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The authors describe a germ-line mutation in the gene for PRKAR1A in three unrelated patients with acrodysostosis and resistance to multiple hormones. The mutated protein subunit impairs the response of protein kinase A to cyclic-AMP stimulation. Numerous hormones activate heterotrimeric G-protein–coupled receptors, which then activate G protein and adenylyl cyclase, generating intracellular cAMP. 1 In turn, cAMP activates protein kinase A, resulting in the phosphorylation of specific proteins that mediate the physiological effects of these hormones. 2 – 4 Loss-of-function mutations in the gene encoding GNAS cause pseudohypoparathyroidism type 1a, a disease with characteristic developmental and skeletal abnormalities (collectively called Albright's hereditary osteodystrophy, i.e., short stature, brachydactyly most frequently affecting the fourth and fifth metacarpals, rounded facies, obesity, and heterotopic subcutaneous ossification) that are associated with hormone resistance. 1 , 5 Acrodysostosis (Online Mendelian Inheritance in Man number 101800) is a . . .

COVID-19 lockdowns have deeply impacted teaching programs. Online teaching has suddenly become the main form of medical education, a form that may be used as long as the pandemic continues. We aimed at analyzing how online teaching was perceived by both teachers and learners to help determine how to adapt curricula in the next few years. An anonymous cross-sectional survey of medical students, pediatric residents, neonatal fellows, and their respective teachers was conducted between June and August 2020 to assess feelings about quality, attendance, equivalence, and sustainability of online teaching programs. 146 Students and 26 teachers completed the survey. 89% of students agreed that the offered online teaching was an appropriate way of teaching during the pandemic. Less than half of learners and teachers felt they have received or provided a training of an equivalent level and quality as in usual courses. About one-third thought that this online teaching should continue after the crisis ends. Medical school students had significantly more mixed opinions on online teaching than residents and fellows did. Attendance of learners significantly improved with synchronous online classes (p < 0.001), and among more advanced learners (p < 0.002). Our study is the first of this kind to assess simultaneously the feelings of learners at different levels (medical students, residents, and fellows) and their respective teachers of pediatric on programs taught online. It showed that online programs were perceived as appropriate ways of teaching during the COVID pandemic. Further studies are, however, needed to assess the efficacy of such teaching methods on medical skills and communication capabilities.

Glucose homeostasis is a real challenge for extremely preterm infants (EPIs) who have both limited substrate availability and immature glucose metabolism regulation. In the first days of life, EPIs frequently develop transient glucose intolerance, which has a complex pathophysiology that associates unregulated gluconeogenesis, immature insulin secretion, and peripheral insulin resistance. In this population, glucocorticoid therapy is frequently administrated to prevent severe bronchopulmonary dysplasia. During this treatment, glucose intolerance classically increases and may lead to hyperglycemia. We report a case of neonatal hypoglycemia that was concomitant to a glucocorticoids administration, and that led to a congenital hyperinsulinism diagnosis in an EPI with a heterozygous ABCC8 variant. The variant was inherited from his mother, who had developed monogenic onset diabetes of the youth (MODY) at the age of 23. ABCC8 encodes a beta-cell potassium channel unit and causes congenital hyperinsulinism or MODY depending on the mutation location. Moreover, some mutations have been observed in the same patient to cause both hyperinsulinism in infancy and MODY in adulthood. In our case, the baby showed repeated and severe hypoglycemias, which were undoubtedly time-associated with the betamethasone intravenous administration. This hyperinsulinism was transient, and the infant has not yet developed diabetes at three years of age. We take the opportunity presented by this unusual clinical presentation to provide a review of the literature, suggesting new insights regarding the pathophysiology of the beta-pancreatic cells’ insulin secretion: glucocorticoids may potentiate basal insulin secretion in patients with ABCC8 mutation.

NAVA could have a place in these cases if Edi signal is detectable from the residual healthy diaphragm. [...]NAVA gives a respiratory assistance proportional to the detected Edi for every spontaneous breath and provides a sort of ‘diaphragmatic training’. [...]NAVA would provide an optimal synchronisation of ventilation with the contractions of the intact hemidiaphragm, compensating for the dysfunctional side, and this could unload the work of breathing while training the diaphragm by reducing the level of assistance (NAVA level).2 In cases like ours, NAVA could be theoretically better than a conventional technique because NAVA provides a variable pressure tailoring to the demand for each respiratory effort. Since spontaneous breathing pattern is irregular and variable in neonates,3 this breath-to-breath adaptation significantly reduces asynchronies1 4 and may allow to exploit every breath for the ‘diaphragmatic training’. Interestingly, NAVA has been already successfully applied in other diaphragmatic conditions such as congenital diaphragmatic hernia with similar encouraging results.5 Even preterm infants with bronchopulmonary dysplasia and superimposed acute respiratory distress syndrome may have a theoretical benefit in using NAVA for the weaning.6 Roosens et al reported on a full-term neonate with diaphragmatic paralysis due to birth trauma treated with NAVA, while we described a case of a preterm neonate with postsurgical diaphragmatic paralysis.7 In both cases, NAVA seemed to ‘train’ the diaphragm and we observed a short-term increment of Edi, and in both patients NAVA allowed a clinical improvement.

Very low birth weight (VLBW) neonates present a high risk of metabolic bone disease (MBD). Our main objective was to determine the easiest way to make an early diagnosis of this disease by identifying surrogate biomarkers before any radiological signs occurred. We conducted in our NICU a 6-month observational prospective study, with inclusion of all singleton VLBW neonates. We collected clinical and biological data, and nutritional intakes during hospitalization. We defined biological MBD (bMBD) as alkaline phosphatase (ALP) levels superior to 600 UI/L at day of life 30 (DOL30) and performed a case-control analysis. Nine out of 30 patients (30%) exhibited bMBD. All have extremely low birth weight and were significantly younger in gestational age (GA) and smaller at birth. There was no statistically significant difference in nutritional intake between bMBD and control groups. In the bMBD group, phosphatemia was lower since DOL3. ALP was already significantly higher at DOL15, and way beyond normal range.Conclusions: Our results showed that even the strict respect of nutritional guidelines cannot completely prevent bMBD in high-risk patients and suggest that an early screening from DOL15, with ALP levels greater than 500 UI/L, could be sufficient for detection of upcoming MBD.What is known: • Metabolic bone disease of prematurity (MBD) definition is not consensual, but biological changes appear earlier than radiological signs of rickets. • MBD management relies on biological evidence. Treatment is based on phosphate and/or calcium and calcitriol supplementation.What is new: • Studying phosphocalcic biological assessment in very low birth weight neonates, we showed respect of nutritional guidelines could not protect from biological MBD. • Increase in alkaline phosphatase (ALP), about 500 UI/l at day of life 15, could be a biomarker of MBD with no need of X-ray evaluation and sufficient to begin a treatment to prevent osteopenia.

Glucose homeostasis is a real challenge for extremely preterm infants (EPIs) who have both limited substrate availability and immature glucose metabolism regulation. In the first days of life, EPIs frequently develop transient glucose intolerance, which has a complex pathophysiology that associates unregulated gluconeogenesis, immature insulin secretion, and peripheral insulin resistance. In this population, glucocorticoid therapy is frequently administrated to prevent severe bronchopulmonary dysplasia. During this treatment, glucose intolerance classically increases and may lead to hyperglycemia. We report a case of neonatal hypoglycemia that was concomitant to a glucocorticoids administration, and that led to a congenital hyperinsulinism diagnosis in an EPI with a heterozygous ABCC8 variant. The variant was inherited from his mother, who had developed monogenic onset diabetes of the youth (MODY) at the age of 23. ABCC8 encodes a beta-cell potassium channel unit and causes congenital hyperinsulinism or MODY depending on the mutation location. Moreover, some mutations have been observed in the same patient to cause both hyperinsulinism in infancy and MODY in adulthood. In our case, the baby showed repeated and severe hypoglycemias, which were undoubtedly time-associated with the betamethasone intravenous administration. This hyperinsulinism was transient, and the infant has not yet developed diabetes at three years of age. We take the opportunity presented by this unusual clinical presentation to provide a review of the literature, suggesting new insights regarding the pathophysiology of the beta-pancreatic cells’ insulin secretion: glucocorticoids may potentiate basal insulin secretion in patients with ABCC8 mutation.

Four indicators of severe neonatal morbidity (SNM) (intraventricular hemorrhage stages 3-4, retinopathy of prematurity (ROP) stage 3, severe bronchopulmonary dysplasia (BPD), and/or necrotizing enterocolitis) are well-known to be associated with poor infancy outcome after very preterm birth. Practice changes according to recent guidelines were implemented after medical team restructuration. We hypothesized that these changes may have improved overall survival and SNM-free survival in extremely preterm infants (EPI). We conducted a monocentric, retrospective, uncontrolled before-after study at our neonatal intensive care unit including all inborn alive neonates with gestational age less than 28 weeks during two periods (period 1 2016-2017, period 2 2019-2020). We compared the global and SNM-free survival rates before and after changes were implemented. Clinical, ventilatory, and nutritional data were also collected for comparison. We included 163 EPI (76 for period 1, 87 for period 2). Twenty-five patients deceased before home discharge in each group. The median duration of invasive ventilation was shorter during period 2 (4 vs 17 days, p < 0.01). Patients of period 2 had an earlier exclusive enteral nutrition (20 vs 34 days, p < 0.01). The composite endpoint of \"death or SNM\" was lower during period 2 (40.2% vs 55.3%, p = 0.06). Neonates of period 2 were more frequently free of any SNM indicators (83.9% vs 66.7%, p = 0.03). ROP and nosocomial infections were less frequent during period 2 (3.2% vs 21.7%, p < 0.005 and 37.1% vs 62.7%, p = 0.006; respectively). We also observed lower rates of moderate and severe BPD during period 2.Conclusion: The evolution of our clinical practices appears to have positive effects on global and SNM-free survival and seems to have reduced the incidence of nosocomial infections.What is known: • Using global survival and severe neonatal morbidity-free survival rates allows to compare inter- and intra-team critical care practices in neonatal intensive care units. • Major changes in clinical procedures, in accordance to recent guidelines, were implemented after the restructuration of the medical team in 2018, with the expected objective of improving morbidity and mortality of extremely premature infants (EPI) in our unit.What is new: • After the changes, EPI exhibit a lower composite endpoint of \"death or severe neonatal morbidity (SNM)\" and were more frequently free of any SNM indicators concomitantly with a shorter median duration of invasive ventilation and parenteral nutrition. • The evolution of local clinical practices may positively impact mortality and morbidity within a few years.

To the Editor: A higher risk of metabolic bone disease (MBD) of prematurity is associated with a lower gestational age (GA) and birth weight (BW) [1, 2]. Urinary assessments exhibited no difference in calcium and phosphate excretion between the two groups. [...]treatment based on supplementation with phosphorus and/or calcium (to reach total intakes of 90 and 150 mg/kg/d, respectively), as suggested in previous studies [1, 4], could be administered earlier to the patients exhibiting biological signs of ongoing MBD.

SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA -mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA -mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1–16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7–6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8–52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95% CI = 1.1–2.1), >5 lines of prior treatments (HR = 1.4, 95% CI = 1.0–2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3–13.6). N  = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Background Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET). Methods This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies. Results In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9–88) and 92.7% (95% CI: 88.2–95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3–4; p  = 0.0001), Ki-67 at surgery (≤10% vs >10%; p  = 0.0093), pathological tumour size (pT1–2 vs pT3–4; p  = 0.0012) and node status (pN negative vs positive; p  = 0.007), adjuvant chemotherapy ( p  = 0.0167) and PEPI score (PEPI group I + II vs III; p  = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS ( p  = 0.0069, hazard ratio = 3.33 (95% CI: 1.39–7.98)). Conclusions Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.