Deconstruction of Corticospinal Circuits for Goal-Directed Motor Skills.

Corticospinal neurons (CSNs) represent the direct cortical outputs to the spinal cord and play important roles in motor control across different species. However, their organizational principle remains unclear. By using a retrograde labeling system, we defined the requirement of CSNs in the execution of a skilled forelimb food-pellet retrieval task in mice. In vivo imaging of CSN activity during performance revealed the sequential activation of topographically ordered functional ensembles with moderate local mixing. Region-specific manipulations indicate that CSNs from caudal or rostral forelimb area control reaching or grasping, respectively, and both are required in the transitional pronation step. These region-specific CSNs terminate in different spinal levels and locations, therefore preferentially connecting with the premotor neurons of muscles engaged in different steps of the task. Together, our findings suggest that spatially defined groups of CSNs encode different movement modules, providing a logic for parallel-ordered corticospinal circuits to orchestrate multistep motor skills.

HRG-9 homologues regulate haem trafficking from haem-enriched compartments.

Haem is an iron-containing tetrapyrrole that is critical for a variety of cellular and physiological processes1-3. Haem binding proteins are present in almost all cellular compartments, but the molecular mechanisms that regulate the transport and use of haem within the cell remain poorly understood2,3. Here we show that haem-responsive gene 9 (HRG-9) (also known as transport and Golgi organization 2 (TANGO2)) is an evolutionarily conserved haem chaperone with a crucial role in trafficking haem out of haem storage or synthesis sites in eukaryotic cells. Loss of Caenorhabditis elegans hrg-9 and its paralogue hrg-10 results in the accumulation of haem in lysosome-related organelles, the haem storage site in worms. Similarly, deletion of the hrg-9 homologue TANGO2 in yeast and mammalian cells induces haem overload in mitochondria, the site of haem synthesis. We demonstrate that TANGO2 binds haem and transfers it from cellular membranes to apo-haemoproteins. Notably, homozygous tango2-/- zebrafish larvae develop pleiotropic symptoms including encephalopathy, cardiac arrhythmia and myopathy, and die during early development. These defects partially resemble the symptoms of human TANGO2-related metabolic encephalopathy and arrhythmias, a hereditary disease caused by mutations in TANGO24-8. Thus, the identification of HRG-9 as an intracellular haem chaperone provides a biological basis for exploring the aetiology and treatment of TANGO2-related disorders.

Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands.

Mutations in the PKD2 gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential (TRP) channel superfamily, PC2 functions as a non-selective cation channel. The activation and regulation of the PC2 channel are largely unknown, and direct binding of small-molecule ligands to this channel has not been reported. In this work, we found that most known small-molecule agonists of the mucolipin TRP (TRPML) channels inhibit the activity of the PC2_F604P, a gain-of-function mutant of the PC2 channel. However, two of them, ML-SA1 and SF-51, have dual regulatory effects, with low concentration further activating PC2_F604P, and high concentration leading to inactivation of the channel. With two cryo-electron microscopy (cryo-EM) structures, a molecular docking model, and mutagenesis results, we identified two distinct binding sites of ML-SA1 in PC2_F604P that are responsible for activation and inactivation, respectively. These results provide structural and functional insights into how ligands regulate PC2 channel function through unusual mechanisms and may help design compounds that are more efficient and specific in regulating the PC2 channel and potentially also for ADPKD treatment.

OsCIPK2 mediated rice root microorganisms and metabolites to improve plant nitrogen uptake.

Crop roots are colonized by large numbers of microorganisms, collectively known as the root-microbiome, which modulate plant growth, development and contribute to elemental nutrient uptake. In conditions of nitrogen limitation, the over-expressed Calcineurin B-like interacting protein kinase 2 (OsCIPK2) gene with root-specific promoter (RC) has been shown to enhance growth and nitrogen uptake in rice. Analysis of root-associated bacteria through high-throughput sequencing revealed that OsCIPK2 has a significant impact on the diversity of the root microbial community under low nitrogen stress. The quantification of nifH gene expression demonstrated a significant enhancement in nitrogen-fixing capabilities in the roots of RC transgenetic rice. Synthetic microbial communities (SynCom) consisting of six nitrogen-fixing bacterial strains were observed to be enriched in the roots of RC, leading to a substantial improvement in rice growth and nitrogen uptake in nitrogen-deficient soils. Forty and twenty-three metabolites exhibiting differential abundance were identified in the roots and rhizosphere soils of RC transgenic rice compared to wild-type (WT) rice. These findings suggest that OSCIPK2 plays a role in restructuring the microbial community in the roots through the regulation of metabolite synthesis and secretion. Further experiments involving the exogenous addition of citric acid revealed that an optimal concentration of this compound facilitated the growth of nitrogen-fixing bacteria and substantially augmented their population in the soil, highlighting the importance of citric acid in promoting nitrogen fixation under conditions of low nitrogen availability. These findings suggest that OsCIPK2 plays a role in enhancing nitrogen uptake by rice plants from the soil by influencing the assembly of root microbial communities, thereby offering valuable insights for enhancing nitrogen utilization in rice cultivation.

Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts.

Developing erythroblasts acquire massive amounts of iron through the transferrin (Tf) cycle, which involves endocytosis, sorting, and recycling of the Tf-Tf receptor (Tfrc) complex. Previous studies on the hemoglobin-deficit (hbd) mouse have shown that the exocyst complex is indispensable for the Tfrc recycling; however, the precise mechanism underlying the efficient exocytosis and recycling of Tfrc in erythroblasts remains unclear. Here, we identify the guanine nucleotide exchange factor Grab as a critical regulator of the Tf cycle and iron metabolism during erythropoiesis. Grab is highly expressed in differentiating erythroblasts. Loss of Grab diminishes the Tfrc recycling and iron uptake, leading to hemoglobinization defects in mouse primary erythroblasts, mammalian erythroleukemia cells, and zebrafish embryos. These defects can be alleviated by supplementing iron together with hinokitiol, a small-molecule natural compound that can mediate iron transport independent of the Tf cycle. Mechanistically, Grab regulates the exocytosis of Tfrc-associated vesicles by activating the GTPase Rab8, which subsequently promotes the recruitment of the exocyst complex and vesicle exocytosis. Our results reveal a critical role for Grab in regulating the Tf cycle and provide new insights into iron homeostasis and erythropoiesis.

Touch and tactile neuropathic pain sensitivity are set by corticospinal projections.

Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain1-4. Mental influence on perception is largely assumed to occur locally within the brain. Here we investigate whether sensory inflow through the spinal cord undergoes direct top-down control by the cortex. Although the corticospinal tract (CST) is traditionally viewed as a primary motor pathway5, a subset of corticospinal neurons (CSNs) originating in the primary and secondary somatosensory cortex directly innervate the spinal dorsal horn via CST axons. Either reduction in somatosensory CSN activity or transection of the CST in mice selectively impairs behavioural responses to light touch without altering responses to noxious stimuli. Moreover, such CSN manipulation greatly attenuates tactile allodynia in a model of peripheral neuropathic pain. Tactile stimulation activates somatosensory CSNs, and their corticospinal projections facilitate light-touch-evoked activity of cholecystokinin interneurons in the deep dorsal horn. This touch-driven feed-forward spinal-cortical-spinal sensitization loop is important for the recruitment of spinal nociceptive neurons under tactile allodynia. These results reveal direct cortical modulation of normal and pathological tactile sensory processing in the spinal cord and open up opportunities for new treatments for neuropathic pain.

Relationship Between Iron Distribution in Deep Gray Matter Nuclei Measured by Quantitative Susceptibility Mapping and Motor Outcome After Deep Brain Stimulation in Patients With Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor deficits in advanced Parkinson's disease (PD) patients, but the degree of motor improvement varies across individuals. PD pathology involves the changes of iron spatial distribution in the deep gray matter nuclei. PURPOSE: To explore the relationship between the iron spatial distribution and motor improvement among PD patients who underwent STN-DBS surgery in three regions: substantia nigra (SN), STN, and dentate nucleus (DN). STUDY TYPE: Prospective. SUBJECTS: Forty PD patients (49.7 ± 8.8 years, 22 males/18 females) who underwent bilateral STN-DBS. FIELD STRENGTH/SEQUENCE: A 3 T preoperative three-dimensional spoiled bipolar-readout multi-echo gradient recalled echo and two-dimensional fast spin echo sequences. ASSESSMENT: Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) scores were assessed 2-3 days before and 6 months after STN-DBS. The first- and second-order texture features in regions of interest were measured on susceptibility maps. STATISTICAL TESTS: Intraclass correlation coefficient was used to determine the consistency of the region of interest volumes delineated by the two raters. Pearson or Spearman's correlation coefficients were used to assess the relationship between motor improvement after DBS and texture features. A P-value <0.05 was considered statistically significant. RESULTS: MDS-UPDRS III scores were reduced by 59.9% after STN-DBS in 40 PD patients. Motor improvement correlated with second-order texture parameters in the SN including angular second moment (r = -0.449), correlation (rho = 0.326), sum of squares (r = 0.402), sum of entropy (rho = 0.421), and entropy (r = 0.410). Additionally, DBS outcome negatively correlated with mean susceptibility values in the DN (r = -0.400). DATA CONCLUSION: PD patients with a more homogeneous iron distribution throughout the SN or a higher iron concentration in the DN responded worse to STN-DBS. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Psoralen induces liver injury and affects hepatic bile acids metabolism in female and male C57BL/6J mice.

Psoralen is a major component of Fructus Psoraleae that could induce liver injury. In this study, C57BL/6J mice were administered with psoralen at doses of 80 mg/kg for 3, 7 and 14 days. Blood and liver samples were collected for serum biochemistry and histopathology examinations, respectively. Psoralen led to liver injury with significantly increased liver weight and liver coefficient and up regulated serum ALT, AST and TG but down regulated serum TC and TP. The expression of bile acid-associated transporters and enzymes was detected by western blot, and the results showed that psoralen significantly down-regulates the expressions of CYP7A1, CYP27A1, BSEP and OSTα protein while up-regulates the expressions of HMGCR and FASN, resulting in the obstacles of bile acid efflux in the liver. The contents of 24 kinds of bile acids in the liver were measured by LC-MS/MS, and the results showed that psoralen led to the accumulation of unconjugated bile acids in the liver, such as ALCA and CA, which were more severe in male mice than female mice. It was indicated that psoralen may disrupt the balance of bile acid metabolism by inhibiting the expression of the efflux transporter, which then leads to liver damage.

Sub-chronic toxicity of an aqueous extract of Epimedium sagittatum (Sieb. Et Zucc.) Maxim. in rats.

Epimedium sagittatum (Sieb. et Zucc.) Maxim., a traditional medicinal plant in Asia, is widely used in clinical settings but its safety in vivo is unclear. This study investigated the sub-chronic toxicity of E. sagittatum aqueous extract to rats with a 13-week daily intragastric administration of 7.5, 15, or 30 g/kg. Nine constituents of the aqueous extract were identified by ultra-performance liquid chromatography (UPLC). Organ weights, organ coefficients, serum biochemistry parameters, histopathology, and metabolomic analysis were performed. In female rats, treatment increased the liver, thymus, and adrenal gland coefficients (p < 0.05). Liver, pancreas, and adrenal gland injury were observed. The levels of six metabolites were altered by the treatment (p < 0.05). In male rats, treatment altered liver, heart, and thymus coefficients (p < 0.05) and liver, adrenal gland, and heart injury were observed. The levels of 11 metabolites were altered (p < 0.05). The no-observed-adverse-effect level was not determined but would be below 7.5 g/kg in rats treated for 13 weeks. In female rats, E. sagittatum may injure the liver and pancreas and dysregulate the biosynthesis of phenylalanine, tyrosine, tryptophan, valine, leucine, and isoleucine and the metabolism of phenylalanine. In male rats, the extract may injure the liver and adrenal gland and dysregulate the biosynthesis of valine, leucine, and isoleucine and the metabolism of pyruvate.

[Exploration of transcriptome SSR markers and its application in genetic diversity assessment of Asarum sieboldii].

To explore the genetic diversity of Asarum sieboldii this study developed SSR markers based on transcriptome sequencing results and five populations of A.sieboldii from different regions were used as samples for genetic diversity assessment using software such as GenALEx 6.5, NTSYS 2.1, and Structure 2.3.4. The results showed that 16 SSR markers with high polymorphism and good repeatability were selected from the A.sieboldii transcriptome. Primers designed based on the flanking sequences of these markers successfully amplified 56 polymorphic fragments from 150 individual samples of the five A.sieboldii populations. On average, each primer amplified 3.5 polymorphic fragments, ranging from 2 to 8. The mean values of expected heterozygosity(H_e), Shannon's diversity index(I), Nei's gene diversity index(H), and the polymorphic information content(PIC) were 0.172, 0.281, 0.429, and 0.382, respectively. The mean population differentiation coefficient(F_(ST)) was 0.588, consistent with the analysis of molecular variance(AMOVA) results, which indicated greater genetic variation among A.sieboldii populations(69%) than that within populations(31%). The percentage of polymorphic loci(PPL) ranged from highest to lowest as SNJ>LN>SY>SZ>TB. Principal coordinate analysis(PCoA) and UPGMA clustering analysis further revealed genetic clustering of A.sieboldii individuals based on their geographical distribution, consistent with the results of the structure clustering analysis. In summary, the SSR markers developed from the transcriptome effectively assessed the genetic differentiation and population structure of natural A.sieboldii populations, revealing a relatively low genetic diversity in A.sieboldii, with genetic variation primarily observed at the population level and a correlation between population differentiation and geographic distance.

Identification of a ferroptosis-related gene pair biomarker with immune infiltration landscapes in ischemic stroke: a bioinformatics-based comprehensive study.

BACKGROUND: Ischemic stroke (IS) is a principal contributor to long-term disability in adults. A new cell death mediated by iron is ferroptosis, characterized by lethal aggregation of lipid peroxidation. However, a paucity of ferroptosis-related biomarkers early identify IS until now. This study investigated potential ferroptosis-related gene pair biomarkers in IS and explored their roles in immune infiltration. RESULTS: In total, we identified 6 differentially expressed ferroptosis-related genes (DEFRGs) in the metadata cohort. Of these genes, 4 DEFRGs were incorporated into the competitive endogenous RNA (ceRNA) network, including 78 lncRNA-miRNA and 16 miRNA-mRNA interactions. Based on relative expression values of DEFRGs, we constructed gene pairs. An integrated scheme consisting of machine learning algorithms, ceRNA network, and gene pair was proposed to screen the key DEFRG biomarkers. The receiver operating characteristic (ROC) curve witnessed that the diagnostic performance of DEFRG pair CDKN1A/JUN was superior to that of single gene. Moreover, the CIBERSORT algorithm exhibited immune infiltration landscapes: plasma cells, resting NK cells, and resting mast cells infiltrated less in IS samples than controls. Spearman correlation analysis confirmed a significant correlation between plasma cells and CDKN1A/JUN (CDKN1A: r = - 0.503, P < 0.001, JUN: r = - 0.330, P = 0.025). CONCLUSIONS: Our findings suggested that CDKN1A/JUN could be a robust and promising gene-pair diagnostic biomarker for IS, regulating ferroptosis during IS progression via C9orf106/C9orf139-miR-22-3p-CDKN1A and GAS5-miR-139-5p/miR-429-JUN axes. Meanwhile, plasma cells might exert a vital interplay in IS immune microenvironment, providing an innovative insight for IS therapeutic target.

Wdr26 regulates nuclear condensation in developing erythroblasts.

Mammalian red blood cells lack nuclei. The molecular mechanisms underlying erythroblast nuclear condensation and enucleation, however, remain poorly understood. Here we show that Wdr26, a gene upregulated during terminal erythropoiesis, plays an essential role in regulating nuclear condensation in differentiating erythroblasts. Loss of Wdr26 induces anemia in zebrafish and enucleation defects in mouse erythroblasts because of impaired erythroblast nuclear condensation. As part of the glucose-induced degradation-deficient ubiquitin ligase complex, Wdr26 regulates the ubiquitination and degradation of nuclear proteins, including lamin B. Failure of lamin B degradation blocks nuclear opening formation leading to impaired clearance of nuclear proteins and delayed nuclear condensation. Collectively, our study reveals an unprecedented role of an E3 ubiquitin ligase in regulating nuclear condensation and enucleation during terminal erythropoiesis. Our results provide mechanistic insights into nuclear protein homeostasis and vertebrate red blood cell development.

Construction of PEGylated boronate-affinity-oriented imprinting magnetic nanoparticles for ultrasensitive detection of ellagic acid from beverages.

Molecularly imprinted polymers (MIPs) can exhibit antibody-level affinity for target molecules. However, the nonspecific adsorption of non-imprinted regions for non-target molecules limits the application range of MIPs. Herein, we fabricated PEGylated boronate-affinity-oriented ellagic acid-imprinting magnetic nanoparticles (PBEMN), which first integrated boronate-affinity-oriented surface imprinting and sequential PEGylation for small molecule-imprinted MIPs. The resultant PBEMN possess higher adsorption capacity and faster adsorption rate for template ellagic acid (EA) molecules than the non-PEGylated control. To prove the excellent performance, the PBEMN were linked with hydrophilic boronic acid-modified/fluorescein isothiocyanate-loaded graphene oxide (BFGO), because BFGO could selectively label cis-diol-containing substances by boronate-affinity and output ultrasensitive fluorescent signals. Based on a dual boronate-affinity synergy, the PBEMN first selectively captured EA molecules by boronate-affinity-oriented molecular imprinted recognition, and then the EA molecules were further labeled with BFGO through boronate-affinity. The PBEMN linked BFGO (PBPF) strategy provided ultrahigh sensitivity for EA molecules with a limit of detection of 39.1 fg mL-1, resulting from the low nonspecific adsorption of PBEMN and the ultrasensitive fluorescence signal of BFGO. Lastly, the PBPF strategy was successfully employed in the determination of EA concentration in a spiked beverage sample with recovery and relative standard deviation in the range of 96.5 to 104.2% and 3.8 to 5.1%, respectively. This work demonstrates that the integration of boronate-affinity-oriented surface imprinting and sequential PEGylation may be a universal tool for improving the performance of MIPs.

CuCo2S4 nanozyme-based stimulus-responsive hydrogel kit for rapid point-of-care testing of uric acid.

An efficient analysis platform composed of nanozyme-based hydrogel kit and smartphone was constructed for on-site detection of uric acid (UA) in a rapid and realiable manner. CuCo2S4 nanoparticles (CuCo2S4 NPs) as a peroxidase mimic were successfully prepared and the peroxidase-like activity and catalytic mechanism were studied in detail. The hydrogen peroxide (H2O2) stimulus-responsive nanozyme-based hydrogel kit was manufactured by integrating agarose, CuCo2S4 NPs, and 3,3',5,5'-tetramethylbenzidine (TMB) into the cap of centrifuge tube. H2O2 generated via UA oxidation acts as stimulus signal, which triggers the oxidation of TMB to form blue product (oxTMB) under the catalysis of CuCo2S4 NPs, resulting in the color response of the constructed kit. The color image of the kit was captured by a smartphone built-in camera and converted into color intensity using ImageJ software, thus achieving the quantitative determination of UA. The portable kit possesses high selectivity and was used to monitor UA in human serum with satisfactory results (recovery was in the range 95.8-107.3% and RSD was not greater than 4.6%). The established sensing platform is convenient and reliable, which provides a new strategy for point-of-care testing of UA and has a broad prospect in the fields of chemical sensing and biomedical.

The changes of hepatic bile acid synthesis and transport and bile acids profiles in isopsoralen-induced liver injury C57BL/6J mice.

CONTEST: Isopsoralen, one of the main active and quality-control compounds in Psoralea corylifolia L. (Fabaceae), has antitumor and oestrogen-like effects. Previous studies demonstrated that isopsoralen induced hepatotoxicity and its long-term exposure led to cholestatic liver injury. OBJECTIVE: This study investigates the effect of three- or seven-day exposure of low dose isopsoralen (80 mg/kg) on bile acid homeostasis in C57BL/6J mice. MATERIALS AND METHODS: Forty-two C57BL/6J mice were randomly divided into control, three- and seven-day groups (n = 14 per group, half female and half male). Isopsoralen suspension was administrated intragastrically at 80 mg/kg once a day. Blood and liver samples were collected to measure biochemical indices and transport of BAs. The histopathology of the liver was also observed. HPLC-MS/MS was also used to measure the BAs profiles and transport activity. RESULTS: In the study, isopsoralen increased the levels of serum AST, ALT in three- and seven-day groups, and caused vacuolar degeneration and swelling in the liver. Canalicular efflux transporters BSEP, OSTα, MRP2, MRP3, and basolateral uptake transporters NTCP, OATP4 were inhibited after seven-day-administration. Moreover, amino acid binding enzymes (BAAT and BACS) were also inhibited after seven-day-administration. The composition of BAs changed greatly and the concentration of some unconjugated-BAs which have stronger hydrophobicity, such as CA, CDCA, was significantly increased. CONCLUSIONS: Isopsoralen (80 mg/kg) caused hepatotoxicity after short-term exposure by inhibiting the expression of efflux transporters, amino acid binding enzymes, and disrupting BAs spectrum.

Zebrafish hhatla is involved in cardiac hypertrophy.

Cardiac hypertrophy is a compensatory response to pathological stimuli, ultimately progresses to cardiomyopathy, heart failure, or sudden death. Although many signaling pathways have been reported to be involved in the hypertrophic process, it is still not fully clear about the underlying molecular mechanisms for cardiac hypertrophy. Hedgehog acyltransferase-like (Hhatl), a sarcoplasmic reticulum-resident protein, exhibits high expression in the heart and muscle. However, the biological role of Hhatl in the heart remains unknown. In this study, we first found that the expression level of Hhatl is markedly decreased in cardiac hypertrophy. We further studied the role of hhatla, homolog of Hhatl with the zebrafish model. The depletion of hhatla in zebrafish leads to cardiac defects, as well as an enhanced level of hypertrophic markers. Besides, we found that calcineurin signaling participates in hhatla depletion-induced cardiac hypertrophy. Together, these results demonstrate a critical role for hhatla in cardiac hypertrophy.

Self-supporting Atmosphere-Assisted Synthesis of 1D Mo2 C-based Catalyst for Efficient Hydrogen Evolution.

One-dimensional materials exhibit fascinating properties in electrocatalytic applications but their fabrication faces the challenge of tedious and complicated operations. We have developed a bottom-up strategy to construct a 1D metal carbide catalyst (Mo2 C@NC) consisting of ultrafine Mo2 C nanoparticles embedded within nitrogen-doped carbon layers by simply calcining a mixture of ammonium molybdate, urea and melamine. Experimental results and thermodynamic calculations demonstrate that the retainable pyrolysis-generated self-supporting atmosphere plays a crucial role in the crystalline phase and morphology of materials. When functioned as an electrocatalyst for the hydrogen evolution reaction (HER), the achieved Mo2 C@NC presents an excellent catalytic activity as well as outstanding stability. This work could shed fresh light onto the facile synthesis of effective HER catalysts with 1D nanostructure.

The cardiovascular disorders and prognostic cardiac biomarkers in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to the outbreak of coronavirus disease 2019 (COVID-19), a worldwide epidemic disease affecting increasing number of patients. Although the virus primarily targets respiratory system, cardiovascular involvement has been reported in accumulating studies. In this review, we first describe the cardiac disorders in human with various types of CoV infection, and in animals infected with coronavirus. Particularly, we will focus on the association of cardiovascular disorders upon SARS-CoV-2 infection, and prognostic cardiac biomarkers in COVID-19. Besides, we will discuss the possible mechanisms underlying cardiac injury resulted from SARS-CoV-2 infection including direct myocardial injury caused by viral infection, reduced level of ACE2, and inflammatory response during infection. Improved understandings of cardiac disorders associated with COVID-19 might predict clinical outcome and provide insights into more rational treatment responses in clinical practice.

The prediction of asymptomatic carotid atherosclerosis with electronic health records: a comparative study of six machine learning models.

BACKGROUND: Screening carotid B-mode ultrasonography is a frequently used method to detect subjects with carotid atherosclerosis (CAS). Due to the asymptomatic progression of most CAS patients, early identification is challenging for clinicians, and it may trigger ischemic stroke. Recently, machine learning has shown a strong ability to classify data and a potential for prediction in the medical field. The combined use of machine learning and the electronic health records of patients could provide clinicians with a more convenient and precise method to identify asymptomatic CAS. METHODS: Retrospective cohort study using routine clinical data of medical check-up subjects from April 19, 2010 to November 15, 2019. Six machine learning models (logistic regression [LR], random forest [RF], decision tree [DT], eXtreme Gradient Boosting [XGB], Gaussian Naïve Bayes [GNB], and K-Nearest Neighbour [KNN]) were used to predict asymptomatic CAS and compared their predictability in terms of the area under the receiver operating characteristic curve (AUCROC), accuracy (ACC), and F1 score (F1). RESULTS: Of the 18,441 subjects, 6553 were diagnosed with asymptomatic CAS. Compared to DT (AUCROC 0.628, ACC 65.4%, and F1 52.5%), the other five models improved prediction: KNN + 7.6% (0.704, 68.8%, and 50.9%, respectively), GNB + 12.5% (0.753, 67.0%, and 46.8%, respectively), XGB + 16.0% (0.788, 73.4%, and 55.7%, respectively), RF + 16.6% (0.794, 74.5%, and 56.8%, respectively) and LR + 18.1% (0.809, 74.7%, and 59.9%, respectively). The highest achieving model, LR predicted 1045/1966 cases (sensitivity 53.2%) and 3088/3566 non-cases (specificity 86.6%). A tenfold cross-validation scheme further verified the predictive ability of the LR. CONCLUSIONS: Among machine learning models, LR showed optimal performance in predicting asymptomatic CAS. Our findings set the stage for an early automatic alarming system, allowing a more precise allocation of CAS prevention measures to individuals probably to benefit most.

Procedural Pain in Hospitalized Children in a Chinese Children's Hospital.

BACKGROUND: Pain prevalence in pediatric hospitals has been investigated in many developed countries, but little is known about this topic in China. AIMS: This study sought to describe the frequency and pain intensity of procedures for medical care in hospitalized children in a Chinese children's hospital. DESIGN: A cross-sectional study was designed to include interviews with children, their parents and the nurses. SETTINGS: This survey was administered in a teaching hospital in southeast China. PARTICIPANTS/SUBJECTS: Infants and children up to 16 years old who were admitted to the study units for more than 6 days were eligible for inclusion. METHODS: Information regarding patient demographics, painful procedures and pain management strategies was obtained during the day shifts of the children's hospitalization. RESULTS: A total of 3886 procedures were performed on 342 children during the data collection period. The reuse of intravenous indwelling needles ( n = 577), removal of tape from the skin (n = 420) and venipuncture on the back of the hand ( n = 401) were the most frequently performed procedures on children. A total of 1941 procedures, accounting for 49.9% (1941/3886) of painful procedures caused moderate to severe pain (pain score ≥4.0). However, only 25.3% (984/3886) received a valid pain assessment, and only 14.4% (560/3886) received pain interventions. CONCLUSIONS: Most children, especially those who are younger (<4 years old), experienced moderate or severe pain during their hospitalization, but did not receive appropriate interventions.