Search

Background: Noonan syndrome (NS) is a congenital genetic disorder with a prevalence of 1 in 1000 to 2500 live births, and is characterized by distinctive facial features, short stature, chest deformities, and congenital heart disease. This study aims to evaluate the prevalence of specific genetic mutations and their impact on cardiovascular and other outcomes in NS. Methods: We conducted a retrospective clinical study of 25 pediatric patients diagnosed with NS at two institutions: The Mother and Child Health Care Institute of Serbia and the Clinic for Children Diseases, University Clinical Center of the Republic of Srpska. Patients underwent whole-exome sequencing (WES) to identify genetic mutations. Clinical data, including cardiovascular manifestations, psychomotor development, and stature, were analyzed in relation to mutation types. Results: The cohort comprised 60% male and 40% female patients, with a median age at diagnosis of 7.2 years. Cardiovascular abnormalities were present in 88% of patients. Mutations in PTPN11 were most commonly associated with pulmonary valve stenosis (PVS), while RAF1 mutations were prevalent in patients with hypertrophic cardiomyopathy (HCM). No significant association was found between cardiac disease and delayed psychomotor development ( p = 0.755), even though the likelihood ratio showed significance in that regard ( p = 0.018). Short stature was observed in 48% of patients but was not significantly correlated with genetic type of disease, presence of cardiac disease, or developmental delay. Conclusions: The study confirms the high prevalence of cardiovascular manifestations in NS and highlights genotype-phenotype correlations. While cardiac abnormalities are common, their impact on psychomotor development and stature is less clear. Further research is needed to explore genetic interactions influencing these outcomes and refine clinical management strategies.

Telomerase Reverse Transcriptase (TERT) encodes the telomerase reverse transcriptase enzyme and is the most frequently mutated gene in patients with telomeropathies. Heterozygous variants impair telomerase activity by haploinsufficiency and pathogenic variants are associated with bone marrow failure syndrome and predisposition to acute myeloid leukaemia. Owing to their rarity, telomeropathies are often unrecognised and misdiagnosed. Herein, we report a novel TERT gene variant, c.2605G > A p.(Asp869Asn) in a family with hereditary aplastic anaemia. This report emphasises the importance of routine deep genetic screening for rare TERT variants in patients with a family history of cytopenia or aplastic anaemia, which could identify clinically inapparent telomere disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled the identification of disease-causing genes and variants in childhood epilepsies. The objective of this study was to use NGS to identify variants in patients with childhood epilepsy, to expand the variant spectrum and discover potential therapeutic targets., Methods: In our study, 55 children with epilepsy of unknown etiology were analyzed by combining clinical-exome and whole-exome sequencing. Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction., Results: The molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in five unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes such as ASH1L, CSNK2B, RHOBTB2, and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, we identified variants in ALDH7A1, KCNQ2, PNPO, SCN1A, and SCN2A resulting in gene-directed therapy decisions for 11 children from our study, including four children who all carried novel SCN1A genetic variants., Conclusions: Described novel variants will contribute to a better understanding of the European genetic landscape, while insights into the genotype-phenotype correlation will contribute to a better understanding of childhood epilepsies worldwide. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target., (© 2024. The Author(s).)

Despite advances in cancer treatment, pancreatic cancer (PC) remains a disease with high mortality rates and poor survival outcomes. The B7 homolog 3 (B7-H3) checkpoint molecule is overexpressed among many malignant tumors, including PC, with low or absent expression in healthy tissues. By modulating various immunological and nonimmunological molecular mechanisms, B7-H3 may influence the progression of PC. However, the impact of B7-H3 on the survival of patients with PC remains a subject of debate. Still, most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC. Furthermore, it has been demonstrated that B7-H3 stimulates the migration, invasion, and metastasis of PC cells, and enhances resistance to chemotherapy. In preclinical models of PC, B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibody-dependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site. Finally, PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies. This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Congenital myotonic dystrophy type 1 (CDM1) is a rare neuromuscular disease. The aim of our study was to evaluate clinical variability of CDM1 and factors that may influence survival in CDM1. Research included 24 pediatric patients with CDM1. Most of our patients had some form of hypoxic ischemic encephalopathy (HIE) (74 %), from mild to severe. Prolonged and complicated deliveries (75 %), high percentage of children resuscitated at birth (57 %) and respiratory insufficiency (46 %) with consequent hypoxia were the main reasons that could explain high percentage of HIE. Therapeutic hypothermia was applied in three children with poor outcome. Median survival of all CDM1 was 14.2 ± 1.5 years. Six patients had a fatal outcome (25 %). Their mean age of death was 3.0 ± 2.8 years. Poor prognostic factors for the survival of our CDM1 patients were: preterm delivery, resuscitation at birth, severe HIE, hypothermia treatment and permanent mechanical ventilation. Respiratory insufficiency was the main life-threatening factor. Our data clearly indicates the need to develop natural history studies in CDM1 in order to enhance the standards of care and to develop clinical trials investigating causative therapies in pediatric patients with CDM1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Celiac disease (CD) is among the diseases most commonly associated with type 1 diabetes (T1D). This study aimed to evaluate the worldwide practices and attitudes of physicians involved in pediatric diabetes care regarding diagnosing and managing CD in children with T1D., Methods: The 30-item survey was conducted between July and December 2023 aimed at targeting pediatricians with special interest in T1D and CD. It was shared by the JENIOUS - young investigators group of the International Society of Pediatric and Adolescent Diabetes (ISPAD) - and the YES - early career group of the European Society for Pediatric Endocrinology (ESPE)., Results: Overall, 180 physicians (67.8% female) from 25 countries responded. Among respondents, 62.2% expected sustaining optimal glycemic control in children with T1D and CD (T1D + CD) to be more difficult than in children with T1D alone. Majority (81.1%) agreed that more specific guidelines are needed. The follow-up routine for patients with T1D + CD differed, and one-quarter of physicians scheduled more frequent follow-up checkups for these patients. Seventy percent agreed multidisciplinary outpatient clinics for their follow-up is needed. In the multivariate ordinal logistic regression model, a statistically significant predictor of a higher degree of practice according to ISPAD 2022 guidelines was a higher level of country income (OR = 3.34; p < 0.001)., Conclusions: These results showed variations in physicians' practices regarding managing CD in children with T1D, emphasizing the need for more specific guidelines and intensive education of physicians in managing this population, especially in lower-income countries. Our data also suggest the implementation of multidisciplinary outpatient clinics for their follow-up., (© 2024 S. Karger AG, Basel.)

This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Splenic hamartomas (SHs) are uncommon, benign vascular lesions of unclear etiology and are mostly found incidentally on abdominal images, at surgery, or at autopsy. Since the first case description, in 1861, less than 50 pediatric SH cases have been reported in the literature. In this article, we have performed an analysis of all SH cases in children published in the literature to date and presented our case of an 8-year-old male with SH. These lesions in children were shown to cause symptoms more often than in the adult population. The observed SH sizes in children ranged from a few millimeters to 18 cm, and the symptomatic lesions were mostly larger or multiple. The most common clinical finding was splenomegaly. Signs of hypersplenism were present in children with a single SH larger than 4.5 cm (diameter range: 4.5-18.0 cm) and in those with multiple hamartomas, ranging from a few millimeters to 5 cm. Eighty percent of patients with available laboratory findings had hematological abnormalities such as anemia, thrombocytopenia, or pancytopenia. Other symptoms and signs included abdominal pain, recurrent infections, fever, night sweats, lethargy, growth retardation, and weight loss. The use of multiple imaging modalities may suggest the preoperative diagnosis of a splenic mass in children and determine the therapeutic approach. However, the final diagnosis of SH relies on histopathological evaluation. Surgery, including total or partial splenectomy (PS), is the mainstay of SH management. Although total splenectomy carries a greater risk of overwhelming post-splenectomy infection than PS it has remained the most performed surgical procedure in children with SH. In the majority of pediatric patients with symptomatic SH, resolution of symptoms and resolution or improvement of cytopenias occurred after surgical treatment., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The etiology of upper gastrointestinal bleeding (UGIB) varies by age, from newborns to adolescents, with some of the causes overlapping between age groups. While particular causes such as vitamin K deficiency and cow's milk protein allergy are limited to specific age groups, occurring only in neonates and infants, others such as erosive esophagitis and gastritis may be identified at all ages. Furthermore, the incidence of UGIB is variable throughout the world and in different hospital settings. In North America and Europe, most UGIBs are non-variceal, associated with erosive esophagitis, gastritis, and gastric and duodenal ulcers. In recent years, the most common causes in some Middle Eastern and Far Eastern countries are becoming similar to those in Western countries. However, variceal bleeding still predominates in certain parts of the world, especially in South Asia. The most severe hemorrhage arises from variceal bleeding, peptic ulceration, and disseminated intravascular coagulation. Hematemesis is a credible indicator of a UGI source of bleeding in the majority of patients. Being familiar with the most likely UGIB causes in specific ages and geographic areas is especially important for adequate orientation in clinical settings, the use of proper diagnostic tests, and rapid initiation of the therapy. The fundamental approach to the management of UGIB includes an immediate assessment of severity, detecting possible causes, and providing hemodynamic stability, followed by early endoscopy. Unusual UGIB causes must always be considered when establishing a diagnosis in the pediatric population because some of them are unique to children. Endoscopic techniques are of significant diagnostic value, and combined with medicaments, may be used for the management of acute bleeding. Finally, surgical treatment is reserved for the most severe bleeding., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background:  Few previous studies indicated the role of oxidative stress in the pathogenesis of childhood idiopathic thrombocytopenic purpura (ITP), but there are little data regarding changes in redox balance in different forms of the disease, and changes after therapeutic procedures. We aimed to investigate the values of pro-oxidants and antioxidative capacity in various forms of ITP before and after the applying therapy., Materials and Methods:  The research included 102 children, classified into the following groups: (1) newly diagnosed ITP (ndITP), (2) persistent ITP, (3) chronic ITP (chITP), and (4) control groups: (A) healthy control and (B) previously experienced ITP-healthy children who had been suffering from ITP earlier. During the clinical assessment, a blood sample was taken from the patients, from which the value of pro-oxidants (index of lipid peroxidation measured as TBARS, nitrites [NO 2 - ], as measurement of nitric oxide [NO] production, superoxide anion radical [O 2 - ], and hydrogen peroxide [H 2 O 2 ]) and the capacity of antioxidant protection (activity of superoxide dismutase and catalase, and quantity of reduced glutathione) were determined spectrophotometrically., Results:  Our results demonstrated that values of pro-oxidants, especially reflected through the TBARS and O 2 - , were the highest in the ndITP and exacerbated chITP groups. Also, the activity of the endogenous antioxidative defense system was the lowest in these groups. Intravenous immunoglobulin therapy in the ndITP group exerted the most prominent effect on the redox balance., Conclusion:  It can be concluded that severity and exacerbation of the ITP are closely related to the redox status., Competing Interests: None declared., (Thieme. All rights reserved.)

Aim: To identify the determinants of self-reported health-related quality of life in children and adolescents with type 1 diabetes mellitus during the coronavirus pandemic., Design: A cross-sectional study., Methods: The study sample included 182 children and adolescents who had been diagnosed with type 1 diabetes mellitus at least 3 months prior. Data collection instruments included sociodemographic and glycaemic control protocol adherence questionnaires, documentation sheet for recording clinical data, and Serbian versions of the EuroQol-5D-Y and KidScreen27 questionnaires, which were used to assess health-related quality of life., Results: Glycaemic control adherence, presence of comorbidities, level of metabolic control, and type of insulin therapy were identified as key determinants of self-reported health-related quality of life., Patient or Public Contribution: No patient or public contributions., (© 2023 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Background: The aim of the present survey was to analyze the knowledge and skills in medical paper writing of physicians who attended the course "how to write successfully a scientific paper.", Methods: A blind survey was used to analyze participants' knowledge on the topic of the course "how to write successfully a scientific paper." Before starting the workshop, participants anonymously filled out the input questionnaire containing 12 preliminary data questions. The three-hour course included a lecture on the steps of creating and writing a scientific article with examples. At the end, all participants anonymously completed the exit questionnaire consisting of 18 questions. Differences and associations between the collected data were analyzed using appropriate statistical tests., Results: The survey included 22 participants, most of whom were women (16, 72.7%). The participants' educational level was proportional to their age. 12 of the participants had an intermediate level, while the others reported higher English proficiency. Half of the participants had never published an article. A significant difference was observed between English level and being the first author of an article published in a scientific journal (p = 0.044). Before class, only 13.6% of participants knew that guidelines are mandatory for making clinical decisions according to evidence- based medicine. There was a significant positive correlation between sex and current affiliation (p = 0.038). A negative correlation was observed between sex and article publication (p = 0.037). A positive correlation was observed between English level and current affiliation (p = 0.020). There was a negative correlation observed between previous sources of learning scientific article writing and having already published an article (p = 0.025). A positive correlation was found between reading an article and publishing it (p = 0.046). Statistical analysis showed a significant difference between reading frequency, number of published articles, being the first author, and knowing the title of a scientific article (p = 0.036, p = 0.027, and p = 0.030, respectively)., Conclusion: The results of the questionnaires revealed discrepancies in prior research engagement and understanding of scientific concepts and rules. This survey highlights the importance of the course "how to successfully write a scientific article" in improving participants' knowledge of scientific work and the process of creating an article for submission to medical journals., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Bronchiolitis is the main acute lower respiratory tract infection in infants. Data regarding SARS-CoV-2-related bronchiolitis are limited., Objective: To describe the main clinical characteristics of infants with SARS-CoV-2-related bronchiolitis in comparison with infants with bronchiolitis associated with other viruses., Setting, Patients, Interventions: A multicentre retrospective study was conducted in 22 paediatric emergency departments (PED) in Europe and Israel. Infants diagnosed with bronchiolitis, who had a test for SARS-CoV-2 and were kept in clinical observation in the PED or admitted to hospital from 1 May 2021 to 28 February 2022 were considered eligible for participation. Demographic and clinical data, diagnostic tests, treatments and outcomes were collected., Main Outcome Measures: The main outcome was the need for respiratory support in infants testing positive for SARS-CoV-2 compared with infants testing negative., Results: 2004 infants with bronchiolitis were enrolled. Of these, 95 (4.7%) tested positive for SARS-CoV-2. Median age, gender, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative infants. Human metapneumovirus and respiratory syncytial virus were the viruses most frequently detected in the group of infants negative for SARS-CoV-2.Infants testing positive for SARS-CoV-2 received oxygen supplementation less frequently compared with SARS-CoV-2-negative patients, 37 (39%) vs 1076 (56.4%), p=0.001, OR 0.49 (95% CI 0.32 to 0.75). They received less ventilatory support: 12 (12.6%) high flow nasal cannulae vs 468 (24.5%), p=0.01; 1 (1.0%) continuous positive airway pressure vs 125 (6.6%), p=0.03, OR 0.48 (95% CI 0.27 to 0.85)., Conclusions: SARS-CoV-2 rarely causes bronchiolitis in infants. SARS-CoV-2-related bronchiolitis mostly has a mild clinical course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Streptococcus pneumoniae is one of the leading bacterial pathogens that can cause severe invasive diseases. The aim of the study was to characterize invasive isolates of S. pneumoniae obtained during the nine-year period in Serbia before the introduction of the pneumococcal conjugate vaccines (PCVs) into routine vaccination programs by determining: serotype distribution, the prevalence and genetic basis of antimicrobial resistance, and genetic relatedness of the circulating pneumococcal clones. A total of 490 invasive S. pneumoniae isolates were included in this study. The serotype, antimicrobial susceptibility, and ST of the strains were determined by the Quellung reaction, disk- and gradient-diffusion methods, and multilocus sequence typing (MLST), respectively. The most common serotypes in this study were 3, 19F, 14, 6B, 6A, 19A, and 23F. The serotype coverages of PCV10 and PCV13 in children less than 2 years were 71.3 and 86.1%, respectively, while PPV23 coverage in adults was in the range of 85-96%, depending on the age group. Penicillin and ceftriaxone-non-susceptible isolates account for 47.6 and 16.5% of all isolates, respectively. Macrolide non-susceptibility was detected in 40.4% of isolates, while the rate of multidrug- and extensive-drug resistance was 20.0 and 16.9%, respectively. The MLST analysis of 158 pneumococci identified 60 different STs belonging to the 16 Clonal Complexes (CCs) (consisting of 42 STs) and 18 singletons. The most common CC/ST were ST1377, CC320, CC15, CC273, CC156, CC473, CC81, and CC180. Results obtained in this study indicate that the pre-vaccine pneumococcal population in Serbia is characterized by high penicillin and macrolides non-susceptibility, worrisome rates of MDR and XDR, as well as a high degree of genetic diversity. These findings provide a basis for further investigation of the changes in serotypes and genotypes that can be expected after the routine introduction of PCVs., Competing Interests: NO acts as a principal investigator for investigator-initiated sponsored research related to the topic conducted on behalf of the Faculty of Medicine, University of Belgrade, for which the Faculty obtained a research grant from Merck Sharp and Dohme doo. There are no patents, products in development, or marketed products associated with this research. We fully adhere to Frontiers policies on data and material sharing. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher., (Copyright © 2023 Opavski, Jovicevic, Kabic, Kekic, Vasiljevic, Tosic, Medic, Laban, Ranin and Gajic.)

Introduction: Myotonic dystrophy type 1 (DM1) is the most prevalent muscular dystrophy in adults. People with DM1 might represent a high-risk population for respiratory infections, including COVID-19. Our aim was to evaluate the characteristics of COVID-19 infection and vaccination rate in DM1 patients., Methods: This cross-sectional cohort study included 89 patients from the Serbian registry for myotonic dystrophies. Mean age at testing was 48.4 ± 10.4 years with 41 (46.1%) male patients. Mean duration of the disease was 24.0 ± 10.3 years., Results: COVID-19 infection was reported by 36 (40.4%) DM1 patients. Around 14% of patients had a more severe form of COVID-19 requiring hospitalization. The severity of COVID-19 was in accordance with the duration of DM1. A severe form of COVID-19 was reported in 20.8% of patients who were not vaccinated against SARS-CoV-2 and in none of the vaccinated ones. The majority of 89 tested patients (66.3%) were vaccinated against SARS-CoV-2. About half of them (54.2%) received three doses and 35.6% two doses of vaccine. Mild adverse events after vaccination were recorded in 20.3% of patients., Conclusions: The percentage of DM1 patients who suffered from COVID-19 was like in general population, but with more severe forms in DM1, especially in patients with longer DM1 duration. The study indicated an overall favorable safety profile of COVID-19 vaccines among individuals with DM1 and its ability to protect them from severe COVID-19., (© 2023. The Author(s).)

Purpose: The International Berlin-Frankfurt-Münster (BFM) study group conducted a study on pediatric acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) was assessed using flow cytometry (FCM), and the impact of early intensification and methotrexate (MTX) dose on survival was evaluated., Patients and Methods: We included 6,187 patients younger than 19 years. MRD by FCM refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, WBC count, unfavorable genetic aberrations, and treatment response measured morphologically. Patients at intermediate risk (IR) and high risk (HR) were randomly assigned to protocol augmented protocol I phase B (IB) versus IB regimen. MTX doses of 2 versus 5 g/m 2 every 2 weeks, four times, were evaluated in precursor B-cell-ALL (pcB-ALL) IR., Results: The 5-year event-free survival (EFS ± SE) and overall survival (OS ± SE) rates were 75.2% ± 0.6% and 82.6% ± 0.5%, respectively. Their values in risk groups were standard risk (n = 624), 90.7% ± 1.4% and 94.7% ± 1.1%; IR (n = 4,111), 77.9% ± 0.7% and 85.7% ± 0.6%; and HR (n = 1,452), 60.8% ± 1.5% and 68.4% ± 1.4%, respectively. MRD by FCM was available in 82.6% of cases. The 5-year EFS rates in patients randomly assigned to protocol IB (n = 1,669) and augmented IB (n = 1,620) were 73.6% ± 1.2% and 72.8% ± 1.2%, respectively ( P = .55), while those in patients receiving MTX doses of 2 g/m 2 (n = 1,056) and MTX 5 g/m 2 (n = 1,027) were 78.8% ± 1.4% and 78.9% ± 1.4%, respectively ( P = .84)., Conclusion: The MRDs were successfully assessed using FCM. An MTX dose of 2 g/m 2 was effective in preventing relapse in non-HR pcB-ALL. Augmented IB showed no advantages over the standard IB.[Media: see text].

Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.

Deficiency of lysosomal acid lipase (LAL-D) is caused by biallelic pathogenic variants in the LIPA gene. Spectrum of LAL-D ranges from early onset of hepatosplenomegaly and psychomotor regression (Wolman disease) to a more chronic course (cholesteryl ester storage disease - CESD). The diagnosis is based on lipid and biomarker profiles, specific liver histopathology, enzyme deficiency, and identification of causative genetic variants. Biomarker findings are a useful for diagnostics of LAL-D, including high plasma concentration of chitotriosidase as well as elevated oxysterols. Current treatment options include enzyme replacement therapy (sebelipase-alpha), statins, liver transplantation, and stem cell transplantation. We present two pairs of siblings from Serbia with a distinctive phenotype resembling LAL-D with a novel variant of unknown significance (VUS) detected in the LIPA gene and residual LAL activity. All patients presented with hepatosplenomegaly at early childhood. In siblings from family 1, compound heterozygosity for a pathogenic c.419G>A (p.Trp140Ter) variant and a novel VUS c.851C>T (p.Ser284Phe) was detected. Patients from family 2 were homozygous for c.851C>T VUS and both have typical histopathologic findings for LAL-D in the liver. Enzyme activity of LAL was tested in three patients and reported as sufficient, and therefore enzyme replacement therapy could not be approved. When confronted with a challenge of diagnosing an inherited metabolic disorder, several aspects are taken into consideration: clinical manifestations, specific biomarkers, enzyme assay results, and molecular genetic findings. This report brings cases to light which have a considerable discrepancy between those aspects, namely the preserved LAL enzyme activity in presence of clinical manifestations and rare variants in the LIPA gene., Competing Interests: Conflict of interest Conflict of interest statement: All authors declare that they have no conflict of interest., (© 2022 Sarajlija A., Armengol L., Maver A., Kitic I., Prokic D., Cehic M., Djuricic M.S., Peterlin B., published by Sciendo.)

Disorders of lipoprotein metabolism and glucose homeostasis are common consequences of insulin resistance and usually co-segregate in patients with metabolic syndrome and type 2 diabetes mellitus (DM). Insulin-resistant subjects are characterized by atherogenic dyslipidemia, a specific lipid pattern which includes hypertriglyceridemia, reduced high-density lipoprotein cholesterol level, and increased proportion of small, dense low-density lipoprotein (LDL). Chronic hyperglycemia favors the processes of non-enzymatic glycation, leading to the increased production of advanced glycation end products (AGEs). Apart from direct harmful effects, AGEs are also potent inducers of oxidative stress and inflammation. In addition, increased AGEs' production may induce further qualitative modifications of small, dense LDL particles, converting them to glycated LDLs. These particles are even more atherogenic and may confer an increased cardiovascular risk. In this narrative review, we summarize the available evidence of the pathophysiological role and clinical importance of circulating AGEs and glycated LDLs in patients with dyslipidemia, particularly those with DM and related complications. In addition, we discuss recent advances and the issues that should be improved regarding laboratory assessment of AGEs and glycated LDLs, as well as the possibilities for their therapeutic modulation.

Type 1 diabetes (T1D) is a condition that affects all aspects of life, and thus is closely related to the quality of life itself. Dealing with it during the COVID-19 pandemic is a big challenge. A case-control study conducted in Montenegro at the end of 2021 included 87 elementary school students with T1D and 248 of their peers as controls matched by gender. Standardized questionnaires were distributed to participants (Peds-QL Generic core 4.0 questionnaire for all participants and Peds-QL Diabetes Module 3.2 only for cases). Based on them, the results of obtained scores were measured and compared using non-parametric statistical methods in relation to gender, region and type of household. Children with T1D reported lower quality of life comparing to matching controls with lower scores in almost all domains. Differences in the same domains among patients and their classmates were also observed in the different gender subgroups, environment type subgroups and in the central region. Results of the study provide insights to prioritizing actions for children with diabetes care as well as for public healthcare planning.

Background: The aim of this meta-analysis was to analyze all available data from studies investigating associations between polymorphisms in genes responsible for innate immunity and neonatal sepsis development., Methods: A comprehensive literature search, reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-S guidelines, was performed with no language restriction. Studies derived using the PICO (population, intervention, comparison and outcomes) strategy, with data on the genotype distribution for innate immunity gene polymorphisms in newborns with and without sepsis. Data were analyzed using Review Manager. The Cochran-Mantel-Haenszel test was used to calculate odds ratios with 95% confidence intervals. Heterogeneity was tested using the I 2 index., Results: From a total of 9428 possibly relevant articles, 33 qualified for inclusion in this systematic review. According to the STrengthening the REporting of Genetic Association Studies, 23 studies were found to be of moderate quality, while 10 were of low quality. The results showed an association of the mannose-binding lectin (MBL) exon 1 genetic polymorphism with the risk of culture-proven sepsis. Toll-like receptor (TLR) 4 rs4986791 genotype distribution suggests its association with the increased risk of culture-proven sepsis. The certainty of evidence per GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) varied from very low to low. Publication bias was not detected., Conclusions: Out of the 11 investigated single-nucleotide polymorphisms, this meta-analysis found a possible association between the risk for culture-proven sepsis and MBL exon 1 and TLR4 rs4986791 polymorphisms. There is an evident need for larger well-designed, multicentric observational studies investigating inflammatory gene polymorphisms in neonatal sepsis., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

Significant and unexplained variations in type 1 diabetes (T1D) incidence through the years were observed all around the world. The update on this disorder's incidence is crucial for adequate healthcare resource planning and monitoring of the disease. The aim of this study was to give an update on the current incidence of pediatric T1D in Montenegro and to analyze incidence changes over time and how the exposure to different factors might have affected it. This retrospective cohort study included a total of 582 patients younger than 15 years who were newly diagnosed with T1D during the past 30 years. The average age at diagnosis was 8.4 ± 3.91 years. The mean annual incidence of T1D in the Montenegro population during the whole study period of 30 years was 15.2/100,000 person-years. Slightly higher incidence rates were observed in male compared to female individuals, and the incidence increased with age, with the highest incidence in the 10-14 age group. If the model is observed as one without jointpoints, the annual percentage change (APC) for the total population is 3.1 (1.8-4.4); for male individuals, 3.8 (2.1-5.5); and for female individuals, 2.1 (0.6-3.5). In 2020, the first year of the coronavirus disease of 2019 (COVID-19) pandemic, in comparison to 2019, the incidence rate increased from 19.7/100,000 to 21.5/100,000, with the highest increase in the age group of 5-9 years. This is the first nationwide report on a 30-year period of T1D incidence trend in Montenegro. It suggests that T1D incidence among Montenegrin children is rising again and that there is a short-term influence of COVID-19 on new-onset T1D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Raicevic, Samardzic, Soldatovic, Curovic Popovic and Vukovic.)

Background: Bronchiolitis is the leading acute respiratory tract infection in infants during the winter season. Since the beginning of the SARS-CoV-2 pandemic, a reduction in the number of bronchiolitis diagnoses has been registered., Objective: The present study aimed to describe the incidence and clinical features of bronchiolitis during the 2020-2021 winter season in a large cohort of children in Europe and Israel, and to clarify the role of SARS-CoV-2., Setting, Patients, Interventions: We conducted a multicentre observational cross-sectional study in 23 paediatric emergency departments in Europe and Israel. Clinical and demographic data about all the cases of infants diagnosed with bronchiolitis from 1 October 2020 to 30 April 2021 were collected. For each enrolled patient, diagnostic tests, treatments and outcomes were reported., Main Outcome Measures: The main outcome was the prevalence of SARS-CoV-2-positive bronchiolitis., Results: Three hundred and fourteen infants received a diagnosis of bronchiolitis during the study period. Among 535 infants who tested positive for SARS-CoV-2, 16 (3%) had bronchiolitis. Median age, male sex predominance, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative groups. Rhinovirus was the most common involved pathogen, while respiratory syncytial virus (RSV) was detected in one case. SARS-CoV-2 bronchiolitis had a mild clinical course, with one patient receiving oxygen supplementation and none requiring paediatric or neonatal intensive care unit admission., Conclusions: During the SARS-CoV-2 pandemic, a marked decrease in the number of bronchiolitis diagnoses and the disappearance of the RSV winter epidemic were observed. SARS-CoV-2-related bronchiolitis was rare and mostly displayed a mild clinical course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Clinical course variability in Duchenne muscular dystrophy (DMD) is partially explained by the mutation location in the DMD gene and variants in modifier genes. We assessed the effect of the SPP1 , CD40 , and LTBP4 genes and DMD mutation location on loss of ambulation (LoA)., Methods: SNPs in SPP1 -rs28357094, LTBP4 -rs2303729, rs1131620, rs1051303, rs10880, and CD40 -rs1883832 were genotyped, and their effect was assessed by survival and hierarchical cluster analysis., Results: Patients on glucocorticoid corticosteroid (GC) therapy experienced LoA one year later ( p = 0.04). The modifying effect of SPP1 and CD40 variants, as well as LTBP4 haplotypes, was not observed using a log-rank test and multivariant Cox regression analysis. Cluster analysis revealed two subgroups with statistical trends in differences in age at LoA. Almost all patients in the cluster with later LoA had the protective IAAM LTBP4 haplotype and statistically significantly fewer CD40 genotypes with harmful T allele and "distal" DMD mutations., Conclusions: The modifying effect of SPP1 , CD40 , and LTBP4 was not replicated in Serbian patients, although our cohort was comparable in terms of its DMD mutation type distribution, SNP allele frequencies, and GC-positive effect with other European cohorts. Cluster analysis may be able to identify patient subgroups carrying a combination of the genetic variants that modify LoA.

Purpose: Gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for diagnosing central precocious puberty (CPP). However, intravenous GnRH is not always readily available. The aim of the present study was to evaluate the diagnostic accuracy of triptorelin-stimulated luteinizing hormone (LH) concentrations in the diagnosis of CPP among girls presenting with premature thelarche compared to the gold standard GnRH test., Methods: A prospective, case-control (CPP vs isolated premature thelarche), clinical study evaluating the diagnostic accuracy of triptorelin-stimulated LH concentrations in 60 girls with premature thelarche was performed. All girls underwent stimulation with subcutaneous triptorelin injection and intravenous GnRH in a randomized order. During the stimulation test with triptorelin, LH and FSH were measured at time 0, 30, 60, 90, 120, and 180 min after the injection. Estradiol was sampled 24 h after the injection. During the GnRH test, LH and FSH were measured at time 0, 30, 45, and 60 min. Girls with peak GnRH-stimulated LH concentrations ≥5.0 IU/L were classified as having CPP. Area under the curve (AUC) for triptorelin-stimulated LH concentrations was assessed using the receiver operating characteristic (ROC) analysis., Results: Triptorelin-stimulated LH concentrations were significantly higher in girls who had CPP according to the GnRH test (53.3%). LH peaked at 180 min after the triptorelin injection. The highest diagnostic accuracy for CPP (AUC = 0.973, sensitivity 96.9%, specificity 89.3%) at 180 min was at a LH concentration ≥3.4 IU/L. The 24 h estradiol concentration did not improve the predictive model., Conclusions: Measuring LH concentrations 180 min after triptorelin injection with a cut-off value of ≥3.4 IU/L demonstrated a high diagnostic accuracy compared to the GnRH test. Thus, stimulation with triptorelin can be used as a reliable alternative for diagnosing CPP in girls with premature thelarche., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The aim of this prospective cohort study was to determine the prevalence of gut colonization with multidrug-resistant (MDR) bacteria, risk factors for colonization, infection risk, and outcomes among preterm neonates hospitalized at a tertiary-care center in Serbia. During the period from December 2017 to April 2018, 103 neonates were screened for rectal carriage at admission and on the seventh day of life. Characterization of MDR strains was done by conventional microbiology and molecular methods. Out of 61 (59.2%) colonized neonates, 12 (11.6%) were found colonized at admission, while 49 (47.6%) became colonized at the study site. Among a total of 72 MDR isolates, extended-spectrum beta-lactamase (ESBL)-producing enterobacteria prevailed (56/72, 77%), followed by Acinetobacter baumannii (14/72, 19%). The majority of ESBL-producing strains carried multiple genes ( bla TEM/ bla CTX-M-15 or bla TEM/ bla SHV). Longer previous hospitalization and delivery by cesarean section were associated with MDR colonization, while mechanical ventilation was a risk factor for colonization at the study site. Infections due to MDR bacteria were more frequent among colonized than non-colonized neonates, but not significantly, and mortality was low (1%) in the studied neonates. These results indicate that hospitalized preterm neonates in Serbia are rapidly colonized with a diversity of MDR species and resistance phenotypes/genotypes.

Background and Aims: A higher frequency of dyslipidemia is reported in children with type 1 diabetes (T1D) and celiac disease (CD). Recently, continuous subcutaneous insulin infusion (CSII) has been associated with better lipid profiles in patients with T1D. The aim of this study was to investigate the association between treatment modality and lipid profile, metabolic control, and body mass index (BMI)-SDS in children with both T1D and CD., Methods: Cross-sectional study in children registered in the international SWEET database in November 2020. Inclusion criteria were children (2-18 years) with T1D and CD with available data on treatment modality (CSII and injections therapy, IT), triglyceride, total cholesterol, HDL, LDL, dyslipidemia, HbA1c, and BMI-SDS. Overweight/obesity was defined as > +1 BMI-SDS for age. Data were analyzed by linear and logistical regression models with adjustment for age, gender, and diabetes duration., Results: In total 1009 children with T1D and CD (female 54%, CSII 54%, age 13.9 years ±3.6, diabetes duration 7.2 years ±4.1, HbA1c 7.9% ±1.4) were included. Significant differences between children treated with CSII vs. IT were respectively found; HDL 60.0 mg/dL vs. 57.8 mg/dL, LDL 89.4 mg/dL vs. 94.2 mg/dL, HbA1c 7.7 vs. 8.1%, BMI-SDS 0.4 vs. 0.6, overweight and obesity 17% vs. 26% (all p < 0.05)., Conclusions: CSII is associated with higher HDL and lower LDL, HbA1c, BMI-SDS, and percentage of overweight and obesity compared with IT in this study. Further prospective studies are required to determine whether CSII improves lipid profile, metabolic control and normalize body weight in children with both T1D and CD.

Background and Objectives : Ovarian cancer is the leading cause of death among gynecological tumors. PD-1/PD-L1 immunoregulatory mechanism is activated in ovarian cancers. Lymphocyte infiltration is a significant factor that affects its expression. We analyzed the correlation between localization of lymphocytic infiltrate and PD-L1 expression in epithelial ovarian tumors. Materials and Methods : PD-L1 expression was analyzed in 328 subjects, 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. Expression in central and invasive tumor parts in epithelial ovarian carcinoma was combined with the most pronounced lymphocyte reaction. Immunohistochemical analysis was performed using the tissue microarray and correlated with a set of histopathology parameters. Results : PD-L1 expression was most prominent in epithelial ovarian carcinoma with different levels of expression observed between invasive and central tumor segments. A high level of PD-L1 expression on tumor cells was more frequently present in the invasive than in the central tumor parts ( p < 0.001) only in high-grade serous ovarian carcinoma (HGSC). There was no significant correlation between peritumoral lymphocytic infiltrate and PD-L1 expression regardless of tumor segment. In the central tumor parts of HGSC, there was a correlation of intratumoral lymphocytic infiltrate with a higher level of PD-L1 expression ( p = 0.003). Conclusions : The most prominent PD-L1 expression was observed in the invasive tumor parts of HGSC. Only the central parts of the HGSC exhibited significant PD-L1 expression in association with considerable intratumoral lymphocytic infiltrate.

Phenylketonuria (PKU) is an inborn error of metabolism caused by variants in the phenylalanine hydroxylase ( PAH ) gene and it is characterized by excessively high levels of phenylalanine in body fluids. PKU is a paradigm for a genetic disease that can be treated and majority of developed countries have a population-based newborn screening. Thus, the combination of early diagnosis and immediate initiation of treatment has resulted in normal intelligence for treated PKU patients. Although PKU is a monogenic disease, decades of research and clinical practice have shown that the correlation between the genotype and corresponding phenotype is not simple at all. Attempts have been made to discover modifier genes for PKU cognitive phenotype but without any success so far. We conducted whole genome sequencing of 4 subjects from unrelated non-consanguineous families who presented with pathogenic mutations in the PAH gene, high blood phenylalanine concentrations and near-normal cognitive development despite no treatment. We used cross sample analysis to select genes common for more than one patient. Thus, the SHANK gene family emerged as the only relevant gene family with variants detected in 3 of 4 analyzed patients. We detected two novel variants, p.Pro1591Ala in SHANK1 and p.Asp18Asn in SHANK2 , as well as SHANK2 :p.Gly46Ser, SHANK2 :p.Pro1388&#95;Phe1389insLeuPro and SHANK3 :p.Pro1716Thr variants that were previously described. Computational analysis indicated that the identified variants do not abolish the function of SHANK proteins. However, changes in posttranslational modifications of SHANK proteins could influence functioning of the glutamatergic synapses, cytoskeleton regulation and contribute to maintaining optimal synaptic density and number of dendritic spines. Our findings are linking SHANK gene family and brain plasticity in PKU for the first time. We hypothesize that variant SHANK proteins maintain optimal synaptic density and number of dendritic spines under high concentrations of phenylalanine and could have protective modifying effect on cognitive development of PKU patients., Competing Interests: none., (© 2021 The Author(s).)

Context: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding., Objective: We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects., Methods: Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel., Results: Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver-Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome)., Conclusion: We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: Even treated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) continues to pose a significant burden in patients' everyday functioning and may continuously affect their quality of life (QoL). The aims of our prospective study were to analyze health-related QoL in CIDP patients during a 1-year follow-up period in real-life settings and to compare QoL changes with changes in disability and with patient impression of change., Methods: The study comprised 59 patients diagnosed with CIDP. SF-36 questionnaire was applied in order to evaluate patients' QoL. Inflammatory neuropathy cause and treatment (INCAT) disability scale was used to assess patients' functionality. The second question from the SF-36 questionnaire was used as an estimation of the patient impression of change (PIC) after 1 year., Results: SF-36 scores did not change over time in the group as a whole. According to INCAT disability scores, worsening was registered in 24 (40%) patients and improvement in 8 (14%). Fifteen (25%) patients reported worsening and the same number reported improvement, according to PIC. Concordant results on INCAT and PIC were registered in 49% of patients. Pooled SF-36 scores moderately correlated with pooled INCAT disability scores (rho = - 0.27 to - 0.59, p < 0.01). One-year changes of SF-36 scores did not differ when compared to different INCAT outcomes (worsening, stable, improvement). On the other hand, significant changes of SF-36 scores in different outcome groups according to PIC (worsening, stable, improvement) were noted (p < 0.01)., Conclusion: INCAT, PIC, and SF-36 are complementary outcome measures that provide neurologists with useful items of information. We propose complementary use of these scales in CIDP patients in everyday clinical practice in order to detect worsening of the disease and/or of related symptoms on time., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients.Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates. What is Known: • Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI). • Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11. What is New: • Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations. • Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The most common digestive system (DS) cancers, including tumors of the gastrointestinal tract (GIT) such as colorectal cancer (CRC), gastric cancer (GC) and esophageal cancer (EC) as well as tumors of DS accessory organs such as pancreatic and liver cancer, are responsible for more than one-third of all cancer-related deaths worldwide, despite the progress that has been achieved in anticancer therapy. Due to these limitations in treatment strategies, oncological research has taken outstanding steps towards a better understanding of cancer cell biological complexity and heterogeneity. These studies led to new molecular target-driven therapeutic approaches. Different in vivo and in vitro studies have revealed significant expression of B7 homologue 3 (B7-H3) among the most common cancers of the GIT, including CRC, GC, and EC, whereas B7-H3 expression in normal healthy tissue of these organs was shown to be absent or minimal. This molecule is able to influence the biological behavior of GIT tumors through the various immunological and nonimmunological molecular mechanisms, and some of them are shown to be the result of B7-H3-related induction of signal transduction pathways, such as Janus kinase 2/signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase/protein kinase B, extracellular signal-regulated kinase, and nuclear factor-κB. B7-H3 exerts an important role in progression, metastasis and resistance to anticancer therapy in these tumors. In addition, the results of many studies suggest that B7-H3 stimulates immune evasion in GIT tumors by suppressing antitumor immune response. Accordingly, it was observed that experimental depletion or inhibition of B7-H3 in gastrointestinal cancers improved antitumor immune response, impaired tumor progression, invasion, angiogenesis, and metastasis and decreased resistance to anticancer therapy. Finally, the high expression of B7-H3 in most common cancers of the GIT was shown to be associated with poor prognosis. In this review, we summarize the established data from different GIT cancer-related studies and suggest that the B7-H3 molecule could be a promising prognostic biomarker and therapeutic target for anticancer immunotherapy in these tumors., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To analyze metabolic parameters, body composition (BC), and bone mineral density (BMD) in childhood-onset GH deficiency (COGHD) patients during the transition period (TP)., Design: Single- center, retrospective study was performed on 170 consecutive COGHD patients (age 19.2 ± 2.0 years, range 16-25) transferred after growth completion from two pediatric clinics to the adult endocrine unit. Two separate analyses were performed: (i) cross-sectional analysis of hormonal status, metabolic parameters, BC, and BMD at first evaluation after transfer from pediatrics to the adult department; (ii) longitudinal analysis of BC and BMD dynamics after 3 years of GH replacement therapy (rhGH) in TP., Results: COGHD was of a congenital cause (CONG) in 50.6% subjects, tumor-related (TUMC) in 23.5%, and idiopathic (IDOP) in 25.9%. TUMC patients had increased insulin and lipids levels (P < 0.01) and lower Z score at L-spine (P < 0.05) compared to CONG and IDOP groups. Patients treated with rhGH in childhood demonstrated lower fat mass and increased BMD compared to the rhGH-untreated group (P < 0.01). Three years of rhGH after growth completion resulted in a significant increase in lean body mass (12.1%) and BMD at L-spine (6.9%), parallel with a decrease in FM (5.2%)., Conclusion: The effect of rhGH in childhood is invaluable for metabolic status, BC, and BMD in transition to adulthood. Tumor-related COGHD subjects are at higher risk for metabolic abnormalities, alteration of body composition, and decreased BMD, compared to those with COGHD of other causes. Continuation of rhGH in transition is important for improving BC and BMD in patients with persistent COGHD.

Lateral neck masses (LNM) often present a diagnostic challenge in the practice of pediatric plastic surgeon. The aim of this study is to investigate the clinical and ultrasound (US) characteristics of pediatric LNM in order to make mutual comparison between their entities and enable the most accurate preoperative diagnosis. A cross-sectional study was conducted among 250 pediatric patients treated by surgical excision or sclerotherapy in our institution in the period from July 2009 to June 2019. Lymphatic malformation was the most frequent congenital LNM (60.9%), while reactive or granulomatous lymphadenitis was the most frequent acquired LNM (47%). Congenital anomalies were significantly more often localized in the upper half of the sternocleidomastoid (SCM) muscle region, and had more often soft consistency than acquired ones. Congenital LNM had a 32.37 (3.44-304.63) times higher likelihood of incorrect (p = 0.002) and 5.86 (1.35-25.48) times higher likelihood of undetermined (p = 0.018) than correct US findings, respectively. Acquired LNM were significantly more often localized in the region behind the SCM muscle and more often had solid US appearance in comparison to the congenital ones. Association of the clinical and US findings is very important in determining the most accurate preoperative diagnosis without exposing the children to unnecessary utilizing ionizing radiation or anesthesia. Although they are mostly benign, extreme caution is necessary due to malignancies which were found in 16.4% of all our patients., Competing Interests: The authors have declared that no competing interests exist.

Cardiovascular diseases, including ischemic heart disease, are the most common causes of morbidity and death in the world, including Serbia, as a middle-income European country. The aim of the study was to determine the costs of preventive examinations for ischemic heart disease in active-duty military personnel, as well as to assess whether this was justified from the point of view of the limited health resources allocated for the treatment of the Republic of Serbia population. This is a retrospective cost-preventive study which included 738 male active-duty military personnel, aged from 23 to 58. The costs of primary prevention of ischemic heart disease in this population were investigated. Out of 738 subjects examined, arterial hypertension was detected in 101 subjects (in 74 of them, arterial hypertension was registered for the first time, while 27 subjects were already subjected to pharmacotherapy for arterial hypertension). Average costs of all services during the periodic-health-examination screening program were €76.96 per subject. However, average costs of all services during the periodic-health-examination screening program for patients with newfound arterial hypertension and poorly regulated arterial hypertension were €767.54 per patient and €2,103.63 per patient, respectively. Since periodic-health-examination screening program in military personnel enabled not only discovery of patient with newfound arterial hypertension but also regular monitoring of those who are already on antihypertensive therapy, significant savings of €690.58 per patient and €2,026.67 per patient can be achieved, respectively. As financial resources for providing health care in Serbia, as a middle-income country, are limited, further efforts should be put on screening programs for ischemic heart disease due to possible significant savings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Simic, Ratkovic, Dragojevic Simic, Savkovic, Jakovljevic, Peric, Pandrc and Rancic.)

At present, neither specific antiviral drugs, nor vaccine is recommended for coronavirus disease 2019 (COVID-19) treatment. In this review we discuss the drugs suggested as therapy for COVID-19 infection, with a focus on chloroquine and hydroxychloroquine. The list of drugs used for COVID-19 treatment includes a combination of lopinavir and ritonavir, remdesivir, favipiravir, alpha-interferon, ribavirin, atazanavir, umifenovir, and tocilizumab. As their efficacy and safety are under investigation, none of the regulatory agencies approved them for the treatment of COVID-19 infection. Although chloroquine and hydroxychloroquine possess antiviral and immunomodulatory effects, in practice benefit of their use for COVID-19 treatment is controversial. Several studies investigating hydroxychloroquine were stopped and the French national medicines regulator suspended its use in clinical trials because of safety concerns. The results from the double-blind, randomised clinical trials, including large number of participants, will add better insight into the role of these two drugs as already available and affordable, antimalarial therapy. The ethical issue on emergency use of chloroquine and hydroxychloroquine in the settings of COVID-19 should be carefully managed, with adherence to the "monitored emergency use of unregistered and experimental interventions" (MEURI) framework or be ethically approved as a trial, as stated by the WHO. Potential shortage of chloroquine/hydroxychloroquine on the market can be overbridged with regular prescriptions by medical doctors and national drug agency should ensure sufficient quantities of these drugs for standard indications., (© 2020 John Wiley & Sons Ltd.)

We aimed to collect data on all paediatric patients who were diagnosed with type 1 diabetes mellitus (T1DM) between the years 2000 and 2019 in Serbia and estimate for the first time its prevalence. Also, the trends of diabetes ketoacidosis (DKA) occurrence at the time of diagnosis are monitored. We collected and retrospectively analysed the data of patients <19 years with newly diagnosed T1DM. T1DM was diagnosed in 3134 patients (53.2% male). Total number of youth <19 years with T1DM was 1735 with prevalence of 135.25/100000 at the end of study period. T1DM was diagnosed most frequently between the ages of 5 and 11 years (42.1%). At the time of diagnosis, 35.7% presented in DKA. The incidence and severity of DKA were more significant at the youngest age (p<0.001). There were significant annual percentage increase (2.2%) in the number of new cases of DKA (p=0.007). Conclusion: This first report of nationwide prevalence of T1DM in youth shows that Serbia is among countries with high prevalence of T1DM in youth. System changes are needed in order to provide better quality of health care to these patients., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

A phalloplasty is a complex genital reconstruction procedure of creating a neophallus. Several techniques to create a neophallus are described, based on different vascularized flaps, and each of them has its advantages and drawbacks. The aim of this study is to present musculocutaneous latissimus dorsi (MLD) flap as a viable option for total phalloplasty, with an interest in clinical outcomes and complications. A comprehensive literature review of all available reports about MLD flap phalloplasty was made. The following keywords were used on PubMed: latissimus dorsi musculocutaneous/myocutaneous free flap and phalloplasty. Research criteria revealed five articles and the results of 182 patients were analyzed. A total number of the patients, indications, operative technique, follow-up period, postoperative results, and complications were presented. In conclusion, MLD free flap presents a good choice for phalloplasty providing sufficient amount of tissue for safe implantation of penile prosthesis and successful penetrative sexual intercourse. The erogenous sensitivity is preserved with clitoris or glans penis incorporated into the base of the neophallus, and voiding in a standing position is achievable after urethral reconstruction. The main drawback is the lack of tactile sensation of the neophallus and the significant advantage is a well-concealed donor site., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Background: A pyogenic liver abscess (PLA) represents a pus-filled cavity within the liver parenchyma caused by the invasion and multiplication of bacteria. The most common offender isolated from the PLA in children is Staphylococcus aureus. Abiotrophia defectiva is a Gram-positive pleomorphic bacterium, commonly found in the oral cavity, intestinal, and genitourinary mucosa as part of the normal microbiota. It has been proven to be an etiological factor in various infections, but rarely in cases of PLA. The case presented here is, to the best of our knowledge, the first pediatric case of PLA caused by A. defectiva., Case Presentation: A 13-year-old Caucasian boy presented with a two-day history of abdominal pain, fever up to 40 °C, and polyuria. Contrast-enhanced computed tomography (CT) scan revealed a single, multiloculated liver lesion, suggestive of a liver abscess. The boy had sustained a bicycle handlebar injury to his upper abdomen 3 weeks before the symptoms appeared and had been completely asymptomatic until 2 days before admission. He was successfully treated with antibiotic therapy and open surgical drainage. A. defectiva was isolated from the abscess material. Histopathology report described the lesion as a chronic PLA., Conclusions: A. defectiva is a highly uncommon cause of liver abscess in children. In such cases, various predisposing factors should be considered, including antecedent blunt abdominal trauma.

Background: In children and adolescents, primary hyperparathyroidism (pHPT) is rare, associated with severe morbidity, and has different clinical characteristics than in adults. The aim of this study was to analyze differences in clinical and laboratory characteristics between children and adolescents with pHPT., Methods: A retrospective cohort study was conducted to analyze pHPT characteristics in young patients, who have been operated at our institution. All patients were divided into two groups: group of patients ≤15 years (children) and group of patients >15 and ≤20 years (adolescents)., Results: Out of 1363 pHPT patients surgically treated during the study period, 14 patients (1%) were younger than 20 years: 6 children and 8 adolescents. Male-to-female ratio in children was 2:1, and in adolescents 1:1.7. Kidney stones were found in 62.5% of the adolescents and in none of the children patients. Bone form of the disease was the most frequent in children (in 83.1%), while in adolescents the kidney form was the most frequent (in 50%). Only 16.7% of children and 25% of adolescents did not have classical symptoms. All adolescent patients had single parathyroid adenoma, while 4 children patients had single parathyroid adenoma, one patient had hyperplasia, and one had parathyroid carcinoma. Both preoperative serum calcium and PTH levels were higher in children than in adolescents (3.87 mmol/L vs. 3.17 mmol/L; 812 ng/mL vs. 392 ng/mL, respectively). In all patients vitamin D level was low. All patients had normal postoperative values of serum calcium and PTH., Conclusion: There is a significant difference in clinical and biochemical characteristics between children and adolescent pHPT patients. Therefore, these two groups should be analyzed and treated separately., Type of Study: Retrospective comparative study., Level of Evidence: Level III., (Copyright © 2019 Elsevier Inc. All rights reserved.)