Evaluation of the impact of pharmaceutical trainings and tools on the proper use of medicines in pediatrics.

Introduction: After six years of medication errors' (MEs) collection and analysis in a pediatric unit of a French University Hospital, the number of MEs was no longer decreasing. We then decided to set up pharmaceutical training and tools and evaluate their impact on the occurrence of ME. Materials and methods: This monocentric prospective study was carried out in the form of audits of prescriptions, preparations, and administrations before and after intervention (A1 and A2). After the analysis of A1 results, feedback was given to the teams, some tools for the proper use of medication (PUM) were distributed, and A2 was conducted. Finally, A1 and A2 results were compared. Results: Each audit included 202 observations. A total of 120 MEs were identified during A1 and 54 for A2 (p < 0.0001). The observation rate with at least 1 ME decreased from 39.11% to 21.29% (p < 0.0001), and no observation had more than two MEs during A2 in contrast to A1 (n = 12). Human factors were responsible for the majority of MEs. The audit feedback allowed professionals to feel concerned about ME. The PUM tools received an average satisfaction rating of 9/10. The staff had never participated in this type of training, and all felt it was useful to apply PUM. Conclusion: This study showed a significant impact of pharmaceutical training and tools on the pediatric PUM. Clinical pharmaceutic actions allowed us to reach our objectives and satisfied all the staff. They must, therefore, be continued to limit human factors' impact and thus contribute to the safety of drug management in pediatrics.

Exploring the genetic causes of isolated short stature. What has happened to idiopathic short stature?

Statural growth is underpinned by development of the growth plate during the process of endochondral ossification, which is strongly regulated by numerous local factors (intracellular, paracrine and extracellular matrix factors) and systemic factors (nutrition, hormones, proinflammatory cytokines and extracellular fluids). This explains why growth retardation can be associated with numerous pathologies, particularly genetic syndromes, hormonal or inflammatory conditions, or gastrointestinal disorders having a nutritional impact. However, in most cases (80%), no specific aetiology is found after clinical investigation and conventional additional tests have been carried out. In such cases, "idiopathic" short stature is diagnosed, which includes patients presenting with constitutional delay of growth and development and familial short stature, but also patients with very subtle constitutional skeletal dysplasia which are not easily identifiable. In recent years, new methods of genetic investigation (e.g. gene panels, exome or genome sequencing) have made it possible to identify many genetic variants associated with apparently isolated short stature. Indeed, it is still difficult to estimate the proportion of patients presenting with idiopathic short stature for which a molecular diagnosis of monogenic conditions could be made. This estimate varies hugely depending on the thoroughness of the clinical, laboratory and radiological assessments performed prior to molecular analysis, since retrospective analysis of positive cases usually reveals subtle signs of underlying syndromes or rare skeletal disorders. Molecular diagnosis in children is important to be able to offer genetic counselling and to organise patient management. Moreover, improved understanding of the molecular basis of these cases of short stature opens up numerous possibilities for more specific treatments targeting the growth plate. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

[Hemolytic uremic syndrome with severe neurological involvement: how should it be managed?]. / Syndrome hémolytique et urémique avec atteinte neurologique sévère: quelle prise en charge?

INTRODUCTION: The management of diarrhea-associated hemolytic and uremic syndrome (D(+) HUS) with severe acute neurological involvement continues to be debated. We report on 2 cases and discuss the treatment. CASE REPORT 1: A 2.5-year-old girl presented with generalized seizures during gastroenteritis. Blood tests revealed features of HUS and a pyramidal syndrome was found on physical examination. Brain MRI, 24h after admission, showed lesions in the periventricular and subcortical area. She was started on peritoneal dialysis (PD) and daily plasma exchanges (PE) for 10 days. Her neurological condition improved quickly as well as the findings of the second brain MRI performed after PE. One year later she had no apparent neurological or renal sequelae. CASE REPORT 2: A 2.5-year-old boy presented with generalized seizures during gastroenteritis for 3 days, leading to a diagnosis of HUS. He also had a severe pyramidal syndrome with spastic tetraparesis and aphasia. Brain MRI, 48 h after admission, revealed severe bilateral and symmetric lesions involving the thalami, internal and external capsules, lenticular nuclei, and brainstem. He was started on PD and daily PE for 10 days. Brain MRI performed after PE was unchanged. Clinically, his neurological condition improved slowly with regression of spastic tetraparesis and progressive recovery of motor skills. Nine months later, his renal function is normal but he is still having intensive physiotherapy. DISCUSSION: Both children have received similar management including 10 PEs started within 48 h after the diagnosis of D(+) HUS with severe neurological involvement, but their neurological outcome appeared to be significantly different. There is no clear proof in the literature concerning the effects of PE in such patients, even when performed very early. Eculizumab, an antibody that inhibits complement factor 5a and the formation of the membrane attack complex, has recently been used in such cases and seems to provide a more specific therapeutic action. Control studies are needed to specify its use in this disease.

Isolation and characterization of extragenic suppressor mutants of the tolA-876 periplasmic-leaky allele in Escherichia coli K-12.

tolA mutants of Escherichia coli K-12 release periplasmic proteins into the extracellular medium; they are sensitive to growth inhibitors such as cholic acid and tolerant to group A colicins and filamentous bacteriophage. Suppressor mutants of the tolA-876 allele were isolated by selecting for cholic acid resistant clones that did not release periplasmic ribonuclease I. One class of tolA suppressor strains carried mutations in the staA gene (for suppressor of tolA) located a 41 min. tolA-876 staA strains partially recovered a wild-type phenotype: they exported alkaline phosphatase and beta-lactamase into the periplasm and only released very low amounts of periplasmic proteins; moreover, they were sensitive to E1 and A colicins and more resistant than tolA-876 staA+ strains to various growth inhibitors. Furthermore, tolA-876 staA-2 and tolA+staA-2 mutants were 10- to 2700-times more resistant than staA+ strains to bacteriophages TuIa, TuIb and T4, and TuII whose receptors are major outer membrane proteins OmpF, OmpC and OmpA, respectively. SDS-PAGE analysis suggested that cell envelopes of staA or staA+ strains contained similar amounts of these proteins but characterization of strains carrying ompF (or C or A)-phoA gene fusions showed that mutation stA-2 reduced ompF gene expression by a factor of two. Analysis of double mutants strains carrying mutation staA-2 and a tolA, tolB, excC or excD periplasmic-leaky mutation showed that staA suppression was allele specific which suggested that proteins TolA and StaA might directly interact.

[Prognosis following mitral valve replacement with the Starr-Edwards 6120 prosthesis]. / Facteurs pronostiques après remplacement valvulaire mitral par la prothèse de Starr-Edwards modèle 6120.

Between 1970-78, 302 mitral valve replacements with the SE 6120 prosthesis were performed, with an average postoperative follow-up of 50,7 months, using the 3 M size (206 cases) and 2 M (96 cases with small left ventricles). Early postoperative mortality was 5,6%, late postoperative mortality: 17,2%, the 5 year actuarial survival rate: 77,4% and the 9 year survival rate 71,8% (early mortality included). There was no significant difference in survival after mono- (143 cases) and polyvalvular replacement (159 cases); only a voluminous left atrium (p less than 0,05) and left atrial thrombosis (p less than 0,01) were statistically significant prognostic factors of global mortality. Late haemorrhage due to anticoagulant therapy (3%) (0,6 per 100 patient years). The most common complication was systemic embolism (3,7 per 100 patient years). Actuarial studies showed that 86,6% at 5 years and 80,1% at 9 years, escaped this complication. Statistically the favorising roles of permanent atrial fibrillation (p less than 0,05), the size of the left atrium (p less than 0,02) of isolated demonstrated. 90,4% of the survivors were clinically improved: the functional result was better when that 86,6% at 5 years and 80,1% at 9 years, escaped this complication. Statistically the favorising roles of permanent atrial fibrillation (p less than 0,05), the size of the left atrium (p less than 0,02) of isolated demonstrated. 90,4% of the survivors were clinically improved: the functional result was better when that 86,6% at 5 years and 80,1% at 9 years, escaped this complication. Statistically the favorising roles of permanent atrial fibrillation (p less than 0,05), the size of the left atrium (p less than 0,02) of isolated demonstrated. 90,4% of the survivors were clinically improved: the functional result was better when the valve replacement was not a reoperation (p less than 0,02), when the patient was not in functional Class IV (p less than 0,01), in permanent excessively dilated (p less than 0,01) and in patients without severe tricuspid regurgitation (p less than 0,01). There was no significant difference in global mortality, the percentage of embolic events and the quality of the functional postoperative result between patients with the 3 M and those with the 2 M SE 6120 prosthesis.

[Early and late term results of triple valve replacements. Use of a tricuspid bioprosthesis]. / Résultats précoces et tardifs des triples remplacements valvulaires. Utilisation d'une bioprothèse en position tricuspidienne.

Triple valve replacement (TVR) is associated with an increased operative and long-term mortality rate. The aim of this study was to reduce operative mortality by effective myocardial protection (coronary perfusion with moderate hypothermia) and to improve long-term results by the optimal choice of valve prosthesis and, in particular, by the systematic use of xenografts for tricuspid valve replacement. Twenty TVR were performed between 1970 and 1977. Björk-Shiley prostheses were used for aortic valve replacement, Starr Edwards 6120 valves for mitral valve replacement and xenografts (7 aortic valve and 13 Hancock xenografts) for tricuspid valve replacement. This series represented 3.2% of the total number of valve replacements carried out during this period. The average postoperative follow-up was 52.6 +/- 15.2 months. Only one patient died in the first postoperative month (early mortality 5%). There were 2 late deaths, one from heart failure and one from accidental causes; the actuarial 5 year survival rate was 87.9%. Seventeen long-term survivors were studied; 6 were functionally improved. Significant (p less than 0.02) but moderate regression of cardiomegaly was observed. Abnormal auscultatory findings in the tricuspid area were found in 64.7% of survivors, and signs of mild right ventricular failure were elicited in 30.4%. There were no early or late complications due to the tricuspid valve xenograft. Thirteen patients had cardiac catheterisation over one year after operation: right atrial and mean pulmonary artery pressures were significantly reduced (p less than 0.001 and p less than 0.01 respectively); there was a moderate increase in cardiac index( p less than 0.001). Late clinical complications were rare, only one regressive cerebral embolism was observed. Triple valve replacement, when necessary, carried a limited early postoperative risk, and satisfactory functional and haemodynamic results may be obtained in the long term.

[Stenosis of the left main coronary artery. Results of aorto-coronary by-pass in 67 patients (author's transl)]. / Sténose du tronc coronaire gauche: résultats des pontages aorto-coronaires chez 67 malades.

Between 1970 and 1978 sixty-seven patients with > 50% stenosis of the left main coronary artery underwent aorto-coronary by-pass operation. The mean follow-up period was 54.7 months. Early and late post-operative mortality rates amounted to 3% and 9.2% respectively. Severe global alteration of left cineventriculography was the primary factor of survival (p < 0.01). The actuarial survival rates were 90.3% at 5 years and 84.5% at 9 years. All survivors had control ECGs. Late myocardial necrosis was rare (0.6 per 100 patient-years). 60.3% of the patients remained free from angina. Deterioration of the results mainly occured during the first 2 years but continued at a slower pace beyond the 8th year. Recurrence of angina was significantly less frequent in patients with isolated left main stenosis (p < 0.05) and when local conditions were not unfavourable to derivative surgery (p. < 0.01). On the other hand, the patient's age, sex, type of angina, history of previous infarction, number of risk factors and number of by-passes (the latter excluding possibly incomplete revascularisation) has no influence on the functional prognosis. Thirty-two patients had control, usually routine coronary arteriography 13.7 months on average after surgery. Overall patency was found in 85.9% and abnormal grafts in 16.7% of the cases. The main benefits of aorto-coronary by-pass, therefore, were a reduction in the spontaneous mortality rate of patients with left main coronary disease and a pronounced functional improvement.

[Myocardial metabolism during coronary perfusion at 10 degrees C with or without cardioplegia associated with potassium]. / Métabolisme myocardique en cours de perfusion coronaire à 10 degrees C avec ou sans cardioplégie associée au potassium.

Myocardial metabolism was studied during coronary perfusion at 10 degrees c with haemodiluted blood by sampling the coronary sinus blood of 20 patients undergoing aortic valve replacement. The patients were divided into four groups : Group 1 with continuous coronary perfusion at 10 degrees c ; Group 2 : continuous perfusion at 10 degrees c with Potassium cardioplegia ; Group 3 : discontinuous coronary perfusion at 10 degrees c ; Group 4 : discontinuous perfusion at 10 degrees c with Potassium cardioplegia. In groups 1 and 2, coronary blood flow remained constant at an average of 200 ml/mn. Cardioplegia did not affect the peripheral coronary resistances at this temperature. During coronary perfusion the average myocardial oxygen consumption was 1.38 vol/mn (Group 1) and 0.18 vol/mn (Group 2), p < 0.01. This reduced oxygen consumption results in a fall in the average amount of oxygen extracted from 4.8 p.100 (Group 1) to 1.2 p.100 (Group 2) p < 0.01. At the end of coronary perfusion lactic acid production was not observed in Groups 1 and 2. Ten minutes after coming off bypass, the percentage of oxygen extraction was nearly the same in both groups (Group 1 : 38.4 p.100 ; Group 2 : 43.2 p.100). Systemic arterial lactic acid levels tended to be higher than those of coronary sinus blood in both groups. With discontinuous coronary perfusion and an average period of myocardial anoxia of 45 mn, metabolic acidosis was observed, greater in Group 3 than in Group 4 (p < 0.05) when the aorta was unclamped. Ten minutes after the end of bypass, despite normal levels of oxygen extraction, myocardial lactate production was observed in both groups. The enzyme levels, in particular the CPK MB isoenzyme, in the coronary sinus blood, remained low throughout operation in all four groups. Deep, stable and constant myocardial hypothermia (10 degrees c) induced by coronary perfusion with haemodiluted blood, affords excellent myocardial protection ; it was not possible to show the complementary benefits of Potassium cardioplegia at such low temperatures.

[Comparative study of myocardial protection by coronary perfusion in deep hypothermia (10 degrees C) with or without potassium cardioplegia. Clinical, electrocardiographic, enzymatic results; biochemical and histological controls]. / Etude comparée de la protection myocardique par perfusion coronaire en hypothermie profonde (10 degrees C) avec ou sans cardioplégie au potassium. Résultats cliniques, électocardiographiques, enzymatiques, contrôles biochimiques et histologiques.

A technique of coronary perfusion with diluted blood, giving homogenous myocardial cooling (10-12 degrees C) under lignocaine perfusion, with or without potassium (K) cardioplegia is presented. The first 75 operated cases were used to adjust the optimal lignocaine (5 mg/min) and K (2 meq/min in continuous coronary perfusion, 5 meq/min in discontinuous coronary perfusion) dosage in the myocardial protection circuit. Then, 123 operated patients (78 aortic valve replacement, 30 mitro-aortic double valve replacement, 15 other operations on the ascending aorta) were classified into four groups prospectively: 1. Continuous coronary perfusion 10 degrees C, 2. Continuous coronary perfusion 10 degrees C with associated K cardioplegia, 3. Discontinuous coronary perfusion 10 degrees C, 4. Discontinuous coronary perfusion 10 degrees C with K cardioplegia. The best return of cardiac activity was observed in Group 1 and this was statistically significant with a high percentage of spontaneous heart beating after declamping the aorta (average 10 minutes), immediate efficacity of left ventricular contraction, and absence of arrhythmias, especially the transient conduction defects observed with K cardioplegia. In Group 1, during mitro-aortic valve replacement, after over 60 minutes aortic clamping, no significant reduction of ATP or myocardial phosphocreatinine or changes of hexosemonophosphates were observed, contrary to the findings after 15 minutes aortic clamping at 28 degrees C in a control group of mitral valve replacements (n = 10). Myocardial changes on electron microscopy in the subendocardial region of the left ventricle were minimal or absent, especially with respect to the mitochondria. The early post-operative course was the same in all four groups: of the 123 patients operated, early mortality was 2.4 p. 100 (1.6 p. 100 from intercurrent causes), severe arrhythmias were observed in 1.6 p. 100, supraventricular arrhythmias in 4.9 p. 100, myocardial infarction in 0.8 p. 100, electrocardiographic ischaemia in 0.8 p. 100, and atrioventricular block in 0.8 p. 100. The average enzyme level (CPK, SGOT, LDH) in the early postoperative period were low, with no correlation with the duration of aortic clamping.

[Myocardial protection by perfusion in deep hypothermia (10 degrees C) with or without cardioplegia (author's transl)]. / Protection myocardique par perfusion en hypothermie profonde (10 degrees C) avec ou sans cardioplégie.

A technique of myocardial protection using a perfusion circuit in deep hypothermia via the ascending aorta or by selective cannulation of the coronaries has been used over a period of 2 years in almost 200 patients undergoing surgery requiring prolonged aortic clamping. It ensures rapid and homogeneous cooling of the myocardium (10-12 degrees C) and meets its reduced oxygen needs. It may be completed by cardioplegia (infusion of potassium chloride or lidocaine using an automatic syringe at a determined level). This simple technique permits a rapid spontaneous return of normal effective cardiac action. No low cardiac output syndromes have been seen since it has been used. Laboratory, histological, biochemical and haemodynamic studies carried out have confirmed its harmless nature.

[Factor analysis fever in the early postoperative period following cardiopulmonary bypass surgery in adults. Correlation with bacteriological data. Statistical study of 518 case histories by computer]. / Analyse des facteurs de fièvre dans les suites prècoces des C.E.C. chez l'adulte. Corrèlations avec les donnèes bactèriologiques. Etude statistique de 518 dossiers traités par informatique.

The results of a continuous series of 518 adults undergoing cardiopulmonary bypass surgery, operated on by the same surgeon, comprising valvular replacement and aorto-coronary bypass surgery with a peroperative protocol of asepsis and a short prophylactic course of Penicillin and Streptomycin, a preoperative and postoperative bacteriological study, were treated by computer. The postoperative temperature chart showed a progressively decreasing pyrexia in the first 8 days after cardiopulmonary bypass. The nature of the operation, the bypass time, the quantity of blood used during operation and the blood loss were statistically significant factors. Patients with a clinical infection had significantly higher temperatures from the first on. 8,9% of patients had a febrile reaction which continued after the 10th day after cardiopulmonary bypass. The cause was not always apparent but the appearance of their temperature graphs was distinguishable after the first week. Analysis of the systematic bacterial specimens showed bacterial contamination of nearly 10% of drains, 10% of blood cultures, over 15% of intravenous infusion catheters and 70% of urinary catheters. The significance of these results is discussed. The normal appearance of the temperature chart after cardiopulmonary bypass surgery in the absence of clinical complications and bacterial contamination has been established.

[Results of mitral-aortic valve replacements]. / Résultats des remplacements valvulaires mitro-aortiques.

Seventy-five combined mitral and aortic valve replacements were done between 1970 and 1976 with a minimum follow-up of 12 months and a mean of 3.72 +/- 17 months using à Björk prosthesis in the aortic position and the Starr 6120 prosthesis in the mitral position. The early post-operative mortality was 5.3% and the late mortality 8.4%. The actuarial survival curve projected a mortality of 16% at 6 years, including the operative mortality. The survival at 6 years did not differ from that of mitral valve replacement alone during the same period, though it was less than the survival of aortic valve replacement for aortic regurgitation. Among the post-operative complications only 3 embolic complications were seen. Surprisingly, the degree of heart failure, the radiological heart size, and the haemodynamic data showed no satistically significant influence on the post-operative mortality. All of the survivors except one showed a functional improvement. Haemodynamic checks in 13 patients showed a significant reduction in mean pulmonary arterial pressure, in mean capillary wedge pressure and in arteriovenous oxygen difference, but not in the cardiac index. The radiological heart size was significantly reduced but this reduction was usually limited.