Changes in oxygen supply-demand balance during induction of general anesthesia: an exploratory study using remimazolam.

PURPOSE: This study was performed to evaluate the changes in oxygen supply-demand balance during induction of general anesthesia using an indirect calorimeter capable of measuring oxygen consumption (VO2) and carbon dioxide production (VCO2). METHODS: This study included patients scheduled for surgery in whom remimazolam was administered as a general anesthetic. VO2 and VCO2 were measured at different intervals: upon awakening (T1), 15 min after tracheal intubation (T2), and 1 h after T2 (T3). Oxygen delivery (DO2) was calculated simultaneously with these measurements. VO2 was ascertained using an indirect calorimeter and further calculated using vital signs, among other factors. DO2 was derived from cardiac output and arterial blood gas analysis performed with an arterial pressure-based cardiac output measurement system. RESULTS: VO2, VCO2, and DO2 decreased significantly from T1 to T2 and T3 [VO2/body surface area (BSA) (ml/min/m2): T1, 130 (122-146); T2, 107 (83-139); T3, 97 (93-121); p = 0.011], [VCO2/BSA (ml/min/m2): T1, 115 (105-129); T2, 90 (71-107); T3, 81 (69-101); p = 0.011], [DO2/BSA (ml/min/m2): T1, 467 (395-582); T2, 347 (286-392); T3, 382 (238-414); p = 0.0020]. Among the study subjects, a subset exhibited minimal reduction in VCO2. Although the respiratory frequency was titrated on the basis of end-tidal CO2 levels, there was no significant difference between the groups. CONCLUSION: General anesthetic induction with remimazolam decreased VO2, VCO2, and DO2.

Comparison of accuracy between augmented reality/mixed reality techniques and conventional techniques for epidural anesthesia using a practice phantom model kit.

BACKGROUND: This study used an epidural anesthesia practice kit (model) to evaluate the accuracy of epidural anesthesia using standard techniques (blind) and augmented/mixed reality technology and whether visualization using augmented/mixed reality technology would facilitate epidural anesthesia. METHODS: This study was conducted at the Yamagata University Hospital (Yamagata, Japan) between February and June 2022. Thirty medical students with no experience in epidural anesthesia were randomly divided into augmented reality (-), augmented reality (+), and semi-augmented reality groups, with 10 students in each group. Epidural anesthesia was performed using the paramedian approach with an epidural anesthesia practice kit. The augmented reality (-) group performed epidural anesthesia without HoloLens2Ⓡ and the augmented reality (+) group with HoloLens2Ⓡ. The semi-augmented reality group performed epidural anesthesia without HoloLens2Ⓡ after 30 s of image construction of the spine using HoloLens2Ⓡ. The epidural space puncture point distance between the ideal insertion needle and participant's insertion needle was compared. RESULTS: Four medical students in the augmented reality (-), zero in the augmented reality (+), and one in the semi-augmented reality groups failed to insert the needle into the epidural space. The epidural space puncture point distance for the augmented reality (-), augmented reality (+), and semi-augmented reality groups were 8.7 (5.7-14.3) mm, 3.5 (1.8-8.0) mm (P = 0.017), and 4.9 (3.2-5.9) mm (P = 0.027), respectively; a significant difference was observed between the two groups. CONCLUSIONS: Augmented/mixed reality technology has the potential to contribute significantly to the improvement of epidural anesthesia techniques.

Prediction of return of spontaneous circulation during cardiopulmonary resuscitation by pulse-wave cerebral tissue oxygen saturation: a retrospective observational study.

BACKGROUND: It is difficult to predict the return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). Cerebral tissue oxygen saturation during CPR, as measured by near-infrared spectroscopy (NIRS), is anticipated to predict ROSC. General markers of cerebral tissue oxygen saturation, such as the tissue oxygenation index (TOI), mainly reflect venous oxygenation, whereas pulse-wave cerebral tissue oxygen saturation (SnO2), which represents hemoglobin oxygenation in the pulse wave within the cerebral tissue, is an index of arterial and venous oxygenation. Thus, SnO2 may reflect arterial oxygenation to a greater degree than does TOI. Therefore, we conducted this study to verify our hypothesis that SnO2 measured during CPR can predict ROSC. METHODS: Cardiac arrest patients who presented at the Emergency Department of Yamagata University Hospital in Japan were included in this retrospective, observational study. SnO2 and TOI were simultaneously measured at the patient's forehead using an NIRS tissue oxygenation monitor (NIRO 200-NX; Hamamatsu Photonics, Japan). We recorded the initial, mean, and maximum values during CPR. We plotted receiver operating characteristic curves and calculated the area under the curve (AUC) to predict ROSC. RESULTS: Forty-two patients were included. SnO2 was significantly greater in the ROSC group than in the non-ROSC group in terms of the initial (37.5% vs 24.2%, p = 0.015), mean (44.6% vs 10.8%, p < 0.001), and maximum (79.7% vs 58.4%, p < 0.001) values. Although the initial TOI was not significantly different between the two groups, the mean (45.1% vs 36.8%, p = 0.018) and maximum (71.0% vs 46.3%, p = 0.001) TOIs were greater in the ROSC group than in the non-ROSC group. The AUC was 0.822 for the mean SnO2 (95% confidence interval [CI]: 0.672-0.973; cut-off: 41.8%), 0.821 for the maximum SnO2 (95% CI: 0.682-0.960; cut-off: 70.8%), and 0.809 for the maximum TOI (95% CI: 0.667-0.951; cut-off: 49.3%). CONCLUSION: SnO2 values measured during CPR, including immediately after arrival at the emergency department, were higher in the ROSC group than in the non-ROSC group.

Tandem Macrolactone Synthesis: Total Synthesis of (-)-Exiguolide by a Macrocyclization/Transannular Pyran Cyclization Strategy.

Tetrahydropyran-containing macrolactones were synthesized by integrating Meyer-Schuster rearrangement, macrocyclic ring-closing metathesis, and transannular oxa-Michael addition under gold and ruthenium catalysis. Single-step access to a variety of 14- to 20-membered macrolactones containing a tetrahydropyran ring was possible from readily available linear precursors in good yields and with moderate to excellent diastereoselectivity. A 13-step synthesis of (-)-exiguolide, an anticancer marine macrolide, showcased the feasibility of our tandem reaction sequence for macrolactone synthesis and also demonstrated the power of transannular reactions for rapid assembly of the tetrahydropyran rings of the target natural product.

Post-extubation oxygenation strategies in acute respiratory failure: a systematic review and network meta-analysis.

BACKGROUND: High-flow nasal cannula oxygenation (HFNC) and noninvasive positive-pressure ventilation (NPPV) possibly decrease tracheal reintubation rates better than conventional oxygen therapy (COT); however, few large-scale studies have compared HFNC and NPPV. We conducted a network meta-analysis (NMA) to compare the effectiveness of three post-extubation respiratory support devices (HFNC, NPPV, and COT) in reducing the mortality and reintubation risk. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. COT, NPPV, and HFNC use were assessed in patients who were aged ≥ 16 years, underwent invasive mechanical ventilation for > 12 h for acute respiratory failure, and were scheduled for extubation after spontaneous breathing trials. The GRADE Working Group Approach was performed using a frequentist-based approach with multivariate random-effect meta-analysis. Short-term mortality and reintubation and post-extubation respiratory failure rates were compared. RESULTS: After evaluating 4631 records, 15 studies and 2600 patients were included. The main cause of acute hypoxic respiratory failure was pneumonia. Although NPPV/HFNC use did not significantly lower the mortality risk (relative risk [95% confidence interval] 0.75 [0.53-1.06] and 0.92 [0.67-1.27]; low and moderate certainty, respectively), HFNC use significantly lowered the reintubation risk (0.54 [0.32-0.89]; high certainty) compared to COT use. The associations of mortality with NPPV and HFNC use with respect to either outcome did not differ significantly (short-term mortality and reintubation, relative risk [95% confidence interval] 0.81 [0.61-1.08] and 1.02 [0.53-1.97]; moderate and very low certainty, respectively). CONCLUSION: NPPV or HFNC use may not reduce the risk of short-term mortality; however, they may reduce the risk of endotracheal reintubation. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: PROSPERO (registration number: CRD42020139112, 01/21/2020).

Esophageal Carcinosarcoma with Basaloid Squamous Cell Carcinoma: A Case Report and Review of the Literature.

Esophageal carcinosarcoma is a rare tumor composed of neoplastic squamous epithelium and sarcomatous spindle cells. The origin of spindle cells remains unknown; however, the majority of sarcomatous components are currently considered to be derived from existing carcinomatous cells via epithelial-mesenchymal transition (EMT). We report a case of esophageal carcinosarcoma harboring basaloid squamous cell carcinoma successfully treated with preoperative chemotherapy. A 78-year-old man complaining dysphagia was diagnosed as esophageal carcinosarcoma. After two courses of preoperative chemotherapy with cisplatin and 5-fluorouracil, curative esophagectomy with lymph node dissection was performed thoracoscopically. Histopathological findings of the resected specimen revealed the mixture of basaloid squamous cell carcinoma and sarcomatous spindle cells. A transitional zone between both components was also detected. As fibrosis was identified around both two components, the findings indicated that both carcinomatous and sarcomatous neoplasms disappeared by preoperative chemotherapy. Final pathological diagnosis was esophageal carcinosarcoma with basaloid squamous cell carcinoma. No recurrent lesions have been detected for 25 months after the surgery. Sarcomatous spindle cells could be derived from the components of basaloid squamous cell carcinoma in our present case due to the presence of histological transition between two components. In addition, the marked immunoreactivity of vimentin (an EMT marker) detected in the tumor cells of basaloid squamous cell carcinoma could be consistent with the concept of monoclonal origin via EMT. The regimen targeting squamous cell carcinoma could also be effective in the treatment of sarcomatous components. Preoperative therapy might achieve the improvement of clinical outcome of patients with esophageal carcinosarcoma.

Reconstructed gastric conduit obstruction caused by a bezoar after esophagectomy: a case report.

BACKGROUND: Bezoars are rare but may cause gastrointestinal obstruction and ulcers. To the best of our knowledge, only two cases of bezoars in the reconstructed gastric conduit have been reported, but there has been no report on reconstructed gastric conduit obstruction due to bezoars. CASE PRESENTATION: A 60-year-old man presented to our clinic with abdominal pain and vomiting that occurred suddenly after dinner. Three years before presentation, he had undergone radical thoracoscopic esophagectomy followed by reconstruction of the gastric conduit through the posterior sternum, for esophageal cancer. Enhanced computed tomography scans showed distension of only the gastric conduit without ischemia and distension of the small intestine. According to our findings, we initially diagnosed the patient with postoperative intestinal obstruction caused by adhesions. After conservative treatment failed, the patient underwent an endoscopic study that showed a bezoar at the pylorus ring. We initially failed to remove the bezoar endoscopically because of its large size; hence, we attempted enzymatic dissolution. Three days after the first endoscopic study, the bezoar was disintegrated using a snare and extracted during a second endoscopy. The patient recovered uneventfully and presented with no complications during the 1-year follow-up interval. CONCLUSION: In cases wherein the discharge of materials in the reconstructed gastric conduit is delayed, bezoars should be considered in the differential diagnosis, and an endoscopic study should be performed to verify the cause of obstruction.

Evaluation of the impact of psoas muscle index, a parameter of sarcopenia, in patients with esophageal squamous cell carcinoma receiving neoadjuvant therapy.

BACKGROUND: The impact of sarcopenia on digestive cancer is widely known. Muscle mass, defined as the psoas muscle index (PMI), is an important parameter of sarcopenia. However, the relationship between esophageal cancer and PMI has not been fully investigated, especially in patients receiving neoadjuvant therapy. METHODS: To elucidate the influence of the PMI on patients with esophageal squamous cell carcinoma receiving neoadjuvant therapy, the progression of sarcopenia defined by the PMI, the relationship between pretherapeutic/preoperative sarcopenia and patient characteristics, and patient survival were retrospectively investigated in 82 patients with esophageal squamous cell carcinoma who underwent neoadjuvant therapy. RESULTS: The PMI decreased by more than 20 mm2/m2 between the pretherapeutic and preoperative periods in 75.6% of the patients. Pretherapeutic sarcopenia (low PMI) correlated with the pathological therapeutic response, postoperative recurrence, and pretherapeutic body mass index. Neoadjuvant chemoradiotherapy was associated with the progression of sarcopenia. The pretherapeutic sarcopenia group (low PMI) had worse disease-free survival (DFS) than the non-sarcopenia group. Furthermore, pretherapeutic sarcopenia (low PMI) was an independent prognostic risk factor of DFS according to univariate and multivariate analyses. CONCLUSIONS: The PMI may decrease during neoadjuvant therapy, especially during neoadjuvant chemoradiotherapy. Pretherapeutic sarcopenic (low PMI) patients should be followed-up more carefully postoperatively because higher risks of recurrence and poorer rates of disease-free survival are associated with these patients.

Esophageal cancer with severe funnel chest treated by simultaneous funnel chest surgery and thoracoscopic esophagectomy: a case report.

BACKGROUND: Funnel chest is the most common chest deformity, occurring in 0.06-0.3% of the general population. When it occurs concomitantly with esophageal cancer, it hinders intrathoracic surgery that is necessary for treatment. Although there are a few reports of esophagectomy performed in patients with funnel chest, simultaneous treatment of esophageal cancer and funnel chest with funnel chest surgery (Nuss method) and esophagectomy has not been reported. We report the first case of advanced esophageal cancer complicated by severe funnel chest that was treated using the Nuss method and radical thoracoscopic esophagectomy. CASE PRESENTATION: A 59-year-old man was diagnosed with advanced thoracic esophageal cancer and severe funnel chest. Because his sternum was almost attached to the vertebral bone, thereby creating a narrow space in the mediastinum, esophageal surgery was expected to be complicated. After the patient underwent neoadjuvant chemotherapy, we used the Nuss method to reconstruct the chest and widen the mediastinum. Subsequently, radical thoracoscopic esophagectomy was performed with the patient in the left decubitus position without any difficulty, and the postoperative course was uneventful. CONCLUSION: Simultaneous funnel chest surgery (Nuss method) and thoracoscopic esophagectomy with the patient in the left decubitus position are recommended for esophageal cancer patients with severe funnel chest.

Definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced cervical esophageal cancer.

BACKGROUND: Recently, definitive chemoradiotherapy (dCRT) has become one of the essential treatment strategies for esophageal squamous cell carcinoma (ESCC) and has been especially gaining prevalence for cervical ESCC to preserve the larynx. Our department recently introduced dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for treating advanced cervical ESCC. This study aims to assess the safety and outcomes of DCF-R in patients with advanced cervical ESCC. METHODS: We retrospectively assessed 11 patients with advanced cervical ESCC (clinical stage: II-IV, including T4b and/or M1 lymph node) who received DCF-R as the first-line treatment between December 2010 and February 2015. RESULTS: Our patient cohort comprised 8 males and 3 females (median age 68 years; range 54-76 years). The pretreatment clinical stage included stage II (1), stage III (7), and stage IV (3) cases [including 3 patients with T4b (2 trachea and 1 thyroid) and 3 patients with M1 lymph node]. We attained complete response (CR) in 10 patients and stable disease in 1 patient. Of 10 patients with CR, 5 experienced recurrence and 5 continued exhibiting CR. Furthermore, grade 3 or more adverse events included leucopenia (91%), neutropenia (91%), febrile neutropenia (45%), and pharyngeal pain (55%). While the 2-year overall survival rate was 72%, the 2-year recurrent-free survival rate was 64%, respectively. CONCLUSIONS: DCF-R treatment for advanced cervical esophageal cancer could be completed by the careful administration; although a strong blood toxicity might occur, this treatment may provide the chance to obtain favorable prognosis with larynx preservation.

Diastereoselective Ring-Closing Metathesis as a Means to Construct Medium-Sized Cyclic Ethers: Application to the Synthesis of a Photoactivatable Gambierol Derivative.

This paper describes a concise synthesis of six- to eight-membered α,α'-substituted cyclic ethers by exploiting diastereoselective ring-closing metathesis (RCM) of 1,4-pentadien-3-yl ether derivatives. The RCM precursors could be efficiently prepared via a vinylation of the corresponding α-acetoxy ether derivatives using divinylzinc. Diastereoselective RCM of 1,4-pentadien-3-yl ether derivatives afforded a series of six- to eight-membered α,α'-substituted cyclic ethers with moderate to good diastereoselectivity. The stereochemical consequence of the diastereoselective RCM appeared to be dependent on the structure of the ring being forged. The diastereoselectivity of six- and seven-membered cyclic ethers appeared to be largely under kinetic control irrespective of the catalyst reactivity, whereas that of an eight-membered cyclic ether could be controlled by the catalyst reactivity. Finally, the diastereoselective RCM chemistry was applied to the synthesis of a biotin-tagged photoactivatable derivative of gambierol.

Association Between Long- Versus Short-Acting Angiotensin II Receptor Antagonists and Hypotension During Anesthesia Induction: A Retrospective Study.

BACKGROUND: The withdrawal or continuation of angiotensin II receptor blockers (ARBs) before surgery continues to be debated. We hypothesized that this is because ARBs with different half-lives have not been studied individually. This retrospective study aimed to clarify whether the degree of hypotension during anesthesia induction differs among ARBs with different half-lives. METHODS: We included patients who received general anesthesia with regular oral administration of telmisartan (group T) or valsartan (group V), which have half-lives of approximately 24 and 6 hours, respectively. The frequency of hypotension and vasopressor frequency and dose during anesthesia induction were compared between the two groups. At our hospital, ARBs were withdrawn on the day of surgery in all patients. RESULTS: Groups T and V included 190 and 132 patients, respectively. Patient backgrounds in group V were significantly more strongly associated with the use of calcium channel blockers. No significant differences were observed in the use of other concomitant antihypertensive medications, cardiovascular complications, or renal function. The time during which the mean arterial blood pressure was < 60 mmHg during anesthesia induction was significantly greater in group T than in group V (11 min vs. 7 min, P=0.030). The proportion of patients who used vasopressors was significantly higher in group T than that in group V (74.2% vs. 56.0%, P < 0.001). CONCLUSION: Patients taking telmisartan showed more hypotensive during the induction of general anesthesia than those taking valsartan, even after withdrawal on the day of surgery.

MEK inhibitor PD0325901 upregulates CD34 expression in endothelial cells via inhibition of ERK phosphorylation.

Introduction: CD34-positive endothelial progenitor cells (EPCs) promote angiogenesis and are a promising tool for regenerative cell therapy of ischemic diseases. However, the number and quality of CD34-positive cells decrease owing to various external and internal factors; thus, an efficient method is needed to establish CD34-positive EPCs. The generation of functional cells by reprogramming, that is, manipulating cell fate via gene transfer and/or treatment with chemical compounds, has recently been reported. Therefore, we aimed to generate CD34-positive cells by the reprogramming of endothelial cells (ECs). Methods: Based on previous reports, seven candidate chemical compounds were selected to reprogram human umbilical vein ECs (HUVECs) to CD34-positive cells. Following stimulation with the chemical compounds, the expression of CD34 was evaluated using quantitative PCR, flow cytometry, and immunocytochemistry. Results: HUVECs treated with the compounds exhibited increased CD34 expression. We cultured cells in alternate media lacking one of the seven compounds and found no CD34 expression in cells treated with PD0325901-free media, suggesting that PD0325901-a MEK inhibitor-mainly contributed to the increase in CD34 expression. We found that 98% of cells were CD34-positive after PD0325901 treatment alone for 7 d. Western blotting revealed that the phosphorylation of ERK was suppressed in PD0325901-treated cells. No upregulation of CD34 was observed in fibroblast cell lines, even after PD0325901 treatment. These results suggested that PD0325901 induces CD34-positive cells by inhibiting ERK phosphorylation in ECs. Conclusions: CD34 expression was strongly induced in ECs by treatment with the MEK inhibitor PD0325901 in vitro. Our study provides a useful reference for the establishment of CD34-positive EPCs and will contribute to the development of regenerative therapies, especially for ischemic diseases.

Terminus-Selective Covalent Immobilization of Heparin on a Thermoresponsive Surface Using Click Chemistry for Efficient Binding of Basic Fibroblast Growth Factor.

Cell therapy using endothelial cells (ECs) has great potential for the treatment of congenital disorders, such as hemophilia A. Cell sheet technology utilizing a thermoresponsive culture dish is a promising approach to efficiently transplant donor cells. In this study, a new method to prepare terminus-selective heparin-immobilized thermoresponsive culture surfaces is developed to facilitate the preparation of EC sheets. Alkynes are introduced to the reducing terminus of heparin via reductive amination. Cu-catalyzed azide-alkyne cycloaddition (CuAAC) facilitates efficient immobilization of the terminus of heparin on a thermoresponsive surface, resulting in a higher amount of immobilized heparin while preserving its function. Heparin-immobilized thermoresponsive surfaces prepared using CuAAC exhibit good adhesion to human endothelial colony-forming cells (ECFCs). In addition, upon further binding to basic fibroblast growth factor (bFGF) on heparin-immobilized surfaces, increased proliferation of ECFCs on the surface is observed. The confluent ECFC monolayer cultured on bFGF-bound heparin-immobilized thermoresponsive surfaces exhibits relatively high fibronectin accumulation and cell number and detaches at 22 °C while maintaining the sheet-like structure. Because heparin has an affinity for several types of bioactive molecules, the proposed method can be applied to facilitate efficient cultures and sheet formations of various cell types.

Blood flow ratio in the gastric conduit measured by laser Doppler flowmetry: A predictor of anastomotic leakage after esophagectomy.

Background: Anastomotic leakage after esophagectomy is a common complication. Laser Doppler flowmetry (LDF) can quantitatively evaluate the blood flow in the gastric conduit. Methods: A total of 326 patients who underwent thoracoscopic/robot-assisted esophagectomy followed by gastric conduit reconstruction and end-to-side anastomosis were enrolled. We divided the gastric conduit into zones I (dominated by the right gastroepiploic vessels), II (dominated by the left gastroepiploic vessels), and III (perfused with short gastric vessels). Before pulling up the gastric conduit to the neck, LDF values were measured at the pylorus, the border between zones I and II (zone I/II), the border between zones II and III (zone II/III), and the gastric conduit tip (tip). The blood flow ratio was calculated as the LDF value divided by the LDF value at the pylorus. Results: Anastomotic leakage developed in 32 of 326 patients. Leakage was significantly associated with the blood flow ratio at the tip (p < 0.001), but not at zone I/II, zone II/III, and the anastomotic site. The receiver-operating characteristic curve analysis identified an anastomotic leakage cutoff ratio of 0.41 (at the tip). A multivariate Cox analysis showed that a blood flow ratio <0.41 at the tip was an independent risk factor for anastomotic leakage (p < 0.001). Conclusion: Anastomotic leakage after esophagectomy was significantly associated with the blood flow ratio at the tip of the gastric conduit. Preservation of the blood supply to the tip via the gastric wall might contribute to a decreased incidence of anastomotic leakage.

Generation of functional liver sinusoidal endothelial-like cells from human bone marrow-derived mesenchymal stem cells.

Introduction: Liver sinusoidal endothelial cells (LSECs) are specialized vascular endothelial cells that play an important role in the maintenance of biological homeostasis. However, the lack of versatile human LSECs has hindered research on LSECs and development of medical technologies for liver diseases including hemophilia A. In this study, we developed a technique to induce LSEC differentiation from human bone marrow-derived mesenchymal stem cells (BM-MSCs). Methods: To induce LSECs from human BM-MSCs, cytokines and chemical compounds associated with signaling implicated in LSEC differentiation and liver development were screened. Then LSEC-related genes and proteins expression in the differentiated cells were analyzed by qPCR and flow cytometry analysis, respectively. LSEC-related functions of the differentiated cells were also examined. Results: We found that the gene expression of LSEC markers, such as LYVE1, was considerably increased by culturing human BM-MSCs with bone morphogenetic protein 4, fibroblast growth factor 8b, transforming growth factor-ß signal inhibitor, and cyclic AMP. Furthermore, the differentiated cells expressed LSEC marker proteins and clearly demonstrated LSEC-specific functions, such as the uptake of hyaluronic acid. Conclusions: Our result indicate that the functional LSEC-like cells were successfully generated from human BM-MSCs using our established protocol.

Prognostic Value of Antithrombin Activity Levels in the Early Phase of Intensive Care: A 2-Center Retrospective Cohort Study.

To investigate the relationship between antithrombin (AT) activity level and prognosis in patients requiring intensive care. Patients whose AT activity was measured within 24 h of intensive care unit (ICU) admission were enrolled for analysis. The primary endpoint was mortality at discharge. Prognostic accuracy was examined using receiver operating characteristic (ROC) curves and cox hazard regression analysis. Patients were divided into 6 groups based on predicted mortality, and a χ2 independence test was performed on the prognostic value of AT activity for each predicted mortality; P < .05 was considered significant. A total of 281 cases were analyzed. AT activity was associated with mortality at discharge (AT% [interquartile range, IQR]): survivor group, 69 (56-86) versus nonsurvivor group, 56 (44-73), P = .0003). We found an increasing risk for mortality in both the lowest level of AT activity (<50%; hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.20-4.89, P = .01) and the middle-low level of AT activity (≥ 50% and < 70%; HR 2.06, 95% CI 1.06-4.02, P = .03), compared with the normal AT activity level (≥ 70%). ROC curve analysis showed that the prediction accuracy of AT was an area under the curve (AUC) of 0.66 (cutoff 58%, sensitivity 61.4%, specificity 68.2%, P = .0003). AT activity was significantly prognostic in the group with 20% to 50% predicted mortality (AUC 0.74, sensitivity: 24.0%-55.5%, specificity: 83.3%-93.0%). An early decrease in AT activity level in ICU patients may be a predictor of mortality at discharge.

Regulation of von Willebrand factor by ADAMTS13 ameliorates lipopolysaccharide-induced lung injury in mice.

The relationship between von Willebrand factor (VWF) and inflammation has attracted considerable attention in recent years. VWF, which is stored in the Weibel-Palade bodies (WPBs) of endothelial cells (ECs), is released from WPBs in response to inflammatory stimuli and is thought to contribute to inflammation by promoting leukocyte extravasation. In this study, lung injury model mice were produced by intratracheal injection with lipopolysaccharides. The severity of lung inflammation was evaluated in mice with different genotypes (wild-type, Vwf-/-, Adamts13-/-) and mice treated with drugs that inhibit VWF function. Lung inflammation was significantly ameliorated in Vwf-/- mice compared with wild-type mice. Furthermore, inflammation was significantly suppressed in wild-type mice treated with anti-VWF A1 antibody or recombinant human ADAMTS13 compared with the untreated control group. The underlying mechanism appears to be an increased VWF/ADAMTS13 ratio at the site of inflammation and the interaction between blood cell components, such as leukocytes and platelets, and the VWF A1 domain, which promotes leukocyte infiltration into the lung. This study suggested that ADAMTS13 protein and other VWF-targeting agents may be a novel therapeutic option for treatment of pulmonary inflammatory diseases.

Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern.

Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.