Characteristics of "do not resuscitate" orders among elderly patients receiving mechanical ventilation in the intensive care unit in Taiwan.

Objective: As patient life expectancy has increased and people are living longer than before, the rate of mechanical ventilation among elderly patients in the intensive care unit has increased. Older patients who receive mechanical ventilation and have multiple comorbidities are more likely to have a do not resuscitate order than are younger patients with fewer comorbidities. The aim of our study was to describe the patient characteristics and predictive factors of do not resuscitate orders during hospitalization among elderly patients who received ventilation in the intensive care unit. Methods: This was a retrospective review of the electronic medical records of patients in the intensive care unit of a teaching hospital in southern Taiwan. We enrolled patients admitted to the general intensive care unit from January 1, 2018, to September 31, 2020, and patients older than 80 years who experienced respiratory failure, were intubated and received mechanical ventilation. We analyzed patient demographics, disease severity during hospitalization and comorbidities. If a patient had multiple admissions to the intensive care unit, only the first admission was recorded. Results: Of the 305 patients over 80 years of age with respiratory failure who were intubated and placed on a ventilator, 66 were excluded because of incomplete data, and 13 were excluded because they had already signed a do not resuscitate order prior to admission to the hospital. Ultimately, 226 patients were included in this study. A higher acute physiology and chronic health evaluation II score (>30) was also associated with an increased likelihood of a do not resuscitate order (odds ratio (OR) = 3.85, 95% CI = 1.09-13.62, p = 0.0362). Patients who had acute kidney injury or cerebrovascular accident were more likely to have a do not resuscitate order (OR = 2.74, 95% CI = 1.03-7.28, p = 0.0428 and OR = 7.32, 95% CI = 2.02-26.49, p = 0.0024, respectively). Conclusion: Our study showed that older age, greater disease severity, and certain critical interventions were associated with a greater propensity for do not resuscitate orders, which is crucial for understanding patient preferences and guiding end-of-life care discussions. These findings highlight the importance of clinical severity and specific health events in predicting end-of-life care preferences in older patient groups.

Optimizing the image quality of peripancreatic blood vessels through the clinical application of single-energy spectral computed tomography (CT) imaging.

Background: With the increase of pancreatic tumor patients in recent years, there is an urgent need to find a way to treat pancreatic tumors. Surgery is one of the best methods for the treatment of pancreatic tumors, the success of which depends on the evaluation of peripancreatic vessels before surgery. Computed tomography (CT), as a non-invasive, fast, and economical auxiliary examination method, is undoubtedly one of the best means of clinical auxiliary examination. In this study, we investigated the impact of single-energy spectral CT imaging on the image quality of peripancreatic blood vessels and the clinical value of low-keV imaging in enhancing the image quality of peripancreatic arteriovenous vessels. Methods: We prospectively enrolled 103 patients who underwent abdominal vascular-enhanced CT examinations at the Affiliated Hospital of Hebei University between December 2022 and May 2023 and who were all scanned with the dual-energy feature on the United Imaging ATLAS scanner. The images were reconstructed at 70 keV, mixed energy, and optimized single energy in the post-processing station of United Imaging Healthcare Technology Co., Ltd. The CT value and contrast-to-noise ratio (CNR) of the superior mesenteric artery (SMA), gastroduodenal artery (GDA), inferior pancreaticoduodenal artery (IPDA), and superior mesenteric vein (SMV) were compared across energy levels, and then the image quality was subjectively evaluated. One-way analysis of variance and rank-sum tests were utilized for the statistical analysis. Results: The CT values of SMA, GDA, IPDA, and SMV in the optimal single energy group were 358.37±70.24, 323.36±88.23, 300.76±76.27, and 257.74±20.56 Hounsfield unit (HU), respectively, which were superior to those in the mixed energy (241.66±47.69, 235.17±53.71, 207.36±45.17, and 187.39±23.21 HU) and 70 keV groups (260.89±54.27, 252.41±58.87, 223.17±43.65, and 203.18±18.17 HU) (P<0.05). The diagnostic efficacy was greater in the optimal single energy group than in the other 2 groups (4.63±0.50, 3.91±0.57, and 4.23±0.83) (P<0.05). Conclusions: The optimal single energy for showing peripancreatic blood vessels is 62±7 keV when utilizing single-energy spectral CT imaging.

Shock index to predict outcomes in patients with trauma following traffic collisions: a retrospective cohort study.

PURPOSE: Taiwan, which has a rate of high vehicle ownership, faces significant challenges in managing trauma caused by traffic collisions. In Taiwan, traffic collisions contribute significantly to morbidity and mortality, with a high incidence of severe bleeding trauma. The shock index (SI) and the modified shock index (MSI) have been proposed as early indicators of hemodynamic instability. In this study, we aimed to assess the efficacy of SI and MSI in predicting adverse outcomes in patients with trauma following traffic collisions. METHODS: This retrospective cohort study was conducted at Chi Mei Hospital from January 2015 to December 2020. The comprehensive analysis included 662 patients, with data collected on vital signs and outcomes such as mortality, blood transfusion, emergent surgical intervention (ESI), transarterial embolization (TAE), and intensive care unit (ICU) admission. Optimal cutoff points for SI and MSI were identified by calculating the Youden index. Logistic regression analysis was used to assess outcomes, adjusting for demographic and injury severity variables. RESULTS: An SI threshold of 1.11 was associated with an increased risk of mortality, while an SI of 0.84 predicted the need for blood transfusion in the context of traffic collisions. Both SI and MSI demonstrated high predictive power for mortality and blood transfusion, with acceptable accuracy for TAE, ESI, and ICU admission. Logistic regression analyses confirmed the independence of SI and MSI as risk factors for adverse outcomes, thus, providing valuable insights into their clinical utility. CONCLUSIONS: SI and MSI are valuable tools for predicting mortality and blood transfusion needs in patients with trauma due to traffic collisions. These findings advance the quality of care for patients with trauma during their transition from the emergency room to the ICU, facilitating prompt and reliable decision-making processes and improving the care of patients with trauma.

Comparison of Machine Learning Models Using Diffusion-Weighted Images for Pathological Grade of Intrahepatic Mass-Forming Cholangiocarcinoma.

Is the radiomic approach, utilizing diffusion-weighted imaging (DWI), capable of predicting the various pathological grades of intrahepatic mass-forming cholangiocarcinoma (IMCC)? Furthermore, which model demonstrates superior performance among the diverse algorithms currently available? The objective of our study is to develop DWI radiomic models based on different machine learning algorithms and identify the optimal prediction model. We undertook a retrospective analysis of the DWI data of 77 patients with IMCC confirmed by pathological testing. Fifty-seven patients initially included in the study were randomly assigned to either the training set or the validation set in a ratio of 7:3. We established four different classifier models, namely random forest (RF), support vector machines (SVM), logistic regression (LR), and gradient boosting decision tree (GBDT), by manually contouring the region of interest and extracting prominent radiomic features. An external validation of the model was performed with the DWI data of 20 patients with IMCC who were subsequently included in the study. The area under the receiver operating curve (AUC), accuracy (ACC), precision (PRE), sensitivity (REC), and F1 score were used to evaluate the diagnostic performance of the model. Following the process of feature selection, a total of nine features were retained, with skewness being the most crucial radiomic feature demonstrating the highest diagnostic performance, followed by Gray Level Co-occurrence Matrix lmc1 (glcm-lmc1) and kurtosis, whose diagnostic performances were slightly inferior to skewness. Skewness and kurtosis showed a negative correlation with the pathological grading of IMCC, while glcm-lmc1 exhibited a positive correlation with the IMCC pathological grade. Compared with the other three models, the SVM radiomic model had the best diagnostic performance with an AUC of 0.957, an accuracy of 88.2%, a sensitivity of 85.7%, a precision of 85.7%, and an F1 score of 85.7% in the training set, as well as an AUC of 0.829, an accuracy of 76.5%, a sensitivity of 71.4%, a precision of 71.4%, and an F1 score of 71.4% in the external validation set. The DWI-based radiomic model proved to be efficacious in predicting the pathological grade of IMCC. The model with the SVM classifier algorithm had the best prediction efficiency and robustness. Consequently, this SVM-based model can be further explored as an option for a non-invasive preoperative prediction method in clinical practice.

Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential.

Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system.

The present letter to the editor is related to the study titled 'Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells'. Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 (PASC).

Symptoms of coronavirus disease 2019 (COVID-19) can persist for months or years after infection, a condition called Post-Acute Sequelae of COVID-19 (PASC). Whole-brain white matter and cortical gray matter health were assessed using multi-shell diffusion tensor imaging. Correlational tractography was utilized to dissect the nature and extent of white matter changes. In this study of 42 male essential workers, the most common symptoms of Neurological PASC (n = 24) included fatigue (n = 19) and headache (n = 17). Participants with neurological PASC demonstrated alterations to whole-brain white matter health when compared to controls made up of uninfected, asymptomatic, or mildly infected controls (n = 18). Large differences were evident between PASC and controls in measures of fractional anisotropy (Cohen's D=-0.54, P = 0.001) and cortical isotropic diffusion (Cohen's D = 0.50, P = 0.002). Symptoms were associated with white matter fractional anisotropy (fatigue: rho = -0.62, P< 0.001; headache: rho = -0.66, P < 0.001), as well as nine other measures of white and gray matter health. Brain fog was associated with improved cerebral functioning including improved white matter isotropic diffusion and quantitative anisotropy. This study identified changes across measures of white and gray matter connectivity, neuroinflammation, and cerebral atrophy that were interrelated and associated with differences in symptoms of PASC. These results provide insights into the long-term cerebral implications of COVID-19.

Discovery of BMP10 as a new gene underpinning congenital heart defects.

OBJECTIVE: Aggregating evidence convincingly establishes the predominant genetic basis underlying congenital heart defects (CHD), though the heritable determinants contributing to CHD in the majority of cases remain elusive. In the current investigation, BMP10 was selected as a prime candidate gene for human CHD mainly due to cardiovascular developmental abnormalities in Bmp10-knockout animals. The objective of this retrospective study was to identify a new BMP10 mutation responsible for CHD and characterize the functional effect of the identified CHD-causing BMP10 mutation. METHODS: Sequencing assay of BMP10 was fulfilled in a cohort of 276 probands with various CHD and a total of 288 non-CHD volunteers. The available family members from the proband harboring an identified BMP10 mutation were also BMP10-genotyped. The effect of the identified CHD-causative BMP10 mutation on the transactivation of TBX20 and NKX2.5 by BMP10 was quantitatively analyzed in maintained HeLa cells utilizing a dual-luciferase reporter assay system. RESULTS: A novel heterozygous BMP10 mutation, NM_014482.3:c.247G>T;p.(Glu83*), was identified in one proband with patent ductus arteriosus (PDA), which was confirmed to co-segregate with the PDA phenotype in the mutation carrier's family. The nonsense mutation was not observed in 288 non-CHD volunteers. Functional analysis unveiled that Glu83*-mutant BMP10 had no transactivation on its two representative target genes TBX20 and NKX2.5, which were both reported to cause CHD. CONCLUSION: These findings provide strong evidence indicating that genetically compromised BMP10 predisposes human beings to CHD, which sheds light on the new molecular mechanism that underlies CHD and allows for antenatal genetic counseling and individualized precise management of CHD.

Evaluation of combination of ALA-PDT and interferon for cervical low-grade squamous intraepithelial lesion (LSIL).

BACKGROUND: Cervical LSIL is a precancerous disease which requires regular follow-up. High risk patients need active interventions. Interferon and topical PDT have been used in the treatment of cervical LSIL. The aim of this study was to evaluate the combination use of topical PDT and interferon in the treatment of cervical LSIL. MATERIALS AND METHODS: A prospective study was carried out involving 159 women with cervical LSIL and high risk human papillomaviruses (hr-HPV) infection. Patients were divided into three groups. Group 1-receiving interferon suppository only, Group 2-receiving 19 mg/cm2 ALA plus post PDT interferon, and Group 3-receiving 38 mg/cm2 ALA plus post PDT interferon. The primary endpoint was pathological regression. The secondary endpoints were the HPV negative conversion rate and the adverse effects of treatment. RESULTS: At 6-12 months after PDT, for Group 1, the effective rate, CR rate and HPV negative conversion rate was 48.3 %, 43.3 % and 24.0 %, respectively. For Group 2, the effective rate, CR rate and HPV negative conversion rate were 89.3 %, 71.4 %, and 72.4 %, respectively. For Group 3, the effective rate, CR rate and HPV negative conversion rate were 91.5 %, 66.1 %, and 64.4 %, respectively, significantly higher than those of interferon only group. Two ALA dose group study showed similar efficacy. No patient experienced serious adverse effects. CONCLUSIONS: ALA-PDT combined with interferon therapy was feasible and tolerable. Two ALA dose groups showed similar outcomes in treating cervical LSIL.

TGF-ß1 Mediates the EndoMt in High Glucose-Treated Human Retinal Microvascular Endothelial Cells.

The purpose of our study was to investigate the role of TGF-ß1 in the endothelial-to-mesenchymal transition (EndoMT) and fibrosis in high glucose (HG)-treated human retinal microvascular endothelial cells (HRMECs). HRMECs were cultured not only under normal glucose (NG) conditions with or without TGF-ß1, but also under HG conditions with or without the TGF-ß1 inhibitor SB431542. The expression of TGF-ß1 was detected by real time-PCR and enzyme-linked immunosorbent assay. Morphological changes and migration of the HRMECs were observed using electron microscopy and scratch-wound assay. Endothelial markers, such as CD31 and vascular endothelial (VE)-cadherin, and the acquisition of fibrotic markers, such as alpha smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1), were determined by immunofluorescent staining and western blot. The level of TGF-ß1 was significantly upregulated in HG-treated HRMECs. And HG stimulation promoted obvious morphological changes and the migration ability in HRMECs. Our results also demonstrated increased expression of α-SMA and FSP-1, and decreased expression of CD31 and VE-cadherin, in HG-treated HRMECs. These EndoMT-related changes were promoted by TGF-ß1 and abrogated by SB431542. The results of this study demonstrated the important role of TGF-ß1 in HG-induced vitreoretinal fibrosis. EndoMT is likely to be involved in the associated effects.

Functional characterization of RIP2 in large yellow croaker (Larimichthys crocea), a protein involved in the host antiviral responses via NF-κΒ, IRF3/7 related signaling.

As an adaptor protein functions essentially in the activation of NF-κΒ and MAPK signaling pathways mediated by NOD1 and NOD2, RIP2 plays important roles in the host innate immune responses. In the present study, the RIP2 ortholog termed Lc-RIP2 was identified and characterized in large yellow croaker (Larimichthys crocea). It was revealed that Lc-RIP2 is consisted of an open reading frame (ORF) of 1695 bp, encoding a protein of 564 aa, with an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD). Subcellular localization assays demonstrated that Lc-RIP2 was a cytosolic protein, which was broadly distributed in the examined tissues/organs, and could be induced in response to poly I:C, LPS, PGN, and Pseudomonas plecoglossicida stimulations in vivo according to qRT-PCR analysis. Notably, Lc-RIP2 overexpression in vitro was sufficient to abolish SVCV proliferation in EPC cells, and could significantly induce the activation of NF-κB, IRF3, IRF7, and IFN1 promoters. In addition, luciferase assays found that Lc-RIP2 could cooperate with Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7 in NF-κB activation, associate with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-IRF3, and Lc-IRF7 in IRF3 activation, enhance Lc-TRIF, Lc-MAVS, Lc-TRAF3, and Lc-TRAF6 mediated IRF7 activation, and Lc-IRF3 mediated IFN1 activation, whereas suppress NF-κB activation when co-expressed with Lc-TRIF. Co-immunoprecipitation (Co-IP) assays also demonstrated that Lc-RIP2 interacts separately with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7. It is thus collectively indicated that Lc-RIP2 function dominantly in the regulation of the host innate immune signaling.

Somatic GATA4 mutation contributes to tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart pathology and causes infant morbidity and mortality worldwide. GATA-binding protein 4 (GATA4) serves as a pivotal transcriptional factor for embryonic cardiogenesis and germline GATA4 mutations are causally linked to TOF. However, the effects of somatic GATA4 mutations on the pathogenesis of TOF remain to be ascertained. In the present study, sequencing assay of GATA4 was performed utilizing genomic DNA derived from resected heart tissue specimens as well as matched peripheral blood specimens of 62 patients with non-familial TOF who underwent surgical treatment for TOF. Sequencing of GATA4 was also performed using the heart tissue specimens as well as matched peripheral venous blood samples of 68 sporadic cases who underwent heart valve displacement because of rheumatic heart disorder and the peripheral venous whole blood samples of 216 healthy subjects. The function of the mutant was explored by dual-luciferase activity analysis. Consequently, a new GATA4 mutation, NM_002052.5:c.708T>G;p.(Tyr236*), was found in the heart tissue of one patient with TOF. No mutation was detected in the heart tissue of the 68 cases suffering from rheumatic heart disorder or in the venous blood samples of all 346 individuals. GATA4 mutant failed to transactivate its target gene, myosin heavy chain 6. Additionally, this mutation nullified the synergistic transactivation between GATA4 and T-box transcription factor 5 or NK2 homeobox 5, two genes causative for TOF. Somatic GATA4 mutation predisposes TOF, highlighting the significant contribution of somatic variations to the molecular pathogenesis underpinning TOF.

Antihypertensive Drugs Affect the Association of Systolic Blood Pressure Variability with Outcomes in Patients with Acute Stroke who had Successful Recanalization after Endovascular Treatment.

AIMS: Blood pressure variability (BPV) was associated with the clinical outcomes in patients with acute ischemic stroke (AIS) due to large-vessel occlusion (LVO) after endovascular treatment (EVT). This study aimed to investigate whether the use of antihypertensive drugs could affect this association in patients with AIS-LVO after EVT. METHODS: We retrospectively screened consecutive patients with AIS-LVO who had successful recanalization after EVT and calculated their systolic BPV (SBPV) during the first 24 h after EVT using eight statistical methodologies based on previously published literature. Poor outcome was defined as a modified Rankin Scale score of 3-6 at 90 days. Logistic regression analysis was performed to assess this association, and different prediction models were constructed to assess the effect of the use of antihypertensive drugs. RESULTS: A total of 214 patients were finally included, including 92 (43.0%) with good outcomes, and 136 (63.6%) who received antihypertensive drugs. SBPV indicators were significantly lower in patients with good outcomes versus those with poor outcomes. The logistic analysis showed that all SBPV indicators were consistently associated with poor outcomes (odds ratio, 1.031-1.282, all P＜0.05) in all populations, which was confirmed in patients not using antihypertensive drugs. However, no SBPV indicator was found to be associated with poor outcomes in patients using antihypertensive drugs. Receiver operating characteristic curves showed that the area under the curve (AUC) was larger in the model adjusting for antihypertensive drugs (AUC 0.774-0.783) compared with the one not adjusted for antihypertensive drugs (AUC 0.739-0.754). CONCLUSION: In the anterior circulation of patients with AIS-LVO who had successful recanalization after EVT, the utilization of antihypertensive drugs may have some impact on the relationship between SBPV and clinical outcomes.

Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway.

BACKGROUND: Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients. METHODS: We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva). RESULTS: A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p < 4.67e-8) related to sensory perception and detection of chemical stimuli, including smell perception (GO:0007606, GO:0007608, GO:0009593, GO:0050906, GO:0050907, and GO:0050911). The same six biological processes were significantly suppressed in the validation dataset (p < 9.02e-14). The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (ppaired-samples = 1.72e-9, psingle-timepoint-blood = 2.03e-15 and psingle-timepoint-saliva = 7.52e-56). CONCLUSION: The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell.

Remote Ischemic Conditioning and Outcomes in Acute Ischemic Stroke With Versus Without Large Artery Atherosclerosis.

BACKGROUND: RICAMIS trial (The Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke) has demonstrated efficacy of remote ischemic conditioning (RIC) in acute ischemic stroke. We conducted a post hoc analysis of RICAMIS to investigate whether large artery atherosclerosis (LAA) subtype contributed to the outcomes. METHODS: This is a post hoc analysis of the RICAMIS trial. Patients randomized to RIC group and Control group in full analysis set of RICAMIS were classified into LAA and non-LAA subtypes. The primary outcome was excellent functional outcome at 90 days, defined as modified Rankin Scale score of 0 to 1. Compared with patients receiving usual care, we investigated the association of RIC effect with outcomes in stroke subtypes and the interaction between RIC effect and stroke subtypes. The primary analysis was adjusted analysis. RESULTS: Among 1773 patients, 516 were assigned to LAA subtype (229 in the RIC group and 287 in the control group) and 1257 to non-LAA subtype (633 in the RIC group and 624 in the control group). Median age was 65 years, and 34.2% were women. A higher proportion of primary outcome was found to be associated with RIC treatment in LAA subtype (adjusted risk difference, 11.4% [95% CI, 3.6%-19.2%]; P=0.004), but not in non-LAA subtype (adjusted risk difference, 4.1% [95% CI, -1.1% to 9.3%]; P=0.12). There was no significant interaction between RIC effect and stroke subtypes (P=0.12). CONCLUSIONS: Patients with LAA subtype may benefit from RIC after stroke with respect to excellent functional outcome at 90 days. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03740971.

Spinosin protects Neuro-2a/APP695 cells from oxidative stress damage by inactivating p38.

OBJECTIVE: To explore the protective mechanism of spinosin (SPI) on Alzheimer's disease (AD) model cells, Neuro-2a/APP695 (N2a/APP695), against HO-induced oxidative stress damage, to reflect the influence of oxidative stress on the development of AD, and to provide a valuable basis for the research and development of therapeutic drug for AD. METHODS: N2a/APP695 cells were exposed to HO and then treated with spinosin. Firstly, the secretion level of amyloid ß (Aß) and the production of malondialdehyde (MDA) and lactate dehydrogenase (LDH) were detected by enzyme linked immunosorbent assay kits. Secondly, the oligomerization degree of Aß was performed by Thioflavin T staining. Thirdly, the expression levels of p-Tau (Ser199/202/396), synaptophysin (SYP), postsynaptic density protein 95 (PSD95), and mitogen-activated protein kinase (MAPK) family-related proteins were detected by Western blot analysis. In addition, FITC-labeled phalloidin was used in cytoskeleton staining to reflect synaptic function. RESULTS: This study showed that HO stimulated N2a/APP695 cells to produce excessive MDA and LDH and secrete a large amount of Aß, promoted the aggregation of Aß, induced Tau protein hyperphosphorylation, and led to synaptic dysfunction. Spinosin reversed these changes caused by HO by inactivating p38, which was verified by treatment with the p38 inhibitor BIRB796. CONCLUSION: Spinosin protects N2a/APP695 cells from oxidative stress damage caused by HO through inactivating p38.

MG132, Attenuates the Retinal Vascular Injury Through the Upregulation of Nrf2 Expression.

Purpose: This study clarifies the beneficial effects of MG132, a proteasomal inhibitor, on retinal vascular injury mediated by diabetes-induced oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2). Methods: Diabetic rats and control animals were randomly assigned to receive MG132 or vehicle for 24 weeks, and human retinal endothelial cells (HRECs) were incubated with normal or high glucose with or without MG132. 26S proteasome activity in the rat retinas or cultured HRECs was measured using Suc-LLVY-7-amido-4-methylcoumarin. NADPH-quinone oxidoreduc-tase (NQO1), heme oxygenase (HO)-1, kelch-like ECH-associated protein 1 (Keap1) and Nrf2 were examined by Western blotting and real-time reverse transcription polymerase chain reaction. Cell apoptosis is measured through flow cytometry assay, mitochondrial reactive oxygen species (ROS) production, and retinal vascular leakage were assayed using CM-H2DCFDA fluorescent probes and Evans blue, respectively. Results: MG132 significantly inhibited the activation of 26S proteasome induced by diabetes or elevated glucose, and subsequently increased the expression of Nrf2, NQO1, and HO-1, and further reduced ROS accumulation. These changes were associated with a decrease of diabetes-induced retinal vascular leakage and retinal capillary cell apoptosis. Conclusions: MG132 decreases diabetes-induced 26S proteasome activation and exerts protective effects against retinal microvascular dysfunction in diabetic rats in association with the alleviation of retinal oxidative stress mediated by Nrf2.

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation.

Atrial fibrillation (AF), the most prevalent type of sustained cardiac dysrhythmia globally, confers strikingly enhanced risks for cognitive dysfunction, stroke, chronic cardiac failure, and sudden cardiovascular demise. Aggregating studies underscore the crucial roles of inherited determinants in the occurrence and perpetuation of AF. However, due to conspicuous genetic heterogeneity, the inherited defects accounting for AF remain largely indefinite. Here, via whole-genome genotyping with genetic markers and a linkage assay in a family suffering from AF, a new AF-causative locus was located at human chromosome 7p14.2-p14.3, a ~4.89 cM (~4.43-Mb) interval between the markers D7S526 and D7S2250. An exome-wide sequencing assay unveiled that, at the defined locus, the mutation in the TBX20 gene, NM_001077653.2: c.695A>G; p.(His232Arg), was solely co-segregated with AF in the family. Additionally, a Sanger sequencing assay of TBX20 in another family suffering from AF uncovered a novel mutation, NM_001077653.2: c.862G>C; p.(Asp288His). Neither of the two mutations were observed in 600 unrelated control individuals. Functional investigations demonstrated that the two mutations both significantly reduced the transactivation of the target gene KCNH2 (a well-established AF-causing gene) and the ability to bind the promoter of KCNH2, while they had no effect on the nuclear distribution of TBX20. Conclusively, these findings reveal a new AF-causative locus at human chromosome 7p14.2-p14.3 and strongly indicate TBX20 as a novel AF-predisposing gene, shedding light on the mechanism underlying AF and suggesting clinical significance for the allele-specific treatment of AF patients.

Additional role of ECC in the detection and treatment of cervical HSIL.

Objective: To probe into the additional role of ECC in the detection of cervical HSIL. The primary objective was to risk-stratify HSIL patients according to ECC so as to provide clinical suggestions for subsequent treatment. Methods: Retrospective analysis of medical records for patients with HSIL. All patients underwent both ECC and cervical biopsy. According to the results of colposcopic targeted biopsy and ECC, the patients were divided into three groups: (1) ECC negative group (those whose colposcopic targeted biopsy indicated HSIL, but ECC indicated LSIL or chronic inflammation); (2) Only the ECC positive group (those whose ECC suggested HSIL, but colposcopic targeted biopsy showed LSIL or chronic inflammation); (3) ECC and biopsy positive group (those whose ECC and targeted biopsy were both HSIL). Chi-square test was used to analyze the differences of lesion residue and biopsy results after LEEP amongst the three groups. Results: A total of 1,146 medical records were analyzed. The diagnostic accuracy of ECC combined with colposcopic targeted biopsy for HSIL was higher than that of colposcopic biopsy alone (72.43% vs. 67.54%). When ECC indicated HSIL, the coincidence rate of ECC combined with colposcopic targeted biopsy and the histological pathology of LEEP was 86.25%, and the proportion of residual lesions after LEEP was 41.43%. When ECC and targeted biopsy both indicated HSIL, HSIL or worse lesions were confirmed in 90.68% of patients after surgery. Of these, 10.77% were confirmed as cervical invasive carcinoma. Moreover, the positive rate of LEEP resection margin and postoperative ECC in these patients was 43.48%. Conclusion: ECC can improve the detection rate of cervical HSIL and reduce missed diagnosis. Also ECC can help clinicians predict the proportion of residual lesions after LEEP. This provides the gynecologists with a reference for the need to increase the depth of the procedure and the need to perform ECC for the residual cervical canal.

Systematic Appraisal of Guidelines for the Diagnosis and Treatment of Choledocholithiasis.

BACKGROUND: To systematically evaluate the methodological quality of the current up-to-date guidelines pertaining to choledocholithiasis, we conducted a comprehensive analysis of key recommendations and corresponding evidence, focusing on the heterogeneity among these guidelines. METHOD: Systematic searches across various databases were performed to identify the latest guidelines. The identified guidelines, which met the inclusion criteria, underwent evaluation using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. The key recommendations and evidence from the included guidelines were extracted and reclassified using the Oxford Centre for Evidence-Based Medicine (OCEBM) grading system, and the obtained results were analyzed. RESULTS: Nine guidelines related to choledocholithiasis were included in this study, out of which 4 achieved an overall standardized score of more than 60%, indicating their suitability for recommendation. Upon closer examination of the main recommendations within these guidelines, we discovered significant discrepancies concerning the utilization of similar treatment techniques for different diseases or different treatment methods under comparable conditions, and discrepancies in the recommended treatment duration. High-quality research evidence was lacking, and some recommendations either failed to provide supporting evidence or cited inappropriate and low-level evidence. CONCLUSION: The quality of guidelines pertaining to choledocholithiasis is uneven. Recommendations for the treatment of choledocholithiasis demonstrate considerable disparities among the guidelines, particularly regarding the utilization of endoscopic retrograde cholangiopancreatography as a treatment method and the management approaches for difficult stone cases. Improvements by guideline developers for these factors contributing to the heterogeneity would be a reasonable approach to further update the guidelines for cholangiolithiasis.