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During hypertension-induced endothelial dysfunction, periodic mechanical stretching (MS) activates related inflammatory pathways and leads to endothelial damage, but the underlying mechanisms remain unknown. The present study aimed to determine the injury of HUVECs caused by overstretching and the role of HMGB1-RAGE pathway in HUVECs after injury.Human umbilical vein endothelial cells (HUVECs) were cultured and seeded in BioFlex™ plates (six wells). Cells were exposed to 5% (physiological state) and 20% (pathological state) mechanical stretch at 1 Hz for 12 or 24 h in a Flexcell-5000™, with unstretched cells serving as controls. It was found that excessive MS can inhibit cell viability, proliferation, and tube-forming ability resulting in disordered cell arrangement and orientation, slowing cell migration. All these changes cause endothelial damage compared to physiological MS. Endothelial cells (ECs) promote cell migration and self-repair after injury by increasing the High-mobility group box 1 (HMGB1) expression. Experiments and protein prediction networks have shown that HMGB1 can also promote the expression of downstream protein bFGF by binding to receptor for advanced glycation end products (RAGE). Interestingly, VEGF protein expression did not change significantly during this repair process, implying that bFGF replaces the role of VEGF in vascular endothelial repair.The present study demonstrates that in the context of endothelial injury caused by excessive MS, the HMGB1/RAGE/bFGF pathway is activated and promotes endothelial repair after injury. Therefore, understanding these mechanisms will help find new therapies for diseases such as hypertension, atherosclerosis, and aneurysm formation.

Previous studies have demonstrated that circST6GALNAC6 is a tumor suppressor in bladder cancer. However, the role of circST6GALNAC6 in ferroptosis remains unclear. In the current study, ferroptosis was induced in bladder cancer cells by erastin. Functional experiments showed that overexpression of circST6GALNAC6 promoted ferroptosis of bladder cancer cells in vitro and in vivo. Mechanistic studies revealed that circST6GALNAC6 bound to the N-terminus of small heat shock protein 1 (HSPB1) and thus blocked the erastin-induced phosphorylation of HSPB1 at the Ser-15 site, a phosphorylation site in the protective response to ferroptosis stress. In addition, protein kinase C inhibited circST6GALNAC6-induced ferroptosis by increasing the overall phosphorylation level of HSPB1, further demonstrating the role of phosphorylation activation of HSPB1 in resistance to ferroptosis. Finally, the involvement of the HSPB1/p38 MAPK pathway in the downstream signal transduction of circST6GALNAC6 in bladder cancer ferroptosis regulation was determined. The regulatory mechanism of ferroptosis sensitivity dependent on circST6GALNAC6 expression levels in bladder cancer was revealed as circRNA regulation of various protein functions. CircST6GALNAC6 inhibits HSPB1 and promotes cell ferroptosis by occupying the phosphorylation site (Ser-15) of HSBP1 and activating the P38 MAPK signaling pathway. Therefore, enhancing the expression of circST6GALNAC6 to promote ferroptosis or using circST6GALNAC6 as a biomarker of ferroptosis sensitivity is of considerable importance to the development and application of ferroptosis intervention methods in bladder cancer.

Background: Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown. Methods: We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)–specific, endothelial cell–specific, and myeloid cell–specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)– and CaPO 4 -induced AAA models. Results: Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO 4 -induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs. Conclusions: Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.

As a family of G protein-coupled receptors (GPCRs) with a seven-span transmembrane structure, frizzled class receptors (FZDs) play crucial roles in regulating multiple biological functions. However, their transcriptional expression profile and prognostic significance in acute myeloid leukemia (AML) are unclear. In AML, the role of FZDs was explored by performing the comprehensive analysis on the relationship between clinical characteristics and mRNA expression profiles from public databases including cBioPortal for Cancer Genomics, Gene Expression Profile Interactive Analysis (GEPIA), and Cancer Cell Line Encyclopedia (CCLE). We identified that in the majority of 27 AML cell lines, frizzled class receptor 6 (FZD6) was high-expressed. A significantly higher expression of FZD6 in AML patients was observed when compared to normal controls ( P < 0.01 ). Compared with intermediate and poor/adverse risk group patients, FZD6 expressed much lower in cytogenetic favorable risk group patients ( P < 0.0001 ). Patients with higher-expressed FZD6 were associated with shorter overall survival (OS) ( P = 0.0089 ) rather than progression-free survival (PFS). However, the predictive effect of FZD6 on OS could be reversed by hematopoietic stem cell transplantation (HSCT). The data of gene set enrichment analysis (GSEA) demonstrated that 4 gene sets, including MYC targets, HEME metabolism, E2F targets, and UV response, were differentially enriched in the high-expression FZD6 group. To conclude, the study suggested that high expression of FZD6 might be a novel poor prognostic biomarker for AML treatment.

Identification of specific leukemia subtypes is a key to successful risk-directed therapy in childhood acute lymphoblastic leukemia (ALL). Although RNA sequencing (RNA-seq) is the best approach to identify virtually all specific leukemia subtypes, the routine use of this method is too costly for patients in resource-limited countries. This study enrolled 295 patients with pediatric ALL from 2010 to 2020. Routine screening could identify major cytogenetic alterations in approximately 69% of B-cell ALL (B-ALL) cases by RT-PCR, DNA index, and multiplex ligation-dependent probe amplification. STIL-TAL1 was present in 33% of T-cell ALL (T-ALL) cases. The remaining samples were submitted for RNA-seq. More than 96% of B-ALL cases and 74% of T-ALL cases could be identified based on the current molecular classification using this sequential approach. Patients with Philadelphia chromosome-like ALL constituted only 2.4% of the entire cohort, a rate even lower than those with ZNF384-rearranged (4.8%), DUX4-rearranged (6%), and Philadelphia chromosome-positive (4.4%) ALL. Patients with ETV6-RUNX1, high hyperdiploidy, PAX5 alteration, and DUX4 rearrangement had favorable prognosis, whereas those with hypodiploid and KMT2A and MEF2D rearrangement ALL had unfavorable outcomes. With the use of multiplex ligation-dependent probe amplification, DNA index, and RT-PCR in B-ALL and RT-PCR in T-ALL followed by RNA-seq, childhood ALL can be better classified to improve clinical assessments.

To produce high-quality, real-world evidence for oncologists by collating scattered gynaecologic oncology (GO) medical records in China.Retrospective study.The National Union of Real-world Gynaecological Oncology Research and Patient Management Platform (NUWA platform).Patient-centred data pool.The NUWA platform integrated inpatient/outpatient clinical, gene and follow-up data. Data of 11 456 patients with ovarian cancer (OC) were collected and processed using 91 345 electronic medical records. Structured and unstructured data were de-identified and re-collated into a patient-centred data pool using a predefined GO data model by technology-aided abstraction.Recent treatment pattern shifts towards precision medicine for OC in China.Thirteen first-tier hospitals across China participated in the NUWA platform up to 7 December 2021. In total, 3504 (30.59%) patients were followed up by a stand-alone patient management centre. The percentage of patients undergoing breast cancer gene (BRCA) mutation tests increased by approximately six-fold between 2017 and 2018. A similar trend was observed in the administration rate of poly(ADP-ribose) polymerase inhibitors as first-line treatment and second-line treatment after September 2018, when olaparib was approved for clinical use in China.The NUWA platform has great potential to facilitate clinical studies and support drug development, regulatory reviews and healthcare decision-making.

The present study aims to (1) follow up with 4-year changes in the efficacy outcome, defense style questionnaire (DSQ) score, and clinical features of patients with obsessive-compulsive disorder (OCD) and (2) analyze the relationship between different levels of efficacy and changes in the patients' psychological defense mechanisms.The following data collection and 4-year follow-up were completed for 153 patients with OCD: (1) the treatment process, efficacy outcome, course of disease, and clinical features of OCD were collected using a self-made general information questionnaire and (2) the control method was used to analyze the changes in clinical symptoms (Yale-Brown obsessive compulsive scale [YBOCS], Hamilton anxiety score [HAMA], and Hamilton depression scale [HAMD]) in patients with OCD. Moreover, the changes in the psychological defense mechanism (measured by DSQ) and the relation between the prognosis and DSQ score were investigated.(1) The HAMA score (8.7 ± 4.8 points), HAMD score (12.0 ± 6.6 points) and YBOCS score (16.4 ± 8.4 points) were significantly lower during the follow-up than at the time of enrollment (p 0.01). In the two DSQ evaluations, there were no significant differences in the factors, with the exception of a significant decrease in the use of "reaction formation" (t = 2.533, p = 0.015). The changes of mature defense factors in the significant efficacy group significantly increased (p 0.01). Which was mainly manifested in the significant increase in the score of "sublimation" item, and the difference was extremely significant (t = -3.093, p = 0.006).An abnormal psychological defense mechanism plays an important role in OCD, and the use of a mature defense mechanism is significantly related to the treatment efficacy.

Aggressive end-of-life (EOL) care that is not aligned with the preferences of persons with cancer has negative impacts on their quality of life. Alzheimer's disease and related dementias (ADRD) could potentially complicate EOL care planning among persons with cancer. Little is known about the aggressive EOL care patterns among Medicare beneficiaries with both cancer and ADRD.A matched retrospective cohort was created using the 2004 to 2016 Surveillance, Epidemiology, End Results-Medicare (SEER-Medicare) data differentiated by beneficiaries' ADRD status. Beneficiaries with breast, lung, colorectal, or prostate cancer who died between January 1, 2005 and December 31, 2016, were included. Six existing domains of aggressive EOL care and one overall indicator were derived. The major predictor was having ADRD comorbidity; other covariates included sex, marital status, census tract poverty indicator, race/ethnicity, metro status, geographic location, Charlson Comorbidity Index (CCI), survival time, cancer site, and histology stage. Multivariable logistic regression models were deployed to estimate the odds of receiving aggressive EOL care.The study sample was 135,380 people after the one-to-one propensity score matching. The prevalence of aggressive EOL care utilization was slightly lower in beneficiaries with both cancer and ADRD when compared to beneficiaries with cancer only (54% vs. 58%, p 0.0001). Beneficiaries with both cancer and ADRD were less likely to receive aggressive EOL care (AOR: 0.88, 95% CI: 0.86, 0.90) versus beneficiaries with cancer only. From the multivariable logistic regression model, certain beneficiaries' characteristics were associated with higher odds of receiving aggressive EOL care, such as: beneficiaries belonging to a racial/ethnic minority, a shorter survival time, and a higher CCI score.The combined presence of ADRD and cancer was associated with lower odds of receiving aggressive EOL care compared to the presence of only cancer; however, the prevalence difference between the cohorts was not huge. Future studies could conduct in-depth evaluations of the ADRD's influence on the EOL care utilization.

Living donor kidney transplantation (LDKT) is an important organ resource, especially in countries with low deceased donation rates. Strategies for expanding access to transplantation should be developed by identifying the modifiable factors. In this study, we evaluated these factors in the relatives of patients from both medical centers and dialysis clinics using questionnaires.The questionnaires were anonymous and confidential. We collected questionnaires from previous donors, relatives of patients on the waitlist in the medical center, and relatives of dialysis patients in three nephrology clinics. The study groups were divided into three categories: donor group (n = 68), willing group (n = 43), and non-donor group (n = 65).Respondents in the clinics had lower cognition and willingness towards LDKT than those in the medical center. More knowledge of LDKT, better relationship with patients, more familial support, and female gender were positively related to donation. The non-donor group tended to want to maintain an intact body for the afterlife. There was no significant difference in age, educational degree, average monthly income, and medical compliance among the three groups.More efforts need to be made in dialysis clinics, where general nephrologists are important for the outreach of information. In addition, dealing with religious ambivalence and reestablishing cultural mindsets with health education programs are important issues in a non-Christian country.

Sanggenon C is a flavonoid extracted from the root bark of white mulberry, which is a traditional Chinese medicine with anti-inflammatory, antioxidative, and antitumor pharmacological effects. In this study, sanggenon C was found to inhibit human gastric cancer (GC) cell proliferation and colony formation, induce GC cell cycle arrest in the G0-G1 phase, and promote GC cell apoptosis. Moreover, sanggenon C was found to decrease the level of mitochondrial membrane potential in GC cells and inhibit mitochondrial fission. Mechanistically, RNA sequencing, bioinformatics analysis, and a series of functional analyses confirmed that sanggenon C inhibited mitochondrial fission to induce apoptosis by blocking the extracellular regulated protein kinases (ERK) signaling pathway, and constitutive activation of ERK significantly abrogated these effects. Finally, sanggenon C was found to suppress the growth of tumor xenografts in nude mice without obvious side effects to the vital organs of animals. This study reveals that sanggenon C could be a novel therapeutic strategy for GC treatment.

Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited.We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications.Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation.In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

Treatments for osteoarthritis would benefit from the enhanced visualization of injured articular cartilage and from the targeted delivery of disease-modifying drugs to it. Here, by using ex vivo human osteoarthritic cartilage and live rats and minipigs with induced osteoarthritis, we report the application of collagen-binding peptides, identified via phage display, that are home to osteoarthritic cartilage and that can be detected via magnetic resonance imaging when conjugated with a superparamagnetic iron oxide. Compared with the use of peptides with a scrambled sequence, hyaluronic acid conjugated with the collagen-binding peptides displayed enhanced retention in osteoarthritic cartilage and better lubricated human osteoarthritic tissue ex vivo. Mesenchymal stromal cells encapsulated in the modified hyaluronic acid and injected intra-articularly in rats showed enhanced homing to osteoarthritic tissue and improved its regeneration. Molecular docking revealed WXPXW as the consensus motif that binds to the α1 chain of collagen type XII. Peptides that specifically bind to osteoarthritic tissue may aid the diagnosis and treatment of osteoarthritic joints.

Optimization of peptide stability is essential for the development of peptides as bona fide alternatives to approved monoclonal antibodies. This is clearly the case for the many peptides reported to antagonize proprotein convertase subtilisin-like/kexin type 9 (PCSK9), a clinically validated target for lowering cholesterol. However, the effects of optimization of stability on in vivo activity and particularly the effects of binding to albumin, an emerging drug design paradigm, have not been studied for such peptide leads. In this study, we optimized a PCSK9 inhibitory peptide by mutagenesis and then by conjugation to a short lipidated tag to design P9-alb fusion peptides that have strong affinity to human serum albumin. Although attachment of the tag reduced activity against PCSK9, which was more evident in surface plasmon resonance binding and enzyme-linked immunosorbent competition assays than in cellular assays of activity, activity remained in the nanomolar range (∼40 nM). P9-alb peptides were exceptionally stable in human serum and had half-lives exceeding 48 h, correlating with longer half-lives in mice (40.8 min) compared to the unconjugated peptide. Furthermore, the decrease in in vitro binding was not deleterious to in vivo function, showing that engendering albumin binding improved low-density lipoprotein receptor recovery and cholesterol-lowering activity. Indeed, the peptide P9-albN2 achieved similar functional endpoints as the approved anti-PCSK9 antibody evolocumab, albeit at higher doses. Our study illustrates that optimization of stability instead of binding affinity is an effective way to improve in vivo function.

Cephalometric analysis relies on accurate detection of craniomaxillofacial (CMF) landmarks from cone-beam computed tomography (CBCT) images. However, due to the complexity of CMF bony structures, it is difficult to localize landmarks efficiently and accurately. In this paper, we propose a deep learning framework to tackle this challenge by jointly digitalizing 105 CMF landmarks on CBCT images. By explicitly learning the local geometrical relationships between the landmarks, our approach extends Mask R-CNN for end-to-end prediction of landmark locations. Specifically, we first apply a detection network on a down-sampled 3D image to leverage global contextual information to predict the approximate locations of the landmarks. We subsequently leverage local information provided by higher-resolution image patches to refine the landmark locations. On patients with varying non-syndromic jaw deformities, our method achieves an average detection accuracy of 1.38± 0.95mm, outperforming a related state-of-the-art method.

Introduction: Opioid use disorder (OUD) is a major public health crisis worldwide. Patients with OUD inevitably experience withdrawal symptoms when they attempt to taper down on their current opioid use, abstain completely from opioids, or attempt to transition to certain medications for opioid use disorder. Acute opioid withdrawal can be debilitating and include a range of symptoms such as anxiety, pain, insomnia, and gastrointestinal symptoms. Whereas acute opioid withdrawal only lasts for 1-2 weeks, protracted withdrawal symptoms can persist for months after the cessation of opioids. Insufficient management of opioid withdrawal often leads to devastating results including treatment failure, relapse, and overdose. Thus, there is a critical need for cost-effective, nonopioid medications, with minimal side effects to help in the medical management of opioid withdrawal syndrome. We discuss the potential consideration of cannabidiol (CBD), a nonintoxicating component of the cannabis plant, as an adjunctive treatment in managing the opioid withdrawal syndrome. Materials and Methods: A review of the literature was performed using keywords related to CBD and opioid withdrawal syndrome in PubMed and Google Scholar. A total of 144 abstracts were identified, and 41 articles were selected where CBD had been evaluated in clinical studies relevant to opioid withdrawal. Results: CBD has been reported to have several therapeutic properties including anxiolytic, antidepressant, anti-inflammatory, anti-emetic, analgesic, as well as reduction of cue-induced craving for opioids, all of which are highly relevant to opioid withdrawal syndrome. In addition, CBD has been shown in several clinical trials to be a well-tolerated with no significant adverse effects, even when co-administered with a potent opioid agonist. Conclusions: Growing evidence suggests that CBD could potentially be added to the standard opioid detoxification regimen to mitigate acute or protracted opioid withdrawal-related symptoms. However, most existing findings are either based on preclinical studies and/or small clinical trials. Well-designed, prospective, randomized-controlled studies evaluating the effect of CBD on managing opioid withdrawal symptoms are warranted.

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17β-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.

Objective. To analyze the clinical intervention effect of transoral endoscopic thyroidectomy on the neck and face during perioperative period. Method. From January 2019 to January 2020, 60 patients included in this study were randomly divided into observation group and control group according to the ratio of 1 : 1, with 30 cases in each group. Both groups underwent rapid surgical intervention during the perioperative period. The patients in the observation group received neck and face management. The degree of jaw swelling, the degree of facial microexpression completion, and the changes in jaw and neck sensation were compared between the two groups. Results. There was no significant difference in neck and face swelling, pain, facial microexpression, and feeling between the two groups before operation. Patients with facial I/II swelling degree in the observation group were significantly more than in the control group, and the patients with III swelling degree were less than in the control group. There was significant difference for facial swelling between the two groups in the three intervention periods after the operation, and the difference was statistically significant ( P < 0.05 ). The scores of facial microexpression in the observation group were higher than those in the control group during the three postoperative intervention periods, with statistical significance ( P < 0.05 ). There was no significant difference in the pain score of the first day after surgery between the two groups ( P = 0.298 ). In the other two postoperative intervention periods, the pain score of the observation group was lower than that of the control group, with a statistically significant difference, and the difference was statistically significant ( P < 0.05 ). The threshold of chin and neck sensory pressure in the two groups was statistically significant ( P < 0.05 ) except that the “cheek in area 4” ( P = 0.290 ). Conclusion. The results showed that these interventions, such as the elevation of bed after operation, 24-hour intermittent cryotherapy, ice cubes in mouth, and the “meter” functional training, have good clinical effects on the symptoms of facial swelling and abnormal sensation of neck and face. It can accelerate the speed of edema dissipation, improve the patients’ postoperative comfort, and improve the satisfaction and quality of life of patients with the effect of surgery and beauty.

OBJECTIVE Dysglycemia influences hospital outcomes and resource utilization. Clinical decision support (CDS) holds promise for optimizing care by overcoming management barriers. This study assessed the impact on hospital length of stay (LOS) of an alert-based CDS tool in the electronic medical record that detected dysglycemia or inappropriate insulin use, coined as gaps in care (GIC). RESEARCH DESIGN AND METHODS Using a 12-month interrupted time series among hospitalized persons aged ≥18 years, our CDS tool identified GIC and, when active, provided recommendations. We compared LOS during 6-month-long active and inactive periods using linear models for repeated measures, multiple comparison adjustment, and mediation analysis. RESULTS Among 4,788 admissions with GIC, average LOS was shorter during the tool’s active periods. LOS reductions occurred for all admissions with GIC (−5.7 h, P = 0.057), diabetes and hyperglycemia (−6.4 h, P = 0.054), stress hyperglycemia (−31.0 h, P = 0.054), patients admitted to medical services (−8.4 h, P = 0.039), and recurrent hypoglycemia (−29.1 h, P = 0.074). Subgroup analysis showed significantly shorter LOS in recurrent hypoglycemia with three events (−82.3 h, P = 0.006) and nonsignificant in two (−5.2 h, P = 0.655) and four or more (−14.8 h, P = 0.746). Among 22,395 admissions with GIC (4,788, 21%) and without GIC (17,607, 79%), LOS reduction during the active period was 1.8 h (P = 0.053). When recommendations were provided, the active tool indirectly and significantly contributed to shortening LOS through its influence on GIC events during admissions with at least one GIC (P = 0.027), diabetes and hyperglycemia (P = 0.028), and medical services (P = 0.019). CONCLUSIONS Use of the alert-based CDS tool to address inpatient management of dysglycemia contributed to reducing LOS, which may reduce costs and improve patient well-being.

To determine the sensitivity of a noncontrast T1 dispersion cardiovascular magnetic resonance technique for detecting diffuse fibrosis in hypertrophic cardiomyopathy (HCM).Thirty-two adult HCM patients and ten age- and gender-matched healthy volunteers were prospectively included in this study. Patients and controls underwent cine, T1ρ-mapping, and pre- and post-contrast T1-mapping imaging using a 3-T magnetic resonance system. Myocardial extracellular volume fraction (ECV) maps were obtained using pre- and post-contrast T1 maps to determine reference values for diffuse fibrosis. Myocardial T1ρ and T1ρ dispersion maps called myocardial fibrosis index (mFI) maps provided 570 myocardial segments for Pearson or Spearman correlation analysis. The left ventricle myocardia of the HCM patients were divided into 16 segments that were further classified as either normal-thickness myocardium (15 mm) (HCM-N) or hypertrophic myocardium (≥15 mm) (HCM-H).ECV and mFI values increased progressively on a per-segment basis from healthy controls to the HCM-N group and then to the HCM-H group (ECV: 27.4 ± 2.8% vs. 31.1 ± 4.2% vs. 37.6 ± 6.9%, respectively [P 0.0001]; mFI: 6.1 ± 0.9 ms vs. 8 ± 1.9 ms vs. 11 ± 3.3 ms, respectively [P 0.0001]). There was a strong positive correlation between the segmented ECV and the mFI (r = 0.878). The mFI was equally or significantly better than the ECV for differentiating fibrosis content in HCM-N and HCM-H according to their receiver operating characteristic curves.A T1ρ dispersion imaging mFI can sensitively detect diffuse myocardial fibrosis in HCM, even in HCM-N.

To compare the effectiveness of penetrating vs intrastromal femtosecond laser corneal relaxing incisions (CRIs) in reducing corneal astigmatism during cataract surgery.Baylor College of Medicine and Mercy Clinic Eye Specialists.Prospective randomized study.248 eyes from 248 patients were included. Patients were randomly assigned to undergo paired penetrating (8 mm optical zone [OZ] at 1 center and 9 mm OZ at the other) or intrastromal CRIs (8 mm OZ at both centers). The lengths of the CRIs were based on published nomograms but modified to take into account posterior corneal astigmatism. Vector analysis was performed, and net corneal changes along the CRI meridian were calculated. Multiple regression analysis was performed to assess factors contributing to net corneal changes.Preoperatively, 9% to 18% of eyes had corneal astigmatism of ≤0.5 diopters (D), and 76% to 93% of eyes had postoperative refractive astigmatism of ≤0.5 D ( P.05). Both penetrating and intrastromal CRIs produced significant mean net corneal changes along the CRI meridian (-0.49 to -1.21 D), and 71% to 84% of eyes had postoperative astigmatism vector prediction errors of ≤0.50 D. The 8 mm penetrating CRIs induced greater net corneal changes but more eyes with overcorrection than did the intrastromal and 9 mm penetrating CRIs (all P.05). Greater net corneal changes occurred with longer CRI length, higher preoperative corneal astigmatism magnitude, and preoperative against-the-rule corneal astigmatism. Nomograms based on anterior and total corneal astigmatism are proposed.Both penetrating and intrastromal CRIs were effective in reducing corneal astigmatism during cataract surgery.

Balanced crystalloids may improve outcomes compared with saline for some critically ill adults. Lower tonicity of balanced crystalloids could worsen cerebral edema in patients with intracranial pathology. The effect of balanced crystalloids versus saline on clinical outcomes in patients with traumatic brain injury (TBI) requires further study. We planned an

Background The aging brain is typically associated with aberrant interactions of large-scale intrinsic networks. However, the dynamic variation of these networks' coactivation or deactivation across the adult lifespan remains unclear. Purpose To promote the interpretation of dynamic brain network variations underlying the complex aging process by quantifying activation levels and obtaining a clear definition of coactivation patterns (CAPs) with resting-state functional MRI (rsfMRI). Materials and Methods In a retrospective study (October 2010 to September 2013), rsfMRI data from healthy participants in the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data repository were used to generate CAPs by applying single-volume temporal clustering analysis. Spatial clustering analysis was then performed to capture dynamic coactivation and deactivation within or between primary sensory networks and high-order cognitive networks (including the default mode network [DMN], attentional network [AN], and frontoparietal network [FPN]). Linear relationships between dynamic metrics and age were revealed with Spearman partial correlations. Results A total of 614 participants (mean age, 54 years ± 18 [SD]; 311 women) ranging in age from 18 to 88 years were evaluated. There was a negative correlation of the CAPs (Spearman correlations

To examine associations between metabolically obese phenotypes or their changes and increased carotid intima-media thickness (CIMT).This prospective cohort included 13,681 Chinese adults aged 20-80 years who completed follow-up health examination with carotid ultrasound and were divided according to metabolic and weight status: metabolically healthy and normal weight (MHNW); metabolically obese but normal weight (MONW); metabolically healthy but obese (MHO); metabolically abnormal and obese (MAO). Cox and logistic regression were used to evaluate the associations of the phenotypes or their changes with increased CIMT. During a mean follow-up of 33 months, 1927 participants developed increased CIMT. After adjusting for age, sex and potential biochemical confounders, MAO was significantly associated with increased CIMT (HR 1.22, 95% CI [1.07, 1.4]); the association remained significant in those 40 years or older. Compared with stable MHNW, increased CIMT risk was higher for stable MAO (OR 1.35 [1.16, 1.57]), transitional MAO from MONW (OR 1.44 [1.04, 1.97]), and transitional MHO from MHNW (OR 1.59 [1.10, 2.26]) in demographic adjusted models; only stable MAO remained significant in the multivariate adjusted model (OR 1.23 [1.05, 1.45]).MAO significantly elevated the risk of increased CIMT. Stable MAO and obese transitions also promoted CIMT progression.

Intracellular transcytosis can enhance the penetration of nanomedicines to deep avascular tumor tissues, but strategies that can improve transcytosis are limited. In this study, we discovered that pyknomorphic extracellular matrix (ECM) is a shield that impairs endocytosis of nanoparticles and their movement between adjacent cells and thus limits their active transcytosis in tumors. We further showed that degradation of pivotal constituent of ECM (i.e., collagen) effectively enhances intracellular transcytosis of nanoparticles. Specifically, a collagenase conjugating transcytosis nanoparticle (Col-TNP) can dissociate into collagenase and cationized gold nanoparticles in response to tumor acidity, which enables their ECM tampering ability and active transcytosis in tumors. The breakage of ECM further enhances the active transcytosis of cationized nanoparticles into deep tumor tissues as well as radiosensitization efficacy of pancreatic adenocarcinoma. Our study opens up new paths to enhance the active transcytosis of nanomedicines for the treatment of cancers and other diseases.

Given the evidence that brachial artery flow-mediated dilation (FMD) is declined in children later after the onset of Kawasaki disease (KD), we hypothesized that indicators that detect the situation of the endothelium are useful parameters that can accurately reflect subclinical dysfunction in resistant patients and assist in differentiating patients with KD at a higher risk of IVIG resistance, which may be valuable in better understanding how to protect patients from endothelial and thrombotic complications.Fifty IVIG-resistant KD children, 120 IVIG-responsive KD children, 35 febrile children with acute upper respiratory infection, and 50 healthy controls were recruited, and indicators reflecting endothelial inflammation, including flow-mediated dilation (FMD), were measured. Receiver operating characteristic (ROC) curve analysis was utilized to determine the threshold values of these indicators of IVIG resistance. Multiple logistic regression analysis was performed to determine whether FMD was an independent predictor of IVIG-resistant patients.In comparison with the lab data, PCT, Na + , and FMD exhibited AUCs of 0.727, 0.653, and 0.698 (P 0.05), respectively, in predicting IVIG resistance in KD through ROC analysis. PCT 1.69 ng/ml, Na + 133.2 mmol/l, and FMD 5.79% were independent predictors of IVIG resistance in KD (OR 4.257, 3.516, 3.563, 95% CI 1.549 ~ 11.700, 1.277 ~ 9.680, 1.299 ~ 9.772, P 0.05).More severe endothelial dysfunction, especially lower FMD, was present in IVIG-resistant patients than in IVIG-responsive patients. It is a helpful diagnostic tool that provides supportive criteria to detect KD patients at a higher risk of IVIG resistance when FMD 5.79% in children. Key Points • IVIG-resistant KD patients have more severe endothelial dysfunction than IVIG-sensitive patients. • FMD 5.79% may indicate an increased risk of IVIG resistance in children with Kawasaki disease.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Highly penetrant copy number variants (CNVs) and genes related to the etiology of TOF likely exist with differences among populations. We aimed to identify CNV contributions to sporadic TOF cases in Han Chinese. Genomic DNA was extracted from peripheral blood in 605 subjects (303 sporadic TOF and 302 unaffected Han Chinese [Control] from cardiac centers in China) and analyzed by genome-wide association study (GWAS). The GWAS results were compared with existing Database of Genetic Variants. These CNVs were further validated by qPCR. Bioinformatics analyses were performed with protein-protein interaction (PPI) network and KEGG pathway enrichment. Across all chromosomes 119 novel "TOF-specific CNVs" were identified with prevalence of CNVs of 21.5% in chromosomes 1-20 and 37.0% including Chr21/22. In chromosomes 1-20, CNVs on 11q25 (encompasses genes ACAD8, B3GAT1, GLB1L2, GLB1L3, IGSF9B, JAM3, LOC100128239, LOC283177, MIR4697, MIR4697HG, NCAPD3, OPCML, SPATA19, THYN1, and VPS26B) and 14q32.33 (encompasses genes THYN1, OPCML, and NCAPD3) encompass genes most likely to be associated with TOF. Specific CNVs found on the chromosome 21 (6.3%) and 22(11.9%) were also identified in details. PPI network analysis identified the genes covering the specific CNVs related to TOF and the signaling pathways. This study for first time identified novel TOF-specific CNVs in the Han Chinese with higher frequency than in Caucasians and with 11q25 and 14q32.33 not reported in TOF of Caucasians. These novel CNVs identify new candidate genes for TOF and provide new insights into genetic basis of TOF.

Japanese encephalitis (JE) is a major reason to cause viral encephalitis, with 50% patients suffering from severe neuro-inflammation and permanent neural injury. Effective anti-viral treatment is urgently needed. Here, we found RNA binding protein quaking (QKI) was involved in the progression of JE by regulating migration and anti-viral response of macrophages. After JE virus (JEV) infection, QKI-deficient mice had lower viral loads in the brain and fewer neurological symptoms. In comparison with control mice, proinflammatory cytokines in the brain of QKI-deficient animals revealed distinct patterns, with lower levels of IL-6 (interleukin-6) and IFN-β (interferon-β) at the early stage but higher levels at the end of JE. Then we found infiltration of CCR2 positive ((C-C motif) receptor 2) peripheral macrophages and CCR2 expression on macrophages were inhibited in QKI-deficient mice, while the expression of CCR2 ligands was not changed. Bioinformatical analysis showed that a QRE (quaking response element) located on 3'UTR (untranslated region) of Ccr2. We further verified that QKI was able to interact with Ccr2 mRNA and regulate its degradation in vitro. Additionally, since the IFN-β production was increased in QKI-ablation mice after JEV infection, the anti-viral response was analyzed. Results in QKI-silenced N9 cells showed that the expression of RIG-I (retinoic acid-inducible gene-I) and TBK1 (TANK binding kinase 1) was increased, thus further inducing IRF3 (interferon regulatory factor 3) phosphorylation and interferon activation. Overall, these results revealed QKI mediated the anti-viral process via interfering migration of macrophages to CNS (central nervous system) and enhancing RIG-I/IRF3/IFN-β pathway to restrict virus dissemination.

Background The abnormal expression of long non-coding RNA (lncRNA) Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) has been observed in many human cancers and the underlying mechanisms have been well studied. However, the function of OIP5-AS1 in acute kidney injury (AKI) remains unclear. Material and methods To explore the role of OIP5-AS1 in the progression of AKI, the cisplatin-induced AKI mouse and cell model were established. To confirm the potential protective effect of OIP5-AS1 during cisplatin-induced AKI, rescue experiments were performed. Targetscan was used to predict the potential targets of miR-144-5p. To further determine whether the effect of miR-144-5p during cisplatin-induced AKI was mediated by PMK2, the recuse experiments using PMK2 overexpressing vector was applied. Results OIP5-AS1 was significantly downregulated both in cisplatin-induced AKI mice and human renal tubular cell line HK-2 cells. Moreover, overexpression of OIP5-AS1 efficiently promoted cell growth and reduced cisplatin-induced apoptosis of HK-2 cells. Furthermore, OIP5-AS1 was identified as a sponge of miR-144-5p, and upregulation of miR-144-5p could significantly reverse overexpression of OIP5-AS1-induced protective effect on the damage of cisplatin to HK-2 cells. In addition, pyruvate kinase M2 (PKM2) was found to be a direct target of miR-144-5p, and overexpression of PKM2 efficiently reversed the effect of miR-144-5p mimics on the damage in cisplatin-stimulated HK-2 cells. Conclusions OIP5-AS1 reduced the apoptosis of cisplatin-stimulated renal epithelial cells by targeting the miR-144-5p/PKM2 axis, which extended the regulatory network of lncRNAs in cisplatin-induced AKI and also provided a novel therapeutic target for AKI treatment.

Background: VitD3 may contribute to a successful pregnancy through modulation of immune responses. Therefore, VitD3 deficiency may have a role in the immunopathogenesis of unexplained recurrent spontaneous abortion (URSA). However, the mechanisms of immunomodulatory actions of VitD3 in decreasing the risk of recurrent spontaneous abortion have not been understood well. Objective: The purpose of this research was to investigate the influence of 1,25VitD3 on regulatory T cells /Th17 axis, the gene expressions and concentrations of related cytokines including, TGF-β, IL-10, IL-6, IL-23, and IL-17A in peripheral blood mononuclear cells (PBMCs) of healthy women as a control group and women with URSA. Method: Isolation of PBMCs was performed from peripheral blood of the subjects of the studied groups (20 women with URSA as a case group, and 20 control women). The effects of 1,25VitD3 (50 nM, for 24 hours) on the studied parameters were evaluated and were compared to the positive and negative controls in vitro. Flow cytometry analysis was used to determine the percentages of regulatory T cells and Th17 cells. For gene expression measurement and cytokines assay, Realtime PCR and ELISA were carried out. Results: The proportion of regulatory T cells was markedly lower, while the proportion of Th17 cells in women with URSA was considerably higher than in the control group (P=0.01, P=0.01). The ratio of the frequency of Tregs to the baseline (1,25VitD3/Untreated) increased, while the ratio of the frequency of Th17 cells to the baseline decreased in women with URSA relative to the controls (P= 0.01, P=0.04). 1,25VitD3 increased IL-10 expressions at both the protein and mRNA levels in PBMCs in women with URSA relative to the control group (P=0.0001, P=0.04). TGF-β levels in the cultured supernatants decreased significantly in the case group in the presence of 1,25Vit- D3 relative to the controls (P=0.03). 1,25VitD3 treatment also significantly decreased gene expressions of IL-6, IL-17A, and IL-23 in PBMCs of women with URSA (P=0.01, P=0.001, P=0.0005), as well as the levels of those cytokines in cell culture supernatants (P=0.03, P=0.02, P=0.01, respectively) in women with URSA relative to the controls. Conclusion: According to the findings of this research, modulation of immune responses by 1,25VitD3 is accomplished by strengthening Tregs function and inhibiting inflammatory responses of Th17 cells, which may have a positive impact on pregnancy outcome. Thus, as an immunomodulating agent, VitD3 may be effective in reducing the risk of URSA.

Preimplantation Genetic Testing - Aneuploidy (PGT-A) for embryo selection has undergone significant advancements in the last 2 decades and yet many studies still fail to demonstrate any clinical benefits over traditional embryo morphology selection (Mo-S). To understand this conundrum, we performed a multi-center clinical study of PGT-A patients, where Mo-S and euploid selection (Eu-S) outcomes were directly compared.All suitable blastocysts were biopsied and analyzed for chromosome copy number. Outcomes (positive beta hCG, implantation, ongoing pregnancy, and live birth rates) for Eu-S were compared to Mo-S using single embryo transfers.Compared to Eu-S embryos, Mo-S embryos resulted in significant reduction of outcomes for positive beta hCG (p = 0.0005), implantation (p = 0.0008), ongoing pregnancy (p = 0.0046), livebirth (p = 0.0112), babies per transfer (p = 0.0112), and babies per embryo transferred (p = 0.0112). Morphology selection resulted in patients of all age groups having non-euploid embryos chosen for transfer. Post-hoc evaluation of individual clinic performances showed variable transfer outcomes that could potentially confound the true benefits of PGT-A.Embryo chromosome status is central to improved embryo transfer outcomes and sole reliance on current morphology-based selection practices, without Eu-S, will always compromise outcomes. Often overlooked but a major effector of successful PGT-A outcomes are individual clinic performances.

The evidence about the association of the essential trace element (ETE) mixture with atherosclerotic cardiovascular disease (ASCVD) amongst older adults is limited. This study aims to evaluate the associations of single ETEs and the ETE mixture with the 10-year ASCVD risks and its predicting factors in Chinese community-dwelling older adults. A total of 607 community-dwelling older adults were included in this study. Blood levels of vanadium (V), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), and selenium (Se) were assessed by inductively coupled plasma mass spectrometry. The predicted 10-year ASCVD risk was calculated using the Prediction for ASCVD Risk in China (China-PAR) equations. Traditional linear regressions and Bayesian kernel machine regression (BKMR) were used to assess the associations of single ETEs and the ETE mixture with the 10-year ASCVD risks and its predicting factors such as systolic blood pressure (SBP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), diabetes, and waist circumference (WC). In linear regression models, blood Cr levels were negatively associated with the 10-year ASCVD risks after adjustment for covariates (β = - 0.07, 95% CI = - 0.11 ~ - 0.03); The 3th quartile (Q3) of Se levels was also associated with a lower 10-year ASCVD risks when compared with the lowest quartile (Q1) of Se levels (β

Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti-SCLC mechanisms of pazopanib remain unclear.Cell viability was evaluated by CCK-8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic-related molecules and ER-stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH-HA staining followed by flow cytometry. An NCI-H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI-H446 cell-bearing NOD-SCID mice.Pazopanib dose- and time-dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved-caspase3 and Bax, and decreased Bcl-2. Moreover, the PERK-related ER-stress pathway was potently activated by pazopanib treatment, inhibiting ER-stress by salubrinal significantly reversing pazopanib-mediated apoptosis in SCLC cell lines. Furthermore, pazopanib-induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib-induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI-H446 xenograft growth and decreased Ki67 positive cells in the tumor.Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER-stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated.

Increasing iron (Fe) and zinc (Zn) concentrations in crop grains with high yield is an effective measure to ensure food supply and alleviate mineral malnutrition in humans. Micronutrient concentrations in grains depend on not only their availability in soils but also their uptake in roots and translocation to shoots and grains. In this three-year field study, we investigated genotypic variation in Fe and Zn uptake and translocation within six wheat cultivars and examined in detail Fe and Zn distributions in various tissues of two cultivars with similar high yield but different grain Fe and Zn concentrations using synchrotron micro-X-ray fluorescence. Results revealed that root Fe and Zn concentrations were 11 and 44% greater in high-nutrient (HN) than in low-nutrient (LN) concentration cultivar. Although both cultivars accumulated similar amounts of Fe in shoots, HN cultivar had greater accumulation of Fe in grain and greater accumulation of Zn in both shoots and grain. Grain Zn concentration was positively correlated with shoot Zn accumulation, and grain Fe concentration was positively correlated with the ability to translocate Fe from leaves/stem to grains. In the first nodes of shoots, HN cultivar had 482% greater Fe and 36% greater Zn concentrations in the enlarged vascular bundle (EVB) than LN cultivar. In top nodes, HN cultivar had 225 and 116% greater Fe and Zn concentrations in the transit vascular bundle and 77 and 71% greater in the EVB when compared to LN cultivar. HN cultivar also had a greater ability to allocate Fe and Zn to the grain than LN cultivar. In conclusion, HN cultivar had greater capacity of Fe and Zn acquirement by roots and translocation and partitioning from shoots into grains. Screening wheat cultivars for larger Fe and Zn concentrations in shoot nodes could be a novel strategy for breeding crops with greater grain Fe and Zn concentrations.

To estimate the prevalence, and patient clinical and demographic profile, as well as risk factors associated with obstructive sleep apnea syndrome (OSAS) in hospitalized patients with type 2 diabetes mellitus in Beijing, China.Hospitalized adult patients with type 2 diabetes mellitus were consecutively screened and invited for an overnight polysomnography from four hospitals in Beijing, China, from May 2016 to February 2017. We used the American Academy of Sleep Medicine 2012 polysomnography recording techniques and scoring criteria to identify the type of apnea and the severity of OSAS. The χA total of 735 patients were found eligible for the study, of whom 309 patients completed the overnight polysomnography. The mean age of the patients was 58.2 ± 10.9 years, and most (67.3%) were men. The prevalence of overall (apnea hypopnea index ≥5/h), moderate-to-severe (apnea hypopnea index ≥15/h) and severe (apnea hypopnea index ≥30/h) OSAS was 66.3% (95% confidence interval 60.8-71.6%), 35.6% (95% confidence interval 30.3-41.2%) and 16.5% (95% confidence interval 12.5-21.1%), respectively. Central and mixed apnea contributed 12% to all sleep-disordered breathing. With the aggravation of OSAS, the combined prevalence for central, mixed and obstructive apnea increased from 57% to 70%. We found OSAS to be associated with older age, obesity, self-reported snoring and apnea, and diabetes complications.Guidelines on screening and treatment of OSAS among hospitalized patients with diabetes are needed to direct the routine practice for diabetes endocrinologists for optimal clinical care of such patients.

BACKGROUND: Invasive mechanical ventilation in critically ill adults involves adjusting the fraction of inspired oxygen to maintain arterial oxygen saturation. The oxygen-saturation target that will optimize clinical outcomes in this patient population remains unknown. METHODS: In a pragmatic, cluster-randomized, cluster-crossover trial conducted in the emergency department and medical intensive care unit at an academic center, we assigned adults who were receiving mechanical ventilation to a lower target for oxygen saturation as measured by pulse oximetry (Spo(2)) (90%; goal range, 88 to 92%), an intermediate target (94%; goal range, 92 to 96%), or a higher target (98%; goal range, 96 to 100%). The primary outcome was the number of days alive and free of mechanical ventilation (ventilator-free days) through day 28. The secondary outcome was death by day 28, with data censored at hospital discharge. RESULTS: A total of 2541 patients were included in the primary analysis. The median number of ventilator-free days was 20 (interquartile range, 0 to 25) in the lower-target group, 21 (interquartile range, 0 to 25) in the intermediate-target group, and 21 (interquartile range, 0 to 26) in the higher-target group (P = 0.81). In-hospital death by day 28 occurred in 281 of the 808 patients (34.8%) in the lower-target group, 292 of the 859 patients (34.0%) in the intermediate-target group, and 290 of the 874 patients (33.2%) in the higher-target group. The incidences of cardiac arrest, arrhythmia, myocardial infarction, stroke, and pneumothorax were similar in the three groups. CONCLUSIONS: Among critically ill adults receiving invasive mechanical ventilation, the number of ventilator-free days did not differ among groups in which a lower, intermediate, or higher Spo(2) target was used. (Supported by the National Heart, Lung, and Blood Institute and others; PILOT ClinicalTrials.gov number, NCT03537937.)

Objectives. Cognitive decline could be seen as the sign of preclinical phase of dementia, which was found to be sex differentiated. Previous studies had discovered that there might be some link between abnormal sleep duration and cognitive performance. Additionally, hypertension was found to be one of the important risk factors for cognitive decline and abnormal sleep duration was also a significant risk factor for hypertension. Therefore, the purpose of this study was to investigate sex differences in the association of sleep duration with cognitive performance and to further explore potential effect modifiers that may exist. Methods. Data analyzed in this study was from the China H-type Hypertension Registry Study. Sleep duration was assessed with a sleep questionnaire and categorized as 63.7 ± 9.8 years. Linear regression analyses showed that the association between long sleep duration (≥8 h) and MMSE score adjusting for pertinent covariables was stronger in female ( β = − 0.95 , 95% CI: -1.23 to -0.68, P < 0.001 ) than in male ( β = − 0.29 , 95% CI: -0.53 to -0.06, P = 0.013 ). Furthermore, there was a significant interaction between sleep duration and age on cognitive performance only in female. Conclusion. In summary, this study found that long sleep duration (≥8 h) was associated with poorer cognitive performance. Furthermore, this association was more pronounced in female than in male, especially in older female.

The study aimed to examine the association of obesity and chronic kidney disease (CKD) after nonalcoholic fatty liver disease (NAFLD) occurrence.The study enrolled 10,311 adult men with newly diagnosed NAFLD and without CKD in the Kailuan cohort (2006-2013). The Fine-Gray model was used to compare advanced CKD risk in NAFLD with different baseline or trajectories in obesity measures.During a median follow-up of 10 years, maintaining normal waist circumference or waist-hip ratio, or transition from obesity to nonobesity determined by BMI, decreased 31% (hazard ratio [HR] = 0.69; 95% CI: 0.51-0.93), 34% (HR = 0.66; 95% CI: 0.45-0.95), and 38% (HR = 0.62; 95% CI: 0.40-0.96) of the CKD hazard compared with the "constantly without obesity" subgroup, respectively. NAFLD patients with at least 10% weight loss (HR = 0.58; 95% CI: 0.34-0.97) and with 7.0% to 9.9% weight loss (HR = 0.53; 95% CI: 0.28-0.99) had a lower risk for CKD than those with weight change ±4.9%. Compared with the stable weight population, the lower risk of ≥7% weight loss was observed only in patients with elevated blood pressure (adjusted HR = 0.48; 95% CI: 0.28-0.81).Short-term weight loss of at least 7% could decrease CKD risk, especially among patients with obesity and elevated blood pressure. It is important to monitor waist circumference, waist-hip ratio, and weight for NAFLD management.

Cerebral cortex development undergoes a variety of processes, which provide valuable information for the study of the developmental mechanism of cortical folding as well as its relationship to brain structural architectures and brain functions. Despite the variability in the anatomy-function relationship on the higher-order cortex, recent studies have succeeded in identifying typical cortical landmarks, such as sulcal pits, that bestow specific functional and cognitive patterns and remain invariant across subjects and ages with their invariance being related to a gene-mediated proto-map. Inspired by the success of these studies, we aim in this study at defining and identifying novel cortical landmarks, termed gyral peaks, which are the local highest foci on gyri. By analyzing data from 156 MRI scans of 32 macaque monkeys with the age spanned from 0 to 36 months, we identified 39 and 37 gyral peaks on the left and right hemispheres, respectively. Our investigation suggests that these gyral peaks are spatially consistent across individuals and relatively stable within the age range of this dataset. Moreover, compared with other gyri, gyral peaks have a thicker cortex, higher mean curvature, more pronounced hub-like features in structural connective networks, and are closer to the borders of structural connectivity-based cortical parcellations. The spatial distribution of gyral peaks was shown to correlate with that of other cortical landmarks, including sulcal pits. These results provide insights into the spatial arrangement and temporal development of gyral peaks as well as their relation to brain structure and function.

This study aimed to monitor the prevalence of HIV-1 drug resistance and risk factors associated with drug resistance in antiretroviral therapy (ART)-failure individuals in Liaoning Province, China. Plasma samples were collected from HIV-1-positive individuals who experienced ART failure in Liaoning Province between April 2018 and September 2019. Genotype resistance test was performed using an in-house assay on these collected samples. Factors associated with drug resistance were identified by logistic regression analysis. We collected a total of 468 ART-failure individuals, of which 256 were successfully included in the final study. Of these, the most predominant genotype was CRF01_AE, accounting for 77.73%. The resistance rate to any of the three classes of antiretroviral drugs (non-nucleoside reverse transcriptase inhibitors [NNRTIs], nucleoside reverse transcriptase inhibitors [NRTIs], and protease inhibitors [PIs]) was 64.84%. Among 256 ART-failure patients, 62.89% showed drug resistance to NNRTIs, 50.39% to NRTIs, and 3.13% to PIs. G190S (31.25%) and Y181C (25.78%) mutations were the most common NNRTIs resistance mutations. K65R (29.69%), M184V (28.52%) were the most common NRTIs resistance mutations. Factors associated with drug resistance included current ART regimen and viral load. The high drug resistance rate among ART-failure individuals in Liaoning Province needs more attention. Corresponding strategies for the risk factors associated with HIV drug resistance can better control and prevent the prevalence of resistance.

Mineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood.Using osteoblast MR knockout (MRMR deficiency in osteoblasts alleviates pathological ventricular remodeling after MI, likely through its regulation on OCN. Spironolactone may work through osteoblast MR/OCN axis to exert its therapeutic effects on pathological ventricular remodeling and heart failure in mice and human patients.

IFITM2 is interferon-induced transmembrane protein 2, which plays an extremely key role in anti-tumor and anti-virus diseases. In this study, the 602 bp cDNA sequence of the yak (Bos grunniens) IFITM2 (BgIFITM2) gene was obtained. Moreover, the prokaryotic expression vector of BgIFITM2 protein was constructed and expressed successfully, with a molecular weight of 33.680 kDa. The proliferation activities and migration abilities of HepG2 cells were significantly inhibited after treatment with BgIFITM2 protein (0.1 and 1 μg/mL) (P 0.05). The expressions of B cell lymphoma-2 (BCL2)/BCL2-associated X (BAX) and molecular target of rapamycin (mTOR) genes were significantly decreased, but the expressions of BAX gene were significantly increased after treatment with BgIFITM2 protein (0.1 and 1 μg/mL) (P 0.05). The expression of BAX protein was also significantly increased after treatment with 1 μg/mL BgIFITM2 protein (P 0.05). Finally, the addition of BgIFITM2 protein attenuated the formation of tumor lesions in mice, and the pathological damage of the lung was less than that in the model group. The expression of Ki67 protein in the model group was significantly higher than that in the control group (P 0.05), but the expression of Ki67 protein in the BgIFITM2 group was significantly lower than that in the model group (P 0.05). Taken together, BgIFITM2 protein could inhibit the proliferative activity of HepG2 cells by regulating apoptosis-related genes, and reduce the invasiveness of HepG2 cells in mice lung tissue. These results facilitate further studies on the function of BgIFITM2 protein.

Leftover food consumption is very prevalent among the Chinese older adults, however, the potential effects of leftover eating consumption on depression have not yet been investigated.The study aims to determine the association between leftover consumption on depression among older adults.Data of leftover consumption frequency was collected in a cross-sectional study with a provincial representative sample of 5992 older adults (aged 60 or older) in 2019. Depression symptoms were assessed by the 9-item screener Patient Health Questionnaire (PHQ-9). Multiple logistic regression models were applied to analyze the association of the frequency of leftover eating consumption and the presence and the severity of depression.After controlling for all the covariates, the participants who consume leftover food everyday had higher risk of having depression symptom comparing to those who had the lowest frequency of leftover eating (OR: 1.675, 95% CI: 1.435-1.956, p 0.001). The participants who consume leftover food every day was also associated with more severe depression symptoms (OR: 1.621, 95% CI: 1.397-1.881, p 0.001), when comparing to the reference group. The associations seemed stronger in men than women.The causal relationship between leftover consumption behavior and depression could not be determined due to the cross-sectional design. Moreover, the variety or handling method of the leftover food was not specified.Leftovers eating frequency was associated with the presence and severity of depression symptoms among older adults.

Background There is no a unified opinion in the treatment of IgA nephropathy. This prospective cohort study was to explore the effectiveness and safety of tacrolimus for treatment of IgA (Immunoglobulin A) nephropathy patients. Methods In this study, we assigned 50 patients with biopsy-proven IgA nephropathy in a 1:1.5 ratio to receive oral tacrolimus or full-dose glucocorticoid for 6 months. All the patients had 24-h urine protein excretion ≥ 2.0 g/24 h and estimated glomerular filtration rate ≥ 50 mL/min/1.73 m2. Primary endpoint was rate of complete remission. Results After 6 months of treatment, seven participants achieved complete remission in the tacrolimus group and twelve participants in the glucocorticoid group, the complete remission rate was 35% and 40%, respectively. There were not significantly differences between two groups (P = 0.7). However, the serum creatinine level from baseline was an increase of 13 ± 13.5 μmol/L in the tacrolimus group and a decrease of 8.2 ± 20 μmol/L in the glucocorticoid group. When patients stopped taking tacrolimus for 3 months, creatinine level can almost fall to normal level. Thus, patients with renal insufficiency have a high incidence in the tacrolimus group. Conclusions Tacrolimus was noninferior to full-dose glucocorticoid in inducing proteinuria remission at 6 months. This suggested that those IgA nephropathy patients who are unwilling to full-dose glucocorticoid could consider tacrolimus, but need to pay attention to the impact on renal function.

Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it was associated with CMI. In a subset of CMI patients, the DISC1 protein misassembles to an insoluble protein. This has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and - possibly - also stress-related symptoms of major mental illnesses.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide because of metastasis. An increasing number of studies have reported that cancer-associated fibroblasts (CAFs) have emerged as the largest component of the stroma and play a critical role in tumor-promoting processes. However, the effects of CAFs on cancer progression and the sensitivity of hepatoma cells to sorafenib are not well characterized. Here, we identified the proteome of CAF-derived exosomes, and unveiled that exosomal Gremlin-1 derived from CAFs contributes to epithelial-mesenchymal transition (EMT) of hepatoma cells and the decrease of the sorafenib sensitivity through regulating Wnt/β-catenin and BMP signaling pathways. Compared to control subjects, the level of plasma exosomal Gremlin-1 was significantly increased in HCC patients. Further studies indicated that plasma exosomal Gremlin-1 may predict sorafenib response in HCC patients. Collectively, our findings uncover CAFs-derived Gremlin-1-rich exosomes promote EMT and decrease the sensitivity of hepatoma cells to sorafenib by Wnt/β-catenin and BMP signaling.

Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed.Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2.Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004).When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.

In clinical trials, almost all key milestone dates can be defined in terms of time to endpoint maturation (TTEM). The real time monitoring and accurate prediction of TTEM have a significant impact on clinical trial planning and execution and can bring significant value to clinical trial practitioners. TTEM is defined as the time to achieve or observe a certain number or percentage of some endpoint of interest. It is a combination of time to site initiation, time to subject enrollment after site initiation and time to event of interest after subject enrollment. To better predict TTEM during the trial, the future site initiation and subject enrollment have to be taken into account while predicting the number of events. In this article, we propose a novel simulation-based framework combining time to site initiation, time to subject enrollment and time to event in order to predict TTEM. A nonhomogeneous Poisson process with a quadratic time-varying rate function is used to model site initiation and subject enrollment and more advanced time to event models had been explored and integrated on top of them, such as Weibull, piecewise exponential, and model averaging which is equivalent to a Bayesian model selection strategy. To evaluate the predictive performance of the proposed methodology, we conducted extensive simulations and applied the methodology to 14 randomly selected real oncology phase 2 and phase 3 studies in both solid tumor and hematology with a total 31 study-endpoint combinations. The predictive performance of the proposed methodology was then compared with popular and commonly available commercial software, for example, East (Cytel, Cambridge, MA, USA). From both simulation and real data, the proposed methodology can significantly improve the prediction accuracy by up to 54% compared to the commonly available method.

Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 β activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 β during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.

To investigate how the National Health Commission of China (NHCC)-recommended Chinese medicines (CMs) modulate the major maladjustments of coronavirus disease 2019 (COVID-19), particularly the clinically observed complications and comorbidities.By focusing on the potent targets in common with the conventional medicines, we investigated the mechanisms of 11 NHCC-recommended CMs in the modulation of the major COVID-19 pathophysiology (hyperinflammations, viral replication), complications (pain, headache) and comorbidities (hypertension, obesity, diabetes). The constituent herbs of these CMs and their chemical ingredients were from the Traditional Chinese Medicine Information Database. The experimentally-determined targets and the activity values of the chemical ingredients of these CMs were from the Natural Product Activity and Species Source Database. The approved and clinical trial drugs against these targets were searched from the Therapeutic Target Database and DrugBank Database. Pathways of the targets was obtained from Kyoto Encyclopedia of Genes and Genomes and additional literature search.Overall, 9 CMs modulated 6 targets discovered by the COVID-19 target discovery studies, 8 and 11 CMs modulated 8 and 6 targets of the approved or clinical trial drugs for the treatment of the major COVID-19 complications and comorbidities, respectively.The coordinated actions of each NHCC-recommended CM against a few targets of the major COVID-19 pathophysiology, complications and comorbidities, partly have common mechanisms with the conventional medicines.