bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Graph Based Semi-Supervised Learning Approach to Identify Pathways Contributing to the Development of Diabetes and Obesity
Authors: Lee Garam , Nam Yonghyan , Shivakumar Manu , Joshi Apoorva , Fu Weixuan , Simmons Rebecca Anne , Wang Paul , Kim Dokyoon , Pinney Sara Elizabeth 
Published: May 2021

Abstract
Background: Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu, induces marked abnormalities in fetal glucose and insulin secretion and is linked to obesity and diabetes in the offspring, but the mechanisms remain largely unknown. Epigenetic modifications in stems cells may be one mechanism by which an in utero exposure can lead to the development of diabetes and obesity later in life.
Objective: To identify novel pathways contributing to the development of diabetes and obesity in offspring exposed to GDM in utero by integrating data generated from transcriptome and methylome analysis from second trimester human amniocytes exposed to GDM in utero.
Methods: We analyzed RNAseq and genome wide DNA methylation data (ERRBS) generated from second trimester amniocytes obtained from women with GDM (n=14). Amniocytes have stem cells-like characteristics and are derived from the fetus. Expression data of 22,271 genes were retrieved from RNAseq data. CpGs with significant changes in DNA methylation were mapped into 20,028 genes by collapsing methylation probes into promoter and gene regions. To better understand the associations among diverse gene sets or among gene sets and GDM,we first constructed two weighted co-expression networks from RNAseq and DNA methylation data, respectively. Then, two co-expression networks were integrated using a linear combination. With the integrated co-expression network, graph-based label propagation algorithm was employed to prioritize GDM-associated genes.
Results: From the differential expression analysis between GDM and control, the top 20 query genes, including 11 genes and 9 methylated genes, were selected for label propagation. Finally, the top 100 genes were picked up for the pathway enrichment testusing an over-representation analysis approach. Significantly enriched pathways included: Interferon Signaling, N-glycan Antennae Elongation, Sphingolipid Pathway and Metabolism, Classical Complement Pathway, Complement and Coagulation Cascades, Tryptophan Metabolism, Peroxisomal Protein Import, Unsaturated Fatty Acid Metabolism, Complement Activation, Human Innate Immune Response, Ceramide Metabolism, Fertilization Pathway, Keratan Sulfate Biosynthesis Pathway, Transport to the Golgi and Modification Pathway (FDR q&lt;0.05 for all pathways).
Conclusion: Using a novel bioinformatic approach to synthesize transcriptome and methylome data derived from human amniocytes exposed to GDM in utero, we identified potential pathways involved in programming of diabetes and obesity in offspring including pathways involving the immune response, complex lipid metabolism, the complement pathway, and protein transport and processing. Further investigation of these pathways may yield new mechanisms contributing to diabetes and obesity.
Association Between Hyperinsulinemia and Helicobacter Pylori Infection
Authors: Hayes Dorado Juan Pablo 
Published: May 2021

Abstract
Introduction: The association between Helicobacter pylori infection and hyperinsulinemia and insulin resistance has been described. Objective: To investigate the frequency of hyperinsulinemia and insulin resistance in adolescents with Helicobacter pylori infection. Materials and Methods: Prospective, observational and analytical study. Adolescents with Helicobacter pylori infection; July 2019 - June 2020 period. Exclusion criteria: Obesity, hypothyroidism, hepatopathy, nephropathy, collagen disease, corticotherapy, use of proton pump inhibitors and H2 antihistamines. Variables: Antibodies against Helicobacter pylori; fasting plasma glucose and insulinemia, 2-hour plasma glucose and insulinemia after oral glucose tolerance test (OGTT); determination of the insulin resistance index by the Homeostasis Model Assessment (HOMA-IR). Two groups of patients: Those with Helicobacter pylori infection and the other of uninfected adolescents. Results: Patients attended: 34; studied: 19; excluded: 15. Group of non-infected: 20. The HOMA-IR value was 2.5 + -0.8 in adolescents with Helicobacter pylori infection and 1.8 + -0.6 (p = 0.02) in uninfected patients. Conclusions:The values of insulinemia and HOMA-IR were higher in the group of adolescents with Helicobacter pylori infection, compared to those evidenced in the group of uninfected.
Hyperglycemic Emergencies in Minority Children and Adolescents With Diabetes Mellitus
Authors: Badran Ahmed , Thakkar Amruta , Galetaki Despoina , Miller Assia , Umpaichitra Vatcharapan , Bargman Renee , Chin Vivian L 
Published: May 2021

Abstract
Introduction: Hyperglycemic emergencies in children with diabetes traditionally include diabetic ketoacidosis (DKA) predominantly associated with T1DM, whereas hyperosmolar hyperglycemic state (HHS) that is associated with relative insulin deficiency in T2DM, rarely occurs (2%). There have been increasing reports of mixed DKA-HHS affecting up to 27%. The purpose of this study is to identify clinical features, risk factors, complications and outcomes among minority children presenting with hyperglycemic emergencies at our center. Methods: This is a retrospective chart review of children and adolescents (ages 1-21 years) admitted for hyperglycemic emergencies including DKA [defined as glucose &gt;200 mg/dL, metabolic acidosis (pH &lt;7.3 or serum bicarbonate &lt;15 mmol/L) and ketonemia (ß-hydroxybuyrate ≥3 mmol/L) or moderate to large ketonuria], or HHS [defined as glucose &gt;600 mg/dL, effective serum osmolality &gt;320 mOsm/kg, venous pH &gt;7.25 or arterial pH &gt;7.30 or serum bicarbonate &gt;15 mmol/L, absent to mild ketonemia] or mixed DKA-HHS between 2004 and 2019. Descriptive statistics, chi-squared analysis and t-tests were used. Results: Of 322 patients, 92% were African American with mean age 13.6 ± 3.5 years, 39% males, consisting of 266 (83%) with DKA, 52 (16%) mixed DKA-HHS, and 4 (1%) HHS. Ninety-eight of the DKA and DKA-HHS groups had T1DM. All 4 patients with HHS had T2DM. Compared to the DKA group, the mixed DKA-HHS group required higher IV fluids rates (p&lt;0.0001), 4.3-fold greater odds of acute kidney injury (AKI, mean serum creatinine of 1.6 mg/dl vs 1.1 mg/dl; ref 0.5-1.0 mg/dL) and 3.3-fold greater odds of developing altered mental status (AMS). Risk factors such as insulin adherence, and precipitating factors like infection or stress were not different between both groups (p=0.06). There was no significant difference in insulin rates or time to resolution (p=0.4) in both groups. Among the HHS group, 50% presented with AMS and AKI (mean Cr 1.1 mg/dl ± 0.31) due to severe dehydration and required higher IV fluids rates (≥2 x maintenance). Creatinine kinase in 2 patients were slightly elevated (mean 1643 units/L, ± 77; ref 39-309). Insulin drip at 0.05 u/kg/hour was started in all 4 patients. None had venous thrombosis, rhabdomyolysis, cerebral edema, or death. Average time of resolution was 10 ±1.63 hours. Conclusion: In this study, 16% of patients with hyperglycemic emergencies presented with mixed DKA-HHS which was associated with more complications compared to the DKA group. Serum osmolality should be calculated and checked at diagnosis. Identification of hyperosmolality whether with or without DKA in the emergency setting is important because treatment should be focused on the degree of dehydration (usually moderate to severe) and other complications such as AKI and mental status changes.
Insulin Basal Dose Is Associated With Better Metabolic Control in Type 1 Diabetes Children and Adolescents
Authors: Arellano-Llamas Abril , Mejía-Carmona Luz Elena , Rojas-Zacarias Alicia , Ochoa-Romero Oscar , Díaz-Rodríguez Irene 
Published: May 2021

Abstract
Basal insulin dose in type 1 diabetes has been established empirically, since 2011 all guidelines suggest insulin basal dose less than 50% of total insulin dose in the pediatric population. However, in real life, basal dose indication has not changed in all patients in the basal-bolus treatment scheme. Objective: To measure how the physician indicates in real-life basal insulin dose in pediatric patients with type 1 diabetes in the basal-bolus scheme, and correlate this dose with metabolic control measured by glycated hemoglobin. Methods. This was a retrospective study, subjects include pediatric T1D (2 to 16 years, non-obese, using insulin more than 0.3 UI/Kg/d), more than 1 year of diagnostic, none of them in ketoacidosis, attended during 2019. The protocol was revised and accepted in the institution. Data were analyzed with Kruskal-Wallis, U Mann Withney, Pearson correlation test. Results: There were 141 subjects, male (51%), median age 13.3 years (3.6-15.9), median evolution time since diagnosis 8 years (1-14), pre-pubertal (Tanner stage 1, 22%), total daily dose 1.02 UI/Kg/d (0.3-2.19 UI/Kg/d). Basal insulin was glargine 50.4%, and NPH 49.6%, prandial insulin was lispro 66.7%, and regular human 29.8%. Children using 50% or less basal insulin of total insulin dose was 40.4%. The basal dose was 38% of total insulin dose in children less than 6 years, and 59% in children older than 6 years. (p=0.033). Glycated hemoglobin was less than 7.5% in 12.8%. The persons with glycated hemoglobin less than 7.5% used less basal insulin 0.38 u/kg/d, than those with higher glycated hemoglobin 0.57 U/kg/d (p=0.02) with no impact in total insulin dose (0.86 vs 1.05 UI/Kg/d, p=0.129). The correlation of the percentage of insulin basal dose and glycated hemoglobin was 0.279, p=0.001, meaning, more basal insulin, worse diabetes control. Conclusion: Lower basal insulin dose percentage from total daily dose is associated with better metabolic control in children treated with the basal-bolus scheme. There is high clinical inertia in the indication of basal insulin in older children.
Insulin Growth Factor 1 Predicts Central Precocious Puberty in Girls 6 to 8 Years-Old: A Retrospective Study
Authors: Escagedo Patricia Diaz , Deal Cheri L , Dwyer Andrew , Hauschild Michael 
Published: May 2021

Abstract
Background: Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal serum LH ≥ 0.3 IU/L or luteinizing hormone-releasing hormone (LHRH)-stimulated LH ≥ 5 IU/L. Stimulation testing is the diagnostic gold standard but is time-consuming and costly. Serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are increased in girls with CPP. Objective: To assess the utility of serum IGF-1 and IGFBP-3 in identifying CPP in girls aged 6 to 8 years old. Methods: The study was a single-center retrospective study. Girls with confirmed CPP (n=44) and isolated premature adrenarche/thelarche (PA/PT, n=16) had baseline biochemical profiling and LHRH stimulation testing. Serum IGF-1 and IGFBP-3 results were converted to standard deviation scores (SDS). Correlations were calculated and receiver operating characteristic curves were plotted. Results: Girls with CPP had higher basal and peak LH, IGF-1 SDS, and growth velocity (p&lt;0.05). IGF-1 SDS correlated positively with basal and peak LH (p&lt;0.05). IGF-1 SDS (1.75-2.15) differentiated CPP and PA/PT with 89% sensitivity and 56% specificity (basal LH) and 94% specificity and 55% sensitivity (peak LH). IGFBP-3 SDS did not differ between groups or by CPP parameters. Conclusions: In clinical practice, IGF-1 SDS may be an additional tool for identifying CPP in girls aged 6 to 8 years-old when baseline clinical and laboratory diagnostic criteria are inconclusive, possibly avoiding more invasive procedures.
Investigating Insulin Resistance in Pediatric Cardiomyopathy - A Pilot Study
Authors: Mak Daniel , Ryan Kaitlin A , Han Joan C 
Published: May 2021

Abstract
Children with cardiomyopathy are a vulnerable population and understanding the factors that contribute to cardiac dysfunction are of great importance. At the biochemical level, energy utilization by cardiomyocytes during stress may provide insight into the progression of cardiomyopathy. There is a large body of literature that describes insulin resistance in adults with cardiomyopathy (1,2). Extensive literature on the topic in adult individuals exists however investigation in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. To study the role of insulin resistance in pediatric cardiomyopathy, we measured the homeostasis model assessment-estimated insulin resistance (HOMA-IR) at baseline in pre-pubertal patients (age 13-18 years old; mean 16 years old; n = 8) with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). In patients with HCM, greater insulin resistance was positively correlated with greater left ventricular (LV) septal thickness (r = 0.55; p = 0.33; n = 5) and LV posterior wall thickness (r = 0.7; p = 0.19; n = 5) during diastole. As expected, insulin resistance was strongly correlated with BMI (r = 0.84; p = 0.08; n = 5) though greater BMI was not as strongly associated with LV septal thickness (r = 0.59; p = 0.3; n = 5) or posterior wall thickness (r = 0.59; p = 0.3; n = 5). In patients with DCM, insulin resistance was positively correlated with LV end diastolic volume (r = 0.59; p = 0.59; n = 3). Interestingly, there was an observed inverse association between insulin resistance and BMI in DCM (r = -0.85; p = 0.34; n =3). Though our sample population is limited, thus affecting statistical significance, results showed that there was a trend towards greater insulin resistance in patients with poorer cardiac measurements. These findings are consistent with adult literature and the proposition that cardiac dysfunction is an insulin resistant state.
References: (1) Riehle C, Abel ED. Insulin Signaling and Heart Failure. Circulation research. 2016;118(7):1151-1169. (2) Shah A, Shannon RP. Insulin resistance in dilated cardiomyopathy. Reviews in cardiovascular medicine. 2003;4 Suppl 6:S50-57
6-Month Subcutaneous Leuprolide Acetate Effectively Suppresses Clinical Signs of Puberty in Children With Central Precocious Puberty
Authors: Eugster Erica A , Atkinson Stuart , Boldt-Houle Deborah , Miller Bradley Scott 
Published: May 2021

Abstract
Objective: Gonadotropin-releasing hormone (GnRH) agonists, such as intramuscular leuprolide acetate, triptorelin and the subcutaneous histrelin implant, are standard treatment for central precocious puberty (CPP). Implants require surgery and sometimes anesthesia, while frequent intramuscular injections can be painful. A shift to longer acting-formulations and subcutaneous injections has been proposed for the treatment of CPP. Therapies with convenient administration, prolonged duration of action and favorable safety profile may be beneficial, improving patient adherence. 87% of subjects achieved stimulated LH suppression to &lt;4 IU/L by Week (W) 24 in a Phase III trial evaluating the efficacy and safety of the first6-month subcutaneous injectable in situ gel leuprolide acetate for CPP. We present secondary analyses of bone age (BA) advancement, weight, BMI, and pubertal maturation from this trial.
Methods: 62 children (60 girls, 2 boys) with CPP (naïve to treatment) received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals, constituting the intent-to-treat population. Radiographs of the left hand and wrist were used to determine BA using the Greulich and Pyle method. BA was assessed by a blinded central reader. Rate of BA advancement was determined by the ratio of BA to chronological age (CA, BA/CA). Pubertal maturation was categorized with the Tanner staging system using breast development, external genitalia, and pubic hair. Safety outcomes were measured.
Results: Mean age at onset of treatment was 7.5 ± 0.9 (SD) (range 4-9) years. BA/CA consistently declined throughout treatment, from 1.4 ± 0.2 at baseline, to 1.3 ± 0.1 at W24 and 1.3 ± 0.1 at W48. Although mean weight increased 8.7% from screening to W24 (34.8 kg vs 37.7 kg) and 16.9% from screening to W48 (40.4 kg), mean BMI remained stable throughout the study. The proportion of girls with early breast Tanner stage development (stage 1 and 2) increased from 9% at baseline to 37% at W48. The proportion of girls with late breast Tanner stage development (stage 4 and 5) decreased from 18% at baseline to 5% at W48. Both boys regressed from Tanner stage 3 to stage 2 for external genitalia development by W48. Tanner staging for pubic hair development remained stable for approximately 80% and decreased for 7% of children by W48. 52/53 treatment emergent adverse events were mild or moderate.
Conclusions: 6-month 45 mg subcutaneous leuprolide acetate is a promising treatment for CPP. It effectively suppressed LH, suppressed clinical signs of pubertal maturation and demonstrated a good safety profile. It also has the beneficial features of subcutaneous administration, small injection volumeand twice a year dosing. This may be a welcome addition to the armamentarium given the proposed shift in CPP therapies towards longer-acting formulations and subcutaneous injections.
A Clinical Experience of Pubertal Induction in Female Patients With Congenital Hypogonadotropic Hypogonadism (CHH) From an Endo-ERN Referral Center
Authors: Federici Silvia , Cangiano Biagio , Goggi Giovanni , Persani Luca , Bonomi Marco 
Published: May 2021

Abstract
Female congenital hypogonadotropic hypogonadism (CHH) is a rare condition, with a strong genetic background, characterized by absent or incomplete pubertal development, for which inductive treatment with sex-hormone is required. Although the available data, mostly coming from studies in patients with Turner syndrome, indicate transdermal estradiol (TDE) as the first-choice formulation, no internationally validated therapeutic schemes are currently available. Furthermore, data on CHH patients are certainly lacking and there is no standard of care for pubertal induction in this specific population. The aim of our work was the retrospective analysis of the data from a collection of case reports of pubertal induction in CHH patients referred to our Center. Six patients underwent induction with transdermal estradiol (TDE) at the starting dose of 0.1µg/kg/day (night-time for the first 4-6 months), increased every 4-6 months up to the adult dose, for a mean period of 2.86 ± 0.45 ys. Micronized progesterone (200 mcg) was introduced at reaching of 50µg dose or if breakthrough bleeding occurred. Treatment was monitored through clinical and anthropometric evaluations at each dose modification. The average age of induction was 17.25 ± 1.41 ys, with each bone age&gt; 13 ys. Three out of six patients already had a Tanner B2 stage at diagnosis. The mean times of pubertal advancement were respectively 1.3 ± 0.46 ys for the achievement of B3, 2.13 ± 0.29 ys for the B4 and 2.35 ± 0.77 ys for menarche; all the patients reached an adult breast conformation (B5) in 2.81 ± 0.28 ys. These data are consistent with physiological pubertal progress. All of them achieved adequate uterine development (medium longitudinal diameter 72.2 ± 3.37mm), except one patient with suboptimal development (54mm). The final height (FH) was adequate in all patients, with SDS FH +1.6 (-0.43 - +3.38), in spite of an average growth of 4.11 cm (2.5-6) ​​during the induction period and a growth rate &gt; 2cm/year only in 50% of patients. No side effects were reported, and individual compliance and satisfaction were quite high. This clinical experience suggests that the adopted regimen, consistent with current literature, guarantees excellent efficacy and safety. However, further studies are needed to identify the optimal treatment in adolescents with CHH, taking into account their higher age at the start of induction, the modest impact on growth and final stature, to focus on the specific clinical objectives in these patients
FSH Stimulated Inhibin B in Disorders of Puberty
Authors: Chaudhary Shakun , Walia Rama , Bhansali Anil , Dayal Devi , Sachdeva Naresh , Singh Tulika 
Published: May 2021

Abstract
Background: Predicting puberty is a clinical challenge. Available tests include basal gonadotropins, GnRH and GnRH analogue stimulation test, hCG stimulation test and basal inhibin B(INHB). Unlike GnRH and GnRH analogue stimulated LH, no study has investigated for possibility of rapidly releasable pool of inhibin B from gonads so far. Therefore, in quest of a better diagnostic test present study was undertaken to explore stimulability of inhibin B and if found stimulable, potential role of FSH stimulated inhibin B(FSH-INHB) as marker of entry into puberty. Methods: A total of forty-two subjects fulfilling eligibility criteria were enrolled into this prospective interventional study. Study cohort was divided into Cohort A (Healthy children in puberty; n=26) and Cohort B (Patients of hypogonadotropic hypogonadism; n=16). All participants were subjected to FSH stimulation test and GnRHa stimulation test as per study protocol. Data was analysed for male and female separately. Results: Mean delta change between INHB and FSH-INHB in cohort A (Male; n=18) was 188.8 pg/ml (p value-0.002) while in cohort B(Male; n=8) was 16.64 pg/ml (p value-0.076). Mean delta change in cohort A(Female; n=8) was 1065 pg/ml (p value- 0.023) while in cohort B (Female; n=8) was 9.8 pg/ml (p value-0.128). On ROC analysis, INHB of 68.88 pg/ml in male had 94.4 % sensitivity and 87.5% specificity while 51.47 pg/ml in female had 75% sensitivity and 100% specificity for entry into puberty. Cut off for FSH-INHB were 116.14 pg/ml and 116.50 pg/ml for male and female respectively (100% sensitivity/100% specificity).
Conclusion: Inhibin B was stimulable in both male and female after entry into puberty, highlighting the presence of rapidly releasable pool in ovaries and testes. FSH stimulated inhibin B may emerge as promising tool for entry into puberty.
Molecular Clues From Testis Involve NHLH2, a DNA Binding Transcription Factor That Controls the Onset of Mini-Puberty via Its Neuronal Activity, in Curative GnRH Treatment of Cryptorchidism Dependent Infertility
Authors: Hadziselimovic Faruk 
Published: May 2021

Abstract
Introduction: GnRHa treatment following surgery to correct cryptorchidism restores mini-puberty via endocrinological and transcriptional effects and prevents adult infertility in most cases. A large group of genes are important for central hypogonadotropic hypogonadism in mammals, including many that are transcribed both in brain and testis. However, the expression of these genes in prepubertal gonads has not been systematically studied and little is known about the effect of hormone therapy on their testicular and neuronal expression levels. Here, we interpret histological sections, data on hormone levels and RNA profiling data from adult normal testis in comparison to pre-pubertal low infertility risk (LIR) and high infertility risk (HIR) patients randomized for treatment with surgery in combination with GnRHa or only surgery. Major Results: We organize 31 target genes relevant for hypogonadotropic hypogonadism and cryptorchidism into five classes depending on their expression levels in HIR versus LIR samples and their response to GnRHa treatment. Only the mRNA encoding the DNA binding transcription factor NHLH2 is decreased in HIR as compared to LIR samples, increased after GnRHa treatment, and expressed in both brain and testis. GnRHa treatment of cryptorchidism that restores mini-puberty and rescues adult fertility increases NHLH2 mRNA levels in testis from HIR patients. Conclusion: This phenomenon may reflect a broader effect of hormone treatment on gene expression in both testicular and central nervous tissues, which could explain why the hypothalamus-pituitary-testicular axis is permanently restored by the administration of GnRHa.