Analytical sameness methodology for the evaluation of structural, physicochemical, and biological characteristics of Armlupeg: A pegfilgrastim biosimilar case study.

Pegfilgrastim is administered as an adjunct to chemotherapy to reduce the incidence of febrile neutropenia and associated infectious complications. Lupin's Pegfilgrastim is a proposed biosimilar to the U.S.-referenced Neulasta®. Demonstration of biosimilarity requires extensive physicochemical and functional characterization of the biosimilar, and demonstration of analytical similarity to the reference product, in addition to clinical studies. This work is a case study for demonstrating the analytical similarity of Armlupeg (Lupin's Pegfilgrastim) to Neulasta® with respect to structural and physicochemical attributes using several robust, orthogonal, and state-of-the-art techniques including high-end liquid chromatography, mass spectrometry, and spectroscopy techniques; circular dichroism; differential scanning calorimetry; nuclear magnetic resonance; analytical ultracentrifugation; and micro-flow imaging. Functional similarity was demonstrated using an in vitro cell proliferation assay to measure relative potency and surface plasmon resonance to measure receptor binding kinetics. Furthermore, comparative forced-degradation studies were performed to study the degradation of the products under stress conditions. The product attributes were ranked based on a critical quality attributes risk score according to their potential clinical impact. Based on criticality, all analyses were statistically evaluated to conclude analytical similarity. Lupin's Pegfilgrastim was comparable to Neulasta® as demonstrated via structural, functional, and purity analyses. Lupin's Pegfilgrastim complied with the quality and statistical ranges established using Neulasta®. Both products follow the same degradation pathways under stress conditions as observed in the forced-degradation studies. No new impurity or degradation product was observed in Lupin's Pegfilgrastim. These data conclusively demonstrate the analytical similarity of Lupin's Pegfilgrastim and Neulasta®.

Adolescent Health Academy Statement on the Care of Transgender Children, Adolescents, and Youth.

JUSTIFICATION: The transgender community has been long stigmatized, and discriminated against, and faces numerous mental and physical problems. Certain indicators of transgender personality appear during childhood and more often before puberty begins. This puts the onus on Pediatricians to identify and offer evidence-based care for their benefit. There is an urgent and deep-felt need to understand the medical, legal, and social aspects of the care of transgender children. Hence, Adolescent Health Academy decided to release a statement on the care of transgender children, adolescents, and youth. OBJECTIVES: To review the existing international and national guidelines and recommendations to formulate a statement for the Pediatricians on (a) terminologies and definitions; (b) legal status in India; and (c) implications for pediatric practice. PROCESS: A task force was convened by the Adolescent Health Academy as the writing committee to draft the guidelines. These were approved by all the members of the task force and the Executive Board of Adolescent Health Academy (2022). RECOMMENDATIONS: Gender identity develops in childhood and adolescence as a feeling of self, and it should be respected to mitigate gender dysphoria. The law permits transgenders the right of self-affirmation and it upholds their dignity in society. The transgender community is prone to victimization, and prejudice leading to a high risk of substance abuse, suicidal ideation, and mental health issues. Pediatricians are the primary care providers of children and adolescents including those with gender incongruence, so they should be abridged with gender-affirmative practices. Gender-affirmative care involves pubertal suppression, hormonal therapy, and surgery which should be done in conjugation with the social transition, by a gender-affirmative care team.

mHealth Apps Delivering Early Intervention to Support Parents of Children With Autism Spectrum Disorder: A Scoping Review.

CONTEXT: Early intervention, and parent-mediated intervention are effective in achieving early childhood development goals for children with autism spectrum disorder. There is a surge in mHealth technologies delivering such interventions. This review aims to explore the concept, context and methodology of implementation of such mHealth apps. EVIDENCE ACQUISITION: A search was conducted using NICE (National Institute of Clinical Excellence) healthcare database, including keyword 'early intervention,' 'mHealth,' 'parent support,' 'apps,' and 'autism.' The quantitative, qualitative, mixed-methods, case reports, grey literature, systematic reviews, clinical trials, and feasibility studies of children between 2 to 6 years with ASD were included from inception of database to December, 2021. Web/Internet-based or computer-dependent programs were excluded. The initial search yielded 3786 studies; 17 were finally included based on the inclusion and exclusion criteria. RESULT: Studies on a total of mhealth apps were reviewed. Nine apps, apart from TOBY (Therapy outcome by you), lacked a holistic approach and instead targeted a specific difficulty in autism. The provision of support to parents using apps was equally beneficial as in-person support, reduced costs, and improved outcomes in children. CONCLUSIONS: The review revealed limited evidence-based mHealth apps available currently in a community setting. This also underscores an opportunity for clinicians to re-direct parents towards evidence-based information and interventions.

mHealth apps delivering early intervention to support parents of children with autism: a scoping review protocol.

OBJECTIVE: This review aims to identify the mhealth apps delivering early intervention to support parents of children with autism spectrum disorders (ASD). We aim to explore the concept, context and methodology of implementation that is, theoretical framework, feasibility, quality of evidence, for such apps. BACKGROUND: To improve outcomes for children with autism, early intervention has been found to be promising. Parental training, parent psychoeducation and parent-mediated intervention are regarded as the gold standard, to achieve early childhood development goals. Digital health technologies like tele-health, web-based services, have been used to deliver this at a reduced cost. There is little evidence about their use and efficacy in empowering parents of children with ASD. INCLUSION CRITERIA: The studies reporting the use of mhealth apps to support parents of children with ASD, in community settings, school settings, special schools, clinics, hospitals or child development centres. There will be no exclusion based on region, gender or sociocultural factors. The types of studies included will be quantitative, qualitative, mixed-methods study designs, case reports, grey literature, systematic reviews, clinical trials and studies reporting feasibility of digital mhealth applications. METHOD: Using the NICE Healthcare Databases Advanced Search, we will search the following databases: MEDLINE, PUBMED, CINAHL, EMBASE, PsycINFO, Cochrane Library, EbscoHost, Sabinet, SAGE Journals, Directory of Open Access Journals, BioMed Central, Scopus, ScienceDirect. Furthermore, grey literature will be searched through Google Scholar, ShodhGanga, JSTOR, CORE, EBSCO, DOAJ, BASE. The searches will be limited to the age range of children between 2 and 6 years with ASD, and the date range is from the inception of the database to the current date. The terms for the ASD will be combined with terms for parent, early intervention and digital mhealth to identify eligible studies.

Autism Spectrum Disorder in the COVID 19 Era: New Challenges - New Solutions.

This survey explored the support available and the effect of lockdown on children with autism spectrum disorder and their families in India and the United Kingdom. Our findings showed significant problems for children and families due to lockdown. App-based information delivered to parents with support showed encouraging feedback.

Recombinant irisin induces weight loss in high fat DIO mice through increase in energy consumption and thermogenesis.

OBJECTIVE: Irisin is known to be an important metabolic regulator of glucose and lipid metabolism. The aims of the present study are to assess the role of mouse Irisin in obesity and energy metabolism and its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) mice model. METHODS: DIO mice were treated with recombinant murine Irisin or vehicle, and parameters such as body weight, feed intake, glucose, and lipid levels, obesity, energy consumption, and insulin sensitivity were assessed. mRNA and protein levels of UCP1 and different thermogenesis biomarker were evaluated by quantitative real-time PCR and Western blot, respectively, in tissues and major metabolic organs. RESULTS: Irisin decreased body weight and whole-body fat mass in DIO mice in a dose dependent manner due to marked increases in total energy expenditure. It also lowered blood glucose, insulin, and lipid levels and possibly reversed hepatic steatosis. Irisin improved hepatic and peripheral insulin sensitivity in DIO mice along with body weight reduction and adiposity. Gene expression of UCP1 in different organs (adipose tissue and major organs, i.e., liver, kidney, heart, brain, and spleen) have suggested the role of irisin is global. Gene expression profile of different biomarkers in spleen suggest a profound role of Irisin in inflammation. Liver tissue have also shown significant increase of UCP1 expression in dose dependent manner which suggest a role of irisin in liver.

Rational design, synthesis, and structure-activity relationships of 5-amino-1H-pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure-activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.

Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F=13-70) bio-availability.

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats.

l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.