Clinical Study Characteristics and Determinants of Partial Remission in Children with Type 1 Diabetes Using the Insulin-Dose-Adjusted A1C Definition

To evaluate the characteristics and determinants of partial remission (PR) in Belgian children with type 1 diabetes (T1D), we analyzed records of 242 children from our center. Clinical and biological features were collected at diagnosis and during follow-up. PR was defined using the insulin-dose-adjusted A1C definition. PR occurred in 56.2% of patients and lasted 9.2 months (0.5 to 56.6). 25.6% of patients entered T1D with DKA, which correlated with lower PR incidence (17.6% versus 82.3% when no DKA). In our population, lower A1C levels at diagnosis were associated with higher PR incidence and in young children (0-4 years) initial A1C levels negatively correlated with longer PR. Early A1C levels were predictive of PR duration since 34% of patients had long PRs (>1 year) when A1C levels were ≤6% after 3 months whereas incidence of long PR decreased with higher A1Cs. C-peptide levels were higher in patients entering PR and remained higher until 3 years after diagnosis. Initial antibody titers did not influence PR except for anti-IA2 titers that correlated with A1C levels after 2 years. Presence of 2 versus 1 anti-islet antibodies correlated with shorter PR. PR duration did not influence occurrence of severe hypoglycemia or diabetes-related complications but was associated with lower A1C levels after 18 months. We show that, at diagnosis of T1D, parameters associated with -cell mass reserve (A1C, C-peptide, and DKA) correlate with the occurrence of PR, which affects post-PR A1C levels. Further research is needed to determine the long-term significance of PR

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Intra‐amniotic levothyroxine infusions in a case of fetal goiter due to novel Thyroglobulin gene variants

Indications and administration of intra-amniotic infusions of L-thyroxine in the context of non-immune fetal hypothyroidism with goiter lack of standardization. Systematic follow-up of clinical features related to thyroid hormonal homeostasis may be useful to evaluate their efficiency and develop standardized management guidelines

Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency

Adrenal insufficiency is defined as impaired adrenocortical hormone synthesis. According to its source, the deficit is classified as primary (adrenal steroidogenesis impairment), secondary (pituitary adrenocorticotropic hormone deficit) or tertiary (hypothalamic corticotropin-releasing hormone deficit). The management of adrenal insufficiency resides primarily in physiological replacement of glucocorticoid secretion. Standard glucocorticoid therapy is shrouded in several controversies. Along the difficulties arising from the inability to accurately replicate the pulsatile circadian cortisol rhythm, come the uncertainties of dose adjustment and treatment monitoring (absence of reliable biomarkers). Furthermore, side effects of inadequate replacement significantly hinder the quality of life of patients. Therefore, transition to circadian hydrocortisone therapy gains prominence. Recent therapeutic advancements consist of oral hydrocortisone modified-release compounds (immediate, delayed and sustained absorption formulations) or continuous subcutaneous hydrocortisone infusion. In addition to illustrating the current knowledge on conventional glucocorticoid regimens, this review outlines the latest research outcomes. We also describe the management of pediatric patients and suggest a novel strategy for glucocorticoid replacement therapy in adults

Amiodarone-induced thyroid dysfunction in children: insights from the THYRAMIO study

Abstract Background: Amiodarone treatment is effective against various types of arrhythmias but is associated with adverse effects affecting, among other organs, thyroid function. Amiodaroneinduced thyroid dysfunction was not thoroughly evaluated in children as it was in adults, yet this affection may lead to irreversible neurodevelopmental complications. Our study aimed to define the incidence and risk factors of amiodarone-induced thyroid dysfunction in children. Methods: The study was designed as an observational study with a retrospective clinical series of 152 children treated by amiodarone in the Pediatric Cardiology Unit of our center from 1990 to 2019. All patients were divided into three groups according to their thyroid status: euthyroid, AIH (amiodarone-induced hypothyroidism) or AIT (amiodarone-induced thyrotoxicosis). Patients from these three groups were compared in terms of key clinical and therapeutic features. Results: Amiodarone-induced thyroid dysfunction was present in 23% of patients. AIT (5.3%) was three times less common than AIH (17.7%), and its occurrence increased with older age (p<0.05), treatment dosage (p<0.05), treatment duration (p<0.05) and the number of loading doses administered (p<0.05). There were no distinctive clinical features between euthyroid and AIH groups. A multivariable prediction model of AIT was built, with a yield of 66.7% as positive predictive value and 96.7% as negative predictive value. Conclusion: We observed that one in five children developed amiodarone-induced thyroid dysfunction. Special attention is required for older children with a high dosage and long-term therapy and who received a large number of loading doses, since these children are at risk to develop AIT, which is more delicate to manage than AIH

Stem cells for liver tissue repair: Current knowledge and perspectives

Stem cells from extra- or intrahepatic sources have been recently characterized and their usefulness for the generation of hepatocyte-like lineages has been demonstrated. Therefore, they are being increasingly considered for future applications in liver cell therapy. In that field, liver cell transplantation is currently regarded as a possible alternative to whole organ transplantation, while stem cells possess theoretical advantages on hepatocytes as they display higher in vitro culture performances and could be used in autologous transplant procedures. However, the current research on the hepatic fate of stem cells is still facing difficulties to demonstrate the acquisition of a full mature hepatocyte phenotype, both in vitro and in vivo. Furthermore, the lack of obvious demonstration of in vivo hepatocyte-like cell functionality remains associated to low repopulation rates obtained after current transplantation procedures. The present review focuses on the current knowledge of the stem cell potential for liver therapy. We discuss the characteristics of the principal cell candidates and the methods to demonstrate their hepatic potential in vitro and in vivo. We finally address the question of the future clinical applications of stem cells for liver tissue repair and the technical aspects that remain to be investigated

Influence of the occurrence and duration of partial remission on short-term metabolic control in type 1 diabetes: the DIABHONEY pediatric study

Objective: To evaluate the residual effect of partial remission (PR) on immediate post-PR glycemic control according to its occurrence and duration in a cohort of children with type 1 diabetes mellitus (T1DM). Patients and Methods: Values of glycemic control parameters [i.e. HbA 1C , insulin dose–adjusted hemoglobin A 1C (IDAA 1C ), glycemic target–adjusted HbA 1C (GTAA 1C )] and data from glucose monitoring devices from 189 pediatric patients with new-onset type 1 diabetes were collected retrospectively from 24 months. Patients were characterized according to their remission status (PR + and PR − ). PR + patients were subdivided into three subgroups regarding PR duration [i.e. short (⩾3–⩽6 months), intermediate (>6–⩽12 months), and long PR (>12–⩽14 months)]. We compared glycemic control data from each PR + subgroup at +6 and +12 months post-PR with PR − patients at the same postdiagnosis time. Second, PR + subgroups were compared with each other. Results: PR + patients showed improved glycemic control (i.e. HbA 1C , IDAA 1C , and GTAA 1C ) at + 6 months post-PR when compared with nonremitters (PR − ), independently of the PR duration subgroups (p < 0.05). Interestingly, patients in long PR + subgroup exhibited higher positive residual effect than short PR + subgroup with lower GTAA 1C scores (p = 0.02), better time in range (TIR) (p = 0.003), less time in hypoglycemia (10.45 versus 16.13%, p = 0.03) and less glycemic variability (83.1 mg/dl versus 98.84 mg/dl, p = 0.03). No significant differences were found for glucose control between PR + and PR − patients at +12 months post-PR. Conclusion: This study supports the positive impact of PR occurrence and duration on short-term metabolic control (better HbA 1C levels, IDAA 1C and GTAA 1C scores, TIR, and less glycemic variability) with the residual effect increasing according to PR duration

Liver cell transplantation for Crigler-Najjar syndrome type I: Update and perspectives

Liver cell transplantation is an attractive technique to treat liver-based inborn errors of metabolism. The feasibility and efficacy of the procedure has been demonstrated, leading to medium term partial metabolic control of various diseases. Crigler-Najjar is the paradigm of such diseases in that the host liver is lacking one function with an otherwise normal parenchyma. The patient is at permanent risk for irreversible brain damage. The goal of liver cell transplantation is to reduce serum bilirubin levels within safe limits and to alleviate phototherapy requirements to improve quality of life. Preliminary data on Gunn rats, the rodent model of the disease, were encouraging and have led to successful clinical trials. Herein we report on two additional patients and describe the current limits of the technique in terms of durability of the response as compared to alternative therapeutic procedures. We discuss the future developments of the technique and new emerging perspectives

RNA-based MAFA over-expression is sufficient to drive human pancreatic duct-derived cells toward a B-cell-like phenotype

RNA-based MAFA over-expression is sufficient to drive human pancreatic duct-derived cells toward a B-cell-like phenotype Elisa Corritore1, Erica Dugnani2, Valentina Pasquale2, Lorenzo Piemonti2, A. Vetere3,Susan Bonner-Weir4, Etienne M. Sokal1, Philippe A. Lysy1,5 1Institut de Recherche Expérimentale et Clinique, Pediatric Research Laboratory,Université Catholique de Louvain, Brussels, Belgium; 2San Raffaele Research Institute, Milan, Italy; 3Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, USA ; 4Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, USA ; 5Pediatric Endocrinology Unit, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium Pancreatic epithelial cells represent an attractive cell source for replacement therapy of type 1 diabetes. Previously, we designed a protocol for expansion of human pancreatic duct-derived cells (HDDCs) and showed their β-cell engineering potential. In this study, we reprogrammed HDDCs into β-cell-like lineage by over-expressing mRNAs of key pancreatic transcription factors (TFs). Pancreatic duct cells (n=6) were purified and propagated into endothelial growth-promoting media. Synthetic modified (sm) RNAs were manufactured by unidirectional subcloning of PDX1, NGN3 and MAFA into a plasmid containing 5’ and 3’ UTR regions. The UTR-flanked inserts were excised and poly(A)-tailed. The final smRNAs were synthesized through in vitro transcription followed by phosphatase and DNase treatments, before being daily transfected in HDDCs. In all donors, transfection of PDX1, NGN3 and MAFA led to upregulation of endogenous target (ex: NGN3) and β-cell marker (ex: INS, synaptophysin, SLC2A2, GCK) genes with the highest expression levels being reached after MAFA transfection. Co-transfection protocols failed to show significant improvement of β-cell differentiation. Acceptable impact on innate immune response and cell viability was noticed after 7 consecutive daily smRNA transfections, based respectively on minimal IFNA and RIG-1 gene expression and on annexin-V/PI staining. After MAFA transfection, HDDCs stained positive for MAFA and insulin (19.3 ± 3.3 %) proteins, while ELISA assays showed detectable amounts of C-peptide content and release (21.45 ± 2.42 pg/mL/106 cells) under basal conditions. In conclusion, we showed that MAFA RNA over-expression is sufficient to efficiently reprogram HDDCs toward β-cell-like phenotype in a timely manner. Further research is mandatory to demonstrate a controlled insulin secretion capacity after differentiation