High frequency deep brain stimulation of the dorsal raphe nucleus prevents methamphetamine priming-induced reinstatement of drug seeking in rats.

Drug addiction represents a multifaceted and recurrent brain disorder that possesses the capability to create persistent and ineradicable pathological memory. Deep brain stimulation (DBS) has shown a therapeutic potential for neuropsychological disorders, while the precise stimulation targets and therapeutic parameters for addiction remain deficient. Among the crucial brain regions implicated in drug addiction, the dorsal raphe nucleus (DRN) has been found to exert an essential role in the manifestation of addiction memory. Thus, we investigated the effects of DRN DBS in the treatment of addiction and whether it might produce side effects by a series of behavioral assessments, including methamphetamine priming-induced reinstatement of drug seeking behaviors, food-induced conditioned place preference (CPP), open field test and elevated plus-maze test, and examined brain activity and connectivity after DBS of DRN. We found that high-frequency DBS of the DRN significantly lowered the CPP scores and the number of active-nosepokes in the methamphetamine-primed CPP test and the self-administration model. Moreover, both high-frequency and sham DBS group rats were able to establish significant food-induced place preference, and no significant difference was observed in the open field test and in the elevated plus-maze test between the two groups. Immunofluorescence staining and functional magnetic resonance imaging revealed that high-frequency DBS of the DRN could alter the activity and functional connectivity of brain regions related to addiction. These results indicate that high-frequency DBS of the DRN effectively inhibits methamphetamine priming-induced relapse and seeking behaviors in rats and provides a new target for the treatment of drug addiction.

Secondary formation of oxygenated and nitrated polycyclic aromatic compounds under stagnant weather conditions: Drivers and seasonal variation.

Severe air pollution tends to occur under stagnant weather conditions. This study focused on the occurrence and formation of PM2.5-bound polycyclic aromatic compounds (PACs) under stagnant weather conditions, in consideration of their adverse human health effect and ecological toxicity. The concentrations of PACs were higher under stagnant weather conditions than in other situations with averaged values of 46.0 ng/m3 versus 12.3-39.9 ng/m3 for total PACs. Secondary formation contributed to over half of the oxygenated and nitrated polycyclic aromatic compounds (OPAHs and NPAHs). Further analyses revealed different formation mechanisms for secondary OPAHs and NPAHs. Secondary production of OPAHs was sensitive to the variations of both temperature (T) and O3 concentration at T < 22 °C but sustained at a high level despite the fluctuation of temperature and O3 concentration at T > 22 °C. Elevated NO2 concentrations favored the formation of inorganic nitrogen-containing products over NPAHs under lower temperatures and higher humidity. Stagnant weather events, accompanied by raised PAC levels occurred in all seasons, but their effects on secondary processes differed among seasons. The elevated temperature, lowered humidity, and increased NO2 level facilitated the secondary formation of OPAHs and/or NPAHs during the stagnant weather events in spring and summer. While under the temperature and humidity conditions in autumn and winter, increased NO2 levels during stagnant weather events promoted the production of secondary inorganic nitrogen-containing compounds over organic products. This study raised concern about the toxic organic pollutants in the atmosphere under stagnant weather conditions and revealed different formation mechanisms between secondary oxygenated and nitrated pollutants as well as among different seasons.

ROS-responsive nano-medicine for navigating autophagy to enhance targeted therapy of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder characterized by immune dysregulation and intestinal inflammation. Rapamycin (Ra), an mTORC1 pathway inhibitor, has shown promise for autophagy induction in IBD therapy but is associated with off-target effects and toxicity. To address these issues, we developed an oral liposome responsive to reactive oxygen species (ROS) using lipids and amphiphilic materials. We combined ketone thiol (TK) for ROS responsive and hyaluronic acid (HA) with high affinity for CD44 receptors to prepare rapamycin-loaded nanoparticle (Ra@TH). Owing to its ROS responsive characteristic, Ra@TH can achieve inflammatory colonic targeting. Additionally, Ra@TH can induce autophagy by inhibiting the mTORC1 pathway, leading to the clearance of damaged organelles, pathogenic microorganisms and oxidative stress products. Simultaneously, it also collaboratively inhibits the NF-κB pathway suppressed by the removal of ROS resulting from TK cleavage, thereby mediating the expression of inflammatory factors. Furthermore, Ra@TH enhances the expression of typical tight junction proteins, synergistically restoring intestinal barrier function. Our research not only expands the understanding of autophagy in IBD treatment but also introduces a promising therapeutic approach for IBD patients.

Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

INTRODUCTION: Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. METHODS: We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). RESULTS: We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. CONCLUSIONS: This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. TRIAL REGISTRATION: PROSPERO CRD42023391562.

Oxygen-Independent Radiodynamic Therapy: Radiation-Boosted Chemodynamics for Reprogramming the Tumor Immune Environment and Enhancing Antitumor Immune Response.

Radiodynamic therapy (RDT) has emerged as a promising modality for cancer treatment, offering notable advantages such as deep tissue penetration and radiocatalytic generation of oxygen free radicals. However, the oxygen-dependent nature of RDT imposes limitations on its efficacy in hypoxic conditions, particularly in modulating and eliminating radioresistant immune suppression cells. A novel approach involving the creation of a "super" tetrahedron polyoxometalate (POM) cluster, Fe12-POM, has been developed for radiation boosted chemodynamic catalysis to enable oxygen-independent RDT in hypoxic conditions. This nanoscale cluster comprises four P2W15 units functioning as energy antennas, while the Fe3 core serves as an electron receptor and catalytic center. Under X-ray radiation, a metal-to-metal charge transfer phenomenon occurs between P2W15 and the Fe3 core, resulting in the valence transition of Fe3+ to Fe2+ and a remarkable 139-fold increase in hydroxyl radical generation compared to Fe12-POM alone. The rapid generation of hydroxyl radicals, in combination with PD-1 therapy, induces a reprogramming of the immune environment within tumors. This reprogramming is characterized by upregulation of CD80/86, downregulation of CD163 and FAP, as well as the release of interferon-γ and tumor necrosis factor-α. Consequently, the occurrence of abscopal effects is facilitated, leading to significant regression of both local and distant tumors in mice. The development of oxygen-independent RDT represents a promising approach to address cancer recurrence and improve treatment outcomes.

Novel small molecule DMAMCL induces differentiation in rhabdomyosarcoma by downregulating of DLL1.

Rhabdomyosarcoma (RMS), a mesenchymal tumor occurring in the soft tissue of children, is associated with a defect in differentiation. This study unveils a novel anti-tumor mechanism of dimethylaminomicheliolide (DMAMCL), which is a water-soluble derivative of Micheliolide. First, we demonstrate that DMAMCL inhibits RMS cell growth without obvious cell death, leading to morphological alterations, enhanced expression of muscle differentiation markers, and a shift from a malignant to a more benign metabolic phenotype. Second, we detected decreased expression of DLL1 in RMS cells after DMAMCL treatment, known as a pivotal ligand in the Notch signaling pathway. Downregulation of DLL1 inhibits RMS cell growth and induces morphological changes similar to the effects of DMAMCL. Furthermore, DMAMCL treatment or loss of DLL1 expression also inhibits RMS xenograft tumor growth and augmented the expression of differentiation markers. Surprisingly, in C2C12 cells DMAMCL treatment or DLL1 downregulation also induces cell growth inhibition and an elevation in muscle differentiation marker expression. These data indicated that DMAMCL induced RMS differentiation and DLL1 is an important factor for RMS differentiation, opening a new window for the clinical use of DMAMCL as an agent for differentiation-inducing therapy for RMS treatment.

Characteristics and efficacy of traditional Chinese medicine in the therapeutic strategy of chronic coronary syndrome: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Chronic coronary syndrome (CCS) has always been controversial in its therapeutic strategy. Although invasive treatment and optimal medication therapy (OMT) are the most commonly used treatments, doctors continue to debate the best strategy. However, traditional Chinese medicine (TCM) for CCS is effective clinically. METHODS: To identify potentially eligible observational and experimental studies, we searched Pubmed, the Web of Science, and the China National Knowledge Internet. To be eligible, studies had to report with end-of treatment outcomes, such as major adverse cardiac events (MACE), deaths from myocardial infarctions (MI), all-cause mortality, angina, cardiac mortality, the effectiveness rate of electrocardiographs, and the reduction rate of the Nitroglycerin tablets. Risk differences (RDs) and 95 % confidence intervals (95 % CIs) were calculated based on random-effects models or fixed-effects models. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers. RESULTS: In Section 1 (13 studies, involving 17,287 patients), showed no significant difference between invasive treatment and medication treatment in MACE (RD = -0.04, 95% CI = -0.08 to 0.00, I2 = 76.4 %), all-cause mortality (RD = -0.01, 95%CI = -0.022 to 0.01, I2 = 73.44 %), MI (RD = 0.00, 95%CI = -0.00 to 0.01, I2 = 0.00 %) and cardiac mortality (RD = 0.00, 95 %CI = -0.01 to 0.01, I2 = 34.9 %). In Section 2 (21 studies, including 1820 patients), compared with WM treatment, TCM + WM treatment increased ECG effectiveness by 18 %, angina effectiveness by 20 %, and stopping or reducing Nitroglycerin tablets by 20 %. In Section 3 (25 studies, including 2859 patients) showed that TCM revealed a better electrocardiogram effective rate (RD = 0.10, 95 %CI = 0.05 to 0.14, I2 = 44.7 %) and angina effective rate (RD = 0.12, 95 %CI = 0.09 to 0.15, I2 = 44.9 %). We identified that TCM treatment properties of "Circulating blood and transforming stasis" and application of warm/heat-properties medicines were frequently used in CCS treatment. CONCLUSIONS: TCM treatment has shown superior beneficial cardioprotective in CCS therapy strategy, among which "Circulating blood and transforming stasis" and the application of warm/heat-properties medicine are its characteristics.

Cardiovascular health metrics defined by Life's Essential 8 scores and subsequent macrovascular and microvascular complications in individuals with type 2 diabetes: A prospective cohort study.

AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.

Alginate oligosaccharide assimilation by gut microorganisms and the potential role in gut inflammation alleviation.

Dietary fiber metabolism by gut microorganisms plays important roles in host physiology and health. Alginate, the major dietary fiber of daily diet seaweeds, is drawing more attention because of multiple biological activities. To advance the understanding of alginate assimilation mechanism in the gut, we show the presence of unsaturated alginate oligosaccharides (uAOS)-specific alginate utilization loci (AUL) in human gut microbiome. As a representative example, a working model of the AUL from the gut microorganism Bacteroides clarus was reconstructed from biochemistry and transcriptome data. The fermentation of resulting monosaccharides through Entner-Doudoroff pathway tunes the metabolism of short-chain fatty acids and amino acids. Furthermore, we show that uAOS feeding protects the mice against dextran sulfate sodium-induced acute colitis probably by remodeling gut microbiota and metabolome. IMPORTANCE: Alginate has been included in traditional Chinese medicine and daily diet for centuries. Recently discovered biological activities suggested that alginate-derived alginate oligosaccharides (AOS) might be an active ingredient in traditional Chinese medicine, but how these AOS are metabolized in the gut and how it affects health need more information. The study on the working mechanism of alginate utilization loci (AUL) by the gut microorganism uncovers the role of unsaturated alginate oligosaccharides (uAOS) assimilation in tuning short-chain fatty acids and amino acids metabolism and demonstrates that uAOS metabolism by gut microorganisms results in a variation of cell metabolites, which potentially contributes to the physiology and health of gut.

Systolic blood pressure as a critical mediator in the association between adult height and 25-year risk of stroke.

BACKGROUND: Adult height is associated with the risk of stroke. However, the underlying mechanism remains unclear. We explored the mediating role of metabolic factors in the association between adult height and stroke incidence. METHODS: We used data from 3306 community-dwelling participants with complete information on adult height, metabolic factors, and 25-year cardiovascular outcomes. Participants were classified into three adult height groups based on sex-specific height quartiles: short (Q1), average (Q2-Q3), and tall (Q4). The primary endpoint was the occurrence of cardiovascular disease, including coronary artery disease and stroke. RESULTS: Taller adult height was associated with a lower risk of stroke. Compared with the short group the risk of stroke reduced with taller height with a hazard ratio (HR) of 0.68 in the average group (95% confidence interval [CI]: 0.50-0.93), and 0.45 in the tall group (95% CI: 0.31-0.65). Low systolic blood pressure was considered as a protective mediator in the effect of adult height on the risk of stroke in the average (HR: 0.86; 95% CI: 0.82-0.93) and the tall group (HR: 0.85; 95% CI: 0.78-0.91). Systolic blood pressure significantly contributed to height-related stroke risk (proportion mediated: 0.41; 95% CI: 0.19-1.56). CONCLUSIONS: This study found an inverse association between adult height and stroke risk, which is partly driven by lower systolic blood pressure. These findings highlight the importance of systolic blood pressure management as a potential preventive strategy against stroke.

Engineering a functional ACL reconstruction graft containing a triphasic enthesis-like structure in bone tunnel for the enhancement of graft-to-bone integration.

Background: Anterior cruciate ligament (ACL) rupture is a common sports injury, which causes knee instability and abnormal joint kinematics. The current ACL graft was single-phasic, and not convenient for the formation of enthesis-like tissue in the bone tunnel, resulting in poor integration of graft-to-bone. Methods: A band-shaped acellular tendon (BAT) was prepared as the core component of the ACL reconstruction graft at first, while sleeve-shaped acellular cartilage (SAC) or sleeve-shaped acellular bone (SAB) was fabricated using a vacuum aspiration system (VAS)-based decellularization protocol. The biocompatibility of the three acellular matrixes was evaluated. Furthermore, a collagen-binding peptide (CBP) derived from the A3 domain of von Willebrand factor was respectively fused into the N-terminal of GDF7, TGFß3, or BMP2 to synthesize three recombinant growth factors capable of binding collagen (named C-GDF7, C-TGFß3, or C-BMP2), which were respectively tethered to the BAT, SAC or SAB for improving their inducibilities in stem cell differentiation. An in-vitro experiment was performed to evaluate theirs osteogenic, chondrogenic, and tenogenic inducibilities. Then, C-TGFß3-tethering SAC (C-TGFß3@SAC) and C-BMP2-tethering SAB (C-BMP2@SAB) were sequentially surrounded at the bone tunnel part of C-GDF7-tethering BAT (C-GDF7@BAT), thus a sleeve-shaped acellular graft with a triphasic enthesis-like structure in bone tunnel part (named tissue-engineered graft, TE graft) was engineered. Lastly, a canine ACL reconstruction model was used to evaluate the in-vivo performance of this TE graft in enhancing graft-to-bone integration. Results: The BAT, SAC, and SAB well preserved the structure and components of native tendon, cartilage, and bone, showing good biocompatibility. C-GDF7, C-TGFß3, or C-BMP2 showed a stronger binding ability to BAT, SAC, and SAB. The C-GDF7@BAT, C-TGFß3@SAC, or C-BMP2@SAB was a controlled delivery system for the scaffold-specific release of GDF7, TGFß3, and BMP2, thus showing superior tenogenic, chondrogenic, or osteogenic inducibility, respectively. Using a canine ACL reconstruction model, abundant newly-formed bone and connective collagen fibers could be observed at the integration site between TE graft and bone tunnel at postoperative 16 weeks. Meanwhile, the failure load of the reconstructed ACL by TE graft was significantly higher than that of the autograft. Conclusion: The TE graft could be used to reconstruct ruptured ACL and augment graft-to-bone integration, thus demonstrating high potential for clinical translation in ACL reconstruction. Translational potential of this article: The findings of the study indicated that the TE graft could be a novel graft for ACL reconstruction with the ability to augment graft-to-bone integration, which may provide a foundation for future clinical application.

Insights into the role of RNA m6A modification in the metabolic process and related diseases.

According to the latest consensus, many traditional diseases are considered metabolic diseases, such as cancer, type 2 diabetes, obesity, and cardiovascular disease. Currently, metabolic diseases are increasingly prevalent because of the ever-improving living standards and have become the leading threat to human health. Multiple therapy methods have been applied to treat these diseases, which improves the quality of life of many patients, but the overall effect is still unsatisfactory. Therefore, intensive research on the metabolic process and the pathogenesis of metabolic diseases is imperative. N6-methyladenosine (m6A) is an important modification of eukaryotic RNAs. It is a critical regulator of gene expression that is involved in different cellular functions and physiological processes. Many studies have indicated that m6A modification regulates the development of many metabolic processes and metabolic diseases. In this review, we summarized recent studies on the role of m6A modification in different metabolic processes and metabolic diseases. Additionally, we highlighted the potential m6A-targeted therapy for metabolic diseases, expecting to facilitate m6A-targeted strategies in the treatment of metabolic diseases.

Fibroblast regulates angiogenesis in assembled oral cancer organoid: A possible role of NNMT.

OBJECTIVE: Tumour angiogenesis is affected by various cell types in the tumour microenvironment (TME), including cancer cells and cancer-associated fibroblasts (CAFs). Here, an assembled organoid model was generated to investigate the mechanism by which the TME regulates angiogenesis in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Secretion of vascular endothelial growth factor-A (VEGFA) was analysed to compare the proangiogenic properties of OSCC cells and corresponding CAFs. Cell aggregates consisting of endothelial cells (ECs), CAFs and cancer cells were generated to construct assembled organoids. Nicotinamide N-methyltransferase (NNMT) was pharmacologically or genetically inhibited to block the activation of CAFs. ATAC-seq was employed to test the transcriptional network of fibroblasts overexpressing NNMT. RESULTS: Compared with cancer cells, CAFs secreted more VEGFA. Coculture with CAFs more effectively promoted the sprouting of ECs. Blockade of CAF activation via inhibition of NNMT drastically reduced the expression of CD31 in the assembled organoids. Overexpression of NNMT enhanced the transcription of genes related to angiogenesis in fibroblasts. Specifically, NNMT orchestrated the enrichment of the transcription factor JUNB at the promoter of VEGFA. CONCLUSIONS: We clarify that stromal NNMT enables the steady reproduction of angiogenesis in assembled oral cancer organoids, providing a novel target for exploiting antiangiogenic therapy.

Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome.

Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFß1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.

FBXO43 promotes cell cycle progression in cancer cells through stabilizing SKP2.

FBXO43 is a member of the FBXO subfamily of F-box proteins, known to be a regulatory hub during meiosis. A body of data showed that FBXO43 is overexpressed in a number of human cancers. However, whether and how FBXO43 affects cell cycle progression and growth of cancer cells remain elusive. In this study, we provide first piece of evidence, showing a pivotal role of FBXO43 in cell cycle progression and growth of cancer cells. Specifically, FBXO43 acts as a positive cell cycle regulator with an oncogenic activity in variety types of human cancer, including non-small cell lung cancer, hepatocellular carcinoma and sarcoma. Mechanistically, FBXO43 interacts with phosphorylated SKP2 induced by AKT1, leading to reduced SKP2 auto-ubiquitylation and subsequent proteasome degradation. Taken together, our study demonstrates that FBXO43 promotes cell cycle progression by stabilizing SKP2, and FBXO43 could serve as a potential anti-cancer target.

Effects of Continuous Quality Improvement on Complication Rate and Treatment Outcome of Extremely Premature Infants.

Background: Extremely premature infants (EPIs) are those less than 32 weeks of gestational age. Preterm birth is the leading cause of neonatal death and poor prognosis, accounting for 25% of neonatal deaths, with extremely premature births accounting for 50% of all premature deaths. Continuous quality improvement (CQI) improves patient outcomes by changing and optimizing clinical practice including increasing participation of neonatologists in prenatal consultation, maintenance of normal body temperature in preterm infants, early use of pulmonary surfactant, reduction of mechanical ventilation time and intensive breastfeeding to reduce clinically avoidable adverse events. Objective: The risk of death and disability is high for very preterm infants, with a mortality rate of 30-50% and a risk of at least 20-50% for survivors. This study aimed to investigate the effect of CQI on the incidence of complications and treatment outcomes in very preterm infants. Design: This was a retrospective study. Setting: This study was conducted in the Maternal and Child Health Hospital of Hubei Province. Participants: A total of 140 EPIs born in our hospital and transferred to the neonatal intensive care unit between August 1, 2020, and July 31, 2022, were enrolled. The EPIs were divided into two groups: before improvement (n=79, 56.4%) and after improvement (n=61, 43.6%) according to the week of birth, and the gestational age ranged from 26 weeks to 26 weeks 6 days into the 26 weeks group. Interventions: From August 2021, the hospital implemented the CQI method, which included neonatologists' participation in consultations before birth, the care of a professionally trained resuscitation team after birth, and the introduction of transport heating tanks and ventilators during transport. Primary Outcome Measures: (1) Apgar score (2) body weight (3) duration of invasive ventilation (4) length of stay (5) treatment expense (6) incidence of complications and (7) survival rate of EPIs. Results: The application of CQI methods resulted in significant improvements in body weight (1305 g vs 1404 g) and duration of invasive ventilation (4.64 d vs 7.40 d) in EPIs (P = .036 and P = .040), reduced the time of invasive mechanical ventilation decreased significantly, from 7.4 days to 4.64 days (P < .01), increased the median temperature of newborn infants (36.2°C vs 35.7°C) (P = 0), increased the proportion of newborn infants with a temperature greater than 36°C (67.2% vs 35.4%) (P < .001), reduced the incidence of complications in EPIs (32.79% vs 45.57%) (P < .05). Conclusion: The application of the CQI approach significantly increases the body temperature, improves the incidence of complications of EPIs, and is conducive to the survival of EPIs. Our study may provide a clinical reference for management of EPIs.

Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration.

PURPOSE: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

Red Blood Cell Distribution Width as a Risk Factor for 30/90-Day Mortality in Patients with Gastrointestinal Bleeding: Analysis of the MIMIC-IV Database.

PURPOSE: The purpose of this research was to assess the relationship between red blood cell distribution width (RDW) and mortality in patients with gastrointestinal (GIB) bleeding in the intensive care unit (ICU). METHODS: The information of the participants was obtained from the Medical Information Mart for Intensive Care IV database. The main outcome of this research was 30/90-day mortality, with ICU mortality and in-hospital mortality as secondary outcomes. RESULTS: This research included 2924 patients with gastrointestinal bleeding in total. Patients with higher RDW had considerably higher 30/90-day and in-hospital mortality rates, as well as longer hospital stays and ICU stays. According to the Kaplan-Meier analysis, the 30/90-day mortality rate was remarkably higher among participants in the higher RDW group (P < 0.0001). In the adjusted multivariate Cox regression analysis, for 30-day mortality, the HR (95% CI) was 1.75 (1.37, 2.24) in comparison to Q1 in the reference group (P < 0.001). Analyses of 90-day mortality and in-hospital mortality both showed the same results. In the subgroup analysis, gender, myocardial infarction, chronic pulmonary disease, cerebrovascular disease and renal disease had no significant effect on the correlation between RDW values and mortality (all P > 0.05). The area under the ROC curve for RDW was 0.599 (95% CI 0.581-0.617) and 0.606 (95% CI 0.588-0.624) in 30/90-day ICU mortality. CONCLUSION: The current research showed that RDW could be utilized as an independent indicator of short-term mortality in critically ill GIB patients at 30 and 90 days of hospital admission.

Repeatability of Online Circular Contrast Perimetry Compared to Standard Automated Perimetry.

PRCIS: Online circular contrast perimetry has good test repeatability and reliability that is comparable with standard automated perimetry. It holds promise for use in disease screening and surveillance to expand the provision of glaucoma care. PURPOSE: To evaluate the repeatability of online circular contrast perimetry (OCCP) compared to standard automated perimetry (SAP) in normal participants and patients with stable glaucoma over 18 weeks. METHODS: Thirty-six participants (13 normal controls and 23 patients with open angle glaucoma) were recruited. OCCP and SAP perimetry tests were performed twice at baseline, then at 6, 12, and 18 weeks. Global perimetric indices were compared between perimetry types and analyzed for short-term and intermediate-term repeatability. RESULTS: There were no statistically significant changes over time for both OCCP and SAP across all groups for mean deviation (MD), pattern standard deviation, and visual index/visual field index (P>0.05). Test-retest intraclass correlation coefficients (ICCs) for OCCP MD were excellent at baseline (0.98, 95% CI: 0.89-0.99) and good at 18 weeks (0.88, 95% CI: 0.51-0.98). SAP test-retest ICCs were excellent at baseline (0.94, 95% CI: 0.70-0.99) and 18 weeks (0.97, 95% CI: 0.84-0.99). Inter-test ICCs were good, ranging from 0.84 to 0.87. OCCP testing time was shorter than SAP (5:29 ± 1:24 vs. 6:00 ± 1:05, P<0.001). OCCP had similar false-positive (3.84 ± 3.32 vs. 3.66 ± 4.53, P=0.48) but lower false-negative (0.73 ± 1.52 vs. 4.48 ± 5.00, P<0.001) and fixation loss responses (0.91 ± 1.32 vs. 2.02 ± 2.17, P<0.001). CONCLUSIONS: OCCP demonstrated good repeatability and reliability with similar performance indices to SAP in both the short term and intermediate term. OCCP has the potential to be utilized as a glaucoma screening and surveillance tool for in-clinic and at-home testing, expanding the provision of care.