Nighttime hypoglycemia in Japanese children with type 1 diabetes mellitus treated with multiple daily injection insulin therapy.

Prevention of hypoglycemia is an important strategy for glycemic management in patients with type 1 diabetes mellitus (T1D). Hypoglycemia is difficult to recognize at night while sleeping, particularly when using multiple daily injection (MDI) insulin therapy rather than sensor-augmented insulin-pump therapy. Therefore, it is possible that patients with T1D are at higher risk of nocturnal hypoglycemia when insulin is administered using an MDI regimen. We investigated nocturnal hypoglycemia in 50 pediatric patients with T1D on MDI insulin therapy using data from an intermittently scanned continuous glucose monitoring (isCGM) system. Hypoglycemia was observed on 446 of the 1,270 nights studied. Most of the hypoglycemic episodes were severe (blood glucose <54 mg/dL). On nights when hypoglycemia occurred, the blood glucose concentrations measured using finger-stick blood glucose monitoring (FSGM) before sleep and the next morning were lower than nights when hypoglycemia did not occur. However, few values were below the normal blood glucose range, suggesting that FSGM alone may be insufficient to detect nocturnal hypoglycemia. Approximately 7% of time was spent below the normal glucose range during the 10 hours from 21:00 to 7:00 the next morning. This result suggests that the patients on MDI insulin therapy could end up spending more time in hypoglycemia than is recommended by the American Diabetes Association (time below range <4.0% of time per day). Monitoring glucose levels overnight using an isCGM sensor may improve glycemic management via automatic detection of blood glucose peaks and troughs.

Pediatric hypertension based on Japanese Society of Hypertension Guidelines (JSH 2019) with actual school blood pressure screening data in Japan.

Blood pressure (BP) in children and adolescents is associated with their growth. BP is most strongly associated with height during height gain and with degree of obesity after reaching final height. BP in childhood and adolescence is correlated with BP in adulthood. The pathophysiology of pediatric essential hypertension is associated with obesity, excess salt intake, and a low birth weight. The common causes of pediatric secondary hypertension are renal parenchymal and renovascular diseases. The significance of diagnosing pediatric hypertension involves detecting secondary hypertension and preventing organ damage due to hypertension as well as tracking essential hypertension in adulthood. Appropriate BP measurement procedures are required for diagnosing pediatric hypertension. The inflatable bladder of an appropriately sized cuff should exceed 40% of the arm circumference. BP measurements should be performed consecutively at least 3 times using an appropriately sized cuff. The diagnosis of hypertension requires that all BP values measured on 3 or more occasions be above the reference value. The criteria for pediatric hypertension are determined based on the distribution of BP in healthy children and adolescents, with values above the 95th percentile of normal representing hypertension. Japanese criteria define pediatric hypertension as ≥120/70 mmHg for preschool children, ≥130/80 mmHg for 1st-3rd graders, ≥135/80 mmHg for 4th-6th graders, ≥140/85 mmHg for 7th-9th grade boys, ≥135/80 mmHg for 7th-9th grade girls, and ≥140/85 mmHg for senior high school boys and girls. The prevalence of Japanese pediatric hypertension was 0.9% based on proper measurement protocols. The basis of managing pediatric essential hypertension is healthy lifestyle modifications. Pharmacotherapy is indicated for persistent hypertension, symptomatic hypertension, secondary hypertension, the development of target organ damage, the presence of chronic kidney disease, and diabetes mellitus. Screening for pediatric hypertension is important; therefore, BP should be routinely measured in children and adolescents.

A case report with functional characterization of a HNF1B mutation (p.Leu168Pro) causing MODY5.

We previously performed next-generation sequencing-based genetic screening in patients with autoantibody-negative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here,we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POUS. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

Efficacy and safety of fast-acting insulin aspart versus insulin aspart in children and adolescents with type 1 diabetes from Japan.

The aim of this post-hoc subgroup analysis, which was based on data from the treat-to-target, 26-week, onset 7 trial, was to confirm the efficacy and safety of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp), both in combination with basal insulin degludec, in children and adolescents from Japan with type 1 diabetes (T1D). Of the onset 7 trial population (1 to <18 years; N = 777), 66 participants from Japan (65 Asian and one non-Asian) were randomized to mealtime faster aspart (n = 24), post-meal faster aspart (n = 19), or IAsp (n = 23). Data for the subgroup from Japan were analysed descriptively. Change from baseline in hemoglobin A1c 26 weeks after randomization was 0.23%, 0.74%, and 0.39%, for mealtime faster aspart, post-meal faster aspart, and IAsp respectively. Change from baseline in 1-h post-prandial glucose increment (based on 8-point self-measured blood glucose profiles) showed numerical differences in favor of mealtime faster aspart versus IAsp at breakfast (-30.70 vs. -2.88 mg/dL) and over all meals (-18.21 vs. -5.55 mg/dL). There were no clinically relevant numerical differences between treatment arms in the overall rate of severe or blood glucose-confirmed hypoglycemia. At week 26, mean total insulin dose was 1.119 U/kg/day for mealtime faster aspart, 1.049 U/kg/day for post-meal faster aspart, and 1.037 U/kg/day for IAsp. In conclusion, in children and adolescents with T1D from Japan, mealtime and post-meal faster aspart with insulin degludec was efficacious in controlling glycemia without additional safety concerns versus IAsp.

Residual endogenous insulin secretion in Japanese children with type 1A diabetes.

We investigated serum C-peptide immunoreactivity (CPR) levels in registered data from a multi-center collaborative nationwide type 1 diabetes study. The CPR levels were obtained from 576 and 409 children during the early registration (2013/2014) and late observation (2016/2017) periods, respectively. The percentages of children with a CPR < 0.1 or < 0.3 ng/mL increased according to the duration since diagnosis. Among patients with 5 or more years since diagnosis, 69% had a CPR < 0.1 and 95% had a CPR < 0.3 in the early registration period. A significant negative correlation was observed between the HbA1c and the CPR levels, and the HbA1c levels were significantly higher among children with a CPR < 0.1 or < 0.3 than among those with a CPR ≥ 0.6 ng/mL. During the late observation period, the prevalence of a CPR < 0.1 ng/mL was 88% among long-standing patients and 77% among patients aged 18-20 yr. Regarding the characteristics of "Responders" with a sustained CPR ≥ 0.6 ng/mL at 5 or more years since diagnosis, six of the seven were adolescent females; five of the seven had an HLA DR4-DQ4 haplotype. When type 1A diabetes mellitus (T1AD) children transit to adult care centers, most of them may have some difficulty in glycemic control because of the depleted endogenous insulin.

Increasing secular trends in height and obesity in children with type 1 diabetes: JSGIT cohort.

BACKGROUND: Recently, anthropometric indices in children with type 1 diabetes mellitus (T1DM) have begun to change. OBJECTIVE: To examine secular trends in patients' anthropometric indices. SUBJECTS: Japanese children with T1DM from the 1995, 2000, 2008 and 2013 cohorts of The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes. METHODS: We analysed serum haemoglobin A1c (HbA1c) levels, the incidence of severe hypoglycaemic events, the types and doses of insulin, height standard deviation scores (SDS), body mass index (BMI) percentiles compared with healthy Japanese children and obesity prevalence over time. We also stratified the patients according to glycaemic control levels of <58 mmol/mol (optimal), 58-75 mmol/mol (suboptimal) and ≥75 mmol/mol (high-risk). RESULTS: Data for 513-978 patients from each of the cohorts were analysed. The incidence of severe hypoglycaemic events decreased over time (from 21 to 4.8/100 patient-years), while the proportion of insulin analogue doses increased (14.6% to 98.6%). In addition, patient height SDS (-0.22 to +0.17), BMI percentile (52.1 to 58.7) and obesity prevalence (2.1% to 5.1%) increased. Height SDS increased in all of the glycaemic control subgroups, while BMI percentile and obesity prevalence increased in the suboptimal and high-risk groups. CONCLUSIONS: Since 1995, the average height of children with T1DM has increased in parallel with increasing insulin doses. Clinicians should be aware of increased BMI in these patients and the associated risk of developing cardiovascular disease in the future.

Need for strict clinical management of patients with carnitine palmitoyltransferase II deficiency: Experience with two cases detected by expanded newborn screening.

In Japan, carnitine palmitoyltransferase II (CPTII) deficiency has been included as one of the primary target diseases in the expanded newborn mass screening program since 2018. However, many cases of the severe infantile hepatocardiomuscular form of CPTII deficiency showed severe neurodevelopmental delay or sudden death, which indicated that management of CPTII deficiency in the acute phase remains to be studied in detail. Herein, we discuss two cases diagnosed by newborn mass screening. Patient 1 was under strict clinical management from the neonatal period, with >20 admissions in 14 months, while Patient 2 was managed using a relatively relaxed approach, with only 2 admissions in the same period. Patient 1 showed normal development; however, Patient 2 expired at the age of 1 year 2 months. To develop strategies for preventing sudden deaths in patients with CPTII deficiency, this retrospective study focused on detailed clinical management practices and biochemical findings during the acute phase. We also investigated the correlation between conventional biomarkers (such as creatine kinase) and long-chain acylcarnitines. We propose that strict monitoring and immediate medical attention, even in case of slight fever or minor abdominal symptoms, can help prevent sudden death in patients with CPTII deficiency. Considering the higher morbidity rate of such patients, strict and acute management of CPTII deficiency cannot be overemphasized.

[A Case of Pneumocystin a Patient with Pneumonia That Developed during Chemotherapy for Sigmoid Cancer].

A 63-year-old man was diagnosed with advanced sigmoid cancer of pT3, pN0, sM1c, sP3, fStage Ⅳ post-operation. After CAPOX plus Bmab as the first-line chemotherapy, he underwent IRIS plus Bmab as the second-line chemotherapy. After 1 course of IRIS plus Bmab, he was admitted to the hospital for fever, dyspnea, and general fatigue. The white blood cell count was 6.2×10 3/mL, and the C-reactive protein was elevated to 12.9 mg/dL. The PaO2 of the artery blood gas analysis in room air was 46.3 mmHg, suggesting respiratory failure. He was diagnosed with PCP based on the bilateral diffused ground-glass opacities on chest CT along with an elevated serum b-D-glucan. The treatment of trimethoprim-sulfamethoxazole and steroid was then initiated. After the patient's clinical condition improved, he was discharged on day 27 post-admission.

Policy statement of enteral nutrition for preterm and very low birthweight infants.

For preterm and very low birthweight infants, the mother's own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible. If the supply of maternal milk is insufficient even though they receive adequate support, or the mother's own milk cannot be given to her infant for any reason, donor human milk should be used. Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association. Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family's financial status. In the future, it will be necessary to create a system to supply an exclusive human milk-based diet (EHMD), consisting of human milk with the addition of a human milk-derived human milk fortifier, to preterm and very low birthweight infants.

A case of secretory breast cancer in a 6 year-old girl: is it possible to make a correct preoperative diagnosis?

Secretory breast carcinoma constitutes the majority of breast cancers in children and young people less than 20 years of age. Noninvasive examination is particularly necessary for the diagnosis of breast carcinoma in children. Herein, we report a case of secretory breast carcinoma in a 6-year-old girl with psychomotor retardation. She was referred to our outpatient clinic for evaluation of a palpable mass in her left breast. A hard mass, rather than the increase in size typical of premature thelarche, was palpated. An excision biopsy was performed. Pathological findings revealed an invasive secretory breast carcinoma. We performed a retrospective review of the preoperative findings of this case, and compared it to the pathological diagnosis. Elastography, which can be performed without deep sedation or general anesthesia and without causing pain, resulted in a stiffness score of 4; however, the distinction between benign and malignant tumors on elastography, which is important to decide the intra-operative procedures, was not sufficient according to the Japanese breast cancer society clinical guidelines. This is the first report of secretory breast carcinoma in a child with a stiffness score determined by tissue elasticity imaging. A breast mass in a child with a high stiffness score of more than 4 on elastography should be referred for invasive diagnostic procedures, such as fine needle aspiration or excisional biopsy. According to our experience, an accurate preoperative diagnosis could be possible for malignant breast tumors in children. Such parameters as stiffness score on elastography are practical, noninvasive, and objective diagnostic tools for the accurate preoperative diagnosis of breast tumors in children.

Increased diagnosis of autoimmune childhood-onset Japanese type 1 diabetes using a new glutamic acid decarboxylase antibody enzyme-linked immunosorbent assay kit, compared with a previously used glutamic acid decarboxylase antibody radioimmunoassay kit.

AIMS/INTRODUCTION: We compared the results of testing for glutamic acid decarboxylase antibodies (GADAb) using a radioimmunoassay (RIA) and an enzyme-linked immunosorbent assay (ELISA) in individuals with childhood-onset type 1 diabetes mellitus. MATERIALS AND METHODS: Serum specimens were collected from 1,024 Japanese children (426 boys and 598 girls) in 2013. The median age at diagnosis was 7 years (0-18 years). The blood specimens were obtained at a median age of 13 years (2-22 years). RESULTS: Among the 628 children whose serum specimens were collected within 5 years after diagnosis, the rate of GADAb positivity was 47.9% using RIA and 69.4% using ELISA. The participants were divided into four groups according to their RIA and ELISA results for GADAb as follows: group I (RIA+/ELISA+), group II (RIA+/ELISA-), group III (RIA-/ELISA+) and group IV (RIA-/ELISA-). The clinical and genetic characteristics of group I and group III were quite similar in terms of age at diagnosis, male/female ratio, relatively high positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and human leukocyte antigen genotype. Group II contained just five patients, and was characterized by a younger age at diagnosis, low positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and a unique human leukocyte antigen genotype. If the positive rates of either autoantibody to protein tyrosine phosphatase IA-2 or autoantibody to the cation efflux transporter zinc transporter 8 or both were added to the GADAb results using RIA, the percentage of autoimmune type 1 diabetes increased from 47.9% to 78.5%. CONCLUSIONS: The diagnosis of autoimmune childhood-onset Japanese type 1 diabetes increased when GADAb results were obtained using a new ELISA method, compared with a previously utilized RIA method.

Current-Induced Modulation of the Interfacial Dzyaloshinskii-Moriya Interaction.

The Dzyaloshinskii-Moriya (DM) interaction is an antisymmetric exchange interaction that is responsible for the emergence of chiral magnetism. The origin of the DM interaction, however, remains to be identified albeit the large number of studies reported on related effects. It has been recently suggested that the DM interaction is equivalent to an equilibrium spin current density originating from spin-orbit coupling, an effect referred to as the spin Doppler effect. The model predicts that the DM interaction can be controlled by spin current injected externally. Here we show that the DM exchange constant (D) in W/CoFeB-based heterostructures can be modulated with external current passed along the film plane. At higher current, D decreases with increasing current, which we infer is partly due to the adiabatic spin transfer torque. At lower current, D increases linearly with current regardless of the polarity of current flow. The rate of increase in D with the current density agrees with that predicted by the model based on the spin Doppler effect. These results imply that the DM interaction at the heavy-metal-ferromagnetic-metal interface partly originates from an equilibrium interface spin (polarized) current which can be modulated externally.

Status and trends in the use of insulin analogs, insulin delivery systems and their association with glycemic control: comparison of the two consecutive recent cohorts of Japanese children and adolescents with type 1 diabetes mellitus.

Background Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients. Methods The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal-bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0-5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.

[A Case of Gastric Large-Cell Neuroendocrine Carcinoma Combined with Adenocarcinoma in the Cecum].

A 74-year-old man with anemia visited our department. Esophagogastroduodenoscopy showed a type 2 lesion from the angulus to the antrum. Histopathological findings indicated gastric neuroendocrine carcinoma. Colonoscopy showed a type 1 lesion at the cecum. Distal gastrectomy was performed with D1+lymph node dissection, Roux-en-Y reconstruction, and ileocecal resection with D3 lymph node dissection. The patient was pathologically diagnosed with large-cell neuroendocrine carcinoma in the stomach, pT4a(SE), med, INF a>>b-c, ly1-2, v1(SM, EVG), pN0, pM0, pStageⅡB, and adenocarcinoma (tub1>tub2)of the cecum, pT2(MP), ly1(HE), v1(EVG, SM), pN0, pM0, pStageⅠ. Postoperatively, he received oral S-1 as an adjuvant chemotherapy. His postoperative course was uneventful without any recurrence over 18 months.

Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.

Omodysplasia-2 (OMOD2; OMIM%16475) is a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies. This clinical phenotype overlaps with that of AD type Robinow syndrome. Recently, a mutation in FZD2 encoding a Frizzled Class Receptor 2 has been identified in a family with AD omodysplasia (an affected girl and her affected mother). Here, we present the second report on a heterozygous novel nonsense FZD2 mutation in OMOD2 or Robinow syndrome-like phenotype. The proband was a 16-year-old boy, who has been followed from infancy to adolescence. He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia. Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends, mildly broad femora, thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals. The abnormal skeletal pattern was persistent in adolescence; however, the humeri and femora became less undermodeled, while the humeri and radii became mildly bowed. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*). The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. Further molecular studies will permit better clarification of the phenotypic spectrum in patients with OMOD2.

Obesity and abnormal glucose tolerance in offspring of diabetic mothers: A systematic review and meta-analysis.

BACKGROUND: Rising prevalence of childhood obesity and type 2 diabetes mellitus (T2DM) is an emerging public health issue. OBJECTIVES: To investigate the association of maternal hyperglycemia exposure during pregnancy with obesity and abnormal glucose tolerance in offspring, and the age at occurrence. METHODS: We searched MEDLINE and EMBASE for observational studies on obesity and diabetes in offspring of diabetic mothers (gestational diabetes mellitus (GDM), type 1 diabetes mellitus (T1DM) and T2DM), and those on non-diabetic mothers. We performed fixed effect meta-analysis for all studies except when heterogeneity was detected. The quality of studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). RESULTS: Twenty observational studies were included involving a total of 26,509 children. Offspring of GDM mother had higher BMI z-score in childhood (pooled MD: 0.14, 95%CI: 0.04-0.24, seven studies, 21,691children, low quality of evidence). Offspring of T1DM mothers had higher BMI z-score from prepubertal to adolescent (pooled MD: 0.35, 95% CI: 0.13-0.58, three studies, 844 children, low quality of evidence) compared with control. After adjustment for maternal pre-pregnancy BMI, this association remained in offspring of T1DM, but disappeared in those of GDM mothers. Offspring of GDM mother had higher 2-hour plasma glucose from prepubertal to early adulthood (pooled MD: 0.43 mmol/L, 95% CI: 0.18-0.69, five studies, 890 children), while those of T1DM mothers had higher rate of T2DM in 2-5 years old to early adulthood (pooled odds ratio [OR], 6.10: 95% CI: 1.23-30.37, two studies, 448 children, very low quality of evidence) compared with control. As there was only one study with offspring of T2DM mothers, evidence is sparse. LIMITATIONS: Only observational studies were included, with a few adequately adjusted for covariables. CONCLUSIONS: Exposure to maternal hyperglycemia was associated with offspring obesity and abnormal glucose tolerance especially in offspring of T1DM mothers, but the evidence relies on observational studies with low quality of evidence only.

Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes.

BACKGROUND: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D). OBJECTIVES: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. METHODS: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers. RESULTS: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis. CONCLUSIONS: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.

Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial.

OBJECTIVE: Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan. DESIGN: Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015. PATIENTS: Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1). MEASUREMENTS: Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development. RESULTS: Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved. CONCLUSION: Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.

Improvement in glycemic control through changes in insulin regimens: findings from a Japanese cohort of children and adolescents with type 1 diabetes.

OBJECTIVE: Although insulin analogs have dramatically changed diabetes treatment, scarce evidence is available on those effects. We aimed to explore whether glycemic control had improved, the use of insulin analogs had been increased, and hypoglycemic events had decreased over time in Japanese pediatric patients with type 1 diabetes (T1D). METHODS: Glycated hemoglobin A1c (HbA1c) values, proportion of insulin regimens, incidence of severe hypoglycemic events, and pubertal increase in HbA1c were compared in three cohorts of childhood-onset Japanese T1D patients (567 subjects in the 1995 cohort, 754 subjects in the 2000 cohort, and 806 subjects in the 2008 cohort). RESULTS: Mean HbA1c values tended to decrease [78.5 mmol/mol (9.33%) in the 1995 cohort, 68.2 mmol/mol (8.39%) in the 2000 cohort, and 61.2 mmol/mol (7.75%) in the 2008 cohort; P < .0001]. The proportion of patients who received basal-bolus treatment tended to increase with statistical significance, as did the proportion on insulin analogs. The incidence of severe hypoglycemic events (events/100 patients/y) had decreased (19.1 in the 2000 cohort and 8.7 in the 2008 cohort; P = .02). The pubertal increase in HbA1c tended to decrease [males, 12.0 mmol/mol (1.10%) in 1995, 9.4 mmol/mol (0.85%) in 2008, and 9.4 mmol/mol (0.86%) in 2008; P = .55; females, 14.0 mmol/mol (1.28%) in 1995, 10.3 mmol/mol (0.94%) in 2000, and 4.2 mmol/mol (0.38%) in 2008; P = .0003]. CONCLUSIONS: Glycemic control and incidence of severe hypoglycemic events were chronologically improved, especially in female adolescents.