Specific convulsions and brain damage in children hospitalized for Omicron BA.5 infection: an observational study using two cohorts.

BACKGROUND: SARS-CoV-2 continues to mutate over time, and reports on children infected with Omicron BA.5 are limited. We aimed to analyze the specific symptoms of Omicron-infected children and to improve patient care. METHODS: We selected 315 consecutively hospitalized children with Omicron BA.5 and 16,744 non-Omicron-infected febrile children visiting the fever clinic at our hospital between December 8 and 30, 2022. Specific convulsions and body temperatures were compared between the two cohorts. We analyzed potential associations between convulsions and vaccination, and additionally evaluated the brain damage among severe Omicron-infected children. RESULTS: Convulsion rates (97.5% vs. 4.3%, P < 0.001) and frequencies (median: 2.0 vs. 1.6, P < 0.001) significantly differed between Omicron-infected and non-Omicron-infected febrile children. The body temperatures of Omicron-infected children were significantly higher during convulsions than when they were not convulsing and those of non-Omicron-infected febrile children during convulsions (median: 39.5 vs. 38.2 and 38.6 °C, both P < 0.001). In the three Omicron-subgroups, the temperature during convulsions was proportional to the percentage of patients and significantly differed ( P < 0.001), while not in the three non-Omicron-subgroups ( P = 0.244). The convulsion frequency was lower in the 55 vaccinated children compared to the 260 non-vaccinated children (average: 1.8 vs. 2.1, P < 0.001). The vaccination dose and convulsion frequency in Omicron-infected children were significantly correlated ( P < 0.001). Fifteen of the 112 severe Omicron cases had brain damage. CONCLUSIONS: Omicron-infected children experience higher body temperatures and frequencies during convulsions than those of non-Omicron-infected febrile children. We additionally found evidence of brain damage caused by infection with omicron BA.5. Vaccination and prompt fever reduction may relieve symptoms.

Boryl radical catalysis enables asymmetric radical cycloisomerization reactions.

The development of functionally distinct catalysts for enantioselective synthesis is a prominent yet challenging goal of synthetic chemistry. In this work, we report a family of chiral N-heterocyclic carbene (NHC)-ligated boryl radicals as catalysts that enable catalytic asymmetric radical cycloisomerization reactions. The radical catalysts can be generated from easily prepared NHC-borane complexes, and the broad availability of the chiral NHC component provides substantial benefits for stereochemical control. Mechanistic studies support a catalytic cycle comprising a sequence of boryl radical addition, hydrogen atom transfer, cyclization, and elimination of the boryl radical catalyst, wherein the chiral NHC subunit determines the enantioselectivity of the radical cyclization. This catalysis allows asymmetric construction of valuable chiral heterocyclic products from simple starting materials.

[Diterpenoid constituents in Pseudolarix amabilis and their antitumor activities in vitro].

By various chromatographic techniques and extensive spectroscopic methods, 17 abietane diterpenoids were isolated from the dichloromethane fraction of the 95% ethanol cold-soak extracts of the seeds of Pseudolarix amabilis, namely pseudoamaol A(1), 12α-hydroxyabietic acid(2), 12-methoxy-7,13-abietadien-18-oic acid(3), 13-hydroxy-8,11,13-podocarpatrien-18-oic acid(4), 15-hydroxy-7,13-abietadien-12-on-18-oic acid(5), 8(14)-podocarpen-13-on-18-oic acid(6), holophyllin K(7), metaglyptin B(8), 7α-hydroxydehydroabietinsaure-methylester(9), 7-oxodehydroabietic acid(10), 15-hydroxy-7-oxodehydroabietinsaure-methy-lester(11), 15-methoxydidehydroabietic acid(12), 7-oxo-15-hydroxy-dehydroabietic acid(13), 15-hydroxydehydroabietic acid(14), 8,11,13-abietatriene-15,18-diol(15), 8,11,13-abietatriene-15-hydroxy-18-succinic acid(16), and 7ß-hydroxydehydroabie-tic acid(17). Compound 1 was a new compound. The isolated compounds were evaluated for their antitumor activities(HepG2, SH-SY5Y, K562), and compounds 8 and 17 showed potential cytotoxic activity against K562 cells, with IC_(50) values of 26.77 and 37.35 µmol·L~(-1), respectively.

Stereoselective hydrogen atom transfer to acyclic radicals: a switch enabling diastereodivergent borylative radical cascades.

Radical cascade reactions are powerful tools to construct structurally complex molecules. However, the stereochemical control of acyclic radical intermediates remains a persistent challenge, due to the low differentiation between the two faces of these species. This hurdle further makes stereodivergent synthesis rather more difficult to be accomplished, in particular for intermediates resulted from complex cascades. Here we report an efficient strategy for stereoselective hydrogen atom transfer (HAT) to acyclic carbon radicals, which are generated via N-heterocyclic carbene (NHC)-boryl radicals triggered addition-translocation-cyclization cascades. A synergistic control by the NHC subunit and a thiol catalyst has proved effective for one facial HAT, while a ZnI2-chelation protocol allows for the preferential reaction to the opposite face. Such a stereoselectivity switch enables diastereodivergent construction of heterocycles tethering a boron-substituted stereocenter. Mechanistic studies suggest two complementary ways to tune HAT diastereoselectivity. The stereospecific conversions of the resulting boron-handled products to diverse functionalized molecules are demonstrated.

Combined effects of air pollutants on gestational diabetes mellitus: A prospective cohort study.

Exposures to multiple air pollutants during pregnancy have been associated with the risk of gestational diabetes mellitus (GDM). However, their combined effects are unclear. We aimed to evaluate the combined associations of five air pollutants from pre-pregnancy to the 2nd trimester with GDM. This study included 20,113 participants from the Born in Guangzhou Cohort Study (BIGCS). The inverse distance-weighted models were used to estimate individual air pollutant exposure, namely ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter less than 10 µm in diameter (PM10), and less than 2.5 µm in diameter (PM2.5). We estimated stage-specific associations of air pollutants with GDM using generalized estimating equation, and departures from additive joint effects were assessed using the relative excess risk (RERI) and the joint relative risk (JRR). Of the 20,113 participants, 3440 women (17.1%) were diagnosed with GDM. In the adjusted model, increased concentrations of O3 and SO2 3-6 months before pregnancy were associated with GDM occurrence, as well as O3 and PM10 in the 1st trimester, the adjusted relative risk (95% confident intervals) [RRs (95%CI)] ranged from 1.05 (1.00, 1.09) to 1.21 (1.04, 1.40). The largest JRR for GDM was the combination of SO2, NO2, and PM10 in the 1st trimester (JRR = 1.32, 95% CI: 1.10, 1.59). The JRR for O3 and SO2 was less than their additive joint effects [RERI = -0.25 (-0.47, -0.04), P for interaction = 0.048]. Associations of air pollutants with GDM differed somewhat by pre-pregnancy BMI and season. This study added new evidence to the current understanding of the combined effects of multiple air pollutants on GDM. Public health strategies were needed to reduce the adverse effects of air pollution exposure on pregnant women.

Surface topography index: a novel deformity severity assessment index for pectus excavatum.

BACKGROUND: The surface topography index (STI) has great potential in both routine computed tomography (CT) scan and emerging optical imaging systems. However, the diagnostic accuracy and stability of the STI as a deformity severity assessment index has not been fully confirmed. Therefore, the aim of the present study was to determine the diagnostic performance of the STI as a novel deformity severity assessment index for pectus excavatum. METHODS: The present study consisted of 722 chest CT images from a single center. The standard CT index (CTI) and STI were calculated for all patients. The between-group difference and the level of compliance between the CTI and STI was analyzed by t-test and Pearson correlation. The diagnostic value and optimum discriminatory values of the CTI and STI were calculated by a receiver-operating characteristic (ROC) curve and DeLong's test. RESULTS: The distributions of the CTI and STI were similar and showed a slight overlap between the pectus excavatum (PE) and non-PE groups. Both the CTI and STI significantly differed between the 2 groups (P<0.001). The STI demonstrated a strong Pearson correlation with the CTI (r=0.91, 95% confidence interval: 0.88-0.91, P<0.001). The ROC curves showed that STI =1.58 (sensitivity: 0.93, specificity: 0.95) could be considered equivalent to CTI =2.72 (sensitivity: 0.93, specificity: 0.97) as the optimum discriminatory values. DeLong's test showed no significant difference in the ROC curve results between the CTI and STI (Z=0.90, P=0.37). CONCLUSIONS: The STI has comparative discrimination ability in PE diagnosis and deformity severity assessment when used with the standard CTI. The STI as a novel index is not only an ideal evaluation metric of PE deformity but also an objective trait for PE patients just as weight and height for everyone.

Selective N-monomethylation of primary anilines with the controllable installation of N-CH2D, N-CHD2, and N-CD3 units.

The selective N-monomethylation of primary anilines was realized by the use of the Me3N-BH3/N,N-dimethylformamide (DMF) system as the methyl source. This method also allows for the controllable introduction of N-CH2D, N-CHD2, and N-CD3 units with high levels of deuterium incorporation using Me3N-BH3/d7-DMF, Me3N-BD3/DMF and Me3N-BD3/d7-DMF systems, respectively.

Association between serum progesterone concentration in early pregnancy and duration of pregnancy: a cohort study.

Objective: To examine the association between progesterone concentration in early pregnancy and duration of pregnancy and risk of preterm delivery.Methods: Women enrolled in the Born in Guangzhou Cohort Study from 2013-2014, with a singleton pregnancy, who had serum progesterone measured at least one time between 4 and 10 weeks of gestation were included. The association between progesterone concentration both continuous and as categorical variable (quartile) and the risk of preterm delivery was assessed with Cox proportional hazards regression. Differences of length of gestation in four progesterone concentration quartiles were assessed using the Log-rank test.Results: We studied 1860 mother-newborn pairs. The mean overall progesterone concentration was 65.7 ± 21.3 nmol/L, with mean progesterone concentrations in the four quartiles of 42.4 ± 6.2 nmol/L (n = 463), 56.2 ± 3.3 nmol/L (n = 462), 68.9 ± 4.5 nmol/L (n = 470), and 95.1 ± 15.3 nmol/L (n = 465). There was no significantly difference in duration of gestation in four progesterone concentration groups (p=.511). There was no relation between progesterone level and preterm delivery (adjusted hazard ratio (HR) per 10 nmol/l progesterone level 1.00 (95% confidence interval (CI) 0.90, 1.11)). After adjusting for potential confounders, the HR of any preterm delivery for quartiles 1, 2 and 3 versus the highest quartile of progesterone level (> 77.3 nmol/L) was 1.04 (95% CI 0.52, 2.07), 1.17 (95% CI 0.60, 2.28), and 1.46 (95% CI 0.76, 2.78), respectively. When analysis was done for spontaneous preterm delivery only, also no association with first trimester progesterone was found.Conclusion: Lower first trimester serum progesterone concentration is not associated with reduction of length of gestation or increased risk of preterm delivery.

Regioselective Radical Hydroboration of gem-Difluoroalkenes: Synthesis of α-Borylated Organofluorines.

A regioselective radical hydroboration of gem-difluoroalkenes was developed for the synthesis of α-difluoroalkylborons. The reaction features excellent regioselectivity, broad substrate scope, and good functional group capability. DFT calculations implicated the remarkable α-selectivity was driven from the kinetically and thermodynamically more favorable α-addition step. The resulting α-difluoroalkylborons could be readily converted into NHC-borane-tethered monofluoroalkenes, which demonstrated unique reactivity and applicability in the synthesis of monofluoroalkene derivatives through transformations of the boron unit.

Family socioeconomic position and abnormal birth weight: evidence from a Chinese birth cohort.

BACKGROUND: Birth weight is a strong determinant of infant short- and long-term health outcomes. Family socioeconomic position (SEP) is usually positively associated with birth weight. Whether this association extends to abnormal birth weight or there exists potential mediator is unclear. METHODS: We analyzed data from 14,984 mother-infant dyads from the Born in Guangzhou Cohort Study. We used multivariable logistic regression to assess the associations of a composite family SEP score quartile with macrosomia and low birth weight (LBW), and examined the potential mediation effect of maternal pre-pregnancy body mass index (BMI) using causal mediation analysis. RESULTS: The prevalence of macrosomia and LBW was 2.62% (n = 392) and 4.26% (n = 638). Higher family SEP was associated with a higher risk of macrosomia (OR 1.30, 95% CI 0.93-1.82; OR 1.53, 95% CI 1.11-2.11; and OR 1.59, 95% CI 1.15-2.20 for the 2nd, 3rd, and 4th SEP quartile respectively) and a lower risk of LBW (OR 0.69, 95% CI 0.55-0.86; OR 0.76, 95% CI 0.61-0.94; and OR 0.61, 95% CI 0.48-0.77 for the 2nd, 3rd, and 4th SEP quartile respectively), compared to the 1st SEP quartile. We found that pre-pregnancy BMI did not mediate the associations of SEP with macrosomia and LBW. CONCLUSIONS: Socioeconomic disparities in fetal macrosomia and LBW exist in Southern China. Whether the results can be applied to other populations should be further investigated.

Direct Csp3-H methylenation of 2-arylacetamides using DMF/Me2NH-BH3 as the methylene source.

A direct Csp3-H methylenation of 2-arylacetamides using DMF/Me2NH-BH3 as the methylene source was developed. The formyl group of DMF delivered the carbon and one hydrogen atoms, and the Me2NH-BH3 donated the remaining one hydrogen atom. This protocol offers a new alternative to make useful 2-arylacrylamides from simple starting materials.

Comparison of the INTERGROWTH-21st standard and a new reference for head circumference at birth among newborns in Southern China.

BACKGROUND: Previous studies proposed that there were racial or ethnic disparities in fetal growth, challenging the use of international standards in specific populations. This study was to evaluate the validity of applying the INTERGROWTH-21st standard to a Chinese population for identifying abnormal head circumference (HC), in comparison with a newly generated local reference. METHODS: There were 24,257 singletons delivered by low-risk mothers in four perinatal health-care centers in Southern China. New HC reference was constructed and comparison in distribution of HC categories was performed between the INTERGROWTH-21st standard and new reference after applying these two tools in study population. Logistic regression was used to examine the association between abnormal HC and adverse neonatal outcomes. RESULTS: There were 4.40% of the newborns identified with microcephaly (HC > 2 standard deviation below the mean) using the INTERGROWTH-21st standard, comparing to the proportion of 2.83% using new reference. The newborns identified with microcephaly only by the INTERGROWTH-21st standard were not at a higher risk of adverse neonatal outcome, compared with those identified as non-microcephaly by both tools (OR 0.73, 95% CI 0.47-1.13). CONCLUSION: The new HC reference may be more appropriate for newborn assessment in Chinese populations than the INTERGROWTH-21st standard.

Identifying risk factors for neurological complications and monitoring long-term neurological sequelae: protocol for the Guangzhou prospective cohort study on hand-foot-and-mouth disease.

INTRODUCTION: Hand-foot-and-mouth disease (HFMD) is a paediatric infectious disease that is particularly prevalent in China. Severe HFMDs characterised by neurological involvement are fatal and survivors who have apparently fully recovered might still be afflicted later in life with neurocognitive impairments. Only when a well-designed, prospective cohort study is in place can we develop clinical tools for early warning of neurological involvement and can we obtain epidemiological evidence regarding the lingering effects of the sequelea. METHODS AND ANALYSIS: A prospective, hospital-based cohort study is underway in Guangzhou, China. Clinical data and biosamples from hospitalised children (<14 years of age) with an admission diagnosis of HFMD will be collected to determine risk factors for subsequent neurological involvement. Clinical tools for early detection of severe HFMDs will be developed by integrating clinical and biological information. Questionnaire surveys and neurocognitive assessments will be conducted at discharge and each year in the first 2 years of follow-up and every 2 years afterwards until study participants turn 16 years of age or show no evidence of neurocognitive deficits. The association between childhood enterovirus infection and neurocognitive impairment later in life will be examined. ETHICS AND DISSEMINATION: A written informed consent from parents/guardians is a prerequisite for study entry. The protocol of this study has been approved by the hospital's ethics committee. Data usage follows the rules of the hospital's data oversight committee. Findings of this study will be disseminated through publications in international peer-reviewed journals and will be presented in academic conferences. TRIAL REGISTRATION NUMBER: ChiCTR-EOC-17013293; Pre-results.

Downregulation of Hes1 expression in experimental biliary atresia and its effects on bile duct structure.

AIM: To analyze the expression and function of the Notch signaling target gene Hes1 in a rhesus rotavirus-induced mouse biliary atresia model. METHODS: The morphologies of biliary epithelial cells in biliary atresia patients and in a mouse model were examined by immunohistochemical staining. Then, the differential expression of Notch signaling pathway-related molecules was investigated. Further, the effects of the siRNA-mediated inhibition of Hes1 expression were examined using a biliary epithelial cell 3D culture system. RESULTS: Both immature (EpCAM+) and mature (CK19+) biliary epithelial cells were detected in the livers of biliary atresia patients without a ductile structure and in the mouse model with a distorted bile duct structure. The hepatic expression of transcripts for most Notch signaling molecules were significantly reduced on day 7 but recovered to normal levels by day 14, except for the target molecule Hes1, which still exhibited lower mRNA and protein levels. Expression of the Hes1 transcriptional co-regulator, RBP-Jκ was also reduced. A 3D gel culture system promoted the maturation of immature biliary epithelial cells, with increased expression of CK19+ cells and the formation of a duct-like structure. The administration of Hes1 siRNA blocked this process. As a result, the cells remained in an immature state, and no duct-like structure was observed. CONCLUSION: Our data indicated that Hes1 might contribute to the maturation and the cellular structure organization of biliary epithelial cells, which provides new insight into understanding the pathology of biliary atresia.

Predictions of Preterm Birth from Early Pregnancy Characteristics: Born in Guangzhou Cohort Study.

Preterm birth (PTB, <37 weeks) is the leading cause of death in children <5 years of age. Early risk prediction for PTB would enable early monitoring and intervention. However, such prediction models have been rarely reported, especially in low- and middle-income areas. We used data on a number of easily accessible predictors during early pregnancy from 9044 women in Born in Guangzhou Cohort Study, China to generate prediction models for overall PTB and spontaneous, iatrogenic, late (34⁻36 weeks), and early (<34 weeks) PTB. Models were constructed using the Cox proportional hazard model, and their performance was evaluated by Harrell's c and D statistics and calibration plot. We further performed a systematic review to identify published models and validated them in our population. Our new prediction models had moderate discrimination, with Harrell's c statistics ranging from 0.60⁻0.66 for overall and subtypes of PTB. Significant predictors included maternal age, height, history of preterm delivery, amount of vaginal bleeding, folic acid intake before pregnancy, and passive smoking during pregnancy. Calibration plots showed good fit for all models except for early PTB. We validated three published models, all of which were from studies conducted in high-income countries; the area under receiver operating characteristic for these models ranged from 0.50 to 0.56. Based on early pregnancy characteristics, our models have moderate predictive ability for PTB. Future studies should consider inclusion of laboratory markers for the prediction of PTB.

Early life vitamin D status and asthma and wheeze: a systematic review and meta-analysis.

BACKGROUND: Vitamin D deficiency has been linked to an increased risk of asthma. This study aimed to quantify the effect of early life vitamin D status on asthma and wheeze later in life. METHODS: PubMed, Embase, CINAHL, and CNKI databases, the Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 2017. We included randomized controlled trials (RCTs) and cohort studies with vitamin D level in blood (maternal or cord or infant) or intake (maternal intake during pregnancy or infant intake) and asthma and/or wheeze. Two reviewers independently extracted data. Fixed- and random-effects models were used to summarize the risk estimates of comparisons between highest vs. lowest vitamin D categories. RESULTS: Of the 1485 studies identified, three RCTs and 33 cohort studies were included. We did not include the RCTs (1619 participants) in the meta-analysis as the comparators and outcome definitions were heterogenous. Three RCTs reported a non-statistically significant effect of vitamin D supplementation during pregnancy on offspring wheeze/asthma at 3 years of age. Pooled estimates of cohort studies suggest no association between antenatal blood vitamin D levels or vitamin D intake and offspring asthma assessed either > 5 years or ≤ 5 years. The estimate for blood vitamin D remained unchanged when two studies assessing asthma in adulthood were excluded, but a significant inverse association emerged between vitamin D intake and childhood asthma. We found no association between antenatal vitamin D level and wheeze. On the other hand, vitamin D intake during pregnancy may have a protective effect against wheeze. CONCLUSIONS: The pooled estimates from cohort studies show no association between antenatal blood vitamin D level and asthma/wheeze in later life. Whereas, the pooled estimates from cohort studies suggest that antenatal vitamin D intake may have an effect on childhood asthma > 5 years or childhood wheeze. The inconsistent results from studies assessing vitamin D either in blood or intake may be explained by previously reported non-linear association between blood vitamin D3 and childhood asthma. Further trials with enough power and longer follow-up time should be conducted to confirm the results.

Selective α-Monomethylation by an Amine-Borane/N,N-Dimethylformamide System as the Methyl Source.

A new and practical α-monomethylation strategy using an amine-borane/N,N-dimethylformamide (R3 N-BH3 /DMF) system as the methyl source was developed. This protocol has been found to be effective in the α-monomethylation of arylacetonitriles and arylacetamides. Mechanistic studies revealed that the formyl group of DMF delivered the carbon and one hydrogen atoms of the methyl group, and R3 N-BH3 donated the remaining two hydrogen atoms. Such a unique reaction pathway enabled controllable assemblies of CDH2 -, CD2 H-, and CD3 - units using Me2 NH-BH3 /d7 -DMF, Me3 N-BD3 /DMF and Me3 N-BD3 /d7 -DMF systems, respectively. Further application of this method to the facile synthesis of anti-inflammatory flurbiprofen and its varied deuterium-labeled derivatives was demonstrated.

Human Cytomegalovirus Immediate Early 1 Protein Causes Loss of SOX2 from Neural Progenitor Cells by Trapping Unphosphorylated STAT3 in the Nucleus.

The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV infection to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here, we show that HCMV infection of NPCs results in loss of the SOX2 protein, a key pluripotency-associated transcription factor. SOX2 depletion maps to the HCMV major immediate early (IE) transcription unit and is individually mediated by the IE1 and IE2 proteins. IE1 causes SOX2 downregulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Deranged signaling resulting in depletion of a critical stem cell protein is an unanticipated mechanism by which the viral major IE proteins may contribute to brain development disorders caused by congenital HCMV infection.IMPORTANCE Human cytomegalovirus (HCMV) infections are a leading cause of brain damage, hearing loss, and other neurological disabilities in children. We report that the HCMV proteins known as IE1 and IE2 target expression of human SOX2, a central pluripotency-associated transcription factor that governs neural progenitor cell (NPC) fate and is required for normal brain development. Both during HCMV infection and when expressed alone, IE1 causes the loss of SOX2 from NPCs. IE1 mediates SOX2 depletion by targeting STAT3, a critical upstream regulator of SOX2 expression. Our findings reveal an unanticipated mechanism by which a common virus may cause damage to the developing nervous system and suggest novel targets for medical intervention.