Introduction: Environmental and psychosocial adversities negatively impact children’s developmental outcomes. When these factors are experienced in early childhood—a sensitive period of development—the developing brain can be altered. While these associations have been drawn in high-income countries, it is necessary to understand child growth, neurodevelopment, and the role of environmental factors in developmental trajectories in low-income settings. The objective of this study is to longitudinally assess how demographic factors, maternal health, maternal development, and child health, are related to child development on a behavioural, cognitive, and neuroimaging level in low-socioeconomic communities. Methods and analysis: Mother–child dyads will be identified in the peri-urban field sites of Rehri Goth and Ibrahim Hyderi, Karachi, Pakistan. Dyads will undergo yearly assessments for 4 years beginning when the child is 1 month, 3 months or 6 months of age (+≤30 days of age) (depending on group assignment). Maternal assessments include anthropometry, behavioural, cognitive, and developmental assessments (Edinburgh Postnatal Depression Scale; Parenting Stress Index; Maternal Autonomy Index; Hurt, Insult, Threaten, Scream Tool; Reynolds Intellectual Assessment Scales (RIAS)), and biological samples collection (breast milk, blood, stool, hair). Children’s assessments include anthropometry, developmental assessments (Global Scales for Early Development (GSED); RIAS), MRI brain assessments, and biological sample collection (blood, stool, hair). Using cross-sectional and longitudinal data with statistical analysis tools, associations will be quantified between brain structure (MRI) and connectivity (resting state connectivity and diffusion tensor imaging), general cognitive skills (RIAS, GSED) and environmental influences (nutrition via biological samples, maternal mental health via questionnaires) through repeated measures analysis of variance tests and χ ² tests. Quantile regression and cortical analyses will be conducted to understand how demographic factors are related to the associations found. Ethics and dissemination: The study has received ethical approval from the Aga Khan University Ethics Review Committee. The study’s findings will be disseminated through scientific publications and project summaries for the participants.

Background: Down syndrome is the most common chromosomal disorder, with a global incidence of 1 in 700 live births. However, the true prevalence, associated morbidities, and health-related quality of life (HRQOL) of these individuals and their families are not well documented, especially in low- and middle-income countries such as Pakistan. Disease-specific documentation in the form of a collaborative registry is required to better understand this condition and the associated health outcomes. This protocol paper describes the aims and processes for developing the first comprehensive, web-based collaborative registry for Down syndrome in a Pakistani cohort. Objective: This study aims to assess the HRQOL, long-term survival, and morbidity of individuals with Down syndrome by using a web-based collaborative registry. Methods: The registry data collection will be conducted at the Aga Khan University Hospital and at the Karachi Down Syndrome Program. Data will be collected by in-person interviews or virtually via telephone or video interviews. Participants of any age and sex with Down syndrome (trisomy 21) will be recruited. After receiving informed consent and assent, a series of tablet-based questionnaires will be administered. The questionnaires aim to assess the sociodemographic background, clinical status, and HRQOL of the participants and their families. Data will be uploaded to a secure cloud server to allow for real-time access to participant responses by the clinicians to plan prompt interventions. Patient safety and confidentiality will be maintained by using multilayer encryption and unique coded patient identifiers. The collected data will be analyzed using IBM SPSS Statistics for Windows, Version 22.0 (IBM Corporation), with the mean and SD of continuous variables being reported. Categorical variables will be analyzed with their percentages being reported and with a P value cutoff of .05. Multivariate regression analysis will be conducted to identify predictors related to the HRQOL in patients with Down syndrome. Survival analysis will be reported using the Kaplan-Meier survival curves. Results: The web-based questionnaire is currently being finalized before the commencement of pilot testing. This project has not received funding at the moment (ethical review committee approval reference ID: 2020-3582-11145). Conclusions: This registry will allow for a comprehensive understanding of Down syndrome in low- and middle-income countries. This can provide the opportunity for data-informed interventions, which are tailored to the specific needs of this patient population and their families. Although this web-based registry is a proof of concept, it has the potential to be expanded to national, regional, and international levels. International Registered Report Identifier (IRRID): PRR1-10.2196/24901

Background/Objectives: Human milk (HM) is recognized as the optimal source of infant nutrition, particularly during the first six months of life. While its nutritional aspects and bioactive components are well studied, the HM metabolome remains less understood, particularly in low- and middle-income countries. This study utilized targeted metabolomics for HM profiling and investigated associations of the HM metabolome with maternal and infant characteristics. Methods: In total, 267 HM samples and demographic data from mothers participating in the Maternal and environmental Impact assessment on Neurodevelopment in Early childhood years (MINE) study were collected during enrolment (up to 6-months postpartum) and analyzed using the MxP^® Quant 500 targeted metabolomics kit from Biocrates. Results: A total of 440 metabolites were quantified, mostly lipids such as triglycerides (59.73%), phosphatidylcholines (14.25%), and diglycerides (8.49%), and small molecules including amino acids (26.67%), amino acid-related compounds (21.33%), hexosylceramides (17.33%), and fatty acids (14.67%). Maternal age was positively correlated with a wide range of metabolites, mainly cholesteryl esters, sphingomyelins, triglycerides, and acylcarnitines, while child age was associated with metabolites belonging to acylcarnitine, phosphatidyl-choline, ceramide, diacylglycerol, sphingomyelin, and triglyceride classes. Child’s gender was associated with metabolites, including ceramides, phosphatidylcholines, and sphingomyelins. Pathway enrichment analysis revealed that the metabolites were significantly enriched in valine, leucine, and isoleucine biosynthesis; arginine biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; and glutathione metabolism; however, these reflect annotation-based clustering rather than evidence of active metabolic processes in HM. Conclusions: The HM metabolome varies with maternal and infant characteristics, particularly infant age, reflecting cross-sectional differences in milk composition among mother–infant dyads. Enrichment of metabolites annotated to amino acid and antioxidant-related pathways highlights coordinated representation of nutritionally relevant compounds. These findings provide new insight into the factors shaping HM composition in a low- and middle-income populations.

BACKGROUND Down syndrome is the most common chromosomal disorder, with a global incidence of 1 in 700 live births. However, the true prevalence, associated morbidities, and health-related quality of life (HRQOL) of these individuals and their families are not well documented, especially in low- and middle-income countries such as Pakistan. Disease-specific documentation in the form of a collaborative registry is required to better understand this condition and the associated health outcomes. This protocol paper describes the aims and processes for developing the first comprehensive, web-based collaborative registry for Down syndrome in a Pakistani cohort. OBJECTIVE This study aims to assess the HRQOL, long-term survival, and morbidity of individuals with Down syndrome by using a web-based collaborative registry. METHODS The registry data collection will be conducted at the Aga Khan University Hospital and at the Karachi Down Syndrome Program. Data will be collected by in-person interviews or virtually via telephone or video interviews. Participants of any age and sex with Down syndrome (trisomy 21) will be recruited. After receiving informed consent and assent, a series of tablet-based questionnaires will be administered. The questionnaires aim to assess the sociodemographic background, clinical status, and HRQOL of the participants and their families. Data will be uploaded to a secure cloud server to allow for real-time access to participant responses by the clinicians to plan prompt interventions. Patient safety and confidentiality will be maintained by using multilayer encryption and unique coded patient identifiers. The collected data will be analyzed using IBM SPSS Statistics for Windows, Version 22.0 (IBM Corporation), with the mean and SD of continuous variables being reported. Categorical variables will be analyzed with their percentages being reported and with a P value cutoff of .05. Multivariate regression analysis will be conducted to identify predictors related to the HRQOL in patients with Down syndrome. Survival analysis will be reported using the Kaplan-Meier survival curves. RESULTS The web-based questionnaire is currently being finalized before the commencement of pilot testing. This project has not received funding at the moment (ethical review committee approval reference ID: 2020-3582-11145). CONCLUSIONS This registry will allow for a comprehensive understanding of Down syndrome in low- and middle-income countries. This can provide the opportunity for data-informed interventions, which are tailored to the specific needs of this patient population and their families. Although this web-based registry is a proof of concept, it has the potential to be expanded to national, regional, and international levels. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/24901

Fahr’s syndrome is a rare neurodegenerative disease characterised by symmetric calcifications in basal ganglia, cerebellum and cerebral cortex, secondary to genetic, infectious and autoimmune aetiologies. It has a wide range of clinical presentations including neurological and psychiatric symptoms leading to cognitive impairment and behavioural changes. In this case report, an adolescent boy with a unique sequence of different manifestations of APS-1 is described who eventually developed Fahr’s syndrome secondary to hypoparathyroidism. The child developed insulin-dependent diabetes mellitus in infancy followed by mucocutaneous candidiasis and then hypoparathyroidism with the clinical and radiological manifestations consistent with Fahr’s syndrome. He was treated for the biochemical abnormalities of Fahr’s syndrome, which led to clinical improvement. APS-1 manifests in early life and affects the endocrine and non-endocrine systems, however, the age of different manifestations varies widely. This case highlights the importance of considering Fahr’s syndrome as a possible cause in patients with polyendocrinopathies having neurological symptoms.