The prevalence of metabolic disorders in Nepal is yet unknown, although many case reports occur in literature. Heel-prick blood samples from newborns were collected on Dried Blood Spot (DBS) collection cards and tested through Tandem Mass Spectroscopy and fluorescence assays for disorders included in the Swiss neonatal screening program; two cases of hypothyroidism and one case of cystic fibrosis were identified. Thyroid stimulating hormone (TSH), immuoreactive trypsinogen (IRT), hydroxyprogesterone (OHP), tyrosine (Tyr), and octanoylcarnitine (C8) showed significant differences with gestation age. Most of the parameters were positively correlated with each other except galactose, galactose 1 phosphate uridyl transferase (GALT), and biotinidase. First and ninety-ninth percentiles in the Nepalese newborns were found to be different when compared with the Swiss newborns. Congenital hypothyroidism and cystic fibrosis are candidates to be considered for a newborn screening program in Nepal. Differences between the Nepalese and Swiss newborns in parametric values that change with gestation age can be attributed to a higher survival rate of pre-term babies in Switzerland. Others could be explained in part by early and exclusive breastfeeding in Nepalese newborns.

Background: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrPC) into a misfolded pathogenic form (PrPSc). One possible strategy to inhibit PrPSc formation is to stabilize the native conformation of PrPC and interfere with the conversion of PrPC to PrPSc. Many compounds have been shown to inhibit the conversion process, however, no promising drugs have been identified to cure prion diseases.Objective: This study aims to identify potential anti-prion compounds from plant phytochemicals by integrating traditional ethnobotanical knowledge with modern in silico drug design approaches. Materials and methods: In the current study medicinal phytochemicals were docked with swapped and non-swapped crystal structures of PrPC in silico to identify potential anti-prions to determine their binding modes and interactions.Results: Eleven new phytochemicals were identified based on their binding energies and pharmacokinetic properties. The binding sites and interactions of the known and new anti-prion compounds are similar, and differences in binding modes occur in structures with very subtle differences in side chain conformations. Binding of these compounds poses steric hindrance to neighbouring molecules. Residues shown to be associated with the inhibition of PrPC to PrPSc conversion form interactions with most of the compounds.Conclusion: Identified compounds might act as potent inhibitors of PrPC to PrPSc conversion. These might be attractive candidates for the development of novel anti-prion therapy although further tests in vitro cell cultures and in vivo mouse models are needed to confirm these findings.& COPY; 2023 The Authors. Published by Elsevier B.V. on behalf of Institute of Transdisciplinary Health Sciences and Technology and World Ayurveda Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Purpose: Pediatric thyroid carcinoma is a rare cancer for which germline genetic factors remain incompletely understood. To gain further insight, we examined the prevalence and spectrum of pathogenic variants (PV) in cancer-predisposing genes (CPG) in a large cohort of children with thyroid carcinoma at our institution. Experimental Design: This retrospective study included 71 children who presented with thyroid carcinoma as a first (n = 52) or subsequent malignant neoplasm (n = 19) and underwent germline testing. The objectives were to determine the proportion of patients harboring PVs and correlate germline information with clinical features, tumor pathology, and outcome. Results: Eighteen patients (25%; 7 primary and 11 subsequent malignant neoplasm) harbored a PV affecting a CPG. Four of these patients had medullary thyroid carcinoma, whereas 14 had nonmedullary thyroid carcinoma. Children diagnosed with thyroid carcinoma before 11 years of age were significantly more likely to harbor PVs (P < 0.01), as were children with medullary histology tumors (P < 0.05) or a prior cancer history (P < 0.001). Both RB1-associated thyroid carcinomas occurred in children who never received prior chemotherapy or radiotherapy. Seventeen patients remain alive at a median of 3 years since diagnosis (1 month–27 years). Twelve of 18 patients with PVs were treated only with thyroidectomy, whereas six required radioactive iodine therapy or chemotherapy. One patient with multiple endocrine neoplasia type 2 expired. Conclusions: A substantial proportion of children with thyroid carcinoma harbor a CPG PV. Accordingly, genetic counseling and testing should be considered for all affected children, especially those who are young, have medullary thyroid carcinoma, or a prior cancer history.

Background: Lynch syndrome (LS) is an autosomal‐dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch‐repair genes MLH1, MSH2/EPCAM, MSH6, or PMS2. Individuals who have MLH1 PVs have high lifetime risks of colorectal cancer (CRC) and endometrial cancer (EC). There is controversy regarding whether a younger age at diagnosis (or anticipation) occurs in MLH1‐associated LS. The objective of this study was to assess anticipation in families with MLH1‐associated LS by using statistical models while controlling for potential confounders.Methods: Data from 31 families with MLH1 PVs were obtained from an academic registry. Wilcoxon signed‐rank tests on parent–child‐pairs as well as parametric Weibull and semiparametric Cox proportional hazards and Cox mixed‐effects models were used to calculate hazard ratios or to compare mean ages at CRC/EC diagnosis by generation. Models were also corrected for ascertainment bias and birth‐cohort effects.Results: A trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in MLH1 PV carrier families. A greater hazard for cancer in younger generations was not precluded by the inclusion of birth cohorts in the model. Individuals who had MLH1 variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity.Conclusions: The current results demonstrated evidence in support of anticipation in families with MLH1‐associated LS across all statistical models. Mutational effects on Mlh1 activity influenced the hazard for CRC/EC. Screening based on the youngest age of cancer diagnosis in MLH1‐LS families is recommended.

Recent studies reveal that a growing proportion of children with hematologic malignancies (HM) harbor germ line pathogenic or likely pathogenic variants (PV) in cancer-predisposing genes (CPG). Identifying these children is critical because the information gained guides leukemia therapy, family testing, and selection of related donors for hematopoietic cell transplantation (HCT). Nevertheless, it remains unclear how often children with HM being considered for HCT undergo genetic evaluation and whether germ line data are used to guide clinical practice. To address this gap, we reviewed the records of 286 children who underwent ≥1 HCT for HM at St. Jude Children's Research Hospital between 1 January 2017 and 31 December 2023. We examined the timeline of genetic evaluation, prevalence of germ line PV, and impact of PV on HCT outcomes. Overall, 227 (79%) children met with a genetic counselor before their first HCT, 192 underwent testing, and 142 had results returned before the HCT. Thirty-six patients (19%) harbored a germ line CPG PV, among whom 12 (6%) had PV aligning with their HM diagnosis. Of 5 patients who received an HCT from a PV-positive relative, 1 patient developed donor-derived leukemia. We observed no significant differences in time to neutrophil engraftment, cumulative incidence of relapse, or overall survival between patients with and without PV, although the cohort was heterogeneous with respect to the underlying PV. Given the high prevalence of PV in children with HM, prompt referral to genetics is warranted to ensure timely counseling and germ line testing to detect a hereditary predisposition and inform donor selection for HCT.

Background: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrPC ) into a misfolded pathogenic form (PrPSC ). Cellular assays and in vivo experiments have identified various compounds with anti-prion activity which work through various mechanisms. Structures of PrPC have revealed the protein to occur in a swapped or non-swapped, monomeric or dimeric forms. Binding modes of known anti-prions is either not known, or has been determined with only the non-swapped structures of PrPC . In the current study medicinal phytochemicals from various databases have been docked with PrPC in silico to identify potential anti-prions in comparison with known anti-prion compounds to determine their binding modes and speculate possible mechanisms of inhibition of PrPC to PrPSC . Results: Eleven new phytochemicals were identified based on their binding energies and pharmacokinetic properties. The binding sites and interactions of the known and new anti-prion compounds are similar, and differences in binding modes occur in structures with very subtle differences in side chain conformations. Binding of these compounds poses steric hindrance to neighbouring molecules. Residues shown to be associated with inhibition of PrPC to PrPSC conversion form interactions with most of the compounds. Conclusions: The new compounds are mostly highly hydrophobic and are derivatives of terpenes, sterols and quinones. They might act as potent inhibitors of the PrPC to PrPSC conversion through a combination of steric hindrance and stabilization of structure through ionic/hydrophobic interactions. Their high binding energies coupled with identical binding sites as those of the known compounds, and their ability to cross the blood brain barrier makes these phytochemicals a promising group of compounds for further studies on prevention of PrPC to PrPSC .