In Vitro Toxicological Insights from the Biomedical Applications of Iron Carbide Nanoparticles in Tumor Theranostics: A Systematic Review and Meta-Analysis.

(1) Background: Despite the encouraging indications regarding the suitability (biocompatibility) of iron carbide nanoparticles (ICNPs) in various biomedical applications, the published evidence of their biosafety is dispersed and relatively sparse. The present review synthesizes the existing nanotoxicological data from in vitro studies relevant to the diagnosis and treatment of cancer. (2) Methods: A systematic review was performed in electronic databases (PubMed, Scopus, and Wiley Online Library) on December 2023, searching for toxicity assessments of ICNPs of different sizes, coatings, and surface modifications investigated in immortalized human and murine cell lines. The risk of bias in the studies was assessed using the ToxRTool for in vitro studies. (3) Results: Among the selected studies (n = 22), cell viability emerged as the most frequently assessed cellular-level toxicity endpoint. The results of the meta-analysis showed that cell models treated with ICNPs had a reduced cell viability (SMD = -2.531; 95% CI: -2.959 to -2.109) compared to untreated samples. A subgroup analysis was performed due to the high magnitude of heterogeneity (I2 = 77.1%), revealing that ICNP concentration and conjugated ligands are the factors that largely influence toxicity (p < 0.001). (4) Conclusions: A dose-dependent cytotoxicity of ICNP exposure was observed, regardless of the health status of the cell, tested organism, and NP size. Inconsistent reporting of ICNP physicochemical properties was noted, which hinders comparability among the studies. A comprehensive exploration of the available in vivo studies is required in future research to assess the safety of ICNPs' use in bioimaging and cancer treatment.

In silico assessment of nanoparticle toxicity powered by the Enalos Cloud Platform: Integrating automated machine learning and synthetic data for enhanced nanosafety evaluation.

The rapid advance of nanotechnology has led to the development and widespread application of nanomaterials, raising concerns regarding their potential adverse effects on human health and the environment. Traditional (experimental) methods for assessing the nanoparticles (NPs) safety are time-consuming, expensive, and resource-intensive, and raise ethical concerns due to their reliance on animals. To address these challenges, we propose an in silico workflow that serves as an alternative or complementary approach to conventional hazard and risk assessment strategies, which incorporates state-of-the-art computational methodologies. In this study we present an automated machine learning (autoML) scheme that employs dose-response toxicity data for silver (Ag), titanium dioxide (TiO2), and copper oxide (CuO) NPs. This model is further enriched with atomistic descriptors to capture the NPs' underlying structural properties. To overcome the issue of limited data availability, synthetic data generation techniques are used. These techniques help in broadening the dataset, thus improving the representation of different NP classes. A key aspect of this approach is a novel three-step applicability domain method (which includes the development of a local similarity approach) that enhances user confidence in the results by evaluating the prediction's reliability. We anticipate that this approach will significantly expedite the nanosafety assessment process enabling regulation to keep pace with innovation, and will provide valuable insights for the design and development of safe and sustainable NPs. The ML model developed in this study is made available to the scientific community as an easy-to-use web-service through the Enalos Cloud Platform (www.enaloscloud.novamechanics.com/sabydoma/safenanoscope/), facilitating broader access and collaborative advancements in nanosafety.

Exploring the Binding Effects of Natural Products and Antihypertensive Drugs on SARS-CoV-2: An In Silico Investigation of Main Protease and Spike Protein.

In this in silico study, we conducted an in-depth exploration of the potential of natural products and antihypertensive molecules that could serve as inhibitors targeting the key proteins of the SARS-CoV-2 virus: the main protease (Mpro) and the spike (S) protein. By utilizing Induced Fit Docking (IFD), we assessed the binding affinities of the molecules under study to these crucial viral components. To further comprehend the stability and molecular interactions of the "protein-ligand" complexes that derived from docking studies, we performed molecular dynamics (MD) simulations, shedding light on the molecular basis of potential drug candidates for COVID-19 treatment. Moreover, we employed Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations on all "protein-ligand" complexes, underscoring the robust binding capabilities of rosmarinic acid, curcumin, and quercetin against Mpro, and salvianolic acid b, rosmarinic acid, and quercetin toward the S protein. Furthermore, in order to expand our search for potent inhibitors, we conducted a structure similarity analysis, using the Enalos Suite, based on the molecules that indicated the most favored results in the in silico studies. The Enalos Suite generated 115 structurally similar compounds to salvianolic acid, rosmarinic acid, and quercetin. These compounds underwent IFD calculations, leading to the identification of two salvianolic acid analogues that exhibited strong binding to all the examined binding sites in both proteins, showcasing their potential as multi-target inhibitors. These findings introduce exciting possibilities for the development of novel therapeutic agents aiming to effectively disrupt the SARS-CoV-2 virus lifecycle.

Turner syndrome: skin, liver, eyes, dental and ENT evaluation should be improved.

Introduction: Turner syndrome association with multi-organ system comorbidities highlights the need for effective implementation of follow-up guidelines. We aimed to assess the adequacy of care with international guidelines published in 2007 and 2017 and to describe the phenotype of patients. Methods: In this multicenter retrospective descriptive cohort study, we collected growth and pubertal parameters, associated comorbidities, treatment, and karyotype in patients diagnosed at age <18 years between 1993 and 2022. We assessed age-appropriate recommendation follow-up (children, adolescents and adults) according to the 2007 guidelines if the last visit was before 2017 (18 recommendations) and the 2017 guidelines if the last visit was after 2017 (19 recommendations). Results: We included 68 patients followed at Lausanne University Hospital (n=64) and at Neuchatel Regional Hospital (RHNe) (n=4). 2.9% of patients underwent all recommended investigations.Overall, 68.9 ± 22.5% and 78.5 ± 20.6% of the recommendations were followed, before and after 2017 respectively. High implementation rates were found for height, weight and BMI (100%), cardiac (80 to 100%) and renal (90 to 100%) imaging. Low implementation rates were found for Ear, Nose and Throat (ENT) (56.5%), skin (38.5%), dental (23.1%), ophthalmological (10%) and cholestasis (0 to 29%) assessments, depending on age and time of visit. In adults (n=33), the mean proportion of followed recommendations was lower before than after 2017: 63.5 ± 25.8% vs. 78.7 ± 23.4%, p=0.039. Conclusion: Growth parameters, cardiac and renal imaging are well followed. However, efforts should be made for dental, ENT, ophthalmological, skin and cholestasis assessments. Adequacy of follow-up improved with the quality of transition to adult care.

Glucose variability in 6-12-month-old healthy infants.

Background: Metabolic programming of glucose homeostasis in the first 1,000 days of life may impact lifelong metabolic and cardiovascular health. Continuous glucose monitoring (CGM) devices may help measure the impact of dietary intake on glucose rhythms and metabolism in infants during the complementary feeding period. Objectives: Demonstrate the feasibility of CGM to measure and quantify glucose variability in response to infant feeding and to evaluate associations between macronutrient meal composition and glucose variability. Methods: The "FreeStyle Libre Pro®" device interstitial glucose meter was applied to the anterior thigh of 10 healthy 6-12-month-old infants. Parents recorded food intake, time of feeding, and used daily dairies to record sleep time and duration. Descriptive statistics were employed for food intake, sleep and key glycemic parameters over three full days. Mixed linear models were used to assess glycemic changes. Results: Mid-day, afternoon, and evening feeds contained >30 g carbohydrate and induced higher 2-h iAUC (3.42, 3.41, and 3.50 mmol/L*h respectively) compared to early and mid-morning feedings with ≤25 g carbohydrates (iAUC 2.72 and 2.81 mmol/L*h, p < 0.05). Early morning and evening milk feedings contained approximately 9 g of fat and induced a longer time to reach maximal glucose value (Tmax; 75 and 68 min, respectively) compared to lower fat feedings (2.9-5.9 g; Tmax range: 34-60 min; p < 0.05). Incremental glucose value at time of food intake (C0) increased significantly from 0.24 ± 0.39 mM in early morning to 1.07 ± 0.57 mM in the evening (p < 0.05). Over the day, 70% of glucose values remained within the normal range (3.5-5.5 mmol/L), 10% were between 5.5-10 mmol/L, and 20% were < 3.5 mmol/L. Conclusion: Our data support the feasibility of using CGM to measure glucose in 6-12-month-old infants. The observation of possible diurnal glucose variability and typical glucose values may have implications for future studies investigating metabolic adaptation to nutritional intake in early life.

Stereoptic serious games as a visual rehabilitation tool for individuals with a residual amblyopia (AMBER trial): a protocol for a crossover randomized controlled trial.

BACKGROUND: Amblyopia is the most common developmental vision disorder in children. The initial treatment consists of refractive correction. When insufficient, occlusion therapy may further improve visual acuity. However, the challenges and compliance issues associated with occlusion therapy may result in treatment failure and residual amblyopia. Virtual reality (VR) games developed to improve visual function have shown positive preliminary results. The aim of this study is to determine the efficacy of these games to improve vision, attention, and motor skills in patients with residual amblyopia and identify brain-related changes. We hypothesize that a VR-based training with the suggested ingredients (3D cues and rich feedback), combined with increasing the difficulty level and the use of various games in a home-based environment is crucial for treatment efficacy of vision recovery, and may be particularly effective in children. METHODS: The AMBER study is a randomized, cross-over, controlled trial designed to assess the effect of binocular stimulation (VR-based stereoptic serious games) in individuals with residual amblyopia (n = 30, 6-35 years of age), compared to refractive correction on vision, selective attention and motor control skills. Additionally, they will be compared to a control group of age-matched healthy individuals (n = 30) to account for the unique benefit of VR-based serious games. All participants will play serious games 30 min per day, 5 days per week, for 8 weeks. The games are delivered with the Vivid Vision Home software. The amblyopic cohort will receive both treatments in a randomized order according to the type of amblyopia, while the control group will only receive the VR-based stereoscopic serious games. The primary outcome is visual acuity in the amblyopic eye. Secondary outcomes include stereoacuity, functional vision, cortical visual responses, selective attention, and motor control. The outcomes will be measured before and after each treatment with 8-week follow-up. DISCUSSION: The VR-based games used in this study have been conceived to deliver binocular visual stimulation tailored to the individual visual needs of the patient, which will potentially result in improved basic and functional vision skills as well as visual attention and motor control skills. TRIAL REGISTRATION: This protocol is registered on ClinicalTrials.gov (identifier: NCT05114252) and in the Swiss National Clinical Trials Portal (identifier: SNCTP000005024).

DNA primase large subunit is an essential plant gene for geminiviruses, putatively priming viral ss-DNA replication.

The family of Geminiviridae consists of more than 500 circular single-stranded (ss) DNA viral species that can infect numerous dicot and monocot plants. Geminiviruses replicate their genome in the nucleus of a plant cell, taking advantage of the host's DNA replication machinery. For converting their DNA into double-stranded DNA, and subsequent replication, these viruses rely on host DNA polymerases. However, the priming of the very first step of this process, i.e. the conversion of incoming circular ssDNA into a dsDNA molecule, has remained elusive for almost 30 years. In this study, sequencing of melon (Cucumis melo) accession K18 carrying the Tomato leaf curl New Delhi virus (ToLCNDV) recessive resistance quantitative trait locus (QTL) in chromosome 11, and analyses of DNA sequence data from 100 melon genomes, showed a conservation of a shared mutation in the DNA Primase Large subunit (PRiL) of all accessions that exhibited resistance upon a challenge with ToLCNDV. Silencing of (native) Nicotiana benthamiana PriL and subsequent challenging with three different geminiviruses showed a severe reduction in titers of all three viruses, altogether emphasizing an important role of PRiL in geminiviral replication. A model is presented explaining the role of PriL during initiation of geminiviral DNA replication, i.e. as a regulatory subunit of primase that generates an RNA primer at the onset of DNA replication in analogy to DNA Primase-mediated initiation of DNA replication in all living organisms.

Maternal and fetal predictors of anthropometry in the first year of life in offspring of women with GDM.

Introduction: Gestational Diabetes Mellitus (GDM) carries an increased risk for adverse perinatal and longer-term cardiometabolic consequences in offspring. This study evaluated the utility of maternal anthropometric, metabolic and fetal (cord blood) parameters to predict offspring anthropometry up to 1 year in pregnancies with GDM. Materials and methods: In this prospective analysis of the MySweetheart study, we included 193/211 women with GDM that were followed up to 1 year postpartum. Maternal predictors included anthropometric (pre-pregnancy BMI, gestational weight gain (GWG), weight and fat mass at the 1st GDM visit), and metabolic parameters (fasting insulin and glucose, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Quantitative insulin-sensitivity check index (QUICKI), HbA1c, triglycerides, and high-density lipoprotein (HDL) at the 1st visit and HbA1c at the end of pregnancy). Fetal predictors (N=46) comprised cord blood glucose and insulin, C-Peptide, HOMA-IR, triglycerides and HDL. Offspring outcomes were anthropometry at birth (weight/weight z-score, BMI, small and large for gestational age (SGA,LGA)), 6-8 weeks and 1 year (weight z-score, BMI/BMI z-score, and the sum of 4 skinfolds). Results: In multivariate analyses, birth anthropometry (weight, weight z-score, BMI and/or LGA), was positively associated with cord blood HDL and HbA1c at the 1st GDM visit, and negatively with maternal QUICKI and HDL at the 1st GDM visit (all p ≤ 0.045). At 6-8 weeks, offspring BMI was positively associated with GWG and cord blood insulin, whereas the sum of skinfolds was negatively associated with HDL at the 1st GDM visit (all p ≤0.023). At 1 year, weight z-score, BMI, BMI z-score, and/or the sum of skinfolds were positively associated with pre-pregnancy BMI, maternal weight, and fat mass at the 1st GDM visit and 3rd trimester HbA1c (all p ≤ 0.043). BMI z-score and/or the sum of skinfolds were negatively associated with cord blood C-peptide, insulin and HOMA-IR (all p ≤0.041). Discussion: Maternal anthropometric, metabolic, and fetal metabolic parameters independently affected offspring anthropometry during the 1st year of life in an age-dependent manner. These results show the complexity of pathophysiological mechanism for the developing offspring and could represent a base for future personalized follow-up of women with GDM and their offspring.

The eRDS v6 Stereotest and the Vivid Vision Stereo Test: Two New Tests of Stereoscopic Vision.

Purpose: To describe two new stereoacuity tests: the eRDS v6 stereotest, a global dynamic random dot stereogram (dRDS) test, and the Vivid Vision Stereo Test version 2 (VV), a local or "contour" stereotest for virtual reality (VR) headsets; and to evaluate the tests' reliability, validity compared to a dRDS standard, and learning effects. Methods: Sixty-four subjects passed a battery of stereotests, including perceiving depth from RDS. Validity was evaluated relative to a tablet-based dRDS reference test, ASTEROID. Reliability and learning effects were assessed over six sessions. Results: eRDS v6 was effective at measuring small thresholds (<10 arcsec) and had a moderate correlation (0.48) with ASTEROID. Across the six sessions, test-retest reliability was good, varying from 0.84 to 0.91, but learning occurred across the first three sessions. VV did not measure stereoacuities below 15 arcsec. It had a weak correlation with ASTEROID (0.27), and test-retest reliability was poor to moderate, varying from 0.35 to 0.74; however, no learning occurred between sessions. Conclusions: eRDS v6 is precise and reliable but shows learning effects. If repeated three times at baseline, this test is well suited as an outcome measure for testing interventions. VV is less precise, but it is easy and rapid and shows no learning. It may be useful for testing interventions in patients who have no global stereopsis. Translational Relevance: eRDS v6 is well suited as an outcome measure to evaluate treatments that improve adult stereodepth perception. VV can be considered for screening patient with compromised stereovision.

Personality as a Predictor of Disability in Multiple Sclerosis.

OBJECTIVE: As personality changes and personality disorders are frequently observed in multiple sclerosis (MS), personality may be a prognostic factor for this disease. The present study investigated the influence of personality on disability, progression, and treatment adherence in MS. METHOD: Personality was assessed in 41 patients with Relapsing-Remitting MS (30 females; mean age = 42.63 years) using the NEO Personality Inventory-3rd edition. Disability was measured with the Expanded Disability Status Scale, and treatment adherence information was collected from the Swiss MS Cohort. Correlation, multiple linear and partial least square regressions were performed to examine relations between personality, disability, and treatment adherence in MS. RESULTS: After accounting for age and time since disease onset, our analysis revealed that Neuroticism (ß = 0.32, p = 0.01) and its Vulnerability facet (ß = 0.28, p < 0.05) predicted greater disability, whereas Extraversion (ß = -0.25, p = 0.04) and its Activity facet (ß = -0.23, p < 0.05) predicted milder disability. Regarding disability progression, correlational analysis revealed that it was negatively correlated with Extraversion (r = -0.44, p = 0.02) and the Feelings facet of Openness (r = -0.41, p = 0.03), but regressions failed to highlight any predictive links. No significant results could be demonstrated for treatment adherence. CONCLUSIONS: Overall, our study showed that some personality traits can impact disability in MS, indicating that these should be considered in clinical practice, as they could be used to adapt and improve patients' clinical support.

Entomological surveillance and spatiotemporal risk assessment of sand fly-borne diseases in Cyprus.

Visceral and cutaneous leishmaniases are important public health concerns in Cyprus. Although the diseases, historically prevalent on the island, were nearly eradicated by 1996, an increase in frequency and geographical spread has recently been recorded. Upward trends in leishmaniasis prevalence have largely been attributed to environmental changes that amplify the abundance and activity of its vector, the phlebotomine sand flies. Here, we performed an extensive field study across the island to map the sand fly fauna and compared the presence and distribution of the species found with historical records. We mapped the habitat preferences of Phlebotomus papatasi and P. tobbi, two medically important species, and predicted the seasonal abundance of P. papatasi at unprecedented spatiotemporal resolution using a climate-sensitive population dynamics model driven by high-resolution meteorological forecasting. Our compendium holds a record of 18 species and the locations of a subset, including those of potential public and veterinary health concern. We confirmed that P. papatasi is widespread, especially in densely urbanized areas, and predicted that its abundance uniformly peaks across the island at the end of summer. We identified potential hotspots of P. papatasi activity even after this peak. Our results form a foundation to inform public health planning and contribute to the development of effective, efficient, and environmentally sensitive strategies to control sand fly populations and prevent sand fly-borne diseases.

Sex-dependent influence of maternal predictors on fetal anthropometry in pregnancies with gestational diabetes mellitus.

BACKGROUND: Third trimester fetal anthropometric parameters are known to predict neonatal complications. A better understanding of predictors of adverse fetal parameters might help to personalize the use and frequency of fetal ultrasound. The objectives of this study were: (a) to evaluate the utility of maternal sociodemographic, anthropometric and metabolic predictors to predict 3rd trimester fetal anthropometric parameters in women with gestational diabetes mellitus (GDM), (b) to assess whether the impact of these maternal predictors is fetal sex-dependent, and (c) to provide a risk stratification for markers of fetal overgrowth (fetal weight centile (FWC) and fetal abdominal circumference centile (FACC) depending on prepregnancy BMI and gestational weight gain (GWG) until the 1st GDM visit. METHODS: This prospective study included 189 women with GDM. Maternal predictors were age, ethnicity, prepregnancy BMI, GWG and excessive weight gain until the 1st GDM visit, fasting, 1-hour and 2-hour blood glucose oral glucose tolerance test values, HbA1c at the 1st visit and medical treatment requirement. Fetal outcomes included FWC, FWC >90% and <10%, FACC, FACC >90% and <10%, at 29 0/7 to 35 6/7 weeks of gestational age. We performed univariate and multivariate regression analyses and probability analyses. RESULTS: In multivariate analyses, prepregnancy BMI was associated with FWC, FWC > 90% and FACC. GWG until the 1st GDM visit was associated with FWC, FACC and FACC > 90% (all p ≤ 0.045). Other maternal parameters were not significantly associated with fetal anthropometry in multivariate analyses (all p ≥ 0.054). In female fetuses, only GWG was associated with FACC (p= 0.044). However, in male fetuses, prepregnancy BMI was associated with FWC, FWC > 90% and FACC and GWG with FWC in multivariate analyses (all p ≤ 0.030). In women with a prepregnancy BMI of ≥ 25 kg/m2 and a GWG until the 1st GDM visit ≥ 10.3 kg (mean GWG), the risk for FWC > 90% and FACC > 90% was 5.3 and 4 times higher than in their counterparts. CONCLUSIONS: A personalized fetal ultrasound surveillance guided by fetal sex, prepregnancy BMI and GWG may be beneficial in reducing adverse fetal and neonatal outcomes.

Phlebotomus (Adlerius) simici NITZULESCU, 1931: first record in Austria and phylogenetic relationship with other Adlerius species.

BACKGROUND: Phlebotomine sand flies are the principal vectors of Leishmania spp. (Kinetoplastida: Trypanosomatidae). Information on sand flies in Central Europe is scarce and, to date, in Austria, only Phlebotomus mascittii has been recorded. In 2018 and 2019, entomological surveys were conducted in Austria with the aim to further clarify sand fly distribution and species composition. RESULTS: In 2019, a Ph. simici specimen was trapped in Austria for the first time. Analyses of two commonly used marker genes, cytochrome c oxidase I (coxI) and cytochrome b (cytb), revealed high sequence identity with Ph. simici specimens from North Macedonia and Greece. Phylogenetic analyses showed high intraspecific distances within Ph. simici, thereby dividing this species into three lineages: one each from Europe, Turkey and Israel. Low interspecific distances between Ph. simici, Ph. brevis and an as yet unidentified Adlerius sp. from Turkey and Armenia highlight how challenging molecular identification within the Adlerius complex can be, even when standard marker genes are applied. CONCLUSION: To our knowledge, this study reports the first finding of Ph. simici in Austria, representing the northernmost recording of this species to date. Moreover, it reveals valuable insights into the phylogenetic relationships among species within the subgenus Adlerius. Phlebotomus simici is a suspected vector of L. infantum and therefore of medical and veterinary importance. Potential sand fly expansion in Central Europe due to climatic change and the increasing import of Leishmania-infected dogs from endemic areas support the need for further studies on sand fly distribution in Austria and Central Europe in general.

Natural fluorescence emission - an indirect measurement of applied ozone dosages to remove pharmaceuticals in biologically treated wastewater.

This study investigated the feasibility of UV-absorbance and fluorescence as monitoring tools for ozone dosages applied to effluents from wastewater treatment plans (WWTPs). Secondary treated effluents from five Swedish WWTPs underwent ozonation (at dosages ranging 0.5-12.0 mg O3/L) in bench-scale experiments. Correlations between ozone dosages and UV-absorbance at 254 and 272 nm were extrapolated with the first one being preferential for the wastewaters used because of its higher signal. UV-absorbance could detect differences in the applied ozone dosage as low as 1 mg/L, making it suitable to monitor effluent ozone treatment processes. Next, fluorescence was investigated at wavelength transitions that have being associated with humic-like fluorescents (Ex249Em450 and Ex335Em450) and protein-like fluorescents (Ex275Em340 and Ex231Em360 and Ex231Em315 and Ex275Em310). The Ex249Em450 transition was found to have the highest signal in all effluents and the best linear regression fitting with the ozone dosages over a wide range. However, low ozone dosages (0.5-3.0 mg O3/L), Ex335Em450 wavelength transition showed a more constant slope among the different domestic wastewater samples with slightly better R 2 values than the Ex249Em450 transition. Fluorescence removal via ozonation correlated with the pharmaceutical removal; however, the wellness of fitting was directly dependent on the pharmaceuticals' reactivity with ozone. Pharmaceuticals with moderate reactivity towards ozone appeared to be linearly correlated with the Ex249Em450 transition, while very reactive or recalcitrant pharmaceuticals had an exponential or a parabolic dependency. This means that fluorescence can potentially be used as a qualitative tool for pharmaceutical removal. Abbreviations: APIs, Active Pharmaceutical Ingredients; DOM, Dissolved organic matter; WWTPs, wastewater treatment plans; NOM, Natural organic matter; UV, Ultra-Violet light; DOC, Dissolved organic carbon.

Congenital hyperinsulinism: 2 case reports with different rare variants in ABCC8.

Congenital hyperinsulinism (CHI) is a rare glucose metabolism disorder characterized by unregulated secretion of insulin that leads to hyperinsulinemic hypoglycemia (HH). Most cases are caused by mutations in the KATP-channel genes ABCC8 and KCNJ11. We report 2 patients that experienced severe HH from the first day of life. Patient 1 developed midgut volvulus after initiating diazoxide and required intestinal resection. He was subsequently managed with a high-dose octreotide and glucose-enriched diet. Consistent with diffuse type CHI by 18F-dihydroxyphenylalanine positron emission tomography-computed tomography, genetic testing revealed a homozygous ABCC8 variant, c.1801G>A, p.(Val601Ile). The rare variant was previously reported to be diazoxide-responsive, and the patient responded well to diazoxide monotherapy, with clinical remission at 2 years of age. Patient 2 responded to diazoxide with spontaneous clinical remission at 15 months of age. However, an oral glucose tolerance test at 7 years of age revealed hyperinsulinism. Genetic testing revealed that the proband and several seemingly healthy family members harbored a novel, heterozygous ABCC8 variant, c.1780T>C, p.(Ser594Pro). Genetic findings identified previously unrecognized HH in the proband's mother. The proband's uncle had been diagnosed with monogenic ABCC8-diabetes and was successfully transitioned from insulin to glibenclamide therapy. We report findings of intestinal malrotation and volvulus occurring 2 days after initiation of diazoxide treatment. We also report a novel, heterozygous ABCC8 variant in a family that exhibited cases of CHI in infancy and HH and monogenic diabetes in adult members. The cases demonstrate the importance and clinical utility of genetic analyses for informing and guiding treatment and care.

Sand fly fauna of Crete and the description of Phlebotomus (Adlerius) creticus n. sp. (Diptera: Psychodidae).

BACKGROUND: The Greek island of Crete is endemic for both visceral leishmaniasis (VL) and recently increasing cutaneous leishmaniasis (CL). This study summarizes published data on the sand fly fauna of Crete, the results of new sand fly samplings and the description of a new sand fly species. METHODS: All published and recent samplings were carried out using CDC light traps, sticky traps or mouth aspirators. The specific status of Phlebotomus (Adlerius) creticus n. sp., was assessed by morphological analysis, cytochrome b (cytb) sequencing and MALDI-TOF protein profiling. RESULTS: Published data revealed the presence of 10 Phlebotomus spp. and 2 Sergentomyia spp. During presented field work, 608 specimens of 8 species of Phlebotomus and one species of Sergentomyia were collected. Both published data and present samplings revealed that the two most common and abundant species were Phlebotomus neglectus, a proven vector of Leishmania infantum causing VL, and Ph. similis, a suspected vector of L. tropica causing CL. In addition, the field surveys revealed the presence of a new species, Ph. (Adlerius) creticus n. sp. CONCLUSIONS: The identification of the newly described species is based on both molecular and morphological criteria, showing distinct characters of the male genitalia that differentiate it from related species of the subgenus Adlerius as well as species-specific sequence of cytb and protein spectra generated by MALDI-TOF mass spectrometry.

[Polycystic ovary syndrome in obese or type 1 diabetic (T1D) adolescent girls]. / Syndrome des ovaires polykystiques chez l'adolescente diabétique ou obèse.

Polycystic ovary syndrome (PCOS) is frequent during adolescence (prevalence ≈ 6 %), and the prevalence increases in obese or type 1 diabetic (T1D) adolescent girls. During puberty, PCOS diagnosis is difficult because of the overlap with some pubertal physiologic signs. The 2017 international consortium suggests two required diagnostic criteria: persistent menstrual disturbances and hyperandrogenism. PCOS physiopathology is complex, including interactions between genetic, epigenetic factors, primary ovarian abnormalities, neuroendocrine alterations, hormonal and metabolic factors. Insulin seems to have a central place in obese or T1D adolescent girls. The treatment is still debated and should be monitored according to the main symptoms.

Le syndrome des ovaires polykystiques (SOPK) est fréquent à l'adolescence (prévalence ≈ 6 %), et la prévalence augmente en cas d'obésité ou de diabète de type 1 (DT1). À l'adolescence, le diagnostic du SOPK est difficile en raison de signes communs avec la puberté physiologique. Le consortium international de 2017 propose deux critères diagnostiques indispensables : les troubles du cycle menstruel et l'hyperandrogénie. La physiopathologie du SOPK, partiellement élucidée, est complexe, impliquant l'interaction entre des facteurs génétiques et épigénétiques, des anomalies ovariennes, des altérations neuroendocrines, des facteurs hormonaux et métaboliques. L'insuline semble avoir un rôle central chez l'adolescente obèse ou avec DT1. Le traitement fait encore l'objet de discussion et doit être adapté selon les signes prédominants.

Main Fetal Predictors of Adverse Neonatal Outcomes in Pregnancies with Gestational Diabetes Mellitus.

The objectives of this study were to (a) assess the utility of fetal anthropometric variables to predict the most relevant adverse neonatal outcomes in a treated population with gestational diabetes mellitus (GDM) beyond the known impact of maternal anthropometric and metabolic parameters and (b) to identify the most important fetal predictors. A total of 189 patients with GDM were included. The fetal predictors included sonographically assessed fetal weight centile (FWC), FWC > 90% and <10%, and fetal abdominal circumference centile (FACC), FACC > 90% and < 10%, at 29 0/7 to 35 6/7 weeks. Neonatal outcomes comprising neonatal weight centile (NWC), large and small for gestational age (LGA, SGA), hypoglycemia, prematurity, hospitalization for neonatal complication, and (emergency) cesarean section were evaluated. Regression analyses were conducted. Fetal variables predicted anthropometric neonatal outcomes, prematurity, cesarean section and emergency cesarean section. These associations were independent of maternal anthropometric and metabolic predictors, with the exception of cesarean section. FWC was the most significant predictor for NWC, LGA and SGA, while FACC was the most significant predictor for prematurity and FACC > 90% for emergency cesarean section. In women with GDM, third-trimester fetal anthropometric parameters have an important role in predicting adverse neonatal outcomes beyond the impact of maternal predictors.

Potentially modifiable predictors of adverse neonatal and maternal outcomes in pregnancies with gestational diabetes mellitus: can they help for future risk stratification and risk-adapted patient care?

BACKGROUND: Gestational diabetes mellitus (GDM) exposes mothers and their offspring to short and long-term complications. The objective of this study was to identify the importance of potentially modifiable predictors of adverse outcomes in pregnancies with GDM. We also aimed to assess the relationship between maternal predictors and pregnancy outcomes depending on HbA1c values and to provide a risk stratification for adverse pregnancy outcomes according to the prepregnancy BMI (Body mass index) and HbA1c at the 1st booking. METHODS: This prospective study included 576 patients with GDM. Predictors were prepregnancy BMI, gestational weight gain (GWG), excessive weight gain, fasting, 1 and 2-h glucose values after the 75 g oral glucose challenge test (oGTT), HbA1c at the 1st GDM booking and at the end of pregnancy and maternal treatment requirement. Maternal and neonatal outcomes such as cesarean section, macrosomia, large and small for gestational age (LGA, SGA), neonatal hypoglycemia, prematurity, hospitalization in the neonatal unit and Apgar score at 5 min < 7 were evaluated. Univariate and multivariate regression analyses and probability analyses were performed. RESULTS: One-hour glucose after oGTT and prepregnancy BMI were correlated with cesarean section. GWG and HbA1c at the end pregnancy were associated with macrosomia and LGA, while prepregnancy BMI was inversely associated with SGA. The requirement for maternal treatment was correlated with neonatal hypoglycemia, and HbA1c at the end of pregnancy with prematurity (all p < 0.05). The correlations between predictors and pregnancy complications were exclusively observed when HbA1c was ≥5.5% (37 mmol/mol). In women with prepregnancy BMI ≥ 25 kg/m2 and HbA1c ≥ 5.5% (37 mmol/mol) at the 1st booking, the risk for cesarean section and LGA was nearly doubled compared to women with BMI with < 25 kg/m2 and HbA1c <  5.5% (37 mmol/mol). CONCLUSIONS: Prepregnancy BMI, GWG, maternal treatment requirement and HbA1c at the end of pregnancy can predict adverse pregnancy outcomes in women with GDM, particularly when HbA1c is ≥5.5% (37 mmol/mol). Stratification based on prepregnancy BMI and HbA1c at the 1st booking may allow for future risk-adapted care in these patients.

A novel CHD7 mutation in an adolescent presenting with growth and pubertal delay.

Mutations in the CHD7 gene, encoding for the chromodomain helicase DNA-binding protein 7, are found in approximately 60% of individuals with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities and/or hearing loss). Herein, we present a clinical case of a 14-year-old male presenting for evaluation of poor growth and pubertal delay highlighting the diagnostic challenges of CHARGE syndrome. The patient was born full term and underwent surgery at 5 days of life for bilateral choanal atresia. Developmental milestones were normally achieved. At age 14 his height and weight were -2.04 and -1.74 standard deviation score respectively. He had anosmia as well as prepubertal testes and micropenis (4 cm×1 cm). The biological profile showed low basal serum testosterone and gonadotropins (testosterone, 0.2 nmol/L; luteinizing hormone, 0.5 U/L; follicle-stimulating hormone, 1.3 U/L), and otherwise normal pituitary function and normal imaging of the hypothalamic-pituitary area. The constellation of choanal atresia, anosmia, mild dysmorphic features, micropenis and delayed puberty were suggestive of CHARGE syndrome. Targeted genetic testing of CHD7 was performed revealing a de novo heterozygous CHD7 mutation (c.4234T>G [p.Tyr1412Asp]). Further paraclinical investigations confirmed CHARGE syndrome. Despite the presence of suggestive features, CHARGE syndrome remained undiagnosed in this patient until adolescence. Genetic testing helps clarify the phenotypic and genotypic spectrum to facilitate diagnosis, thus promoting optimal follow-up, treatment, and appropriate genetic counselling.