Berberine ameliorates chronic intermittent hypoxia-induced cardiac remodelling by preserving mitochondrial function, role of SIRT6 signalling.

Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH-induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH-induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno-associated virus 9 (AAV9) carrying SIRT6 or SIRT6-specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK-FOXO3a signalling. BBR dose-dependently ameliorated cardiac injury in CIH-induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6-specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6-AMPK-FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1-Parkin-mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH-induced cardiac dysfunction. BBR attenuates CIH-induced myocardial injury by improving mitochondrial biogenesis and PINK1-Parkin-dependent mitophagy via the SIRT6-AMPK-FOXO3a signalling pathway.

Radiation-induced nasopharyngeal ulcers after re-irradiation with intensity-modulated radiotherapy in locoregional recurrent nasopharyngeal carcinoma patients: a dose-volume-outcome analysis.

OBJECTIVE: To analyze the interrelation between radiation dose and radiation-induced nasopharyngeal ulcer (RINU) in locoregional recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS: Clinical data were collected from 363 patients with locoregional recurrent NPC who received re-irradiated with definitive IMRT from 2009 to 2017. Twenty-nine patients were diagnosed with RINU. Univariate and multivariate analyses were used to re-evaluate the first and second radiotherapy plans and to identify predictive dosimetric factors. RESULTS: All dosimetric parameters were notably associated with the progression to RINU (p < 0.01) using paired samples Wilcoxon signed rank tests. Multivariate analysis showed that EQD2_ [Formula: see text]D80 (dose for 80 percent volume of the unilateral nasopharynx lesion) was an independent prognostic factor for RINU (p = 0.001). The area under the ROC curve for EQD2_ [Formula: see text]D80 was 0.846 (p < 0.001), and the cutoff point of 137.035 Gy could potentially be the dose tolerance of the nasopharyngeal mucosa. CONCLUSIONS: The sum of equivalent dose in 2 Gy fractions (EQD2) in the overlapping volumes between initial and re-irradiated nasopharyngeal mucosal tissue can be effective in predicting the hazard of developing RINU in NPC patients undergoing radical re­irradiation with IMRT and we propose a EQD2_ [Formula: see text]D80 threshold of 137.035 Gy for the nasopharynx.

Identifying High-Quality Non-Instrumental Dysphagia Screening Tools for Detection of Adult Dysphagia Case in Acute-Care Settings: A Systematic Review.

INTRODUCTION: As patients nowadays tend to have multiple diseases and complex medical histories, our aim was to identify high-quality, non-instrumental dysphagia screening tools used for the detection of adult dysphagia cases in all disease categories in acute-care settings. METHOD: A literature search was conducted in five databases from each database's earliest inception to 31 July 2021 and guided by five keywords: 'dysphagia', 'deglutition', 'screening', 'test' and 'measure'. Without limiting the search in any specific disease category, reviewers assessed original studies and identified tools if they had been validated against instrumental evaluations and if they had been designed as a pass-fail procedure to screen whether dysphagia is absent or present. We further excluded any tool if it was (1) for pediatric focus, or (2) a patient self-report questionnaire. All final tool candidates underwent a methodological quality appraisal using the Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). RESULT: Out of 195 studies with 165 tools identified, 20 tool candidates underwent QUADAS-2 review. We found six high-quality, non-instrumental screening tools for detecting adult dysphagia cases in acute-care settings, including the Yale Swallow Protocol, Gugging Swallowing Screen, Toronto Bedside Swallowing Screening Test (both English and Portuguese versions), Sapienza Global Bedside Evaluation of Swallowing and Two-Step Thickened Water Test. These high-quality tools were developed primarily for patients with stroke. Only Yale Swallow Protocol was originally tested for heterogeneous populations with stroke, multiple sclerosis, traumatic brain injury, oesophageal surgery, neurosurgery and head-and-neck cancer. CONCLUSIONS: The results highlight the gap in the unavailability of high-quality dysphagia screening tool in several emerged high-risk populations including elderly inpatients, or patients following endotracheal extubation. Further research is needed to determine whether these six tools can be effectively applied across different high-risk populations in acute-care settings to screen for cases finding.

Microglia and macrophages in the neuro-glia-vascular unit: From identity to functions.

Although both are myeloid cells located surrounding cerebral vasculature, vessel-associated microglia (VAM) and perivascular macrophages (PVMs) can be distinguished by their distinct morphologies, signatures and microscopic location. As key component of neuro-glia-vascular unit (NGVU), they play prominent roles in neurovasculature development and pathological process of various central nervous system (CNS) diseases, including phagocytosis, angiogenesis, vessel damage/protection and blood flow regulation, therefore serving as potential targets for therapeutics of a broad array of CNS diseases. Herein, we will provide a comprehensive overview of heterogeneity of VAM/PVMs, highlight limitations of current understanding in this field, and discuss possible directions of future investigations.

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood-brain barrier integrity after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI. METHODS: We employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood-brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, sensorimotor function and cognitive function were assessed by a battery of behavioral tests. RESULTS: The activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI. CONCLUSION: ASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI.

Chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy.

Chaperone-mediated autophagy (CMA) is the selective degradation process of intracellular components by lysosomes, which is required for the degradation of aggregate-prone proteins and contributes to proteostasis maintenance. Proteostasis is essential for normal cell function and survival, and it is determined by the balance of protein synthesis and degradation. Because postmitotic neurons are highly susceptible to proteostasis disruption, CMA is vital for the nervous system. Since Parkinson's disease (PD) was first linked to CMA dysfunction, an increasing number of studies have shown that CMA loss, as seen during aging, occurs in the pathogenetic process of neurodegenerative diseases. Here, we review the molecular mechanisms of CMA, as well as the physiological function and regulation of this autophagy pathway. Following, we highlight its potential role in neurodegenerative diseases, and the latest advances and challenges in targeting CMA in therapy of neurodegenerative diseases.

Polychaete Bioturbation Alters the Taxonomic Structure, Co-occurrence Network, and Functional Groups of Bacterial Communities in the Intertidal Flat.

Polychaetes are important benthic macrofauna that lives in sediments, usually in intertidal flats with high organic content and high sulfide. It has been suggested that polychaete bioturbation could perform environmental remediation. During the process, the microbial community plays important roles. Here, we used high-throughput sequencing technology to study the bioturbation effects on the bacterial community in the polychaete (Perinereis aibuhitensis) burrows at different tidal positions in intertidal flat. The results showed that the bacterial communities were dramatically influenced by the polychaete bioturbation. The ACE, Chao, and Shannon indices of the polychaete burrows increased in summer. Dominant phyla in the polychaete burrows were Proteobacteria, Campilobacterota, Desulfobacterota, Chloroflexi, and Bacteroidota, and the dominant bacterial families were Sulfurvaceae, Flavobacteriaceae, Rhodobacteraceae, Woeseiaceae, Desulfobulbaceae, and Sulfurimonadaceae. Results of linear discriminant analysis effect size (LEfSe) showed that groups that include organic matter degraders, such as Bacteroidota, Flavobacteriaceae, Rhodobacteraceae, Woeseiaceae, and groups that include sulfur oxidizers, such as Campilobacterota, Sulfurovaceae, Rhodobacteraceae, Desulfobulbaceae, and Sulfurimonadaceae, were significantly increased due to the polychaete bioturbation. The polychaete bioturbation reduced the complexity of the bacterial co-occurrence network while increased its modularity and homogeneity. The polychaete bioturbation also changed the functional groups, which significantly enhanced in functional groups of aerobic nitrite oxidation, nitration, dark thiosulfate oxidation, dark sulfur oxidation, and dark sulfite oxidation, while nitrogen respiration and nitrate respiration decreased. These results provide insight into the impact of bacterial communities under the intertidal polychaete bioturbation.

Association between Cesarean section delivery and increased risk of childhood Kawasaki disease.

AIM: Cesarean section delivery is associated with microbiota disruption and immuno-dysregulation during childhood, but the association with Kawasaki disease remains uncertain. We aimed to evaluate the association between Cesarean section and Kawasaki disease. METHODS: We examined the association between Kawasaki disease between six and eighteen months and Cesarean section within a birth cohort of 15,796 mother-infant pairs in Taiwan. The associations were assessed with Poisson regression in the study population, in the 1:2 propensity score-matched subpopulation, and compared with febrile convulsion, trauma and accidents during the same interval as negative control outcomes. RESULTS: Cesarean section was found to increase the risk of Kawasaki disease among overall population (adjusted relative risk [aRR]: 2.22, 95 % confidence interval (CI): 1.14-4.34) and the matched subpopulation (aRR: 2.29, 95 % CI: 1.14-4.68 in PS-matched subpopulation). Meanwhile, there was no association between Cesarean section and the clinic visits for febrile convulsion, trauma and accidents. CONCLUSION: In conclusion, this study identified a potential association between Cesarean section delivery and a higher risk of Kawasaki disease during six-to eighteen months of the prospective birth cohort in Taiwan.

Absence of the lectin-like domain of thrombomodulin reduces HSV-1 lethality of mice with increased microglia responses.

BACKGROUND: Herpes simplex virus 1 (HSV-1) can induce fatal encephalitis. Cellular factors regulate the host immunity to affect the severity of HSV-1 encephalitis. Recent reports focus on the significance of thrombomodulin (TM), especially the domain 1, lectin-like domain (TM-LeD), which modulates the immune responses to bacterial infections and toxins and various diseases in murine models. Few studies have investigated the importance of TM-LeD in viral infections, which are also regulated by the host immunity. METHODS: In vivo studies comparing wild-type and TM-LeD knockout mice were performed to determine the role of TM-LeD on HSV-1 lethality. In vitro studies using brain microglia cultured from mice or a human microglia cell line to investigate whether and how TM-LeD affects microglia to reduce HSV-1 replication in brain neurons cultured from mice or in a human neuronal cell line. RESULTS: Absence of TM-LeD decreased the mortality, tissue viral loads, and brain neuron apoptosis of HSV-1-infected mice with increases in the number, proliferation, and phagocytic activity of brain microglia. Moreover, TM-LeD deficiency enhanced the phagocytic activity of brain microglia cultured from mice or of a human microglia cell line. Co-culture of mouse primary brain microglia and neurons or human microglia and neuronal cell lines revealed that TM-LeD deficiency augmented the capacity of microglia to reduce HSV-1 replication in neurons. CONCLUSIONS: Overall, TM-LeD suppresses microglia responses to enhance HSV-1 infection.

Near-eye display with a triple-channel waveguide for metaverse.

We present a near-eye display featuring a triple-channel waveguide with chiral liquid crystal gratings. Our triple-channel waveguide is capable of dividing one field of view into three through both the polarization orthogonality and angular separation. To illustrate its principle, a k-space diagram, which takes into account the aspect ratio of field of view, is depicted. Our results demonstrate that its diagonal field of view reaches 90°, eye relief is 10 mm, exit pupil is 4.9 × 4.9 mm2, transmittance is 4.9%, and uniformity is 89%.

Caspase-1 variant influencing CSF tau and FDG PET levels in non-demented elders from the ADNI cohort.

BACKGROUND: Genetic variations in the inflammatory Caspase-1 gene have been shown associated with cognitive function in elderly individuals and in predisposition to Alzheimer's disease (AD), but its detailed mechanism before the typical AD onset was still unclear. Our current study evaluated the impact of Caspase-1 common variant rs554344 on the pathological processes of brain amyloidosis, tauopathy, and neurodegeneration. METHODS: Data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the relationship between Caspase-1 rs554344 allele carrier status with AD-related cerebrospinal fluid (CSF), PET, and MRI measures at baseline by using a multiple linear regression model. We also analyzed the longitudinal effects of this variant on the change rates of CSF biomarkers and imaging data using a mixed effect model. RESULTS: We found that Caspase-1 variant was significantly associated with FDG PET levels and CSF t-tau levels at baseline in total non-demented elderly group, and especially in mild cognitive impairment (MCI) subgroup. In addition, this variant was also detected associated with CSF p-tau levels in MCI subgroup. The mediation analysis showed that CSF p-tau partially mediated the association between Caspase-1 variant and CSF t-tau levels, accounting for 80% of the total effect. CONCLUSIONS: Our study indicated a potential role of Caspase-1 variant in influencing cognitive function might through changing tau related-neurodegeneration process.

Dynamic changes of CSF clusterin levels across the Alzheimer's disease continuum.

BACKGROUND: Clusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD. METHODS: Following the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aß42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aß42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aß42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aß42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aß42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups. RESULTS: Compared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P <  0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aß42 (ß = 0.040, P <  0. 001), CSF p-tau (ß = 0.325, P <  0.001) and CSF t-tau (ß = 0.346, P <  0.001). CONCLUSIONS: Our results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aß pathology; and the increased levels are associated with tau pathology and neurodegeneration.

Inhibition of caspase-1 ameliorates tauopathy and rescues cognitive impairment in SAMP8 mice.

The inflammasome assembles leading to increased cleavage and activity of caspase-1 and downstream IL-1ß release, which plays a significant role in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that caspase-1-mediated neuroinflammation occurs early in AD process. However, the detailed role of caspase-1 in aging-related AD-like neuropathology is still unclear so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we detected the levels of caspase-1 in brains of 3-, 7-, and 11-month-old mice and observed that caspase-1 was activated during aging process. More importantly, we provided the evidence that VX-765, a selective inhibitor of caspase-1, significantly rescued spatial learning and memory impairments and reduced tau hyperphosphorylation in brains of SAMP8 mice at early stages of the disease. This amelioration might be attributed to IL-1ß-induced hypoactivation of tau kinases. Our results imply that caspase-1 may represent as a potential therapeutic target for neurodegenerative tauopathies.

HMG20A Inhibit Adipogenesis by Transcriptional and Epigenetic Regulation of MEF2C Expression.

Obesity and its associated metabolic disease do serious harm to human health. The transcriptional cascade network with transcription factors as the core is the focus of current research on adipogenesis and its mechanism. Previous studies have found that HMG domain protein 20A (HMG20A) is highly expressed in the early stage of adipogenic differentiation of porcine intramuscular fat (IMF), which may be involved in regulating adipogenesis. In this study, HMG20A was found to play a key negative regulatory role in adipogenesis. Gain- and loss-of-function studies revealed that HMG20A inhibited the differentiation of SVF cells and C3H10T1/2 cells into mature adipocytes. RNA-seq was used to screen differentially expressed genes after HMG20A knockdown. qRT-PCR and ChIP-PCR confirmed that MEF2C was the real target of HMG20A, and HMG20A played a negative regulatory role through MEF2C. HMG20A binding protein LSD1 was found to alleviate the inhibitory effect of HMG20A on adipogenesis. Further studies showed that HMG20A could cooperate with LSD1 to increase the H3K4me2 of the MEF2C promoter and then increase the expression of MEF2C. Collectively, these findings highlight a role for HMG20A-dependent transcriptional and epigenetic regulation in adipogenesis.

[Improvement on compactibility of the alcoholic extract of Zingiberis Rhizoma by co-spray drying with HPMC].

Aiming to solve the poor compactibility of the alcoholic extract of Zingiberis Rhizoma(ZR), this study explored the feasibility of its physical modification using co-spray drying with a small amount of hydroxypropyl methyl cellulose(HPMC). Based on the univariate analysis, the influence of two independent variables(the HPMC content in the product and the solid content of spray material) on the powder properties and tablet properties of the dried product was investigated by the central composite design. With the tensile strength and disintegration time of the tablets as the evaluation indexes, the optimal prescription was determined as follows: the HPMC content was 15% and the solid content of spray material was 25.6%. The accuracy of the regression model established for predicting tensile strength and disintegration time of tablets was verified, and the results revealed that the measured values were close to the predicted ones with deviations of 0.47% and-8.2%, indicating good prediction and reproducibility of the model. The tensile strength(4.24 MPa) of tablets prepared with the optimal prescription was 3.59 times that(1.18 MPa, far lower than the baseline of 2 MPa for qualified tablets) with the spray-dried powder of the ZR. On the other hand, due to the addition of HPMC, the disintegration time of tablets increased from 7.3 min to 24.6 min. On the whole, this study provided a new strategy to solve the common problem of poor compactibility of raw Chinese medicinal materials, which facilitated the successful preparation of Chinese medicinal tablets with high drug loads.

Genome-wide association analysis reveals genetic variations and candidate genes associated with salt tolerance related traits in Gossypium hirsutum.

BACKGROUND: Cotton is more resistant to salt and drought stresses as compared to other field crops, which makes itself as a pioneer industrial crop in saline-alkali lands. However, abiotic stresses still negatively affect its growth and development significantly. It is therefore important to breed salt tolerance varieties which can help accelerate the improvement of cotton production. The development of molecular markers linked to causal genes has provided an effective and efficient approach for improving salt tolerance. RESULTS: In this study, a genome-wide association study (GWAS) of salt tolerance related traits at seedling stage was performed based on 2 years of phenotype identification for 217 representative upland cotton cultivars by genotyping-by-sequencing (GBS) platform. A total of 51,060 single nucleotide polymorphisms (SNPs) unevenly distributed among 26 chromosomes were screened across the cotton cultivars, and 25 associations with 27 SNPs scattered over 12 chromosomes were detected significantly (-log10p > 4) associated with three salt tolerance related traits in 2016 and 2017. Among these, the associations on chromosome A13 and D08 for relative plant height (RPH), A07 for relative shoot fresh matter weight (RSFW), A08 and A13 for relative shoot dry matter weight (RSDW) were expressed in both environments, indicating that they were likely to be stable quantitative trait loci (QTLs). A total of 12 salt-induced candidate genes were identified differentially expressed by the combination of GWAS and transcriptome analysis. Three promising genes were selected for preliminary function verification of salt tolerance. The increase of GH_A13G0171-silenced plants in salt related traits under salt stress indicated its negative function in regulating the salt stress response. CONCLUSIONS: These results provided important genetic variations and candidate genes for accelerating the improvement of salt tolerance in cotton.

Prevalence of childhood wheeze and modified DNA methylation at 7 years of age according to maternal folate levels during pregnancy in the Hokkaido Study.

BACKGROUND: A high dose of folic acid during pregnancy may increase the risk of asthma, wheezing, and respiratory disease in childhood. Folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated associations between maternal folate levels during pregnancy and childhood wheezing; furthermore, the study assessed whether maternal folate-modified DNA methylation is related to asthma. Methods Participants in the current study were 6651 mother-child pairs who had complete data on characteristics and who had completed at least one of the International Study of Asthma and Allergies in Childhood questionnaires when the child was 1, 2, 4, and 7 years of age. Moreover, a case-control study to assess DNA methylation at 7 years of age was conducted among 136 children who experienced wheezing and a control group of 139 children with no history of allergies. Results The median of maternal serum was 16.76 nmol/L, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheezing at 2 years age according to maternal folate levels, compared with the lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second, 1.27 [1.05, 1.55]); however, no changes were observed at 1, 4, and 7 years of age. In a case-control study, no association of maternal folate levels with DNA methylation was observed. Conclusion Our results suggest that maternal folate did not affect persistent wheezing in school-aged children, or DNA methylation of gasdermin B, orosomucoid-like 3, and Ikaros family zinc finger 3 at 7 years of age.

Associations Between Infant Developmental Delays and Secondhand Smoke Exposure Modified by Maternal Prepregnancy Overweight and Obesity Status.

INTRODUCTION: Secondhand smoke exposure during pregnancy has long been associated with adverse health outcomes in children, but only a few studies have examined its effect modifiers. In this study, we applied effect modification analysis for maternal prepregnancy weight status on detrimental neurodevelopmental effect of secondhand smoke exposure during pregnancy and infancy in a nationwide representative population. AIMS AND METHODS: Term singleton mother-infant pairs with nonsmoking mothers were included for main analysis (N = 15 987) from the Taiwan Birth Cohort Study (TBCS), and were further matched with propensity score (n = 5434). We extracted secondhand smoke exposure during pregnancy and infancy, and eight neurodevelopmental milestones from the responses in the baseline visit at 6 months, and 18-month follow-up of TBCS. The associations between secondhand smoke exposure and neurodevelopmental achievement were analyzed with multivariable logistic regression and Cox model. Propensity score weighting and matching were applied for high-versus-low analysis, and relative excess risk due to interaction were used to estimate effect modification. RESULTS: Higher secondhand smoke exposure was associated with increased likelihood of delayed milestone achievement across gross motor, fine motor, language-related, and social-related domains. The associations in fine motor domains remained observable in propensity score-weighted and -matched models. We identified additive interaction with self-reported maternal overweight and obesity status before pregnancy in milestone development for walking with support, scribbling, and waving goodbye. CONCLUSIONS: Secondhand smoke exposure during pregnancy and infancy were associated with delayed neurodevelopmental milestone achievement at 18 months, and the associations were modified by maternal prepregnancy overweight and obesity status. IMPLICATIONS: The study results suggested the association between maternal secondhand smoke exposure during pregnancy and infancy and delayed fine motor and language-related milestone achievement at 18 months in multivariable, propensity score weighting, and matching populations. The results of positive effect modifications for maternal prepregnancy overweight and obesity status suggested the importance of concurrent interventions on smoke-free environment and maternal health during pregnancy.

Intrauterine exposure to per- and polyfluoroalkyl substances may harm children's lung function development.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUA), are common persistent environmental organic pollutants. Animal studies have indicated that PFAS influence inflammatory responses and lung development. However, whether prenatal or childhood PFAS exposure affects children's lung function remains unclear. This study aimed to investigate both in utero exposure and childhood exposure to PFAS and the relationships between them and lung function development in childhood. METHODS: In total, 165 children were recruited from the Taiwan Birth Panel Study (TBPS). Cord blood plasma and children's serum were collected when they were eight years old. PFAS levels were analysed by ultra-high-performance liquid chromatography/tandem mass spectrometry. When these children reached eight years of age, we administered detailed questionnaires and lung function examinations. RESULTS: The mean concentrations of PFOA, PFOS, PFNA and PFUA in cord blood among the 165 study children were 2.4, 6.4, 6.0, and 15.4 ng/mL, respectively. The mean concentrations in serum from eight-year-olds were 2.7, 5.9, 0.6, and 0.3 ng/mL, respectively. At eight years of age, the mean FEV1 (forced expiratory volume per sec), FVC (forced vital capacity), PEF (peak expiratory flow) and FEV1/FVC values were 1679 mL, 1835 mL, 3846 mL/s and 92.0%, respectively. PFOA, PFOS, PFNA and PFUA levels in cord blood were inversely associated with FEV1, FVC and PEF values. The PFOS concentration in cord blood was the most consistently correlated with decreasing lung function before and after adjusting for confounding factors. The PFOS concentration was also significantly inversely correlated with lung function in subgroups with lower birth weight and allergic rhinitis. CONCLUSIONS: Our cohort study revealed that the concentrations of PFOA, PFOS, PFNA and PFUA were higher in cord blood than in serum from eight-year-olds. Some trends were also noted between intrauterine PFOS exposure and children's decreasing FEV1, FVC and PEF, especially in subgroups with lower birth weight and allergic rhinitis. Therefore, intrauterine PFAS exposure, especially PFOS, may play a vital role in lung development.

Associations between household incense burning and delayed motor development among preterm infants modified by gestational age and maternal educational status.

BACKGROUND: Household incense burning is a common ritual behavior in the Asia-Pacific region but has been associated with inferior developmental outcomes in term infants. We aimed to examine these associations among preterm infants. METHODS: Information from 1190 mother-infant pairs during 6- and 18-month follow-up to the Taiwan Birth Cohort Study was examined for associations between household incense burning exposure and infant neurodevelopmental milestone achievement using multivariable Cox proportional hazard model with propensity score weighting, along with stratified, sensitivity, and decomposition analysis. RESULTS: Household incense burning exposure was associated with delayed gross motor milestone achievement among all preterm infants according to the Cox model and after propensity score weighting. Meanwhile, associations for delayed development were found in gross motor domain milestones among late preterm infants, while fine motor domain delay was found among other preterm infants. Furthermore, the associations between household incense burning status and gross motor milestone delays were attenuated by the interaction between higher education level and household incense burning exposure status. CONCLUSIONS: Household incense burning exposure was associated with delays, and the motor domains affected differed according to degree of prematurity. These associations were modified by the attenuation upon higher maternal educational status and exposure status interaction.