Differences In Z-scores Research Articles

Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: Findings from three birth cohorts over eight years.

BackgroundShigella infections cause inflammation, which has been hypothesized to mediate the associations between Shigella and child development outcomes among children in low-resource settings. We aimed to assess whether early life inflammation and Shigella infections affect school-aged growth and cognitive outcomes from 6–8 years of age.Methodology/principal findingsWe conducted follow-up assessments of anthropometry, reasoning skills, and verbal fluency in 451 children at 6–8 years of age in the Brazil, Tanzania, and South Africa sites of MAL-ED, a longitudinal birth cohort study. We estimated the associations between Shigella burden and inflammation with linear growth at 2, 5, and 6–8 years of age, and with the cognitive test scores using linear regression and adjusting for potential confounding variables. We also assessed whether inflammation mediated the associations between Shigella and school-aged outcomes using a regression-based approach to mediation analysis. A high prevalence of Shigella was associated with a 0.32 (95% CI: 0.08, 0.56) z-score lower height-for-age z-score (HAZ) at 6–8 years compared to a low prevalence of Shigella. Intestinal inflammation had a smaller association with HAZ at 6–8 years. Shigella burden had small and consistently negative associations with cognitive outcomes in Brazil and Tanzania, but not South Africa, and the estimates were not statistically significant. Systemic inflammation was strongly associated with lower verbal fluency scores in Brazil (semantic fluency z-score difference: -0.57, 95% CI: -1.05, -0.10; phonemic fluency z-score difference: -0.48, 95% CI: -0.93, -0.03). There was no evidence that intestinal inflammation mediated the association between Shigella and HAZ or cognitive outcomes.Conclusions/significanceWhile Shigella infections were consistently associated with long-term deficits in linear growth, the estimates of the negative associations between Shigella and cognitive outcomes were imprecise and only observed in the Brazil and Tanzania sites. Systemic inflammation was strongly associated with lower semantic and phonemic fluency scores in Brazil only, highlighting the site-specificity of effects.

Growth patterns among late preterm infants of mothers with diabetes

Objective Exposure to diabetes mellitus during pregnancy increases the risk of offspring obesity and cardiometabolic disease. Limited information exists regarding growth patterns among preterm infants exposed to maternal diabetes. This study describes growth differences during early childhood among late preterm infants of mothers with and without diabetes during pregnancy. Materials and methods In a retrospective longitudinal analysis, weight trajectories from birth to age 2 years were compared between diabetes exposure groups (N = 1554) using mixed effects modeling and adjusting for maternal and infant demographic covariates. Results Overall, 134 (9%) infants were exposed to diabetes (DM-group). DM-group had higher average weight (adjusted difference 300 g [95% CI: 228, 371]) and weight z-score (adjusted difference 0.67 standard deviation scores (SDS) [95% CI: 0.50, 0.84]) compared with unexposed infants. DM-group infants had accelerated weight gain from birth to discharge (adjusted weight difference 31.8 g [95% CI: 12.5, 51.1], adjusted weight z-score difference 0.07 SDS [95% CI: 0.02, 0.11]) compared with unexposed infants, including in the first postnatal week (adjusted weight gain velocity difference, day 0–3: 6.07 g/day [95% CI: 0.88, 11.25]; day 3–7: 8.37 g/day [95% CI: 1.60, 15.13]). Through age two, infants in the DM-group maintained higher average weight (adjusted difference 185.7 g [95% CI: 37.2, 334.3]) and weight z-score (adjusted difference 0.32 SDS [95% CI: 0.09, 0.55]) than unexposed infants, with greater weight gain between 18 and 24 months (adjusted difference 28.5 g/week [95% CI: 2.6, 54.4]). Conclusions Maternal diabetes exposed late preterm infants had higher weight from birth to age two and greater weight gain in the first postnatal week than unexposed infants. Long term risk associated with weight trajectories in this population requires further study.

Anticholinergic and Sedative Medications Are Associated With Neurocognitive Performance of Well Treated People With Human Immunodeficiency Virus.

BackgroundWe previously showed that anticholinergic (ACH) medications contribute to self-reported neurocognitive impairment (NCI) in elderly people with human immunodeficiency virus (PWH). The current cross-sectional study further evaluated the effect of ACH and sedative drugs on neurocognitive function in PWH who underwent comprehensive neuropsychological evaluation.MethodsA medication review was performed in PWH enrolled in the prospective Neurocognitive Assessment in Metabolic and Aging Cohort within the Swiss HIV Cohort Study. Neurocognitive functions were analyzed in 5 domains (motor skills, speed of information, attention/working memory, executive functions, and verbal learning memory). The effect of ACH and sedative medications on neurocognitive functioning was evaluated using linear regression models for the continuous (mean z-score) outcome and multivariable logistic regression models for the binary (presence/absence) outcome.ResultsA total of 963 PWH (80% male, 92% Caucasian, 96% virologically suppressed, median age 52) were included. Fourteen percent of participants were prescribed ≥1 ACH medication and 9% were prescribed ≥1 sedative medication. Overall, 40% of participants had NCI. Sedative medication use was associated with impaired attention/verbal learning and ACH medication use with motor skills deficits both in the continuous (mean z-score difference −0.26 to −0.14, P < .001 and P = .06) and binary (odds ratio [OR], ≥1.67; P < .05) models. Their combined use was associated with deficits in overall neurocognitive functions in both models (mean z-score difference −0.12, P = .002 and OR = 1.54, P = .03). These associations were unchanged in a subgroup analysis of participants without depression (n = 824).ConclusionsAnticholinergic and sedative medications contribute to NCI. Clinicians need to consider these drugs when assessing NCI in PWH.

Early life organophosphate ester exposures and bone health at age 12 years: The Health Outcomes and Measures of the Environment (HOME) Study

BackgroundNo human studies have evaluated early life organophosphate ester (OPE) exposures with bone health outcomes, despite evidence of osteotoxicity. ObjectivesWe assessed associations of urinary OPE metabolites measured across early life with areal bone mineral density (aBMD) and bone mineral content (BMC) at age 12 years. MethodsAmong 223 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment (HOME) Study, we quantified concentrations of bis-2-chloroethyl phosphate (BCEP), bis-(1,3-dichloro-2-propyl) (BDCIPP), di-n-butyl phosphate (DnBP), and diphenyl phosphate (DPHP) in urine collected from mothers during pregnancy and children at ages 1, 2, 3, 5, and 8 years. At age 12 years, we performed dual energy x-ray absorptiometry and calculated aBMD and BMC z-scores at six skeletal sites. We estimated overall and sex-stratified BMD/BMC z-score differences per interquartile range (IQR) increase in OPE concentrations at multiple exposure timepoints: gestation (average) and 1–3 (average), 5, and 8 years. ResultsIn adjusted models, overall associations of BCEP and BDCIPP with total hip and 1/3rd distal radius aBMD and BMC varied significantly by exposure timepoint, as did BDCIPP with whole body aBMD. For example, differences (95 % CI) in total hip aBMD z-score per IQR increase in BDCIPP were 0.33 (0.01, 0.64), −0.10 (−0.34, 0.14), −0.18 (−0.40, 0.05), and 0.14 (−0.09, 0.38) for concentrations during gestation and at 1–3, 5, and 8 years, respectively. Overall DnBP and DPHP associations were generally null at all timepoints. We observed sex-specific associations for some timepoints and skeletal sites. For example, an IQR increase in 8-year DPHP was associated with a 0.21 (0.05, 0.38) greater total hip aBMD z-score among females but −0.19 (−0.43, 0.05) lower z-score among males. DiscussionEarly life OPE exposures may be associated with sex- and exposure period-dependent alterations in early adolescent bone mineral accrual and strength.

An improved algorithm to harmonize child overweight and obesity prevalence rates.

Prevalence rates of child overweight and obesity for a group of children vary depending on the BMI reference and cut-off used. Previously we developed an algorithm to convert prevalence rates based on one reference to those based on another. To improve the algorithm by combining information on overweight and obesity prevalence. The original algorithm assumed that prevalence according to two different cut-offs A and B differed by a constant amount on the z-score scale. However the results showed that the z-score difference tended to be greater in the upper tail of the distribution and was better represented by , where was a constant that varied by group. The improved algorithm uses paired prevalence rates of overweight and obesity to estimate for each group. Prevalence based on cut-off A is then transformed to a z-score, adjusted up or down according to and back-transformed, and this predicts prevalence based on cut-off B. The algorithm's performance was tested on 228 groups of children aged 6-17 years from 20 countries. The revised algorithm performed much better than the original. The standard deviation (SD) of residuals, the difference between observed and predicted prevalence, was 0.8% (n=2320 comparisons), while the SD of the difference between pairs of the original prevalence rates was 4.3%, meaning that the algorithm explained 96.7% of the baseline variance (88.2% with original algorithm). The improved algorithm appears to be effective at harmonizing prevalence rates of child overweight and obesity based on different references.

Shorter telomere length is associated with COVID-19 hospitalization and with persistence of radiographic lung abnormalities

BackgroundAge and comorbidity are the main determinants of COVID-19 outcome. Shorter leukocyte telomere length (TL), a hallmark of biological aging, has been associated with worse COVID-19 outcomes. We sought to determine TL in patients with severe COVID-19 requiring hospitalization to analyze whether clinical outcomes and post-COVID-19 manifestations are associated with shorter TL.ResultsWe analyzed 251 patients with PCR-confirmed COVID-19, hospitalized in the first months of the pandemics. We determined TL in PBL at admission by quantitative-PCR (qPCR) analysis in patients. A healthy cohort from the same area with a similar age range (n = 169) was used to calculate TL Z-scores. After hospital discharge, 144 COVID-19 survivors were followed-up for persistent COVID-19 manifestations. A second TL determination was performed in a smaller group of 63 patients 1 year later and compared with baseline TL.Hospitalized COVID-19 patients had a decreased baseline age-adjusted TL Z-score compared to the reference group. No differences in Z-scores were observed in patients with different COVID-19 outcomes, classified as WHO ordinal scores. In 144 patients, followed for a median of 8 months, post-COVID manifestations were not associated to differences in TL. Persistence of lung radiographic abnormalities was associated with shorter baseline TL. In patients with a second TL determination, further telomere shortening (TS) was observed in 35% and telomere lengthening in 49%. Patients with further TS had suffered a more severe disease.ConclusionShorter TL is associated with COVID-19 hospitalization but not with hospital clinical outcomes nor with persistent post-COVID-19 manifestations. Delayed resolution of radiographic lung abnormalities was also associated with shorter TL.

Pulmonary Parameters in Adolescents with Severe Thoracic Idiopathic Scoliosis: Comparison Girls versus Boys.

The study compared pulmonary parameters, registered at the preoperative examination, in adolescent boys versus girls, both with severe thoracic idiopathic scoliosis. Thirty consecutive boys and 30 consecutive girls with Lenke 1 or 3 type, in the age range 14–18 years, with a Cobb angle of >50° and Risser sign ≥ 3 were enrolled. Corrected body height was used to calculate pulmonary parameters according to the Global Lung Function (GLI 2012) reference values. Significantly higher values of the calculated predicted pulmonary parameters and the upper and lower limit of normal (ULN and LLN), as well as significantly higher absolute values of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), were observed in boys than girls; however, the registered FVC and FEV1, expressed as percentages of the predicted values, tended to be lower in boys. The FEV1 z-score difference between boys and girls may suggest a need for more intensive preoperative pulmonary rehabilitation in boys.

Effects of caffeine, methylliberine, and theacrine on vigilance, marksmanship, and hemodynamic responses in tactical personnel: a double-blind, randomized, placebo-controlled trial

ABSTRACTBackgroundTactical athletes require fast reaction times (RT) along with high levels of vigilance and marksmanship performance. Caffeine has been shown to improve these measures but also results in increased blood pressure and jitteriness. Research on other purine alkaloids, such as methylliberine and theacrine, has suggested they do not increase blood pressure or jitteriness to the same extent, but their impact on tactical performance is unknown.MethodsA between-subjects, randomized, placebo-controlled design was used to test the effects of placebo (PLA), 300 mg caffeine (CAF), and a combination of 150 mg caffeine, 100 mg methylliberine, and 50 mg theacrine (CMT) on RT and marksmanship along with hemodynamic and arousal measures following a sustained vigilance task in tactical personnel (n = 48). Following consumption of the supplement, participants underwent a 150-min protocol consisting of two rounds. Each round began with leisurely reading followed by a 30-min vigilance task before beginning two trials of movement and marksmanship tasks. Hemodynamics and felt arousal were assessed throughout the protocol. Composite Z-scores were calculated for overall performance measures at each timepoint, and mixed-effects models were used to assess differences in RT, accuracy, and composite Z-scores along with hemodynamics and felt arousal. An α-level of 0.05 was used to determine statistical significance, and Cohen’s d was used to quantify effect sizes.ResultsA Group-by-Time interaction for vigilance RT (P = 0.038) indicated improvements for both CAF and CMT from round 1 to round 2 (P < 0.01) while PLA did not change (P = 0.27). No Group main effects or Group-by-Time interactions were found for movement or marksmanship performance (P > 0.20). Group main effects for systolic (SBP; P = 0.001) and diastolic blood pressure (DBP; P = 0.028) indicated higher SBP in CAF (P = 0.003, d= 0.84) and CMT (P = 0.007, d= 0.79) compared to PLA but only higher DBP in CAF (P = 0.025, d= 0.74). No Group-by-Time interaction or Group main effect was found for felt arousal (P > 0.16).ConclusionsThese findings suggest similar benefits on RT during a vigilance task between CAF, containing 300 mg caffeine, and CMT above PLA, though CAF resulted in slightly less favorable hemodynamic changes. This study is the first to provide data showing similar efficacy of combined caffeine, methylliberine, and theacrine compared to double the caffeine dose consumed alone on vigilance RT but without a significant rise in DBP above PLA in tactical personnel.

Building community capacity to stimulate physical activity and dietary behavior in Dutch secondary schools: Evaluation of the FLASH intervention using the REAIM framework.

BackgroundBuilding community capacity in secondary schools is a promising strategy for the sustainable implementation of school-based health promotion. The Fit Lifestyle at School and at Home (FLASH) intervention explored how building community capacity works for the prevention of overweight following four strategies: leadership, participatory school culture, tailored health-promotion activities, and local networks. This study evaluates the intervention's impact on community capacity and capacity-building processes over a period of 3 years, as well as its effects on adolescents' BMI and waist circumference.MethodsA mixed-methods design guided by the RE-AIM framework was used. Impact on community capacity was evaluated with semi-structured interviews at the start and end of the intervention and analyzed using an anchored coding scale. Capacity-building processes were evaluated using interviews, journals, questionnaires, and the minutes of meetings. The effects on BMI z-scores and waist circumference were evaluated using a quasi-experimental design comparing an intervention (IG) and reference group (RG), based on multi-level analyses.ResultsCommunity capacity improved across all intervention schools but varied between capacity-building strategies. Leadership recorded the greatest improvements, aided by the appointment of Healthy School Coordinators, who increasingly focused on coordinating processes and fostering collaborations. Participatory school culture also improved through the adoption and implementation of participatory methods and a general increase in awareness concerning the importance of the Healthy School approach. Although additional health-promotion activities were implemented, stakeholders struggled with tailoring these to the specific dynamics of their schools. Limited improvements were observed in setting-up local networks that could help schools encourage healthy behavior among pupils. Differences in BMI z-scores between IG and RG over the total sample were negligible whereas waist circumference increased slightly more in IG (0.99 cm, 95% CI [.04; 1.93]). However, differences were inconsistent over time and between cohorts.ConclusionsThis study highlights the potential of building community capacity. It emphasizes that this is a process in which stakeholders must become acquainted with new leadership roles and responsibilities. To navigate this process, schools need support in improving communication, establishing local networks, and sustaining capacity-building efforts in school policy.Trial registrationISRCTN67201841; date registered: 09/05/2019, retrospectively registered.

Avaliação do desenvolvimento motor e do efeito da intervenção fisioterapêutica em recém-nascidos cirúrgicos em Unidade de Terapia Intensiva Neonatal

ABSTRACT This study aimed to verify the applicability of the Test of Infant Motor Performance (TIMP) in surgical neonates as a tool for evaluating motor performance and to evaluate the benefit of physical therapy. Surgical neonates, divided into group without physical therapy (n=38) and group with motor physical therapy (n=38), were evaluated by TIMP and reasssment two weeks later. The physical therapy group performed standardized exercises for motor sensory stimulation once a day, whereas the other group received the usual care from the Neonatal Intensive Care Unit. The predominant surgical diagnosis in both groups was gastroschisis, followed by congenital diaphragmatic hernia. In the initial evaluation, motor performance was equal between the groups, classified as “below average” for age, with z-score=−1.28 (p=0.992). In the reassessment, the physical therapy group presented better scores (p&lt;0.001) and a higher difference in z-score (p&lt;0.001), higher percentage of neonates classified as “within average” (44% in the physical therapy group and 2.6% in the no physical therapy group), as well as a higher weight gain percentage (p=0.038). We found a worsening of motor performance in 10.5% of the no physical therapy group (p&lt;0.001) in the reassment. Motor performance improved in 81.6% of the physical therapy group and in only 13.2% of the no physical therapy group individuals (p&lt;0.001). Conclusion: TIMP was safely and effectively applied to newborns; notably, the test must be performed by professionals experienced in care of neonates. Motor intervention was beneficial, significantly improving motor performance, and if applied early, it may adequate the motor development of these neonates, even before hospital discharge.

Effect of neurodevelopmental treatment in children with congenital Zika syndrome: A pilot study.

To evaluate the effects of neurodevelopmental treatment (NDT) in children with congenital Zika syndrome (CZS). This prospective, interventional cohort study involved children with CZS undergoing follow-up at a specialist centre in northeastern Brazil. The duration of the proposed NDT protocol was 1 year, with 45-min sessions delivered one to five times weekly. Motor function, weight, height, head circumference and the incidence of comorbidities were evaluated in children before protocol initiation and then at 3, 6 and 12 months of treatment. Thirty children were evaluated (age mean 30.1 ± 3months). Motor function improved from baseline to 6 months (P=0.001).No difference in weight and head circumference z-score (P=0.51 and P=0.29, respectively), but an increase in height z-score (P < 0.001) was observed over the evaluation period. There was a reduction in the incidence of upper respiratory tract infections, pneumonia and urinary tract infections over the follow-up period. NDT proved to be a viable treatment approach that can improve motor function and reduce the incidence of comorbidities in children with CZS, while having no harmful effects on their growth.

The Physical Behaviour Intensity Spectrum and Body Mass Index in School-Aged Youth: A Compositional Analysis of Pooled Individual Participant Data.

We examined the compositional associations between the intensity spectrum derived from incremental acceleration intensity bands and the body mass index (BMI) z-score in youth, and investigated the estimated differences in BMI z-score following time reallocations between intensity bands. School-aged youth from 63 schools wore wrist accelerometers, and data of 1453 participants (57.5% girls) were analysed. Nine acceleration intensity bands (range: 0–50 mg to ≥700 mg) were used to generate time-use compositions. Multivariate regression assessed the associations between intensity band compositions and BMI z-scores. Compositional isotemporal substitution estimated the differences in BMI z-score following time reallocations between intensity bands. The ≥700 mg intensity bandwas strongly and inversely associated with BMI z-score (p < 0.001). The estimated differences in BMI z-score when 5 min were reallocated to and from the ≥700 mg band and reallocated equally among the remaining bands were −0.28 and 0.44, respectively (boys), and −0.39 and 1.06, respectively (girls). The time in the ≥700 mg intensity band was significantly associated with BMI z-score, irrespective of sex. When even modest durations of time in this band were reallocated, the asymmetrical estimated differences in BMI z-score were clinically meaningful. The findings highlight the utility of the full physical activity intensity spectrum over a priori-determined absolute intensity cut-point approaches.

Local Patterns in 2-Year T1ρ and T2 Changes of Hip Cartilage Are Related to Sex and Functional Data: A Prospective Evaluation on Hip Osteoarthritis Participants.

Although T1ρ and T2 have emerged as early indicators for hip osteoarthritis (OA), there is little information regarding longitudinal changes across the cartilage in the early stages of this disease. To characterize the variability in 2-year hip cartilage T1ρ and T2 changes and investigate associations between these patterns of change and common indicators of hip OA. Prospective. A total of 25 women (age: 51.9 ± 16.3 years old; BMI: 22.6 ± 2.0 kg/m2 ) and 17 men (age: 55.8 ± 14.9 years old; body mass index (BMI): 24.4 ± 3.8kg/m2 ) who were healthy or with early-to-moderate hip OA. A 3 T MRI (GE), 3D combined T1ρ /T2 magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots. Principal component (PC) analysis of Z-score difference maps of 2-year changes in hip cartilage T1ρ and T2 relaxation times, participant hip disability and osteoarthritis outcome scores (HOOS) and functional tests at 2-year follow-up. Shapiro-Wilk test, unpaired t-tests, Kruskal Wallis tests, Pearson or Spearman (ρ) correlations. Significance was set at P < 0.05. Women (-6.40 ± 14.48) had significantly lower T1ρ PC1 scores than men (10.05 ± 26.15). T1ρ PC4 was significantly correlated with HOOSsport , HOOSsymptoms , HOOSpain , HOOSadl , and HOOSqol at 2-year follow-up (ρ: [0.36, 0.50]). T1ρ PC2 and PC4 were significantly correlated with 30-second chair test (ρ=-0.39 and ρ=0.24, respectively) and side plank (ρ=-0.32 and ρ=0.21). T1ρ and T2 PC2 were significantly correlated with 40 m walk test (ρ=0.34 and ρ=0.31) and 30-second chair rise test (ρ=-0.39 and ρ=-0.32). Men exhibited accelerated T1ρ increases across the femoral cartilage compared to women, suggesting sex should be considered when evaluating early hip OA. Participants with poorer HOOS and function exhibited greater T1ρ and T2 increases in superior and anterior femoral cartilage and greater T1ρ increases in the anterior femoral cartilage. These patterns of short-term relaxometry increases could indicate hip OA progression. 2 TECHNICAL EFFICACY: Stage 3.

Identification of a novel splicing mutation and genotype–phenotype correlations in rare PLS3-related childhood-onset osteoporosis

BackgroundX-linked early-onset osteoporosis, caused by mutations in plastin3 (PLS3), is an extremely rare disease characterized by low bone mineral density (BMD) and recurrent osteoporotic fractures. There is limited information on genetic and phenotypic spectrum, as well as genotype–phenotype correlations of the disease. Moreover, whether decreased PLS3 levels were also involved in osteoporosis among subjects without PLS3 pathogenic mutations remains unknown.MethodsWhole-exome sequencing and bidirectional Sanger sequencing were performed for screening and validation of pathogenic mutations. Serum biochemical parameters and clinical information of the subjects were retrospectively collected. ELISA and online datasets were utilized to investigate the association between PLS3 expression and BMD.ResultsWe identified a novel splicing mutation (c.892-2A > G) which led to the skipping of exon 9 in a family with X-linked early-onset osteoporosis. Scoliosis represents a potential new phenotype in the patients harboring PLS3 mutations, which may be corrected by brace treatment. Genotype–phenotype analysis reveals that there was no significant difference in BMD z-scores between different types of reported mutations including this study (p = 0.5). There is a marginally significant negative correlation between age and BMD z-score (p = 0.059, r = − 0.30). The conditions of osteoporosis in all patients were improved after bisphosphonates therapy, with mean BMD z-score increased from − 2.9 to − 0.57 (p < 0.0001). Serum PLS3 levels in adolescents and adults without PLS3 pathogenic mutations but representing osteoporosis were also evaluated, while no association was found between bone mineral density and PLS3 levels (p > 0.05).ConclusionsOur findings expanded the mutation and phenotype spectrum of the rare disease and highlights the importance of early diagnosis and early treatment with bisphosphonates. More reports of cases with PLS3 mutation and function studies of the gene are warranted to understand genotype–phenotype correlations.

Mortality after 36 weeks postmenstrual age of extremely preterm infants in neonatal care: The impact of growth impairment and bronchopulmonary dysplasia

BackgroundA small group of extremely preterm infants survive to 36 weeks postmenstrual age (PMA), but die before discharge from neonatal care. AimsTo investigate which epidemiological and clinical parameters were related to death after 36 weeks PMA in extremely preterm infants. Study designRetrospective whole-population study. SubjectsAll infants born <28 weeks of gestation admitted to a neonatal unit in England between 2014 and 2018. Outcome measuresMortality after 36 weeks PMA and before discharge from neonatal care. Bronchopulmonary dysplasia (BPD) defined as any respiratory support at 36 weeks PMA. ResultsDeath after 36 weeks PMA occurred in 156 of a total of 11.747 included infants (1.3 %) and at a median (IQR) age of 130 (93–164) days. A lower gestational age [Odds Ratio: 0.82, 95 % CI:0.72–0.94, adjusted p = 0.005], lower birth weight z-score [Odds Ratio: 0.45, 95 % CI:0.36–0.56, adjusted p < 0.001], greater absolute difference in weight z-score from birth to 36 weeks PMA [Odds Ratio: 0.46, 95 % CI:0.38–0.56, adjusted p < 0.001] were independently associated with death after 36 weeks PMA. A diagnosis of BPD [Odds Ratio: 4.57, 95 % CI:2.19–9.54, adjusted p < 0.001] and of necrotising enterocolitis requiring surgery [Odds Ratio: 2.81, 95 % CI:1.82–4.34, adjusted p < 0.001] were also independently associated with death after 36 weeks PMA. ConclusionsMortality of extremely preterm infants after 36 weeks postmenstrual age is associated with lower gestational age and more impaired growth. The diagnoses of bronchopulmonary dysplasia and necrotising enterocolitis were associated with a higher risk of death after 36 weeks postmenstrual age and before discharge from neonatal care.

DHA status influences effects of B-vitamin supplementation on cognitive ageing: a post-hoc analysis of the B-proof trial

PurposeTrials aiming to lower homocysteine by B-vitamin supplementation have reported mixed results on slowing cognitive decline. We investigated if efficacy of B-vitamin supplementation is affected by baseline plasma omega-3 fatty acid levels.MethodsThis post-hoc analysis of the B-proof trial included 191 adults aged 65 years or older with baseline plasma total homocysteine ≥ 12 μmol/L, randomly assigned to 400 µg folic acid and 500 µg vitamin B12 or placebo daily for 2 years. Global and domain-specific cognitive functioning were assessed at baseline and after 2 years. The effect of B-vitamin supplementation was analyzed according to tertiles of baseline plasma omega-3 fatty acids concentrations combined, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) individually using multiple linear regression analyses.ResultsThe mean ± SD age of the participants was 71.6 ± 5.9 years and median [IQR] Mini-Mental State Examination was 29 [28–30]. The treatment effect of B-vitamins on global cognition was larger in participants in the high compared to the middle DHA tertile (difference in z-score, mean ± SE 0.22 ± 0.10, p = 0.03). There was no significant interaction between B-vitamin supplementation and combined omega-3 fatty acid (p = 0.49) and EPA (p = 0.99) tertiles. Similarly, the efficacy of B-vitamin treatment on domain-specific cognitive functioning did not link to omega-3 fatty acid, DHA, or EPA plasma levels.ConclusionThis post-hoc analysis indicated that efficacy of B-vitamin supplementation in slowing cognitive decline relates to DHA status, with individuals with higher plasma DHA levels benefitting more from vitamin B12 and folic acid use. The results support earlier observations that positive effects of B-vitamins in cognitive ageing may be subgroup-specific.Trial registration: Registered at clinicaltrials.gov (NCT00696514) on June 12, 2008.

Landscape of endocytosis pathway in colorectal cancer (CRC).

3148 Background: Recent proteogenomic analyses of CRC revealed that driver gene alterations are enriched in the endocytosis pathway (Vasaikar S, et al. Cell 2019;177:1035-49). Endocytosis is a cellular system involving post-translational modification of plasma membrane proteins through internalization, intracellular trafficking, degradation, and recycling. Clathrin-mediated endocytosis (CME) is the main endocytic portal, and endosomal sorting complexes required for transport (ESCRT) play a critical role in the lysosomal degradation pathway. Besides the well-known function of endocytosis attenuating signaling pathways through receptor clearance from the cell surface, the opposite function contributing to signal maintenance has also been reported. However, the clinical implications of the endocytosis pathway alterations in CRC are largely unclear. Methods: We retrospectively reviewed CRC patient samples (n = 15025) submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix AZ). Next-generation sequencing of DNA and RNA (whole-transcriptome sequencing) and immunohistochemistry (IHC) were performed. CME-related (47 genes) and ESCRT-related (35 genes) expression signatures were calculated as composite z-scores and compared between subgroups stratified by RAS/ BRAF mutation status, MSS/MSI status, tumor sidedness, and consensus molecular subtype (CMS). VPS4A/ VPS4B expression correlation with major oncogenic pathway signatures (composite z-scores) and CMTM6/ CMTM4/ HIP1R expression association with PD-L1+ IHC were also assessed. Results: Among 17 endocytosis-related genes, no pathogenic/likely pathogenic mutations were identified. The CME-related signature was increased in RAS/ BRAF wild type vs. mutant (0.93 z-score difference, p= 0.04) and MSS vs. MSI-high (6.0 z-score difference, p&lt; 0.01), while the ESCRT-related signature was higher in MSS compared to MSI-high (2.7 z-score difference; p&lt; 0.01). No differences between tumor sidedness were observed in both CME- and ESCRT-related signatures (0.81 and 1.17 z-score differences, respectively). CMS4 had the highest expression of both signatures, while CMS3 had the lowest, of both CME- and ESCRT-related genes (each &gt; 20 z-score difference, p&lt; 0.01). VPS4A and VPS4B expression had a strong positive correlation with WNT, EGFR/MAPK, TGF-beta, and Notch pathway signatures (0.65-0.83 Spearman, all p&lt; 0.01). CMTM6 expression was positively associated with PD-L1+ IHC (1.2-fold increase vs PD-L1-negative, p&lt; 0.01), while CMTM4 and HIP1R expression showed a negative association (0.7- and 0.9-fold decrease, respectively, p&lt; 0.01). Conclusions: This large study indicates endocytosis pathway expression is positively associated with oncogenic pathway signaling in CRC. Further analysis of RAS/ BRAF wild type, MSS, and CMS4 patient subgroups are warranted to determine the efficacy of targeting endocytosis pathways in CRC.

Associations of physical condition with lung function and asthma in adolescents from the general population.

BackgroundThe relation of physical condition with respiratory outcomes in adolescents is unclear. We examined the hypothesis that adolescents with a lower physical condition represented by a lower cardiorespiratory fitness and physical activity, and a higher screen time have a lower lung function and higher risk of asthma.MethodsIn a population‐based prospective cohort study on 4854 children aged 13 years, we assessed cardiorespiratory fitness by using the peak work rate measured by the steep ramp test. Information on physical activity and screen time was obtained by self‐reported questionnaires. Lung function was measured by spirometry and current asthma was assessed by a parental‐reported questionnaire.ResultsTaking sociodemographic, lifestyle, and growth‐related confounders and multiple hypothesis testing into account, a 1 SD lower cardiorespiratory fitness was associated with a lower FEV1, FVC, and FEF75 (Z‐score difference (95% CI): −0.31 (−0.35, −0.28), −0.30 (−0.33, −0.26), −0.13 (−0.17, −0.10), respectively), and a higher risk of asthma (Odds Ratio (95% CI) 1.25 (1.06, 1.46)). A 1 SD higher screen time was associated with a lower FVC (Z‐score difference (95% CI): −0.06 (−0.10, −0.03)). Physical activity and screen time were not related to asthma. Results did not materially change after additional adjustment for respiratory outcomes at an earlier age.ConclusionAdolescents with a lower cardiorespiratory fitness had a lower lung function and a higher risk of asthma. Those with a higher screen time had a lower FVC. Further studies are needed to explore the effect of improvements in physical condition on long‐term respiratory outcomes.

248-OR: MiTy Kids: Follow-Up of Offspring Exposed to Metformin In-Utero in Mothers with Type 2 Diabetes in the MiTy Trial

Background: Offspring of mothers with T2D are at increased risk of obesity and diabetes. In the MiTy trial [pregnant T2D randomized to metformin vs. placebo], infants exposed to metformin were lighter, had lower fat-mass and risk of large-for-gestational-age, but at higher risk of small-for-gestational-age. There are questions on the long-term effects of in-utero exposure to metformin on offspring of women with T2D. Aim: To examine adiposity in children of women with T2D, with and without exposure to metformin, up to 24 months. Methods: We included infants of women who participated in MiTy. Anthropometric measurements were made at 3, 6, 12, 18 and 24 months of age. At 24 months, t-tests and linear regression were used to estimate differences in BMI z-score and sum of skinfolds by metformin group, adjusted for confounders. Comparisons over time used longitudinal models, with fractional polynomials for growth trajectories. Results: Of the 465 eligible children from MiTy, 283 (60.8%) participated in MiTy Kids. At 24 months, there was no difference in BMI z-score (0·84±1·52 in metformin vs. 0·91±1·38 in placebo (p=0.72)) or sum of skinfolds (23·0±5·2 in metformin vs. 23·8±5·3 in placebo (p=0.31)) between groups. There was no difference in BMI trajectory by treatment overall but in males, treatment had significantly different trajectories (p=0.048) ; the metformin BMI was higher from 8 to 24 months. At 24 months, reduced sleep time (p=0.0125) and increased screen time (p=0.0549) were associated with increased BMI z-score. Offspring of women with T2D were approximately 1 SD heavier than the WHO reference population. Conclusion: Offspring of women with T2D with and without exposure to metformin in-utero had similar anthropometrics overall. In males, metformin led to higher BMI growth trajectory between 8 and 24 months. Future follow-up is needed to see if these findings continue. Disclosure D.Feig: Advisory Panel; Novo Nordisk, Research Support; Apotex. A.Armson: None. J.F.R.Barrett: None. L.E.Donovan: Other Relationship; Dexcom, Inc., Inner Analytics, Medtronic, Tandem Diabetes Care, Inc. P.Karanicolas: Research Support; Baxter. G.Klein: None. S.Tobin: None. K.Mangoff: None. G.Tomlinson: None. J.Hamilton: Advisory Panel; Novo Nordisk Canada Inc., Research Support; Mead Johnson &amp; Company, LLC. J.Sanchez: None. K.Murphy: None. E.Asztalos: None. B.Zinman: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk Canada Inc., Sanofi K.K. D.Simmons: Other Relationship; Elsevier, Research Support; Abbott, Hitachi, Ltd., Novo Nordisk, Speaker's Bureau; Sanofi. A.Haqq: None. I.G.Fantus: None. L.Lipscombe: n/a. Funding Canadian Health Institute for Research

Sex-Specific Pathways Lead to Statural Growth Impairment in Children with Crohn's Disease

To examine the underlying mechanisms that lead growth impairment to occur more commonly in males than females with Crohn's disease (CD). Children and adolescents with CD were enrolled in a prospective multicenter longitudinal cohort study. Height Z-score difference was computed as height Z-score based on chronological age (height chronological age-Z-score) minus height Z-score based on bone age (height bone age-Z-score) using longitudinal data. Specific serum cytokines were measured, hormone Z-scores were calculated based on bone age (bone age-Z), and their longitudinal associations were examined. There were 122 children with CD (63% male) who completed 594 visits. The mean±SD chronological age was 11.70±1.79years. The mean±SD height chronological age-Z-score was -0.03±0.99 in males and -0.49±0.87 in females. The mean±SD height bone age-Z-score was 0.23±0.93 in males and 0.37±0.96 in females. The magnitude of the mean height Z-score difference was greater in females (-0.87±0.94) than males (-0.27±0.90; P=.005), indicating growth was better in females than males. The following negative associations were identified: in females, interleukin (IL)-8 (P<.001) and IL-12p70 (P=.035) with gonadotropin-bone age-Z-scores; IL-8 (P=.010), IL-12p70 (P=.020), and interferon-γ (P=.004) with sex hormone-bone age-Z-scores, and IL-8 (P=.044) and interferon-γ (P<.001) with insulin-like growth factor 1-bone age-Z-scores; in males, IL-1 beta (P=.019) and IL-6 (P=.025) with insulin-like growth factor 1-bone age-Z-scores. Our data suggest that sex-specific molecular pathways lead to growth impairment in children with CD (primarily growth hormone/insulin-like growth factor-1 axis in males and primarily hypothalamic-pituitary-gonadal axis in females). Mapping these sex-specific molecular pathways may help in the development of sex-specific treatment approaches targeting the underlying inflammation characteristic of CD.