Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Des formes de gaufres imprimées en 3D pourraient-elles remplacer la préparation magistrale des gélules d'hydrocortisone pour la médecine personnalisée des enfants ?

INTRODUCTION Adrenal insufficiency (AS) is a pathology that results in a disruption of the production of endogenous hormones, notably the adrenocorticotropic hormone (ACTH) and cortisone. Hydrocortisone (HCT) is mainly used in the substitution treatment of AS. The magistral preparation of HCT capsules in community pharmacies remains the only oral treatment adapted to paediatric population due to the low doses administered. However, these preparations show non-compliance in mass and content uniformity. Given the risk of overdose or underdose, a possible adrenal crisis as well as poor control of the disease cannot be excluded. Three-dimensional (3D) printing appears as a potential solution. Indeed, the use of 3D printing for drug manufacturing has considerably increased in the pharmaceutical field in recent years. The possibility to print, on demand, solid oral forms with dosages adapted to the patient, thus to practise personalized medicine, is a reason why Fused Deposition Modeling (FDM) appears as a promising tool. Elaboration of new solid oral forms by hot-melt extrusion (HME) coupled to FDM can be a solution to improve the pharmaceutical quality of single-dose magistral preparations in comparison with the capsules currently produced in community pharmacies. Nevertheless, the FDM technique poses a challenge given the small size of the forms intended for children and the possibility of HCT degradation due to the high temperatures of the processes used. The goal of this work is therefore to develop low-dose solid oral forms containing HCT, of sufficient pharmaceutical quality, by HME and FDM for the treatment of the paediatric population against AS. MATERIALS AND METHODS Materials : The elaborated formulation contained 20% of HCT; 53.83% of Affinisol® 15LV (hydroxypropylmethylcellulose) and 23.07% of Kollidon® VA 64 (vinylpyrrolidone-vinyl acetate copolymer) as polymers; 3% of tri(ethyl)citrate as plasticizer and 0.1% of red iron oxide as dye. Methods : HME and FDM 3D Printing : HME (Pharma 11, ThermoFisher Scientific®, Waltham, MA, USA) was performed at 140°C and 50 rpm to produce three batches of filaments. 20 waffle shapes with diameters of 4.5, 6.0, 7.25 mm, heights of 2.0, 2.8 and 3.2 mm and drug loads of 2, 5 and 8 mg were respectively printed (Prusa® i3MK3 3D printer, Prague, Czech Republic). The settings were: extrusion temperature, 155 °C; infill density, 30%; nozzle diameter, 0.25 mm; outside shell thickness, 0 mm. Since there is no monograph about printed forms, the monograph of uncoated tablets in European Pharmacopoeia 11th edition was used to characterize the printed forms. High Performance Liquid Chromatography (HPLC) : The HCT content was evaluated on 10 printed forms by a validated HPLC method (Agilent® 1100, Santa Clara, USA). The limit set by the European Pharmacopoeia for content uniformity (monograph 2.9.40) is an acceptance value lower than 15.0, calculated with the following equations: VA = ks (98.5 < X < 101.5%) VA = 98.5 – X + ks (X < 98.5%) VA = X – 101.5 + ks (X > 101.5%) VA = Acceptance value; k = 2.4; s = standard deviation; X = Average of the individual contents expressed as a percentage of the content indicated on the label. Dissolution Test : Dissolution studies were performed on six printed forms using the USPII paddle method in a Sotax® AT7 apparatus (Allschwil, Switzerland) in 500 mL of HCl 0.1 M during 2 h at 50 rpm and 37 °C. The limit set by the European Pharmacopoeia for conventional release solid forms (monograph 2.9.3) is a quantity of API released of at least 80% in 45 min or less. One-way ANOVA and Tuckey tests (p value of 0.01) were performed to statistically analyze inter-batch variabilities on GraphPad Prism® software (v. 5) Friability : Friability test was performed on 20 printed forms using the friability tester (Fribilator USP F2, Sotax®). After rotating at 25 rpm for 4 min, the difference in total weight (%) before and after the test was calculated for the printed forms. The limit set by the European Pharmacopoeia (monograph 2.9.7) is a loose of total weight of 1% after the assay. Stability study : The stability study was set-up according to the International Council for Harmonisation (ICH) guideline “Q1A(R2)” (2003). The printed forms were placed in climate chambers at the following condition of temperature and relative humidity (RH): 25°C ± 0.1°C/60% RH ± 0.5% RH. Tests were carried out every four weeks during 12 weeks. RESULTS AND DISCUSSION Formulation and Design Development Drug Content : TEC acts as a plasticizer in the formulation to decrease the glass transition temperature (Tg) of polymers in order to print at lower temperatures. Indeed, HCT concentration decreased when the printing temperature exceeded 155°C, indicating drug degradation. Drug Dissolution : In order to obtain a conventional release of the drug, like HCT capsules, printed forms with a low infill density (30%) have been developed because the more the infill density decreases, the more the dissolution rate of the active pharmaceutical ingredient (API) increases. In addition, the cylindrical design with an outline traditionally used did not give HCT the desired release. The outline of the shape has therefore been removed, to form a new 3D design similar to a waffle, increasing the release rate of HCT. Finally, a 0.25 mm diameter nozzle was used, unlike the 0.4 mm diameter nozzle traditionally used in FDM. Thus, the width of the layer of material deposited was finer and the dissolution rate of HCT was faster. Final Formulation and Design Content Uniformity : According to a study of Neumann et al. about the magistral preparation of HCT capsules in community pharmacies, out of 61 batches sent, 21.4% of them showed non-compliance. The content uniformity of 3D printed waffle shapes containing 2, 5 and 8 mg of HCT has shown encouraging results with a maximum acceptance value of 2.7, which was lower than the requested value of 15.0. Printed Forms Friability : The difference in total weight (%) before and after the test was respectively of 0.40%, 0.55% and 0.77% for 3D printed waffle shapes containing 2, 5 and 8 mg of HCT. Thus, the printed forms comply with the specifications. Drug Dissolution : 95.80 +/- 4.45%, 89.37 +/- 5.40%, 83.85 +/- 8.16% of HCT was released in 45 min for 3D printed waffle shapes containing 2, 5 and 8 mg of HCT respectively, indicating a conventional release. No significant difference in the amount of HCT released was shown between the different batches for printed forms containing the same HCT dosage. Printed Forms Stability : Filaments and 3D printed waffle shapes containing 2, 5 and 8 mg of HCT demonstrated stability in terms of drug dissolution rate and content during 12 weeks of conservation under the applied conditions of storage. CONCLUSION Red 3D printed waffle shapes containing low-dose HCT for pediatric use were successfully developed by HME coupled to FDM. Content uniformity, drug dissolution and printed forms friability complied with the European Pharmacopoeia specifications, despite the considerable challenge of the their small dimensions. Furthermore, filament and printed forms demonstrated stability in terms of drug content and drug dissolution rate for 12 weeks. These results therefore indicate that 3D-printed solid oral forms would make it possible to offer patients a higher pharmaceutical quality than those of the magistral preparations of capsules containing low-dose corticosteroids currently used. Solid oral forms containing different dosages of API can be printed with the same filament, offering the prospect of practicing personalized medicine in community pharmacies. In the future, reproducibility studies could be carried out with a variation of the printer model and this technique could be transferred to other APIs

Développement de mini-formes de gaufres imprimées en 3D contenant de l'hydrocortisone pour la médecine personnalisée des enfants

peer reviewedHydrocortisone is mainly used in the substitution treatment of adrenal insufficiency which results in a dysregulation of cortisol. Compounding of hydrocortisone capsules remains the only low-dose oral treatment suitable for the pediatric population. However, capsules often show non-compliance in mass and content uniformity. Three-dimensional printing offers the prospect of practising personalized medicine for vulnerable patients like children. The goal of this work is to develop low-dose solid oral forms containing hydrocortisone by hot-melt extrusion coupled with fused deposition modeling for the pediatric population. Formulation, design and processes temperatures were optimized to produce printed forms with the desired characteristics. Red mini-waffle shapes containing drug loads of 2, 5 and 8 mg were successfully printed. This new 3D design allow to release more than 80% of the drug in 45 minutes indicating a conventional release like the one obtained with capsules. Mass and content uniformity, hardness and friability tests complied with European Pharmacopeia specifications, despite the considerable challenge of the small dimensions of the forms. This study demonstrates that FDM can be used to produce innovative pediatric-friendly printed shapes of an advanced pharmaceutical quality to practice personalize medicine.Development of new oral formulations produced by hot-melt extrusion technique coupled with fused deposition modeling 3D printin

Les formes de gaufres imprimées en 3D pourraient-elles remplacer les gélules d'hydrocortisone préparées dans les pharmacies d'officine pour la médecine personnalisée des enfants ?

Development of new oral formulations produced by the hot melt extrusion technique coupled with 3D printing in order to increase the solubility of active molecules like BCSI

L'avenir de l'impression 3D pour la médecine personnalisée : Les formes de gaufres imprimées en 3D pourraient-elles remplacer la préparation magistrale des gélules d'hydrocortisone ?

INTRODUCTION Hydrocortisone (HCT) is mainly used in the substitution treatment of adrenal insufficiency (AS) which results in a disruption of the production of cortisol. The magistral preparation of HCT capsules in community pharmacies remains the only oral treatment adapted to the paediatric population due to the low doses administered. However, these preparations show non-compliance in mass and content uniformity. Three-dimensional (3D) printing appears as a potential solution because of the possibility to practise personalized medicine. The goal of this work is therefore to develop low-dose solid oral forms, of advanced pharmaceutical quality, containing HCT by HME and Fused Deposition Modeling (FDM) for the treatment of children against AS. MATERIALS AND METHODS The formulation contained HCT, Affinisol® 15LV (hydroxypropylmethylcellulose), Kollidon® VA 64 (vinylpyrrolidone-vinyl acetate), tri(ethyl)citrate and red iron oxide. HME was performed at 140°C and 50 rpm. Waffle shapes with diameters of 4.5, 6.0, 7.25 mm, heights of 2.0, 2.8 and 3.2 mm and drug loads of 2, 5 and 8 mg were printed at 155°C (Figure 1). The monograph uncoated tablets in European Pharmacopoeia 11th edition was used to characterize the printed forms. Dissolution studies were performed in 500 mL of HCl 0.1 M during 2 h. The HCT content was evaluated by a validated HPLC method. Friability test was performed at 25 rpm for 4 min. RESULTS AND DISCUSSION More than 80% of HCT was released in 45 min from waffle shapes containing 2, 5 and 8 mg of HCT, indicating a conventional drug release. The content uniformity of all 3D printed waffle shapes has shown encouraging results with maximum acceptance values lower than the requested value of 15.0. The differences in total weight before and after the test were lower than 1.0% for all 3D printed waffle shapes, which complied with the specifications. CONCLUSION Red 3D printed waffle shapes containing low-dose HCT for pediatric use were successfully developed by HME coupled to FDM. Content uniformity, drug dissolution and friability complied with the specifications, despite the considerable challenge of their small dimensions. 3D-printed solid oral forms could offer patients a higher pharmaceutical quality than capsules containing low-dose corticosteroids. Solid oral forms containing different dosages of API can be printed with the same filament, offering the prospect of practicing personalized medicine.Development of new oral formulations produced by the hot melt extrusion technique coupled with 3D printing in order to increase the solubility of active molecules like BCSI

Establishing core outcome domains in pediatric kidney disease: report of the Standardized Outcomes in Nephrology—Children and Adolescents (SONG-KIDS) consensus workshops

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology—Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease