Discovery of ganoderic acid A (GAA) PROTACs as MDM2 protein degraders for the treatment of breast cancer.

Breast cancer is one of the most common female malignant tumors, with triple-negative breast cancer (TNBC) being the most specific, highly invasive, metastatic and associated with a poor prognosis. Our previous study showed that the natural product ganoderic acid A (GAA) has a certain affinity for MDM2. In this study, two series of novel GAA PROTACs C1-C10 and V1-V10 were designed and synthesized for the treatment of breast cancer. The antitumor activity of these compounds was evaluated against four human tumor cell lines (MCF-7, MDA-MB-231, SJSA-1, and HepG2). Among them, V9 and V10 showed stronger anti-proliferative effects against breast cancer cells, and V10 showed the best selectivity in MDA-MB-231 cells (TNBC), which was 5-fold higher than that of the lead compound GAA. Preliminary structure-activity analysis revealed that V-series GAA PROTACs had better effects than C-series, and the introduction of 2O-4O PEG linkers could significantly improve the antitumor activity. Molecular docking, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and Western blot researches showed that both V9 and V10 could bind with MDM2, and degrade the protein through the ubiquitin-proteasome system. Molecular dynamics simulation (MD) revealed that V10 is a bifunctional molecule that can bind to von Hippel-Lindau (VHL) at one end and target MDM2 at the other. In addition, V10 promoted the upregulation of p21 in p53-mutant MDA-MB-231 cells, and induced apoptosis via down-regulation of the bcl-2/bax ratio and the expression of cyclin B1. Finally, in vivo experiments showed that, V10 also exhibited good tumor inhibitory activity in xenografted TNBC zebrafish models, with an inhibition rate of 27.2% at 50 µg/mL. In conclusion, our results suggested that V10 has anti-tumor effects on p53-mutant breast cancer in vitro and in vivo, and may be used as a novel lead compound for the future development of TNBC.

The effect of Le Fort III procedure in the treatment of obstructive sleep apnea in children with syndromic craniosynostosis.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is common in children with Syndromic Craniosynostosis (SC). The efficacy of Fort III procedure in managing OSA in children with SC remains a subject of ongoing debate. This study aimed to explore the efficacy of Le Fort III procedure in the management of OSA in children with SC. METHODS: A retrospective study was performed in children with SC and OSA diagnosed by polysomnography (PSG), which was defined as an apnea and hypopnea index (AHI) ≥ 1. Patients meeting the inclusion criteria were those who underwent Le Fort III surgery and had both baseline PSG and follow-up sleep studies. Relevant clinical and demographic data were collected from all subjects who participated in the study. RESULTS: Overall, forty-five OSA children with SC were identified, with a mean age of 6.8 ± 4.7 years. Twenty-five received the Le Fort III procedure and follow-up sleep studies. The Le Fort III procedure resulted in a significant reduction in AHI (6.0 [2.6, 10.1] versus 37.6 [20.9, 48.0] events/h; P < 0.001). However, normalization of OSA was only achieved in one patient (4%). CONCLUSIONS: The Le Fort III procedure is efficacious in the treatment of OSA in children with SC. However, despite the observed improvement, residual OSA following treatment remains common.

Years of life lost due to insufficient sleep and associated economic burden in China from 2010-18.

Background: Research on the health and economic costs due to insufficient sleep remains scant in developing countries. In this study we aimed to estimate the years of life lost (YLLs) due to short sleep and quantify its economic burden in China. Methods: We estimated both individual and aggregate YLLs due to short sleep (ie, ≤6 hours) among Chinese adults aged 20 years or older by sex and five-year age groups in 2010, 2014, and 2018. YLL estimates were derived from 1) the prevalence of short sleep using three survey waves of the China Family Panel Studies, 2) relative mortality risks from meta-analyses, and 3) life tables in China. YLL was the difference between the estimated life expectancy of an individual in the short sleep category vs in the recommended sleep category. We estimated the economic cost using the human capital approach. Results: The sample sizes of the three survey waves were 31 393, 31 207, and 28 618. Younger age groups and men had more YLLs due to short sleep compared to their counterparts. For individuals aged 20-24, men had an average YLL of nearly 0.95, in contrast to the approximate 0.75 in women across the observed years of 2010, 2014, and 2018. The trend in individual YLLs remained consistent over these years. In aggregate, China experienced a rise from 66.75 million YLLs in 2010 to 95.29 million YLLs in 2014, and to 115.05 million YLLs in 2018. Compared to 2010 (USD 191.83 billion), the associated economic cost in 2014 increased to USD 422.24 billion, and the cost in 2018 more than tripled (USD 628.15 billion). The percentage of cost to Chinese gross domestic product in corresponding years was 3.23, 4.09, and 4.62%. Conclusions: Insufficient sleep is associated with substantial YLLs in China, potentially impacting the population's overall life expectancy. The escalating economic toll attributed to short sleep underscores the urgent need for public health interventions to improve sleep health at the population level.

The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.

The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.

SOX6 AU controls myogenesis by cis-modulation of SOX6 in cattle.

Long non-coding RNAs (lncRNAs) have been shown to be involved in the regulation of skeletal muscle development through multiple mechanisms. The present study revealed that the lncRNA SOX6 AU (SRY-box transcription factor 6 antisense upstream) is reverse transcribed from upstream of the bovine sex-determining region Y (SRY)-related high-mobility-group box 6 (SOX6) gene. SOX6 AU was significantly differentially expressed in muscle tissue among different developmental stages in Xianan cattle. Subsequently, knockdown and overexpression experiments discovered that SOX6 AU promoted primary skeletal muscle cells proliferation, apoptosis, and differentiation in bovine. The overexpression of SOX6 AU in bovine primary skeletal muscle cells resulted in 483 differentially expressed genes (DEGs), including 224 upregulated DEGs and 259 downregulated DEGs. GO functional annotation analysis showed that muscle development-related biological processes such as muscle structure development and muscle cell proliferation were significantly enriched. KEGG pathway analysis revealed that the PI3K/AKT and MAPK signaling pathways were important pathways for DEG enrichment. Notably, we found that SOX6 AU inhibited the mRNA and protein expression levels of the SOX6 gene. Moreover, knockdown of the SOX6 gene promoted the proliferation and apoptosis of bovine primary skeletal muscle cells. Finally, we showed that SOX6 AU promoted the proliferation and apoptosis of bovine primary skeletal muscle cells by cis-modulation of SOX6 in cattle. This work illustrates our discovery of the molecular mechanisms underlying the regulation of SOX6 AU in the development of beef.

20(S)-Ginsenoside Rh2 inhibits hepatocellular carcinoma by suppressing angiogenesis and the GPC3-mediated Wnt/ß­catenin signaling pathway.

20(S)-Ginsenoside Rh2 has significant anti-tumor effects in various types of cancers, including human hepatocellular carcinoma (HCC). However, its molecular targets and mechanisms of action remain largely unknown. Here, we aim to elucidate the potential mechanisms by which Rh2 suppresses HCC growth. We first demonstrate the role of Rh2 in inhibiting angiogenesis. We observe that Rh2 effectively suppresses cell proliferation and induces apoptosis in HUVECs. Furthermore, Rh2 significantly inhibits HepG2-stimulated HUVEC proliferation, migration and tube formation, accompanied by the downregulation of VEGF and MMP-2 expressions. We also reveal that Rh2 inhibits HCC growth through the downregulation of glypican-3-mediated activation of the Wnt/ß-catenin pathway. We observe a dose-dependent inhibition of proliferation and induction of apoptosis in HepG2 cells upon Rh2 treatment, which is mediated by the inhibition of glypican-3/Wnt/ß-catenin signaling. Moreover, downregulation of glypican-3 expression enhances the effects of Rh2 on the glypican-3/Wnt/ß-catenin signaling pathway, resulting in greater suppression of tumor growth in HepG2 cells. Collectively, our findings shed light on the molecular mechanisms through which Rh2 modulates HCC growth, which involve the regulation of angiogenesis and the glypican-3/Wnt/ß-catenin pathway. These insights may pave the way for the development of novel therapeutic strategies targeting these pathways for the treatment of HCC.

Elucidating the cardioprotective mechanisms of sodium-glucose cotransporter-2 inhibitors beyond glycemic control.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a pivotal intervention in diabetes management, offering significant cardiovascular benefits. Empagliflozin, in particular, has demonstrated cardioprotective effects beyond its glucose-lowering action, reducing heart failure hospitalizations and improving cardiac function. Of note, the cardioprotective mechanisms appear to be inde-pendent of glucose lowering, possibly mediated through several mechanisms involving shifts in cardiac metabolism and anti-fibrotic, anti-inflammatory, and anti-oxidative pathways. This editorial summarizes the multifaceted cardiovascular advantages of SGLT2 inhibitors, highlighting the need for further research to elucidate their full therapeutic potential in cardiac care.

Clinical features, polysomnography, and genetics association study of restless legs syndrome in clinic based Chinese patients: A multicenter observational study.

STUDY OBJECTIVES: To systemically describe the clinical features, polysomnography (PSG) finding, laboratory tests and single-nucleotide polymorphisms (SNPs) in a clinic based Chinese primary restless legs syndrome (RLS) population. METHODS: This observational study, conducted from January 2020 to October 2021 across 22 sleep labs in China, recruited 771 patients diagnosed with RLS following the 2014 RLSSG criteria. Clinical data, PSG testing, and laboratory examination and SNPs of patients with RLS were collected. A total of 32 SNPs in 24 loci were replicated using the Asian Screening Array chip, employing data from the Han Chinese Genomes Initiative as controls. RESULTS: In this study with 771 RLS patients, 645 had primary RLS, and 617 has DNA available for SNP study. Among the 645 primary RLS, 59.7% were women. 33% had a family history of RLS, with stronger familial influence in early-onset cases. Clinical evaluations showed 10.4% had discomfort in body parts other than legs. PSG showed that 57.1% of RLS patients had periodic leg movement index (PLMI) of >5/h and 39.1% had PLMI >15/h, respectively; 73.8% of RLS patients had an Apnea-Hypopnea Index (AHI) > 5/h, and 45.3% had an AHI >15/h. The laboratory examinations revealed serum ferritin levels <75 ng/ml in 31.6%, and transferrin saturation (TSAT) of <45% in 88.7% of RLS patients. Seven new SNPs in 5 genes showed a significant allelic association with Chinese primary RLS, with one previously reported (BTBD9) and four new findings (TOX3, PRMT6, DCDC2C, NOS1). CONCLUSIONS: Chinese RLS patients has specific characters in many aspects. A high family history with RLS not only indicates strong genetic influence, but also reminds us to consider the familial effect in the epidemiological study. Newly developed sequencing technique with large samples remains to be done.

Functional significance of DNA methylation: epigenetic insights into Sjögren's syndrome.

Sjögren's syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets.

Detecting potential cooperative network for tourist attractions in a destination using search data.

This study addresses the critical need for regional tourism integration and sustainable development by identifying cooperation opportunities among tourist attractions within a region. We introduce a novel methodology that combines association rule mining with complex network analysis and utilizes search index data as a dynamic and contemporary data source to reveal cooperative patterns among tourist attractions. Our approach delineates a potential cooperative network within the destination ecosystem, categorizing tourist attractions into three distinct communities: core, intermediary, and periphery. These communities correspond to high, medium, and low tourist demand scales, respectively. The study uncovers a self-organizing network structure, driven by congruences in internal tourist demand and variances in external tourist experiences. Functionally, there is a directed continuum of cooperation prospects among these communities. The core community, characterized by significant tourist demand, acts as a catalyst, boosting demand for other attractions. The intermediary community, central in the network, links the core and periphery, enhancing cooperative ties and influence. Peripheral attractions, representing latent growth areas within the destination matrix, benefit from associations with the core and intermediary communities. Our findings provide vital insights into the dynamics, systemic characteristics, and fundamental mechanisms of potential cooperation networks among tourist attractions. They enable tourism management organizations to employ our analytical framework for real-time monitoring of tourism demand and flow trends. Additionally, the study guides the macro-control of tourism flows based on the tourism network, thereby improving the tourist experience and promoting coordinated development among inter-regional tourist attractions.

Whole-Genome Sequencing Analyses Reveal the Whip-like Tail Formation, Innate Immune Evolution, and DNA Repair Mechanisms of Eupleurogrammus muticus.

Smallhead hairtail (Eupleurogrammus muticus) is an important marine economic fish distributed along the northern Indian Ocean and the northwest Pacific coast; however, little is known about the mechanism of its genetic evolution. This study generated the first genome assembly of E. muticus at the chromosomal level using a combination of PacBio SMRT, Illumina Nova-Seq, and Hi-C technologies. The final assembled genome size was 709.27 Mb, with a contig N50 of 25.07 Mb, GC content of 40.81%, heterozygosity rate of 1.18%, and repetitive sequence rate of 35.43%. E. muticus genome contained 21,949 protein-coding genes (97.92% of the genes were functionally annotated) and 24 chromosomes. There were 143 expansion gene families, 708 contraction gene families, and 4888 positively selected genes in the genome. Based on the comparative genomic analyses, we screened several candidate genes and pathways related to whip-like tail formation, innate immunity, and DNA repair in E. muticus. These findings preliminarily reveal some molecular evolutionary mechanisms of E. muticus at the genomic level and provide important reference genomic data for the genetic studies of other trichiurids.

Resting cell formation in the marine diatom Thalassiosira pseudonana.

Resting cells represent a survival strategy employed by diatoms to endure prolonged periods of unfavourable conditions. In the oceans, many diatoms sink at the end of their blooming season and therefore need to endure cold and dark conditions in the deeper layers of the water column. How they survive these conditions is largely unknown. We conducted an integrative analysis encompassing methods from histology, physiology, biochemistry, and genetics to reveal the biological mechanism of resting-cell formation in the model diatom Thalassiosira pseudonana. Resting-cell formation was triggered by a decrease in light and temperature with subsequent catabolism of storage compounds. Resting cells were characterised by an acidic and viscous cytoplasm and altered morphology of the chloroplast ultrastructure. The formation of resting cells in T. pseudonana is an energy demanding process required for a biophysical alteration of the cytosol and chloroplasts to endure the unfavourable conditions of the deeper ocean as photosynthetic organisms. However, most resting cells (> 90%) germinate upon return to favorable growth conditions.

Soybean-mediated suppression of BjaI/BjaR1 quorum sensing in Bradyrhizobium diazoefficiens impacts symbiotic nitrogen fixation.

The acyl-homoserine lactones (AHLs)-mediated LuxI/LuxR quorum sensing (QS) system orchestrates diverse bacterial behaviors in response to changes in population density. The role of the BjaI/BjaR1 QS system in Bradyrhizobium diazoefficiens USDA 110, which shares homology with LuxI/LuxR, remains elusive during symbiotic interaction with soybean. Here this genetic system in wild-type (WT) bacteria residing inside nodules exhibited significantly reduced activity compared to free-living cells, potentially attributed to soybean-mediated suppression. The deletion mutant strain ΔbjaR1 showed significantly enhanced nodulation induction and nitrogen fixation ability. Nevertheless, its ultimate symbiotic outcome (plant dry weight) in soybeans was compromised. Furthermore, comparative analysis of the transcriptome, proteome, and promoter activity revealed that the inactivation of BjaR1 systematically activated and inhibited genomic modules associated with nodulation and nitrogen metabolism. The former appeared to be linked to a significant decrease in the expression of NodD2, a key cell-density-dependent repressor of nodulation genes, while the latter conferred bacterial growth and nitrogen fixation insensitivity to environmental nitrogen. In addition, BjaR1 exerted a positive influence on the transcription of multiple genes involved in a so-called central intermediate metabolism within the nodule. In conclusion, our findings highlight the crucial role of the BjaI/BjaR1 QS circuit in positively regulating bacterial nitrogen metabolism and emphasize the significance of the soybean-mediated suppression of this genetic system for promoting efficient symbiotic nitrogen fixation by B. diazoefficiens.IMPORTANCEThe present study demonstrates, for the first time, that the BjaI/BjaR1 QS system of Bradyrhizobium diazoefficiens has a significant impact on its nodulation and nitrogen fixation capability in soybean by positively regulating NodD2 expression and bacterial nitrogen metabolism. Moreover, it provides novel insights into the importance of suppressing the activity of this QS circuit by the soybean host plant in establishing an efficient mutual relationship between the two symbiotic partners. This research expands our understanding of legumes' role in modulating symbiotic nitrogen fixation through rhizobial QS-mediated metabolic functioning, thereby deepening our comprehension of symbiotic coevolution theory. In addition, these findings may hold great promise for developing quorum quenching technology in agriculture.

Magnetic resonance imaging with upconversion nanoprobes capable of crossing the blood-cerebrospinal fluid barrier.

The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.

C1QBP is a critical component in the immune response of large yellow croaker (Larimichthys crocea) against visceral white spot disease caused by Pseudomonas plecoglossicida.

The large yellow croaker (Larimichthys crocea) stands as a cornerstone of mariculture in China due to its significant value. However, the threat of Pseudomonas plecoglossicida infection looms large, capable of triggering "visceral white spot disease" and subsequently inflicting severe economic ramifications. Through a prior genome-wide association analysis (GWAS) aimed at understanding the resistance of the large yellow croaker to this ailment, a pivotal player emerged: the complement component 1q binding protein, aptly named LcC1qbp. This protein assumes a crucial role in the activation of the complement system. This study delves deeper into the immune response by examining the expression patterns of LcC1QBP when confronted with P. plecoglossicida. The investigation into gene expression patterns reveals LcC1qbp's widespread presence, with its highest transcriptional abundance identified in the kidney tissues. Upon infection by P. plecoglossicida, the up-regulation of LcC1qbp in major immune organs manifests at both the transcriptional and translational levels. In the context of RNA interference, transcriptome analysis of C1qbp in HEK 293T cells uncovers 1327 differentially expressed genes (DEGs), featuring 41 significant immune genes. This includes pivotal components such as C1S and C3 of the complement system, along with IL11, IL12RB2, and Myd88, among others. The outcomes of enrichment analysis spotlight the prevalence of DEGs within key pathways like immune system development, myeloid leukocyte-mediated immunity, MAPK signaling, and other immune-related routes. By unveiling the immune response mechanisms of the large yellow croaker to P. plecoglossicida infection, this study bolsters our understanding. Furthermore, it lays the groundwork for pursuing effective strategies in both preventing and treating "visceral white spot disease" in the large yellow croaker.

The effect of continuous positive airway pressure on obstructive sleep apnea in children with syndromic craniosynostosis.

BACKGROUND: Obstructive sleep apnea (OSA) is common in children with syndromic craniosynostosis (SC). However, objective data on the treatment of OSA in children with SC remain inadequate. This study aimed to explore the efficacy of continuous positive airway pressure (CPAP) in the management of OSA in children with SC. METHODS: A retrospective study was performed in children with SC and OSA diagnosed by polysomnography (PSG), which was defined as an apnea hypopnea index (AHI) ≥ 1. Patients were included if they were treated with CPAP and had baseline PSG and follow-up sleep studies. Clinical and demographic data were collected from all enrolled subjects. RESULTS: A total of 45 children with SC and OSA were identified, with an average age of 6.8 ± 4.7 years. Among them, 36 cases had moderate to severe OSA (22 with severe OSA) and received CPAP therapy followed by post-treatment sleep studies. Notably, there was a significant reduction in the AHI observed after CPAP treatment (3.0 [IQR: 1.7, 4.6] versus 38.6 [IQR: 18.2, 53.3] events/h; P < 0.001). CONCLUSIONS: CPAP is effective and acceptable in treating severe OSA in children with SC.

[Determination of 118 pesticide residues in urine by ultra-high performance liquid chromatography-tandem mass spectrometry].

Pesticide residues in food and their hazardous effects have attracted much attention given the increased and widespread use of pesticides. The long-term consumption of food containing pesticide residues is an important pathway for the gradual accumulation of pesticides in the human body. Urine is often monitored as a biological sample for low-dose exposure to pesticides, and urine collection is a relatively convenient sampling technique in general population research. In order to effectively monitor residual levels of multiple pesticides in human urine and provide an important technological approach for health risk assessment, a rapid screening and confirmatory detection method for 118 pesticides in urine was established using QuEChERS method as a pretreatment combined with ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-MS/MS). The 118 pesticides analyzed included organophosphorus, carbamate, neonicotinoid, and strobilurin fungicides and other widely used pesticides. Following systematic optimization of the pretreatment process, LC separation conditions, and MS/MS parameters, 118 pesticides were extracted from urine samples and analyzed within 2 h. In brief, the target analytes in 5 mL urine samples were extracted with 10 mL of acetonitrile and added with 5 g of anhydrous MgSO4 and 1 g of NaCl as water-removal and salting-out agents, respectively. After centrifugation, 6 mL of the supernatant was cleaned using the QuEChERS method with 300 mg of C18, 300 mg of primary secondary amine (PSA) and 900 mg of anhydrous MgSO4 as the purification adsorbent. After nitrogen blowing and solubilization, the 118 target analytes were separated on a ZORBAX Eclipse Plus C18 analytical chromatographic column (100 mm×2.1 mm, 1.8 µm) with gradient elution using (A) 0.01% formic acid aqueous solution (containing 2 mmol/L ammonium formate) and (B) 0.01% formic acid methanol solution (containing 2 mmol/L ammonium formate) as mobile phases. The gradient elution program was as follows: 0-0.5 min, 5%B; 0.5-1.5 min, 5%B-20%B; 1.5-2.5 min, 20%B-50%B; 2.5-8.0 min, 50%B-80%B; 8.0-9.0 min, 80%B-98%B; 9.0-11.0 min, 98%B; 11.0-11.5 min, 98%B-5%B; 11.5-15.0 min, 5%B. The analytes were then determined by UHPLC-MS/MS with positive/negative ion switching in dynamic multiple-reaction monitoring mode and quantified using the external standard method. The results indicated that the proposed method can determine 118 pesticides in urine simultaneously and rapidly. The limits of detection and limits of quantification were 0.10 and 0.50 µg/L, respectively, and the matrix effects were less than 20%for all targeted compounds. The recoveries of the 118 pesticides in urine were between 70.2% and 104% at three spiked levels of 0.50, 1.00, and 5.00 µg/L, and the relative standard deviations ranged from 2.8% to 9.3%. The method was applied to 10 actual urine samples, and the results revealed the presence of six pesticides, including thiamethoxam, clothianidin, acetamiprid, dinotefuran, isoproturon, and dimethomorph, with contents ranging from

Efficacy of intranasal administration of dexmedetomidine in combination with midazolam for sedation in infant with cleft lip and palate undergoing CT scan: a randomized controlled trial.

BACKGROUND: There is a great challenge to sedation for infants with cleft lip and palate undergoing CT scan, because there is the younger age and no consensus on the type, dosage, and route of drug administration. OBJECTIVE: This study aimed to evaluate the efficacy of intranasal administration of dexmedetomidine combined with midazolam as a sedative option for infants with cleft lip and palate under imaging procedures. METHODS: Infants scheduled for cleft lip and palate repair surgery were randomly assigned to the IND group (intranasal dexmedetomidine 2 µg/kg alone) and the INDM group (intranasal dexmedetomidine 2 µg/kg combined with midazolam 0.05 mg/kg). The primary outcome was the proportion of infants underwent successful computed tomography (CT) scans under intranasal sedation. The secondary outcomes included onset time and duration of sedation, recovery time, Ramsay sedation scale, hemodynamic parameters during sedation, and adverse events. Data analyses involved the unpaired t-test, the repeated-measures analysis of variance test, and the continuity correction χ2 test. RESULTS: One hundred five infants were included in the analysis. The proportion of infants underwent successful CT scans under sedation was significantly greater in the INDM group than in the IND group (47 [95.9%] vs. 45 [80.4%], p = 0.016). Additionally, the INDM group had a shorter onset time and a longer duration of sedation statistically (12 [8.5, 17] min vs. 16 [12, 20] min, p = 0.001; 80 [63.6, 92.5] min vs. 68.5 [38, 89] min, p = 0.014, respectively), and their recovery time was significantly longer (43 [30, 59.5] min vs. 31.5 [20.5, 53.5] min, p = 0.006). The difference in Ramsay sedation scale values 20 min after administration was statistically significant between the groups. No statistically significant difference was found between the groups in changes in heart rate and respiratory rate. CONCLUSION: Intranasal administration of dexmedetomidine in combination with midazolam resulted in higher sedation success in comparison with sole dexmedetomidine. However, it has a relatively prolonged duration of sedation and recovery time. TRIAL REGISTRATION: ChiCTR2100049122, Clinical trial first registration date: 21/07/2021.

Telemedicine management of obstructive sleep apnea disorder in China: a randomized, controlled, non-inferiority trial.

PURPOSE: Previous studies assessed different components of telemedicine management pathway for OSA instead of the whole pathway. This randomized, controlled, and non-inferiority trial aimed to assess whether telemedicine management is clinically inferior to in-person care in China. METHODS: Adults suspected of OSA were randomized to telemedicine (web-based questionnaires, self-administered home sleep apnea test [HSAT], automatically adjusting positive airway pressure [APAP], and video-conference visits) or in-person management (paper questionnaires, in-person HSAT set-up, APAP, and face-to-face visits). Participants with an apnea-hypopnea index (AHI) ≥ 15 events/hour received APAP for 3 months. The non-inferiority analysis was based on the change in Functional Outcomes of Sleep Questionnaire (FOSQ) score and APAP adherence. Cost-effectiveness analysis was performed. RESULTS: In the modified intent-to-treat analysis set (n = 111 telemedicine, 111 in-person), FOSQ scores improved 1.73 (95% confidence interval [CI], 1.31-2.14) points with telemedicine and 2.05 (1.64-2.46) points with in-person care. The lower bound of the one-sided 95% non-inferiority CI for the difference in change between groups of - 0.812 was larger than the non-inferiority threshold of - 1. APAP adherence at 3 months was 243.3 (223.1-263.5) minutes/night for telemedicine and 241.6 (221.3-261.8) minutes/night for in-person care. The lower bound of the one-sided 95% non-inferiority CI of - 22.2 min/night was higher than the non-inferiority delta of - 45 min/night. Telemedicine had lower total costs than in-person management (CNY 1482.7 ± 377.2 vs. 1912.6 ± 681.3; p < 0.0001), driven by patient costs, but no significant difference in QALYs. CONCLUSIONS: Functional outcomes and adherence were not clinically inferior in patients managed by a comprehensive telemedicine approach compared to those receiving in-person care in China. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn , Registration number ChiCTR2000030546. Retrospectively registered on March 06, 2020.

Unraveling the role of the FHL family in cardiac diseases: Mechanisms, implications, and future directions.

Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.