Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of once-weekly somatrogon with once-daily somatropin in children with GHD. METHODS: Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS. RESULTS: This post hoc subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children. CONCLUSIONS: This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.

Higher Risk of Psychiatric Disorders in Children With Febrile Seizures: A Nationwide Cohort Study in Taiwan.

BACKGROUND: Febrile seizures occur commonly in children aged between six months and six years. A previous Danish study found a positive correlation between febrile seizures and the overall incidence of psychiatric disorders. This population-based nationwide observational study was conducted to investigate the association between febrile seizures and different psychiatric disorders in Taiwan and the associated risk factors. METHODS: This cohort study used data from the National Health Insurance Research Database in Taiwan-a nationwide claims database covering >99% of the Taiwanese population. The study period was from January 2000 to December 2015; the overall median follow-up time was 11.04 ± 10.95 years. Overall, 2464 children with febrile seizures diagnosed between 2000 and 2015 met the inclusion criteria, and 7392 children without febrile seizures matched by index year, age, and sex were included in the control cohorts. Febrile seizures and psychiatric disorders were measured as the exposure and main outcomes, respectively. RESULTS: Children with febrile seizures (n = 2463) were at a high risk of psychiatric disorders (adjusted hazard ratio, 4.70; 95% confidence interval [CI], 2.44 to 7.30; P < 0.001). The risk for anxiety was the highest (adjusted hazard ratio, 21.92; 95% CI, 11.40 to 34.05; P < 0.001). CONCLUSIONS: When treating children with febrile seizures, particular attention should be paid to the symptoms of psychiatric disorders, as early referral may be beneficial for these children.

New insights into precocious puberty and ADHD: a nationwide cohort study.

BACKGROUND: Attention deficit-hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children; however, studies delineating the association between ADHD and central precocious puberty are limited. This study aimed to understand whether children with ADHD are at a higher risk of central precocious puberty. METHODS: This population-based retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan to investigate the association between ADHD and the incidence of central precocious puberty between 2000-2015. We identified ADHD individuals treated with methylphenidate, atomoxetine or not. The control cohort consisted of individuals without ADHD. The outcome measure was central precocious puberty diagnosis. RESULTS: Among 290,148 children (mean age: 5.83 years), central precocious puberty incidence was 4.24 and 1.95 per 105 person-years in the ADHD and control groups, respectively. Children with ADHD treated with medication had a higher risk than those without ADHD. However, medication use did not affect the incidence of central precocious puberty among children with ADHD. CONCLUSION: This study showed an association between ADHD and a higher risk of central precocious puberty. Early referral of children with ADHD to a pediatric endocrinologist for evaluation may facilitate correct diagnoses and early interventions. IMPACT: ADHD is associated with a higher risk of central precocious puberty. This study provides relevant findings, as it is the first nationwide, population-based cohort study to investigate the association between ADHD and the risk of central precocious puberty with a 15-year follow-up. Early referral of children with ADHD to a pediatric endocrinologist for the evaluation of suspected precocious puberty could facilitate correct diagnosis. Early intervention treatment with gonadotropin-releasing hormone agonist might improve final height in children with central precocious puberty.

Association between child abuse exposure and the risk of psychiatric disorders: A nationwide cohort study in Taiwan.

BACKGROUND: Child abuse affects children physiologically and psychologically, increasing the risk of future psychiatric disorders. OBJECTIVE: To assess whether child abuse victims have a higher incidence of future psychiatric disorders or substance abuse. PARTICIPANTS AND SETTING: The participants consisted of a nationwide, population-based cohort selected in accordance with the Taiwan National Health Insurance Research Database. All children were enrolled between 2000 and 2015. METHODS: This was a retrospective study with a matched-cohort design. Children who experienced child abuse were identified using International Classification of Disease codes and compared with children who had not experienced child abuse by measuring rates of anxiety disorders, depressive disorders, bipolar disorders, sleep disorders, posttraumatic stress disorder/acute stress disorder, eating disorders, substance-related disorders (alcohol use disorder and illicit drug use disorder), psychotic disorders, and organic mental disorders. RESULTS: The psychiatric disorder risk was significantly higher in victims of child abuse than in controls (adjusted hazard ratio, 2.15; 95 % confidence interval, 1.92-2.40; P < 0.001). The Kaplan-Meier analysis revealed a significantly higher 15-year cumulative incidence of psychiatric disorders among child abuse victims than among controls (394.57 vs. 317.56 events per 100,000 person-years; log-rank test, P <  0.001). CONCLUSIONS: In Taiwan, child abuse is associated with increased psychiatric disorder and substance abuse risk. Individuals involved in caring for abused children, including family members, pediatricians, nurses, and social workers, as well as policy makers, should be aware of this risk. Early referral of child abuse victims to pediatric psychiatrists may help detect high-risk cases and facilitate early intervention.

Elevated serum tartrate-resistant acid phosphatase isoform 5a levels in metabolic syndrome.

BACKGROUND: Tartrate-resistant phosphatase isoform 5a is expressed in tumor-associated macrophages and is a biomarker of chronic inflammation. Herein, we correlated serum tartrate-resistant phosphatase isoform 5a levels with metabolic syndrome status and made comparisons with traditional markers of inflammation, including c-reactive protein and interleukin-6. METHODS: One hundred healthy volunteers were randomly selected, and cut-off points for metabolic syndrome related inflammatory biomarkers were determined using receiver operating characteristic curves. Linear and logistic regression models were subsequently used to correlate inflammatory markers with the risk of metabolic syndrome. RESULTS: Twenty-two participants met the criteria for metabolic syndrome, and serum tartrate-resistant phosphatase isoform 5a levels of >5.8 µg/L were associated with metabolic syndrome (c-statistics, 0.730; p = 0.001; 95% confidence interval, 0.618-0.842). In addition, 1 µg/L increases in tartrate-resistant phosphatase isoform 5a levels were indicative of a 1.860 fold increase in the risk of metabolic syndrome (p = 0.012). CONCLUSIONS: Elevated serum tartrate-resistant phosphatase isoform 5a levels are associated with the risk of metabolic syndrome, with a cut-off level of 5.8 µg/L.

Sex difference determined the role of sex hormone-binding globulin in obese children during short-term weight reduction program.

The relationship between hyperinsulinemia and decreased sex hormone-binding globulin (SHBG) levels has been observed in obese adults and children. Weight reduction not only increased insulin sensitivity but also elevated serum SHBG levels in obese adults and children. However, the correlation between the changes in insulin resistance indices and serum SHBG concentration during weight reduction program (WRP) is not fully understood, particularly in obese children. This study is to evaluate whether SHBG level is a potential biomarker that can be used to assess insulin resistance in obese children during a short-term WRP. Forty-eight obese Taiwanese children (11.7 ±â€Š2.2 years; 25 boys and 23 girls) participating in 8-week WRP were studied. Anthropometric measurements, lipid profiles, insulin resistance indices, and serum SHBG concentration were recorded at baseline and at the end of the WRP. The results showed body weight (BW), body mass index (BMI), body fat percentage (BF%), body fat weight (BFW), and insulin resistance indices such as fasting insulin, fasting insulin to glucose ratio, homeostasis model assessment (HOMA) of insulin resistance, log (HOMA) all significantly decreased after the 8-week WRP. With respect to lipid profiles, only high-density lipoprotein cholesterol (HDL-C) levels increased in both sexes. At baseline, insulin resistance indices were inversely correlated with SHBG concentrations in girls, but not in boys. The difference in SHBG after WRP was 2.58 nmol/L (95% confidence interval [CI]: -3.51, 8.66) in boys and 0.58 nmol/L (95% CI: -5.23, 6.39) in girls. There was a trend toward increased serum SHBG levels in boys (P = .39) and girls (P = .84) after weight loss, but a significantly negative correlation between the change in SHBG and in each of the insulin resistance indices only in the girls after adjusting age and ΔBFW during WRP.In conclusion, short-term WRP has the potential effects of decreased BW, BMI, BF%, and BFW, as well as increased serum HDL-C levels and insulin sensitivity in obese Taiwanese children. Although serum SHBG levels moderately increased in both sexes during short-term WRP, measuring the change in SHBG concentrations might be a potential biomarker to evaluate improvement in insulin resistance in girls only, and not in boys.

Potential effects of valproate and oxcarbazepine on growth velocity and bone metabolism in epileptic children- a medical center experience.

BACKGROUND: Children with longstanding use of antiepileptic drugs (AEDs) are susceptible to developing low bone mineral density and an increased fracture risk. However, the literature regarding the effects of AEDs on growth in epileptic children is limited. The aim of this study was to investigate the potential effects of valproate (VPA) and/or oxcarbazepine (OXC) therapy on growth velocity and bone metabolism. METHODS: Seventy-three ambulatory children (40 boys and 33 girls) with epilepsy, aged between 1 and 18 years (mean age 9.8 ± 4.1 years), were evaluated for growth velocity before and for 1 year after VPA and/or OXC treatment. The bone resorption marker serum tartrate-resistant acid phosphatase 5b (TRAcP5b) and the bone formation marker serum bone-specific alkaline phosphatase (BAP) were measured post-AEDs therapy for 1 year. RESULTS: The difference in growth velocity (ΔHt) and body weight change (ΔWt) between pre- and post-AEDs treatment were -1.0 ± 2.8 cm/year (P < 0.05) and 0.1 ± 3.9 kg/year (P = 0.84), respectively. The study population had serum TRAcP5b-SDS of -1.6 ± 1.2 and BAP-SDS of 1.7 ± 3.7 compared with sex- and age-matched healthy children. Significant correlation between serum TRAcP 5b and BAP activities was noted (r = 0.60, p < 0.001). There was a positive correlation between growth velocity and serum TRAcP 5b activity after AED treatment (r = 0.42, p < 0.01). No correlation was found between ΔHt, ΔWt, serum TRAcP 5b, BAP activity and types of AEDs. CONCLUSION: Growth velocity was significantly decreased in epileptic children after 1 year of VPA and/or OXC treatment. The effect of VPA and/or OXC therapy on dysregulation of bone metabolism might play a crucial role in physical growth.

Association between Gastroenterological Malignancy and Diabetes Mellitus and Anti-Diabetic Therapy: A Nationwide, Population-Based Cohort Study.

BACKGROUND: The relationship between diabetes mellitus (DM) and cancer incidence has been evaluated in limited kinds of cancer. The effect of anti-diabetic therapy (ADT) on carcinogenesis among diabetic patients is also unclear. MATERIALS AND METHODS: Using population-based representative insurance claims data in Taiwan, 36,270 DM patients and 145,080 comparison subjects without DM were identified from claims from 2005 to 2010. The association between the top ten leading causes of cancer-related death in Taiwan and DM was evaluated. Whether ADT altered the risk of developing cancer was also investigated. RESULTS: Incidence of cancer at any site was significantly higher in patients with DM than in those without (p<0.001). The risk of carcinogenesis imparted by DM was greatest in gastroenterological malignancies (liver, pancreas, and colorectal cancer) as well as lung, breast and oral cancer (p<0.001). Among the oral types of ADT, metformin decreased the risk of lung and liver cancer, but had less effect on reducing the risk of colorectal cancer. α-glucosidase inhibitor decreased the risk of developing liver, colorectal, and breast cancer. Apart from intermediate-acting insulin, rapid-acting, long-acting, and combination insulin treatment significantly reduced the overall cancer risk among all DM patients. In subgroup analysis, long-acting insulin treatment significantly decreased the risk of lung, liver, and colorectal cancer. CONCLUSION: Our results supported the notion that pre-existing DM increases the incidence of gastroenterological cancer. ADT, especially metformin, α-glucosidase inhibitor, and long-acting insulin treatment, may protect patients with DM against these malignancies. It is crucial that oncologists should closely collaborate with endocrinologists to provide an optimal cancer-specific therapy and diabetic treatment to patients simultaneously with cancer and DM.

Symptomatic hypercalcemia in a rabies survivor underwent hemodialysis.

Adrenal insufficiency is an uncommon and easily ignored cause among most etiologies of hypercalcemia because not all cases of adrenal insufficiency presented with hypercalcemia. In most cases of adrenal insufficiency, viral encephalitis-related panhypopituitarism is a rare complication that is sporadically encountered in previous studies. However, this complication has never been reported in rabies encephalitis because of the extremely high rate of mortality. Rapid recovery from hypercalcemia state after glucocorticoid supplement is a direct hint of adrenal insufficiency related hypercalcemia.

Neonatal vaccination with plasmid DNA encoding Cyn d 1 effectively prevents allergic responses in mice.

BACKGROUND: Allergic rhinitis is one of the most common atopic disorders in children. There is no available method to prevent airway sensitization in newborns except allergen avoidance. Recombinant DNA plasmids encoding allergens have been proven to activate Th1 but attenuate Th2-deviated allergic responses in adult animal studies. However, their preventive effects are not presumptive in neonates because of their immature immune function. The aim of this study was to examine the potential preventive effect of a DNA vaccine encoding grass pollen allergen Cyn d 1 on allergic reaction to grass pollen in neonatal mice. METHODS: Recombinant plasmid Cyn d 1 (pCyn d 1) vaccine was constructed by insertion of Cyn d 1 cDNA into the vector pcDNA3. Neonatal BALB/c mice received the vaccine once on the 3rd day of life or a second dose 2 days later. Control mice received PBS only. Mice were sensitized twice with recombinant Cyn d 1 and alum beginning at 7 weeks of age. Serum antibody responses and cytokine profiles of spleen cells were examined. RESULTS: Neonatal injection with pCyn d 1 vaccine resulted in IgG2a responses and production of interferon gamma in spleen cells. Vaccination with pCyn d 1 also reduced specific IgE responses and spleen cell secretion of IL-4. CONCLUSION: This study shows the prophylactic effects of DNA vaccine encoding Bermuda grass pollen allergen Cyn d 1 on specific IgE responses in neonatal mice.

Characterization of cross protection of Swine-Origin Influenza Virus (S-OIV) H1N1 and reassortant H5N1 influenza vaccine in BALB/c mice given a single-dose vaccination.

BACKGROUND: Influenza virus has antigen drift and antigen shift effect, vaccination with some influenza vaccine might not induce sufficient immunity for host to the threat of other influenza virus strains. S-OIV H1N1 and H5N1 influenza vaccines in single-dose immunization were evaluated in mice for cross protection to the challenge of A/California/7/2009 H1N1 or NIBRG-14 H5N1 virus. RESULTS: Both H1N1 and H5N1 induced significant homologous IgG, HAI, and microneutralization antibody responses in the mice, while only vaccines plus adjuvant produced significant heterogeneous IgG and HAI antibody responses. Both alum and MPLA adjuvants significantly reduced the S-OIV H1N1 vaccine dose required to elicit protective HAI antibody titers from 0.05 µg to 0.001 µg. Vaccines alone did not protect mice from challenge with heterogeneous influenza virus, while H5N1 vaccine plus alum and MPLA adjuvants did. Mouse body weight loss was also less significant in the presence of adjuvant than in the vaccine without adjuvant. Furthermore, both H1N1 and H5N1 lung viral titers of immunized mice were significantly reduced post challenge with homologous viruses. CONCLUSION: Only in the presence of MPLA adjuvant could the H5N1 vaccine significantly reduce mouse lung viral titers post H1N1 virus challenge, and not vice versa. MPLA adjuvant induced cross protection with a single dose vaccination to the challenge of heterogeneous influenza virus in mice. Lung viral titer seemed to be a better indicator compared to IgG, neutralization antibody, and HAI titer to predict survival of mice infected with influenza virus.

Hypoglycemia revisited in the acute care setting.

Hypoglycemia is a common finding in both daily clinical practice and acute care settings. The causes of severe hypoglycemia (SH) are multi-factorial and the major etiologies are iatrogenic, infectious diseases with sepsis and tumor or autoimmune diseases. With the advent of aggressive lowering of HbA1c values to achieve optimal glycemic control, patients are at increased risk of hypoglycemic episodes. Iatrogenic hypoglycemia can cause recurrent morbidity, sometime irreversible neurologic complications and even death, and further preclude maintenance of euglycemia over a lifetime of diabetes. Recent studies have shown that hypoglycemia is associated with adverse outcomes in many acute illnesses. In addition, hypoglycemia is associated with increased mortality among elderly and non-diabetic hospitalized patients. Clinicians should have high clinical suspicion of subtle symptoms of hypoglycemia and provide prompt treatment. Clinicians should know that hypoglycemia is associated with considerable adverse outcomes in many acute critical illnesses. In order to reduce hypoglycemia-associated morbidity and mortality, timely health education programs and close monitoring should be applied to those diabetic patients presenting to the Emergency Department with SH. ED disposition strategies should be further validated and justified to achieve balance between the benefits of euglycemia and the risks of SH. We discuss relevant issues regarding hypoglycemia in emergency and critical care settings.

Genetic typing, based on the 56-kilodalton type-specific antigen gene, of Orientia tsutsugamushi strains isolated from chiggers collected from wild-caught rodents in Taiwan.

Orientia tsutsugamushi is the etiological agent of scrub typhus, a mite-borne, febrile illness that occurs in the Asia-Pacific region. We conducted strain characterization of O. tsutsugamushi isolates from chiggers obtained from rodents based the nucleotide sequence of the 56-kDa outer membrane protein gene. With the use of PCR, a total of 68 DNA sequences of 56-kDa antigen genes were amplified. Phylogenetic analysis revealed that there were at least six definable clusters among the 68 isolates: 37% Karp-related strains (25/68), 27% TA763 strains (18/68), 12% JG-related strains (8/68), 19% Kato-related strains (13/68), 4% divergent strains (3/68), and 1% representing a Gilliam prototype strain (1/68). Overall, the O. tsutsugamushi genotypes exhibited a high degree of diversity, similar to that seen in strains from the rest of the areas where scrub typhus is endemic. Moreover, the 56-kDa protein sequence similarity between O. tsutsugamushi isolates from mites and those from human patients (H. Y. Lu et al., Am. J. Trop. Med. Hyg. 83:658-663, 2010) were striking, thus highlighting potential risk factors for this emerging zoonotic disease.

Evaluation of the activity of tartrate-resistant acid phosphatase isoform 5b in normal Chinese children--a novel marker for bone growth.

BACKGROUND: Most parents are very concerned about the height of their children. Biochemical markers of bone formation and resorption may provide useful clinical predictors for bone growth. Tartrate-resistant acid phosphatase 5b (TRAcP 5b) has been advocated as a biomarker of osteoclast activity and bone resorption. However, the TRAcP 5b levels of children at different ages are still unknown. It is necessary to accumulate and analyze the data for healthy children at different ages. OBJECTIVES: We use an improved immunoassay for bone TRAcP 5b to examine sera from children to see whether it is a significant marker of bone growth. METHODS: Serum, including cord blood, was collected from 404 normal Chinese children (age range 0-17 years; 225 male, 179 female). The venous blood was withdrawn from the peripheral vein and stored at 4 degrees C before centrifugation for serum collection. All sera were stored at -70 degrees C and thawed at 37 degrees C immediately before TRAcP 5b levels were measured. Bone-specific alkaline phosphatase (BAP) was also used for comparison with TRAcP 5b levels at different ages. RESULTS: TRAcP 5b levels were extremely high in infants of both genders, gradually decreasing with age (p <0.001). A second peak in TRAcP 5b values occurred at 12-13 and 10-11 years in males and females, respectively (p <0.001). Age alone, as well as age-related changes between the male and female groups, were independent predictors of TRAcP 5b levels (p <0.001). There was no significant between-gender difference in serum TRAcP 5b levels for any age group (p = 0.682). BAP values did not show a significant second peak in females. Age and gender alone, as well as the age-related changes between male and female groups, were independent predictors of BAP values (p <0.001). CONCLUSION: Preliminary results were established for serum TRAcP 5b and BAP values of normal Chinese children of different ages. Elevated serum TRAcP 5b values were observed during infancy and puberty for both genders. The pattern of this age-related change in serum TRAcP 5b levels is similar to the shape of the standard height velocity curve for healthy children. Values of BAP were less specific than TRAcP 5b. These data may prove valuable as a normal reference in future research about bone markers.

Osteoblast and osteoclast activity in a malignant infantile osteopetrosis patient following bone marrow transplantation.

The authors treated a 6-month-old boy with malignant infantile osteopetrosis using bone marrow transplantation. The patient's clinical response was compared with his biochemical response for bone metabolic markers such as tartrate-resistant acid phosphatase 5b (TRAcP 5b) and bone-specific alkaline phosphatase (BAP). Treatment was successful, resulting in a decrease in the serum TRAcP 5b level. These bone-specific markers may be useful for the early assessment of malignant infantile osteopetrosis patients with stem cell transplantation.

A randomized controlled trial of early kangaroo care for preterm infants: effects on temperature, weight, behavior, and acuity.

Kangaroo care (KC) has been the intervention for preterm infants in numerous published studies. However, most well designed studies to date have used a one-group repeated measure design. This methodology is not as definitive as an experimental design. Because of the absence of a comparable control group, change between pretest and posttest may be due to any other environmental variables or normal variation of subjects (Kirk, 1995). This randomized controlled trial (RCT) was done to test the hypotheses that KC infants would have higher mean tympanic temperatures, less weight loss, more optimal behavioral states, and lower acuity (length of stay). Thirty-four eligible mother-infant dyads were randomly assigned to the KC or the control group by computerized minimization on the day following birth. Stratification variables included infant gender, birth weight, delivery method, and parity. KC infants compared to control infants had higher mean tympanic temperature (37.3 degrees C vs. 37.0 degrees C), more quiet sleep (62% vs. 22%), and less crying (2% vs. 6%) all at p=.000. No significant difference was found for weight loss and acuity (length of stay). These findings can be used for evidence-based nursing practice in Taiwan. With the knowledge attained from this RCT, nurses can educate and motivate mothers to keep their stable preterm infants warm by skin-to- skin contact inside their clothing, thereby encouraging self-regulatory feeding.