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To determine the impact of direct-acting antiviral (DAA) therapy on the long-term prognosis of decompensated cirrhotic patients.Thirty-seven patients with hepatitis C virus (HCV)-induced decompensated cirrhosis treated with sofosbuvir and velpatasvir (SOF/VEL group) were prospectively enrolled. For historical control, 65 HCV-positive decompensated cirrhotic patients who did not receive DAA therapy were included (control group). The incidence rates of hepatocellular carcinoma (HCC), decompensated events with hospitalization, and overall survival were compared between both groups.Forty-one patients experienced decompensated events during 15.0 months in the control group, and 6 patients during 21.6 months in the SOF/VEL group. The cumulative incidence rates of decompensated events after 2 years were significantly higher in the control group (53.1%) than in the SOF/VEL group (14.5%) (P0.001). Twenty-seven patients died within 22.0 months in the control group, and 3 patients died within 25.6 months in the SOF/VEL group. The overall survival rates after 2 years were significantly lower in the control group (67.6%) than in the SOF/VEL group (91.3%) (P = 0.010). Thirteen patients in the control group developed HCC during 15.8 months, and 10 patients during 17.3 months in the SOF/VEL group. The HCC incidence rates after 2 years were 20.3% and 29.6% in the control and SOF/VEL groups, respectively, with no significant difference (P = 0.327).SOF/VEL therapy may suppress the development of decompensated events and improve the prognosis in decompensated cirrhotic patients; however, the incidence of HCC remains prevalent in these patients irrespective of SOF/VEL therapy. This article is protected by copyright. All rights reserved.

A 63-year-old man with hypertrophic cardiomyopathy (HCM), mid-ventricular obstruction, and an apical aneurysm had an episode of cardiac arrest due to sustained ventricular tachycardia (VT). He was resuscitated and an implantable cardioverter-defibrillator (ICD) was implanted. In the following years, several episodes of VT and ventricular fibrillation were successfully terminated by antitachycardia pacing or ICD shocks. Three years after ICD implantation, he was re-admitted because of refractory electrical storm (ES). Since aggressive pharmacological treatments, direct current cardioversions, and deep sedation were not effective, he underwent epicardial catheter ablation which was successful to terminate ES. However, because of the recurrence of refractory ES after one year, he proceeded to surgical left ventricular myectomy with apical aneurysmectomy which provided him a relatively stable clinical course for six years. Although epicardial catheter ablation may be an acceptable option, surgical resection of apical aneurysm seems to be most efficacious for ES in patients with HCM and an apical aneurysm. LEARNING OBJECTIVES: In patients with hypertrophic cardiomyopathy (HCM), implantable cardioverter-defibrillators (ICDs) are the gold standard of therapy for prophylaxis against sudden death. Electrical storm (ES) caused by recurrent episodes of ventricular tachycardia can cause sudden death even in patients with ICDs. Although epicardial catheter ablation may be an acceptable option, surgical resection of apical aneurysm is most efficacious for ES in patients with HCM, mid-ventricular obstruction, and an apical aneurysm.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation^{1,2}. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole^3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of 8.4_{-1.1}^{+0.5} Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow., 50 pages, 18 figures, 3 tables, author's version of the paper published in Nature

We evaluated the impact of discontinuing universal preadmission screening for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) on the occurrence of nosocomial clusters of coronavirus disease 2019 (COVID-19) during the SARS-CoV-2 o (omicron) variant period. No increasing trend in nosocomial clusters was observed during community-based surges before and after discontinuation. This finding supports the safety of the practice change.

In clinical trials, missing data may lead to serious misinterpretation of trial results. To address this issue, it is important to collect post-randomization data (such as efficacy measurement data and adverse event onset data). Such post-randomization data are called auxiliary variables and they can be useful for constructing missingness and imputation models. A multiply robust estimator using an empirical likelihood method was previously proposed by Han and Wang (2013) and Han (2014). However, that estimator was developed for cross-sectional data and situations in which no auxiliary variables are missing. This is contrary to actual clinical trial settings, in which some auxiliary variables will invariably be missing. Consequently, to apply Han’s method to longitudinal data, missing auxiliary variables need to be imputed. This paper proposes a new method that extends Han’s method to a longitudinal outcome model by applying weighted generalized estimating equations with new weights. Monte Carlo simulations of a repeated binary response with missing at random dropouts demonstrated that the proposed estimator is multiply robust and exhibits better performance than that of augmented inverse probability weighted complete-case estimating equations under several simulation scenarios. We also successfully applied the proposed method to plaque psoriasis study data.

Background Special subtypes of pancreatic cancer, such as acinar cell carcinoma (ACC), adenosquamous carcinoma (ASC), and anaplastic carcinoma of the pancreas (ACP), are rare, and so data on them are limited. Using the C-CAT database, we analyzed clinical and genomic characteristics of patients with these and evaluated differences on comparison with pancreatic ductal adenocarcinoma (PDAC) patients. Methods We retrospectively reviewed data on 2691 patients with unresectable pancreatic cancer: ACC, ASC, ACP, and PDAC, entered into C-CAT from June 2019 to December 2021. The clinical features, MSI/TMB status, genomic alterations, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) on receiving FOLFIRINOX (FFX) or GEM + nab-PTX (GnP) therapy as first-line treatment were evaluated. Results Numbers of patients with ACC, ASC, ACP, and PDAC were 44 (1.6%), 54 (2.0%), 25 (0.9%), and 2,568 (95.4%), respectively. KRAS and TP53 mutations were prevalent in ASC, ACP, and PDAC (90.7/85.2, 76.0/68.0, and 85.1/69.1%, respectively), while their rates were both significantly lower in ACC (13.6/15.9%, respectively). Conversely, the rate of homologous recombination-related (HRR) genes, including ATM and BRCA1/2, was significantly higher in ACC (11.4/15.9%) than PDAC (2.5/3.7%). In ASC and ACP, no significant differences in ORR, DCR, or TTF between FFX and GnP were noted, while ACC patients showed a trend toward higher ORR with FFX than GnP (61.5 vs. 23.5%, p = 0.06) and significantly more favorable TTF (median 42.3 vs. 21.0 weeks, respectively, p = 0.004). Conclusions ACC clearly harbors different genomics compared with PDAC, possibly accounting for differences in treatment efficacy.

Background: Remimazolam is a novel ultrashort-acting benzodiazepine that has recently become available for general anesthesia. However, the incidence of postoperative nausea and vomiting (PONV) associated with remimazolam remains unknown. In this propensity score-matched, retrospective, observational study, we compared the rates of PONV between remimazolam and propofol.Methods: In this retrospective observational study, propensity score-matching was performed to minimize selection bias. Patients who received total intravenous anesthesia with remimazolam or propofol at the Hamamatsu University Hospital between August 2020 and July 2021 were enrolled in the study. Data on patient demographics, anesthetic agents, and PONV within the first 24 h were collected and analyzed.Results: Of the 1,239 patients who met the study selection criteria, 585 received remimazolam and 684 received propofol. After propensity score matching, 333 matched pairs were further analyzed. Patient demographics and the anesthetic agents used were comparable between the matched cohorts. The incidence of PONV was significantly higher in the remimazolam group than in the propofol group (35% vs. 21%, P < 0.001).Conclusions: The incidence of PONV is higher with remimazolam anesthesia than with propofol anesthesia. The findings of this study require confirmation in larger prospective randomized controlled trials.

Purpose: To compare the effects of macular intraretinal hemorrhage (IRH) and macular hole (MH) on best-corrected visual acuity (BCVA) after displacement of submacular hemorrhage (SMH) due to retinal arterial macroaneurysm (RAM) rupture. Methods: This multicenter retrospective study included 48 eyes with SMH due to RAM rupture. Cases underwent vitrectomy to displace SMH and were followed up for 6 months. We classified cases according to the presence of IRH and MH and compared the postoperative BCVA among the groups. Results: We classified the eyes into IRH(+)MH(+) group (10 eyes), IRH(+)MH(−) group (23 eyes), and IRH(−)MH(−) group (15 eyes). The postoperative BCVA was significantly worse in the IRH(+)MH(+) and IRH(+)MH(−) groups than in the IRH(−)MH(−) group (0.91 ± 0.41 in logarithm of the minimal angle of resolution units, Snellen equivalent 20/163, 0.87 ± 0.45, 20/148, and 0.18 ± 0.21, 20/30, respectively; P < 0.001). The postoperative central retinal thickness was significantly lower in the IRH(+) group (IRH(+)MH(+) and IRH(+)MH(−) groups combined) than in the IRH(−) group (IRH(−)MH(−) group) (121.4 ± 70.1 µm and 174.3 ± 32.9 µm, respectively, P = 0.008). The postoperative external limiting membrane and ellipsoid zone continuities were significantly discontinuous in the IRH(+) group (P < 0.001, P = 0.001, respectively). The multiple linear regression analysis showed that both IRH(+)MH(+) and IRH(+)MH(−) were associated with the postoperative BCVA (regression coefficient, 0.799 and 0.711, respectively; P < 0.001 for both). Conclusion: Both IRH and MH were poor prognostic indicators in cases with SMH due to RAM rupture.

Cell replacement therapy is expected as a new and more radical treatment against brain damage. We previously reported that transplanted human cerebral organoids extend their axons along the corticospinal tract in rodent brains. The axons reached the spinal cord but were still sparse. Therefore, this study optimized the host brain environment by the adeno-associated virus (AAV)-mediated expression of axon guidance proteins in mouse brain. Among netrin-1, SEMA3, and L1CAM, only L1CAM significantly promoted the axonal extension of mouse embryonic brain tissue-derived grafts. L1CAM was also expressed by donor neurons, and this promotion was exerted in a haptotactic manner by their homophilic binding. Primary cortical neurons cocultured on L1CAM-expressing HEK-293 cells supported this mechanism. These results suggest that optimizing the host environment by the AAV-mediated expression of axon guidance molecules enhances the effect of cell replacement therapy., 遺伝子治療によるホスト脳の環境最適化が細胞移植効果を高める --ホスト脳へのL1CAMの強制発現によるマウス胎仔脳移植片の軸索伸長促進効果--. 京都大学プレスリリース. 2023-03-24., Combining cell transplantation and gene therapy to enhance axonal outgrowth in the central nervous system. 京都大学プレスリリース. 2023-04-06.

Lipid interaction with α-synuclein (αSyn) has been long implicated in the pathogenesis of Parkinson’s disease (PD). However, it has not been fully determined which lipids are involved in the initiation of αSyn aggregation in PD. Here exploiting genetic understanding associating the loss-of-function mutation in Synaptojanin 1 (SYNJ1), a phosphoinositide phosphatase, with familial PD and analysis of postmortem PD brains, we identified a novel lipid molecule involved in the toxic conversion of αSyn and its relation to PD. We first established a SYNJ1 knockout cell model and found SYNJ1 depletion increases the accumulation of pathological αSyn. Lipidomic analysis revealed SYNJ1 depletion elevates the level of its substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3). We then employed Caenorhabditis elegans model to examine the effect of SYNJ1 defect on the neurotoxicity of αSyn. Mutations in SYNJ1 accelerated the accumulation of αSyn aggregation and induced locomotory defects in the nematodes. These results indicate that functional loss of SYNJ1 promotes the pathological aggregation of αSyn via the dysregulation of its substrate PIP3, leading to the aggravation of αSyn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3 itself or with PIP3 phosphatase inhibitor resulted in intracellular formation of αSyn inclusions. Indeed, in vitro protein–lipid overlay assay validated that phosphoinositides, especially PIP3, strongly interact with αSyn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates the fibrillation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brains of PD patients. Notably, the immunohistochemical and lipidomic analyses on postmortem brain of patients with sporadic PD showed increased PIP3 level and its colocalization with αSyn. Taken together, PIP3 dysregulation promotes the pathological aggregation of αSyn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD.

Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody–drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal.

Objectives We evaluated the clinical characteristics and outcomes of patients with COVID-19 who received three-drug combination regimens for treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) infections during a single-centre outbreak. Our objective was to describe the clinical outcomes and molecular characteristics and in vitro synergy of antibiotics against CRAB isolates. Materials and methods Patients with severe COVID-19 admitted between April and July 2020 with CRAB infections were retrospectively evaluated. Clinical success was defined as resolution of signs/symptoms of infection without need for additional antibiotics. Representative isolates underwent whole-genome sequencing (WGS) and in vitro synergy of two- or three-drug combinations was assessed by checkerboard and time-kill assays, respectively. Results Eighteen patients with CRAB pneumonia or bacteraemia were included. Treatment regimens included high-dose ampicillin-sulbactam, meropenem, plus polymyxin B (SUL/MEM/PMB; 72%), SUL/PMB plus minocycline (MIN; 17%) or other combinations (12%). Clinical resolution was achieved in 50% of patients and 30-day mortality was 22% (4/18). Seven patients had recurrent infections, during which further antimicrobial resistance to SUL or PMB was not evident. PMB/SUL was the most active two-drug combination by checkerboard. Paired isolates collected before and after treatment with SUL/MEM/PMB did not demonstrate new gene mutations or differences in the activity of two- or three-drug combinations. Conclusions Use of three-drug regimens for severe CRAB infections among COVID-19 resulted in high rates of clinical response and low mortality relative to previous studies. The emergence of further antibiotic resistance was not detected phenotypically or through WGS analysis. Additional studies are needed to elucidate preferred antibiotic combinations linked to the molecular characteristics of infecting strains.

Over-luminous type Ia supernovae (SNe Ia) show peculiar observational features, for which an explosion of a super-massive white dwarf (WD) beyond the classical Chandrasekhar-limiting mass has been suggested, largely based on their high luminosities and slow light-curve evolution. However, their observational features are diverse, with a few extremely peculiar features whose origins have not been clarified; strong and persisting C II lines, late-time accelerated luminosity decline and red spectra, and a sub-day time-scale initial flash clearly identified so far at least for three over-luminous SNe Ia. In the present work, we suggest a scenario that provides a unified solution to these peculiarities, through hydrodynamic and radiation transfer simulations together with analytical considerations; a C+O-rich envelope (~0.01 - 0.1 Msun) attached to an exploding WD. Strong C II lines are created within the shocked envelope. Dust formation is possible in the late phase, providing a sufficient optical depth thereafter. The range of the envelope mass considered here predicts an initial flash with time-scale of ~0.5 - 3 days. The scenario thus can explain some of the key diverse observational properties by a different amount of the envelope, but additional factors are also required; we argue that the envelope is distributed in a disc-like structure, and also the ejecta properties, e.g., the mass of the WD, plays a key role. Within the context of the hypothesized super-Chandrasekhar-mass WD scenario, we speculatively suggest a progenitor WD evolution including a spin-up accretion phase followed by a spin-down mass-ejection phase., Comment: 11 pages, 5 figures, 1 table. Accepted for publication in MNRAS. Typos corrected and references updated

The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential benefits of graft viability preservation and assessment before liver transplantation.With the Food and Drug Administration and institutional review board approval, 17 expanded criteria donor livers underwent sequential hypothermic oxygenated perfusion and normothermic machine perfusion using our institutionally developed perfusion device.Expanded criteria donor livers were from older donors, donors after cardiac death, with steatosis, hypertransaminasemia, or calcified arteries. Perfusion duration ranged between 1 and 2 hours for the hypothermic oxygenated perfusion phase and between 4 and 9 hours for the normothermic machine perfusion phase. Three livers were judged to be untransplantable during normothermic machine perfusion based on perfusate lactate, bile production, and macro-appearance. One liver was not transplanted because of recipient issue after anesthesia induction and failed reallocation. Thirteen livers were transplanted, including 9 donors after cardiac death livers (donor warm ischemia time 16-25 minutes) and 4 from donors after brain death. All livers had the standardized lactate clearance60% (perfusate lactate cleared to4.0 mmol/L) within 3 hours of normothermic machine perfusion. Bile production rate was 0.2 to 10.7 mL/h for donors after brain death livers and 0.3 to 6.1 mL/h for donors after cardiac death livers. After transplantation, 5 cases had early allograft dysfunction (3 donors after cardiac death and 2 donors after brain death livers). No graft failure or patient death has occurred during follow-up time of 6 to 13 months. Two livers developed ischemic cholangiopathy. Compared with our previous normothermic machine perfusion study, the bile duct had fewer inflammatory cells in histology, but the post-transplant outcomes had no difference.Sequential hypothermic oxygenated perfusion and normothermic machine perfusion preservation is safe and feasible and has the potential benefits of preserving and evaluating expanded criteria donor livers.

The emergence of the Alpha variant of novel coronavirus 2019 (SARS-CoV-2) is a concerning issue but their clinical implications have not been investigated fully.We conducted a nested case-control study to compare severity and mortality caused by the Alpha variant (B.1.1.7) with the one caused by the wild type as a control from December 2020 to March 2021, using whole-genome sequencing. 28-day mortality and other clinically important outcomes were evaluated.Infections caused by the Alpha variant were associated with an increase in the use of oxygen (43.4% vs 26.3%. p = 0.017), high flow nasal cannula (21.2% vs 4.0%, p = 0.0007), mechanical ventilation (16.2% vs 6.1%, p = 0.049), ICU care (30.3% vs 14.1%, p = 0.01) and the length of hospital stay (17 vs 10 days, p = 0.031). More patients with the Alpha variant received medications such as dexamethasone. However, the duration of each modality did not differ between the 2 groups. Likewise, there was no difference in 28-day mortality between the 2 groups (12% vs 8%, p = 0.48), even after multiple sensitivity analyses, including propensity score analysis.The Alpha variant was associated with a severe form of COVID-19, compared with the non-Alpha wild type, but might not be associated with higher mortality.

A 58-year-old man with diabetes, alcoholic cirrhosis and a history of cerebral contusion and traumatic subarachnoid haemorrhage visited the hospital after his first convulsion, which lasted for 30 s. He was intubated because of the prolonged disturbance of consciousness caused by his intermittent