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Abstract Tolvaptan-associated hepatic disorder is a rare, but lethal adverse event; however, the precise risk and time of onset remain unclear. This study aimed to characterize the severity, time‑to‑onset, and outcomes of hepatic disorder based on patient age and sex. Patient data were acquired from the Japanese Adverse Drug Event Report database (JADER) and the JAPIC AERS database, which consists of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) processed by the Japan Pharmaceutical Information Center. Hepatic disorder was classified as severe or nonsevere. Tolvaptan use was associated with hepatic disorder in analyses using the FAERS [Severe hepatic disorder: reporting odds ratio (ROR) 4.93, 95% confidence interval (CI) 4.33‒5.61; information component (IC) 2.11, 95% CI 1.92‒2.29; nonsevere hepatic disorder: ROR 6.78, 95% CI 6.01‒7.65; IC 2.51, 95% CI 2.33‒2.68] and the JADER (severe hepatic disorder: ROR 4.21, 95% CI 3.57‒4.97; IC 1.86, 95% CI 1.63‒2.10; nonsevere hepatic disorder: ROR 4.27, 95% CI 3.68‒4.95; IC 1.83, 95% CI 1.62‒2.04). A time‑to‑onset analysis revealed that the median onset time was significantly longer in patients aged < 60 years compared with patients aged ≥ 60, regardless of the severity (FAERS: severe hepatic disorder 7 vs. 58 days, p < 0.0001; nonsevere hepatic disorder 8 vs. 52.5 days, p < 0.0001; JADER: severe hepatic disorder 9.5 vs. 32 days, p = 0.0017; nonsevere hepatic disorder 9 vs. 89 days, p < 0.0001). Severe outcomes were observed, regardless of the severity of hepatic disorder. Patients should be monitored for liver function based on age to prevent fatal outcomes.

Abstract Ovarian cancer (OvCa) is one of the most lethal gynecological malignancies, and most patients are diagnosed at advanced stage with peritoneal dissemination. Although age at diagnosis is considered an independent prognostic factor, its impact on peritoneal recurrence after combined cytoreductive surgery and chemotherapy is not clear. The objective of this study was to investigate the impact of aging on peritoneal recurrence from stealth dissemination and gain insight of the pathophysiology of OvCa in elderly patients. A total of 243 patients with pT2b-pT3 epithelial ovarian who achieved complete surgery, no-residual tumor at first surgery, were selected to be analyzed the risk of peritoneal seeding and recurrence. We found that age over 65 years was independently associated with an increased risk of peritoneum-specific (PS) recurrence (. Furthermore, pT3 stages and positive ascites cytology also worsen the PS-relapse-free survival. Collectively, our findings suggest that age, especially over 65 years, predicts reduced peritoneum-specific tumor recurrence in patients with advanced ovarian cancer after complete cytoreduction surgery, particularly those with pT3 tumors and positive ascites cytology.

Abstract Human mesenchymal stem cells (hMSCs) with extended lifespan and differentiation potential that can recapitulate in vivo characteristics could significantly contribute to basic research, drug development, and cell therapy. Specifically, they could ensure a stable supply of specific cellular resources, and possibly extracellular vesicles. Here, we established a technology for extending the lifespan while maintaining differentiation potential, termed “rejuvenation,” of hMSCs (rej-hMSCs) using nonintegrative and conditionally removable temperature-sensitive Sendai virus (SeV) vectors. Various immortalizing factors (i.e., Bmi-1, hTERT, SV40T, and/or HPV E6/E7) were first introduced by the SeV vector into the cells. A combination of three SeVs with Bmi-1, hTERT, or SV40T conferred markedly improved cell proliferation and cloning ability while maintaining differentiation potential and a normal karyotype. An extended lifespan was also demonstrated in other cell types. The rejuvenation of long-passaged or aged hMSCs was also confirmed. SeV vectors were rapidly removed as a function of cell doubling by increasing the temperature from 35 °C to 37 °C or higher, while proliferative ability was maintained. Following FACS sorting, the complete removal of SeV vectors was confirmed by qPCR analyses. Therefore, our cell rejuvenation technology could contribute to research and clinical applications by enabling the supply of modified cells without damaging host chromosomes.

Background: Alagille syndrome (AGS) is a rare cause of prolonged jaundice. It has an autosomal dominant inheritance pattern expressed variably, with a reported incidence of 1:100,000 live births in the United States. The objective is to highlight the clinical features and diagnostic challenges to this rare cause of cholestatic jaundice. Case Report: T.O, Female 11 years, had a history of recurrent episodes of yellowness of the eyes, first noticed soon after birth, associated with pale stools, dark urine, and body itching. From age three she was noticed to have progressive loss of sight, recurrent body swellings and irrational talks. She was diagnosed to have a cardiac murmur at age six, when diagnosis of ALS was made due to features of, recurrent jaundice and perculiar facies of broad forehead, flat nasal bridge, prognathia and genetic report of no mutation in JAG 1 gene, karyotype 46XX. At the time of current hospital admission she was in addition small for age, had hepatosplenomegy, ascities and talked irrationally. Chest radiograph showed multiple butterfly vertebrae; Echocardiograph aortic and pulmonary stenosis; Liver aminotransferase were marked elevated. Brain MRI showed multiple chronic infarcts. She was diagnosed with Allagille syndrome presenting in hepatic failure with encephalopathy. Conclusion: Allagille syndrome should be considered early in older children with persistent cholestatic jaundice.

Abstract The prognostic significance of unconventional histology (UH) subtypes including intraductal carcinoma of the prostate (IDC-P), ductal adenocarcinoma, and cribriform pattern has been investigated for prostate cancer (PCa). However, little is known about magnetic resonance imaging (MRI) features and the oncological impact of tumor localization in localized PCa with UH. Clinical data of 211 patients with acinar adenocarcinoma (conventional histology [CH]) and 82 patients with UH who underwent robotic-assisted radical prostatectomy (RARP) were reviewed. Patients with UH are more likely to be older and have higher Gleason grade group, higher Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 score, and larger tumor volume (TV) than those with CH. Multivariate analysis identified the presence of UH as an independent prognostic factor for progression-free survival (PFS) (hazard ration (HR) 2.41, 95% confidence interval (CI) 0.22–0.79, P = 0.0073). No significant difference in PFS was seen regarding tumor localization (transition zone [TZ] or peripheral zone [PZ]) in patients with UH (P = 0.8949), whereas PZ cancer showed shorter PFS in patients with CH (P = 0.0174). PCa with UH was associated with higher progression than PCa with CH among resection margin (RM)-negative cases (P

Abstract Despite high vaccination rates globally, countries are still grappling with new COVID infections, and patients diagnosed as mild dying at home during outpatient treatment. Hence, this study aim to identify, then validate, biomarkers that could predict if newly infected COVID-19 patients would subsequently require hospitalization or could recover safely with medication as outpatients. Serum cytokine/chemokine data from 129 COVID-19 patients within 7 days after the onset of symptoms in Bangladesh were used as training data. The majority of patients were infected with the Omicron variant and over 88% were vaccinated. Patients were divided into those with mild symptoms who recovered, and those who deteriorated to moderate or severe illness. Using the Lasso method, 15 predictive markers were identified and used to classify patients into these two groups. The biomarkers were then validated in a cohort of 194 Covid patients in Japan with a predictive accuracy that exceeded 80% for patients infected with Delta and Omicron variants, and 70% for Wuhan and Alpha variants. In an environment of widespread vaccination, these biomarkers could help medical practitioners determine if newly infected COVID-19 patients will improve and can be managed on an out-patient basis, or if they will deteriorate and require hospitalization.

BackgroundStroke is a global societal challenge. Annually, 13 million people experience stroke, and the prevalence of stroke is increasing in low-income countries; hence, accessible rehabilitation needs to be developed. Information and communication technology can help by providing access to rehabilitation support through information, self-evaluation, and self-management of rehabilitation. The F@ce 2.0 rehabilitation program provides support in goal-setting and problem-solving strategies through phone calls from the interventionist twice a week and daily SMS text message reminders over 8 weeks to improve performance in valued activities in everyday life. Our hypothesis is that F@ce 2.0 will increase functioning in daily activities and participation in everyday life as well as improve performance and satisfaction in valued daily activities and self-efficacy (ie, confidence in own ability to perform activities) among people living with the consequences of stroke. ObjectiveThis study aims to implement F@ce 2.0, a mobile phone–supported and family-centered rehabilitation program, and evaluate its effects on performance in daily activities and participation in everyday life in comparison to ordinary rehabilitation among persons with stroke and their family members in Uganda. An additional aim is to explore experiences of participating in F@ce 2.0 and plausible mechanisms of impact that might explain the potential effects of F@ce 2.0. MethodsA randomized controlled trial will be conducted to compare the outcomes of the F@ce 2.0 group and a control group receiving ordinary rehabilitation. Health care professionals will recruit 90 clients from both urban and rural areas. The primary outcomes for persons with stroke are perceived performance in daily activities assessed using the Canadian Occupational Performance Measure and self-efficacy assessed using the Self-Efficacy Scale; for family members, the primary outcome is caregiver burden evaluated using the Caregiver Burden Scale. Descriptive statistics will be used to present characteristics and outcomes at 3 and 6 months. All statistical analyses comparing the outcomes at the different time points between the F@ce 2.0 and control groups will be performed using intention-to-treat analysis. Qualitative interviews will be used to explore the experiences of persons with stroke and their family members participating in F@ce 2.0, using a grounded theory approach to data collection and analysis. A process evaluation will be conducted using a single-case study design with mixed methods to explore the implementation process. ResultsRecruitment and data collection in the randomized controlled trial were initiated in January 2022 and have been completed. The intervention has been provided to 51 participants in the intervention group. Interviews of persons with stroke, family members, and health care professionals have been conducted. Data analysis will be performed during autumn 2024 and spring 2025. ConclusionsThis study will provide evidence of the plausible effects of F@ce 2.0 and the process of implementing the program in low-income countries. International Registered Report Identifier (IRRID)DERR1-10.2196/60955

Abstract Breccia and pulverized rock are typical textures in off-fault damage adjacent to a main seismogenic zone. Previously, by estimating the energy required to advance the rupture in this zone using particle size distribution at sub-millimeter/micrometer scales, we could constrain the energy budget during coseismic events. However, whether microscopic estimation is sufficient to capture surface energy fragmentation during an earthquake and the effect of measurement scale variation on calculation of co-seismic energy partitioning remained unclear. Here, we investigated the mechanism of coseismic off-fault damage based on field and microstructural observations of a well-exposed breccia body in Ichinokawa, Japan. We used in situ clast measurements coupled with thin-section analysis of breccia clasts to estimate the energy budget of the damage zone adjacent to the principal slip zone of the Median Tectonic Line (MTL). The total surface energy density and corresponding surface energy per unit fault for a width of ~ 500 m of the dynamical damage zone were estimated. The moment magnitude estimated based on surface energy was 5.8–8.3 Mw. In Ichinokawa, off-fault fragmentation is initiated by coseismic activity and is followed by fluid activity. Under dynamic fragmentation conditions, the scale is important to calculate the surface energy.

Abstract Recent research has highlighted the importance of the gut microbiome in regulating aging, and probiotics are interventions that can promote gut health. In this study, we surveyed several novel lactic acid bacteria to examine their beneficial effect on organismal health and lifespan in C. elegans. We found that animals fed some lactic acid bacteria, including L. acidophilus 1244 and L. paracasei subsp. paracasei 2004, grew healthy. Supplementation with the lactic acid bacterial strains L. acidophilus 1244 or L. paracasei subsp. paracasei 2004 significantly improved health, including food consumption, motility, and resistance to oxidative stressor, hydrogen peroxide. Our RNA-seq analysis showed that supplementation with L. paracasei subsp. paracasei 2004 significantly increased the expression of daf-16, a C. elegans FoxO homolog, as well as genes related to the stress response. Furthermore, daf-16 deletion inhibited the longevity effect of L. paracasei subsp. paracasei 2004 supplementation. Our results suggest that L. paracasei subsp. paracasei 2004 improves health and lifespan in a DAF-16-dependent manner.

Abstract Background In Rwanda, nurses manage all primary care at health centres, and therefore are their clinical reasoning skills important. In this study, a web-based software that allows the creation of virtual patient cases (VP cases) has been used for studying the possibility of using VP cases for the continuous professional development of nurses in primary health care in Rwanda. Previous studies in pre-service education have linked VP cases with the enhancement of clinical reasoning, a critical competence for nurses. This study investigated the feasibility of continuous professional development through VP cases to further train in-service nurses in clinical reasoning. Method The study used a pre-post test design. Initially, seventy-six participants completed a questionnaire as part of the pre-test phase, subsequently invited to engage with all four VP cases, and finally responded to the post-test questionnaire evaluating clinical reasoning skills. Fifty-six participants successfully completed the entire study process and were considered in the analysis. The primary outcomes of this study were evaluated using a paired t-test for the statistical analysis. Results The results show that the mean score of clinical reasoning increased significantly from the pre-test to the post-test for all four illness areas (p

Abstract Understanding the factors that influence people’s decisions regarding vaccination is essential to promote vaccination. We aimed to clarify the motivations for receiving booster vaccines. We conducted a paper-based questionnaire distributed during January–February 2022 involving students and faculty staff who received the first COVID-19 vaccination at the mass vaccination program during June–September 2021 at Keio University. A total of 1725 participants were enrolled, and all completed the survey. Among these, 64.9% reported a significant adverse event (AEs) affecting daily life after the second vaccine. “Fear of severe COVID-19 illness” (72.6%) was the most common reason for getting vaccinated, followed by “concern of infecting others” (68.4%) and “fear of COVID-19 infection itself” (68.3%). Television emerged as the most influential source of information (80%), followed by university information (50.2%) and social networking sites (42.8%). Multivariate analysis revealed “fear of severe COVID-19 illness”, “fear of COVID-19 infection itself”, and “trust in the efficacy and safety of the vaccines in general” were significantly correlated with willingness to receive paid vaccinations. The severity of AEs and source of information were not related to participants’ willingness to receive booster vaccinations. Participants with positive reasons for vaccination were more likely to accept a third dose.

Abstract Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to contract multiple muscle groups simultaneously. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly through mitochondrial biosynthesis. This study examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for one week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague–Dawley rats using belt electrodes attached to both ankle joints. After acute stimulation, a significant decrease in the glycogen content was observed in the left and right TA and GAS, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN + electrically stimulated with B-SES (DEN + ES) groups. After seven days of treatment, the wet weight (n = 8–11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN + ES groups compared with that in the CON group. The DEN + ES group showed significantly higher muscle weight and CSA than those in the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial biogenesis is a critical event in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 18S (n = 6) levels in the DEN + ES group were higher than those in the DEN group, even though RNA-seq showed that the ribosome biogenesis pathway was reduced by electrical stimulation. The mRNA levels of the muscle proteolytic molecules atrogin-1 and MuRF1 were significantly higher in DEN than those in CONT. However, they were more suppressed in DEN + ES than those in DEN. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes effectively reduced denervation-induced atrophy in multiple muscle groups. Furthermore, ribosomal biosynthesis plays a vital role in this phenomenon.

Introduction In an MRI-guided linear accelerator (MR-LINAC) system, the planned doses for organs at risk and for tumours are assessed by MR imaging and re-contouring at every treatment. This allows treatment to be safer and more precise by ensuring that it is suitable for the state of the patient’s organs on that day, as well as by allowing images to be acquired during radiation therapy to prevent radiation while organs are in motion.Here, we will conduct a confirmatory study of two-fractionated stereotactic magnetic resonance-guided adaptive radiation therapy for patients with localised prostate cancer.Methods and analysis This will be a single-arm study to demonstrate the safety and efficacy of ultra-hypofractionated radiation (26 Gy/2 Fr) using an MR-LINAC system in patients with very low-intermediate risk prostate cancer.The primary endpoint will be the incidence of grade ≥2 acute urinary tract adverse events occurring within 90 days of the start of radiation therapy.The sample size has been determined to be 58.Ethics and dissemination This study is performed in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects, published by Japan’s Ministry of Education, Science and Technology and the Ministry of Health, Labour and Welfare and the modified act on the Protection of Personal Information as well as the Declaration of Helsinki. This study was approved by the institutional ethics committee of the National Cancer Center on 20 November 2021.The findings of this trial will be submitted to an international peer-reviewed journal and the key findings will be presented at an international scientific conference.Authorship will be ascribed in accordance with the International Committee of Medical Journal Editors guidance.Trial registration number UMIN000049746.

Introduction To date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that provides real-time, objective and quantifiable kinetic data, including changes in the lung area (Rs), tracheal diameter, diaphragmatic kinetics and pulmonary ventilation during respiration, at a lower radiation dose than that used by fluoroscopic or CT imaging. However, the therapeutic effect of dual bronchodilators on respiratory kinetics, such as chest wall dynamics and respiratory muscle function, has not yet been prospectively evaluated using DCR.Aim This study aims to evaluate the effects of bronchodilator therapy on respiratory kinetics in patients with COPD using DCR.Methods and analysis This is an open-label, prospective, single-centre, non-controlled, comparative study. A total of 35 patients with COPD, aged 40–85 years, with a forced expiratory volume in the first second of 30–80%, will be enrolled. After a 2–4 weeks washout period, patients will receive tiotropium/olodaterol therapy for 6 weeks. Treatment effects will be evaluated based on DCR findings, pulmonary function test results and patient-related outcomes obtained before and after treatment. The primary endpoint is the change in Rs after therapy. The secondary endpoints include differences in other DCR parameters (diaphragmatic kinetics, tracheal diameter change and maximum pixel value change rate), pulmonary function test results and patient-related outcomes between pre-therapy and post-therapy values. All adverse events will be reported.Ethics and dissemination Ethical approval for this study was obtained from the Ethics Committee of Chiba University Hospital. The results of this trial will be published in a peer-reviewed journal.Trial registration number jRCTs032210543.

Introduction Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications.Methods and analysis The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age

Abstract Each year, new influenza virus vaccine formulations are generated to keep up with continuously circulating and mutating viral variants. A next-generation influenza virus vaccine would provide long-lasting, broadly-reactive immune protection against current and future influenza virus strains for both seasonal and pre-pandemic viruses. Next generation immunogens were designed using computationally optimized broadly reactive antigen (COBRA) methodology to protect against a broad range of strains over numerous seasons. Novel HA and NA amino acid sequences were derived from multilayered consensus sequence alignment for multiple subtypes of influenza. This multivalent formulation was hypothesized to elicit broadly protective immune responses against both seasonal and pre-pandemic influenza viruses. Mice were vaccinated with multivalent mixtures of HA and NA (H1, H2, H3, H5, H7, N1, N2) proteins. Multivalent COBRA vaccinations elicited antibodies that recognized a broad panel of strains and vaccinated mice were protected against viruses representing multiple subtypes. This is a promising candidate for a universal influenza vaccine that elicits protective immune responses against seasonal and pre-pandemic strains over multiple seasons.

Synanthropic wild rodents associated with agricultural operations may represent a risk path for transmission of high pathogenicity avian influenza viruses (HPAIVs) from wild birds to poultry birds. However, their susceptibility to HPAIVs remains unclear. In the present study, house mice (Mus musculus), brown rats (Rattus norvegicus), and black rats (Rattus rattus) were experimentally exposed to H5N1 subtype HPAIVs to evaluate their vulnerability to infection. After intranasal inoculation with HA clade 2.2 and 2.3.2.1 H5N1 subtype HPAIVs, wild rodents did not show any clinical signs and survived for 10- and 12-day observation periods. Viruses were isolated from oral swabs for several days after inoculation, while little or no virus was detected in their feces or rectal swabs. In euthanized animals at 3 days post-inoculation, HPAIVs were primarily detected in respiratory tract tissues such as the nasal turbinates, trachea, and lungs. Serum HI antibodies were detected in HA clade 2.2 HPAIV-inoculated rodents. These results strongly suggest that synanthropic wild rodents are susceptible to infection of avian-origin H5N1 subtype HPAIVs and contribute to the virus ecosystem as replication-competent hosts. Detection of infectious viruses in oral swabs indicates that wild rodents exposed to HPAIVs could contaminate food, water, and the environment in poultry houses and play roles in the introduction and spread of HPAIVs in farms.

The widespread presence of Fusarium mycotoxins in animal feed is a global issue, not only for the health of livestock but also for ensure the safety of food as an end product. High concentrations of zearalenone (ZEN) and deoxynivalenol (DON) have been detected in the diets of Japanese Black (JB) and Holstein Friesian (HF) breeding herds. Consequently, we monitored serum biochemical parameters over a long time in both herds, focusing on anti-Müllerian hormone (AMH) levels and acute-phase inflammation. Additionally, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and progesterone levels were measured in the HF herd. The JB herd, a ZEN-dominant model with low DON contamination, demonstrated ZEN levels that exceeded the Japanese limit in the purchased total mixed rations (TMR). Conversely, the HF herd, which primary consumes DON-dominant feed with low ZEN contamination, had high DON levels in the dent corn silage. Specifically, the JB herd’s TMR contained 1.79 mg/kg ZEN and 0.58 mg/kg DON, whereas the HF herd’s silage had 15.3 mg/kg DON (dried sample) and 0.1 mg/kg ZEN. Enzyme-linked immunoassay were used to measure urinary ZEN-DON levels following confirmation through liquid chromatography-tandem mass spectrometry. Urinary ZEN-DON levels measured were significantly correlated (p < 0.05, r > 0.6) in both herds. In the HF herd, AMH levels increased (p = 0.01) and serum amyloid A (SAA) levels decreased (p = 0.02) when contaminated and at the end of the monitoring period. Additionally, urinary ZEN and DON levels were significantly correlated with SAA levels (ZEN: p = 0.00, r = 0.46; DON: p = 0.03, r = 0.33), with an increase in ZEN and DON levels resulting in higher SAA levels. The JB herd showed no significant differences. Additionally, in the HF herd, 8-OHdG/Cre levels increased significantly during major contamination periods (p < 0.05). Clinical data from the HF herd indicated an increase in mastitis cases and treatment rates during periods of major contamination. Abortion rates in the HF herd decreased from 22.9% (before monitoring) to 8.9% (during the high contamination period) and finally to 1% (at the end of the monitoring period), with corresponding increases in progesterone levels. ZEN-DON contamination adversely affects breeding cattle’s productivity, reproductive performance, and health. Therefore, monitoring urinary ZEN-DON is valuable for detecting contaminants and ensuring the safety of food products.

Abstract Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25–50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

Abstract Although Sepsis-3 doesn’t require evidence of bacteremia to diagnose sepsis, clinicians often want to identify the causative pathogen at autopsy. In principle, if the blood cultures are the same at ante- and postmortem, the cause of death is obvious. However, interpretations of postmortem blood cultures are often difficult due to discordance, negativity, mixed infection, and contamination, of pathogens occupying ≥ 50% of the tests. To increase specificity identifying agonal phase sepsis in the situations where blood cultures are discordant, multiple or negative at postmortem, we established a scoring system using blood cultures, procalcitonin (PCN) showing highest sensitivity and specificity for postmortem serum, and bone marrow polyhemophagocytosis (PHP). Histological sepsis showed significantly higher levels of culture score (2.3 ± 1.5 vs. 0.4 ± 0.5, p

[This corrects the article DOI: 10.1371/journal.pone.0253178.].

Abstract Silicone is often used in environments where water repellency is an advantage. Contact with water promotes the adhesion of microorganisms and biofilm formation. Depending on the application, this may increase the possibility of food poisoning and infections, the material's degrading appearance, and the likelihood of manufacturing defects. The prevention of microbial adhesion and biofilm formation is also essential for silicone-based elastomeric foams, which are used in direct contact with human bodies but are often difficult to clean. In this study, the microbial attachment in and the retention from the pores of silicone foams of different compositions is described and compared to those of commonly used polyurethane foams. The growth of the gram-negative Escherichia coli in the pores and their leaching during wash cycles is characterised by bacterial growth/inhibition, adhesion assay, and SEM imaging. The structural and surface properties of the materials are compared. Despite using common antibacterial additives, we have found that non-soluble particles stay isolated in the silicone elastomer layer, thus affecting surface microroughness. Water-soluble tannic acid dissolves into the medium and seems to aid in inhibiting planktonic bacterial growth, with a clear indication of the availability of tannic acid on the surfaces of SIFs.

Abstract Dystrophin maintains membrane integrity as a sarcolemmal protein. Dystrophin mutations lead to Duchenne muscular dystrophy, an X-linked recessive disorder. Since dystrophin is one of the largest genes consisting of 79 exons in the human genome, delivering a full-length dystrophin using virus vectors is challenging for gene therapy. Human artificial chromosome is a vector that can load megabase-sized genome without any interference from the host chromosome. Chimeric mice carrying a 2.4-Mb human dystrophin gene-loaded human artificial chromosome (DYS-HAC) was previously generated, and dystrophin expression from DYS-HAC was confirmed in skeletal muscles. Here we investigated whether human dystrophin expression from DYS-HAC rescues the muscle phenotypes seen in dystrophin-deficient mice. Human dystrophin was normally expressed in the sarcolemma of skeletal muscle and heart at expected molecular weights, and it ameliorated histological and functional alterations in dystrophin-deficient mice. These results indicate that the 2.4-Mb gene is enough for dystrophin to be correctly transcribed and translated, improving muscular dystrophy. Therefore, this technique using HAC gives insight into developing new treatments and novel humanized Duchenne muscular dystrophy mouse models with human dystrophin gene mutations.

Lower back pain, a common issue among pregnant women, often complicates daily activities like standing up from a chair. Therefore, research into the standing motion of pregnant women is important, and many research studies have already been conducted. However, many of these studies were conducted in highly controlled environments, overlooking everyday scenarios such as using a desk for support when standing up, and their effects have not been adequately tested. To address this gap, we measured multimodal signals for a sit-to-stand (STS) movement with hand assistance and verified the changes using a t-test. To avoid imposing strain on pregnant women, we used 10 non-diseased young adults who wore jackets designed to simulate pregnancy conditions, thus allowing for more comprehensive and rigorous experimentation. We attached surface electromyography (sEMG) sensors to the erector spinae muscles of participants and measured changes in muscle activity, skeletal positioning, and center of pressure both before and after wearing a Maternity-Simulation Jacket. Our analysis showed that the jacket successfully mimicked key aspects of the movement patterns typical in pregnant women. These results highlight the possibility of developing practical strategies that more accurately mirror the real-life scenarios met by pregnant women, enriching the current research on their STS movement.

Key Clinical Message Acute pancreatitis can present with a colon cutoff sign. The colon cutoff sign can also occur in gastric cancer, splenic artery bleeding, and ruptured abdominal aortic aneurysm. A CT scout image can also be an important laboratory finding for diagnosing a disease. Abstract A 22‐year‐old woman visited our hospital with a complaint of epigastric pain. An abdominal contrast‐enhanced computed tomography (CT) scan revealed that intestinal gas was interrupted at the splenic flexure on the CT scout image (colon cutoff sign). Scan images showed a poorly contrasted area in the pancreatic tail. Based on these results, the patient was diagnosed with acute pancreatitis. The colon cutoff sign is an image showing the spread of inflammation to the colon. A CT scout image can also be an important laboratory finding for diagnosing a disease.

Abstract High-density lipoprotein (HDL) cholesterol efflux capacity (CEC), which is a conventional metric of HDL function, has been associated with coronary heart disease risk. However, the CEC assay requires cultured cells and takes several days to perform. We previously established a cell-free assay to evaluate cholesterol uptake capacity (CUC) as a novel measure of HDL functionality and demonstrated its utility in coronary risk stratification. To apply this concept clinically, we developed a rapid and sensitive assay system based on a chemiluminescent magnetic particle immunoassay. The system is fully automated, providing high reproducibility. Measurement of CUC in serum is completed within 20 min per sample without HDL isolation, a notably higher throughput than that of the conventional CEC assay. CUC decreased with myeloperoxidase-mediated oxidation of HDL or in the presence of N-ethylmaleimide, an inhibitor of lecithin: cholesterol acyltransferase (LCAT), whereas CUC was enhanced by the addition of recombinant LCAT. Furthermore, CUC correlated with CEC even after being normalized by ApoA1 concentration and was significantly associated with the requirement for revascularization due to the recurrence of coronary lesions. Therefore, our new assay system shows potential for the accurate measurement of CUC in serum and permits assessing cardiovascular health.

Abstract Homology-directed repair-mediated knock-in (HDR-KI) in combination with CRISPR-Cas9-mediated double strand break (DSB) leads to high frequency of site-specific HDR-KI. While this characteristic is advantageous for generating genetically modified cellular and animal models, HDR-KI efficiency in mammalian cells remains low. Since avian DT40 cells offer distinct advantage of high HDR-KI efficiency, we expanded this practicality to adapt to mammalian research through sequential insertion of target sequences into mouse/human artificial chromosome vector (MAC/HAC). Here, we developed the simultaneous insertion of multiple fragments by HDR method termed the simHDR wherein a target sequence and selection markers could be loaded onto MAC simultaneously. Additionally, preparing each HDR donor containing homology arm by PCR could bypass the cloning steps of target sequence and selection markers. To confirm the functionality of the loaded HDR donors, we constructed a MAC with human leukocyte antigen A (HLA-A) gene in the DT40 cells, and verified the expression of this genomic region by reverse transcription PCR (RT-PCR) and western blotting. Collectively, the simHDR offers a rapid and convenient approach to generate genetically modified models for investigating gene functions, as well as understanding disease mechanisms and therapeutic interventions.

Abstract Cross-modal correspondences refer to associations between feature dimensions of stimuli across sensory modalities. Research has indicated that correspondence between audiovisual stimuli influences whether these stimuli are integrated or segregated. On the other hand, the audiovisual integration process plastically changes to compensate for continuously observed spatiotemporal conflicts between sensory modalities. If and how cross-modal correspondence modulates the “recalibration” of integration is unclear. We investigated whether cross-modal correspondence between auditory pitch and visual elevation affected audiovisual temporal recalibration. Participants judged the simultaneity of a pair of audiovisual stimuli after an adaptation phase in which alternating auditory and visual stimuli equally spaced in time were presented. In the adaptation phase, auditory pitch and visual elevation were manipulated to fix the order within each pairing of audiovisual stimuli congruent with pitch-elevation correspondence (visual leading or auditory leading). We found a shift in the point of subjective simultaneity (PSS) between congruent audiovisual stimuli as a function of the adaptation conditions (Experiment 1, 2), but this shift in the PSS was not observed within incongruent pairs (Experiment 2). These results indicate that asynchronies between audiovisual signals congruent with cross-modal correspondence are selectively recalibrated.

Abstract Belt electrode skeletal muscle electrical stimulation (B-SES) can simultaneously contract multiple muscle groups. Although the beneficial effects of B-SES in clinical situations have been elucidated, its molecular mechanism remains unknown. In this study, we developed a novel rodent B-SES ankle stimulation system to test whether low-frequency stimulation prevents denervation-induced muscle atrophy. Electrical stimulations (7‒8 Hz, 30 min) with ankle belt electrodes were applied to Sprague–Dawley rats daily for one week. All animals were assigned to the control (CONT), denervation-induced atrophy (DEN), and DEN + electrical stimulation (ES) groups. The tibialis anterior (TA) and gastrocnemius (GAS) muscles were used to examine the effect of ES treatment. After seven daily sessions of continuous stimulation, muscle wet weight (n = 8–11), and muscle fiber cross-sectional area (CSA, n = 4–6) of TA and GAS muscles were lower in DEN and DEN + ES than in CON. However, it was significantly higher in DEN than DEN + ES, showing that ES partially prevented muscle atrophy. PGC-1α, COX-IV, and citrate synthase activities (n = 6) were significantly higher in DEN + ES than in DEN. The mRNA levels of muscle proteolytic molecules, Atrogin-1 and Murf1, were significantly higher in DEN than in CONT, while B-SES significantly suppressed their expression (p

Abstract Background Due to outbreaks of new diseases, development of new treatment regimens and requirement of evidence-based practice, health professionals continuously need to acquire updated knowledge and skills. This type of learning is known as continuous professional development (CPD). The scarcity of skilled health care professionals in developing countries further increases the need of CPD. Traditionally, face-to-face approach has been preferred as the best mode of CPD. Currently, health professionals have started using online learning for continued professional growth in different parts of the world. Consequently, research studies from different settings are needed to investigate the significance of online learning for CPD. Therefore, the aim of this study was to investigate the importance and challenges attributed to online learning by the managers of health facilities in Rwanda. Moreover, the study aimed to identify the status of infrastructures that could support online CPD, and assess the perceived enhancement and barriers for implementing online CPD. Methods The study used a convergence mixed-method design to explore quantitative and qualitative data from 42 health care managers. A descriptive analysis was conducted on quantitative data while qualitative data were thematically analyzed to inform the study findings. Results It was revealed that 90.5% of managers, who participated in this study, consider positively the use of online learning for CPD. All managers acknowledged that online learning could improve the knowledge and practice skills of health care professionals. Nevertheless, 52.4% of health institutions who participated in this study currently do not use online for CPD. Participants demonstrated challenges such as the lack of access to digital devices, poor or lack of internet access, poor online learning design, low digital skills of healthcare professionals, lack of time dedicated to online learning, and heavy workload of staff. Conclusion These findings indicate then that the managers of health institutions value the importance of online learning for CPD of health professionals. However, online learning should be designed to fit for the purpose and with a high consideration on needs and preferences of healthcare professionals and thereby improve information communication technology infrastructure that support online learning for CPD. Traditional in-person CPD courses are still recommended in health institutions with shortage in resources and technology. Also, the barriers of online CPD delivery such as low internet connectivity and lack of access to digital devices by healthcare professionals need to be co-creatively addressed through the pyramidal structure of the Rwandan health system.

Introduction Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO.Methods and analysis The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged

This study investigated the effects of visual conditions associated with progressive eye disease on movement patterns and anxiety levels during gap-crossing tasks. Notably, 15 healthy young adults performed crossover platforms with a 10 cm gap at three different heights, namely equal (0 cm), raised (+15 cm), and lowered (−15 cm) levels, under four vision conditions, namely normal or corrected eyesight, 10° tunnel vision, 5° tunnel vision, and 5° tunnel vision with 0.04 occlusion. Leg movements during gap crossing were analyzed using three-dimensional motion analysis. The results highlighted a distinct motion pattern in the trajectories of participants’ legs under the different visual conditions. Specifically, at the point where the gap-crossing movement began (D1), the normal or corrected eyesight conditions resulted in further separation between the steps compared with the other visual conditions. The highest point of the foot during movement (D2) did not differ between the visual conditions, except for the 0 cm step. Furthermore, anxiety levels, as quantified by the State-Trait Anxiety Inventory (STAI-S) questionnaire, were exacerbated under conditions of restricted visual information. In conclusion, visual impairments associated with progressive ocular diseases may perturb complex motor movement patterns, including those involved in gap-crossing tasks, with heightened anxiety potentially amplifying these disturbances.

Abstract The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.

Abstract Bank erosion is an important source of sediment and phosphorus to inland fluvial systems and is generally responsible for more than half of the total watershed sediment export. Numerous studies have quantified bank erosion and the spatio-temporal variation of sediment flux in different watersheds. However, there is sparse research to date on the linkages between bank erosion/accretion and sediment export under different land uses, especially in rapidly evolving peri-urban watersheds. This research, therefore, integrated remote sensing techniques and repeated field survey of erosion pin plots to quantify bank erosion and sediment flux in the 80 km2 Nkisi River watershed (NRW), southeast Nigeria, over a three-year period. The impact of land use change on streambank erosion was evaluated by utilising remotely sensed Landsat datasets of 2003, 2010, 2016 and 2019. Geotechnical tests were used to characterise the lithologic properties of the banks, while the Bank Stability and Toe Erosion Model (BSTEM) was used to determine the stability of the banks under various hydrological conditions and mechanical properties of the riparian vegetation. Mean bank recession rates increased from 10.7 cm during the 2017–2018 monitoring period to 17.5 cm for the 2019–2020 monitoring period. The percentage of total watershed export ascribed to bank erosion in the three stream reaches varied from 6.6 to 44.9%. The high rates of bank erosion and accretion within the NRW were attributed to rapid changes in land use, which evolved from grassland and woodland to cropland, built-up and bare land. The BSTEM accurately predicted the high erosion rates of the streambanks and showed that riparian vegetation has a mechanical effect on bank stability. However, the mechanical effect diminishes as the depth to water table rises during high streamflow events.

BackgroundMore than 75% of patients with breast cancer treated with chemotherapy experience cognitive impairments (eg, memory and attention problems), commonly known as chemo-brain. Exercise, especially aerobic high-intensity interval training (HIIT), is associated with better cognitive function in healthy populations. However, clinical trials testing the impact of exercise interventions on chemotherapy-induced cognitive decline in patients with cancer are lacking, and the mechanisms through which exercise could improve cognitive function are unclear. ObjectiveThe objective of the Improving Cognitive Function Through High-Intensity Interval Training in Breast Cancer Patients Undergoing Chemotherapy trial is to examine the effects of HIIT on cognitive function in patients with breast cancer undergoing chemotherapy. MethodsThis 2-arm, single-center, pilot randomized controlled trial will randomize 50 patients with breast cancer undergoing chemotherapy to HIIT or attention control. The HIIT group will perform a supervised 16-week, thrice-weekly intervention, with each session including a 5-minute warm-up at 10% maximal power output (POmax), 10 sets of alternating 1-minute high-intensity (90% POmax) and 1-minute recovery (10% POmax) intervals, and a 5-minute cooldown (10% POmax). The attention control group will receive a stretching program with no exercise components and be asked to maintain their exercise levels for 16 weeks. The primary outcomes of the study are executive function and memory measured using the National Institutes of Health toolbox and resting-state connectivity and diffusion tensor imaging microstructure evaluated using magnetic resonance imaging. The secondary and tertiary outcomes include cardiorespiratory fitness, body composition, physical fitness, and psychosocial health. The study has been approved by the institutional review board of the Dana-Farber Cancer Institute (20-222). ResultsThe trial was funded in January 2019, with recruitment started in June 2021. As of May 2022, a total of 4 patients have consented and been randomized (n=2, 50% to exercise; n=1, 25% to control; and n=1, 25% nonrandomized). Trial completion is expected in January 2024. ConclusionsThis first-of-its-kind study incorporates a novel exercise intervention (ie, HIIT) and comprehensive cognitive measures. If positive, our findings will establish the pilot efficacy of HIIT on chemotherapy-induced cognitive function in patients with breast cancer, providing the foundation for future larger phase-II and phase-III trials to confirm the findings and potentially establish HIIT as a standard of care for women undergoing chemotherapy for breast cancer. Trial RegistrationClinicalTrials.gov NCT04724499; https://clinicaltrials.gov/ct2/show/NCT04724499 International Registered Report Identifier (IRRID)DERR1-10.2196/39740

Objectives To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.Design Retrospective study.Setting Six hundred and thirty-one primary care institutions in Japan.Participants Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.Primary and secondary outcome measures Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).Results In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.Conclusions The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

Abstract A cytokine storm induces acute respiratory distress syndrome, the main cause of death in coronavirus disease 2019 (COVID-19) patients. However, the detailed mechanisms of cytokine induction due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. To examine the cytokine production in COVID-19, we mimicked the disease in SARS-CoV-2-infected alveoli by adding the lysate of SARS-CoV-2-infected cells to cultured macrophages or induced pluripotent stem cell-derived myeloid cells. The cells secreted interleukin (IL)-6 after the addition of SARS-CoV-2-infected cell lysate. Screening of 25 SARS-CoV-2 protein-expressing plasmids revealed that the N protein-coding plasmid alone induced IL-6 production. The addition of anti-N antibody further enhanced IL-6 production, but the F(ab’)2 fragment did not. Sera from COVID-19 patients also enhanced IL-6 production, and sera from patients with severer disease induced higher levels of IL-6. These results suggest that anti-N antibody promotes IL-6 production in SARS-CoV-2-infected alveoli, leading to the cytokine storm of COVID-19.

Abstract Magnetic resonance vessel wall imaging is desirable for evaluating Kawasaki disease (KD)-associated coronary arterial lesions. To evaluate the reproducibility of three-dimensional turbo spin-echo (3D-TSE) and two-dimensional dual inversion-recovery turbo spin-echo (2D-DIR-TSE) for coronary vessel wall imaging in KD. Ten patients were prospectively enrolled. Coronary vessel wall imaging with axial-slice orientation 3D-TSE and 2D-DIR-TSE were acquired for cross-sectional images in aneurysmal and normal regions. Lumen area (LA), wall area (WA), and normalized wall index (NWI) of cross-sectional images were measured in both regions. Reproducibility between 3D-TSE and 2D-DIR-TSE was evaluated via intraclass correlation coefficients (ICCs) and Bland–Altman plots. 48 points (aneurysmal, 27; normal, 21) were evaluated. There were high ICCs between 3D-TSE and 2D-DIR-TSE in LA (0.95) and WA (0.95). In aneurysmal regions, 95% limits of agreement were LA, WA, and NWI of − 29.9 to 30.4 mm2, − 18.8 to 15.0 mm2, and − 0.22 to 0.20, respectively. In normal regions, the 95% limits of agreement were LA, WA, and NWI of − 4.44 to 4.38 mm2, − 3.51 to 4.30 mm2, and − 0.14 to 0.16, respectively. No fixed and proportional biases between 3D-TSE and 2D-DIR-TSE images in aneurysmal and normal regions were noted. 3D-TSE was reproducible with conventional 2D-DIR-TSE for coronary vessel wall assessment on KD.

Abstract Changes in the aerosol composition of sulfate (SO4 2−) and nitrate (NO3 −) from 2012 to 2019 have been captured as a paradigm shift in the region downwind of China. Specifically, SO4 2− dramatically decreased and NO3 − dramatically increased over downwind locations such as western Japan due to the faster reduction of SO2 emissions than NO x emissions and the almost constant trend of NH3 emissions from China. Emissions from China sharply decreased during COVID-19 lockdowns in February–March 2020, after which China’s economic situation seemed to recover going into 2021. Given this substantial change in Chinese emissions, it is necessary to clarify the impact of long-range PM2.5 transport into the leeward of East Asia. In this study, ground-based aerosol compositions observed at three sites in western Japan were analysed. The concentrations of PM2.5, SO4 2− and NO3 − decreased in 2020 (during COVID-19) compared with 2018–2019 (before COVID-19). In 2021 (after COVID-19), PM2.5 and NO3 − increased and SO4 2− was unchanged. This suggests the returning long-range PM2.5 transport in 2021. From numerical simulations, the status of Chinese emissions during COVID-19 did not explain this returning impact in 2021. This study shows that the status of Chinese emissions in 2021 recovered to that before COVID-19.

Abstract Most patients with ovarian cancer experience recurrence and develop resistance to platinum-based agents. The diagnosis of platinum resistance based on the platinum-free interval is not always accurate and timely in clinical settings. Herein, we used laser ablation inductively coupled plasma mass spectrometry to visualize the platinum distribution in the ovarian cancer tissues at the time of interval debulking surgery after neoadjuvant chemotherapy in 27patients with advanced high-grade serous ovarian cancer. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum throughout the tumor and adjacent stroma. The type A patients treated post-surgery with platinum-based adjuvant chemotherapy showed significantly shorter periods of recurrence after the last platinum-based chemotherapy session (p = 0.020) and were diagnosed with “platinum-resistant recurrence”. Moreover, type A was significantly correlated with worse prognosis (p = 0.031). Post-surgery treatment with non-platinum-based chemotherapy could be effective for the patients classified as type A. Our findings indicate that the platinum resistance can be predicted prior to recurrence, based on the platinum distribution; this could contribute to the selection of more appropriate adjuvant chemotherapy, which may lead to improves prognoses.

Abstract Human artificial chromosomes (HACs) and mouse artificial chromosomes (MACs) are non-integrating chromosomal gene delivery vectors for molecular biology research. Recently, microcell-mediated chromosome transfer (MMCT) of HACs/MACs has been achieved in various human cells that include human immortalised mesenchymal stem cells (hiMSCs) and human induced pluripotent stem cells (hiPSCs). However, the conventional strategy of gene introduction with HACs/MACs requires laborious and time-consuming stepwise isolation of clones for gene loading into HACs/MACs in donor cell lines (CHO and A9) and then transferring the HAC/MAC into cells via MMCT. To overcome these limitations and accelerate chromosome vector-based functional assays in human cells, we established various human cell lines (HEK293, HT1080, hiMSCs, and hiPSCs) with HACs/MACs that harbour a gene-loading site via MMCT. Model genes, such as tdTomato, TagBFP2, and ELuc, were introduced into these preprepared HAC/MAC-introduced cell lines via the Cre-loxP system or simultaneous insertion of multiple gene-loading vectors. The model genes on the HACs/MACs were stably expressed and the HACs/MACs were stably maintained in the cell lines. Thus, our strategy using this HAC/MAC-containing cell line panel has dramatically simplified and accelerated gene introduction via HACs/MACs.

Abstract In this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation. In BCR/ABL+ leukemic cells, pterostilbene decreased the BCR/ABL fusion protein levels and suppressed AKT and NF-κB activation. We further demonstrated that pterostilbene along with U0126, an inhibitor of the MEK/ERK signaling pathway, synergistically induced apoptosis of BCR/ABL+ cells. Our results further suggest that pterostilbene-promoted downregulation of BCR/ABL involves caspase activation triggered by proteasome inhibition-induced endoplasmic reticulum stress. Moreover, oral administration of pterostilbene significantly suppressed tumor growth in mice transplanted with BCR/ABL+ leukemic cells. Taken together, these results suggest that pterostilbene may hold potential for the treatment of BCR/ABL+ leukemia, in particular for those showing ABL-dependent TKI resistance.

Abstract The mass transfer history of rocks provides direct evidence for fluid–rock interaction within the lithosphere and is recorded by compositional changes, especially in trace elements. The general method adopted for mass transfer analysis is to compare the composition of the protolith/precursor with that of metamorphosed/altered rocks; however, in many cases the protolith cannot be sampled. With the aim of reconstructing the mass transfer history of metabasalt, this study developed protolith reconstruction models (PRMs) for metabasalt using machine-learning algorithms. We designed models to estimate basalt trace-element concentrations from the concentrations of a few (1–9) trace elements, trained with a compositional dataset for fresh basalts, including mid-ocean ridge, ocean-island, and volcanic arc basalts. The developed PRMs were able to estimate basalt trace-element compositions (e.g., Rb, Ba, U, K, Pb, Sr, and rare-earth elements) from only four input elements with a reproducibility of ~ 0.1 log10 units (i.e., ± 25%). As a representative example, we present PRMs where the input elements are Th, Nb, Zr, and Ti, which are typically immobile during metamorphism. Case studies demonstrate the applicability of PRMs to seafloor altered basalt and metabasalt. This method enables us to analyze quantitative mass transfer in regional metamorphic rocks or alteration zones where the protolith is heterogeneous or unknown.

Abstract Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CLpro) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CLpro revealed that the Kcat/Km of the 3CLpro enzyme containing Ser108 was 58% lower than that of Pro108 3CLpro. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CLpro enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CLpro inhibitor.

Summary: Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression. Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations. Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy. Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types. Funding: Swedish Cancer Society, Lions Cancer Foundation, Selanders Foundation, P.O. Zetterling Foundation, U-CAN supported by SRA CancerUU, Uppsala University and Region Uppsala.

Healthcare-associated infections have become a major health issue worldwide. One route of transmission of pathogenic bacteria is through contact with "high-touch" dry surfaces, such as handrails. Regular cleaning of surfaces with disinfectant chemicals is insufficient against pathogenic bacteria and alternative control methods are therefore required. We previously showed that warming to human-skin temperature affected the survival of pathogenic bacteria on dry surfaces, but humidity was not considered in that study. Here, we investigated environmental factors that affect the number of live bacteria on dry surfaces in hospitals by principal component analysis of previously-collected data (n = 576, for CFU counts), and experimentally verified the effect of warming to human-skin temperature on the survival of pathogenic bacteria on dry surfaces under humidity control. The results revealed that PCA divided hospital dry surfaces into four groups (Group 1~4) and hospital dry surfaces at low temperature and low humidity (Group 3) had much higher bacterial counts as compared to the others (Group 1 and 4) (p