High Areal Capacity, Long Cycle Life Li-Air Batteries Enabled by Nano/Micro Hierarchical Porous Cathode.

The limited cycle life of Li-air batteries (LABs) with high areal capacity remains the chief challenge that hinders their practical applications. Here, the study proposes a hierarchical porous electrode (HPE) design strategy, in which porous MnO nanoflowers are built into mesopore/macropore electrodes through a combination of chemical dealloying and physical de-templating procedures. The MnO nanoflowers with 10-30 nm pore provides active sites to catalyze the O2 reduction and decomposition of discharged products. The 5-10 µm macroscopic pores in the cathode serve as channels of O2 transportation and facilitate the electrolyte permeation. The proposed HPE exhibits a full discharge capacity of 17.49 mAh cm-2 and stable cycle life >2000 h with a limited capacity of 6 mAh cm-2 . These results suggest that the HPE design strategy for LABs can simultaneously provide large capacity and robust cycle life, which is promising for advanced metal-air batteries.

DeepLensNet: Deep Learning Automated Diagnosis and Quantitative Classification of Cataract Type and Severity.

PURPOSE: To develop deep learning models to perform automated diagnosis and quantitative classification of age-related cataract from anterior segment photographs. DESIGN: DeepLensNet was trained by applying deep learning models to the Age-Related Eye Disease Study (AREDS) dataset. PARTICIPANTS: A total of 18 999 photographs (6333 triplets) from longitudinal follow-up of 1137 eyes (576 AREDS participants). METHODS: Deep learning models were trained to detect and quantify nuclear sclerosis (NS; scale 0.9-7.1) from 45-degree slit-lamp photographs and cortical lens opacity (CLO; scale 0%-100%) and posterior subcapsular cataract (PSC; scale 0%-100%) from retroillumination photographs. DeepLensNet performance was compared with that of 14 ophthalmologists and 24 medical students. MAIN OUTCOME MEASURES: Mean squared error (MSE). RESULTS: On the full test set, mean MSE for DeepLensNet was 0.23 (standard deviation [SD], 0.01) for NS, 13.1 (SD, 1.6) for CLO, and 16.6 (SD, 2.4) for PSC. On a subset of the test set (substantially enriched for positive cases of CLO and PSC), for NS, mean MSE for DeepLensNet was 0.23 (SD, 0.02), compared with 0.98 (SD, 0.24; P = 0.000001) for the ophthalmologists and 1.24 (SD, 0.34; P = 0.000005) for the medical students. For CLO, mean MSE was 53.5 (SD, 14.8), compared with 134.9 (SD, 89.9; P = 0.003) for the ophthalmologists and 433.6 (SD, 962.1; P = 0.0007) for the medical students. For PSC, mean MSE was 171.9 (SD, 38.9), compared with 176.8 (SD, 98.0; P = 0.67) for the ophthalmologists and 398.2 (SD, 645.4; P = 0.18) for the medical students. In external validation on the Singapore Malay Eye Study (sampled to reflect the cataract severity distribution in AREDS), the MSE for DeepSeeNet was 1.27 for NS and 25.5 for PSC. CONCLUSIONS: DeepLensNet performed automated and quantitative classification of cataract severity for all 3 types of age-related cataract. For the 2 most common types (NS and CLO), the accuracy was significantly superior to that of ophthalmologists; for the least common type (PSC), it was similar. DeepLensNet may have wide potential applications in both clinical and research domains. In the future, such approaches may increase the accessibility of cataract assessment globally. The code and models are available at https://github.com/ncbi/deeplensnet.

Analgesic effect of ultrasound-guided erector spinae plane block (espb) in general anesthesia for cesarean section: a randomized controlled trial.

BACKGROUND: The analgesic effects of erector spinae plane block in general anesthesia for cesarean section and recovery from puerperae remain unclear. METHODS: Sixty patients with contraindications for spinal anesthesia who required general anesthesia for cesarean section were enrolled and randomly divided into the erector spinal plane block (ESPB) combined with the general anesthesia group (group E) and general anesthesia group (group G). Group E received bilateral ESPB (20 ml of 0.25% ropivacaine on each side) under ultrasound guidance 30 min before general anesthesia. The primary outcomes were the number of patient-controlled intravenous analgesia (PCIA) boluses, and Bruggemann comfort scale (BCS) scores at 2 h, 6 h, 12 h, and 24 h after operation. The second outcome was intraoperative anesthesia dosage, fetal delivery time, puerperae emergence time, visual analog scale (VAS) at 2 h, 6 h, 12 h, and 24 h after operation, and incidence of nausea and vomiting. Heart rate (HR) and mean arterial pressure (MAP) were recorded 10 min before the start of anesthesia (T0), at the induction of anesthesia (T1), at skin incision (T2), and fetal delivery (T3), and immediately after surgery (T4). RESULTS: The number of PCIA boluses was lower in group E than in group G (P < 0.001). The BCS score increased at 2 h and 6 h after the operation in group E (P < 0.05), while the VAS score significantly decreased in group E at the same time (P < 0.05). Compared with group G, the doses of propofol and remifentanil were significantly decreased in group E (P < 0.001), the emergence time of puerperae was shortened (P = 0.003), and the incidence of nausea and vomiting was significantly decreased (P = 0.014). CONCLUSION: Ultrasound-guided ESPB applied to general anesthesia for a cesarean section can significantly reduce the required dose of general anesthetic drugs, shorten the recovery time of the puerperae, and improve postoperative analgesia. TRIAL REGISTRATION: www. CLINICALTRIALS: gov under the number ChiCTR2200056337 (04-02-2022).

STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

AIMS: Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-ß) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. CONCLUSION: Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

Deep learning-based natural language processing in ophthalmology: applications, challenges and future directions.

PURPOSE OF REVIEW: Artificial intelligence (AI) is the fourth industrial revolution in mankind's history. Natural language processing (NLP) is a type of AI that transforms human language, to one that computers can interpret and process. NLP is still in the formative stages of development in healthcare, with promising applications and potential challenges in its applications. This review provides an overview of AI-based NLP, its applications in healthcare and ophthalmology, next-generation use case, as well as potential challenges in deployment. RECENT FINDINGS: The integration of AI-based NLP systems into existing clinical care shows considerable promise in disease screening, risk stratification, and treatment monitoring, amongst others. Stakeholder collaboration, greater public acceptance, and advancing technologies will continue to shape the NLP landscape in healthcare and ophthalmology. SUMMARY: Healthcare has always endeavored to be patient centric and personalized. For AI-based NLP systems to become an eventual reality in larger-scale applications, it is pertinent for key stakeholders to collaborate and address potential challenges in application. Ultimately, these would enable more equitable and generalizable use of NLP systems for the betterment of healthcare and society.

Ferrous hemoglobin and hemoglobin-based oxygen carriers acting as a peroxidase can inhibit oxidative damage to endothelial cells caused by hydrogen peroxide.

Oxidative damage caused by the ferryl hemoglobin is one of the major clinical adverse reactions of hemoglobin-based oxygen carriers (HBOCs), while the production of reactive oxygen species in a pathological state can oxidize hemoglobin (HbFe2+ ) to ferryl Hb, which can then enter the pseudoperoxidase cycle, making hemoglobin highly toxic. In this study, we found that ferrous hemoglobin and polymerized porcine hemoglobin (one of the HBOCs) have the peroxidase activity different from the pseudoperoxidase activity of ferric hemoglobin. Ferrous hemoglobin can catalyze the reaction of tyrosine (Tyr) with hydrogen peroxide. In addition, the results also indicated that ferrous hemoglobin and pPolyHb have a strong inhibitory effect on the pseudoperoxidase activity of ferric hemoglobin. Therefore, hydrogen peroxide was consumed in a large amount, which greatly prevented hemoglobin from becoming oxidized and entering the pseudoperoxidase cycle, thus inhibiting ferryl Hb toxicity. We further cultured human umbilical vein endothelial cells and monitored cell morphology, viability, cell cycle, apoptosis, lactate dehydrogenase (LDH) release, and malondialdehydes (MDAs) formation when incubated with H2 O2 , Tyr, and HbFe2+ . HbFe2+ and pPolyHb reduced cell cycle arrest, apoptosis, LDH release, and MDA formation. These results showed that reducing oxidative damage induced by H2 O2 and converted hemoglobin from a molecule that is toxic to one that inhibits oxidative damage, suggesting a new strategy for development of a safer HBOCs.

Flexible Lithium-Air Battery in Ambient Air with an In†Situ Formed Gel Electrolyte.

Flexible Li-air batteries (LABs) have been considered as promising power sources for wearable electronics owing to its higher energy density. However, when operated in ambient air, problems arise, such as Li anode passivation, poor cycle life as well as leakage of liquid electrolyte. Herein, we present a LAB with a tetraethylene glycol dimethyl ether (TEGDME, G4) gel electrolyte, in which the gel is formed in situ through a cross-linking reaction between the liquid G4 and the lithium ethylenediamine (LiEDA) grown on the surface of Li anode. We demonstrate that the gel can efficiently alleviate the corrosion of the Li anode, and thus the LAB shows a cycle performance over 1175 hours (humidity: 10 % to 40 %), which is much superior to previous reports. Furthermore, the in situ formed gel enhances the electrode/electrolyte interfacial contact, which thus enables the cable-type LAB to exhibit a great flexibility.

Ankyrin exposure induced by activated protein kinase C plays a potential role in erythrophagocytosis.

BACKGROUND: In physiological and pathological conditions activated protein kinace C (PKC) has been observed in the erythrocytes. Externalization of ankyrin followed by Arg-Gly-Asp (RGD)/integrin recognition also triggers erythrophagocytosis. In the present study, to test whether activated PKC is associated with ankyrin exposure in erythrophagocytosis. METHODS: Phorbol 12-myristate-13-acetate (PMA)-induced PKC activation and ankyrin phosphorylation were tested, and under different treatment conditions the subpopulation of erythrocytes with ankyrin exposure and the levels of intracellular calcium were analyzed by flow cytometry. RESULTS: Results showed that treatment of erythrocytes with PMA in a calcium-containing buffer led to ankyrin exposure. In the absence of extracellular calcium, no ankyrin exposure was observed. PKC inhibition with calphostin C, a blocker of the PMA binding site, completely prevented the calcium entry, protein phosphorylation and ankyrin exposure. PKC inhibition with chelerythrine chloride, an inhibitor of the active site, diminished the level of ankyrin-exposing cells and ankyrin phosphorylation; however it even led to a higher percentage of cells with increased levels of calcium than with PMA treatment alone. Although PKC was activated and ankyrin phosphorylation occurred, no ankyrin exposure was observed in the absence of extracellular calcium. CONCLUSION: Analyses of results suggested that PMA induces calcium influx into the erythrocytes, leading to the activation of calcium-dependent enzymes and the phosphorylation of membrane proteins, ultimately inducing ankyrin exposure and erythrophagocytosis. This study may provide insights into the molecular mechanisms of removing aged or diseased erythrocytes.

Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells.

RATIONALE: Janus kinase/signal transducer and activator of transcription (JAK/STAT) signals and their endogenous inhibitor, suppressor of cytokine signaling 3 (SOCS3), in vascular endothelial cells (ECs) reportedly dominate the pathological angiogenesis. However, how these inflammatory signals are potentiated during pathological angiogenesis has not been fully elucidated. We suspected that an intracellular protease calpain, which composes the multifunctional proteolytic systems together with its endogenous inhibitor calpastatin (CAST), contributes to the JAK/STAT regulations. OBJECTIVE: To specify the effect of EC calpain/CAST systems on JAK/STAT signals and their relationship with pathological angiogenesis. METHODS AND RESULTS: The loss of CAST, which is ensured by several growth factor classes, was detectable in neovessels in murine allograft tumors, some human malignant tissues, and oxygen-induced retinopathy lesions in mice. EC-specific transgenic introduction of CAST caused downregulation of JAK/STAT signals, upregulation of SOCS3 expression, and depletion of vascular endothelial growth factor (VEGF)-C, thereby counteracting unstable pathological neovessels and disease progression in tumors and oxygen-induced retinopathy lesions in mice. Neutralizing antibody against VEGF-C ameliorated pathological angiogenesis in oxygen-induced retinopathy lesions. Small interfering RNA-based silencing of endogenous CAST in cultured ECs facilitated µ-calpain-induced proteolytic degradation of SOCS3, leading to VEGF-C production through amplified interleukin-6-driven STAT3 signals. Interleukin-6-induced angiogenic tube formation in cultured ECs was accelerated by CAST silencing, which is suppressible by pharmacological inhibition of JAK/STAT signals, antibody-based blockage of VEGF-C, and transfection of calpain-resistant SOCS3, whereas transfection of wild-type SOCS3 exhibited modest angiostatic effects. CONCLUSIONS: Loss of CAST in angiogenic ECs facilitates µ-calpain-induced SOCS3 degradation, which amplifies pathological angiogenesis through interleukin-6/STAT3/VEGF-C axis.

Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice.

BACKGROUND & AIM: Hydrogen peroxide-inducible clone-5 (Hic-5), also named as transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was found to be induced by TGF-ß. Previous studies have shown that TGF-ß is a principal mediator of hepatic stellate cell (HSC) activation in liver fibrosis. However, this process remains elusive. In this study, we aimed to define the role of Hic-5 in HSC activation and liver fibrosis. METHODS: We examined the expression levels of Hic-5 during HSCs activation and in fibrotic liver tissues by quantitative real-time reverse transcriptase polymerase chain reaction, Western blot and immunohistochemistry. Hic-5 knockout (KO) and wild-type (WT) mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) injection to induce liver fibrosis. RESULTS: Hic-5 expression was strongly upregulated in activated HSCs of the human fibrotic liver tissue and BDL or CCl4-induced mouse liver fibrosis. Hic-5 deficiency significantly attenuated mouse liver fibrosis and HSC activation. Furthermore, Hic-5 knockdown by siRNA in vivo repressed CCl4-induced liver fibrosis in mice. Mechanistically, the absence of Hic-5 significantly inhibited the TGF-ß/Smad2 signaling pathway, proved by increasing Smad7 expression, resulting in reduced collagen production and α-smooth muscle actin expression in the activated HSCs. CONCLUSION: Hic-5 deficiency attenuates the activation of HSCs and liver fibrosis though reducing the TGF-ß/Smad2 signaling by upregulation of Smad7. Thus, Hic-5 can be regarded as a potential therapeutic target for liver fibrosis.

NADPH oxidase deficiency exacerbates angiotensin II-induced abdominal aortic aneurysms in mice.

OBJECTIVE: Although nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) is reportedly essential for phagocyte host defenses, it has been found to aggravate atherosclerosis in apolipoprotein E (Apoe)-null mice through excess production of superoxide. We therefore assessed the role of NOX2 in an experimental model of abdominal aortic aneurysm (AAA) and assessed the mechanism of NOX2 action in AAA. APPROACH AND RESULTS: AAA was induced in low-density lipoprotein receptor-null (Ldlr(-/-)) mice by infusing angiotensin II. Nox2 expression was elevated in the abdominal aortae of these mice during infusion of angiotensin II, with enhanced Nox2 expression mainly because of the recruitment of NOX2-enriched macrophages into AAA lesions. Unexpectedly, systemic Nox2 deficiency promoted AAA development but reduced the level of reactive oxygen species in AAA lesions. Nox2 deficiency stimulated macrophage conversion toward the M1 subset, enhancing expression of interleukin (IL)-1ß and matrix metalloproteinase-9/12 mRNA. Administration of neutralizing antibody against IL-1ß abolished AAA development in Nox2-deficient mice. Bone marrow transplantation experiments revealed that AAA aggravation by Nox2 deficiency is because of bone marrow-derived cells. Isolated bone marrow-derived macrophages from Nox2-null mice could not generate reactive oxygen species. In contrast, IL-1ß expression in peritoneal and bone marrow-derived macrophages, but not in peritoneal neutrophils, was substantially enhanced by Nox2 deficiency. Pharmacological inhibition of Janus kinase/signal transducers and activators of transcription signaling inhibited excess IL-1ß expression in Nox2-deficient macrophages, whereas matrix metalloproteinase-9 secretion was constitutively stimulated via nuclear factor-κB signals. CONCLUSIONS: Nox2 deficiency enhances macrophage secretion of IL-1ß and matrix metalloproteinase-9, disrupting tissue-remodeling functions in AAA lesions. These actions are unfavorable if NOX2 is to serve as a molecular target for AAA.

Favorable efficacy of S-1 treatment for locoregionally advanced cutaneous squamous cell carcinoma in the head and neck region.

Cutaneous squamous cell carcinoma is usually treated with surgery; however, locoregionally advanced cutaneous squamous cell carcinoma can be difficult to resect. Although recent guidelines from Western countries recommend using anti-programmed cell death protein 1 (PD-1) antibodies, including cemiplimab and pembrolizumab, there are no approved anti-PD-1 antibodies for locoregional cutaneous squamous cell carcinoma in Asian countries. S-1 is an oral drug with a low incidence of severe toxicity that can be used for head and neck cancers, including head and neck locoregional cutaneous squamous cell carcinoma, in Japan. We retrospectively evaluated patients with head and neck locoregional cutaneous squamous cell carcinoma treated with S-1 at two Japanese institutions (2008-2022). The initial dosage was determined by the body surface area (<1.25 m2 : 80 mg/day, 1.25-1.5 m2 : 100 mg/day, ≥1.5 m2: 120 mg/day) for 28 consecutive days. The outcome measures were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Fourteen patients were included. The ORR was 78%, and the complete response (CR) rate was 64.3%. The median PFS and OS were not reached (NR) (95% confidence interval [CI], 5.9 months-NR) and NR (95% CI, 13.8 months-NR), respectively. The 12-month PFS and OS rates were 51% and 85%, respectively. Six of the nine patients who achieved CR showed no recurrence during the follow-up period (median follow-up, 24.7 months). After CR, three patients experienced recurrence. Among these, two resumed S-1 treatment and subsequently underwent salvage surgery, resulting in a sustained absence of recurrence. One patient developed lung metastasis and died, although S-1 therapy was resumed. Only one patient (7.1%) developed grade 3 anemia. S-1 showed favorable efficacy and low toxicity in patients with head and neck locoregionally advanced cutaneous squamous cell carcinoma. S-1 may be a good alternative to the anti-PD-1 antibody for treating head and neck locoregionally advanced squamous cell carcinoma.

Anesthetic management of fetal pulmonary valvuloplasty: A case report.

Anesthesia management of fetal pulmonary valvuloplasty (FPV) is difficult, requiring careful consideration of both the mother and the fetus. Few reports have been published on specific anesthesia implementation and intraoperative management. We report the case of a pregnant woman who was treated with FPV under combined spinal epidural anesthesia (CSEA) with dexmedetomidine in the second trimester of pregnancy. Meanwhile, the application of fetal anesthesia through the umbilical vein was optimal. During the operation, the vital signs of the pregnant woman were stable with no complications and the fetal bradycardia was corrected by intracardiac injection of epinephrine. Four months postoperatively, a boy was born alive by full-term transvaginal delivery. CSEA may be a suitable anesthesia method for FPV surgery. Nevertheless, maternal hemodynamic stability maintenance, effective fetal anesthesia, and timely fetal resuscitation were necessary.

Remifentanil at a Relatively Elevated Dose in Active Phase is Safe and More Suitable Than Fixed Lower Dose for Intravenous Labor Analgesia.

Background: Intravenous labor analgesia is recommended as an alternative for parturients who have contraindications to epidural analgesia. There are several opioid analgesics and different administering regimens used in the clinic. This study aimed to compare the effectiveness and safety of two intravenous remifentanil dosage regimens in the first labor stage. Patients and Methods: One hundred and fifteen parturients with a contraindication to epidural analgesia but were willing to receive systemic labor analgesia were randomized into group A received a fixed dose of remifentanil throughout the first stage of labor, and group B received an elevated dose of remifentanil during the active phase of the first stage both by patient-controlled analgesia (PCA). Maternal numerical rating scale (NRS) pain score and oxygen desaturation, sedation efficacy, satisfaction, as well as maternal and fetal adverse reactions were recorded and compared. Results: The mean NRS pain scores before analgesia and in the latent phase showed no statistically significant difference between the two groups (P > 0.05). However, during the active phase, group B demonstrated significantly lower mean NRS pain scores and lowest pain score compared to group A (P < 0.05). Furthermore, group B exhibited higher overall sedation scores and satisfaction scores in comparison to group A (P < 0.05). The incidence of adverse reactions between the two groups was similar (P > 0.05). Conclusion: Relatively elevated intravenous dosage of remifentanil with PCA during the active phase in the first stage of labor is safe and more effective than a fixed-dosage regimen for labor analgesia. Trial Registration: This study was registered with ChiCTR on 24/08/2021 with trial identification number: ChiCTR2100050247. First participant was recruited on 31/08/2021. The last patient was recruited on 12/08/2022.

Prolonged Anesthesia Induction to Delivery Time Did Not Influence Plasma Remifentanil Concentration in Neonates.

Objective: Remifentanil, in combination with etomidate and sevoflurane, is commonly used in clinics for general anesthesia induction in cesarean section (CS). This study aimed to evaluate the correlation between the induction to delivery (I-D) time and neonatal plasma drug concentration and anesthesia, as well as its effects on neonates. Methods: Fifty-two parturients in whom general anesthesia was induced for CS were divided into group A (I-D<8 min) and group B (I-D≥8 min). Maternal arterial (MA), umbilical venous (UV), and umbilical arterial (UA) blood samples were collected at delivery to analyze the remifentanil and etomidate concentrations using liquid chromatography-tandem mass spectrometry. Results: There were no statistically significant differences between the two groups in terms of plasma concentrations of remifentanil in the MA, UA, and UV blood (P > 0.05). The plasma concentration of etomidate in MA and UV was higher in group A than that in group B (P<0.05), whereas the UA/UV ratio of etomidate was higher in group B than that in group A (P<0.05). The Spearman rank correlation test showed no correlation between the I-D time and plasma remifentanil concentration in the MA, UA, and UV plasma (P>0.05). The concentrations of etomidate in the MA and UV were negatively correlated with the I-D time (P < 0.05). Conclusion: Prolonged I-D time did not significantly influence the maternal or neonatal plasma concentration of remifentanil. It is safe to administer remifentanil target-controlled infusion in combination with etomidate and sevoflurane for general anesthesia induction during CS.

Knockdown of mechanosensitive adaptor Hic-5 ameliorates post-traumatic osteoarthritis in rats through repression of MMP-13.

Osteoarthritis (OA) is the most common joint disease associated with articular cartilage destruction. Matrix metalloproteinase-13 (MMP-13) has an essential role in OA pathogenesis by degradation of collagen II, a major component of articular cartilage. Hydrogen peroxide-inducible clone-5 (Hic-5; TGFB1I1), a transforming growth factor-ß-inducible mechanosensor, has previously been reported to promote OA pathogenesis by upregulating MMP-13 expression in mouse osteoarthritic lesions. In our current study, immunohistochemical analysis showed that Hic-5 protein expression was increased in human OA cartilage compared with normal cartilage. Functional experiments demonstrated that Hic-5 and MMP-13 expression was increased by mechanical stress, and mechanical stress-induced MMP-13 expression was suppressed by Hic-5 siRNA in human chondrocytes. Moreover, intracellular localization of Hic-5 shifted to the nucleus from focal adhesions in human chondrocytes subjected to mechanical stress, and nuclear Hic-5 increased MMP-13 gene expression. In vivo, intra-articular injection of Hic-5 siRNA decreased the Osteoarthritis Research Society International score and MMP-13 protein expression in articular cartilage of OA rats. Our findings suggest that Hic-5 regulates transcription of MMP-13 in human chondrocytes, and Hic-5 may be a novel therapeutic target for OA because OA progression was suppressed by intra-articular injection of Hic-5 siRNA in rats.

Anesthetic drug concentrations and placental transfer rate in fetus between term and preterm infants, twins, and singletons.

Objective: This study aims to determine the drug concentration of etomidate, remifentanil, and rocuronium bromide for general anesthesia in fetus as well as the placental transport rate between term and preterm delivery, twins, and singleton. Study design: Sixty parturients with 72 fetuses undergoing cesarean section under general anesthesia were included. According to whether the fetus was a twin or premature, parturients were divided into Group I (term singleton), Group II (premature singleton), Group III (term twins), and Group IV (premature twins). The preoperative demographic characteristics and laboratory examination of parturients, hemodynamic indicators, the Apgar score of neonates at 1, 5, and 10 min after delivery and at specific assigned values, umbilical artery blood gas analysis results, neonatal weight, and resuscitative measures were recorded. Anesthetic drug concentrations in maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood were detected by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). Result: No significant differences were observed in the concentrations of etomidate, remifentanil, and rocuronium bromide in MA, UV, and UA blood, or in the UV/MA and UA/UV ratios between term and preterm infants, twins, and singletons. Moreover, there was no variation in the anesthetic drug concentration among each pair of twins. Additionally, no correlation was found between the neonatal weight and the plasma concentrations of anesthetic drugs in UV and UA blood, except for remifentanil in UA blood. Conclusion: Preterm or twin deliveries do not affect the neonatal concentration of etomidate, remifentanil, and rocuronium bromide used in general anesthesia for cesarean sections. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2100046547.

Contrastive domain adaptation with consistency match for automated pneumonia diagnosis.

Pneumonia can be difficult to diagnose since its symptoms are too variable, and the radiographic signs are often very similar to those seen in other illnesses such as a cold or influenza. Deep neural networks have shown promising performance in automated pneumonia diagnosis using chest X-ray radiography, allowing mass screening and early intervention to reduce the severe cases and death toll. However, they usually require many well-labelled chest X-ray images for training to achieve high diagnostic accuracy. To reduce the need for training data and annotation resources, we propose a novel method called Contrastive Domain Adaptation with Consistency Match (CDACM). It transfers the knowledge from different but relevant datasets to the unlabelled small-size target dataset and improves the semantic quality of the learnt representations. Specifically, we design a conditional domain adversarial network to exploit discriminative information conveyed in the predictions to mitigate the domain gap between the source and target datasets. Furthermore, due to the small scale of the target dataset, we construct a feature cloud for each target sample and leverage contrastive learning to extract more discriminative features. Lastly, we propose adaptive feature cloud expansion to push the decision boundary to a low-density area. Unlike most existing transfer learning methods that aim only to mitigate the domain gap, our method instead simultaneously considers the domain gap and the data deficiency problem of the target dataset. The conditional domain adaptation and the feature cloud generation of our method are learning jointly to extract discriminative features in an end-to-end manner. Besides, the adaptive feature cloud expansion improves the model's generalisation ability in the target domain. Extensive experiments on pneumonia and COVID-19 diagnosis tasks demonstrate that our method outperforms several state-of-the-art unsupervised domain adaptation approaches, which verifies the effectiveness of CDACM for automated pneumonia diagnosis using chest X-ray imaging.

Innate Immune System Regulated by Stimulator of Interferon Genes, a Cytosolic DNA Sensor, Regulates Endothelial Function.

Background Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin-induced diabetic mice. Methods and Results Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild-type mice. Streptozotocin elevated blood glucose and lipid levels in both wild-type and STING-deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (P<0.001) and increased endothelial nitric oxide synthase phosphorylation in the aorta (P<0.05) in STZ-injected mice. Endothelium-independent vascular response to sodium nitroprusside did not differ. Treatment with a direct STING agonist, cyclic GMP-AMP, or mitochondrial DNA increased inflammatory molecule expression (eg, VCAM1 and IFNB) and decreased endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells, partially through the STING pathway. Cyclic GMP-AMP significantly impaired endothelial function of aortic segments obtained from wild-type mice, which was ameliorated in the presence of C-176, a STING inhibitor, or a neutralizing interferon-ß antibody. Furthermore, the administration of C-176 ameliorated endothelial dysfunction in STZ-induced diabetic mice (P<0.01). Conclusions The DNA damage response regulated by STING impairs endothelial function. STING signaling may be a potential therapeutic target of endothelial dysfunction caused by hyperglycemia.

Deep Neural Network Augments Performance of Junior Residents in Diagnosing COVID-19 Pneumonia on Chest Radiographs.

Chest X-rays (CXRs) are essential in the preliminary radiographic assessment of patients affected by COVID-19. Junior residents, as the first point-of-contact in the diagnostic process, are expected to interpret these CXRs accurately. We aimed to assess the effectiveness of a deep neural network in distinguishing COVID-19 from other types of pneumonia, and to determine its potential contribution to improving the diagnostic precision of less experienced residents. A total of 5051 CXRs were utilized to develop and assess an artificial intelligence (AI) model capable of performing three-class classification, namely non-pneumonia, non-COVID-19 pneumonia, and COVID-19 pneumonia. Additionally, an external dataset comprising 500 distinct CXRs was examined by three junior residents with differing levels of training. The CXRs were evaluated both with and without AI assistance. The AI model demonstrated impressive performance, with an Area under the ROC Curve (AUC) of 0.9518 on the internal test set and 0.8594 on the external test set, which improves the AUC score of the current state-of-the-art algorithms by 1.25% and 4.26%, respectively. When assisted by the AI model, the performance of the junior residents improved in a manner that was inversely proportional to their level of training. Among the three junior residents, two showed significant improvement with the assistance of AI. This research highlights the novel development of an AI model for three-class CXR classification and its potential to augment junior residents' diagnostic accuracy, with validation on external data to demonstrate real-world applicability. In practical use, the AI model effectively supported junior residents in interpreting CXRs, boosting their confidence in diagnosis. While the AI model improved junior residents' performance, a decline in performance was observed on the external test compared to the internal test set. This suggests a domain shift between the patient dataset and the external dataset, highlighting the need for future research on test-time training domain adaptation to address this issue.