model yields travelling wave solutions and we analyse the behaviour of the travelling waves. Approximations for the rate of healing and maximum values for both the active healing and the healed cell densities are obtained

Pneumomediastinum in the neonatal and paediatric intensive care unit

The incidence, aetiology and pathophysiology of pneumomediastinum (PM), an uncommon and potentially serious disease in neonates and children, were evaluated. A retrospective chart review of all patients diagnosed with PM who were hospitalised in the intensive care unit of the University Children’s Hospital Zürich, Switzerland, from 2000 to 2006, was preformed. We analysed the incidence, severity and causes of PM and investigated the possible differences between neonatal and non-neonatal cases. Seven children and nine neonates were identified with PM. All patients had a good outcome. Six cases of PM in the group of children older than 4 weeks were deemed to be caused by trauma, infection and sports, whereas one case was idiopathic. All nine neonatal cases presented with symptoms of respiratory distress. We were able to attribute four cases of neonatal PM to pulmonary infection, immature lungs and ventilatory support. Five neonatal cases remained unexplained after careful review of the hospital records. In conclusion, PM in children and neonates has a good prognosis. Mostly, it is associated with extrapulmonary air at other sites. It is diagnosed by chest X-ray alone. We identified mechanical events leading to the airway rupture in most children >4 weeks of life, whereas we were unable to identify a cause in half of the neonates studied (idiopathic PM)

Selecting short-statured children needing growth hormone testing: Derivation and validation of a clinical decision rule

<p>Abstract</p> <p>Background</p> <p>Numerous short-statured children are evaluated for growth hormone (GH) deficiency (GHD). In most patients, GH provocative tests are normal and are thus in retrospect unnecessary.</p> <p>Methods</p> <p>A retrospective cohort study was conducted to identify predictors of growth hormone (GH) deficiency (GHD) in children seen for short stature, and to construct a very sensitive and fairly specific predictive tool to avoid unnecessary GH provocative tests. GHD was defined by the presence of 2 GH concentration peaks < 10 ng/ml. Certain GHD was defined as GHD and viewing pituitary stalk interruption syndrome on magnetic resonance imaging. Independent predictors were identified with uni- and multi-variate analyses and then combined in a decision rule that was validated in another population.</p> <p>Results</p> <p>The initial study included 167 patients, 36 (22%) of whom had GHD, including 5 (3%) with certain GHD. Independent predictors of GHD were: growth rate < -1 DS (adjusted odds ratio: 3.2; 95% confidence interval [1.3–7.9]), IGF-I concentration < -2 DS (2.8 [1.1–7.3]) and BMI z-score ≥ 0 (2.8 [1.2–6.5]). A clinical decision rule suggesting that patients be tested only if they had a growth rate < -1 DS and a IGF-I concentration < -2 DS achieved 100% sensitivity [48–100] for certain GHD and 63% [47–79] for GHD, and a specificity of 68% [60–76]. Applying this rule to the validation population (n = 40, including 13 patients with certain GHD), the sensitivity for certain GHD was 92% [76–100] and the specificity 70% [53–88].</p> <p>Conclusion</p> <p>We have derived and performed an internal validation of a highly sensitive decision rule that could safely help to avoid more than 2/3 of the unnecessary GH tests. External validation of this rule is needed before any application.</p

POS0724 GENDER DIFFERENCES IN THROMBOTIC PRIMARY ANTIPHOSPHOLIPID SYNDROME IN A LARGE COHORT OF PATIENTS FROM FOUR EUROPEAN CENTERS

Background:Autoimmune diseases occur more frequently in females and their course and severity can be affected by gender. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder in which antiphospholipid antibodies (aPL) exert a pathogenic role resulting in vascular thrombosis and/or pregnancy morbidities. Data about gender differences in thrombotic APS (t-APS) are still scarce1,2.Objectives:To evaluate the differences in frequency, disease expression and severity between females and males affected by primary t-APS.Methods:Retrospective study enrolling subjects with a formal diagnosis of primary APS (Miyakis 2006) with vascular thrombosis at onset. Women who presented with obstetric events as first aPL-related manifestation were excluded. All the patients were followed from 1967 to 2019 in four European centers: three French centers and one Italian center.Results:The study included 433 patients (68% females, 32% males). Median age at t-APS onset [31 (24-46) vs 41 (29-53) years, p<0.001] and at diagnosis [34 (27-50) vs 46 (34-57) years, p<0.001] was significantly lower in females.The most common presenting manifestations were venous thrombosis (60%) followed by arterial events (37%) and catastrophic APS (3%). Venous events were more frequent in women as compared to men (64% vs 51% p:0.012 OR:1.7 [1.1-2.5]). Sites of venous thrombosis included: limbs (35%), pulmonary (17%), cerebral (3%), portal and inferior cava (2%) and retinal (1%) veins, without gender differences. The arterial events were more frequent among men (43% vs 34% p:0.053). Strokes (27%) and myocardial infarctions (4%) were the most frequent manifestations, followed by thrombosis of limbs (2%), retina (2%) and abdominal organs (1%). Noteworthy, only men presented with visceral ischemia.During the follow-up, new thrombosis occurred in 41% of patients (179/433). 33% out of them had at least two episodes and these occurred especially among males (22% vs 10% p:0.001 OR:2.5 [1.3-4.8]). New events were mostly of the same type, but ⅓ of patients presented a switch from venous to arterial side and viceversa, with no gender differences.Complete aPL profile was available in 357 subjects: 33% had single aPL positivity, 24% double positivity and 43% triple positivity, with no differences between women and men. About 80% of the patients had a concomitant risk factor (RF) for thrombosis. Established cardiovascular RFs were more represented among men as shown in table 1. In women, estrogenic exposure was the main RFs, present in almost 40% of them.Table 1.MALESn= 137FEMALESn= 296POR [IC 95%]Traditional cardiovascular RFs, n (%)Smoke66 (48)81 (27)<0.0012.5 [1.6-3.8]Arterial hypertension59 (43)75 (25)<0.0012.2 [1.5-3.4]Dyslipidemia52 (38)72 (24)0.0041.9 [1.2-2.9]Diabetes16 (12)15 (5)0.0142.5 [1.8-5.1]Obesity13 (10)38 (13)nsOther thrombophilic factors, n (%)Estrogenic stimuli*0116 (39)-Trauma / surgery / immobilization21 (15)32 (11)nsCongenital thrombophilia9/94 (10)33/204 (16)nsData were compared using contingency tables, p value was calculated with Chi-Squared or Fisher exact test. *= hormonal therapy, pregnancy, post-partumConclusion:This gender-oriented analysis of patients with primary t-APS showed that women had the first vascular event at a younger age and mostly on the venous side, while men presented mainly with arterial events, later in life and suffered from more recurrent events. No differences were observed in the distribution of the aPL profile. The different frequency of arterial and venous events in the two groups could be attributed mainly to the presence of additional RFs rather than to biological gender-specific issues. However, it should be underlined that some RFs, such as the use of estrogens or classic cardiovascular RFs, are exclusive or more represented in one gender rather than the other, making it difficult to assess the link of causality between gender and manifestations of t-APS.References:[1]JF de Carvalho. Rheumatol Int. 2011.[2]LJ Jara. Lupus. 2005.Disclosure of Interests:None declare

Relapsing polychondritis: state of the art on clinical practice guidelines

Due to the rarity of relapsing polychondritis (RP), many unmet needs remain in the management of RP. Here, we present a systematic review of clinical practice guidelines (CPGs) published for RP, as well as a list of the most striking unmet needs for this rare disease. We carried out a systematic search in PubMed and Embase based on controlled terms (medical subject headings and Emtree) and keywords of the disease and publication type (CPGs). The systematic literature review identified 20 citations, among which no CPGs could be identified. We identified 11 main areas with unmet needs in the field of RP: the diagnosis strategy for RP; the therapeutic management of RP; the management of pregnancy in RP; the management of the disease in specific age groups (for instance in paediatric-onset RP); the evaluation of adherence to treatment; the follow-up of patients with RP, including the frequency of screening for the potential complications and the optimal imaging tools for each involved region; perioperative and anaesthetic management (due to tracheal involvement); risk of neoplasms in RP, including haematological malignancies; the prevention and management of infections; tools for assessment of disease activity and damage; and patient-reported outcomes and quality of life indicators. Patients and physicians should work together within the frame of the ReCONNET network to derive valuable evidence for obtaining literature-informed CPGs

Idiopathic central precocious puberty in girls: presentation factors

<p>Abstract</p> <p>Background</p> <p>It is sometimes difficult to distinguish between premature thelarche and precocious puberty in girls who develop breasts before the age of 8 years. We evaluated the frequencies of the signs associated with breast development and the factors influencing the presentation of girls with idiopathic central precocious puberty (CPP).</p> <p>Methods</p> <p>353 girls monitored 0.9 ± 0.7 year after the onset of CPP.</p> <p>Results</p> <p>The age at CPP was < 3 years in 2%, 3–7 years in 38% and 7–8 years in 60% of cases. Pubic hair was present in 67%, growth rate greater than 2 SDS in 46% and bone age advance greater than 2 years in 33% of cases. Breast development was clinically isolated in 70 (20%) cases. However, only 31 of these (8.8% of the population) had a prepubertal length uterus and gonadotropin responses to gonadotropin releasing hormone and plasma estradiol. The clinical picture of CPP became complete during the year following the initial evaluation.</p> <p>25% of cases were obese. The increase in weight during the previous year (3.7 ± 1.4 kg) and body mass index were positively correlated with the statural growth and bone age advance (P < 0.0001).</p> <p>There was no relationship between the clinical-biological presentation and the age at puberty, the interval between the onset of puberty and evaluation, or the presence of familial CPP.</p> <p>Conclusion</p> <p>The variation in presentation of girls with CPP does not depend on their age, interval between the onset and evaluation, or familial factors. This suggests that there are degrees of hypothalamic-pituitary-ovarian activation that are not explained by these factors.</p