Neutrophil responses to RSV infection show differences between infant and adult neutrophils.

INTRODUCTION: Respiratory syncytial virus (RSV) causes a severe respiratory condition, bronchiolitis, in infants but not in adults. Bronchiolitis is characterised by neutrophilic infiltration in the airways, but whether neutrophils enhance recovery from infection or contribute to its pathology remains unknown. METHODS: We used a novel in-vitro model to compare term umbilical cord blood (infant) (n=17 donors) and adult neutrophils (n=15 donors) during migration across RSV-infected differentiated human nasal airway epithelial cells (AECs) in a basolateral to apical direction. RESULTS: Greater numbers of infant neutrophils (mean (95% CI)) (336 684 (242 352 to 431 015)) migrated across RSV-infected AECs to the apical compartment (equivalent to the airway lumen) compared with adult neutrophils (56 586 (24 954 to 88 218)) (p<0.0001). Having reached the apical compartment of infected AECs, much greater numbers of infant neutrophils (140 787 (103 117 to 178 456)) became apoptotic compared with adult (5853 (444 to 11 261)) (p=0.002). Infant neutrophils displayed much greater expression of CD11b, CD64, neutrophil elastase (NE) and myeloperoxidase (MPO) than adult neutrophils at baseline and at all points of migration. However, as adult neutrophils migrated, expression of CD11b, CD64, NE and MPO became greater than at baseline. DISCUSSION: The high proportion of infant neutrophils migrating across RSV-infected AECs correlates with the neutrophilic infiltrate seen in infants with severe RSV bronchiolitis, with large numbers undergoing apoptosis, which may represent a protective mechanism during infection. Compared with adult neutrophils, infant neutrophils already have high expression of surface markers before contact with AECs or migration, with less capacity to increase further in response to RSV infection or migration.

Distribution-free hyperrectangular tolerance regions for setting multivariate reference regions in laboratory medicine.

Reference regions are important in laboratory medicine to interpret the test results of patients, and usually given by tolerance regions. Tolerance regions of p ( ≥ 2 ) $$ p\;\left(\ge 2\right) $$ dimensions are highly desirable when the test results contains p $$ p $$ outcome measures. Nonparametric hyperrectangular tolerance regions are attractive in real problems due to their robustness with respect to the underlying distribution of the measurements and ease of intepretation, and methods to construct them have been recently provided by Young and Mathew [Stat Methods Med Res. 2020;29:3569-3585]. However, their validity is supported by a simulation study only. In this paper, nonparametric hyperrectangular tolerance regions are constructed by using Tukey's [Ann Math Stat. 1947;18:529-539; Ann Math Stat. 1948;19:30-39] elegant results of equivalence blocks. The validity of these new tolerance regions is proven mathematically in [Ann Math Stat. 1947;18:529-539; Ann Math Stat. 1948;19:30-39] under the only assumption that the underlying distribution of the measurements is continuous. The methodology is applied to analyze the kidney function problem considered in Young and Mathew [Stat Methods Med Res. 2020;29:3569-3585].

Developing survey weights to ensure representativeness in a national, matched cohort study: results from the children and young people with Long Covid (CLoCk) study.

BACKGROUND: Findings from studies assessing Long Covid in children and young people (CYP) need to be assessed in light of their methodological limitations. For example, if non-response and/or attrition over time systematically differ by sub-groups of CYP, findings could be biased and any generalisation limited. The present study aimed to (i) construct survey weights for the Children and young people with Long Covid (CLoCk) study, and (ii) apply them to published CLoCk findings showing the prevalence of shortness of breath and tiredness increased over time from baseline to 12-months post-baseline in both SARS-CoV-2 Positive and Negative CYP. METHODS: Logistic regression models were fitted to compute the probability of (i) Responding given envisioned to take part, (ii) Responding timely given responded, and (iii) (Re)infection given timely response. Response, timely response and (re)infection weights were generated as the reciprocal of the corresponding probability, with an overall 'envisioned population' survey weight derived as the product of these weights. Survey weights were trimmed, and an interactive tool developed to re-calibrate target population survey weights to the general population using data from the 2021 UK Census. RESULTS: Flexible survey weights for the CLoCk study were successfully developed. In the illustrative example, re-weighted results (when accounting for selection in response, attrition, and (re)infection) were consistent with published findings. CONCLUSIONS: Flexible survey weights to address potential bias and selection issues were created for and used in the CLoCk study. Previously reported prospective findings from CLoCk are generalisable to the wider population of CYP in England. This study highlights the importance of considering selection into a sample and attrition over time when considering generalisability of findings.

Rapid desensitization through immunoadsorption during cardiopulmonary bypass. A novel method to facilitate human leukocyte antigen incompatible heart transplantation.

BACKGROUND: Anti-human leukocyte antigen (HLA)-antibody production represents a major barrier to heart transplantation, limiting recipient compatibility with potential donors and increasing the risk of complications with poor waiting-list outcomes. Currently there is no consensus to when desensitization should take place, and through what mechanism, meaning that sensitized patients must wait for a compatible donor for many months, if not years. We aimed to determine if intraoperative immunoadsorption could provide a potential desensitization methodology. METHODS: Anti-HLA antibody-containing whole blood was added to a Cardiopulmonary bypass (CPB) circuit set up to mimic a 20 kg patient undergoing heart transplantation. Plasma was separated and diverted to a standalone, secondary immunoadsorption system, with antibody-depleted plasma returned to the CPB circuit. Samples for anti-HLA antibody definition were taken at baseline, when combined with the CPB prime (on bypass), and then every 20 min for the duration of treatment (total 180 min). RESULTS: A reduction in individual allele median fluorescence intensity (MFI) to below clinically relevant levels (<1000 MFI), and in the majority of cases below the lower positive detection limit (<500 MFI), even in alleles with a baseline MFI >4000 was demonstrated. Reduction occurred in all cases within 120 min, demonstrating efficacy in a time period usual for heart transplantation. Flowcytometric crossmatching of suitable pseudo-donor lymphocytes demonstrated a change from T cell and B cell positive channel shifts to negative, demonstrating a reduction in binding capacity. CONCLUSIONS: Intraoperative immunoadsorption in an ex vivo setting demonstrates clinically relevant reductions in anti-HLA antibodies within the normal timeframe for heart transplantation. This method represents a potential desensitization technique that could enable sensitized children to accept a donor organ earlier, even in the presence of donor-specific anti-HLA antibodies.

Pattern visual evoked potentials show an inferior-superior topographic shift through maturation in childhood.

The pattern-reversal visual evoked potential (prVEP) is an established routine clinical test. Its objectivity is particularly valuable for assessing visual pathway function in children. International standards specify at a minimum that an active electrode is placed on the occiput at Oz, but we find an additional inferior electrode at the inion (Iz) provides larger and more sensitive prVEPs in young persons. This study assesses the significance and age-dependence of these observations. PrVEPs were recorded from 1487 patients considered ophthalmologically normal aged <20 years old, to a range of check widths including International Society for Clinical Electrophysiology of Vision (ISCEV) standard large (50') and small (12.5') check widths. P100 peak-time and amplitude from both electrode sites were analysed. A subset of 256 children were studied longitudinally by fitting logistic regression models including a random effect on subjects. PrVEPs were largest over the Iz electrode for the majority of infants and children. This transitioned with age to become equal or smaller at Oz as a function of check width. For ISCEV standard large and small check widths, transition periods were ∼8 and ∼12 years of age, respectively. We estimated abnormal result classifications of 3.7% with use of an Oz electrode alone, which decreases to 0.0-0.5% when adding or using an Iz electrode. The inferior dominance of prVEP topography in children may be explained by age-related anatomical changes altering the cortical dipole, combined with physiological maturation of the neural generators of the prVEP. We recommend the Iz electrode is used routinely in recording of prVEPs in children. KEY POINTS: Pattern visual evoked potentials (PVEPs) are an established clinical test which provide objective assessment of visual pathway function. These are particularly valuable in providing objective information of vision in children. International standards specify the active recording electrode should be placed at the mid-occiput (Oz), but we find that pattern-reversal visual evoked potential amplitudes are larger for a lower placed electrode (Iz) in young persons. This was assessed in 1487 patients who had simultaneous PVEP recording at both electrode positions, and it was found that the majority of PVEPs in children were larger over the Iz electrode. The developmental differences in PVEP distribution transitioned to be equal between Iz and Oz with increasing age as a function of check width, at ∼8 and ∼12 years old for large and small check widths, respectively. These differences will improve diagnostic accuracy of paediatric PVEPs. We hypothesise these changes reflect developmental anatomical and neurophysiological changes altering the PVEP dipole.

Model Based Estimation of Posaconazole Tablet and Suspension Bioavailability in Hospitalized Children Using Real-World Therapeutic Drug Monitoring Data in Patients Receiving Intravenous and Oral Dosing.

Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included a priori. Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.

Performance on the iSTEP and 10 m-ISWT in boys with haemophilia.

INTRODUCTION: Boys with haemophilia (BwH) have improved health outcomes. Measures of physical function in haemophilia are not challenging or sensitive enough to reflect physical limitations or guide rehabilitation. To identify meaningful tests, we aimed to: evaluate the performance of BwH on two physical performance measures: iSTEP and 10 m-ISWT; identify factors which predict performance and compare BwH to their unaffected peers. METHODS: BwH completed both iSTEP and 10 m-ISWT. Disease severity, age, BMI, HJHS, lower limb muscle torque, time spent in moderate to vigorous physical activity, sedentary time, were included as factors to predict performance. Results were compared to unaffected peers. RESULTS: 43 boys median age 10 (10 mild/moderate, 26 severe, 7 inhibitors) were recruited. BwH were less likely to complete the iSTEP and performed less well on the 10 m-ISWT than age matched peers. Ceiling effects were apparent for iSTEP, but not the 10 m-ISWT test. Age was the only significant predictor for performance in the iSTEP, with older boys being more likely to achieve a higher level or complete the test. Greater age, lower BMI, milder disease severity and more time spent in MVPA all predicted better performance on the 10 m-ISWT, with BMI and habitual physical activity a potential rehabilitation focus for underperforming individuals. HJHS and muscle strength did not predict performance on either test. CONCLUSION: Despite the space need to conduct the 10 m-ISWT, it appears to be a superior performance measure than the iSTEP in BwH and provides clinically meaningful information, which can be interpreted using age-specific normative reference equations.

Trends in the long-term impact of childhood visual impairment on health and social outcomes in the UK: a cross-cohort study across three decades of disability-related legislation and policy implementation.

BACKGROUND: Childhood vision impairment (VI) can adversely impact health and social outcomes and limit life chances. We investigated whether its adverse impacts into adult life changed during a period in which legislation, policy and services to address inequalities relating to disability were implemented. METHODS: Cross-cohort study comprising 14 247 participants from the 1946, 1958 and 1970 British birth cohorts (BC). Participants dichotomized as VI at age 15/16 (distance visual acuity was 6/12 or worse in the better-seeing eye) or normally sighted. Associations of childhood VI with health, well-being, socioeconomic and social participation outcomes in mid-adult life were investigated using regression models adjusted for participants' early life socioeconomic markers and sex. Change in adjusted odds ratios of >10% in the same direction in successive cohorts, or a > 20% difference between 1970BC and one older cohort were considered meaningful. RESULTS: Trends over time in impacts of childhood onset VI into mid-adult life were complex. This included worsening of odds of poorer physical health (odds ratio 1.47; 95% confidence interval 1.02-2.14), living in unsatisfactory (1.54; 1.03-2.29) or overcrowded (2.34; 1.26-4.06) households, being unemployed (2.19; 1.19-3.97) and not gaining additional educational qualifications during mid-adult life (1.61; 1.08-2.47). By contrast the odds of not participating in some social activities (e.g. seeing friends) improved over time. Associations with other outcomes were unchanged. CONCLUSIONS: Many adverse impacts of childhood VI do not appear ameliorated over time by legislation, policies and provision that would have been expected to reduce inequalities. Moreover, some were increased. Childhood VI continues to cast a life-long shadow.

The role of education in child and adolescent marriage in rural lowland Nepal.

Marriage during childhood and adolescence adversely affects maternal and child health and well-being, making it a critical global health issue. Analysis of factors associated with women marrying ≥18 years has limited utility in societies where the norm is to marry substantially earlier. This paper investigated how much education Nepali women needed to delay marriage across the range of ages from 15 to ≥18 years. Data on 6,406 women aged 23-30 years were analysed from the Low Birth Weight South Asia Trial on the early-marrying and low-educated Maithili-speaking Madhesi population in Terai, Nepal. Multivariable logistic regression models assessed the associations of women's education with marrying aged ≥15, ≥16, ≥17 and ≥18 years. Cox proportional hazards regression models quantified the hazard of marrying. Models adjusted for caste affiliation. Women married at median age of 15 years and three-quarters were uneducated. Women's primary and lower-secondary education were weakly associated with delaying marriage, whether the cut-off to define early marriage was 15, 16, 17 or 18 years, with stronger associations for secondary education. Caste associations were weak. Overall, models explained relatively little of the variance in the likelihood of marriage at different ages. The joint effects of lower-secondary and higher caste affiliation and of secondary/higher education and mid and higher caste affiliation reduced the hazard of marrying. In early-marrying and low-educated societies, changing caste-based norms are unlikely to delay women's marriage. Research on broader risk factors and norms that are more relevant for delaying marriage in these contexts is needed. Gradual increases in women's median marriage age and increased secondary education may, over time, reduce child and adolescent marriage.

Trends in antiretroviral use in pregnancy in the UK and Ireland, 2008-2018.

INTRODUCTION: HIV treatment recommendations have evolved over time, reflecting both growing availability of new antiretrovirals and accumulating evidence on their safe and effective use. We analysed patterns of antiretroviral use among diagnosed pregnant women living with HIV delivering in the UK and Ireland between 2008 and 2018 using national surveillance data. METHODS: All singleton pregnancies with known outcomes and known timing of antiretroviral initiation reported to the National Surveillance of HIV in Pregnancy and Childhood were included. Every individual instance of specific antiretroviral use was the unit of analysis in generating a snapshot of antiretroviral use overall and over calendar time. The final analysis was restricted to the 14 most frequently prescribed antiretrovirals. RESULTS: There were 12 099 singleton pregnancies reported during 2008-2018 and a total of 38 214 individual uses of the 14 most commonly prescribed antiretrovirals, the majority of which were started before conception (70.9%). In 2008, 37.7% (482/1279) of pregnancies were conceived under treatment, reaching 80.9% (509/629) by 2018. Patterns of antiretroviral use have changed over time, particularly for third agents. Between 2008 and 2018 the most frequently used protease inhibitor shifted from lopinavir to darunavir, whereas use of integrase inhibitors increased steadily over time. CONCLUSIONS: These national surveillance data enable investigation of the 'real-world' use of antiretrovirals in pregnancy on a population level. Findings demonstrate mixed responsiveness of antiretroviral prescription to changes in pregnancy guideline recommendations and may also reflect changes in commissioning and in the characteristics of pregnant women living with HIV.

Associations between early marriage and preterm delivery: Evidence from lowland Nepal.

OBJECTIVES: Preterm delivery (<37 weeks gestation) is the largest cause of child mortality worldwide. Marriage and pregnancy during adolescence have been associated with an increased risk of preterm delivery. We investigate independent associations of age at marriage and age at first pregnancy with preterm delivery in a cohort of women from rural lowland Nepal. METHODS: We analyzed data from 17 974 women in the Low Birth Weight South Asia Trial. Logistic regression models tested associations of age at marriage and age at first pregnancy with preterm delivery, for primigravida (n = 6 243) and multigravida (n = 11 731) women. Models were adjusted for maternal education, maternal caste, and household asset score. RESULTS: Ninety percent of participants had married at <18 years and 58% had their first pregnancy at <18 years. 20% of participants delivered preterm. Primigravida participants married at ≤14 years had higher odds of preterm delivery than those married ≥18 years, when adjusting for study design (adjusted odds ratio (aOR) 1.45, 95% CI: 1.15-1.83), confounders (aOR 1.28: 1.01-1.62) and confounders + age at pregnancy (aOR 1.29: 1.00-1.68). Associations were insignificant for multigravida women. No significant associations were observed between age at first pregnancy and preterm delivery. DISCUSSION: In this population, early marriage, rather than pregnancy, is a risk factor for preterm delivery. We hypothesize that psychological stress, a driver of preterm delivery which is increased among those marrying young, rather than physiological immaturity, drives this association. Further research into the psychological consequences of child marriage in Nepal is needed.

Differences in maternal and early child nutritional status by offspring sex in lowland Nepal.

OBJECTIVE: On average, boys grow faster than girls in early life but appear more susceptible to undernutrition. We investigated sex differences in early child growth, and whether maternal nutritional status and diet differed by offspring sex during and after pregnancy in an undernourished population. METHODS: We analyzed longitudinal data from a cluster-randomized trial from plains Nepal, stratifying results by child or gestational age. Children's outcomes (0-20 months) were weight, length, and head circumference and their z-scores relative to WHO reference data in 2-monthly intervals (n range: 24837 to 25 946). Maternal outcomes were mid-upper arm circumference (MUAC), and body mass index (BMI) during pregnancy (12-40 weeks) (n = 5550 and n = 5519) and postpartum (n = 15 710 and n = 15 356), and diet in pregnancy. We fitted unadjusted and adjusted mixed-effects linear and logistic regression models comparing boys with girls. RESULTS: Boys were larger than girls, however relative to their sex-specific reference they had lower length and head circumference z-scores from birth to 12 months, but higher weight-for-length z-scores from 0 to 6 months. Mothers of sons had higher MUAC and BMI around 36 weeks gestation but no other differences in pregnancy diets or pregnancy/postpartum maternal anthropometry were detected. Larger sex differences in children's size in the food supplementation study arm suggest that food restriction in pregnancy may limit fetal growth of boys more than girls. CONCLUSIONS: Generally, mothers' anthropometry and dietary intake do not differ according to offspring sex. As boys are consistently larger, we expect that poor maternal nutritional status may compromise their growth more than girls. Copyright © 2021 John Wiley & Sons, Ltd.

The association between childhood hearing loss and self-reported peer victimisation, depressive symptoms, and self-harm: longitudinal analyses of a prospective, nationally representative cohort study.

BACKGROUND: Childhood hearing loss (HL) predicts poor mental health and is associated with a higher risk of communication difficulties. The relationship of childhood HL with specific types of poor mental health (such as depressive symptoms or self-harm) and peer victimisation remains unclear. METHODS: We analysed data from the Millennium Cohort Study (MCS), a prospective observational cohort study of children living in the UK at age 9 months and born between 2000 to 2002. Data were available on the children and their families at ages 9 months, then at 3, 5, 7, 11, and 14 years. Participants were 10,858 singleton children with self-reported data on peer victimisation, depressive symptoms, and self-harm at age 14 years. Multivariable logistic regression models were fitted to estimate odds ratios (OR) for HL with peer victimisation, depressive symptoms, and self-harm. HL presence was examined in terms of any HL between ages 9 months and 14 years, as well as by HL trajectory type (defined by onset and persistence). Analyses were adjusted for potential sources of confounding, survey design, and attrition at age 14 years. Interactions between sex and HL were examined in each model and multiple imputation procedures used to address missing data. RESULTS: Children with any HL had increased odds of depressive symptoms (OR: 1.32, 95% CI: 1.09-1.60), self-harm (1.41, 1.12-1.78) and, in girls only, peer victimisation (girls: 1.81, 1.29-2.55; boys: 1.05, 0.73-1.51), compared to those without HL. HL with later age at onset and persistence to age 14 years was the only trajectory associated with all outcomes. CONCLUSIONS: Childhood HL may predict peer victimisation (in girls), depressive symptoms, and self-harm. Further research is needed to identify HL trajectories and methods to facilitate good mental health in children with HL.

Determinants of accident and emergency attendances and emergency admissions in infants: birth cohort study.

BACKGROUND: There is limited understanding of the drivers of increasing infant accident and emergency (A&E) attendances and emergency hospital admissions across England. We examine variations in use of emergency hospital services among infants by local areas in England and investigate the extent to which infant and socio-economic factors explain these variations. METHODS: Birth cohort study using linked administrative Hospital Episode Statistics data in England. Singleton live births between 1-April-2012 and 31-March-2019 were followed up for 1 year; from 1-April-2013 (from the discharge date of their birth admission) until their first birthday, death or 31-March-2019. Mixed effects negative binomial models were used to calculate incidence rate ratios for A&E attendances and emergency admissions and mixed effects logistic regression models estimated odds ratio of conversion (the proportion of infants subsequently admitted after attending A&E). Models were adjusted for individual-level factors and included a random effect for local authority (LA). RESULTS: The cohort comprised 3,665,414 births in 150 English LAs. Rates of A&E attendances and emergency admissions were highest amongst: infants born < 32 weeks gestation; with presence of congenital anomaly; and to mothers < 20-years-old. Area-level deprivation was positively associated with A&E attendance rates, but not associated with conversion probability. A&E attendance rates were highest in the North East (916 per 1000 child-years, 95%CI: 911 to 921) and London (876 per 1000, 95%CI: 874 to 879), yet London had the lowest emergency admission rates (232 per 1000, 95%CI: 231 to 234) and conversion probability (25% vs 39% in South West). Adjusting for individual-level factors did not significantly affect variability in A&E attendance and emergency admission rates by local authority. CONCLUSIONS: Drivers of A&E attendances and emergency admissions include individual-level factors such being born premature, with congenital anomaly and from socio-economically disadvantaged young parent families. Support for such vulnerable infants and families should be provided alongside preventative health care in primary and community care settings. The impact of these services requires further investigation. Substantial geographical variations in rates were not explained by individual-level factors. This suggests more detailed understanding of local and underlying service-level factors would provide targets for further research on mechanisms and policy priority.

Relative power: Explaining the effects of food and cash transfers on allocative behaviour in rural Nepalese households.

We estimate the effects of antenatal food and cash transfers with women's groups on household allocative behaviour and explore whether these effects are explained by intergenerational bargaining among women. Interventions were tested in randomised-controlled trial in rural Nepal, in a food-insecure context where pregnant women are allocated the least adequate diets. We show households enrolled in a cash transfer intervention allocated pregnant women with 2-3 pp larger shares of multiple foods (versus their mothers-in-law and male household heads) than households in a control group. Households in a food transfer intervention only increased pregnant women's allocation of staple foods (by 2 pp). Intergenerational bargaining power may partly mediate the effects of the cash transfers but not food transfers, whereas household food budget and nutrition knowledge do not mediate any effects. Our findings highlight the role of intergenerational bargaining in determining the effectiveness of interventions aiming to reach and/or empower junior women.

Independent associations of women's age at marriage and first pregnancy with their height in rural lowland Nepal.

OBJECTIVES: In many South Asian communities, the majority of women are married during adolescence and reproduce before 20 years. Early reproduction may adversely affect maternal nutrition and linear growth, however whether early marriage has similar effects is unknown. Shorter women might also be preferentially chosen for earlier marriage. We hypothesized that early marriage and early pregnancy may each be associated with women's shorter height, independent of any selection effects. MATERIALS AND METHODS: We analyzed cross-sectional data on 7,146 women aged 20-30 years from rural lowland Nepal. Linear regression models tested associations of early marriage and early reproduction with height, adjusting for women's education and husbands' characteristics (education and wealth) that might index preferential selection of short young women for marriage. RESULTS: Median ages at marriage and first pregnancy were 15 and 18 years, respectively, with 20% pregnant <16 years. Both early marriage and early pregnancy were independently associated with shorter stature, accounting for a decrement of 1.4 cm, which decreased to 1 cm after adjusting for women's education. Effects of early marriage and reproduction persisted after adjusting for the tendency of poorer and less educated men to marry young and short women, indicating a role for social selection. DISCUSSION: The decrements in height associated with early marriage and reproduction are indicative of broader adverse effects on maternal metabolism during a "critical period" of growth and maturation in the life-course of women. Although the magnitudes of effect are relatively small, they affect large numbers of women in this population.

Maternal physical, socioeconomic, and demographic characteristics and childbirth complications in rural lowland Nepal: Applying an evolutionary framework to understand the role of phenotypic plasticity.

OBJECTIVES: Evolutionary perspectives on human childbirth have primarily focused on characteristics of our species in general, rather than variability within and between contemporary populations. We use an evolutionary framework to explore how physical and demographic characteristics of mothers shape the risks of childbirth complications in rural lowland Nepal, where childbearing typically commences in adolescence and chronic undernutrition is widespread, though maternal overweight is increasing in association with nutrition transition. METHODS: We conducted secondary analyses of data from a cluster-randomized trial. Women aged 14-35 years were categorized by age, number of previous pregnancies, height, body mass index (BMI), husband's education, and household wealth. Multivariable logistic regression models tested whether these characteristics independently predicted risks of episiotomy and cesarean section (CS, n = 14 261), and obstructed labor (OL, n = 5185). RESULTS: Risks were greatest among first-time adolescent mothers, though associations with age varied by outcome. Independent of age and parity, short stature and high BMI increased risks of CS and OL, whereas associations were weaker for episiotomy. Male offspring had increased risk of CS and OL but not episiotomy. Wealth was not associated with OL, but lower wealth and lower husband's education were associated with lower likelihood of episiotomy and CS. CONCLUSIONS: At the individual level, the risk childbirth complications is shaped by trade-offs between fertility, growth, and survival. Some biological markers of disadvantage (early childbearing, short stature) increased the risk, whereas low socio-economic status was associated with lower risk, indicating reduced access to relevant facilities. Independent of these associations, maternal age showed complex effects.

Comprehensive analysis of the association of seasonal variability with maternal and neonatal nutrition in lowland Nepal.

OBJECTIVE: To provide a comprehensive seasonal analysis of pregnant mothers' eating behaviour and maternal/newborn nutritional status in an undernourished population from lowland rural Nepal, where weather patterns, agricultural labour, food availability and disease prevalence vary seasonally. DESIGN: Secondary analysis of cluster-randomised Low Birth Weight South Asia Trial data, applying cosinor analysis to predict seasonal patterns. OUTCOMES: Maternal mid-upper arm circumference (MUAC), BMI, dietary diversity, meals per day, eating down and food aversion in pregnancy (≥31 weeks' gestation) and neonatal z-scores of length-for-age (LAZ), weight-for-age (WAZ) and head circumference-for-age (HCAZ) and weight-for-length (WLZ). SETTING: Rural areas of Dhanusha and Mahottari districts in plains of Nepal. PARTICIPANTS: 2831 mothers aged 13-50 and 3330 neonates. RESULTS: We found seasonal patterns in newborn anthropometry and pregnant mothers' anthropometry, meal frequency, dietary diversity, food aversion and eating down. Seasonality in intake varied by food group. Offspring anthropometry broadly tracked mothers'. Annual amplitudes in mothers' MUAC and BMI were 0·27 kg/m2 and 0·22 cm, with peaks post-harvest and nadirs in October when food insecurity peaked. Annual LAZ, WAZ and WLZ amplitudes were 0·125, 0·159 and 0·411 z-scores, respectively. Neonates were the shortest but least thin (higher WLZ) in winter (December/January). In the hot season, WLZ was the lowest (May/June) while LAZ was the highest (March and August). HCAZ did not vary significantly. Food aversion and eating down peaked pre-monsoon (April/May). CONCLUSIONS: Our analyses revealed complex seasonal patterns in maternal nutrition and neonatal size. Seasonality should be accounted for when designing and evaluating public heath nutrition interventions.

Patient-reported outcomes in young adults with osteonecrosis secondary to developmental dysplasia of the hip - a longitudinal and cross-sectional evaluation.

BACKGROUND: Osteonecrosis of the femoral head is a common complication in the treatment of developmental dysplasia of the hip (DDH). While functional outcomes of affected patients are good in childhood, it is not clear how they change during the transition to young adulthood. This study determined the relationship between osteonecrosis and hip function, physical function and health status in adolescents and young adults. METHODS: We performed a cross-sectional study of 169 patients with a mean age of 19.7 ± 3.8 years with and without osteonecrosis following an open or closed reduction (1995-2005). We also performed a separate longitudinal evaluation of an historical cohort of 54 patients with osteonecrosis, embedded in this sample. All completed patient-reported outcome measures in 2015/2016 to quantify hip function (maximum score 100); physical function (maximum score 100); and general health status (maximum score 1). We graded all radiographs for subtype of osteonecrosis (Bucholz-Ogden); acetabular dysplasia (centre-edge angle); subluxation (Shenton's line); and osteoarthritis (Kellgren-Lawrence). Analyses were adjusted for the number of previous surgical procedures on the hip and for the severity of residual hip dysplasia. RESULTS: In 149 patients (186 hips) with and without osteonecrosis, the mean differences (95% confidence interval) in hip function, physical function and quality of life were - 4.7 (- 10.26, 0.81), - 1.03 (- 9.29, 7.23) and 0.10 (- 1.15, 1.18), respectively. Adjusted analyses stratified across types of osteonecrosis showed that only patients with Bucholz-Odgen grade III had reduced hip function (p < 0.01) and physical function (p < 0.05) but no difference in health-related quality of life when compared to no osteonecrosis. CONCLUSION: Osteonecrosis secondary to DDH is a relatively benign disorder in adolescents and young adulthood. Affected patients demonstrated minimal physical disability, a normal quality of life but reduced hip function.

An Age- and Stage-Appropriate Patient-Reported Outcome Measure of Vision-Related Quality of Life of Children and Young People with Visual Impairment.

PURPOSE: Developmentally sensitive measures of vision-related quality of life (VQoL) are needed to capture age-specific concerns about the impact of living with visual impairment (VI) in children and young people. Our objective was to use our validated VQoL instrument for children and young people 10 to 15 years of age (the VQoL_CYP) as the foundation for development of age-specific extensions. DESIGN: Questionnaire development. PARTICIPANTS: A representative sample of children and young people 6 to 19 years of age with VI, defined as visual acuity worse than 0.50 logarithm of the minimum angle of resolution in the better eye. They were recruited from pediatric ophthalmology clinics at Great Ormond Street Hospital and Moorfields Eye Hospital and, in the final phase of the study, from 20 additional United Kingdom hospitals. METHODS: Standard instrument development processes were followed across 4 phases. Twenty-nine semistructured interviews with children and young people permitted draft age-appropriate extensions. Twenty-eight cognitive interviews informed items and response options. Age-appropriate extensions were prepiloted with 49 participants to ensure feasibility and administered via a postal survey to a national sample of 160 participants for psychometric evaluation using Rasch analysis. Construct validity was evaluated through correlations with the Pediatric Quality of Life Inventory. MAIN OUTCOME MEASURES: Psychometric indices of validity and reliability of the instrument versions. RESULTS: Interviews confirmed that the existing VQoL_CYP content and format were relevant across a wider age range. Age-appropriate extensions were drafted for children (8-12 years) and young people (13-17 years). Psychometric item reduction produced 20-item child and 22-item young person versions, each with acceptable fit values, no notable differential item functioning, good measurement precision, ordered response categories and acceptable targeting, and no notable differential item functioning on items common to both. Construct validity was demonstrated through correlations with health-related quality of life (r = 0.698). CONCLUSIONS: Using an efficient child- and young person-centered approach, we developed 2 robust, age-appropriate versions of an instrument capturing VQoL that can be used cross-sectionally or sequentially across the age range of 8 to 17 years in research and clinical practice. This approach may be applicable in other rare childhood ophthalmic disorders.