Integration of an interpretable machine learning algorithm to identify early life risk factors of childhood obesity among preterm infants: a prospective birth cohort.

BACKGROUND: The early life risk factors of childhood obesity among preterm infants are unclear and little is known about the influence of the feeding practices. We aimed to identify early life risk factors for childhood overweight/obesity among preterm infants and to determine feeding practices that could modify the identified risk factors. METHODS: A total of 338,413 mother-child pairs were enrolled in the Jiaxing Birth Cohort (1999 to 2013), and 2125 eligible singleton preterm born children were included for analyses. We obtained data on health examination, anthropometric measurement, lifestyle, and dietary habits of each participant at their visits to clinics. An interpretable machine learning-based analytic framework was used to identify early life predictors for childhood overweight/obesity, and Poisson regression was used to examine the associations between feeding practices and the identified leading predictor. RESULTS: Of the eligible 2125 preterm infants (863 [40.6%] girls), 274 (12.9%) developed overweight/obesity at age 4-7 years. We summarized early life variables into 25 features and identified two most important features as predictors for childhood overweight/obesity: trajectory of infant BMI (body mass index) Z-score change during the first year of corrected age and maternal BMI at enrollment. According to the impacts of different BMI Z-score trajectories on the outcome, we classified this feature into the favored and unfavored trajectories. Compared with early introduction of solid foods (≤ 3 months of corrected age), introducing solid foods after 6 months of corrected age was significantly associated with 11% lower risk (risk ratio, 0.89; 95% CI, 0.82 to 0.97) of being in the unfavored trajectory. CONCLUSIONS: The trajectory of BMI Z-score change within the first year of life is the most important predictor for childhood overweight/obesity among preterm infants. Introducing solid foods after 6 months of corrected age is a recommended feeding practice for mitigating the risk of being in the unfavored trajectory.

Pre-conceptional intake of folic acid supplements is inversely associated with risk of preterm birth and small-for-gestational-age birth: a prospective cohort study.

Associations of folic acid supplementation with risk of preterm birth (PTB) and small-for-gestational-age (SGA) birth were unclear for the Chinese populations. The aim of the present study was to investigate the associations in a large Chinese prospective cohort study: the Jiaxing Birth Cohort. In the Jiaxing Birth Cohort, 240 954 pregnant women visited local clinics or hospitals within their first trimester in Southeast China during 1999-2012. Information on anthropometric parameters, folic acid supplementation and other maternal characteristics were collected by in-person interviews during their first visit. Pregnancy outcomes were recorded during the follow-up of these participants. Multinomial logistic regression was used to examine the association of folic acid supplementation with pregnancy outcomes. The prevalence of folic acid supplementation was 24·9% in the cohort. The prevalence of PTB and SGA birth was 3·48 and 9·2%, respectively. Pre-conceptional folic acid supplementation was associated with 8% lower risk of PTB (relative risk (RR) 0·92; 95% CI 0·85, 1·00; P=0·04) and 19% lower risk of SGA birth (RR 0·81; 95% CI 0·70, 0·95; P=0·008), compared with non-users. Higher frequency of pre-conceptional folic acid use was associated with lower risk of PTB (P trend=0·032) and SGA birth (P trend=0·046). No significant association between post-conceptional initiation of folic acid supplementation and either outcome was observed. In conclusion, the present study suggests an association between pre-conceptional, but not post-conceptional, folic acid supplementation and lower risk of PTB and SGA birth in the Jiaxing Birth Cohort. Further research in other cohorts of large sample size is needed to replicate these findings.

[Decreased insulin sensitivity in rat hepatocytes with intrauterine growth retardation and establishment of insulin resistance cell model in vitro].

OBJECTIVE: To explore the hepatocyte insulin sensitivity of intrauterine growth retardation (IUGR) rats and establish an insulin resistance cell model in vitro. METHODS: An IUGR animal model was established by protein malnutrition during the mother pregnancy. On 60 d and 90 d after birth, the offspring rats were fasted for 12 hours and then their angular vein blood was collected to measure the fasting plasma glucose and fasting serum insulin level, then the insulin resistance index (HOMA-IR) and insulin sensitivity index (ISI) were calculated. The insulin sensitivity was evaluated by HOMA-IR and ISI. Primary hepatocytes from each group were respectively isolated by two-step perfusion with collagenase and were defined as normal hepatocytes group and IUGR hepatocytes group. The normal hepatocyte group was divided into two groups: control group and insulin induction group. Insulin induction group was established by primary cultures of normal hepatocyte incubated with varying dilutions of insulin. CCK-8 was used to detect the viability of the cultured hepatocytes. Glucose oxidase-peroxidase method kit was used to measure glucose consumption of the hepatocytes. RESULTS: HOMA-IR was significantly higher in IUGR rats than in the normal rats at the age of 60 days (t=-17.02, P<0.05) and 90 days (t=-12.52, P<0.05). ISI was significantly lower than in the normal rats aged 60 days (t=5.61, P<0.05) and 90 days (t=12.42, P<0.05). There were no significant differences in hepatocyte viability among the control group, IUGR group and insulin induction group after incubation of 48 h on day 60 (F=1.34, P=0.29) and day 90 (F=0.22, P=0.81). The glucose consumption of the IUGR group and insulin induction group were significantly decreased compared with the control group on day 60 (F=9.28, P=0.002) and day 90 (F=56.60, P<0.001), while there was no significant difference between the IUGR group and insulin induction group (P=0.08, P=0.10). CONCLUSION: The insulin sensitivity of hepatocytes of IUGR rats decreased from adolescence to adulthood. High-dilution insulin may induce insulin resistance cell model in vitro.

Early supplementation of folate and vitamin B12 improves insulin resistance in intrauterine growth retardation rats.

Background: Insulin sensitivity is changed during the neonatal period in small for gestational age (SGA) infants. Yet, the interventional strategies are still limited. We aimed to investigate the effects of supplementation with high folate and vitamin B12 diets in the early postnatal period on the changes in insulin sensitivity in an intrauterine growth retardation (IUGR) rat model. Methods: IUGR rat model was established by both low-protein diet feeding and daily diet restriction. High folate and vitamin B12 diet was supplied in IUGR as nutritional interventional group (IUGR-I), otherwise, the non-intervened IUGR group (IUGR-NI). In this study, male rats were studied in order to avoid hormonal and gender influence. At 21, 60 and 120 days, fasting plasma glucose, insulin, triglyceride, cholesterol, and homocysteine levels were measured among the control, IUGR-I, and IUGR-NI groups. Pearson analysis was used to evaluate the correlation between homocysteine and fasting blood glucose, insulin, HOMA-IR, triglyceride, and cholesterol levels. Results: We established IUGR rat model by both low protein and restricted diet feeding during pregnancy and the incidence of IUGR pups was 93.33%. There was no difference in fasting glucose, insulin, HOMA-IR, triglyceride and cholesterol levels between the control, the IUGR-NI and the IUGR-I group at day 21. At day 60, insulin, HOMA-IR and triglyceride levels in the IUGR-I group were remarkably lower than those in the IUGR-NI group, but still higher than those in the control group (F=38.34, P=0.02; F=49.48, P=0.02; F=17.93, P<0.001, respectively). At day 120, glucose, insulin, HOMA-IR and Hcy levels in the IUGR-I group were obviously lower than those in the IUGR-NI group, although still higher than those in the control group (F=21.60, P<0.001; F=164.46, P<0.001; F=75.15, P<0.001; F=35.46, P<0.001, respectively). There were no significant differences in triglyceride and cholesterol levels between the IUGR-I group and the control group at day 120. At 120-day, homocysteine in IUGR-I group was highly positively correlated with fasting glucose and HOMA-IR (r=0.863, P=0.006; r=0.725, P=0.042, respectively); Only homocysteine was positively correlated with fasting glucose in IUGR-NI group (r=0.721, P=0.044). Conclusions: Early supplementation of folate and vitamin B12 improved insulin resistance and lipid levels in IUGR rats to some extent, along with decreasing homocysteine levels, but not enough to completely repair glucose and lipid metabolism.

Long-Term Azithromycin Treatment in Pediatric Primary Ciliary Dyskinesia: A Retrospective Study.

Objectives: Primary ciliary dyskinesia (PCD) is a rare genetic disease mainly involved in lung dysfunction. PCD patient outcomes after azithromycin (AZM) treatment have rarely been reported. This study was aimed to assess AZM treatment effects on disease progression of pediatric PCD patients. Study Design: This retrospective follow-up study involved PCD patients diagnosed from 2009 to 2021. Changes of clinical outcomes, pulmonary function, and chest computed tomography findings were compared between untreated and AZM-treated patients. Results: Of 71 enrolled patients (median follow-up duration of 3.1 years), 34 received AZM (AZM-treated group) and 37 received no AZM (AZM-untreated group). At diagnosis, no significant intergroup differences in age, sex, height, weight, number of respiratory exacerbations, and FEV1% and FVC% predicted values were found, although FEF25-75% predicted was lower in AZM-treated group. Between treatment initiation and follow-up, patients in AZM-treated group had less respiratory exacerbations than that of AZM-untreated group (mean ± SD, 1.4 ± 0.8 vs. 3.0 ± 2.1, times/year P = 0.001) and fewer AZM-treated group patients exhibited exercise intolerance. Increases above baseline of AZM-treated FEV1% and FVC% predicted values exceeded that of AZM-untreated group, but intergroup differences were insignificant (FEV1% predicted: (median, IQR) 5.3 [-13.4, 9.4] vs. 1.8 [-12.1, 9.5], P = 0.477; FVC% predicted: (median, IQR) 6.7 [-7.6, 18.8] vs. 1.6 [-5.6, 7.6], P = 0.328). Conclusion: Long-term AZM treatment can reduce respiratory infection frequency and may maintain pulmonary diseases stable in pediatric PCD patients with worse lung function.

Bronchiolitis Obliterans and Primary Ciliary Dyskinesia: What Is the Link?

Bronchiolitis obliterans (BO) is a rare form of chronic obstructive lung disease characterized by obliteration of the small airways caused by inflammation and fibrosis. In children, BO most commonly appears following a severe lower respiratory tract infection. This phenomenon has been described as post-infectious BO (PIBO). PIBO presents with dyspnea, tachypnea, and persistent hypoxemia, as well as characteristic radiographic findings on high-resolution CT (HRCT) of the lungs. A few DNAH1 genetic variants have been postulated to have a role in the development of BO in patients with primary ciliary dyskinesia (PCD), but there is limited evidence regarding this, and etiologies are uncertain. PCD is a genetically heterogeneous autosomal recessive disorder characterized by ciliary dysfunction that causes impaired mucociliary clearance, leading to bronchiectasis and recurrent lower respiratory tract infections due to several pathogenic organisms including Pseudomonas aeruginosa. The link between rare PCD genetic variants and BO remains undetermined. We report the first case in Puerto Rico with Pseudomonal PIBO as the initial presentation of PCD; the patient was a four-year-old male. We also engage in a comparison of our case with previously reported cases of PIBO in PCD patients.

Clinical and Genetic Spectrum of Children With Primary Ciliary Dyskinesia in China.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a heterogeneous disease with a diverse clinical and genetic spectrum among populations worldwide. Few cases of pediatric PCD have been reported from China. RESEARCH QUESTION: What are the clinical and genotypic characteristics of children with PCD in China? STUDY DESIGN AND METHODS: Clinical characteristics, laboratory findings, and genetic results obtained for 75 patients with PCD were reviewed retrospectively at a single center in China. Genetic sequencing was conducted using whole-exome screening. RESULTS: Patient median age at diagnosis was 7.0 years (range, 2 months-14 years). Of 75 patients, 88% (66/75) had chronic wet cough, 77% (58/75) had recurrent sinusitis, 76% (57/75) had bronchiectasis, 40% (30/75) had neonatal respiratory distress, and 28% (21/75) had coexistent asthma. Notably, postinfectious bronchiolitis obliterans (PIBO) as first presentation was found in 8% of children (6/75). Genes with the highest incidence of mutations were DNAH11 (15/51), followed by DNAH5 (9/51), CCDC39 (5/51), DNAH1 (4/51), and CCNO (3/51). Four genes (DNAI1, HEATR2, RSPH9, and DNAAF3) each were respectively found in two patients, and seven genes (CCDC40, LRRC6, SPAG1, RSPH4A, ARMC4, CCDC114, and DNAH14, a novel gene) each were mutated once. No differences in classical clinical features were observed among patients with commonly observed PCD-associated genotypes. However, three of six PIBO patients carried DNAH1 mutations. INTERPRETATION: Besides typical clinical features, PIBO was observed as the first presentation of pediatric PCD in China. An association of the novel gene DNAH14 with PCD was observed, expanding the PCD genotypic spectrum.

Reduction of the PI3K/Akt related signaling activities in skeletal muscle tissues involves insulin resistance in intrauterine growth restriction rats with catch-up growth.

Individuals with intrauterine growth retardation (IUGR) are prone to insulin resistance, whereas the underlying molecular mechanisms remain unclear. In this study, we investigated if the PI3K/Akt signaling pathway in skeletal muscle tissues involves insulin resistance in IUGR offsprings, particularly ones with catch-up growth. An IUGR rat model was established by feeding rats an isocaloric (30.50 Kcal/g) diet containing 8% protein (low-protein diet) from day 1 of pregnancy until the birth of their pups. Glucometabolic parameters were measured and compared. Quantitative PCR and western blot were performed to assess mRNA and protein expression changes of the PI3K/Akt related signals in skeletal muscle tissues. Pearson analysis was used to assess the correlation of the PI3K/Akt signaling level and catch-up growth with the insulin resistance index (IRI). The values of fasting plasma glucose, fasting insulin and IRI were significantly higher, whereas insulin sensitivity index was significantly lower in IUGR offsprings than those in the controls. The PI3K mRNA and protein levels as well as the phospho-AktSer473 levels were significantly lower in IUGR offsprings compared to the controls. Reductions of GLUT4 as well as increases of PTEN and nuclear fractional PPARγ were detected in IUGR offsprings. Catch-up growth IUGR rats were positively correlated with insulin resistance and underwent more remarkable alterations of the PI3K, PTEN and GLUT4 expressions. Our results demonstrated that rats born IUGR developed insulin resistance later in life, which was likely mediated by reductions of the PI3K/Akt related signaling activities, particularly in those with excess catch-up growth.

Maternal Blood Pressure Rise During Pregnancy and Offspring Obesity Risk at 4 to 7 Years Old: The Jiaxing Birth Cohort.

Context: Maternal hypertensive disorders during pregnancy are suggested to affect obesity risk in offspring. However, little is known about the prospective association of rise in maternal blood pressure within normal range during pregnancy with this risk for obesity. Objective: To clarify the associations of diastolic and systolic blood pressure during pregnancy among normotensive women with the risk for obesity in offspring. Design: Prospective cohort study. Setting: Southeast China. Participants: Up to 2013, a total of 88,406 mother-child pairs with anthropometric measurements of offspring age 4 to 7 years were included in the present analysis. Main Outcome Measures: Overweight/obesity risk in offspring. Results: Among normotensive women, second- and third-trimester diastolic and systolic blood pressures were positively associated with risk for overweight/obesity in offspring: odds ratios per 10-mm Hg higher second- and third-trimester diastolic blood pressure were 1.05 [95% confidence interval (CI), 1.01 to 1.09] and 1.05 (95% CI, 1.02 to 1.10), respectively, and for systolic blood pressure were 1.08 (95% CI, 1.05 to 1.11) and 1.06 (95% CI, 1.03 to 1.09). Each 10-mm Hg greater rise in blood pressure between first and third trimesters was associated with a higher risk for offspring overweight/obesity: diastolic, 1.06 (95% CI, 1.01 to 1.10); systolic, 1.05 (95% CI, 1.02 to 1.07). Among all women (combining normotensive and hypertensive women), maternal hypertension in the second and third trimesters was associated with 49% and 14% higher risks for overweight/obesity in offspring, respectively. Conclusions: These results suggest that rise in maternal blood pressure during pregnancy and hypertension during pregnancy, independent of maternal body size before pregnancy, are risk factors for offspring childhood obesity.

Analysis of the relationship of insulin-like growth factor-1 to the growth velocity and feeding of healthy infants.

CONTEXT: Infancy is the fastest growth period in a child's development after birth, but little is known about hormonal regulation mechanism for the growth and development of this period. OBJECTIVE: The objective of this study is to analyze the trend of serum IGF-1 levels in healthy infants and the relationship of IGF-1 to the growth velocity and feeding method of infants. DESIGN: Population-based birth cohort study. SETTING: The study was conducted in the Third Hospital of Peking University. PARTICIPANTS: Study participants were 484 healthy infants, all of whom were full-term and appropriate for gestational age (238 boys and 246 girls). INTERVENTIONS: Interventions were anthropometrical measurements, feeding methods recorded every 1 to 2 months and serum samples (2, 4, 6, 8, 10,12 months). MAIN OUTCOME MEASURES: Height, weight, feeding methods and serum IGF-1 were the main outcome measures. RESULTS: Serum IGF-1 levels decreased in the following 2 months in boys but in females levels remained relatively high between 2 to 3 months after birth and then started to decrease. It reached the lowest point at Months 7-8, and was on a slow rise in both male infants and female infants thereafter. Serum IGF-1 levels were significantly higher in female infants [112.65 ng/ml (CI 91.82, 133.89)] than in male infants [74.38 ng/ml (CI 53.14, 95.61)] at early infancy. Infants fed with human milk had lower serum IGF-1 levels than infants fed with formula milk or human milk plus formula milk (66.94 ± 45.85 ng/ml, 72.56 ± 36.55 ng/ml, 79.89 ± 51.79 ng/ml, respectively; P = 0.019). IGF-1 levels were positively correlated to the growth velocity of body length (P<0.01). CONCLUSION: This study provides the trend for IGF-1 levels at infancy. It is highly possible that IGF-1 plays an important role in the regulation and control of length increases in infants, and feeding method influences serum IGF-1 levels.