Sex-specific association between maternal mild anemia and children's behavioral development: a birth cohort study.

There has been limited research on maternal anemia affecting children's behavioral development, with a lack of studies focusing on sex differences in this association. Based on the Ma'anshan Birth Cohort, 2132 mother-child pairs were included. Maternal anemia was evaluated based on the hemoglobin concentration and children's behavioral development was assessed by Achenbach Child Behavior Checklist 1.5-5. Binary logistic regression models indicated that compared with children born of mothers without anemia throughout pregnancy, maternal mild anemia during pregnancy or only anemia in the 3rd trimester was associated with increased risks of aggressive behaviors in boys. Maternal mild anemia only in the 2nd trimester was associated with increased risks of attention problems in boys. In girls, maternal mild anemia during pregnancy was associated with increased risks of withdrawn, internalizing problems and total problems. Girls born of mothers with mild anemia only in the 2nd trimester had higher risks of total problems. Maternal mild anemia in both 2nd and 3rd trimesters was associated with increased risks of internalizing problems in girls. Our study identified sex-specific effects of maternal mild anemia during pregnancy on children's behavioral development problems.

Maternal pregnancy-related anxiety and children's physical growth: the Ma'anshan birth cohort study.

BACKGROUND: Epidemiological studies have identified maternal antenatal anxiety and several adverse birth outcomes, but limited studies have focused on the relationship with the long-term physical growth of children. The study aimed to assess the influence of maternal pregnancy-related anxiety on physical growth in children at different exposure periods during pregnancy. METHODS: 3,154 mother-child pairs were included based on the Ma'anshan birth cohort study. Maternal prenatal anxiety was obtained by administering a questionnaire using the pregnancy-related anxiety questionnaire (PRAQ) scale during the 1st, 2nd and 3rd trimesters of pregnancy. Body fat (BF) (48 to 72 months) and Body Mass Index (BMI) (birth to 72 months) were collected repeatedly for children. Group-based trajectory models were applied to fit the different trajectories of BMI and BF. RESULTS: Maternal anxiety in the 2nd (OR = 0.81; 95% CI: 0.68 to 0.98; P < 0.025) and 3rd (OR = 0.80; 95% CI: 0.67 to 0.97; P = 0.020) trimesters was associated with a decreased risk of rapid weight gain (RWG) in the first year of life. Children aged 48 to 72 months of mothers with anxiety in the 3rd trimester had lower BMI (ß = -0.161; 95% CI, -0.293 to -0.029; P = 0.017) and BF (ß = -0.190; 95% CI, -0.334 to -0.046; P = 0.010), and these children were less likely to develop a very high BMI trajectory (OR = 0.54; 95% CI: 0.34 to 0.84; P = 0.006), and a high BF trajectory (OR = 0.72; 95% CI: 0.53 to 0.99; P = 0.043). Similar associations were found between maternal anxiety in both 2nd and 3rd trimesters and children's physical growth. CONCLUSIONS: Offspring of mothers with prenatal anxiety in the 2nd and 3rd trimesters predicts poorer growth in infancy and preschool age. Early improvement and treatment of prenatal anxiety could benefit physical health and development in early childhood.

Effect modification of greenness on PM2.5 associated all-cause mortality in a multidrug-resistant tuberculosis cohort.

RATIONALE: Evidence for the association between fine particulate matter (PM2.5) and mortality among patients with tuberculosis (TB) is limited. Whether greenness protects air pollution-related mortality among patients with multidrug-resistant tuberculosis (MDR-TB) is completely unknown. METHODS: 2305 patients reported in Zhejiang and Ningxia were followed up from MDR-TB diagnosis until death, loss to follow-up or end of the study (31 December 2019), with an average follow-up of 1724 days per patient. 16-day averages of contemporaneous Normalised Difference Vegetation Index (NDVI) in the 500 m buffer of patient's residence, annual average PM2.5 and estimated oxidant capacity Ox were assigned to patients regarding their geocoded home addresses. Cox proportional hazards regression models were used to estimate HRs per 10 µg/m3 exposure to PM2.5 and all-cause mortality among the cohort and individuals across the three tertiles, adjusting for potential covariates. RESULTS: HRs of 1.702 (95% CI 1.680 to 1.725) and 1.169 (1.162 to 1.175) were observed for PM2.5 associated with mortality for the full cohort and individuals with the greatest tertile of NDVI. Exposures to PM2.5 were stronger in association with mortality for younger patients (HR 2.434 (2.432 to 2.435)), female (2.209 (1.874 to 2.845)), patients in rural (1.780 (1.731 to 1.829)) and from Ningxia (1.221 (1.078 to 1.385)). Cumulative exposures increased the HRs of PM2.5-related mortality, while greater greenness flattened the risk with HRs reduced in 0.188-0.194 on average. CONCLUSIONS: Individuals with MDR-TB could benefit from greenness by having attenuated associations between PM2.5 and mortality. Improving greener space and air quality may contribute to lower the risk of mortality from TB/MDR-TB and other diseases.

From Bartter's syndrome to renal tubular acidosis in a patient with Hashimoto's thyroiditis: A case report
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Hashimoto's thyroiditis (HT) is an autoimmune disease that can cause the dysfunction of glands. Moreover, autoimmune disease is an under-recognized cause of several types of tubular dysfunction such as renal tubular acidosis (RTA), Gitelman's syndrome (GS), and Bartter's syndrome (BS). However, the potential mechanism of acquired BS and RTA associated with autoimmune diseases remains unclear. A 55-year-old female patient presented with numbness in both lower extremities for 6 months. She had a 2-year history of HT. Laboratory findings showed hypokalemia, metabolic alkalosis, and elevated plasma aldosterone concentration and renin activity. Urinary analysis revealed renal wasting of potassium, sodium, and chloride. Therefore, she was diagnosed as having HT and secondary BS and was treated with oral methylprednisolone, potassium chloride, and spironolactone. Two weeks later, her serum potassium levels restored to normal. After that, however, the patient was lost to follow-up. Two years later, she was re-hospitalized for progressive muscle weakness and quadriplegia. Laboratory results demonstrated severe hypokalemia, hyperchloremic metabolic acidosis, and inappropriate alkaline urine. Thus, distal RTA (dRTA) was confirmed, and she was prescribed potassium citrate and prednisone, resulting in the correction of hypokalemia and acid-base disturbance within 2 weeks after discharge. We report an HT patient who initially developed hypokalemic metabolic alkalosis and then developed metabolic acidosis within a few years. To our knowledge, this is the first report of two completely opposite acid-base disturbances associated with renal tubular diseases occurring consecutively in the same patient with HT. Our case may provide a valuable clue for exploring the mechanism of renal involvement in autoimmune diseases.

Novel compound heterozygous ATP6V1B1 mutations in a Chinese child patient with primary distal renal tubular acidosis: a case report.

BACKGROUND: Distal renal tubular acidosis (dRTA) is a heterogeneous disorder characterized by normal anion gap metabolic acidosis. Autosomal recessive dRTA is usually caused by mutations occurring in ATP6V1B1 and ATP6V0A4 genes,encoding subunits B1 and a4 of apical H+-ATPase, respectively. The heterogeneous clinical manifestations of dRTA have been described in different ethnic groups harboring distinct mutations. Most of the reported cases are from Europe and Africa. At present, the prevalence of primary dRTA is still poorly elucidated in Chinese population. CASE PRESENTATION: A 2-year and six-month-old female patient was hospitalized because of recurrent hypokalemia, hyperchloremic metabolic acidosis and growth retardation. Laboratory investigations presented a normal anion gap hyperchloremic metabolic acidosis, hypokalemia, and inappropriate alkaline urine. Renal ultrasound indicated bilateral nephrocalcinosis. Bilateral sensorineural hearing loss (SNHL) was confirmed with moderately severe (45 dB) on the left ear and severe (80 dB) on the right ear, which was accompanied with enlarged vestibular aqueduct (EVA) on both sides. According to these findings, a diagnosis of dRTA was made. To identify the pathogenic gene mutation, all coding regions of ATP6V1B1 and ATP6V0A4 gene, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. The splicing variants were verified in peripheral blood leucocytes of the patient by RT-PCR. As a result, two novel heterozygous mutations in ATP6V1B1 were identified in the child. One mutation was a successive 2-nucleotide deletion in exon 2(c.133-134delTG), which caused a marked nonsense mediated mRNA decay. The other was a guanine to adenine substitution of the first nucleotide of intron 8(c.785 + 1 G > A), which led to the exclusion of exon 8. After treatment with sodium citrate, potassium citrateand citric acid, metabolic acidosis and hypokalemia were corrected, but her hearing decreased gradually during the 2 years and had to accept the use of bilateral hearing aids. CONCLUSIONS: We described two novel dRTA associated mutations in ATP6V1B1 identified in a Chinese child patient accompanying with SNHL and EVA. Our study will help to expand the understanding of this rare disease in Chinese population.

Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: a case report.

BACKGROUND: Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine-tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype. CASE PRESENTATION: A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co-segregation in the family. As a result, a novel homozygous mutation (c.346C > G, p.Leu116Val) in 115G-L-W117 motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation. CONCLUSIONS: We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved 115G-L-W117 motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient.

Genotype/Phenotype Analysis in 67 Chinese Patients with Gitelman's Syndrome.

BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder, which is caused by the mutations in SLC12A3. This study was designed to analyze the characteristics of the genotype and phenotype, and follow-up in the largest group of Chinese patients with GS. METHODS: Sixty-seven patients with GS underwent SLCl2A3 analysis, and their clinical characteristics and biochemical findings as well as follow-up were reviewed, aiming to achieve a better description of GS. Additionally, the association of genotype and phenotype was explored. RESULTS: Forty-one different mutations were identified within these 67 GS patients, including 11 novel mutations and 5 recurrent ones. Typical hypocalciuria and hypomagnesemia were not found in 6 (9%) and 8 (11.9%) patients, respectively. Male patients and those harboring severe mutations in both alleles had significant higher urinary fractional excretion (FE) of potassium, magnesium and chlorine. In addition, there were 2 patients who had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2) and 32 patients with abnormal glucose metabolism. CONCLUSIONS: We identified 41 mutations related to GS, containing 11 novel variants and 5 high-frequency ones, which should facilitate earlier and more accurate diagnosis of GS. FE of electrolytes in urine may be more sensitive in the phenotype evaluation and differential diagnosis than corresponding serum electrolytes. Hypokalemia and hypomagnesemia in GS were difficult to correct; however, spironolactone might be helpful for hypokalemia to some degree. Compared with normal people, patients with GS were at higher risk of developing type 2 diabetes.

Association between hyperglycemia during pregnancy and offspring's refractive error: A focused review.

This review article explores the relationship between hyperglycemia during pregnancy and the visual development of offspring, specifically focusing on refractive error. The authors conducted a comprehensive search for relevant articles in various databases and assessed the methodological quality of the included studies. The findings consistently indicate that hyperglycemia during pregnancy can have a detrimental impact on the structural and functional aspects of visual development in offspring. The intrauterine hyperglycemic environment appears to negatively affect the retina and lens, leading to refractive errors. In conclusion, there is likely an association between hyperglycemia during pregnancy and the development of refractive errors in offspring.

Association of gestational weight gain rate in pregnant women with children's cognitive and behavioral development: A birth cohort study.

BACKGROUND: The evidences on the relationship between gestational weight gain rate (GWGR) and children's cognitive and behavioral development have been limited. METHODS: A total of 3273 singleton live birth mother-child pairs from the Ma'anshan Birth Cohort in China were included in the study. Maternal GWGR was calculated based on the weights measured at multiple antenatal checkups. Children's cognitive and behavioral development were assessed by Chinese version of Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition and Achenbach Child Behavior Checklist 1.5-5. Then generalized linear models were performed for analyses. RESULTS: In the field of children's cognitive development, excessive GWGR in the second trimester was associated with increased visual space index (VSI), fluid reasoning index (FRI) and full scale intelligence quotient (FSIQ) scores, while excessive GWGR in the third trimester was associated with decreased VSI, working memory index (WMI) and FSIQ scores. In the field of children's behavioral development, excessive GWGR in the second trimester was associated with decreased aggressive behaviors and externalizing problems scores. LIMITATIONS: Children's behavioral development was assessed by main caregivers and might cause a certain degree of bias. There might be other potential confounders that we did not take into account. CONCLUSIONS: A high GWGR in the second trimester might be beneficial for children's cognitive and behavioral development, while a high GWGR in the third trimester might be harmful.

Are there bidirectional associations between maternal thyroid function and glucose metabolism in singleton live births? A birth cohort study.

(1) Aims: To examine the associations between maternal thyroid function and glucose metabolism during pregnancy. (2) Methods: This study was based on Ma' anshan Birth Cohort in China. Totally 2375 pregnant women were included in data analysis. Maternal thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb) and fasting plasma glucose (FPG) levels during the first, second and third trimesters of pregnancy were measured retrospectively. Mplus 8.0 was used to construct a cross-lagged panel model to examine the potential bidirectional association between thyroid function and FPG levels throughout pregnancy. (3) Results: FT4 levels were positively correlated with FPG levels in the first trimester and negatively correlated with FPG levels in the second trimester. TSH levels were negatively associated with FPG levels in the second trimester, and in the first trimester, it could positively predict FPG levels in the second trimester. No significant association was found between TPOAb levels and FPG levels during pregnancy. (4) Conclusions: There was a non-bidirectional association between maternal thyroid function and glucose metabolism during pregnancy. FT4 and TSH levels influence FPG concentrations in the first and second trimesters of pregnancy.

Association between maternal fasting glucose levels throughout pregnancy and preschoolers' refractive errors.

PURPOSE: We aimed to investigate the association between maternal fasting plasma glucose (FPG) trajectories during pregnancy and children's refractive errors at 6 years old. DESIGN: Based on the Ma'anshan Birth Cohort (MABC) in China, a total of 1987 mother-child pairs were included in this study. METHODS: Using the group-based trajectory model, trajectory fitting was performed on fasting blood glucose levels during the first, second, and third trimesters of pregnancy. Children's vision was measured at 6 years of age using the standard logarithmic visual acuity E-chart and cycloplegic refraction examination. Logistic regression models and multi-informant generalized estimating equations were used to analyze the association between maternal blood glucose level and 6-year-old children's visual acuity. RESULTS: Children born of mothers with high level FPG trajectory had a higher risk of developing refractive error [OR=1.46 (95% CI 1.08 1.97)], hypermetropia [OR=1.64 (95% CI 1.09, 2.46)] and astigmatism [OR=1.60 (95% CI 1.06, 2.41)] at age six compared to those with low level trajectory. Maternal blood glucose level in the first [ß=-0.012 (95% CI -0.024, -0.001)] and the second [ß=-0.016 (95% CI -0.025, -0.006)] trimesters was associated with 6 year children's distance vision value. CONCLUSIONS: High level of fasting plasma glucose trajectories during pregnancy has been observed to be associated with 6-year-old children's refractive error, hypermetropia and astigmatism. The first and the second trimesters may be critical periods for the effects of maternal blood glucose on children's vision. The long-term effect of maternal glucose metabolism on children's visual development deserves further study.

The impact of maternal anxiety during pregnancy on children's eczema and allergic rhinitis: The Ma'anshan birth cohort study.

OBJECTIVE: The objective of this study was to investigate the associations between maternal exposure to anxiety during pregnancy and the susceptibility of offspring to eczema and allergic rhinitis and the possibility of sensitivity periods and cumulative effects. METHODS: The study's sample consisted of 3160 mother-child pairs from the Ma'anshan Birth Cohort Study. Maternal anxiety was repeatedly measured in the 1st, 2nd, and 3rd trimesters of pregnancy using the Chinese version of the Pregnancy-Related Anxiety Scale. Information regarding children's eczema and allergic rhinitis diagnoses was collected through parental reports at 12, 24, 36 and 48 months of age. Binary logistic regression models were used for statistical analysis and corrected for multiple comparisons using the false discovery rate (FDR) method. RESULTS: Children whose mothers experienced anxiety throughout pregnancy had the highest odds of developing total eczema (aOR 1.45, 95% CI 1.02-2.07) and total allergic rhinitis (aOR 1.67, 95% CI 1.17-2.37) between the ages of 6 and 48 months. The higher the trajectory of the maternal anxiety scores throughout pregnancy, the higher the odds of total eczema (aOR 1.65, 95% CI 1.14-2.40) and allergic rhinitis (aOR 1.84, 95% CI 1.28-2.66) in their offspring. The association between maternal anxiety and children's eczema was mainly concentrated in the first 24 months, whereas the association with allergic rhinitis was mainly concentrated in the 36-48 months. CONCLUSION: Maternal anxiety during any trimester of pregnancy, especially with a consistently high trajectory of anxiety scores, was associated with higher odds of children's eczema and allergic rhinitis.

Chiral, air stable, and reliable Pd(0) precatalysts applicable to asymmetric allylic alkylation chemistry.

Stereoselective carbon-carbon bond formation via palladium-catalyzed asymmetric allylic alkylation is a crucial strategy to access chiral natural products and active pharmaceutical ingredients. However, catalysts based on the privileged Trost and Pfaltz-Helmchen-Williams PHOX ligands often require high loadings, specific preactivation protocols, and excess chiral ligand. This makes these reactions uneconomical, often unreproducible, and thus unsustainable. Here we report several chiral single-component Pd(0) precatalysts that are active and practically-applicable in a variety of asymmetric allylic alkylation reactions. Despite the decades-long history and widespread use of Trost-type ligands, the precatalysts in this work are the only reported examples of stable, isolable Pd(0) complexes with these ligands. Evaluating these precatalysts across nine asymmetric allylic alkylation reactions reveals high reactivity and selectivity at low Pd loading. Importantly, we also report an unprecedented Pd-catalyzed enantioselective allylation of a hydantoin, achieved on gram scale in high yield and enantioselectivity with only 0.2 mol% catalyst.

Maternal anxiety during pregnancy and children's asthma in preschool age: The Ma'anshan birth cohort study.

BACKGROUND: The fetal immune system and consequent elevated risk of asthma in childhood may be impacted by maternal anxiety during pregnancy. Limited studies have evaluated whether there was a sensitive period and cumulative effect of the relationship between prenatal anxiety and children's asthma. METHODS: 3131 mother-child pairs made up the study's sample from the Ma'anshan Birth Cohort Study in China. Maternal anxiety status was repeated three times using the pregnancy-related anxiety questionnaire in the 1st, 2nd and 3rd trimesters of pregnancy. Diagnostic information on asthma was collected three times at 24, 36, and 48 months of age. RESULTS: After adjusting for confounders, children born to mothers with anxiety in the 1st, 2nd and 3rd trimesters of pregnancy all had an elevated risk of total asthma from 12 to 48 months of age. After further adjusting prenatal anxiety in the other trimesters, no association was observed between prenatal anxiety in any trimester and preschoolers' asthma. Children of mothers with persistently high anxiety score trajectory during pregnancy had an elevated risk of total asthma and high prevalence trajectory of asthma. Cumulative effects analysis showed that the more frequent the mother's anxiety, the higher the risk of her offspring developing a high prevalence trajectory of asthma from 12 to 48 months of age. The results of the subgroup analysis by age showed similar associations overall. CONCLUSIONS: Maternal antenatal anxiety was associated with an elevated risk of preschool children's asthma, and a possible cumulative effect was observed. Maternal mental health conditions during pregnancy should receive constant attention throughout pregnancy, not just during one period.

A reactivity model for oxidative addition to palladium enables quantitative predictions for catalytic cross-coupling reactions.

Making accurate, quantitative predictions of chemical reactivity based on molecular structure is an unsolved problem in chemical synthesis, particularly for complex molecules. We report an approach to reactivity prediction for catalytic reactions based on quantitative structure-reactivity models for a key step common to many catalytic mechanisms. We demonstrate this approach with a mechanistically based model for the oxidative addition of (hetero)aryl electrophiles to palladium(0), which is a key step in myriad catalytic processes. This model links simple molecular descriptors to relative rates of oxidative addition for 79 substrates, including chloride, bromide and triflate leaving groups. Because oxidative addition often controls the rate and/or selectivity of palladium-catalyzed reactions, this model can be used to make quantitative predictions about catalytic reaction outcomes. Demonstrated applications include a multivariate linear model for the initial rate of Sonogashira coupling reactions, and successful site-selectivity predictions for Suzuki, Buchwald-Hartwig, and Stille reactions of multihalogenated substrates relevant to the synthesis of pharmaceuticals and natural products.

A broadly applicable quantitative relative reactivity model for nucleophilic aromatic substitution (SNAr) using simple descriptors.

We report a multivariate linear regression model able to make accurate predictions for the relative rate and regioselectivity of nucleophilic aromatic substitution (SNAr) reactions based on the electrophile structure. This model uses a diverse training/test set from experimentally-determined relative SNAr rates between benzyl alcohol and 74 unique electrophiles, including heterocycles with multiple substitution patterns. There is a robust linear relationship between the experimental SNAr free energies of activation and three molecular descriptors that can be obtained computationally: the electron affinity (EA) of the electrophile; the average molecular electrostatic potential (ESP) at the carbon undergoing substitution; and the sum of average ESP values for the ortho and para atoms relative to the reactive center. Despite using only simple descriptors calculated from ground state wavefunctions, this model demonstrates excellent correlation with previously measured SNAr reaction rates, and is able to accurately predict site selectivity for multihalogenated substrates: 91% prediction accuracy across 82 individual examples. The excellent agreement between predicted and experimental outcomes makes this easy-to-implement reactivity model a potentially powerful tool for synthetic planning.

Identification of Four Novel COL4A5 Variants and Detection of Splicing Abnormalities in Three Chinese X-Linked Alport Syndrome Families.

Chronic renal disease associated with X-linked Alport syndrome (XLAS) is relatively rare. However, due to the lack of specificity in the pathologic and clinical manifestations of the disease, it is easy to be misdiagnosed. In this study, we included three Chinese families with XLAS and used targeted NGS to find gene variants. In family X1, the 36-year-old male proband had hematuria, massive proteinuria, sensorineural deafness and ESRD at 33. In silico prediction showed the novel c.1424-4C > G variant reduced the score of the normal 3' splice site from 0.47 to 0.00 (according to BDGP). Transcriptional analysis from his peripheral blood cells indicated that it caused the insertion of an amino acid [p.(Lys474_Gly475insVal)]. In family X2, the proband was a 32-year-old male, who had hematuria, proteinuria, hypertension, hearing loss and progressed into ESRD at 30 years. He carried a novel missense variant c.2777G > T p.(Gly926Val). In family X3, the proband, a 16-year-old male, had hematuria, massive proteinuria, sensorineural deafness and ESRD; the results of renal pathological findings were consistent with AS. He carried a novel variant c.4529-2A > T, so did his mother with ESRD and probable XLAS. Bioinformatic analysis with BDGP showed that it abolished the acceptor site from 0.83 to 0.00. RT-PCR analysis from his kidney tissue indicated that it caused exon 50 skipping and exon 50 skipping along with inserting a cryptic exon derived from intron 49 p.[Gly1510Aspfs*11, Gly1510Alafs*35]. Another novel missense variant c.1552G > A p.(Gly518Arg) was identified in his mother and his aunt. No skewed X-chromosome inactivation was involved in these two female patients. In conclusion, four novel variants in COL4A5 were identified and transcriptional analysis is essential to investigate the pathogenicity of intronic variants. Thus we found a rare event in a female patient with XLAS caused by two COL4A5 variants in trans.

Maternal Pre-Pregnancy Body Mass Index, Gestational Weight Gain and Children's Cognitive Development: A Birth Cohort Study.

To investigate the joint effect of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) on children's cognitive development. We recruited 1685 mother-child pairs from the Ma'anshan Birth Cohort in China. Pre-pregnancy BMI and GWG were calculated based on the height and weights measured at multiple antenatal checkups. Children's cognition was assessed by Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition. Poisson regression model was used to analyze the association between maternal pre-pregnancy BMI and children's cognitive dimensions under different GWG categories. Women with overweight or obese before pregnancy were more likely to obtain excessive GWG. When women had excessive GWG, pre-pregnancy overweight was associated with low children's PSI (OR = 1.69, 95%CI: 1.02-2.81) and pre-pregnancy obesity was related to poor VCI in children (OR = 3.71, 95%CI: 1.49-9.22), after adjusting for potential confounders. In pre-pregnancy underweight mothers, adequate GWG reduced the risk of below-average VSI in children (OR = 0.22, 95%CI: 0.05-0.92), but excessive GWG was related to low FSIQ in children (OR = 2.53, 95%CI: 1.34-4.76). In women with excessive GWG, maternal pre-pregnancy BMI displays an inverted U-shape association with children's cognition. Moreover, adequate GWG in women with pre-pregnancy underweight was beneficial for children's cognition.

Non-Linear and Sex-Specific Effect of Maternal Pre-Pregnancy BMI on Emotional and Behavioral Development of Preschool Children: A Population-Based Cohort Study.

(1) Background: The aim was to examine the non-linear and sex-specific outcomes of maternal pre-pregnancy BMI on emotional and behavioral development of preschool children; (2) Methods: This study was based on the China-Anhui Birth Cohort (C-ABCS), including 3648 mother-child pairs. Maternal pre-pregnancy BMI was calculated from the maternal pre-pregnancy height and weight measured at the first antenatal checkup. Main caregivers completed the Strengths and Difficulties Questionnaire (SDQ) to assess children's preschool emotional and behavioral development. A restricted cubic spline model was drawn using Stata version 15.1 to analyze the association between maternal pre-pregnancy BMI and preschoolers' SDQ scores by sex; (3) Results: Among boys, maternal pre-pregnancy underweight was associated with the increased risk of conduct problems and pro-social behaviors, and pre-pregnancy overweight/obesity related with the increased risk of peer problems. Interestingly, when maternal pre-pregnancy BMI was between 18.50 kg/m2 and 18.67 kg/m2, boys had the increased risk of conduct problems. When pre-pregnancy BMI was between 18.50 kg/m2 and 19.57 kg/m2, boys had the increased risk of pro-social problems. No significant associations were observed; (4) Conclusions: A non-linear effect of maternal pre-pregnancy BMI on emotional and behavioral development has been found in preschool boys. In particular, pre-pregnancy normal weight may still affect boys' emotional and behavioral development.

Body Mass Index and Risk of Diabetic Nephropathy: A Mendelian Randomization Study.

CONTEXT: The associations of obesity and diabetic nephropathy (DN) in type 2 diabetes are inconsistent in observational studies, and causality remains unclear. OBJECTIVE: To explore the causal effect of body mass index (BMI) on DN, estimated glomerular filtration rate (eGFR), and proteinuria in type 2 diabetes by a 2-sample Mendelian randomization (MR) analysis. METHODS: A total of 56 genetic variants were selected as instrumental variables for BMI in 158 284 participants from BioBank Japan, and their effects on DN risk, eGFR, and proteinuria were estimated in 3972 individuals with type 2 diabetes. Then, sex-stratified MR analysis was performed between BMI and DN. We selected generalized summary MR analysis as the primary method and 6 other robust methods to test MR assumptions. RESULTS: One SD increase in BMI was causally associated with higher DN risk [odds ratio (OR) 3.76, 95% CI 1.88-7.53, P < 0.001] and lower eGFR level (OR 0.71, 95% CI 0.59-0.86, P < 0.001). However, BMI was not causally associated with proteinuria (P = 0.22). Sex-stratified analyses indicated the causal effect of BMI on DN was stronger in women (OR 14.81, 95% CI 2.67-82.05, P = 0.002) than in men (OR 3.48, 95% CI 1.18-10.27, P = 0.02). Sensitivity analyses did not show evidence for violation of the MR assumptions. CONCLUSIONS: Genetic evidence showed that higher BMI levels were causally associated with increased risk of DN and decreased eGFR levels. Moreover, the increase in BMI level had a greater impact on DN risk in women.