An acidic pH environment converts necroptosis to apoptosis.

Cardiac ischemia results in anaerobic metabolism and lactic acid accumulation and with time, intracellular and extracellular acidosis. Ischemia and subsequent reperfusion injury (IRI) lead to various forms of programmed cell death. Necroptosis is a major form of programmed necrosis that worsens cardiac function directly and also promotes inflammation by the release of cellular contents. Potential effects of increasing acidosis on programmed cell death and their specific components have not been well studied. While apoptosis is caspase-dependent, in contrast, necroptosis is mediated by the receptor-interacting protein kinases 1 and 3 (RIPK1/3). In our study, we observed that at physiological pH = 7.4, caspase-8 inhibition did not prevent TNFα-induced cell death in mouse cardiac vascular endothelial cells (MVECs) but promoted necroptotic cell death. As expected, necroptosis was blocked by RIPK1 inhibition. However, at pH = 6.5, TNFα induced an apoptosis-like pattern which was inhibited by caspase-8 inhibition. Interestingly phosphorylation of necroptotic molecules RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) was enhanced in an acidic pH environment. However, RIPK3 and MLKL phosphorylation was self-limited which may have limited their participation in necroptosis. In addition, an acidic pH promoted apoptosis-inducing factor (AIF) cleavage and nuclear translocation. AIF RNA silencing inhibited cell death, supporting the role of AIF in this cell death. In summary, our study demonstrated that the pH of the micro-environment during inflammation can bias cell death pathways by altering the function of necroptosis-related molecules and promoting AIF-mediated cell death. Further insights into the mechanisms by which an acidic cellular micro-environment influences these and perhaps other forms of regulated cell death, may lead to therapeutic strategies to attenuate IRI.

Specialized cis-Acting RNA Elements Balance Genome Cyclization to Ensure Efficient Replication of Yellow Fever Virus.

Genome cyclization is essential for viral RNA (vRNA) replication of the vertebrate-infecting flaviviruses, and yet its regulatory mechanisms are not fully understood. Yellow fever virus (YFV) is a notorious pathogenic flavivirus. Here, we demonstrated that a group of cis-acting RNA elements in YFV balance genome cyclization to govern efficient vRNA replication. It was shown that the downstream of the 5'-cyclization sequence hairpin (DCS-HP) is conserved in the YFV clade and is important for efficient YFV propagation. By using two different replicon systems, we found that the function of the DCS-HP is determined primarily by its secondary structure and, to a lesser extent, by its base-pair composition. By combining in vitro RNA binding and chemical probing assays, we found that the DCS-HP orchestrates the balance of genome cyclization through two different mechanisms, as follows: the DCS-HP assists the correct folding of the 5' end in a linear vRNA to promote genome cyclization, and it also limits the overstabilization of the circular form through a potential crowding effect, which is influenced by the size and shape of the DCS-HP structure. We also provided evidence that an A-rich sequence downstream of the DCS-HP enhances vRNA replication and contributes to the regulation of genome cyclization. Interestingly, diversified regulatory mechanisms of genome cyclization, involving both the downstream of the 5'-cyclization sequence (CS) and the upstream of the 3'-CS elements, were identified among different subgroups of the mosquito-borne flaviviruses. In summary, our work highlighted how YFV precisely controls the balance of genome cyclization to ensure viral replication. IMPORTANCE Yellow fever virus (YFV), the prototype of the Flavivirus genus, can cause devastating yellow fever disease. Although it is preventable by vaccination, there are still tens of thousands of yellow fever cases per year, and no approved antiviral medicine is available. However, the understandings about the regulatory mechanisms of YFV replication are obscure. In this study, by a combination of bioinformatics, reverse genetics, and biochemical approaches, it was shown that the downstream of the 5'-cyclization sequence hairpin (DCS-HP) promotes efficient YFV replication by modulating the conformational balance of viral RNA. Interestingly, we found specialized combinations for the downstream of the 5'-cyclization sequence (CS) and upstream of the 3'-CS elements in different groups of the mosquito-borne flaviviruses. Moreover, possible evolutionary relationships among the various downstream of the 5'-CS elements were implied. This work highlighted the complexity of RNA-based regulatory mechanisms in the flaviviruses and will facilitate the design of RNA structure-targeted antiviral therapies.

Prediction of poststroke independent walking using machine learning: a retrospective study.

BACKGROUND: Accurately predicting the walking independence of stroke patients is important. Our objective was to determine and compare the performance of logistic regression (LR) and three machine learning models (eXtreme Gradient Boosting (XGBoost), Support Vector Machines (SVM), and Random Forest (RF)) in predicting walking independence at discharge in stroke patients, as well as to explore the variables that predict prognosis. METHODS: 778 (80% for the training set and 20% for the test set) stroke patients admitted to China Rehabilitation Research Center between February 2020 and January 2023 were retrospectively included. The training set was used for training models. The test set was used to validate and compare the performance of the four models in terms of area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score. RESULTS: Among the three ML models, the AUC of the XGBoost model is significantly higher than that of the SVM and RF models (P < 0.001, P = 0.024, respectively). There was no significant difference in the AUCs between the XGBoost model and the LR model (0.891 vs. 0.880, P = 0.560). The XGBoost model demonstrated superior accuracy (87.82% vs. 86.54%), sensitivity (50.00% vs. 39.39%), PPV (73.68% vs. 73.33%), NPV (89.78% vs. 87.94%), and F1 score (59.57% vs. 51.16%), with only slightly lower specificity (96.09% vs. 96.88%). Together, the XGBoost model and the stepwise LR model identified age, FMA-LE at admission, FAC at admission, and lower limb spasticity as key factors influencing independent walking. CONCLUSION: Overall, the XGBoost model performed best in predicting independent walking after stroke. The XGBoost and LR models together confirm that age, admission FMA-LE, admission FAC, and lower extremity spasticity are the key factors influencing independent walking in stroke patients at hospital discharge. TRIAL REGISTRATION: Not applicable.

Prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy: a retrospective study of 420 biopsy-proven cases.

BACKGROUND: This retrospective study aims to investigate the prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy (HBV-MN). METHODS: Clinicopathologic and serologic records of 420 patients with histologically confirmed HBV-MN between January 2014 and July 2021 were examined to determine the prevalence of seropositive and seronegative HBV-MN. Serum anti-PLA2R antibody testing was conducted on 280 patients with HBV-associated membranous nephropathy (HBV-MN) from August 2018 to July 2021. Immunopathologic characteristics of HBV-MN patients and anti-PLA2R antibody positivity were analyzed. RESULTS: Among 420 pathologically confirmed HBV-MN patients, 230 (54.8%) were seropositive for HBV. The seropositive group exhibited higher blood creatinine values and incidence of liver function abnormalities than the seronegative group (p < .05). Serum anti-PLA2R antibody testing on 280 HBV-MN patients revealed a total positive rate of 44.6%, with the seronegative group showing a significantly higher rate (62.6%) compared to the seropositive group (32.1%) (p < .01). The anti-PLA2R antibody-positive group displayed higher levels of urine protein (p < .05), serum cholesterol (p < .01), and IgG4 subtypes (p < .05) compared to the negative group. Additionally, the positive group had significantly lower levels of serum albumin and IgG than the negative group (p < .01). CONCLUSIONS: This comprehensive study reveals a significantly higher prevalence of seronegative HBV-MN than previously thought. The blood creatinine values and incidence of liver function abnormalities was higher in the serology-positive group than in the serology-negative group. Notably, the seronegative group displayed a higher positive rate of anti-PLA2R antibodies compared to the seropositive group, indicating distinctive clinical and immunopathologic features.

The CaMK Family Differentially Promotes Necroptosis and Mouse Cardiac Graft Injury and Rejection.

Organ transplantation is associated with various forms of programmed cell death which can accelerate transplant injury and rejection. Targeting cell death in donor organs may represent a novel strategy for preventing allograft injury. We have previously demonstrated that necroptosis plays a key role in promoting transplant injury. Recently, we have found that mitochondria function is linked to necroptosis. However, it remains unknown how necroptosis signaling pathways regulate mitochondrial function during necroptosis. In this study, we investigated the receptor-interacting protein kinase 3 (RIPK3) mediated mitochondrial dysfunction and necroptosis. We demonstrate that the calmodulin-dependent protein kinase (CaMK) family members CaMK1, 2, and 4 form a complex with RIPK3 in mouse cardiac endothelial cells, to promote trans-phosphorylation during necroptosis. CaMK1 and 4 directly activated the dynamin-related protein-1 (Drp1), while CaMK2 indirectly activated Drp1 via the phosphoglycerate mutase 5 (PGAM5). The inhibition of CaMKs restored mitochondrial function and effectively prevented endothelial cell death. CaMKs inhibition inhibited activation of CaMKs and Drp1, and cell death and heart tissue injury (n = 6/group, p < 0.01) in a murine model of cardiac transplantation. Importantly, the inhibition of CaMKs greatly prolonged heart graft survival (n = 8/group, p < 0.01). In conclusion, CaMK family members orchestrate cell death in two different pathways and may be potential therapeutic targets in preventing cell death and transplant injury.

Functional metabolomics revealed the dual-activation of cAMP-AMP axis is a novel therapeutic target of pancreatic cancer.

Pancreatic cancer (PC) is one of the most malignant cancers, owing to extremely high aggressiveness and mortality. Yet, this condition currently incurs widely drug resistance and therapeutic deficiency. In this study, we proposed a novel functional metabolomics strategy as Spatial Temporal Operative Real Metabolomics (STORM) to identify the determinant functional metabolites in a dynamic and visualized pattern whose level changes are mechanistically associated with therapeutic efficiency of gemcitabine against PC. Integrating quantitative analysis and spatial-visualization characterization of functional metabolites in vivo, we identified that the AMP-cAMP axis was a novel therapeutic target of PC to intermediate therapeutic efficiency of gemcitabine. Gemcitabine could induce the dual accumulation of cyclic AMP (cAMP) and AMP in tumor tissues. Quantitative analysis of associated biosynthetic enzymes and genes revealed that two independent intracellular ATP derived biosynthetic pathways to promote the dual activation of AMP-cAMP axis in a lower-level energetic environment. Then, gemcitabine induced the dual accumulation of AMP and cAMP can separately activate signaling pathways of AMPK and PKA, leading to the inhibition of tumor growth by the upregulation of the downstream tumor suppressor GADD45A. Collectively, our new STORM strategy was the first time to identify novel target of PC from a metabolic perspective as the dual activation of AMP-cAMP axis induced by gemcitabine can efficiently suppress PC tumor growth. In addition, such discovery has the capability to lower drug resistance of gemcitabine by specifically interacting with novel target, contributing to the improvement of therapeutic efficiency.

Utility of shear wave-based ultrasound elastography in chronic kidney disease and related pathological quantitative analysis.

OBJECTIVES: The purpose of this study was to investigate the effects of tissue fibrosis and microvessel density on shear wave-based ultrasound elastography (SWUE) of chronic kidney disease (CKD). In addition, we were looking to see whether SWUE could predict stage of CKD, correlating with the histology on kidney biopsy. METHODS: Renal tissue sections from 54 patients diagnosed with suspected CKD were subjected to immunohistochemistry (CD31 and CD34), and the degree of tissue fibrosis was assessed using Masson staining. Before renal puncture, both kidneys were examined using SWUE. Comparative analysis was used to assess the correlation between SWUE and microvessel density, and between SWUE and the degree of fibrosis. RESULTS: Fibrosis area according to Masson staining (p < 0.05) and integrated optical density (IOD) (p < 0.05) were positively correlated with CKD stage. The percentage of positive area (PPA) and IOD for CD31 and CD34 were not correlated with CKD stage (p > 0.05). When stage 1 CKD was removed, PPA and IOD for CD34 were negatively correlated with CKD stage (p < 0.05). Masson staining fibrosis area and IOD were not correlated with SWUE (p > 0.05), PPA and IOD for CD31 and CD34 were not correlated with SWUE (p > 0.05) and, finally, no correlation between SWUE and CKD stage was found (p > 0.05). CONCLUSION: The diagnostic value of SWUE for CKD staging was very low. The utility of SWUE in CKD was affected by many factors and its diagnostic value was limited. KEY POINTS: • There was no correlation between SWUE and the degree of fibrosis, or between SWUE and microvessel density among patients with CKD. • There was no correlation between SWUE and CKD stage and the diagnostic value of SWUE for CKD staging was very low. • The utility of SWUE in CKD is affected by many factors and its value was limited.

A functional near-infrared spectroscopy study on hemodynamic changes of patients with prolonged disorders of consciousness responding to different auditory stimuli.

Treating prolonged disorders of consciousness (pDoC) is challenging. Thus, accurate assessment of residual consciousness in patients with pDoC is important for the management and recovery of patients. Functional near-infrared spectroscopy (fNIRS) can be used to detect brain activity through changes of oxygenated hemoglobin/deoxygenated hemoglobin (HbO/HbR) concentrations changes and has recently gained increasing attention for its potential applications in assessing residual consciousness. However, the number of fNIRS studies assessing residual awareness in patients with pDoC is still limited. In this study, fNIRS was used to evaluate the brain function in 18 patients with pDoC, including 14 vegetative states (VS) and 4 minimally conscious states (MCS), and 15 healthy controls (HC). All participants accepted two types of external stimuli, i.e., active stimulation (motor imagery, MI) and passive stimulation (subject's own name, SON). The results showed that the mean concentrations of HbO/HbR in the prefrontal cortex of the HC during the passive stimulation were significantly lower than those of the active stimulation, and the fitting slope was high. However, the hemodynamic responses of the patients with pDoC were opposite to those of the HC. Additionally, the mean concentrations of HbO/HbR increased as the level of consciousness decreased during passive stimulation. Our findings suggest that the residual level of consciousness in pDoC patients can be assessed by measuring brain responses to different stimulations using fNIRS. The present study further demonstrates the feasibility and reliability of fNIRS in assessing residual consciousness in patients with pDoC, providing a basis for its expanded clinical application.

Evaluation and subgroup analysis of the efficacy and safety of intensive rosuvastatin therapy combined with dual antiplatelet therapy in patients with acute ischemic stroke.

OBJECTIVES: We investigated the efficacy of intensive rosuvastatin therapy plus 7-day dual antiplatelet therapy (DAPT) in reducing stroke recurrence for patients with acute ischemic stroke (AIS) and compared subgroups of patients. METHODS: We enrolled patients with AIS whose time of onset to medication was ≤ 72 h, and the baseline scores of NIHSS (bNIHSS) were 0-10. The patients received intensive rosuvastatin therapy plus 7-day DAPT with aspirin and clopidogrel (study group) or rosuvastatin plus single antiplatelet therapy (SAPT, control group). The primary outcomes were recurrence of ischemic stroke, bleeding, statin-induced liver injury, and statin-associated myopathy (SAM) within 90 days. We also performed a subgroup analysis to assess the heterogeneity of the two therapy regimens in reducing recurrent stroke. RESULTS: Recurrent stroke occurred in 10 patients in the study group and 42 patients in the control group (hazard ratio [HR], 0.373, 95% confidence interval [CI], 0.178-0.780; P = 0.009). Bleeding events occurred in 9 patients in the study group and 14 patients in the control group (HR, 1.019; 95%CI, 0.441-2.353; P = 0.966). Statin-induced liver injury and SAM were not recorded. Intensive rosuvastatin plus 7-day DAPT was generally effective in reducing the risk of recurrent stroke, except in the subgroup with bNIHSS ≤ 2. The therapy was particularly efficient in the elderly, male, high-bNIHSS, and hypertension, diabetes, and hyperlipidemia subgroups, with P < 0.02. CONCLUSIONS: Without increasing bleeding and statin-associated adverse events, intensive rosuvastatin therapy plus 7-day DAPT significantly reduced the risk of recurrent stroke, especially for subgroups with high-risk factors. CLINICAL TRIAL REGISTRATION: China Clinical Trial Registration Center (ChiCTR1800017809).

Efficacy and safety of low-dose rituximab as induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement: a Chinese case series.

BACKGROUND: Rituximab (RTX) is a standard therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the most frequently used dose may lead to severe adverse effects (SAEs). We explored the efficacy and safety of low-dose RTX in Chinese patients with AAV. METHODS: A total of 22 Chinese patients diagnosed with AAV with renal involvement, including 8 treated with low-dose RTX (400 mg of RTX total over 4 weeks) and 14 treated with cyclophosphamide (CYC), were evaluated. The baseline clinical and pathological data and laboratory parameters during follow-up at months 1, 3, 6, and 12 were collected retrospectively. RESULTS: The baseline data showed no significant differences between the two groups. The median peripheral CD19+ cell counts in the RTX group decreased from 315.0/µL to 1.5/µL at 2 weeks, and to 2.5/µL at 1 month after the first dose. The median SCr level decreased from 267.8 µmol/L before treatment to 151.45 µmol/L at 1 month, 132.75 µmol/L at 3 months, 123.2 µmol/L at 6 months, and 151.9 µmol/L at 12 months in RTX-treated patients. The improvements in renal function, proteinuria, and ANCA titre were not significantly different between the two groups. The SAE rate was significantly lower in the RTX group (one SAE of pneumonia) compared with the CYC group. CONCLUSIONS: This is the first report that low-dose RTX could be effective for the treatment of Chinese patients with AAV with renal involvement.

Application of preparative high-speed countercurrent chromatography for the separation and purification of three flavonoids from Oroxylum indicum.

An efficient method was established by high-speed countercurrent chromatography (HSCCC) for the separation and purification of three flavonoids from Oroxylum indicum. Optimized by single-factor and orthogonal experiments, the optimal extraction conditions were an extraction temperature of 50°C, a solid-to-liquid ratio of 1:50 (g/ml), an ethanol concentration of 75% and an extraction time of 45 min. Using a two-phase solvent system composed of chloroform-methanol-water (6:10:5, v/v/v), the preparative separation was successfully performed by HSCCC in head-to-tail elution mode. Totals of 12.63 mg of oroxin A at a purity of 97.61% with 96.46% recovery, 10.96 mg oroxin B at a purity of 98.32% with 98.81% recovery, and 9.34 mg baicalein at a purity of 98.64% with 97.87% recovery were obtained in one-step separation from 200 mg crude extract. Their chemical structures were confirmed by melting points, HPLC, UV, FTIR, MS, 1 H and 13 C NMR data. Furthermore, they were efficient scavengers of 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radicals in a concentration-dependent manner.

Clinical Study of Percutaneous Endoscopic Large-channel Fusion and Transforaminal Lumbar Interbody Fusion in the Treatment of Degenerative Lumbar Spinal Stenosis.

Context: Degenerative changes in the lumbar spine more commonly cause spinal stenosis and with the aging of society, its incidence is on the rise. Endoscopic spinal surgery is a minimally invasive technique for decompression. The efficacy of percutaneous, endoscopic, large-channel fusion and transforaminal lumbar interbody fusion (TLIF) need confirmation by more studies. Objective: The study intended to investigate the clinical efficacy of percutaneous endoscopic large-channel fusion and TLIF in the treatment of degenerative lumbar spinal stenosis, to find the best treatment plan. Design: The research team performed a retrospective study. Setting: The study took place at Nanjing Lishui People's Hospital in Nanjing, Jiangsu Province, PR China. Participants: Participants were 100 patients with degenerative, lumbar, spinal stenosis who had been admitted to the hospital between October 2018 and October 2022. Intervention: The research team randomly divided participants into an intervention group and a control group, with 50 participants in each group. The intervention group received percutaneous, endoscopic, large-channel fusion and internal fixation, and the control group received foraminal, lumbar, interbody fusion. Outcome Measures: The research team measured: (1) perioperative indexes, (2) clinical efficacy at a postoperative follow-up at 6 months postintervention, (3) indexes for inflammatory responses at baseline and postintervention, (4) postoperative pain at baseline and at months 3 and 6 postintervention using a visual analog scale (VAS), (6) lumbar function at baseline and months 3 and 6 postintervention using the Oswestry Disability Index (ODI) and the Japanese Orthopedic Association (JOA) scale, and (7) complications. Results: Compared with the control group, the intervention group's perioperatively related and inflammatory-response indexes were significantly better: (1) amount of bleeding- 112.67 ± 17.38 for the control group and 78.62 ± 10.52 for the intervention group (P = .002); (2) volume of drainage-79.63 ± 14.21 for the control group and 52.18 ± 8.21 for the intervention group (P = .001); (3) ESR at baseline and postintervention-22.41 ± 5.62 and 15.18 ± 5.26, respectively, for the control group and 22.58 ± 5.82 and 10.54 ± 3.18, respectively, for the intervention group, with P = .013 postintervention; and (4) CRP at baseline and postintervention-17.42 ± 3.52 and 13.98 ± 3.65 for the control group, respectively, and 18.65 ± 3.78 and 10.14 ± 2.78 for the intervention group, with P = .008 postintervention; Also, compared to the control group, the intervention group's: (1) total effective rate was significantly higher (P = .018); (2) incidence of postoperative complications was significantly lower (P = .006); (3) VAS pain score was significantly lower at months 3 and 6, with P = .028 and P = .021, respectively; (4) Oswestry Disability Index (ODI) function score was significantly lower at months 3 and 6, with P = .016 and P = .014, respectively; and (5) postoperative JOA function score was significantly higher at months 3 and 6, with P = .011 and P = .007, respectively. Conclusions: Both percutaneous, endoscopic, large-channel fusion and TLIF had good therapeutic effects in the treatment of degenerative lumbar spinal stenosis. However, compared with the latter, the former was more effective, with better comprehensive efficacy and more obvious benefits for patients, so it's worthy of clinical promotion and use.

A Printed Dipole Array with Bidirectional Endfire Radiation for Tunnel Communication.

Tunnel communication always suffers from path loss and multipath effects caused by surrounding walls. Meanwhile, the traditional leaky coaxial cables are expensive to deploy, inconvenient to operate, and difficult to maintain, leading to many problems in practical use. To solve the abovementioned problems, a low-profile printed dipole array operating at 3.5 GHz with bidirectional endfire radiation is designed based on the method of maximum power transmission efficiency (MMPTE). By setting two virtual test receiving dipoles at the two opposite endfire directions and then maximizing the power transmission efficiency between the printed dipole array to be designed and the test receiving antennas, the optimal amplitudes and phases for the array elements are obtained. Based on the optimal distributions of excitations, the simulation results show that the proposed eight-element printed dipole array can simultaneously generate two mirrored endfire beams towards opposite directions. Furthermore, the corresponding normalized cross-polarization levels are lower than -22.3 dBi both in the azimuth and elevation planes. The peak endfire gain is 10.7 dBi with maintenance of higher than 10 dBi from 3.23 GHz to 3.66 GHz, which is suitable for tunnel communication.

Functional metabolomics revealed functional metabolic-characteristics of chronic hepatitis that is significantly differentiated from acute hepatitis in mice.

Diagnosis and therapeutics of acute- and chronic- hepatitis (A-H and C-H) cannot be distinguished during clinical practice because functional molecular-characteristics of two conditions remains elusive. Here, we employed a functional metabolomics strategy to discover functional metabolites that can readily distinguish C-H from A-H in CCl4 treated mice. Metabolic-differentiation between A-H and C-H was identified as A-H was largely characterized by the dysregulated purine cycle and amino acid metabolism, while the disorders of hepatic taurine-conjugated bile acids and glycerolipid biosynthesis were observed with C-H. Excitingly, we found that the enhanced conversation of C18-22 PUFA-containing TAGs to MUFA-containing TAGs promoted the development of C-H, which was also closely associated with the changes of TCA intermediates regulated by gut microbiota (Muribaculaceae and Prevotellaceae). Such metabolic discovery on hepatitis was validated by the functional annotation of metabolic genes, as the decreased expressions of Slc27a2, Acaa1a and Acaa1b mostly account for the dysregulation of purine degradation with AH, then the lowered expressions of Cyp2e1, Cat, Slc27a5 and Klb are significantly related to the dysregulated bile acids with C-H. Collecting clinical samples from the patients with hepatitis to compare serum metabolomes with A-H and C-H mice, the determinant functional metabolites were identified to significantly distinguish C-H from A-H in both experimental and clinical settings, suggesting metabolic discovery with CCl4 treated mice could be further efficiently explored to guide clinical research of A-H and C-H. Collectively, our study is providing novel insight into distinctive metabolic-characteristics of A-H and C-H underlying the innovative diagnosis and therapeutics of hepatitis.

Emerging pharmacotherapy for inflammatory bowel diseases.

Inflammatory bowel disease (IBD) refers to a gamut of disorders that are characterized by chronic intestinal inflammation, including ulcerative colitis (UC) and Crohn's disease (CD), which often leads to mucosal ulceration and progressive loss of intestinal function. The etiopathogenesis of IBD has not been completely clarified, although multiple factors involving genetic modifications, host immune dysfunction, intestinal dysbiosis and environmental effects have been implicated. Currently, pharmacotherapies including both non-targeted and targeted biological agents are widely used for the clinical treatment of IBD. In addition, novel therapeutic approaches that target the intestinal microorganisms, such as fecal microbiota transplantation, antibiotics, probiotics and microbial metabolite inhibitors, are also under development. However, these treatments are either accompanied by side effects or cannot achieve complete clinical remission when used alone. The efficacy and safety of drugs are currently a clinical challenge. Thus, advanced drug delivery systems are needed for targeted delivery of drugs to the inflammatory sites and avoid absorption by healthy tissues. In this review, we have summarized the latest research on the pathogenesis of IBD and the emerging pharmacotherapies, and discussed potential therapeutic targets for innovative therapies.

Percutaneous intravenous catheter forceps biopsy in right atrial mass: two case reports and literature review.

BACKGROUND: Primary malignant tumors of the heart are rare. Although preoperative histological diagnosis is difficult, it has paramount value in therapeutic strategy development and prognostic estimation. Herein, we reported 2 cases of intracardiac tumors. CASES PRESENTATION: Both patients presented to the hospital with heart-related symptoms. Echocardiography showed massive masses in the atrium and positron emission tomography-computed tomography (PET/CT) revealed hypermetabolism and invasiveness. One patient cannot take surgery due to extensive metastasis and poor condition. The other patient was primarily diagnosed with lymphoma, and surgery was not recommended. They successfully underwent intravenous atrial biopsy, and histological samples confirmed intimal sarcoma and diffuse large B cell lymphoma. Based on immunohistochemical and molecular assessments, targeted chemotherapy was administered, resulting in clinical and imaging remission at discharge. CONCLUSIONS: Percutaneous intravenous catheter biopsy as a safe invasive test provides an accurate pathological diagnosis after imaging evaluation, and offers a therapeutic direction. Nonmalignant masses and some chemo-radiosensitive malignant tumors in the atrium could have good prognosis after targeted therapy.

Electrically supported mediator Co(II)-activated peroxydisulfate synergistic process for organic contaminants elimination.

Among homogeneous catalysts, cobalt ions exhibit ultra-high persulfate activation performance. In this work, an electrically supported medium Co(II) activated peroxydisulfate synergistic process was established to eliminate organic contaminants in water. The synergistic catalytic effect was verified by comparing the oxidative degradation performance and reaction rate constant of different coupling systems. The decolorization ability of E-Co(II)-PDS on reactive black 5 (RB5) was explored, and the results showed that the removal rate of RB5 can reach 93.21% under the optimized conditions of current density of 5.71 mA/cm2, initial pH of 4, Co(II) concentration of 0.2 mM and PDS concentration of 5 mM. The effect of water matrix on the removal of RB5 was studied, and it was found that HCO3- and humic acid significantly inhibited the degradation of RB5, while Cl- and H2PO4- could effectively promote it at a certain concentration. Notably, the degradation of RB5 in E-Co(II)-PDS system achieved lower energy consumption, with an energy consumption per unit volume (EE/O) value of 0.4304 kWh·m-3. EPR test, quenching experiments and contribution rate analysis showed that the oxidation active species in E-Co(II)-PDS process were Co(III), sulfate radicals and hydroxyl radicals, and their oxidation contribution rates were 15.72%, 12.69% and 53.25%, respectively. Finally, the decomposition process of RB5 was proposed by the mass spectrometry results. The electric current promotes cobalt ion cycling and PDS activation through electron transfer, and induces Co(II) to promote the activation of PDS, which is the main mechanism of E-Co(II)-PDS system to achieve the robust degradation ability of RB5.

Prevalence and associated factors of frailty and sarcopenia in multiple system atrophy and progressive supranuclear palsy: a cross-sectional study.

OBJECTIVE: To investigate the prevalence of, and clinicodemographic factors associated with, frailty and sarcopenia in patients with multiple system atrophy or progressive supranuclear palsy. METHODS: A total of 264 participants were recruited in this study. Demographic and clinical data were collected through structured interviews. Frailty was assessed with the clinical frailty scale (CFS), and sarcopenia was assessed with the simple five-item scoring questionnaire (SARC-F). RESULTS: The prevalence of frailty and sarcopenia was 48.57% and 35.71% in multiple system atrophy, and 51.09% and 39.13% in progressive supranuclear palsy. Multiple system atrophy patients with frailty or sarcopenia were more likely to be female and have longer disease duration, greater motor impairment, greater non-motor burden, and lower life quality. In multiple system atrophy, frailty was associated with reduced motor function and sarcopenia was associated with female sex, reduced motor function, and orthostatic hypotension. Progressive supranuclear palsy patients with frailty or sarcopenia had more severe motor impairment and non-motor burden, longer disease duration, and lower life quality. In progressive supranuclear palsy, frailty was associated with mentation and gait/midline symptoms, while sarcopenia was associated with reduced daily activity and severe gait/midline symptoms. CONCLUSION: Frailty and sarcopenia may be more common among patients with multiple system atrophy or progressive supranuclear palsy than among the general population, and they are associated with more severe forms of the two diseases. Prospective studies are necessary to clarify causal relationships between frailty/sarcopenia and clinical manifestations of multiple system atrophy and progressive supranuclear palsy.

Robust operation of distribution network based on photovoltaic/wind energy resources in condition of COVID-19 pandemic considering deterministic and probabilistic approaches.

In this paper, optimal allocation and planning of wind and photovoltaic energy resources are performed in a distribution network with the objective of reducing losses, improving reliability, and minimizing energy generation cost in terms of changes in load consumption pattern during the COVID-19 pandemic condition. The main goal is identifying the best operating point, ie the optimal location and size of clean energy resources in the worst load change conditions, which ensures the best network operation in all conditions during the COVID-19 condition via the turbulent flow of water-based optimization (TFWO). First, the deterministic approach is implemented in Hybrid and Distributed cases before and during COVID-19 conditions. The probabilistic approach is performed considering generation uncertainty during the COVID-19 conditions. The results showed better performance in the Distributed case with the lowest losses and higher reliability improvement. Moreover, the losses are significantly reduced and the reliability is improved during the COVID-19 pandemic conditions. The findings indicate that the allocation and planning during the COVID-19 conditions is a robust option in network operating point changes. Also, the probabilistic results showed that considering the uncertainty has increased active and reactive losses (4.67% and 5.82%) and weakened the reliability (10.26%) of the deterministic approach.

Visualization of Thrombus Enhancement on Thin-Slab Maximum Intensity Projection of CT Angiography: An Imaging Sign for Predicting Stroke Source and Thrombus Compositions.

Background Thrombus enhancement (TE) in large vessel occlusion in patients with acute ischemic stroke can be visualized with thin-slab maximum intensity projection (TS-MIP) image reconstruction of CT angiograms. Purpose To evaluate whether TE on TS-MIP reconstructed CT angiograms can be used to predict thrombus composition and stroke source. Materials and Methods This retrospective study included consecutive patients with acute ischemic stroke who underwent thrombectomy in the anterior circulation between August 2016 and July 2019. Stroke types were classified according to the Trial of ORG 10172 in Acute Stroke Treatment. TE on TS-MIP reconstructed CT angiograms was evaluated by two readers. Various clinical and interventional parameters and histopathologic thrombi examination results were compared between the TE-positive and TE-negative groups. The associations between TE and thrombus compositions and stroke sources were analyzed by using multivariable linear and logistic regression models. Results A total of 148 patients (mean age, 71 years ± 11 [standard deviation]; 94 men) were included. TE was confirmed in 80% (119 of 148) of the patients. TE-positive thrombi contained a higher fibrin and platelet proportion (mean, 46% ± 16 vs 34% ± 13; P = .02) and fewer erythrocytes (mean, 33% ± 14 vs 48% ± 20, P = .002) than the TE-negative thrombi. The proportion of cardioembolic and cryptogenic strokes in the TE-positive and TE-negative groups was 92% (110 of 119) and 24% (seven of 29), respectively (P < .001). In adjusted analysis, the presence of TE (odds ratio, 155; 95% CI: 17, 1438; P < .001) was associated with a combination of cardioembolic and cryptogenic strokes. A multiple logistic regression model showed that TE (odds ratio, 23; 95% CI: 1.8, 288; P = .02) was significantly associated with cardioembolic stroke. Conclusion Thrombus enhancement on thin-slab maximum intensity projection of CT angiography can be used to predict cardioembolic and cryptogenic strokes and identify thrombi with a higher fibrin-to-platelet fraction and a lower erythrocyte proportion. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kansagra and Goyal in this issue.