Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

Evaluation of the social skills of low birthweight infants using the Interaction Rating Scale.

[Purpose] This study aimed to examine, using the Interaction Rating Scale, the effect of social skills at 18 months of life on the subsequent development of low birthweight infants. [Participants and Methods] The study participants were made up of a total of 23 infants who were admitted to the neonatal intensive care unit of Hospital A and whose developmental indexes were followed up at the outpatient clinic for up to 3 years of age. The survey was conducted twice in each infant, at a corrected age of 18 months and at 36 full months of age. Social skills and developmental indexes were assessed at the corrected age of 18 months, meanwhile only developmental indexes were assessed at 36 full months, to examine associations. The Interaction Rating Scale was used to assess social skills. This scale measures various aspects of social development by observing caregiver-child interactions in situations wherein children are engaged in tasks more difficult for their age. [Results] The results demonstrated that social skills at 18 months were associated with the developmental indexes at 18 and 36 months, whereas more items were associated with the developmental index at 36 months. [Conclusion] The results indicate the need for early prediction of developmental delay and timely intervention, by assessing social skills in low birthweight infants.

Introduction of laryngeal mask airway in Japan, and its rescue use for newborns.

BACKGROUND: In neonatal resuscitation, laryngeal mask airway (LMA) is recommended when both face mask ventilation and endotracheal intubation fail. Experience of LMA among obstetricians, nurses and midwives in Japan, however, is limited. The aims of the present study were to (i) offer an LMA training course to professionals dealing with low-risk pregnancies at institutions across Japan; and (ii) assess the subsequent use and value of LMA at the participating institutions. METHODS: Between August 2016 and March 2017, a total of 18 training courses for 60 min were provided for around 350 medical personnel from 51 institutes. LMA use over the subsequent 12 months was assessed via a postal questionnaire. RESULTS: After training, a total of 38 institutes introduced LMA. Of 13 254 live births, seven cases of rescue use LMA in "cannot ventilate, cannot intubate" situations were reported. None of these seven newborns had any malformation of the upper airway. LMA insertion resulted in adequate ventilation in all seven cases. CONCLUSION: LMA can be a life-saving tool in neonatal resuscitation. All medical institutions dealing with low-risk pregnancies in Japan should be equipped with this device.

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann, Sotos, and Kabuki syndromes: A nationwide survey in Japan.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is occasionally associated with hyperinsulinemic hypoglycemia (HH) in the neonatal period. Sotos syndrome (SS) and Kabuki syndrome (KS) are other malformation syndromes that may be complicated with HH, however, the detailed clinical characteristics of HH accompanied with these syndromes remain unclear. We herein conducted a nationwide questionnaire survey in Japan. We sent a primary questionnaire concerning the clinical experience for these syndromes to 347 perinatal care institutions. As a result, 222 departments or hospitals returned the questionnaires and the total numbers of BWS, SS, and KS patients were 113, 88, and 51, respectively. We sent a secondary questionnaire to 31 institutions where patients with these syndromes presented with HH during infancy. The secondary questionnaires were returned from the institutions and the numbers of patients were 16 for BWS, 9 for SS, and 3 for KS, respectively. Then, we compared the clinical characteristics of infants suffering from transient HH with and without these dysmorphic syndromes. As a result, BWS, SS, and KS patients showed significantly larger body size, lower Apgar scores, higher insulin levels at HH, and shorter durations of HH than non-dysmorphic infants with transient HH. We propose that a careful observation for the signs of HH, even if not specific to the syndromes, is important for the diagnosis of patients with BWS, SS, and KS in the postnatal period. © 2016 Wiley Periodicals, Inc.

Intraday glucose fluctuation is common in preterm infants receiving intermittent tube feeding.

BACKGROUND: We previously reported on three preterm infants with blood glucose abnormalities after reaching full enteral feeding. Recently, it has been shown that clinically stable preterm infants may have large fluctuations in blood glucose after the establishment of enteral nutrition. We hypothesized that intraday glucose fluctuation is a common finding in preterm infants, but improves at term post-conceptual age. This report describes a case series. METHODS: From June 2010 to July 2012, 13 preterm infants (29.5 ± 2.1 post-conceptual weeks, 1144 ± 319 g) were enrolled in this study. Continuous glucose monitoring (CGM) was conducted on average at 33.5 ± 1.4 post-conceptual weeks, when they received gastric tube feeding every 3 h in the absence of i.v. glucose supply. RESULTS: Eight infants (62%) had large intraday glucose fluctuation with repeated hyperglycemic (>150 mg/dL) and hypoglycemic (<50 mg/dL) events. In five infants, follow-up CGM at 36-38 weeks post-conceptual age showed more stable glycemic changes without any abnormal glucose levels. CONCLUSIONS: On CGM, in some preterm infants intermittent tube feeding resulted in large intraday glucose fluctuation at 31-35 post-conceptual weeks, but the pattern disappeared before discharge (36-38 post-conceptual weeks).

Expiratory CO2 as the first sign of successful ventilation during neonatal resuscitation.

Three-lead electrocardiography and expired CO2 monitoring were used during positive pressure ventilation of seven non-intubated newborns (gestational age, 31-37 weeks; birthweight, 1503-2885 g). In all cases, adequate CO2 (>15 mmHg) was detected prior to the achievement of stable heart rate (>100 beats/min). The delay between detection of adequate CO2 and improvement of bradycardia ranged from 8 to 73 s (median, 15 s). Inadequate expired CO2 during positive pressure ventilation indicates airway obstruction or poor aeration of the newborn lungs. Thus, positive expiratory CO2 can be the first recognizable sign of successful ventilation during neonatal resuscitation.

Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome.

Sotos syndrome (OMIM #117550) is a congenital syndrome characterized by overgrowth with advanced bone age, macrocephaly, and learning difficulties. Endocrine complications of this syndrome have not yet been fully described in previous reports. We here investigated the clinical manifestations of Sotos syndrome in Japanese patients who presented with hyperinsulinemic hypoglycemia of infancy. We recruited patients diagnosed as having Sotos syndrome who presented with the complication of hyperinsulinemia during the neonatal period using a survey of the abstracts of Pediatric Meetings in domestic areas of Japan from 2007 to 2011. As a result, five patients (four females and one male) were recruited to evaluate the clinical presentation of Sotos syndrome by reference to the clinical record of each patient. A 5q35 deletion including the NSD1 gene was detected in all patients. Major anomalies in the central nervous, cardiovascular, and genito-urinary systems were frequently found. Hypoglycemia occurred between 0.5 and 3 hr after birth and high levels of insulin were initially found within 3 days of birth. The patients were treated with intravenous glucose infusion at a maximum rate of 4.6-11.0 mg/kg/min for 12-49 days. Three of the five patients required nasal tube feeding. One patient received medical treatment with diazoxide. This study shows that patients with Sotos syndrome may present with transient hyperinsulinemic hypoglycemia in the neonatal period.

Continuous glucose monitoring for suspected dumping syndrome in infants after Nissen fundoplication.

Dumping syndrome is infrequently reported, but known to occur after Nissen fundoplication in children. However, it may be difficult both to diagnose and manage. Here we presented four infants who received Nissen fundoplication for severe gastroesophageal reflux disease, two of whom developed dumping syndrome whilst the other two did not. Continuous glucose monitoring (CGM) was very useful to clearly detect large glycemic fluctuation around each feeding. CGM was also helpful to prove the effect of treatment to avoid abnormal glucose levels. We believe that dumping syndrome in children may be underdiagnosed if clinicians rely solely on the recognition of symptoms or limited frequency of blood samplings. CGM might be the most sensitive diagnostic tool.

Glycemic variability in preterm infants receiving intermittent gastric tube feeding: report of three cases.

Late-onset hypoglycemia (day 12-16, blood glucose <50 mg/dL) was detected in three preterm infants (birthweight 998-1780 g; gestational age 27-30 weeks) by routine screening. All infants showed high serum insulin levels and extremely low ketone levels at the time of hypoglycemia. Continuous glucose monitoring was conducted at 31-34 weeks' postconceptual age when the infants were receiving intermittent gastric tube feeding with no intravenous glucose infusion. The continuous glucose monitoring results showed characteristic postprandial glucose increases and subsequent sharp deceases along with many hyper- and hypoglycemic events. This fluctuating pattern disappeared at 38-40 weeks' postconceptual age. These observations suggest that prolonged insulin oversecretion may be associated with early aggressive intravenous nutrition, and that large glycemic variability is a common feature of tube-fed preterm infants that can be explained by immature glucose homeostasis.

Refeeding syndrome in a small-for-dates micro-preemie receiving early parenteral nutrition.

This report describes a small-for-date extremely low birth weight infant who manifested bradycardic events, respiratory failure, and hemolytic jaundice during her first week of life. These complications were attributed to severe hypophosphatemia and hypokalemia. Inadequate supply and refeeding syndrome triggered by early aggressive parenteral nutrition were responsible for electrolyte abnormalities.

Electrocardiogram shows reliable heart rates much earlier than pulse oximetry during neonatal resuscitation.

BACKGROUND: The aim of this study was to determine the usefulness of the three-lead electrocardiogram (ECG) during neonatal resuscitation. METHODS: Both pulse oximetry (PO) and ECG were applied immediately after delivery to measure heart rate (HR). We reviewed video recordings of the respective monitors, and checked the time at which each monitor started to display reliable rate values. RESULTS: In 20 deliveries, ECG showed HR much earlier than PO (median 38 s vs 122 s after delivery). ECG displayed reliable HR throughout resuscitation. We were able to confirm the effectiveness of the initial respiratory support from the elevation in HR. CONCLUSIONS: ECG was a safe and reliable method for showing HR, and was used to determine the initiation and the effectiveness of resuscitation in the delivery room.

One-rescuer newborn CPR using a face mask or an i-gel supraglottic airway and two-finger compressions - A manikin study with cross-over desgin.

Introduction: When unanticipated neonatal asphyxia occurs, it may be necessary for a single resuscitator to commence advanced resuscitation before others arrive. We hypothesised that a single rescuer can provide positive pressure ventilations and chest compressions using higher inflation pressures and better adherence to the recommended compression rate with an i-gel supraglottic airway than with a face mask. Method: A manikin-based cross-over study was conducted. Twenty-one midwives performed both positive pressure ventilation using a T-piece and chest compressions with the two-finger technique on a newborn manikin alone. They performed ventilation with a face mask or an i-gel. The peak inspiratory pressure (PIP) was set to 30 cmH2O. The actual PIPs were evaluated based on the values displayed on the manometer. The total amount of time taken to complete 30 cycles of three compressions and one ventilation was also evaluated. Results: The mean of the average PIP for each participant was significantly lower with a face mask than with an i-gel (17.3 ± 4.4 vs 28.2 ± 2.0 cmH2O, p < 0.00001). The amount of time taken to complete 30 cycles was significantly longer with a face mask than with an i-gel (66.2 ± 6.1 vs 60.6 ± 3.4 seconds, p < 0.0001). Conclusion: During one-rescuer newborn resuscitation using a T-piece and the two-finger technique, the PIPs are consistently high and 30 cycles of CPR are better adhered to 60 seconds using an i-gel.

[Decreased Serum Copper Concentrations by Zinc Administration in Preterm Infants with Hypozincemia Are Associated with a Lower Postmenstrual Age: A Single-center Retrospective Observational Study].

Copper is one of the essential trace elements in humans, and its deficiency causes various diseases. Zinc acetate dihydrate is administered to treat hypozincemia in preterm infants; however, zinc inhibits the gastrointestinal absorption of copper, which may cause copper deficiency. To safely treat hypozincemia in preterm infants, we retrospectively analyzed the factors reducing serum copper concentrations when zinc is administered to preterm infants with hypozincemia. Seventy preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. The administration of zinc acetate dihydrate decreased serum copper concentrations in 21 out of 70 patients. In comparisons between the two groups with and without a decrease in serum copper concentrations, significant differences were observed in postmenstrual age (34.9 and 35.9 weeks, respectively) and serum zinc concentrations (62.0 and 58.0 µg/dL, respectively) at the start of the zinc acetate dihydrate treatment. A logistic regression analysis identified postmenstrual age as a significant factor decreasing serum copper concentrations. In the ROC curve, the cut-off value for postmenstrual age for a decrease in serum copper concentrations was 34.143 weeks. The present results suggest that when zinc acetate dihydrate is administered to preterm infants with a low postmenstrual age who are at higher risk of decreased serum copper concentrations, particularly to those with a postmenstrual age <34 weeks, it is important to consider copper deficiency and periodically measure serum copper concentrations.

Depressed levels of interferon-gamma and HLA-DR+CD3+ T cells in infants with transient hyperferritinemia.

Familial hemophagocytic lymphohistiocytosis (FHL), which typically has its onset during infancy, is uniformly fatal if not treated. It therefore requires prompt therapeutic intervention. Although hyperferritinemia has been emphasized as a useful marker for FHL, some nonfatal cases in infants with spontaneous remission also manifest with hyperferritinemia. However, distinguishing them is difficult because initial clinical features of these infants are similar. The authors encountered 14 infants with hyperferritinemia (serum ferritin >674 ng/mL), which normalized within 3 weeks following a benign clinical course. The authors compared the levels of HLA-DR+CD3+ T-cell subsets and interferon-gamma (IFN-γ) in the peripheral blood between these infants and FHL cases: one of the authors' own patients and others from the literature. Serum IFN-γ was not detected in infants with hyperferritinemia. Moreover, levels of HLA-DR+CD3+ T cells were extremely depressed. In contrast, serum IFN-γ was elevated and HLA-DR+CD3+ T cells were not depressed in FHL. Measurement of activated T cells and serum IFN-γ might help differentiate FHL in febrile infants with transient hyperferritinemia.

Administration of zinc to preterm infants with hypozincemia does not reduce serum copper concentrations in most cases: a single-center retrospective observational study.

BACKGROUND: Zinc is an essential trace element involved in various physiological functions. In Japan, zinc acetate dihydrate is administered to neonates and infants with hypozincemia. Since serum copper concentrations are reduced by the administration of zinc, we retrospectively investigated changes in serum zinc and copper concentrations in preterm infants with hypozincemia receiving zinc acetate dihydrate. METHODS: Sixty-three preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. RESULTS: The medians and interquartile ranges of the dosage and duration of zinc acetate dihydrate were 2.1 (1.8-2.5) mg/kg/day and 12.0 (10.0-13.0) days, respectively. Its administration increased serum zinc concentrations in 39 patients (61.9%) and to more than 70 µg/dL in 16 patients (25.4%). The group with a serum zinc concentration of 70 µg/dL or higher after administration had a significantly higher zinc dose of 2.5 mg/kg/day than the group with a serum zinc concentration of less than 70 µg/dL. Serum copper concentrations did not decrease in 44 patients (69.8%). In the group with a decreased serum copper concentration, postmenstrual age and body weight were significantly lower, while serum zinc concentrations were significantly higher at the start of administration. CONCLUSION: The present results showed that when zinc acetate dihydrate was administered to preterm infants with hypozincemia, it was possible to increase serum zinc concentrations without decreasing serum copper concentrations in many cases. However, caution may be required when administering zinc to preterm infants with a lower postmenstrual age or milder hypozincemia because serum copper concentrations may decrease.

Normothermic machine perfusion system satisfying oxygen demand of liver could maintain liver function more than subnormothermic machine perfusion.

Liver transplantation plays an important role in the medical field. To improve the quality of a donor liver, there is a need to establish a preservation system to prevent damage and maintain liver function. In response to this demand, machine perfusion (MP) has been proposed as a new liver preservation method instead of the conventional static cold storage. There is controversy about the optimal MP temperature of the donor liver. Since the oxygen consumption of the liver differs depending on the temperature, construction of a system that satisfies the oxygen demand of the liver is crucial for optimizing the preservation temperature. In this study, an MP system, which satisfies the oxygen demand of liver at each temperature, was constructed using an index of oxygen supply; the overall volumetric oxygen transfer coefficient, the amount of oxygen retention of perfusate and oxygen saturation. Both subnormothermic MP (SNMP, 20-25 °C) and normothermic MP (NMP, 37 °C) could maintain liver viability at a high level (94%). However, lactate metabolism of the liver during NMP was more active than that during SNMP. Furthermore, the ammonia metabolism of liver after NMP was superior to that after SNMP. Hence, NMP, which maintains the metabolic activity of the liver, is more suitable for preservation of the donor liver than SNMP, which suppresses the metabolic activity. In summary, normothermia is the optimal temperature for liver preservation, and we succeeded in constructing an NMP system that could suppress liver damage and maintain function.