The longitudinal dynamics and natural history of clonal haematopoiesis.

Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Clonal dynamics of haematopoiesis across the human lifespan.

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

The SickKids Caribbean Initiative to improve care for children with cancer and blood disorders.

To improve pediatric hematology and oncology outcomes, there is a recognized potential for partnerships between low- and high-resource institutions within health care systems. The SickKids Caribbean Initiative is a partnership between health care professionals at the Hospital for Sick Children in Toronto, Canada, and seven Caribbean institutions across six countries (Bahamas, Barbados, Jamaica, Saint Lucia, Saint Vincent and the Grenadines, and Trinidad and Tobago). The primary aim of the SickKids Caribbean Initiative has been to improve the outcomes and the quality of life of children in the Caribbean aged <18 years who have cancer and blood disorders. This article describes five key activities undertaken within the SickKids Caribbean Initiative, including providing education and training, assisting with case consultations and diagnostic services, developing local oncology databases, engaging in advocacy and ensuring stakeholder engagement, and coordinating administration and project management.

Las colaboraciones de instituciones de recursos bajos y altos dentro de los sistemas de atención de salud tienen un potencial reconocido para mejorar las respuestas a los tratamientos hematológicos y oncológicos pediátricos. La iniciativa SickKids para el Caribe es una asociación entre profesionales de la salud del Hospital for Sick Children de Toronto (Canadá) y siete instituciones de seis países del Caribe (Bahamas, Barbados, Jamaica, Santa Lucía, San Vicente y las Granadinas y Trinidad y Tabago). El objetivo principal de la iniciativa SickKids para el Caribe ha sido mejorar la respuesta a los tratamientos y la calidad de vida de los menores de 18 años del Caribe con cáncer o trastornos hematológicos. En este artículo se describen cinco actividades clave emprendidas en el marco de la iniciativa SickKids para el Caribe, consistentes en impartir formación y capacitación, prestar asistencia en materia de consultas de pacientes y servicios de diagnóstico, crear bases de datos locales en el área de la oncología, participar en actividades de promoción y garantizar la participación de las partes interesadas, y coordinar la administración y gestión de proyectos.

Há um potencial reconhecido para parcerias entre instituições com poucos e muitos recursos dentro dos sistemas de saúde para melhorar os resultados de hematologia e oncologia pediátricas. A iniciativa SickKids no Caribe é uma parceria entre profissionais de saúde do Hospital for Sick Children em Toronto, Canadá, e sete instituições em seis países do Caribe (Bahamas, Barbados, Jamaica, Santa Lúcia, São Vicente e Granadinas e Trinidad e Tobago). O objetivo principal da iniciativa SickKids no Caribe tem sido melhorar os desfechos e a qualidade de vida das crianças caribenhas com menos de 18 anos que têm câncer e doenças hematológicas. Este artigo descreve cinco atividades principais realizadas no âmbito da iniciativa SickKids no Caribe: oferecimento de educação e capacitação; assistência em consultas de casos e serviços diagnósticos; desenvolvimento de bancos de dados locais em oncologia; promoção da causa, assegurando o envolvimento das partes interessadas; e coordenação da administração e da gestão de projetos.

Fortification of salt with iron and iodine versus fortification of salt with iodine alone for improving iron and iodine status.

BACKGROUND: Iron deficiency is an important micronutrient deficiency contributing to the global burden of disease, and particularly affects children, premenopausal women, and people in low-resource settings. Anaemia is a possible consequence of iron deficiency, although clinical and functional manifestations of anemia can occur without iron deficiency (e.g. from other nutritional deficiencies, inflammation, and parasitic infections). Direct nutritional interventions, such as large-scale food fortification, can improve micronutrient status, especially in vulnerable populations. Given the highly successful delivery of iodine through salt iodisation, fortifying salt with iodine and iron has been proposed as a method for preventing iron deficiency anaemia. Further investigation of the effect of double-fortified salt (i.e. with iron and iodine) on iron deficiency and related outcomes is warranted.  OBJECTIVES: To assess the effect of double-fortified salt (DFS) compared to iodised salt (IS) on measures of iron and iodine status in all age groups. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, five other databases, and two trial registries up to April 2021. We also searched relevant websites, reference lists, and contacted the authors of included studies. SELECTION CRITERIA: All prospective randomised controlled trials (RCTs), including cluster-randomised controlled trials (cRCTs), and controlled before-after (CBA) studies, comparing DFS with IS on measures of iron and iodine status were eligible, irrespective of language or publication status. Study reports published as abstracts were also eligible. DATA COLLECTION AND ANALYSIS: Three review authors applied the study selection criteria, extracted data, and assessed risk of bias. Two review authors rated the certainty of the evidence using GRADE. When necessary, we contacted study authors for additional information. We assessed RCTs, cRCTs and CBA studies using the Cochrane RoB 1 tool and Cochrane Effective Practice and Organisation of Care (EPOC) tool across the following domains: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other potential sources of bias due to similar baseline characteristics, similar baseline outcome assessments, and declarations of conflicts of interest and funding sources. We also assessed cRCTs for recruitment bias, baseline imbalance, loss of clusters, incorrect analysis, and comparability with individually randomised studies. We assigned studies an overall risk of bias judgement (low risk, high risk, or unclear).  MAIN RESULTS: We included 18 studies (7 RCTs, 7 cRCTs, 4 CBA studies), involving over 8800 individuals from five countries. One study did not contribute to analyses. All studies used IS as the comparator and measured and reported outcomes at study endpoint.  With regards to risk of bias, five RCTs had unclear risk of bias, with some concerns in random sequence generation and allocation concealment, while we assessed two RCTs to have a high risk of bias overall, whereby high risk was noted in at least one or more domain(s). Of the seven cRCTs, we assessed six at high risk of bias overall, with one or more domain(s) judged as high risk and one cRCT had an unclear risk of bias with concerns around allocation and blinding. The four CBA studies had high or unclear risk of bias for most domains. The RCT evidence suggested that, compared to IS, DFS may slightly improve haemoglobin concentration (mean difference (MD) 0.43 g/dL, 95% confidence interval (CI) 0.23 to 0.63; 13 studies, 4564 participants; low-certainty evidence), but DFS may reduce urinary iodine concentration compared to IS (MD -96.86 µg/L, 95% CI -164.99 to -28.73; 7 studies, 1594 participants; low-certainty evidence), although both salts increased mean urinary iodine concentration above the cut-off deficiency. For CBA studies, we found DFS made no difference in haemoglobin concentration (MD 0.26 g/dL, 95% CI -0.10 to 0.63; 4 studies, 1397 participants) or urinary iodine concentration (MD -17.27 µg/L, 95% CI -49.27 to 14.73; 3 studies, 1127 participants). No studies measured blood pressure. For secondary outcomes reported in RCTs, DFS may result in little to no difference in ferritin concentration (MD -3.94 µg/L, 95% CI -20.65 to 12.77; 5 studies, 1419 participants; low-certainty evidence) or transferrin receptor concentration (MD -4.68 mg/L, 95% CI -11.67 to 2.31; 5 studies, 1256 participants; low-certainty evidence) compared to IS. However, DFS may reduce zinc protoporphyrin concentration (MD -27.26 µmol/mol, 95% CI -47.49 to -7.03; 3 studies, 921 participants; low-certainty evidence) and result in a slight increase in body iron stores (MD 1.77 mg/kg, 95% CI 0.79 to 2.74; 4 studies, 847 participants; low-certainty evidence). In terms of prevalence of anaemia, DFS may reduce the risk of anaemia by 21% (risk ratio (RR) 0.79, 95% CI 0.66 to 0.94; P = 0.007; 8 studies, 2593 participants; moderate-certainty evidence). Likewise, DFS may reduce the risk of iron deficiency anaemia by 65% (RR 0.35, 95% CI 0.24 to 0.52; 5 studies, 1209 participants; low-certainty evidence).  Four studies measured salt intake at endline, although only one study reported this for both groups. Two studies reported prevalence of goitre, while one CBA study measured and reported serum iron concentration. One study reported adverse effects. No studies measured hepcidin concentration. AUTHORS' CONCLUSIONS: Our findings suggest DFS may have a small positive impact on haemoglobin concentration and the prevalence of anaemia compared to IS, particularly when considering efficacy studies. Future research should prioritise studies that incorporate robust study designs and outcome measures (e.g. anaemia, iron status measures) to better understand the effect of DFS provision to a free-living population (non-research population), where there could be an added cost to purchase double-fortified salt. Adequately measuring salt intake, both at baseline and endline, and adjusting for inflammation will be important to understanding the true effect on measures of iron status.

Dietary diversity and social determinants of nutrition among late adolescent girls in rural Pakistan.

The conditions in which adolescent girls mature shape their health, development and nutrition. Nutrient requirements increase to support growth during adolescence, but gaps between consumption and requirements exist in low- and middle-income countries. We aimed to identify and quantify the relationship between dietary intake and diverse social determinants of nutrition (SDN) among a subset of adolescent girls 15-18.9 years (n = 390) enrolled within the Matiari emPowerment and Preconception Supplementation (MaPPS) Trial. The primary outcome, dietary diversity score (DDS), was derived by applying the Minimum Dietary Diversity for Women 10-item scale to 24-h dietary recall data collected three times per participant. To examine the associations between the SDN-related explanatory variables and DDS, we generated a hierarchical, causal model using mixed effects linear regression to account for the cluster-randomized trial design. Using all data, diets lacked diversity (DDS mean ± SD: 3.35 ± 1.03 [range: 1-7; n = 1170]), and the minimum cut-off for dietary diversity was infrequently achieved (13.5%; 95% CI: 11.6-15.6%). Consumption of starches was reported in all recalls, but micronutrient-rich food consumption was less common. Of the SDN considered, wealth quintile had the strongest association with DDS (P < 0.0001). The diets of the sampled Pakistani adolescent girls were insufficient to meet micronutrient requirements. Poverty was the most important predictor of a diet lacking in diversity, indicating limited purchasing power or access to nutritious foods. Dietary diversification and nutrition education strategies alone are unlikely to lead to improved diets without steps to tackle this barrier, for example, through fortification of staple foods and provision of supplements.

Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies.

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.

Effect of life skills building education and micronutrient supplements provided from preconception versus the standard of care on low birth weight births among adolescent and young Pakistani women (15-24 years): a prospective, population-based cluster-randomized trial.

BACKGROUND: Risk factors known to impact maternal and newborn nutrition and health can exist from adolescence. If an undernourished adolescent girl becomes pregnant, her own health and pregnancy are at an increased risk for adverse outcomes. Offering preconception care from adolescence could provide an opportunity for health and nutrition promotion to improve one's own well-being, as well as future pregnancy outcomes and the health of the next generation. METHODS: The Matiari emPowerment and Preconception Supplementation (MaPPS) Trial is a population-based two-arm, cluster-randomized, controlled trial of life skills building education and multiple micronutrient supplementation provided in a programmatic context to evaluate the impact on pre-identified nutrition and health outcomes among adolescent and young women (15-24 years) in Matiari district Pakistan, and the infants born to them within the context of the trial. The primary aim is to assess the effect of the intervention on the prevalence of low birth weight births (< 2500 g). The intervention includes bi-monthly life skills building education provided from preconception, and supplementation with multiple micronutrients during preconception (twice-weekly), pregnancy (daily), and post-partum (daily to 6 months). The standard of care includes non-regulated community-based health sessions and daily iron and folic acid supplementation during pregnancy. Additional outcome information will also be collected at set time periods. Among participants, these relate to nutrition (anthropometry, nutritional status), morbidity, and mortality. Among infants, these include birth outcomes (stillbirth, preterm birth, length of gestation, small for gestational age, birth defects), anthropometry, morbidity, and mortality. DISCUSSION: Preconception care from adolescence that includes interventions targeting life skills development and nutrition is suggested to be important to improving the health and nutrition of adolescent and young women and their future offspring. This study is expected to offer insight into providing such an intervention both within a programmatic context and with an extended exposure period prior to conception. TRIAL REGISTRATION: The MaPPS Trial was registered retrospectively on clinicaltrials.gov (Identifier: NCT03287882 ) on September 19, 2017.

Feasibility and effect of life skills building education and multiple micronutrient supplements versus the standard of care on anemia among non-pregnant adolescent and young Pakistani women (15-24 years): a prospective, population-based cluster-randomized trial.

BACKGROUND: Adolescence is a critical period for physical and psychological growth and development, and vitamin and mineral requirements are correspondingly increased. Health and health behaviours correspond strongly from adolescence to adulthood. Developing a preconception care package for adolescent and young women in resource-limited settings could serve to empower them to make informed decisions about their nutrition, health, and well-being, as well as function as a platform for the delivery of basic nutrition-related interventions to address undernutrition. METHODS: In this population-based two-arm, cluster-randomized, controlled trial of life skills building education (provided bi-monthly) and multiple micronutrient supplementation (provided twice-weekly; UNIMMAP composition), we aim to evaluate the effectiveness of the intervention on the prevention of anemia (hemoglobin concentration < 12 g/dL) among adolescent and young women (15-24 years) in Matiari district, Pakistan compared to the standard of care. Several secondary objectives related to nutrition (anthropometry [height, weight, middle upper arm circumference (MUAC)], nutritional status [iron, vitamin A, vitamin D]); general health (morbidity, mortality); and empowerment (age at marriage, completion of the 10th grade, use of personal hygienic materials during menstruation) will also be assessed. Participants will be enrolled in the study for a maximum of 2 years. DISCUSSION: Empowering adolescent and young women with the appropriate knowledge to make informed and healthy decisions will be key to sustained behavioural change throughout the life-course. Although multiple micronutrient deficiencies are known to exist among adolescent and young women in low-resource settings, recommendations on preconception multiple micronutrient supplementation do not exist at this time. This study is expected to offer insight into providing an intervention that includes both education and supplements to non-pregnant adolescent and young women for a prolonged duration of time within the existing public health programmatic context. TRIAL REGISTRATION: This study is part of the Matiari emPowerment and Preconception Supplementation (MaPPS) Trial. The MaPPS Trial was registered retrospectively on clinicaltrials.gov (Identifier: NCT03287882 ) on September 19, 2017.

Tablets are preferred and more acceptable than powdered prenatal calcium supplements among pregnant women in Dhaka, Bangladesh.

Prenatal calcium supplementation is recommended by the WHO to decrease the risk of preeclampsia in women with low dietary calcium intake; yet, this recommendation has not been successfully implemented to date. One component of an effective population-based prenatal calcium intervention will be the selection of a widely accepted calcium vehicle to promote consistent, long-term consumption of the supplement. We aimed to evaluate preference and acceptability of 4 different options for delivering prenatal calcium (conventional tablets, chewable tablets, unflavored powder, and flavored powder) to pregnant women in urban Bangladesh. In a modified discrete-choice trial, pregnant women (n = 132) completed a 4-d "run-in period" in which each delivery vehicle was sampled once, followed by a 21-d "selection period" during which participants were instructed to freely select a single delivery vehicle of their choice each day. Preference was empirically defined as the probability that each delivery vehicle was selected on a given day, and measured from participants' daily delivery vehicle selections; acceptability was assessed by using mid- and post-trial questionnaires. Conventional tablets demonstrated the highest probability of selection (62%); the probability of selection of chewable tablets (19%), flavored powder (12%), and unflavored powder (5%) were all significantly lower than for conventional tablets (P < 0.001). The palatability and product characteristics of the conventional tablets were more acceptable than for the other 3 delivery vehicles. Our rigorous methodologic approach used both quantitative and self-reported measures that consistently identified the most preferred and accepted prenatal calcium delivery form. Through observation of pregnant women's actual supplement use, and perceptions of acceptability (i.e., ease of use, palatability), we demonstrated that conventional tablets are likely to be the most accepted and successful calcium delivery vehicle in future field studies and scale-up of the WHO recommendation in Bangladesh.

Design and development of a combined calcium-iron-folic acid prenatal supplement to support implementation of the new World Health Organization recommendations for calcium supplementation during pregnancy.

BACKGROUND: Hypertensive diseases of pregnancy are important causes of maternal and perinatal mortality. Based on meta-analyses of efficacy trials of prenatal calcium supplementation to reduce the risk of hypertensive diseases of pregnancy, the World Health Organization recommends 1.5 to 2.0 g of elemental calcium per day for pregnant women with low dietary calcium intakes (as well as 60 mg of iron and 400 microg of folic acid). However, implementation of this recommendation is challenged by the size and number of calcium tablets required and the need to avoid concurrent ingestion of calcium and iron due to intraintestinal interactions. OBJECTIVE: We developed a novel micronutrient powder containing microencapsulated pH-sensitive calcium in addition to iron and folic acid, designed to facilitate early intestinal iron release and delayed calcium release. METHODS: Two pharmaceutical companies were contracted to develop a prototype, one of which was chosen for clinical testing. Calcium carbonate granules were coated with a trilayer pH-sensitive enteric coating using a fluid-bed spray coater. Iron and folic acid granules were encapsulated with a time-release coating. Iron and calcium dissolution profiles were assessed during exposure to acidic (pH 1.2) and/or basic (pH 5.8) media using a modified USP apparatus 1 (basket) method. RESULTS: At pH 1.2, calcium and iron release was < or = 10% and > 90% after 120 minutes, respectively. At pH 5.8, > 80% of total calcium was released after 90 minutes. CONCLUSIONS: Based on in vitro criteria, the supplement may be a promising approach for delivering calcium, iron, and folic acid as a single daily dose to pregnant women in settings of low dietary intake of calcium.

Prevalence of malnutrition at the time of admission among patients admitted to a Canadian tertiary-care paediatric hospital.

BACKGROUND: Malnutrition among hospitalized children is known to negatively influence their response to therapy and to prolong their admission. It also has short- and long-term consequences for growth, development and well-being. It is commonly regarded as a condition affecting children in low-income countries; however, malnutrition has been found to be variably prevalent among hospitalized children in higher-income countries. At the time the present study was conducted, it had been >30 years since the nutritional status of Canadian hospitalized children was last published. OBJECTIVES: To determine and communicate the prevalence of malnutrition among children in a Canadian tertiary-care paediatric hospital at the time of their admission. METHODS: In the present cross-sectional study, anthropometric measures were obtained from 322 children admitted to The Hospital for Sick Children in Toronto, Ontario. Nutritional indexes (BMI for age, weight for age, weight for length/height and length/height for age) were generated from anthropometric measures using the WHO igrowup software, and summarized according to WHO definitions. RESULTS: The overall prevalence of malnutrition using BMI for age was 39.6% (95% CI 33% to 46%), of which 8.8% and 30.8% of participants were under- and overnourished, respectively. Furthermore, 6.9% (95% CI 3% to 13%) were determined to be acutely malnourished (weight for length/height <-2 SD) and 13.4% (95% CI 10% to 18%) chronically malnourished (length/height for age <-2 SD). CONCLUSION: The high prevalence of overall malnutrition observed among study participants suggests that initial screening using simple anthropometric measures should be conducted on hospital admission so that patients can receive appropriate nutrition-specific care.

HISTORIQUE: On sait que la malnutrition chez les enfants hospitalisés nuit à leur réponse au traitement et prolonge leur hospitalisation. Elle a également des conséquences à court et à long terme sur la croissance, le développement et le bien-être. Elle est souvent considérée comme un problème chez les enfants de pays à faible revenu, mais sa prévalence est variable chez les enfants hospitalisés dans les pays à revenu élevé. Au moment de la présente étude, les dernières publications sur l'état nutritionnel des enfants canadiens hospitalisés remontaient à plus de 30 ans. OBJECTIFS: Déterminer et communiquer la prévalence de malnutrition chez les enfants au moment de leur admission dans un hôpital pédiatrique canadien de soins tertiaires. MÉTHODOLOGIE: Dans la présente étude transversale, les mesures anthropométriques ont été recensées auprès de 322 enfants admis à The Hospital for Sick Children de Toronto, en Ontario. Les indices nutritionnels (IMC par rapport à l'âge, poids par rapport à l'âge, poids par rapport à la taille et taille par rapport à l'âge) étaient tirés de mesures anthropométriques calculées au moyen du logiciel igrowup de l'OMS. Ces indices étaient résumés d'après les définitions de l'OMS. RÉSULTATS: D'après l'IMC en fonction de l'âge, la prévalence globale de malnutrition s'élevait à 39,6 % (95 % IC 33 % à 46 %). Ainsi, 8,8 % et 30,8 % des participants étaient sous-alimentés et suralimentés, respectivement. De plus, il a été établi que 6,9 % (95 % IC 3 % à 13 %) souffraient de malnutrition aiguë (poids par rapport à la taille <−2 ÉT), et 13,4 % (95 % IC 10 % à 18 %), de malnutrition chronique (taille par rapport à l'âge <−2 ÉT). CONCLUSION: D'après la forte prévalence de malnutrition globale chez les participants à l'étude, le dépistage initial faisant appel à des mesures anthropométriques simples devrait être effectué au moment de l'admission à l'hôpital, afin que les patients puissent recevoir des soins pertinents en matière de nutrition.

Evaluation of HIV and highly active antiretroviral therapy on the natural history of human papillomavirus infection and cervical cytopathologic findings in HIV-positive and high-risk HIV-negative women.

BACKGROUND: The Canadian Women's HIV Study (CWHS) enrolled human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women in a longitudinal cohort. This analysis considered the effects of HIV and highly active antiretroviral therapy (HAART) on HPV persistence and cervical squamous intraepithelial lesions (SILs). METHODS: Longitudinal cytopathologic and HPV DNA results were analyzed using multistate models. States of cervical SIL were defined as absent, present, and treatment; HPV states were defined as negative or positive. Demographic variables and markers of sexual activity were considered predictors. Results were calculated on the basis of transition probabilities and reported as hazard ratios (HRs). RESULTS: The CWHS followed 750 HIV-positive and 323 HIV-negative women during 1993-2002. A total of 467 and 456 women were included in the longitudinal cervical cytopathologic and HPV DNA analyses, respectively. HIV-positive women had increased prevalence (46.6% vs 28.7%; P < .0001), increased acquisition (HR, 2.3; P = .03), and decreased clearance (HR, 0.4; P < .001) of oncogenic HPV as compared to HIV-negative women. Oncogenic HPV infection predicted progression of cervical dysplasia from normal to abnormal SIL (HR, 2.8; P = .002). Among HIV-positive participants, HAART increased the likelihood of regression (from present to absent) of cervical SIL (HR, 3.3; P = .02) and increased the clearance of oncogenic HPV types other than HPV-16 or HPV-18 (HR, 2.2; P = .01). CONCLUSIONS: This analysis demonstrated beneficial effects of HAART on cervical SIL in HIV-positive women.

Is Maternal Body Weight or Composition Associated with Onset of Lactogenesis II, Human Milk Production, or Infant Consumption of Mother's Own Milk? A Systematic Review and Meta-Analysis.

Maternal adiposity impacts lactation performance, but the pathways are unclear. We conducted a systematic review to understand whether maternal adiposity (body mass index [BMI] or percentage fat mass) is associated with onset of lactogenesis II (copious milk; hours), human milk production (expressed volume/24 h), and infant consumption of mother's own milk (volume/24 h). We used random-effects standard meta-analyses to compare the relative risk (RR) of delayed lactogenesis II (>72 h) between mothers classified as underweight (BMI <18.5 kg/m2), healthy weight (BMI, 18.5-24.9 kg/m2), and overweight/obese (BMI ≥25 kg/m2) and random-effects meta-regressions to examine associations with hours to lactogenesis II and infant milk consumption. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. We included 122 articles. Mothers with underweight (RR: 0.64; 95% CI: 0.49, 0.83; I2 = 39.48%; 8 articles/data points) or healthy weight status (RR: 0.67; 95% CI: 0.57, 0.79; I2 = 70.91%; 15 articles/data points) were less likely to experience delayed lactogenesis II than mothers with overweight/obesity. We found no association between maternal BMI and time to onset of lactogenesis II (ß: 1.45 h; 95% CI: -3.19, 6.09 h; P = 0.52, I2 = 0.00%; 8 articles, 17 data points). Due to limited data, we narratively reviewed articles examining BMI or percentage fat mass and milk production (n = 6); half reported an inverse association and half no association. We found no association between maternal BMI (ß: 6.23 mL; 95% CI: -11.26, 23.72 mL; P = 0.48, I2 = 47.23%; 58 articles, 75 data points) or percentage fat mass (ß: 7.82 mL; 95% CI: -1.66, 17.29 mL; P = 0.10, I2 = 28.55%; 30 articles, 41 data points) and infant milk consumption. The certainty of evidence for all outcomes was very low. In conclusion, mothers with overweight/obesity may be at risk of delayed lactogenesis II. The available data do not support an association with infant milk consumption, but the included studies do not adequately represent mothers with obesity. This study was registered in PROSPERO as 285344.

Elucidating the dynamics and impact of the gut microbiome on maternal nutritional status during pregnancy, effect on pregnancy outcomes and infant health in rural Pakistan: study protocol for a prospective, longitudinal observational study.

INTRODUCTION: Undernutrition during pregnancy is linked to adverse pregnancy and birth outcomes and has downstream effects on the growth and development of children. The gut microbiome has a profound influence on the nutritional status of the host. This phenomenon is understudied in settings with a high prevalence of undernutrition, and further investigation is warranted to better understand such interactions. METHODS AND ANALYSIS: This is a prospective, longitudinal observational study to investigate the relationship between prokaryotic and eukaryotic microbes in the gut and their association with maternal body mass index (BMI), gestational weight gain, and birth and infant outcomes among young mothers (17-24 years) in Matiari District, Pakistan. We aim to enrol 400 pregnant women with low and normal BMIs at the time of recruitment (<16 weeks of gestation). To determine the weight gain during pregnancy, maternal weight is measured in the first and third trimesters. Gut microbiome dynamics (bacterial and eukaryotic) will be assessed using 16S and 18S rDNA surveys applied to the maternal stool samples. Birth outcomes include birth weight, small for gestational age, large for gestational age, preterm birth and mortality. Infant growth and nutritional parameters include WHO z-scores for weight, length and head circumference at birth through infancy. To determine the impact of the maternal microbiome, including exposure to pathogens and parasites on the development of the infant microbiome, we will analyse maternal and infant microbiome composition, micronutrients in serum using metallomics (eg, zinc, magnesium and selenium) and macronutrients in the stool. Metatranscriptomics metabolomics and markers of inflammation will be selectively deployed on stool samples to see the variations in dietary intake and maternal nutritional status. We will also use animal models to explore the bacterial and eukaryotic components of the microbiome. ETHICS AND DISSEMINATION: The study is approved by the National Bioethics Committee (NBC) in Pakistan, the Ethics Review Committee (ERC) at Aga Khan University and the Research Ethics Board (REB) at the Hospital for Sick Children, and findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05108675.

Drivers of malnutrition among late adolescent and young women in rural Pakistan: a cross-sectional assessment of the MaPPS trial.

OBJECTIVE: This study aimed to characterise the burden of malnutrition and assess how underlying determinants at the structural and intermediary levels contributed to malnutrition among late adolescent and young women in rural Pakistan. DESIGN: Cross-sectional enrolment data assessment. SETTING AND PARTICIPANTS: This study was conducted using data from adolescent and young women (n=25 447) enrolled in the Matiari emPowerment and Preconception Supplementation Trial, collected from June 2017 to July 2018 in Matiari District, Pakistan. The WHO-based cut-offs were applied to anthropometric measures to estimate body mass index (BMI) categories (underweight, overweight, obese) and stunting. Hierarchical models were generated to evaluate the association between the determinants with BMI categories and stunting among late adolescent girls and young women, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcomes of interest were BMI categories and stunting. Explanatory variables included measures of socioeconomic status, education, occupation, health, well-being, food security, empowerment and food practices. RESULTS: Regardless of age group, the prevalence of underweight was high (36.9%; 95% CI 36.3% to 37.5%). More late adolescent girls were underweight, while more young women were overweight/obese (p<0.001). Stunting affected 9.2% (95% CI 8.9% to 9.6%) of participants, of which 35.7% were additionally underweight and 7.3% overweight/obese. Compared with those in the normal weight category, those underweight were more likely to be impoverished and less empowered. Those overweight/obese were more likely to be from a higher wealth quintile and food secure. Increased education level and food security were associated with reductions stunting risk. CONCLUSIONS: This study informs the data gap and need for comprehensive research on adolescent nutritional status. Findings suggest factors related to poverty played an important, underlying role in undernutrition among participants. Commitment to improving the nutritional status of all adolescent and young women in Pakistan will be critical given the observed burden of malnutrition. TRIAL REGISTRATION NUMBER: NCT03287882.

Developing a partnership to improve health care delivery to children <18 years with cancer and blood disorders in the English-speaking Caribbean: lessons from the SickKids-Caribbean Initiative (SCI).

In 2013, the SickKids-Caribbean Initiative (SCI) was formalised among The Hospital for Sick Children in Toronto, Canada, the University of the West Indies, and Ministries of Health in six Caribbean countries (Barbados, The Bahamas, Jamaica, St. Lucia, St. Vincent and the Grenadines, and Trinidad and Tobago). The aim was to improve the outcomes and quality of life of children (<18 years) with cancer and blood disorders in the partner countries. Core activities included filling a human resource gap by training paediatric haematologists/oncologists and specialised registered nurses; improving capacity to diagnose and treat diverse haematology/oncology cases; developing and maintaining paediatric oncology databases; creating ongoing advocacy activities with international agencies, decision makers, and civil society; and establishing an integrated administration, management, and funding structure. We describe core program components, successes, and challenges to inform others seeking to improve health service delivery in a multidisciplinary and complex partnership.

Mental health interventions in adolescence.

Adolescent mental health (MH) disorders with striking prominence include anxiety, self-harm and depression. The current review aims to highlight high-quality reviews of novel interventions, mainly Cochrane reviews, and/or quality meta-analyses published between 2019 and 2022 on three adolescent mental health challenges. Recent evidence about the effectiveness of psychosocial interventions is encouraging. However, the shift to virtual treatment methods during the pandemic was supported by a relatively thin body of research. Future research and policy in child and youth MH must address the consequences of the pandemic or comparable disruptions on adolescent MH, as well as mitigation strategies. An emphasis on integrated digital, community and school platforms for mental health within child and adolescent health services would benefit from a greater focus on early recognition and prevention.

Rider Skill Affects Time and Frequency Domain Postural Variables When Performing Shoulder-in.

In equestrian sports the novice rider learns first to follow the movements of the horse's back and then how to influence the horse's performance. One of the rider's challenges is to overcome inherent horse and/or rider asymmetry patterns when riding in straight lines, mirroring the movements on the left, and right sides when turning. This study compares the performance of novice and advanced riders when riding in sitting trot on straight lines and when riding shoulder-in to the left and right sides. Eight novice and eight advanced horse-rider combinations performed sitting trot in a straight line, shoulder-in left and shoulder-in right while wearing a full body set of inertial sensors. An experienced dressage judge indicated when the movements were being performed correctly and assigned scores on a scale of 0-10 for the quality of performance. Kinematic data from the inertial sensors were analyzed in time and frequency domain. Comparisons were made between trotting on the straight, shoulder-in left, and shoulder-in right. Advanced riders received higher dressage scores on all three movements, but significantly (P < .05) lower scores were found for shoulder-in right across the two groups. When riding shoulder-in, advanced riders had greater hip extension (advanced = -5.8 ± 17.7; novice = 7.8 ± 8.9 degrees) and external rotation (advanced = -32.4 ± 15.5; novice = -10.8 ± 13.2 degrees) in the outside leg compared with novices (P < .05), which reflects an important cue in achieving the required body rotation in the horse. Lower scores for shoulder-in right may be linked to significant (P < .05) changes in harmonics of trunk to pelvis rotation.

Characterizing Retail Food Environments in Peri-Urban Pakistan during the COVID-19 Pandemic.

(1) Background: To date, there are limited data in low- and middle-income countries (LMICs) that collect, monitor, and evaluate food environments in standardized ways. The development of a pilot survey tool, tailored to LMICs and focused on retail food environments, is necessary for improving public health nutrition. (2) Methods: A novel survey tool was developed and piloted in a sample of village retail food environments (n = 224) in Matiari, Pakistan between October 2020 to April 2021. Villages were randomly selected, and food outlets were surveyed within a 500-m radius from each village center. Descriptive statistics (counts and percentages) were used to describe the characteristics of food outlets and the availability of food. To test whether there was a difference in characteristics or in the mean of number of healthy, unhealthy, and total food items available by village size, a χ2 test or one-way ANOVA was conducted, respectively. (3) Results: In total, 1484 food outlets were surveyed for food accessibility, availability, and promotion across small (n = 54), medium (n = 112), and large villages (n = 58). In small and medium-sized villages, mobile food vendors were the predominant food outlet type (47.8% and 45.1%, respectively), whereas in large villages, corner stores (36%) were more prominent. The mean number of total food items (p < 0.006) and unhealthy food items (p < 0.001) available in food outlets differed by village size. The proportion of food outlets with available fruits, meat and poultry, water, and sugar-sweetened beverages also differed by village size (p < 0.001). (4) Conclusions: This study informs the global evidence gap in the current understanding of food environments in various ethnically diverse and dynamic LMICs, and the developed methodology will be useful to other LMICs for measuring and monitoring the food environment, especially among vulnerable population groups. This work complements current national and provincial survey efforts in Pakistan.

Practices and predictors of menstrual hygiene management material use among adolescent and young women in rural Pakistan: A cross-sectional assessment.

Background: In low- and middle-income countries (LMICs), women often use inappropriate materials to manage menstruation, which can threaten their health. Improper practices can also have critical downstream consequences beyond physiologic health, including restricting adolescent girls' access to academic pursuits. Methods: We used cross-sectional data collected through a structured questionnaire from the menstruating adolescents and young women 15-23 years of age living in rural Pakistan (n = 25 305). We aimed to describe menstrual hygiene management (MHM) practices and generate a predictive model of the socioeconomic and demographic factors related to the use of MHM materials. Beliefs and barriers around MHM were also summarized. The outcome variable included: those who practiced appropriate and inappropriate MHM practices. Logistic regression was used to generate the predictive model, with results presented as odds ratios (OR) and 95% confidence interval (CI). Results: Inappropriate MHM practices were reported by 75% (n = 19 006) of participants. The majority 61.9% (n = 15 667) reported using old cloths, 12.6% (n = 3191) used nothing, and 0.5% (n = 136) used old cloth with a sanitary pad. One-fourth of participants reported appropriate MHM material use, including 16.2% (n = 4087) sanitary pads, 8.6% (n = 2167) new cloth, and a few reported using sanitary pads with new cloth 0.2% (n = 45). Inappropriate MHM practices were more common in lowest wealth quintile (OR = 4.41; 95% CI = 2.77-7.01, P < 0.0001), followed by those with no education (OR = 3.9; 95% CI = 3.36-4.52, P < 0.0001). Conclusions: The study indicates the need for multi-sectoral efforts to introduce MHM-specific and MHM-sensitive interventions to improve MHM practices, ranging from the availability of low-cost MHM materials to the inclusion of MHM education in school curriculums and within the community platforms.