Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here we report that bilirubin (BIL)-dependent cell death in auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mediated current (Ih), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih and death, compromising audition at young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.Significance Statement This study demonstrated that bilirubin preferentially targets GABAergic interneurons where it facilitates not only gating of HCN1 channels but also targeting of intracellular HCN1 to plasma membrane in calcium-dependent manner, resulting in neuronal hyperexcitability, injury and sensory dysfunction. These findings implicate HCN1 channel not only as a potential driver for auditory abnormalities in neonatal patients with bilirubin encephalopathy, but also potential intervention target for clinical management of neurological impairments associated with severe jaundice. Selective vulnerability of interneurons to neurotoxicity may be of general significance for understanding other forms of brain injury.

Development and its reliability and validity of the Knowledge, Attitude and Practice Scale for Informal Caregivers of Pressure Injury Patients. / åŽ‹åŠ›æ€§æŸä¼¤æ‚£è€ éžæ­£å¼ç §é¡¾è€ çŸ¥ä¿¡è¡Œé‡è¡¨çš„ç¼–åˆ¶åŠä¿¡æ•ˆåº¦æ£€éªŒ.

OBJECTIVES: There is a lack of scientifically validated tools to measure the knowledge attitude and practice (KAP) of informal caregivers for patients with pressure injury (PI). This study aims to develop a KAP Scale for Informal Caregivers of PI Patients and to evaluate its reliability and validity. METHODS: Based on the KAP theory framework and relevant literature, an initial pool of items was created through expert brainstorming sessions. The initial scale was formed after a Delphi expert consultation and a preliminary survey. From April to October 2023, a convenient sample of informal caregivers for PI patients was recruited from an inpatient department of the Third Xiangya Hospital of Central South University, as well as its associated community and nursing homes. The first round included 186 participants, and the second round included 213 participants, who were used for item analysis and reliability and validity testing. After a 3-week interval, 20 participants from the initial group were randomly selected for a retest to assess the test-retest reliability of the scale. RESULTS: The KAP Scale for informal caregivers of PI patients consists of 3 dimensions with 19 items. The overall internal consistency (Cronbach's α) of the scale was 0.916. The item-level content validity index (I-CVI) ranged from 0.826 to 1.000, and the scale level-content validity index/average (S-CVI/Ave) was 0.94. Exploratory factor analysis extracted 3 common factors, accounting for 64.643% of the total variance. Confirmatory factor analysis showed that the model fit the data well, with χ2/df=2.54, root mean square error of approximation (RMSEA)=0.085, comparative fit index (CFI)=0.920, and standardized root mean square residual (SRMR)=0.059. CONCLUSIONS: The KAP scale for informal caregivers of PI patients demonstrates good reliability and validity and can be used to assess the KAP levels of informal caregivers regarding PI.

Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Summary of best evidence for rehabilitation management of patients with motor dysfunction after stroke. / è„‘å’ä¸­è¿åŠ¨åŠŸèƒ½éšœç¢æ‚£è€ åº·å¤ç®¡ç†çš„æœ€ä½³è¯æ®æ€»ç»“.

OBJECTIVES: The rehabilitation work for patients with motor dysfunction after stroke is crucial. However, there is currently a lack of summarized evidence regarding the rehabilitation management of stroke patients in rehabilitation wards, communities, and at home. This study aims to compile relevant evidence on the rehabilitation management of patients with motor dysfunction after stroke, providing a reference for clinical and community health professionals to carry out rehabilitation interventions. METHODS: A systematic search was conducted in BMJ Best Practice, UpToDate, National Guidebook Clearinghouse, American Heart Association/American Stroke Association, Canadian Medical Association, National Institute for Health and Clinical Excellence, United States Department of Veterans Affairs/ Department of Defense, Registered Nurses Association of Ontario, JBI Evidence-Based Healthcare Center Database, The Cochrane Library, PubMed, Web of Science, Embase, CINAHL, CNKI, Wanfang Database, SinoMed, and other databases for all literature on the rehabilitation management of patients with motor dysfunction after stroke. This included clinical decision-making, guidelines, expert consensuses, recommended practices, systematic reviews, and evidence summaries, with the search period spanning from the establishment of each database to October 2023. Two researchers independently evaluated the quality of the literature. RESULTS: A total of twenty-one documents were included, consisting of 11 guidelines, 2 expert consensus, and 8 systematic reviews. Evidence was extracted and integrated from the included literature, summarizing forty-five pieces of evidence across nine areas: rehabilitation management model, rehabilitation institutions, rehabilitation teams, timing of rehabilitation interventions, rehabilitation assessment, rehabilitation programs, rehabilitation duration and frequency, rehabilitation intensity, and rehabilitation support These covered comprehensive rehabilitation management content for stroke patients in the early, subacute, and chronic phases. CONCLUSIONS: The best evidence summarized in this study for the rehabilitation management of patients with motor dysfunction after stroke is comprehensive and of high quality. It provides important guidance for clinical and community healthcare professionals in carrying out rehabilitation interventions. When applying the evidence, it is recommended to consider the current condition of the stroke patient, the extent of motor dysfunction, environmental factors, and the patient's preferences. Then, select the most appropriate rehabilitation plan, and adjust the type and intensity of training according to each patient's specific needs and preferences.

Smooth-Muscle-Cell-Specific Deletion of CD38 Protects Mice from AngII-Induced Abdominal Aortic Aneurysm through Inhibiting Vascular Remodeling.

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.

[An analysis of clinical efficacy of microvascular decompression for 21 inpatients suffering from primary hemifacial spasm].

Objective:To assess the effectiveness of microvascular decompression（MVD） in treating inpatients suffering from primary hemifacial spasm（HFS）. Methods:A total of 21 inpatients with HFS underwent MVD. The clinical effect was follow up evaluated according to the clinical symptoms until post operative 6 months. Results:The effective rate of MVD for 1 day, 14 days, 1 month, 3 months and 6 months post-operation was 95.2%, 100%, 100%, 100% and 100%, respectively.one patient had transient tinnitus and the symptom disappeared within 6 days postoperatively.one patient developed postoperative incomplete facial paralysis（HB grade IV facial nerve function, grade Ⅱ） and recovered 6 days after surgery; There was no cerebrospinal fluid leakage, intracranial infection, death or disability occurred during follow-up. Conclusion:Microvascular decompression is a safe and effective method for the treatment of primary hemifacial spasm, which is worthy of clinical promotion.

Observational retrospective clinical study on clinical features of macrolide-resistant Mycoplasma pneumoniae pneumonia in Chinese pediatric cases.

This study aimed to investigate differences in clinical characteristics and laboratory findings between children infected with Macrolide-Sensitive Mycoplasma pneumoniae (MSMP) and Macrolide-Resistant Mycoplasma pneumoniae (MRMP). Additionally, the research sought to identify laboratory markers for rapidly distinguishing refractory Mycoplasma pneumoniae pneumonia (RMPP) from ordinary Mycoplasma pneumoniae pneumonia (OMPP). In total, 265 Mycoplasma pneumoniae (MP) patients were included, with MRMP identified by specific point mutations in domain V of the 23S rRNA gene. A retrospective analysis compared the clinical courses and laboratory data, revealing that MRMP patients experienced prolonged febrile days (P = 0.004), elevated CRP levels (P < 0.001), and higher MP DNA loads than MSMP patients (P = 0.037). Based on clinical symptoms, MRMP was divided into RMPP (n = 56) and OMPP (n = 70), with RMPP demonstrating significantly increased IL-18, community-acquired respiratory distress syndrome (CARDS) toxins in nasopharyngeal aspirate, and serum CRP levels (P < 0.001; P = 0.006; P < 0.001). In conclusion, timely recognition of RMPP is crucial for enhancing prognosis. The identification of MRMP, coupled with proinflammatory cytokines such as IL-18, CARDS toxins, and CRP, emerges as promising markers with the potential to contribute significantly to diagnostic accuracy and prognosis assessment.

Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer.

BACKGROUND: Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a micro-barrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells. METHODS: The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin ß8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. RESULTS: Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts. CONCLUSIONS: The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Effect of precision management scheme based on the best evidence summary on reducing catheter-associated urinary tract infection. / åŸºäºŽæœ€ä½³è¯æ®æ€»ç»“çš„ç²¾å‡†åŒ–ç®¡ç†æ–¹æ¡ˆå¯¹é™ä½ŽåŒ»é™¢å¯¼å°¿ç®¡ç›¸å ³å°¿è·¯æ„ŸæŸ“çš„æ•ˆæžœ.

OBJECTIVES: Catheter-associated urinary tract infection (CAUTI) is an important cause of prolonged hospital stay, which increases economic and medical burden for patients and hospitals, and it is a key focus of hospital infection prevention and control. However, there are currently few studies that convert evidence-based scientific evidence on CAUTI prevention and control into clinical applications and evaluation on its practical effects in combination with standardized infection ratio (SIR), the critical indicator of infection prevention and control. This study aims to establish a precision management plan for reducing the incidence of CAUTI, driven by the findings of a comprehensive evidence summary, to apply this plan across all the nursing units within the entire hospital, followed by a comparative analysis of CAUTI incidence, SIR, the average duration of indwelling urinary catheter for each patient, and the compliance rate on hand hygiene protocols for medical staff before and after the implementation of the precision management plan. METHODS: Based on a comprehensive review of the best evidence for preventing CAUTI, a precision management plan was meticulously developed through panel discussions and 2 rounds of expert consultations using Delphi technique. Subsequently, a historical control study was conducted to evaluate the plan's effectiveness. A total of 17 658 patients with indwelling urinary catheter in inpatient departments from January to December 2021 comprised the control group. These patients received standard nursing measures for CAUTI. Another 18 753 patients with indwelling urinary catheters in the inpatient departments from January to December 2022 comprised the intervention group, underwent the precision management scheme based on the best available evidence, to enhance CAUTI prevention. The incidence and SIR of CAUTI, the average duration of indwelling urinary catheter for each patient, and the compliance rate on hand hygiene protocols for medical staff were compared between the 2 groups. RESULTS: Compared with the control group, the incidence of CAUTI in the intervention group was significantly decreased (0.48‰ vs 1.12‰, χ2=20.814, P<0.001), SIR was decreased in the intervention group (0.55 vs 1.37); the average duration of indwelling urinary catheter for each patient was significantly decreased [(4.33±1.55) d vs (4.43±1.79) d, t=11.941, P<0.001]. The ratio of compliance rate of medical staff with strict hand hygiene protocols higher than 95% in the intervention group was significantly higher than that in the control group (93.3% vs 83.3%, χ2=5.822, P=0.016). CONCLUSIONS: The implementation of the precision management plan for reducing CAUTI based on a summary of the best available evidence on CAUTI prevention and control in patients with indwelling urinary catheters has found to be effective. This approach significantly reduces the incidence of CAUTI, reduces the average duration of indwelling urinary catheter, and enhances hand hygiene compliance among medical staff. It provides a scientific and efficient strategy for preventing and controlling CAUTI in the hospital, ultimately saving patients from unnecessary medical expense.

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression.

BACKGROUND: Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment. METHODS: The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays. RESULTS: ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa. CONCLUSIONS: In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.

PointSee: Image Enhances Point Cloud.

There is a prevailing trend towards fusing multi-modal information for 3D object detection (3OD). However, challenges related to computational efficiency, plug-and-play capabilities, and accurate feature alignment have not been adequately addressed in the design of multi-modal fusion networks. In this paper, we present PointSee, a lightweight, flexible, and effective multi-modal fusion solution to facilitate various 3OD networks by semantic feature enhancement of point clouds (e.g., LiDAR or RGB-D data) assembled with scene images. Beyond the existing wisdom of 3OD, PointSee consists of a hidden module (HM) and a seen module (SM): HM decorates point clouds using 2D image information in an offline fusion manner, leading to minimal or even no adaptations of existing 3OD networks; SM further enriches the point clouds by acquiring point-wise representative semantic features, leading to enhanced performance of existing 3OD networks. Besides the new architecture of PointSee, we propose a simple yet efficient training strategy, to ease the potential inaccurate regressions of 2D object detection networks. Extensive experiments on the popular outdoor/indoor benchmarks show quantitative and qualitative improvements of our PointSee over thirty-five state-of-the-art methods.

Different doses of methimazole treatment of children and adolescents with graves' disease: a clinical study based on 161 cases of outpatients.

OBJECTIVE: This study aimed to evaluate the association between the initial dose of MMI and the clinical course, as well as adverse effects on young people with GD. METHODS: One hundred and sixty-one children and adolescents with newly diagnosed GD were enrolled for this study and categorized into four groups based on initial serum-free T3 and T4 levels and daily MMI doses: Group A (mild, 0.3-0.5 mg/kg/day, n = 78), Group B (moderate, 0.6-0.8 mg/kg/day, n = 37), Group C (severe, 0.6-0.8 mg/kg/day, n = 24), and Group D (severe, 0.8-1.0 mg/kg/day, n = 22). The thyroid function, blood cell analysis and liver function were examined before treatment and at 4, 8 and 12 weeks after treatment. Outcome of long-term follow-up were also observed. RESULTS: After 12 weeks of treatment, 91.0% of the patients in group A and 90.9% of the patients in group D recovered to normalization of FT3, which was slightly higher than the other two groups; 70.8% of the patients in group C recovered to normalization of FT4, which was slightly lower than that in the other three groups. The incidence of minor adverse effects was 12.8% in group A, 13.5% in group B, 16.7% in group C and 40.9% in group D (P < 0.01). Remission was achieved in 38 patients (23.6%). CONCLUSIONS: Lower doses of MMI (0.3-0.5 mg/kg/day) are suitable for mild GD, and higher doses of MMI (0.6-0.8 mg/kg/day) are advisable for moderate or severe GD. Much higher doses of MMI (0.8-1.0 mg/kg/day) are harmful for initial use in children and adolescents with GD patients.

Measuring endogenous levels of unconjugated bilirubin released from isolated murine brain tissue during oxygen-glucose deprivation.

Quantitative assessment of endogenously synthesized and released bilirubin from brain tissue remains a challenge. Here, we present a sensitive and reproducible experimental paradigm to quantify, in real time, unconjugated bilirubin (UCB) from isolated murine brain tissue during oxygen-glucose deprivation (OGD). We describe steps for perfusion, brain dissection, brain slice preparation and incubation, glucose depletion, and OGD processing. We then detail procedures for standard calibration plotting and sample UCB measurement. For complete details on the use and execution of this protocol, please refer to Liu et al.1.

Assessment on Application Effect of Intelligent Pressure Ulcer Information Management System Software.

Background: We aimed to apply the intelligent pressure ulcer information management system software to hospitalized patients with pressure ulcer and to evaluate its application effect. Method: Fifty patients hospitalized in the Third Xiangya Hospital of Central South University, Changsha, China, a grade-A tertiary hospital from March 2021 to May 2021 were grouped into the control group. For these subjects, conventional electronic forms were used to report and manage pressure ulcer information. Another 50 patients with pressure ulcer were selected as the experimental group who were hospitalized the same hospital from June 2021 to August 2021. They were managed with Intelligent Pressure Ulcer Information Management System Software. Results: The effects of the two management methods were assessed by comparing the reporting time, the degree of pressure ulcer healing 1 week after the occurrence of pressure ulcer and after discharge, and the nurse satisfaction. The reporting time and Design-R scores 1 week after the occurrence of pressure ulcer and after discharge were significantly lower than those of the control group (P<0.05). Conclusion: The pressure ulcer information management system makes the reporting process simple and convenient, which saves the reporting time, improves the accuracy of the pressure ulcer staging. It achieved the guidance for various stages of pressure ulcer treatment program, the use of dressing guidance, improved the accuracy of pressure ulcer treatment program, which is worthy of clinical reference.

The TSC2 c.2742+5G>A variant causes variable splicing changes and clinical manifestations in a family with tuberous sclerosis complex.

Background: Tuberous sclerosis complex (TSC) is a genetic, variably expressed, multisystem disease characterized by benign tumors. It is caused by pathogenic variants of the TSC complex subunit 1 gene (TSC1) and the TSC complex subunit 2 gene (TSC2). Genetic testing allows for early diagnosis, genetic counseling, and improved outcomes, but it did not identify a pathogenic variant in up to 25% of all TSC patients. This study aimed to identify the disease-causing variant in a Han-Chinese family with TSC. Methods: A six-member, three-generation Han-Chinese family with TSC and three unrelated healthy women were recruited. A comprehensive medical examination, a 3-year follow-up, whole exome sequencing, Sanger sequencing, and segregation analysis were performed in the family. The splicing analysis results obtained from six in silico tools, minigene assay, and patients' lymphocyte messenger RNA were compared, and quantitative reverse transcription PCR was used to confirm the pathogenicity of the variant. Results: Two affected family members had variable clinical manifestations including a rare bilateral cerebellar ataxia symptom. The 3-year follow-up results suggest the effects of a combined treatment of anti-epilepsy drugs and sirolimus for TSC-related epilepsy and cognitive deficits. Whole exome sequencing, Sanger sequencing, segregation analysis, splicing analysis, and quantitative reverse transcription PCR identified the TSC2 gene c.2742+5G>A variant as the genetic cause. This variant inactivated the donor splice site, a cryptic non-canonical splice site was used for different splicing changes in two affected subjects, and the resulting mutant messenger RNA may be degraded by nonsense-mediated decay. The defects of in silico tools and minigene assay in predicting cryptic splice sites were suggested. Conclusions: This study identified a TSC2 c.2742+5G>A variant as the genetic cause of a Han-Chinese family with TSC and first confirmed its pathogenicity. These findings expand the phenotypic and genetic spectrum of TSC and may contribute to its diagnosis and treatment, as well as a better understanding of the splicing mechanism.

Phototrophic Biofilms Transform Soil-Dissolved Organic Matter Similarly Despite Compositional and Environmental Differences.

Dissolved organic matter (DOM) is the most reactive pool of organic carbon in soil and one of the most important components of the global carbon cycle. Phototrophic biofilms growing at the soil-water interface in periodically flooding-drying soils like paddy fields consume and produce DOM during their growth and decomposition. However, the effects of phototrophic biofilms on DOM remain poorly understood in these settings. Here, we found that phototrophic biofilms transformed DOM similarly despite differences in soil types and initial DOM compositions, with stronger effects on DOM molecular composition than soil organic carbon and nutrient contents. Specifically, growth of phototrophic biofilms, especially those genera belonging to Proteobacteria and Cyanobacteria, increased the abundance of labile DOM compounds and richness of molecular formulae, while biofilm decomposition decreased the relative abundance of labile components. After a growth and decomposition cycle, phototrophic biofilms universally drove the accumulation of persistent DOM compounds in soil. Our results revealed how phototrophic biofilms shape the richness and changes in soil DOM at the molecular level and provide a reference for using phototrophic biofilms to increase DOM bioactivity and soil fertility in agricultural settings.

Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage.

Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity. Knocking in a loss of binding point mutation for bilirubin, TRPM2-D1066A, effectively antagonizes ischemic neurotoxicity in mice. These findings suggest a vicious cycle of stroke injury in which initial ischemic insults trigger the release of endogenous bilirubin from injured cells, which potentially acts as a volume neurotransmitter to activate TRPM2 channels, aggravating Ca2+-dependent brain injury.

Genetic recombination of Orientia tsutsugamushi strains from scrub typhus patients in Guangxi, Southwest China, and the analysis of clinical features.

Three Orientia tsutsugamushi genotypic groups belonging to two prototypes (Gilliam and Karp) were identified in scrub typhus patients from Guangxi, Southwest China. Fever, headache, pneumonia, fatigue, chill, and anorexia were the most common clinical signs. Frequent recombination was observed for their 47-kDa gene compared to 56-kDa and 16S genes. Furthermore, patients infected with the Gilliam prototype represent a much higher proportion of pneumonia (6/6, 100%) than those infected with the Karp prototype (4/8, 50%) (p-value = 0.040). This discrepancy is consistent with recent animal tests on rhesus and may indicate different virulence and tissue tropism between different O. tsutsugamushi prototypes.

Development and validation of a LASSO-based prediction model for immunosuppressive medication nonadherence in kidney transplant recipients.

INTRODUCTION: To establish a prediction model to predict immunosuppressive medication (IM) nonadherence in kidney transplant recipients (KTRs) based on a combined theory framework. METHODS: This polycentric, cross-sectional study included 1191 KTRs from October 2020 to February 2021 in China, with 1011 KTRs enrolled in the derivation set and 180 in the external validation set. Variables selected based on the combined theory of planned behavior (TPB)/health belief model (HBM) theory were analyzed by the least absolute shrinkage and selection operator (LASSO). Internal 10 cross-validation was conducted to determine the optimal lambda value. The receiver operating characteristic (ROC) curve, specificity, and sensitivity were used to evaluate the prediction model, and further assessment was run by external validation. RESULTS: IM nonadherence rate was 38.48% in the derivation set and 37.22% in the validation set. The LASSO model was developed with eight predictors for IM nonadherence: age, preoperative drinking history, education, marital status, perceived barriers, social support, perceived behavioral control, and perceived susceptibility. The model demonstrated acceptable discrimination with the area under the ROC curve of 0.797 (95% CI: 0.745-0.850) in the internal validation set and 0.757 (95% CI: 0.684-0.829) in the external validation set. The specificity and sensitivity in the internal validation and external validation set were 0.741, 0.748, 0.673, and 0.716, respectively. CONCLUSIONS: The LASSO model was developed to guide identifying high-risk nonadherent patients and timely and effective interventions to improve their prognosis and survival.

Uterine fibroids are associated with increased risk of pre-eclampsia: A case-control study.

Purpose: Uterine fibroids are associated with hypertension in non-pregnant women. We aimed to evaluate the association between uterine fibroids and pre-eclampsia (PE). Patients and methods: Participants were pregnant women who delivered in the Department of Obstetrics of the People's Hospital of Xinjiang Uygur Autonomous Region between January and December 2021. Patients with PE were identified as the case group, whereas those without PE were selected as the control group, using age-matching and a ratio of 1:5. Ultrasound examination during early pregnancy was used to detect uterine fibroids. Multivariable logistic regression was applied to evaluate the association between uterine fibroids and PE. Results: In total, 121 cases with PE and 578 controls without PE were included, with mean age of 32.9 years and gestational age of 37.7 weeks. Time of ultrasound examination was 12.0 ± 2.6 weeks. The case group had a significantly higher exposure rate of uterine fibroids than the control group (14.0 vs. 6.9%, P = 0.009). Multivariable Logistic regression models adjusted for potential confounding factors, including gestational age and blood pressure in early gestation, showed that pregnant women with uterine fibroids in early pregnancy exhibited three-fold higher odds for PE (OR, 3.02; 95% CI, 1.20-7.60; P = 0.019). Sensitivity analysis, which excluded those with gestational diabetes, further confirmed the robustness of the results. The association between uterine fibroids and PE was stronger in pregnant women aged ≥35 years and multiparas. Conclusion: Uterine fibroids are significantly associated with an increased risk of PE in pregnant women. Uterine fibroids may serve as a new factor for identifying pregnant women at high risk of PE, and the effect of myomectomy before pregnancy on prevention of PE is worth further exploring.