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We aimed to evaluate the efficacy, safety, and immunogenicity profile of Etanercept (ETA) and Adalimumab (ADA) biosimilars (BIOs) compared to their originators in children with juvenile idiopathic arthritis (JIA). Eighty-one JIA children treated with ETA or ADA originators or BIOs were examined at baseline (T0) and after 3- (T1), 6- (T2), 12- (T3), and 24-(T4) months after starting treatment. Lower Juvenile Arthritis Disease Activity Score 10 (JADAS-10) scores were reported at T1, T2, T3, and T4 in JIA children treated with BIOs than originators (all p < 0.05). At T1 and T3, anti-drugs antibodies levels were lower in children receiving BIOs than originators (p = 0.04 and p = 0.0007, respectively), even after adjustments (both p < 0.05). Relapses were lower for BIOs compared to originators (p < 0.001). Safety profile was comparable between the groups (p > 0.05). A better overall profile of BIOs than originators was demonstrated in JIA children, but larger confirmatory studies are needed. [ABSTRACT FROM AUTHOR]

Background and Aim: To compare cardiometabolic risk profile and preclinical signs of target organ damage in youth with normal and elevated blood pressure (BP), according to the American Academy of Pediatrics (AAP) guidelines.Methods and Results: This cross-sectional multicenter study included 2739 youth (5-17 year-old; 170 normal-weight, 610 overweight and 1959 with obesity) defined non hypertensive by the AAP guidelines. Anthropometric, biochemical and liver ultrasound data were available in the whole population; carotid artery ultrasound and echocardiographic assessments were available respectively in 427 and 264 youth. Elevated BP was defined as BP ≥ 90th to <95th percentile for age, gender and height in children or BP ≥ 120/80 to <130/80 in adolescents. The overall prevalence of elevated BP was 18.3%, and significantly increased from normal-weight to obese youth. Young people with elevated BP showed higher levels of body mass index (BMI), insulin resistance and a higher prevalence of liver steatosis (45% vs 36%, p < 0.0001) than normotensive youth, whilst they did not differ for the other cardiometabolic risk factors, neither for carotid intima media thickness or left ventricular mass. Compared with normotensive youth, individuals with elevated BP had an odds ratio (95%Cl) of 3.60 (2.00-6.46) for overweight/obesity, 1.46 (1.19-1.78) for insulin-resistance and 1.45 (1.19-1.77) for liver steatosis, controlling for centers, age and prepubertal stage. The odds for insulin resistance and liver steatosis persisted elevated after correction for BMI-SDS.Conclusion: Compared to normotensive youth, elevated BP is associated with increased BMI, insulin resistance and liver steatosis, without significant target organ damage. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD. We examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors. We recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system. The overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75–0.88] vs. 0.77 [0.70–0.84] without SNPs; p = 0.047). NAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD. [ABSTRACT FROM AUTHOR]

INTRODUCTION Gynecomastia is the benign proliferation of the glandular tissue in the male breast. This condition is thought to be caused by the imbalance between estrogen action relative to androgen action at the breast tissue level. Bilateral gynecomastia is frequently found in the neonatal period, early in puberty, and with increasing age. Prepubertal unilateral gynecomastia in the absence of endocrine abnormalities is extremely rare, with only a few cases in literature. PRESENTATION OF CASE We present an otherwise healthy boy of 12 years old with unilateral breast masses. No abnormalities were found on ultrasonography and on all endocrine parameters. Treatment consisted in a new “modified” Webster technique. DISCUSSION The results confirmed validity of this technique in terms of esthetic and functional results, and patient satisfaction. Atypical presentations of gynecomastia are often not recognized. The main pathophysiology of gynecomastia is alteration in the balance between the stimulatory effect of estrogen and the inhibitory effects of androgens on the development of the breast. If there is no causal treatment, surgical resection is the therapy of first choice. CONCLUSION The exact mechanism of unilateral gynecomastia formation in our case is unclear. The evaluation of unilateral gynecomastia can therefore be complex. In conclusion, the surgical treatment of unilateral gynecomastia requires an individual approach, based on an appropriate diagnostic algorithm. [ABSTRACT FROM AUTHOR]

Background & Aims: The cannabinoid receptor 2 (CB2) has been implicated in liver disease. The single-nucleotide polymorphism rs35761398 in cannabinoid receptor 2 gene (CNR2), which encodes the CB2, substitutes glutamine (Q) 63 with arginine (R), and reduces the function of the gene product. We investigated the effects of CNR2 rs35761398 in patients with hepatitis C virus (HCV) infection. Methods: We studied 169 consecutive patients with asymptomatic chronic hepatitis (tested positive for anti-HCV and HCV RNA) at 2 liver units in southern Italy. First, liver biopsy samples were collected from July 2009 through December 2011. All patients were naive to antiviral therapy; CNR2 genotype was determined by polymerase chain reaction analysis. Results: Patients with the CB2-63 QQ variant had higher serum levels of aminotransferase than those with the CB2-63 QR or RR variants; they also had higher histologic activity index (HAI) scores (8.6 ± 3.8) than patients without the CB2-63 RR variant (5.3 ± 3.6; P < .005) or those with the CB2-63 QR variant (5.8 ± 3.3; P < .001). Patients with the different variants of CNR2 did not differ in fibrosis stage or steatosis score. Moderate or severe chronic hepatitis (HAI score, >8) was identified more frequently (55.5%) in patients with the CB2-63 QQ variant than in those with the 63 QR (20%; P < .005) or RR variants (17.4%; P < .005). In logistic regression analysis, the CB2-63 QQ variant and fibrosis score were independent predictors of moderate or severe chronic hepatitis (HAI score, >8; P < .0001). Conclusions: The CB2-63 QQ variant of CNR2 is associated with more severe inflammation and hepatocellular necrosis in patients with HCV infection. [Copyright &y& Elsevier]

When very low doses of insulin are used insulin dilution, a procedure prone to errors, is recommended. We managed a neonate with pancreas agenesis with insulin pump therapy from the first days of life to 16 months of age without insulin dilution. Predictive low glucose suspend mode first and then closed loop control were used. No episodes of severe hypoglycemia were observed. Though limited to a single patient with pancreas agenesis we believe that the use of pump should be warranted in patients with permanent neonatal diabetes mellitus and intestinal malabsorption, even with undiluted insulin. [ABSTRACT FROM AUTHOR]

Abstract: Early onset of absence seizures (<3 years) is rare and usually associated with a poor cognitive prognosis. Familial cases have not been reported to date. We observed a family in which two out of three sibs showed early-onset absences and mild mental retardation. Linkage to the ECA1 locus, where one clinical subtype of CAE is mapped, was excluded by haplotype analysis. Direct sequencing of the candidate genes CLCN2 ,GABRG2 and CHRNA4 showed no mutations. We suggest the possibility of a specific epileptic syndrome with a putative AR inheritance. Further report of affected patients might allow a better classification. [Copyright &y& Elsevier]

Background: In our clinical practice we observed that -differently from patients with defined glomerulopathies- children with persistent isolated microscopic hematuria (PImH) usually shows at dipstick on first compared with second morning voiding lower degree of hematuria. We hypothesized that comparison of hematuria degree between first and second morning voiding (dipstick comparison test) could help in selection of patients needing of specific investigations. In this study, we aimed preliminarily validating our hypothesis.Methods: To define the risk of active glomerulopathies we used patients with defined glomerulopathies as cases. We prospectively enrolled 103 children during a one-year period. Sixty-nine of them had PImH, 16 microscopic/macroscopic hematuria (mMH), and 18 defined glomerulopathies. Inclusion criteria were: 1) persistent microscopic hematuria (≥1+ at dipstick) with or without defined glomerulopathy and/or previous episodes of macroscopic hematuria; 2) for the patients without defined glomerulopathy, having made regular biannual follow-up visits for at least 2 years in our department; 3) normal renal function and blood pressure at enrollment visit. We compared hematuria degree between first and second morning voiding. Possible findings were absence (NH), less degree (LH), similar degree (SH), and higher degree (HH) of hematuria in the first compared with second voiding.Results: At dipstick comparison test, 27.2% of patients presented NH, 44.7% LH, 28.1% SH, and none HH. NH showed specificity and PPV of 100% and significant area under receiver operating characteristic curve (AUROC = 0.66; 95%CI:0.55-0.78; p = 0.03) for absence of defined glomerulopathies. LH showed better sensitivity (76.9% Vs 33%) and NPV (78.9% Vs 24%) and lower specificity (88.2% Vs 100%) and PPV (87.0% Vs 100%) than NH for absence of defined glomerulopathies. Moreover, the LH showed a non-significant AUROC curve for presence of defined glomerulopathies. SH showed specificity of 80%, NPV of 91.9% and significant AUROC curve for presence of defined glomerulopathies (0.67; 95%CI:0.55-0.80; p = 0.009). The ROC curve analysis examining the delta of hematuria degree comparing first with second morning urine voiding showed a significant AUROC curve (AUROC = 0.78; 95%CI,0.68-0.89; p = 0.0002) with delta ≤ 1 showing the best sensitivity (80%) and specificity (66.7%) for defined glomerulopathies. None of the patients with defined glomerulopathies presented NH. Having SH presented relative risk for defined glomerulopathy of 5.1 (95%CI:1.9-13.6; p = 0.0007). Conversely, taken together NH and LH the RR was 0.2 (95%CI 0.1-0.5; p = 0.0007).Interpretations: The dipstick on the first urine voiding underestimates the hematuria in about 70% of patients. The dipstick comparison test might easily screen patients with PImH and mMH needing of further investigations and treatment. [ABSTRACT FROM AUTHOR]

Bladder ultrasound is becoming pivotal in the management and treatment of lower urinary tract dysfunction. There is a paucity of data regarding intra-observer and interobserver reliability of bladder ultrasound, especially in children. A previous study assessed interobserver agreement for both the postvoid residual volume and measurement of the bladder dimensions in adults showing excellent agreement. To examine the interobserver and intra-observer reliability of bladder wall thickness, bladder urinary and postvoid residual urinary volume using ultrasound evaluated by paediatricians having different training levels. Four sonographers, 3 pediatric trainees and one experienced pediatric urologist measured the full bladder volume, the voiding residual volume, and the bladder wall thickness. Each sonographer made 3 measurements of each parameter. We assessed the interobserver and intra-observer variability by using intraclass correlations (ICCs). ICCs were calculated and tested with a significance level of 5%. The interrater ICC was calculated from the mean of the three measurements of each variable (full bladder volume, postvoid residual, bladder wall thickness). ICC ≥0.75 was considered excellent. Bland-Altman plots were also used to assess the interobserver agreement. Sixty children were recruited (7.3 ± 1.1 years). The interobserver ICCs for bladder volume and voiding residual volume were 0.91 (confidence interval 0.85–0.95) for both. The interobserver ICCs for the bladder wall thickness was satisfactory 0.43, with a minimum detectable difference of 2 mm. The observed values for intra-observer analysis showed an excellent (ICC ≥ 0.90) agreement between the three measurements performed by each one of the sonographers. Bland-Altman plots showed that the bias (mean difference) was −0.35 and the limits of agreement were −3.43 and 2.73 for the bladder wall thickness measurements (Figure). The interobserver reliability for both the postvoid residual volume and full bladder volume were excellent even in operators with different levels of training, pointing out the role of bladder ultrasound in the routine clinical practice. Weaker agreement was found for the bladder wall thickness measurement. The intra-observer agreement was excellent for all the measurements. These results showed a good reliability of urinary bladder ultrasound in children aged 7.3 ± 1.1 years as far as bladder volume measurement is concerned. Given the variability of bladder wall thickness, a standardized methodology is desirable to increase its reliability. [ABSTRACT FROM AUTHOR]

Summary Introduction Since standardization of the ICCS terminology, only two small case series of children with extraordinary daytime only urinary frequency (EDOUF) have been published. The aims of the present study were i) to describe a large cohort of children affected by EDOUF, to evaluate its rate among the main micturition pediatric disturbances, and to determine if there is different EDOUF onset among seasons; ii) to investigate possible associations with urodynamic abnormalities by non-invasive techniques; iii) to evaluate whether postponing micturition exercise (PME) can objectively verify the anamnestic data hinting at the EDOUF diagnosis; and iv) to determine the effect of postponing micturition at home. Material and methods We reviewed the records of all patients with EDOUF, nocturnal enuresis, and/or overactive bladder firstly examined from March 2012 to February 2016. We evaluated post-void residual and bladder wall thickness by urinary ultrasound and uroflowmetry and recorded the season in which the EDOUF started. Through the PME, the EDOUF diagnosis was confirmed if patients were able to postpone micturition reaching at least 80% of the expected bladder capacity without showing urinary incontinence. At home, we recommended postponing micturition for a maximum of 3 h if EDOUF affected the normal daily activities of both children and parents. We set a telephone interview for 3 months later. Results The clinical characteristics of the EDOUF population are shown in the Table. The EDOUF rate was 12.1%. The rate of EDOUF onset was significantly lower during the summer than in other seasons ( p = 0.02) and the OR for onset of EDOUF in the summer – compared with the other seasons – was 0.37 (95% CI 0.18–0.74; p = 0.005). Eighty-five (80.2%) patients reported an intermittent trend of the EDOUF with variable periods of improvement and worsening. All the EDOUF patients had normal uroflowmetry, 1/106 had post-micturition bladder wall thickness >5 mm and one post-void residual. At the PME, 106 out of 106 (100%) patients with EDOUF were able to reach at least 80% of the EBC without showing urinary incontinence or urgency incontinence. After 3 months, in 98.1% of the patients the symptoms had disappeared or improved. Discussion and conclusions Childhood EDOUF is rather common and is generally associated with normal non-invasive urodynamic patterns. The PME allows verification of anamnestic data of EDOUF. The sole recommendation to postpone micturition for a maximum of 3 h or until the micturition postponement became stressful could be considered as a possible approach. Table Clinical characteristics of the 106 patients with EDOUF. Age at EDOUF diagnosis, yr 6.8 ± 2.3 Female sex, no. (%) 53 (50) SBP, SDS 0.31 ± 0.7 DBP, SDS 0.17 ± 0.8 Age at continence, yr 2.3 ± 0.5 Nocturia, no. (%) 1 (0.9) Constipation, no. (%) 19 (17.4) Urgency, no. (%) 0 (0) Incontinence, no. (%) 0 (0) EBC >80% at PME, no. (%) 106 (100) Post-micturition bladder wall thickness >5 mm, no. (%) 1 (0.9) Presence of post-void residual, no. (%) 1 (0.9) a Maximum flow, mL/s 19.34 ± 10.2 Normal uroflowmetry, no. (%) 106 (100) Normal urinalysis, no. (%) 106 (100) Previous UTIs, % 2 (1.9) b Daily micturitions, no. 20.1 ± 7.2 Mean daily voided volumes (% of the EBC) 28.7 ± 9.2 Data are given as means ± SDS, unless stated otherwise. DBP, diastolic blood pressure; EBC, expected bladder capacity; EDOUF, extraordinary daytime only urinary frequency; PME, postponing micturition exercise; SBP, systolic blood pressure; SDS, standard deviation score; UTI, urinary tract infection. a Only one patient presented a post-void residual of 30 mL. b All the UTIs were not febrile. [ABSTRACT FROM AUTHOR]

To investigate fear of hypoglycemia (FoH) in parents of children with type 1 diabetes (T1D) before and after undergoing training to learn intranasal (IN) glucagon administration. In this pre-test/post-test uncontrolled study 364 caregivers of patients with T1D (6–18 years) completed questionnaires measuring sociodemographic characteristics, diabetes-related factors (e.g., type of insulin therapy, glycemic control), and parents' trait anxiety. Parents' FoH was assessed at baseline (T0, training) and after nine months (T1). Two repeated-measure mixed analyses of covariance (ANCOVA) compared the FoH at T0 and at T1 and analyzed the moderating roles of anxiety proneness and type of insulin therapy, as well as of anxiety proneness and use of sensor. Age, T1D duration, HbA1c values, and SES were included as covariates. Parental FoH at T1 (M = 1.72; SE = 0.06/M = 1.57; SE = 0.09) was significantly lower than parental FoH at T0 (M = 1.89; SE = 0.06/M = 1.77; SE = 0.09). The group with high trait-anxiety had a higher level of FoH (M = 2.05; SE = 0.08/M = 1.89; SE = 0.12) than the group with low trait-anxiety (M = 1.57; SE = 0.08/M = 1.46; SE = 0.09) at both time points. SES was negatively associated with FoH at T0 (t = −2.87; p =.004/ t = −2.87; p =.005). No other significant effects were found. Training and educating parents on IN glucagon use can help them effectively manage hypoglycemic episodes and alleviate the fear that generally accompany such events. • Intranasal glucacon training helps to reduce parental fear of hypoglycemia. • Parents with high trait anxiety showed higher fear of hypoglycemia. • Parental fear of hypoglycemia was not associated with the clinical factors. [ABSTRACT FROM AUTHOR]

Abstract: The mutational analysis of potassium (KCNQ2, KCNQ3), sodium (SCN1A, SCN2A), and chloride (CLCN2) ion channels was performed in three children with typical features of the recently described syndrome of migrating partial seizures in infancy. Mutational analysis was performed by PCR and automatic sequencing. The coding regions, including the exon–intron boundaries, were amplified in the patients using appropriate primers sets. No mutations associated to migrating partial seizures have been found. Mutational screening of CLCN2 gene, revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. The same variation has been found in 38 out of 100 control alleles. The identification of the genetic basis of this new epileptic encephalopathy requires further studies that might be enforced by familial cases. [Copyright &y& Elsevier]

KCNQ2 and KCNQ3 K+ channel subunits underlie the muscarinic-regulated K+ current (IKM), a widespread regulator of neuronal excitability. Mutations in KCNQ2- or KCNQ3-encoding genes cause benign familiar neonatal convulsions (BFNCs), a rare autosomal-dominant idiopathic epilepsy of the newborn. In the present study, we have investigated, by means of electrophysiological, biochemical, and immunocytochemical techniques in transiently transfected cells, the consequences prompted by a BFNC-causing 1-bp deletion (2043ΔT) in the KCNQ2 gene; this frameshift mutation caused the substitution of the last 163 amino acids of the KCNQ2 C terminus and the extension of the subunit by additional 56 residues. The 2043ΔT mutation abolished voltage-gated K+ currents produced upon homomeric expression of KCNQ2 subunits, dramatically reduced the steady-state cellular levels of KCNQ2 subunits, and prevented their delivery to the plasma membrane. Metabolic labeling experiments revealed that mutant KCNQ2 subunits underwent faster degradation; 10-h treatment with the proteasomal inhibitor MG132 (20 μM) at least partially reversed such enhanced degradation. Co-expression with KCNQ3 subunits reduced the degradation rate of mutant KCNQ2 subunits and led to their expression on the plasma membrane. Finally, co-expression of KCNQ2 2043ΔT together with KCNQ3 subunits generated functional voltage-gated K+ currents having pharmacological and biophysical properties of heteromeric channels. Collectively, the present results suggest that mutation-induced reduced stability of KCNQ2 subunits may cause epilepsy in neonates. [ABSTRACT FROM AUTHOR]

In this study, we have compared the functional consequences of three mutations (R218Q, V260M, and Q266H) in the α1 subunit of the glycine receptor (GIyRA1) causing hyperekplexia, an inherited neurological channelopathy. In HEK-293 cells, the agonist EC50s for glycine-activated C1- currents were increased from 26 μM in wtGlyRA1, to 5747, 135, and 129 μM in R218Q, V260M, and Q266H GlyRA1 channels, respectively. C1- currents elicited by β-alanine and taurine, which behave as agonists at wtGlyRA1, were decreased in V260M and Q266H mutant receptors and virtually abolished in GlyRA1 R218Q receptors. Gly-gated C1- currents were similarly antagonized by low concentrations of strychnine in both wild-type (wt) and R218Q GlyRA1 channels, suggesting that the Arg-218 residue plays a crucial role in GIyRA1 channel gating, with only minor effects on the agonist/ antagonist binding site, a hypothesis supported by our molecular model of the GlyRA1 subunit. The R218Q mutation, but not the V260M or the Q266H mutation, caused a marked decrease of receptor subunit expression both in total cell lysates and in isolated plasma membrane proteins. This decreased expression does not seem to explain the reduced agonist sensitivity of GlyRA1 R218Q channels since no difference in the apparent sensitivity to glycine or taurine was observed when wtGlyRA1 receptors were expressed at levels comparable with those of R218Q mutant receptors. In conclusion, multiple mechanisms may explain the dramatic decrease in GIyR function caused by the R218Q mutation, possibly providing the molecular basis for its association with a more severe clinical phenotype. [ABSTRACT FROM AUTHOR]

Takenouchi-Kosaki syndrome (TKS) is a recently delineated syndromic form of thrombocytopenia strictly related to an hot-spot missense variant, p.Tyr64Cys, in CDC42 (Cell Division Control protein 42). Herein we report an additional patient with the p.Tyr64Cys aminoacidic substitution who showed the well-defined phenotypical TKS features and an intermittent, very mild, macrothrombocytopenia at 10.7 years of age (93,000/mL), that was only retrospectively valorized. Outside of this value the PLT count had always been higher than 100,000/mL. We also review literature data from patients carrying this recurrent variant. Our female patient presented with prenatal onset of short stature and microcephaly, camptodactyly, heart defects, typical facial gestalt, developmental delay, and not specific brain abnormalities. After several genetic investigations (karyotype, CGH-Array, targeted NGS analysis for short stature genes), by whole exome sequencing we identified the p.Tyr64Cys in CDC42, occurring de novo. The case presented here provides further evidence that macrothrombocytopenia can be intermittent and thus it might escape attention of clinicians. Without this key feature, TKS clinical presentation can overlap other syndromic forms of short stature. Immunodeficiency, autoimmunity, and malignancies were recently reported in patients with the p.Tyr64Cys substitution, making imperative an early diagnosis of Takenouchi-Kosaki syndrome to organize the most proper follow-up of these pediatric patients. The whole exome sequencing can be a solving tool in the challenge to the rare diseases. [ABSTRACT FROM AUTHOR]