The developmental phenotype of motor delay in extremely preterm infants following early-life respiratory adversity is influenced by brain dysmaturation in the parietal lobe.

BACKGROUND: Research indicates that preterm infants requiring prolonged mechanical ventilation often exhibit suboptimal neurodevelopment at follow-up, coupled with altered brain development as detected by magnetic resonance imaging (MRI) at term-equivalent age (TEA). However, specific regions of brain dysmaturation and the subsequent neurodevelopmental phenotype following early-life adverse respiratory exposures remain unclear. Additionally, it is uncertain whether brain dysmaturation mediates neurodevelopmental outcomes after respiratory adversity. This study aims to investigate the relationship between early-life adverse respiratory exposures, brain dysmaturation at TEA, and the developmental phenotype observed during follow-up in extremely preterm infants. METHODS: 89 infants born < 29 weeks' gestation from 2019 to 2021 received MRI examinations at TEA for structural and lobe brain volumes, which were adjusted with sex-and-postmenstrual-age expected volumes for volume residuals. Assisted ventilation patterns in the first 8 postnatal weeks were analyzed using kmlShape analyses. Patterns for motor, cognition, and language development were evaluated from corrected age 6 to 12 months using Bayley Scales of Infant Development, third edition. Mediation effects of brain volumes between early-life respiratory exposures and neurodevelopmental phenotypes were adjusted for sex, gestational age, maternal education, and severe brain injury. RESULTS: Two distinct respiratory trajectories with varying severity were identified: improving (n = 35, 39%) and delayed improvement (n = 54, 61%). Compared with the improving group, the delayed improvement group exhibited selectively reduced brain volume residuals in the parietal lobe (mean - 4.9 cm3, 95% confidence interval - 9.4 to - 0.3) at TEA and lower motor composite scores (- 8.7, - 14.2 to - 3.1) at corrected age 12 months. The association between delayed respiratory improvement and inferior motor performance (total effect - 8.7, - 14.8 to - 3.3) was partially mediated through reduced parietal lobe volume (natural indirect effect - 1.8, - 4.9 to - 0.01), suggesting a mediating effect of 20%. CONCLUSIONS: Early-life adverse respiratory exposure is specifically linked to the parietal lobe dysmaturation and neurodevelopmental phenotype of motor delay at follow-up. Dysmaturation of the parietal lobe serves as a mediator in the connection between respiratory adversity and compromised motor development. Optimizing respiratory critical care may emerge as a potential avenue to mitigate the consequences of altered brain growth and motor developmental delay in this extremely preterm population.

Efficient Biodegradation of the Neonicotinoid Insecticide Flonicamid by Pseudaminobacter salicylatoxidans CGMCC 1.17248: Kinetics, Pathways, and Enzyme Properties.

Nitrile-containing insecticides can be converted into their amide derivatives by Pseudaminobacter salicylatoxidans. N-(4-trifluoromethylnicotinoyl) glycinamide (TFNG-AM) is converted to 4-(trifluoromethyl) nicotinoyl glycine (TFNG) using nitrile hydratase/amidase. However, the amidase that catalyzes this bioconversion has not yet been fully elucidated. In this study, it was discovered that flonicamid (FLO) is degraded by P. salicylatoxidans into the acid metabolite TFNG via the intermediate TFNG-AM. A half-life of 18.7 h was observed for P. salicylatoxidans resting cells, which transformed 82.8% of the available FLO in 48 h. The resulting amide metabolite, TFNG-AM, was almost all converted to TFNG within 19 d. A novel amidase-encoding gene was cloned and overexpressed in Escherichia coli. The enzyme, PmsiA, hydrolyzed TFNG-AM to TFNG. Despite being categorized as a member of the amidase signature enzyme superfamily, PsmiA only shares 20-30% identity with the 14 previously identified members of this family, indicating that PsmiA represents a novel class of enzyme. Homology structural modeling and molecular docking analyses suggested that key residues Glu247 and Met242 may significantly impact the catalytic activity of PsmiA. This study contributes to our understanding of the biodegradation process of nitrile-containing insecticides and the relationship between the structure and function of metabolic enzymes.

Very Long-Term Functional Outcomes and Dependency in Children With Anti-NMDA Receptor Encephalitis.

OBJECTIVES: To assess the daily function of children with anti-N-methyl-d-aspartate receptor encephalitis (NMDARe) after a minimal follow-up of 5 years. METHODS: Patients 18 years and younger by the time of disease onset, whose serum and CSF were studied in our center between 2013 and 2017, were included in the study. Patients' daily life function was assessed by their physicians using a 15-domain question format (Liverpool Outcome Score). RESULTS: Of 76 patients, 8 (11%) died and 68 were followed for a mean of 7.1 years (SD 1.5 years, range: 5.0-10.1). Three outcome patterns were identified: full recovery (50; 73%); behavioral and school/working deficits (12; 18%); and multidomain deficits (6; 9%) involving self-care ability, behavioral-cognitive impairment, and seizures. Younger age of disease onset was significantly associated with multidomain deficits (OR 1.6, 95% CI 1.02-2.4, p = 0.04), particularly in children younger than 6 years, among whom 8 of 23 (35%) remained sociofamiliar dependent. DISCUSSION: After a minimal follow-up of 5 years, most children with NMDARe had substantial or full functional recovery, but approximately one-fifth remained with behavioral and school/working deficits. The younger the patient at disease onset, the more probable it was to remain with multidomain deficits and dependent on sociofamiliar support.

MOG Antibodies Restricted to CSF in Children With Inflammatory CNS Disorders.

OBJECTIVES: To assess the clinical significance of myelin oligodendrocyte glycoprotein antibodies (MOG-abs) restricted to CSF in children with inflammatory CNS disorders. METHODS: Patients included 760 children (younger than 18 years) from 3 multicenter prospective cohort studies: (A) acquired demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM); (B) non-ADEM encephalitis; and (C) noninflammatory neurologic disorders. For all cases, paired serum/CSF samples were systematically examined using brain immunohistochemistry and live cell-based assays. RESULTS: A total of 109 patients (14%) had MOG-abs in serum or CSF: 79 from cohort A, 30 from B, and none from C. Of these, 63 (58%) had antibodies in both samples, 37 (34%) only in serum, and 9 (8%) only in CSF. Children with MOG-abs only in CSF were older than those with MOG-abs only in serum or in both samples (median 12 vs 6 vs 5 years, p = 0.0002) and were more likely to have CSF oligoclonal bands (86% vs 12% vs 7%, p = 0.0001) and be diagnosed with multiple sclerosis (6/9 [67%] vs 0/37 [0%] vs 1/63 [2%], p < 0.0001). DISCUSSION: Detection of MOG-abs in serum or CSF is associated with CNS inflammatory disorders. Children with MOG-abs restricted to CSF are more likely to have CSF oligoclonal bands and multiple sclerosis than those with MOG-abs detectable in serum.

The Quartile Levels of Thyroid-Stimulating Hormone by Newborn Screening Stratified Risks of Neurodevelopmental Impairment in Extremely Preterm Infants - A Population Cohort Study.

BACKGROUND: To evaluate whether thyroid-stimulating hormone (TSH) by newborn screening (NBS) at birth and at discharge can be surrogate markers for neurodevelopmental impairment (NDI) in extremely preterm infants. METHODS: The population cohort enrolled infants born <29 weeks' gestation in 2008 - 2020 in southern Taiwan. Infants with a maternal history of thyroid disorders and infants who required thyroxine supplementation during hospitalization were excluded. TSH levels by NBS at birth and at term-equivalent age (TEA)/discharge were respectively categorized into the lowest quartile, the interquartile range, and the highest quartile, which were correlated to NDI outcomes. RESULTS: Among 392 patients with paired TSH data, 358 (91%) were prospectively followed until corrected age 24 months. At birth, infants with lowest-quartile TSH had higher NDI risks (OR 2.3, 95% CI 1.3 - 4.1, P = 0.004) compared to infants with interquartile-range TSH. Conversely, by TEA/discharge, infants with highest-quartile TSH had increased NDI (OR 1.9, 1.0 - 3.4, P = 0.03). By paired TSH categories, infants persistently in the lowest TSH quartile (48%, aOR 4.4, 1.4 - 14.5, P = 0.01) and those with a shift from interquartile range to the highest quartile (32%, aOR 2.7, 1.0 - 7.4, P = 0.046) had increased NDI risks compared with the reference with consistent interquartile-range TSH. CONCLUSIONS: Extremely preterm infants persistently in the lowest-quartile TSH level at birth and at discharge had the highest NDI risk. TSH quartile levels by NBS may serve as a population surrogate biomarker for assessing NDI risks in infants born extremely preterm.

Dust detection and cleanliness assessment based on S-YOLOv5s for NPP reactor containment wall-climbing cleaning robot.

NPP reactor containment dust can easily turn into radioactive dust, endangering staff health and the environment. However, the nuclear reactor containment wall-climbing cleaning robot cleans blindly without the ability to clean the dust in a timely and thoroughly. In this paper, ShuffleNetV2-YOLOv5s (S-YOLOv5s) model is proposed to solve the problem of wall-climbing robots unable to detect different categories of dust in time. The use of ShuffleNetV2 in the backbone of the network not only ensures a large number of characterized channels and a large network capacity, but also reduces the complexity of the model; SIoU is chosen for the loss function to improve the model accuracy. Then, planar cleaning index (PCI) is proposed by combining the results of S-YOLOv5s to evaluate whether the wall-climbing cleaning robot cleans thoroughly. Compared to other methods, PCI considers amount and area occupation of different classes of dust. The dust data set is collected to train the designed model, and the model size is reduced to 14 % of the original model, and the FPS is 7.313 higher than the original model. Especially when compared with the state-of-the-art lightweight methods, our model has smaller model size and higher recognition speed. Experimental results have shown that our dust detection and cleanliness assessment method can be used on a wall-climbing cleaning robot to clean dust in time and thoroughly.

Association of Neonatal Antibiotic Exposure with Long-Term Growth Trajectory Faltering in Preterm-Birth Children.

INTRODUCTION: Preterm neonates often receive a variety of duration of antibiotic exposure during admission. The aim of the study was to evaluate whether neonatal antibiotic exposure is relevant with longitudinal growth problems in preterm-birth children. METHODS: This prospective study enrolled 481 infants who were born <32 weeks of gestation, discharged, and longitudinally followed from corrected age (CA) 6-60 months. After excluding 153 infants with blood culture-confirmed bacteremia, necrotizing enterocolitis, severe cerebral palsy, intestinal ostomy, and congenital anomaly, 328 infants were included for analysis. Covariates included perinatal demographics, neonatal morbidities, extrauterine growth restriction, and antibiotic exposure accumulated by term equivalent age. The primary outcome was the anthropometric trajectories in z-score of bodyweight (zBW), body height (zBH), and body mass index (zBMI) from CA 6-60 months. RESULTS: Antibiotic exposure duration was significantly negatively associated with zBW and zBH at CA 6, 12, and 60 months, and zBMI at CA 60 months. Multivariate generalized estimating equation analyses showed antibiotic exposure duration had significantly faltering z-score increment from CA 6 to 60 months in zBW and zBH (adjusted mean [95% CI]; ΔzBW: -0.021 [-0.041 to -0.001], p = 0.042; ΔzBH: -0.019 [-0.035 to -0.002], p = 0.027) after adjustment. Children with neonatal antibiotic exposure duration >15 days were significantly lower in the mean anthropometric zBW, zBH, and zBMI at CA 6, 12, 24, and 60 months compared with children with neonatal antibiotic exposure ≤15 days (all p < 0.01). CONCLUSIONS: Growth increments were negatively associated with antibiotic exposure duration in preterm neonates implicating that antibiotic stewardship and growth follow-up for preterm neonates are thus warranted.

Alleviative Effect of Ficus formosana Extract on Peripheral Neuropathy in Ovariectomized Diabetic Mice.

In diabetes mellitus, Ficus formosana has been reported to ameliorate blood sugar levels and inhibit inflammation through its polyphenol and flavonoid contents. However, its effect on diabetic peripheral neuropathy (DPN) remains unknown. This study aimed to investigate the effect of Ficus formosana extract (FFE) on DPN in ovariectomized diabetic mice. Ovariectomized female C57BL/6J mice fed a high-fat diet plus streptozotocin injections to induce type 2 diabetes were orally administered FEE at 20 or 200 mg/kg BW daily, for 6 weeks. To evaluate the pain responses in the paws of the mice, a von Frey filament test and a thermal hyperalgesia test were performed. Additionally, the intraepidermal and sciatic nerve sections were examined, along with an assessment of inflammation- and pain response-related mRNA expression in the paws of the mice. The results showed that the oral administration of both 20 and 200 mg/kg BW FEE significantly alleviated the hypersensitivity of the paw and the abnormal proliferation and rupture of the C fiber, and reduced the mRNA expression of interleukin-1ß, interleukin-6, interferon-γ, cyclooxygenase-2, and voltage-gated sodium channel 1.8 in the sciatic nerve of ovariectomized diabetic mice. We propose that FFE ameliorates peripheral neuropathy by suppressing oxidative damage in ovariectomized diabetic mice.

Neonicotinoid Imidacloprid Affects the Social Behavior of Adult Zebrafish by Damaging Telencephalon Neurons through Oxidation Stress, Inflammation, and Apoptosis.

The neonicotinoid imidacloprid is a widely used insecticide worldwide. We assessed the effects of acute and chronic imidacloprid exposure on the social behavior of adult zebrafish. We assembled simple apparatus to detect 2D locomotion: a single camera capture system and two specially designed water tanks. We then used the tracking and heat maps of the behavior trajectories of zebrafish subjected to sham and imidacloprid exposure and compared their social behavior. Furthermore, histomorphology and immunohistochemistry of their brain tissue sections were performed to clarify possible neurotoxicity due to imidacloprid exposure in our adult zebrafish. Our results showed that imidacloprid exposure significantly reduced the zebrafish's swimming speed, distance traveled, acceleration, and deceleration. The longer the imidacloprid exposure, the more severe the locomotor behavior disability. Furthermore, imidacloprid exposure significantly reduced heterosexual attractive behavior between the different sexes, as well as defensive alert behavior among males. Our histomorphology and immunohistochemistry evidence showed imidacloprid exposure may lead to neuronal oxidative stress, inflammation, apoptosis, and damage in the telencephalon of adult zebrafish. Thus, we suggested that neonicotinoid imidacloprid exposure can damage the telencephalon neurons of adult zebrafish through oxidative stress, inflammation, and apoptosis and then affect the social behavior of adult zebrafish.

The associations between prenatal phthalate exposure and childhood glycolipid metabolism and blood pressure: An updated systematic review and a pilot meta-analysis of prospective cohort studies.

This is the first pilot meta-analysis on the association of prenatal phthalate exposure with childhood cardiometabolic risks. A systematic literature search was performed in MEDLINE, Web of Science and CNKI (Chinese National Knowledge Infrastructure) until June 5, 2023. A total of seven studies with 5746 children (2646 girls and 3100 boys) were finally included. Four, three and two studies investigated the effects of maternal phthalate exposure on childhood blood pressure (BP), blood lipids and blood glucose profiles, respectively. The pilot meta-analysis suggested that di-2-ethylhexyl phthalate (DEHP) metabolite exposure was associated with a decrease in childhood z-systolic BP (SBP, ß = -0.169, 95% CI = -0.338-0.001). Furthermore, the pooled results showed negative relationships of prenatal ∑DEHP exposure with z-SBP (ß = -0.109, 95% CI = -0.163 to -0.055) and z-diastolic BP (DBP, ß = -0.126, 95% CI = -0.182 to -0.069) in girls. In addition, MEP exposure was associated with z-SBP in girls (ß = -0.227, 95% CI = -0.387 to -0.066). The pooled result showed a positive relationship between prenatal ∑DEHP exposure and triglycerides (ß = 0.103, 95% CI = 0.028-0.178). The overall results revealed that exposure to ∑DEHP throughout gestation was associated with a decrease in insulin (ß = -0.074, 95% CI = -0.144 to -0.004) and glucose (ß = -0.129, 95% CI = -0.199 to -0.058) in boys. Interestingly, there was an inverse relationship of prenatal mono- 3 -carboxypropyl phthalate (MCPP) exposure with glucose in pubertal boys (ß = -3.749, 95% CIs = -6.758 to -0.741) but not found in postpubertal children. In conclusion, prenatal phthalate exposure interfered with cardiovascular risk in children with gender-specific differences and was influenced by puberty. Overall, prenatal ∑DEHP was negatively associated with systolic blood pressure in girls and with insulin and glucose in boys but increased the level of triglycerides.

Associating phthalate exposure during pregnancy with preschooler's FMI, ABSI and BRI trajectories via putative mechanism pathways.

Phthalates are well-known obesogens, but a few studies have explored their impacts on the childhood fat mass index (FMI), body shape index (ABSI) and body roundness index (BRI). Information from 2950 participants recruited in the Ma'anshan Birth Cohort was analyzed. The relationships between six maternal phthalate metabolites and their mixture and childhood FMI, ABSI and BRI were investigated. FMI, ABSI and BRI in children aged 3.5 y, 4.0 y, 4.5 y, 5.0 y, 5.5 y and 6.0 y were calculated. The latent class trajectory modeling categorized the FMI trajectories into "rapidly increasing FMI" (4.71%) and "stable FMI" (95.29%) groups; ABSI trajectories were categorized as "decreasing ABSI" (32.74%), "stable ABSI" (46.55%), "slowly increasing ABSI" (13.26%), "moderately increasing ABSI" (5.27%) and "rapidly increasing ABSI" (2.18%) groups; BRI trajectories were categorized as "increasing BRI" (2.82%), "stable BRI" (19.85%), and "decreasing BRI" (77.34%) groups. Prenatal MEP exposure was associated with repeated measurements of FMI (ß = 0.111, 95% CI = 0.002-0.221), ABSI (ß = 0.145, 95% CI = 0.023-0.268) and BRI (ß = 0.046, 95% CI = -0.005-0.097). Compared with each stable trajectory group, prenatal MEP (OR = 0.650, 95% CI = 0.502-0.844) and MBP (OR = 0.717, 95% CI = 0.984-1.015) were linked to a decreased risk of "decreasing BRI" in children; there was a negative relationship between MBP and the "decreasing ABSI" group (OR = 0.667, 95% CI = 0.487-0.914), and MEP increased the risks of "slowly increasing ABSI" (OR = 1.668, 95% CI = 1.210-2.299) and "rapidly increasing ABSI" (OR = 2.522, 95% CI = 1.266-5.024) in children. Phthalate mixture during pregnancy showed significant relationships with all anthropometric indicator trajectories, with MEP and MBP always being of the largest importance. In conclusion, this study suggested that prenatal phthalate coexposure increased the childhood probability of being in higher ABSI and BRI trajectory groups. That is, children were more likely to be obese when they were exposed to higher levels of some phthalate metabolites and their mixture. The low-molecular weight phthalates, including MEP and MBP, contributed the greatest weights.

Causal relationships of neonatal jaundice, direct bilirubin and indirect bilirubin with autism spectrum disorder: A two-sample Mendelian randomization analysis.

Background: Multiple systematic reviews and meta-analyses have examined the association between neonatal jaundice and autism spectrum disorder (ASD) risk, but their results have been inconsistent. This may be because the included observational studies could not adjust for all potential confounders. Mendelian randomization study can overcome this drawback and explore the causal relationship between the both. Methods: We used the data of neonatal jaundice, direct bilirubin (DBIL), indirect bilirubin (IBIL), and ASD collected by genome-wide association study (GWAS) to evaluate the effects of neonatal jaundice, DBIL and IBIL on ASD by using a two-sample Mendelian randomized (MR). The inverse variance-weighted method (IVW) was the main method of MR analysis in this study. Weighted median method, MR-Egger regression and mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analysis. Results: There was no evidence of an effect of neonatal jaundice (OR, 1.002, 95% CI, 0.977-1.027), DBIL (OR, 0.970, 95% CI, 0.884-1.064) and IBIL (OR, 1.074, 95% CI, 0.882-1.308) on ASD risk by IVW test. In the weighted median method, MR-Egger regression and leave-one-out analysis, the results were robust and no heterogeneity or pleiotropy was observed. Conclusions: We found that neonatal jaundice, DBIL and IBIL were not associated with ASD in this study. However, this paper did not explore the effect of severity and duration of jaundice on ASD in different ethnic populations, which may require further research.

B7-H3 but not PD-L1 is involved in the antitumor effects of Dihydroartemisinin in non-small cell lung cancer.

Dihydroartemisinin (DHA), an active antimalaria metabolite derived from artemisinin, has received increasing attention for its anticancer activities. However, little is known about the anticancer mechanisms of DHA, although the existing data define its antimalaria effects by producing excessive reactive oxygen species (ROS). In this study, we showed that DHA effectively suppresses in vitro and in vivo tumor growth of non-small cell lung cancer (NSCLC) without perceptible toxicity on heart, liver, spleen, lung, and kidney tissues. Of note, DHA inhibited the expression of B7-H3 rather than PD-L1, whereas overexpression of B7-H3 completely rescued DHA's inhibition on cell proliferation and migration of NSCLC A549 and HCC827 cells. B7-H3 overexpression also largely inhibited DHA's induction on the apoptosis of the two cell lines. Furthermore, DHA treatment led to increased infiltration of CD8+ T Lymphocytes in the xenografts as compared with that of negative controls. Taken together, our results suggest that B7-H3 but not PD-L1 is involved in the antitumor effects of DHA in NSCLC, which may be indicative of an effective B7-H3 blockade and further combination with anti-PD-L1/PD-1 immunotherapy.

Associations between Early Thyroid-Stimulating Hormone Levels and Morbidities in Extremely Preterm Neonates.

INTRODUCTION: High-end cutoffs of thyroid-stimulating hormone (TSH) have been emphasized for hypothyroidism therapy in extremely preterm infants, but the significance of low TSH levels remains unknown. This study hypothesized that the spectrum of TSH levels by newborn screening after birth signifies specific morbidities in extremely preterm neonates. METHODS: The multicenter population cohort analyzed 434 extremely preterm neonates receiving TSH screening at 24-96 h of age in 2008-2019. Neonates were categorized by blood TSH levels into group 1: TSH <0.5 µU/mL, group 2: 0.5 ≤ TSH <2 µU/mL, group 3: 2 ≤ TSH <4 µU/mL, and group 4: TSH ≥4 µU/mL. Neonatal morbidities were categorized using the modified Neonatal Therapeutic Intervention Scoring System. RESULTS: The four groups differed in gestational age, birth weight, and the postnatal age at blood sampling so did the proportions of mechanical ventilation usage (p = 0.01), hypoxic respiratory failure (p = 0.005), high-grade intraventricular hemorrhage (p = 0.007), and periventricular leukomalacia (p = 0.048). Group 1 had higher severity scores for respiratory distress syndrome (RDS; effect size 0.39 [95% confidence interval [CI]: 0.18-0.59]) and brain injury (0.36 [0.15-0.57]) than group 2, which remained significant after adjusting for gestational age, birth weight, dopamine usage, and the postnatal age at TSH screening (RDS: mean + 0.45 points [95% CI: 0.11-0.79]; brain injury: +0.32 [0.11-0.54]). CONCLUSIONS: Low TSH levels in extremely preterm neonates are associated with severe RDS and brain injuries. Studies recruiting more neonates with complete thyroid function data are necessary to understand central-peripheral interactions of the hypothalamic-pituitary-thyroid axis.

Predictors of Remission in Severe Childhood Immune Thrombocytopenia.

Childhood immune thrombocytopenia (ITP; platelet count < 100 × 109/L) is the most common bleeding disorder in children. A total of 3-5% of children with ITP face a greater risk of bleeding, resulting in significant morbidity and mortality. Childhood ITP is often benign and self-limited; however, children with severe ITP (platelet count < 30 × 109/L) require investigation and monitoring. In addition, 20% of ITP patients may not go into remission (platelet counts < 100 × 109/L by 12 months after diagnosis) and may develop chronic ITP. The early identifying predictors associated with the resolution of severe ITP at the time of diagnosis may be helpful for family guidance. However, there is still controversy about the associations between the clinical factors at the time of initial diagnosis and the definitions of disease remission assessed at different timepoints after diagnosis. This retrospective study aimed to analyze the shared clinical factors among the disease remission definitions at three arbitrarily set timepoints-3, 6, and 12 months after diagnosis. This study retrieved records for hospitalized children aged under 18 years and diagnosed with ITP from the hospital registry in a tertiary university hospital. Clinical variables were recorded by reviewing the medical records with structured data entry for ITP admission. The serial follow-up platelet counts within 12 months after diagnosis were recorded. The times of ITP remission were identified by experienced pediatric hematologists. Patients with mild-form ITP (platelet counts ≥ 30 × 109/L) at diagnosis or who were lost to follow-up within 3 months were excluded. From 1988 to 2019, 546 children were enrolled, and a total of 497 children with severe ITP were included in the further analysis. In total, one (0.2%) died of an intracranial hemorrhage, 363 (73.2%) children went into remission at 3 months, 40 (8.1%) went into remission between 6 and 12 months, and 104 (20.9%) developed chronic ITP. The shared significant predictors for remission by the third, sixth, and twelfth months included pre-adolescent age (<10 years) at diagnosis, abrupt onset (duration of symptoms prior to admission ≤ 2 weeks), and speedy recovery (platelet count > 100 × 109/L at 1 month post diagnosis). ITP patients with positive viral serology tests or vaccination within 4 weeks had trends of delayed remission. In conclusion, diagnosis before preadolescent age, abrupt onset, and speedy recovery may share favorable factors for the remission of childhood ITP assessed at different timepoints.

Preterm birth and weight-for-gestational age for risks of autism spectrum disorder and intellectual disability: A nationwide population-based cohort study.

PURPOSE: To evaluate gestational age (GA) and small-for-gestational age (SGA) as continuums and gender on the incidences of autism spectrum disorder (ASD) and co-occurring intellectual disability (ID). METHODS: This is a population-based cohort study using the 2004-2008 Taiwan Maternal and Child Health Database. The diagnosis of ASD was determined by International Classification of Diseases, 9th Revision (ICD-9). Generalized estimating equations models were fit to evaluate associations between perinatal variables and ASD. RESULTS: This study included 916,315 individuals. A total of 9474 (1.0%) children were diagnosed with ASD, among whom 1594 (16.8%) had co-occurring ID. Lower GA carried higher odds of ASD with ID (GA < 28 weeks, aOR: 4.26, 95% CI: 2.13, 8.50; GA 28-30 weeks, aOR: 2.80, 95% CI: 1.57, 4.97; GA 31-33 weeks, aOR: 1.63, 95% CI: 1.05, 2.55; GA 34-36 weeks, aOR: 1.39, 95% CI: 1.16, 1.67) and ASD without ID (GA < 28 weeks, aOR:2.05, 95% CI: 1.25, 3.36; GA 28-30 weeks, aOR: 2.02, 95% CI: 1.46, 2.79; GA 31-33 weeks, aOR: 1.42, 95% CI: 1.13, 1.77; GA 34-36 weeks, aOR: 1.18, 95% CI: 1.08, 1.29). Male preterm infants had ASD risks negatively correlated to GA, while ASD risks were significantly increased only among female infants born late preterm. The degree of SGA showed a stepwise increased risk for ASD with and without ID in both male and female infants. CONCLUSION: Lower GA and the degree of SGA are both associated with ASD susceptibility, either with or without co-occurring ID, and remarkably increased the risk of ID.

Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation.

Lung cancer is the leading cause of cancer-related death worldwide. The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) has brought favorable survival benefits to patients with non-small-cell lung cancer (NSCLC); unfortunately, acquired drug resistance remains a major barrier to the treatment of NSCLC. Recent studies have demonstrated that the transcriptional co-activator with a PDZ-binding motif (TAZ, also called WWTR1) induces tumor immune evasion by directly modulating the expression of programmed death ligand 1 (PD-L1), a key therapeutic target for checkpoint immunotherapy. Moreover, aberrant activation of TAZ is also a major mechanism of acquired resistance to EGFR-TKIs in NSCLC. Therefore, TAZ signaling blockade might be an effective strategy to overcome resistance to ICIs and EGFR-TKIs in NSCLC. In this study, we showed for the first time that artesunate effectively reduced TAZ and PD-L1 expression in NSCLC. We further demonstrated that artesunate suppressed TAZ/PD-L1-induced T-cell growth inhibition in vitro and enhanced anti-tumor immunity by recruiting infiltrating CD8 + T-cells in syngeneic mouse models. Artesunate also inhibited the stem cell-like properties of NSCLC cells and suppressed tumor growth in xenografts bearing gefitinib-resistant tumors. In addition, our results of molecular docking and cellular thermal shift assay analysis suggested that artesunate might directly target the TAZ-TEAD complex and induce proteasome-dependent TAZ degradation in NSCLC cells. These results suggest that artesunate enhanced anti-tumor immunity and overcame EGFR-TKI resistance in NSCLC at least in part by suppressing TAZ/PD-L1 signaling.

Total serum bile acids predict therapy for HBeAg-negative chronic hepatitis B patients with borderline ALT and high HBV DNA.

INTRODUCTION: The introduction of antiviral therapy in chronic hepatitis B (CHB) infection depends on precise evaluation of hepatic lesions. Total serum bile acids (TSBAs) are highly sensitive in monitoring liver dysfunction. We evaluated the predictive role of TSBAs for hepatic lesions in CHB patients with borderline alanine aminotransferase (ALT) and high level of hepatitis B virus (HBV) DNA copies. METHODOLOGY: 328 CHB patients were enrolled, 241 were hepatitis B e antigen (HBeAg)-positive and 87 were HBeAg-negative. Patients were further divided into two entities according to inflammation/fibrosis evaluated by liver biopsy, low-grade (inflammation grade < 2 and fibrosis stage < 2) and high-grade (inflammation grade ≥ 2 or/and fibrosis stage ≥ 2) cohorts. TSBAs were compared with noninvasive tools including aspartate aminnotransferase (AST)-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) and red cell distribution width (RDW)-to-platelet ratio (RPR) to predict high-grade hepatic lesions in CHB subgroups. RESULTS: TSBAs, APRI, FIB-4 and RPR were statistically different between low- and high-grade patients in HBeAg-positive cohort. Only TSBAs showed significant difference between low and high grade in HBeAg-negative patients. Similarly, APRI, FIB-4 and RPR were correlated with different division of inflammation/fibrosis only in HBeAg-positive while TSBAs were correlated with inflammation/fibrosis levels in both HBeAg-positive and HBeAg-negative groups. Of the four indicators, the receiver operating characteristic (ROC) curve analysis showed that TSBAs have the maximum AUC (area under the curve) in HBeAg-negative group but the minimum in HBeAg-positive cohort. CONCLUSIONS: TSBAs can be used for predicting antiviral therapy in CHB patients with HBeAg-negative, borderline ALT and high HBV DNA.

Prognostic factors for functional recovery in children with moderate to severe acute disseminated encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an immune-mediated encephalopathy with heterogeneous disease courses. However, clinical characteristics for a prognostication of functional recovery from acute episodes of ADEM remain limited. The study aims to characterize the clinical presentations and neuroimaging findings of children with poor functional recoveries from acute episodes of moderate to severe ADEM. METHODS: The multicenter retrospective cohort study included children under 18 years of age who presented with moderate to severe ADEM (modified Rankin Scale [mRS] ≥ 3 at nadir) from 2002 to 2019. Children were assigned to a good recovery group (mRS ≤ 2) and a poor recovery group (mRS ≥ 3) after mean 4.3 months of follow-up. The clinical presentations and the distribution of brain lesions on magnetic resonance imaging were compared between the two groups by the t-test for numerical variables and Fisher's exact test for categorical variables. Analyses of logistic regression were conducted and significant variables in the multivariate model were examined by the receiver operating characteristic curve for the prediction of functional recovery. RESULTS: Among the 73 children with moderate to severe ADEM, 56 (77%) had good functional recoveries and 17 (23%) showed poor functional recoveries. Children with poor recoveries had a lower rate of prodromal headache (12% vs. 39%, p = 0.04), and presented with higher proportions of dystonia (29% vs. 9%, p = 0.046), myoclonus (24% vs. 2%, p = 0.009), and cerebellar lesions on neuroimages (59% vs. 23%, p = 0.01). The multivariate analyses identified that a lack of prodromal headache (OR 0.1, 95% CI 0.005 - 0.7, p = 0.06) and the presentations of myoclonus (OR 21.6, 95% CI 1.7 - 874, p = 0.04) and cerebellar lesions (OR 4.8, 95% CI 1.3 - 19.9, p = 0.02) were associated with poor functional recoveries. These three factors could prognosticate poor outcomes in children with moderate to severe ADEM (area under the receiver operating characteristic curve 0.80, 95% CI 0.68 - 0.93, p = 0.0002). CONCLUSION: Nearly one-fourth of children with moderate to severe ADEM had a poor functional recovery from acute episodes, who were characterized by a lack of prodromal headache, the presentation of myoclonus, and the neuroimaging finding of cerebellar lesions. The clinical variables associated with poor functional recoveries could assist in the planning of immunotherapies during hospitalization for a better outcome in moderate to severe ADEM.