Upright CT-based evaluation of the effects of posture on skull-base reconstruction after endoscopic endonasal surgery.

Cerebrospinal fluid (CSF) leakage is a common complication associated with endoscopic endonasal skull-base surgery (EESBS). Postoperative mobilization-associated postural changes are considered to cause CSF leakage. However, no study has demonstrated a robust relationship between postural changes and CSF leakage. We used upright computed tomography (CT) to clarify the effects of postural changes on the reconstructed skull base (RSB) after EESBS. Thirty patients who underwent EESBS at our institution were prospectively included, and their upright and supine CTs were compared to measure morphological changes in the RSB. Patient clinical data were also collected from medical charts and surgical videos, and their relationships with morphological changes were assessed. In upright CTs, the RSB shifted intracranially by 0.94 (0.0-2.9) mm on average. This shift was larger in cases with lesions extending to the sphenoid sinus, dural defects, intraoperative pulsation of the RSB, and large bone windows. The direction of the change was opposite to intuitive movement driven by gravity because of reduced intracranial pressure in the sitting position. Thus, these shifts can be directly associated with postoperative CSF leakage caused by reconstruction material displacement. Skull-base reconstruction and postoperative postural management accounting for these morphological changes may be necessary for preventing CSF leakage.

Proton gradient across the chloroplast thylakoid membrane governs the redox regulatory function of ATP synthase.

Chloroplast ATP synthase (CFoCF1) synthesizes ATP by using a proton electrochemical gradient across the thylakoid membrane, termed ΔµH+, as an energy source. This gradient is necessary not only for ATP synthesis but also for reductive activation of CFoCF1 by thioredoxin, using reducing equivalents produced by the photosynthetic electron transport chain. ΔµH+ comprises two thermodynamic components: pH differences across the membrane (ΔpH) and the transmembrane electrical potential (ΔΨ). In chloroplasts, the ratio of these two components in ΔµH+ is crucial for efficient solar energy utilization. However, the specific contribution of each component to the reductive activation of CFoCF1 remains unclear. In this study, an in vitro assay system for evaluating thioredoxin-mediated CFoCF1 reduction is established, allowing manipulation of ΔµH+ components in isolated thylakoid membranes using specific chemicals. Our biochemical analyses revealed that ΔpH formation is essential for thioredoxin-mediated CFoCF1 reduction on the thylakoid membrane, whereas ΔΨ formation is nonessential.

High frequency variability index in predicting postoperative pain in video/robotic-assisted thoracoscopic surgery under combined general anesthesia and peripheral nerve block: an observational study.

The high frequency variability index (HFVI)/analgesia nociception index (ANI) is purported to assess the balance between nociception and analgesia in patients under general anesthesia. This observational study investigated whether intraoperative HFVI/ANI correlates with postoperative pain in patients performed with nerve block under general anesthesia in video/robotic-assisted thoracoscopic surgery (VATS/RATS). We investigated whether maximum postoperative pain at rest and postoperative morphine consumption are associated with HFVI/ANI just before extubation, mean HFVI/ANI during anesthesia, the difference in HFVI/ANI between before and 5 min after the start of surgery, and the difference in HFVI/ANI between before and 5 min after the nerve block. Data obtained from 48 patients were analyzed. We found no significant association between HFVI/ANI just before extubation and postoperative Numerical Rating Scale (NRS) score. Receiver operating characteristic curve analysis revealed that moderate (NRS > 3) or severe (NRS > 7) postoperative pain could not be predicted by HFVI/ANI just before extubation. In addition, there were no associations between postoperative morphine consumption and HFVI/ANI at any time points. The present study demonstrated that it is difficult to predict the degree of postoperative pain in patients undergoing VATS/RATS under general anesthesia combined with peripheral nerve block, by using HFVI/ANI obtained at multiple time points during general anesthesia.

[Development of Organocatalytic Reactions for the Synthesis of Natural Products and Pharmaceuticals].

This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

Highly regio- and stereoselective (3 + 2) annulation reaction of allenoates with 3-methyleneindolin-2-ones catalyzed by a planar chiral [2.2]paracyclophane-based bifunctional phosphine-phenol catalyst.

A planar chiral [2.2]paracyclophane-based phosphine-phenol catalyst catalyzed the (3 + 2) annulation reaction of ethyl 2,3-butadienoate with 3-methyleneindolin-2-ones to produce 2,5-disubstituted cyclopentene-fused C3-spirooxindoles in high yields with high regio-, diastereo-, and enantioselectivities. This catalyst was suitable for reactions of not only benzylideneindolinones but also alkylideneindolinones, the chiral phosphine-catalyzed reactions of which have not yet been reported. Density functional theory calculations suggested that the formation of hydrogen bonds between the phenolic OH group of the catalyst and the allenoate carbonyl group, rather than between the OH group and the carbonyl group of indolinone, contributed to the formation of an efficient reaction space at the enantiodetermining step.

Release of Exosomal PD-L1 in Bone and Soft Tissue Sarcomas and Its Relationship to Radiotherapy.

(1) Background: Exosomal PD-L1 has garnered attention owing to its role in instigating systemic immune suppression. The objective of this study is to elucidate whether bone and soft tissue sarcoma cells possess the capacity to secrete functionally active exosomal PD-L1 and whether radiotherapy (RT) induces the exosomal PD-L1 release. (2) Methods: Human osteosarcoma cell line 143B and human fibrosarcoma cell line HT1080 were utilized. Exosomes were isolated from the culture medium and blood via ultracentrifugation. The expression of PD-L1 on both tumor cells and exosomes was evaluated. The inhibitory effect on PBMC was employed to assess the activity of exosomal PD-L1. Post radiotherapy, changes in PD-L1 expression were compared. (3) Results: Exosomal PD-L1 was detected in the culture medium of tumor cells but was absent in the culture medium of PD-L1 knockout cells. Exosomal PD-L1 exhibited an inhibitory effect on PBMC activation. In tumor-bearing mice, human-derived exosomal PD-L1 was detected in the bloodstream. Following radiotherapy, tumor cells upregulated PD-L1, and human-derived exosomal PD-L1 were detected in the bloodstream. (4) Conclusions: Exosomal PD-L1 emanates from bone and soft tissue sarcoma cells and is disseminated into the circulatory system. The levels of PD-L1 in tumor cells and the release of exosomal PD-L1 were augmented after irradiation with RT.

Evaluation of PET/CT imaging with [89Zr]Zr-DFO-girentuximab: a phase 1 clinical study in Japanese patients with renal cell carcinoma (Zirdac-JP).

BACKGROUND: PET/CT imaging with Zirconium-89 labeled [89Zr]Zr-DFO-girentuximab, which targets tumor antigen CAIX, may aid in the differentiation and characterization of clear cell renal cell carcinomas (RCC) and other renal and extrarenal lesions, and has been studied in European and American cohorts. We report results from a phase I study that evaluated the safety profile, biodistribution, and dosimetry of [89Zr]Zr-DFO-girentuximab in Japanese patients with suspected RCC. METHODS: Eligible adult patients received 37 MBq (± 10%; 10 mg mass dose) of intravenous [89Zr]Zr-DFO-girentuximab. Safety and tolerability profile was assessed based on adverse events, concomitant medications, physical examination, vital signs, hematology, serum chemistry, urinalysis, human anti-chimeric antibody measurement, and 12-lead electrocardiograms at predefined intervals. Biodistribution and normal organ and tumor dosimetry were evaluated with PET/CT images acquired at 0.5, 4, 24, 72 h and Day 5 ± 2 d after administration. RESULTS: [89Zr]Zr-DFO-girentuximab was administered in six patients as per protocol. No treatment-emergent adverse events were reported. Dosimetry analysis showed that radioactivity was widely distributed in the body, and that the absorbed dose in healthy organs was highest in the liver (mean ± standard deviation) (1.365 ± 0.245 mGy/MBq), kidney (1.126 ± 0.190 mGy/MBq), heart wall (1.096 ± 0.232 mGy/MBq), and spleen (1.072 ± 0.466 mGy/MBq). The mean effective dose, adjusted by the radioactive dose administered, was 0.470 mSv/MBq. The radiation dose was highly accumulated in the targeted tumor, while any abnormal accumulation in other organs was not reported. CONCLUSIONS: This study demonstrates that [89Zr]Zr-DFO-girentuximab administered to Japanese patients with suspected RCC has a favorable safety profile and is well tolerated and has a similar dosimetry profile to previously studied populations.

Comprehensive Treatment of Total Arch Replacement in a Patient With Liver Cirrhosis: A Case Report.

A 78-year-old woman with liver cirrhosis due to chronic hepatitis C visited our department for treatment of a thoracic aortic aneurysm. Her Child-Pugh classification was class A, and her model for end-stage liver (MELD) disease score was 8. As she also had thrombocytopenia associated with splenomegaly and esophageal varices, endoscopic injection sclerotherapy and partial splenic embolization were performed before total arch replacement surgery for treating esophageal varices to reduce the bleeding risk during transesophageal echocardiography and for thrombocytopenia, respectively. After endoscopic injection sclerotherapy and partial splenic embolization, the platelet count increased; hence, total arch replacement surgery was performed. By combining partial splenic embolization and endoscopic injection sclerotherapy, we were able to safely perform transesophageal echocardiography and total arch replacement surgery in the perioperative period.

What are standard monitoring devices for anesthesia in future?

Monitoring the patient's physiological functions is critical in clinical anesthesia. The latest version of the Japanese Society of Anesthesiologists' Guidelines for Safe Anesthesia Monitoring, revised in 2019, covers various factors, including electroencephalogram monitoring, oxygenation, ventilation, circulation, and muscle relaxation. However, with recent advances in monitoring technologies, the information provided has become more detailed, requiring practitioners to update their knowledge. At a symposium organized by the Journal of Anesthesia in 2023, experts across five fields discussed their respective topics: anesthesiologists need to interpret not only the values displayed on processed electroencephalogram monitors but also raw electroencephalogram data in the foreseeable future. In addition to the traditional concern of preventing hypoxemia, monitoring for potential hyperoxemia and the effects of mechanical ventilation itself will become increasingly important. The importance of using AI analytics to predict hypotension, assess nociception, and evaluate microcirculation may increase. With the recent increase in the availability of neuromuscular monitoring devices in Japan, it is important for anesthesiologists to become thoroughly familiar with the features of each device to ensure its effective use. There is a growing desire to develop and introduce a well-organized, integrated "single screen" monitor.

Indentation of an elastic arch on a frictional substrate: Pinning, unfolding, and snapping.

In this study, we investigate the morphology and mechanics of a naturally curved elastic arch loaded at its center and frictionally supported at both ends on a flat, rigid substrate. Through systematic numerical simulations, we classify the observed behaviors of the arch into three configurations in terms of the arch geometry and the coefficient of static friction with the substrate. A linear theory is developed based on a planar elastica model combined with Amontons-Coulomb's frictional law, which quantitatively explains the numerically constructed phase diagram. The snapping transition of a loaded arch in a sufficiently large indentation regime, which involves a discontinuous force jump, is numerically observed. The proposed model problem enables a fully analytical investigation and demonstrates a rich variety of mechanical behaviors owing to the interplay among elasticity, geometry, and friction. This study provides a basis for understanding more common but complex systems, such as a cylindrical shell subjected to a concentrated load and simultaneously supported by frictional contact with surrounding objects.

Phosphoproteomic Analysis Identified Mutual Phosphorylation of FAK and Src as a Mechanism of Osimertinib Resistance in EGFR-Mutant Lung Cancer.

Introduction: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. Methods: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. Results: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA-mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. Conclusions: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

A Case of Successful Hybrid Treatment of Dual Arterial Bypass Using Indocyanine Green Fluorescence Angiography and Endovascular Treatment for Recurrent Superior Mesenteric Artery Aneurysm.

A 54-year-old woman with a mycotic superior mesenteric artery (SMA) aneurysm underwent emergent aneurysm resection with a great saphenous vein bypass. Follow-up computed tomography revealed a rapidly growing recurrent SMA aneurysm at the stump. Under the diagnosis of recurrent pseudoaneurysm of SMA with a fragile stump, we performed an open dual arterial bypass using indocyanine green fluorescence angiography and endovascular coil embolization. Subsequently, the patient's recurrent mycotic SMA aneurysm was successfully managed without mesenteric ischemic complications. This method may help prevent fatal mesenteric ischemia during SMA aneurysm surgery.

Exploration of postural effects on the external jugular and diploic venous system using upright computed tomography scanning.

PURPOSE: Few studies have investigated the influence of posture on the external jugular and diploic venous systems in the head and cranial region. In this study, we aimed to investigate the effects of posture on these systems using upright computed tomography (CT) scanning. METHODS: This study retrospectively analysed an upright CT dataset from a previous prospective study. In each patient, the diameters of the vessels in three external jugular tributaries and four diploic veins were measured using CT digital subtraction venography in both supine and sitting positions. RESULTS: Amongst the 20 cases in the original dataset, we eventually investigated 19 cases due to motion artifacts in 1 case. Compared with the supine position, most of the external jugular tributaries collapsed, and the average size significantly decreased in the sitting position (decreased by 22-49% on average). In contrast, most of the diploic veins, except the occipital diploic veins, tended to increase or remain unchanged (increased by 12-101% on average) in size in the sitting position compared with the supine position. However, the changes in the veins associated with this positional shift were not uniform; in approximately 5-30% of the cases, depending on each vein, an opposite trend was observed. CONCLUSION: Compared to the supine position, the contribution of external jugular tributaries to head venous drainage decreased in the sitting position, whilst most diploic veins maintained their contribution. These results could enhance our understanding of the physiology and pathophysiology of the head region in upright and sitting positions.

Point-of-Care Ultrasound for the Diagnosis of Congestive Kidney Due to Severe Acidemia: A Case Report.

A 51-year-old woman with mitochondrial myopathy and congestive heart failure with reduced left ventricular ejection fraction was admitted due to loss of appetite and progressive frailty. She presented with acute kidney injury (AKI) and severe acidemia. Given her medical history and physical examination (jugular vein distention was not obvious), prerenal causes (hypovolemia/hypotension) of AKI were considered most likely. However, with a significantly elevated N-terminal pro-b-type natriuretic peptide level of 14,700 pg/mL, a congestive kidney was also considered. Bedside echocardiography showed no evidence of low output syndrome, whereas venous excess ultrasound (VExUS) score was assessed as Grade 2 (moderate congestion). In addition to administering fluids for the suspected prerenal causes (hypovolemia/hypotension), sodium bicarbonate was administered suspecting a negative impact of severe acidemia on cardiac function. With the improvement of acidemia and only a small volume of fluid therapy, there was a rapid improvement in AKI with the normalization of the VExUS score. This suggested that the main cause of AKI was congestive kidney. In this case, VExUS helped us make a correct diagnosis of acidemia-induced congestive kidney rather than hypovolemia as a cause of AKI, leading to the appropriate treatment.

An Exploratory Study on Seasonal Variation in the Gut Microbiota of Athletes: Insights from Japanese Handball Players.

Despite accumulating evidence that suggests a unique gut microbiota composition in athletes, a comprehensive understanding of this phenomenon is lacking. Furthermore, seasonal variation in the gut microbiota of athletes, particularly during the off-season, remains underexplored. This study aimed to compare the gut microbiotas between athletic subjects (AS) and non-athletic subjects (NS), and to investigate variations between athletic and off-season periods. The data were derived from an observational study involving Japanese male handball players. The results revealed a distinct gut microbiota composition in AS compared with NS, characterized by significantly higher alpha-diversity and a greater relative abundance of Faecalibacterium and Streptococcus. Moreover, a comparative analysis between athletic and off-season periods in AS demonstrated a significant change in alpha-diversity. Notably, AS exhibited significantly higher alpha-diversity than NS during the athletic season, but no significant difference was observed during the off-season. This study demonstrates the characteristics of the gut microbiota of Japanese handball players and highlights the potential for changes in alpha-diversity during the off-season. These findings contribute to our understanding of the dynamic nature of the gut microbiota of athletes throughout the season.