Search

Abstract The air-water interface of microbubbles represents a crucial microenvironment that can dramatically accelerate reactive oxidative species (ROS) reactions. However, the dynamic nature of microbubbles presents challenges in probing ROS behaviors at the air-water interface, limiting a comprehensive understanding of their chemistry and application. Here we develop an approach to investigate the interfacial ROS via coupling microbubbles with a Fenton-like reaction. Amphiphilic single-Co-atom catalyst (Co@SCN) is employed to efficiently transport the oxidant peroxymonosulfate (PMS) from the bulk solution to the microbubble interface. This triggers an accelerated generation of interfacial sulfate radicals (SO4 •−), with 20-fold higher concentration (4.48 × 10−11 M) than the bulk SO4 •−. Notably, the generated SO4 •− is preferentially situated at the air-water interface due to its lowest free energy and the strong hydrogen bonding interactions with H3O+. Moreover, it exhibits the highest oxidation reactivity toward gaseous pollutants like toluene, with a rate constant of 1010 M−1 s−1-over 100 times greater than bulk reactions. This work demonstrates a promising strategy to harness the air-water interface for accelerating ROS-induced reactions, highlighting the importance of interfacial ROS and its potential application.

Abstract Background Ligament tension balance is a major determinant for the success of total knee replacement (TKR). The present study aimed at determining the inter-rater and intra-rater reliability in performing ligament tension assessment using an imageless robotic-assisted TKR. Methods Twenty-four knees in 21 patients who received robotic-assisted TKR for end-stage varus osteoarthritis were examined. Three orthopedic specialists and six orthopedic trainees participated in the operations. Data from the ligament tension assessment were collected during the operations. Results For the inter-rater reliability, “extension medial” and “flexion medial” had excellent reliability whilst “extension lateral” and “flexion lateral” had good-to-excellent reliability. For the intra-rater reliability, “extension medial” showed excellent reliability, “extension lateral” and “flexion medial” showed good-to-excellent reliability, and “flexion lateral” showed moderate-to-excellent reliability. Conclusions Robotic-assisted technology provides a reliable solution to improve ligament tension assessment. All ligament tension assessments with the use of the technology could demonstrate at least good-to-excellent reliability except for the intra-rater reliability of “flexion lateral”.

Affective engagement is critical if environmental education is to promote pro-environmental behaviors. Given the contextual complexities impacting the affective domain in environmental education, affective engagement may vary depending on the programs, cohorts and classes. In this ethnographic case study, we used point-of-view (POV) camera glasses along with written and verbal student reflections to track the moment-to-moment first-person experiences and the post-trip reflections of secondary school students associated with an ecology field trip to a local coastal area. This case study offers an in-depth account of two students' affective engagement during the field trip. One student demonstrated great interest and curiosity when learning about nature despite being scared to touch wildlife, whereas another student demonstrated limited interest in the field trip but showed a strong desire to protect nature. These findings suggest a complicated, unpredictable relationship between interest in and curiosity about nature, motivation and constraints to learn, environmental consciousness, intention, and ability to act on behalf of nature. Future research should attend to why students feel the way they feel and how they achieve affective learning outcomes during planned and chance encounters in natural outdoor settings.

Efficient quantum memories will be an essential building block of large-scale networked quantum systems and provide a link between flying photonic qubits and atomic or quasi-atomic local quantum processors. Memory efficiencies above 50% are required to be operating above the quantum no-cloning limit. High efficiency operation necessitates tailored photon source and memory pairs with matched bandwidths. In this paper, we explore the combination of an ultralow spectral bandwidth source of single photons from cavity-enhanced spontaneous parametric down-conversion with a hot gas-ensemble atomic memory. Our rubidium vapor gradient echo memory achieves 84% ± 3% recall efficiency of single photons: a record for single photon storage in a warm vapor platform that avoids bulky and complex systems, such as high vacuum and low temperature cryogenics.

Abstract The full data set of the Daya Bay reactor neutrino experiment is used to probe the effect of the charged current non-standard interactions (CC-NSI) on neutrino oscillation experiments. Two different approaches are applied and constraints on the corresponding CC-NSI parameters are obtained with the neutrino flux taken from the Huber-Mueller model with a 5% uncertainty. For the quantum mechanics-based approach (QM-NSI), the constraints on the CC-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ are extracted with and without the assumption that the effects of the new physics are the same in the production and detection processes, respectively. The approach based on the weak effective field theory (WEFT-NSI) deals with four types of CC-NSI represented by the parameters [ε X ] eα . For both approaches, the results for the CC-NSI parameters are shown for cases with various fixed values of the CC-NSI and the Dirac CP-violating phases, and when they are allowed to vary freely. We find that constraints on the QM-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ from the Daya Bay experiment alone can reach the order O $$ \mathcal{O} $$ (0.01) for the former and O $$ \mathcal{O} $$ (0.1) for the latter, while for WEFT-NSI parameters [ε X ] eα , we obtain O $$ \mathcal{O} $$ (0.1) for both cases.

Abstract The purpose of this study was to assess the risks of hyperthyroidism and hypothyroidism related to gynecological cancers. Population-based retrospective cohort study. We conducted a cohort study using the Taiwan National Health Insurance Research Database to explore hyperthyroidism and hypothyroidism associated with site-specific gynecologic cancers in women from January 1, 2000 to December 31, 2018. The examined gynecologic cancers included endometrial (EC), uterine corpus cancer (UC), and ovarian cancer (OC). The incidence and hazard ratios were quantified using Cox proportional hazards models. The incidence of developing gynecological (Gyn) cancers in the hyperthyroid and hypothyroid women was 0.29 and 0.44 per 1000 person-years, which was 0.86 fold lower and 1.13 fold higher than that in the comparison cohort (p 65 years: aHR = 0.94; for hypothyroid, adjusted hazard ratio (aHR) = 1.26; > 65 years: aHR = 1.38). Compared with the non-hypothyroid women and non-hyperthyroid women beyond 6 years of follow-up, hypothyroid and hyperthyroid women showed decreased risk of Gyn cancers. Medication treatment for hyperthyroid and hypothyroid disease did not showed significant association in subgroup analyses (aHR = 0.99 and 0.80, respectively). Our results show that women with hyperthyroidism have a significantly reduced risk of gynecological cancers, whereas women with hypothyroidism have a slightly increased risk of gynecological cancers suggesting an association between thyroid function level and risk of gynecological cancers.

Abstract The Greater Bay Area (GBA) is to become a major innovation and technology hub of global impact. Such a transformation is to take place in the midst of a policy-driven economy in GBA’s Mainland region and a market-driven economy in Hong Kong and Macau. In this paper, we examine the uniqueness and complexities of logistics and trade facilitation in GBA. This study establishes a discourse in GBA’s logistics and trade facilitation between government and non-government stakeholders. Based on the discourse, we provide a conceptual context on the unique aspects of GBA, pinpointing critical issues such as the coexistence of differing institutional systems and interplay between state planning and market economy. A major objective of the paper is to identify and conceptualize unique logistics and trade features of GBA development, and to highlight opportunities for academic and policy research.

BackgroundPortal vein tumor thrombus (PVTT) is a common complication and an obstacle to treatment, with a high recurrence rate and poor prognosis. There is still no global consensus or standard guidelines on the management of hepatocellular carcinoma (HCC) with PVTT. Increasing evidence suggests that more aggressive treatment modalities, including transarterial chemoembolization, radiotherapy, targeted therapy, and various combination therapies, may improve the prognosis and prolong the survival of advanced hepatocellular carcinoma (aHCC) patients with PVTT. We aim to comprehensively review and compare the efficacy and safety of these advanced options for aHCC with PVTT.MethodsA comprehensive literature search was conducted on PubMed and EMBASE for phase II or III randomized controlled trials (RCTs) investigating multimodality treatments for aHCC with PVTT. Kaplan–Meier curves for overall survival (OS) and progression-free survival were constructed to retrieve individual patient-level data to strengthen the comparison of the benefits of all multimodality treatments of interest. Each study was pooled in a fixed-effects network meta-analysis (NMA). We also conducted subgroup analyses using risk ratios extracted from each study, including viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion or portal vein tumor thrombosis, and extrahepatic spread. Multimodality treatments were ranked using SUCRA scores.ResultsWe identified 15 randomized controlled trials with 16 multimodality regimens that met the inclusion criteria. Among them, 5,236 patients with OS results and 5,160 patients with PFS results were included in the analysis. The hepatic arterial infusion chemotherapy of fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) showed OS and PFS benefits over all the other therapies. In terms of OS, HAIC-FO, nivolumab, and TACE+Len were superior to sorafenib, lenvatinib, and donatinib monotherapies, as well as HAIC-FO+Sor. In terms of PFS, TACE+Len showed better benefits than lenvatinib, donatinib, and tremelimumab+durvalumab. A low heterogeneity (I2 < 50%) and consistency were observed. The SUCRA score for OS ranked HAIC-FO+sorafenib as the best treatment option among all multimodality treatments in hepatitis B, MVI, or PVTT with EHS and AFP 400 μg/L subgroups.ConclusionHAIC-FO and HAIC-FO+sorafenib are statistically better options for unresectable hepatocellular carcinoma with PVTT among the multimodality treatments, and their effective and safe implementation may provide the best outcomes for HCC-PVTT patients.

The challenges brought by a growing number of large-scale land development projects (e.g., Northern Metropolis, Lantau Tomorrow, and related infrastructures) in Hong Kong must be met by innovative land acquisition planning and processes. A recent quick win solution to land supply for Works projects has been in trial commissioning the provisional draft land resumption plan preparations and related survey works from the government to consultants, specifically the Authorized Land Surveyor (ALS) in the private sector. The industry therefore must consider the necessary and diverse sources of expertise available, and the existing land surveying technical resources that will render support to such new initiatives. Collaboration is called for between the spheres of public sector, education, and works industry to successfully move the use of cadastral survey for land management forwards, bridging the gap between lands and works practices for efficient processing of Works projects, and smart city development of Hong Kong.This paper will examine the new approach of professional surveying that private practicing ALSs bring, and why the overall number of ALS and engineering surveyors in the construction industry is growing so slowly. It will additionally compare Hong Kong's practice with that of the mainland China, Singapore, and the UK to grasp global learning points. The paper recommends the establishment of a Cadastral Survey Lab (CSL) firstly to explore the policy implementation of a sound cadastral system. The processing of lot boundary determination by ALS is reviewed. The regulatory roles of the Land Survey Authority (LSA) are requested in approving new land boundary plans; this both replaces the Demarcation District (DD) Sheet boundary and improves land boundary records. Secondly, the CSL can serve as a coordinating body in curating various kinds of land records from diverse sources, and aids the research and knowledge management of cadastral survey, land law, land tenure, land registration systems, land boundary record keeping, problematic lot boundary determination, etc. These topics can be considered in the refining geomatics education curriculum, and furthermore developed into guidance notes for geomatics survey practitioners.The evolution of the traditional land surveying profession into the geomatics services has become a recent international trend that is growing in popularity in the survey profession. Combining geo-spatial data from the planning and design stages, alongside the use of standardised survey data processing in project implementation and asset management, would encourage data sharing, avoid duplicate efforts, and facilitate the formation of a digital city. The spectrums of geomatics education in universities should be widened with a refined curriculum on combining geomatics with cadastral survey that has evolved from the traditional lot boundary survey to multi-purpose cadastre, city information modelling, urban informatics, smart city administration, and a full-blown Spatial Data Infrastructure (SDI).

Abstract Emus (Dromaius novaehollandiae), a large flightless omnivorous ratite, are farmed for their fat and meat. Emu fat can be rendered into oil for therapeutic and cosmetic use. They are capable of gaining a significant portion of its daily energy requirement from the digestion of plant fibre. Despite of its large body size and low metabolic rate, emus have a relatively simple gastroinstetinal (GI) tract with a short mean digesta retention time. However, little is known about the GI microbial diversity of emus. The objective of this study was to characterize the intraluminal intestinal bacterial community in the different segments of small intestine (duodenum, jejunum, and ileum) using pyrotag sequencing and compare that with the ceca. Gut content samples were collected from each of four adult emus (2 males, 2 females; 5–6 years old) that were free ranged but supplemented with a barley-alfalfa-canola based diet. We amplified the V3-V5 region of 16S rRNA gene to identify the bacterial community using Roche 454 Junior system. After quality trimming, a total of 165,585 sequence reads were obtained from different segments of the small intestine (SI). A total of 701 operational taxonomic units (OTUs) were identified in the different segments of small intestine. Firmicutes (14–99%) and Proteobacteria (0.5–76%) were the most predominant bacterial phyla in the small intestine. Based on species richness estimation (Chao1 index), the average number of estimated OTUs in the small intestinal compartments were 148 in Duodenum, 167 in Jejunum, and 85 in Ileum, respectively. Low number of core OTUs identified in each compartment of small intestine across individual birds (Duodenum: 13 OTUs, Jejunum: 2 OTUs, Ileum: 14 OTUs) indicated unique bacterial community in each bird. Moreover, only 2 OTUs (Escherichia and Sinobacteraceae) were identified as core bacteria along the whole small intestine. PICRUSt analysis has indicated that the detoxification of plant material and environmental chemicals seem to be performed by SI microbiota, especially those in the jejunum. The emu cecal microbiome has more genes than SI segments involving in protective or immune response to enteric pathogens. Microbial digestion and fermentation is mostly in the jejunum and ceca. This is the first study to characterize the microbiota of different compartments of the emu intestines via gut samples and not fecal samples. Results from this study allow us to further investigate the influence of the seasonal and physiological changes of intestinal microbiota on the nutrition of emus and indirectly influence the fatty acid composition of emu fat.

Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative cholangitis. The pathogenesis of PBC is multifactorial and involves immune dysregulation, abnormal bile metabolism, and progressive fibrosis, ultimately leading to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are currently used as first- and second-line treatments, respectively. However, many patients do not respond adequately to UDCA, and the long-term effects of these drugs are limited. Recent research has advanced our understanding the mechanisms of pathogenesis in PBC and greatly facilitated development of novel drugs to target mechanistic checkpoints. Animal studies and clinical trials of pipeline drugs have yielded promising results in slowing disease progression. Targeting immune mediated pathogenesis and anti-inflammatory therapies are focused on the early stage, while anti-cholestatic and anti-fibrotic therapies are emphasized in the late stage of disease, which is characterized by fibrosis and cirrhosis development. Nonetheless, it is worth noting that currently, there exists a dearth of therapeutic options that can effectively impede the progression of the disease to its terminal stages. Hence, there is an urgent need for further research aimed at investigating the underlying pathophysiology mechanisms with potential therapeutic effects. This review highlights our current knowledge of the underlying immunological and cellular mechanisms of pathogenesis in PBC. Further, we also address current mechanism-based target therapies for PBC and potential therapeutic strategies to improve the efficacy of existing treatments.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a necrotizing vasculitis mainly involving small blood vessels. It is demonstrated that T cells are important in the pathogenesis of AAV, including regulatory T cells (Treg) and helper T cells (Th), especially Th2, Th17, and follicular Th cells (Tfh). In addition, the exhaustion of T cells predicted the favorable prognosis of AAV. The immune checkpoints (ICs) consist of a group of co-stimulatory and co-inhibitory molecules expressed on the surface of T cells, which maintains a balance between the activation and exhaustion of T cells. CD28, inducible T-cell co-stimulator (ICOS), OX40, CD40L, glucocorticoid induced tumor necrosis factor receptor (GITR), and CD137 are the common co-stimulatory molecules, while the programmed cell death 1 (PD-1), cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), T cell immunoglobulin (Ig) and mucin domain-containing protein 3 (TIM-3), B and T lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), T‐cell Ig and ITIM domain (TIGIT), CD200, and lymphocyte activation gene 3 (LAG-3) belong to co-inhibitory molecules. If this balance was disrupted and the activation of T cells was increased, autoimmune diseases (AIDs) might be induced. Even in the treatment of malignant tumors, activation of T cells by immune checkpoint inhibitors (ICIs) may result in AIDs known as rheumatic immune-related adverse events (Rh-irAEs), suggesting the importance of ICs in AIDs. In this review, we summarized the features of AAV induced by immunotherapy using ICIs in patients with malignant tumors, and then reviewed the biological characteristics of different ICs. Our aim was to explore potential targets in ICs for future treatment of AAV.

Abstract COVID-19 has imposed a very substantial direct threat to the physical health of those infected, although the corollary impact on mental health may be even more burdensome. Here we focus on assessing the mental health impact of COVID-19 and of other epidemics in the community. We searched five electronic databases until December 9, 2020, for all peer-reviewed original studies reporting any prevalence or correlates of mental disorders in the general population following novel epidemics in English, Chinese or Portuguese. We synthesised prevalence estimates from probability samples during COVID-19 and past epidemics. The meta-analytical effect size was the prevalence of relevant outcomes, estimated via random-effects model. I 2 statistics, Doi plots and the LFK index were used to examine heterogeneity and publication bias. This study is pre-registered with PROSPERO, CRD42020179105. We identified 255 eligible studies from 50 countries on: COVID-19 (n = 247 studies), severe acute respiratory syndrome (SARS; n = 5), Ebola virus disease (n = 2), and 1918 influenza (n = 1). During COVID-19, we estimated the point prevalence for probable anxiety (20.7%, 95% CI 12.9–29.7), probable depression (18.1%, 13.0–23.9), and psychological distress (13.0%, 0–34.1). Correlates for poorer mental health include female sex, lower income, pre-existing medical conditions, perceived risk of infection, exhibiting COVID-19-like symptoms, social media use, financial stress, and loneliness. Public trust in authorities, availability of accurate information, adoption of preventive measures and social support were associated with less morbidity. The mental health consequences of COVID-19 and other epidemics could be comparable to major disasters and armed conflicts. The considerable heterogeneity in our analysis indicates that more random samples are needed. Health-care professionals should be vigilant of the psychological toll of epidemics, including among those who have not been infected.

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease. Despite the wide use of conventional synthetic, targeted and biologic disease modifying anti-rheumatic drugs (DMARDs) to control its radiological progress, nearly all DMARDs are immunologically non-selective and do not address the underlying immunological mechanisms of RA. Patients with RA often need to take various DMARDs long-term or even lifelong and thus, face increased risks of infection, tumor and other adverse reactions. It is logical to modulate the immune disorders and restore immune balance in patients with RA by restoring immune tolerance. Indeed, approaches based on stem cell transplantation, tolerogenic dendritic cells (tolDCs), and antigen-based tolerogenic vaccination are under active investigation, and some have already transformed from wet bench research to clinical investigation during the last decade. Among them, clinical trials on stem cell therapy, especially mesenchymal stem cells (MSCs) transplantation are most investigated and followed by tolDCs in RA patients. On the other hand, despite active laboratory investigations on the use of RA-specific peptide-/protein-based tolerogenic vaccines for T cell, clinical studies on RA patients are much limited. Overall, the preliminary results of these clinical studies are promising and encouraging, demonstrating their safety and effectiveness in the rebalancing of T cell subsets; particular, the recovery of RA-specific Treg with increasing anti-inflammatory cytokines and reduced proinflammatory cytokines. Future studies should focus on the optimization of transplanted stem cells, the preparation of tolDCs, and tolerogenic vaccines with RA-specific protein or peptide, including their dosage, course, and route of administration with well-coordinated multi-center randomized clinical control researches. With the progress of experimental and clinical studies, generating and restoring RA-specific immune tolerance may bring revolutionary changes to the clinical management of RA in the near future.

Background/aimsPrimary sclerosing cholangitis (PSC) is a chronic inflammatory biliary disease for which the immunopathological basis remains an enigma. Natural killer (NK) cells are key components of innate immunity and seemingly play diversified roles in different autoimmune disorders (AIDs). The aim of this study was to determine the role of NK cells in the pathogenesis of PSC.MethodsThe frequency and phenotype of circulating NK cells in a large cohort of patients with PSC and healthy controls (HCs) were systematically examined. In addition, the functional capacity of NK cells including cytotoxicity and cytokine production was studied.ResultsThe frequency of CD3−CD56dimCD16+ (defined as CD56dim) NK cells in PSC patients was significantly lower in comparison to HCs. CD56dim NK cells from PSC displayed a more immature phenotype including high expression of the natural killing receptor NKp46 and downregulation of the highly differentiated NK cell marker CD57. Interestingly, the reduction of CD57 expression of NK cells was associated with the disease severity of PSC. In addition, PSC CD56dim NK cells exhibited increased CD107a degranulation and cytolytic activity toward target cells compared with HCs. Further analysis demonstrated that CD57−CD56dim NK cells from PSC had elevated expression of NKp46, NKp30, IL-2 receptor, and KLRG1 and higher cytotoxic capacity as compared to CD57+CD56dim NK cells.ConclusionsOur data demonstrate that the differentiation of PSC NK cells is dysregulated with enhanced cytotoxic activity. This change is likely to be functionally involved in pathogenesis and disease progression, deducing the potential of NK-directed immunotherapy for PSC.

BackgroundElectrical impedance myography (EIM) has been applied to assess muscle health conditions in neuromuscular disorders. This study aimed to detect immediate muscle electrical impedance property alterations in lower extremity of chronic stroke survivors immediately after functional electrical stimulation (FES)-assisted cycling training.MethodsFourteen chronic stroke survivors were recruited for the current study. EIM measurements were conducted before and immediately after 40-min FES-assisted cycling training for each subject. Four interested muscle groups [rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and the medial head of gastrocnemius (MG)] were selected. Correlation analysis was performed to reveal a significant correlation between changes in EIM parameters and clinical scales [Fugl–Meyer Assessment of the lower extremity (FMA-LE); 6-min walking test (6MWT)].ResultsImmediately after training, reactance (X) and phase angle (θ) values significantly increased on the TA and MG muscles. Significant correlation was observed between X value and FMA-LE scores (r = 0.649, p = 0.012) at MG as well as X and FMA scores of the ankle joint (r = 0.612, p = 0.02). Resistance (R) and θ were significantly correlated with 6MWT score (R-6MWT: r = 0.651, p = 0.012; θ-6MWT: r = 0.621, p = 0.018).ConclusionThis brief report demonstrated that EIM can reveal the intrinsic property alteration in the paretic muscle of chronic stroke survivors immediately after FES-assisted cycling training. These alterations might be related to muscle hypertrophy (i.e., increases in muscle fiber size). This brief report might aid the understanding of the mechanism of electrical stimulation-assisted exercise in improving muscle function of stroke survivors.

Objectives: This retrospective cohort study aims to explore head-to-head clinical outcomes and complications associated with tocilizumab or baricitinib initiation among hospitalized COVID-19 patients receiving dexamethasone.Methods: Among 10,445 COVID-19 patients hospitalized between January 21st 2020 and January 31st 2021 in Hong Kong, patients who had received tocilizumab (n = 165) or baricitinib (n = 76) while on dexamethasone were included. Primary study outcome was time to clinical improvement (at least one score reduction on WHO clinical progression scale). Secondary outcomes were disease progression, viral dynamics, in-hospital death, hyperinflammatory syndrome, and COVID-19/treatment-related complications. Hazard ratios (HR) of event outcomes were estimated using Cox regression models.Results: The initiation of tocilizumab or baricitinib had no significant differences in time to clinical improvement (HR = 0.86, 95%CI 0.57-1.29, p = 0.459), hospital discharge (HR = 0.85, 95%CI 0.57-1.27, p = 0.418), recovery without the need for oxygen therapy (HR = 1.04, 95%CI 0.64-1.67, p = 0.883), low viral load (HR = 1.49, 95%CI 0.85-2.60, p = 0.162), and positive IgG antibody (HR = 0.97, 95%CI 0.61-1.54, p = 0.909). Time to viral clearance (HR = 1.94, 95%CI 1.01-3.73, p = 0.048) was shorter in the tocilizumab group with marginal significance, compared to that of baricitinib. Meanwhile, the two treatment modalities were not significantly different in their associated risks of in-hospital death (HR = 0.63, 95%CI 0.29-1.35, p = 0.233), severe liver injury (HR = 1.15, 95%CI 0.43-3.08, p = 0.778), acute renal failure (HR = 2.33, 95%CI 0.61-8.82, p = 0.213), hyperinflammatory syndrome (HR = 2.32, 95%CI 0.87-6.25, p = 0.091), thrombotic and bleeding events (HR = 1.39, 95%CI 0.32-6.00, p = 0.658), and secondary infection (HR = 2.97, 95%CI 0.62-14.31, p = 0.173).Conclusion: Among hospitalized patients with moderate-to-severe COVID-19 on background dexamethasone, the initiation of tocilizumab or baricitinib had generally comparable effects on time to clinical improvement, hospital discharge, recovery, low viral load, and positive IgG antibody; risks of in-hospital death, hepatic and renal complications, hyperinflammatory syndrome, thrombotic and bleeding events, and secondary infection. On the other hand, tocilizumab users might achieve viral clearance slightly faster than baricitinib users. Further studies and clinical trials are needed to confirm our findings regarding the evaluation of tocilizumab and baricitinib in COVID-19 patients with different disease severities, at varying stages or timing of drug initiation, and considering the concomitant use of other therapeutics.

ObjectivePrimary biliary cholangitis (PBC) is an autoimmune disease with significant gender difference. X chromosome inactivation (XCI) plays important roles in susceptibility to diseases between genders. This work focuses on the differences of LncRNA XIST in several defined immune cells populations as well as its effects on naive CD4+ T cells proliferation and differentiation in patients with PBC.MethodsNKs, B cells, CD4+ T, and CD8+ T cells were separated by MicroBeads from peripheral blood mononuclear cells (PBMCs) of PBC patients and healthy control (HC). The expression levels of LncRNA XIST in these immune cells were quantified by qRT-PCR and their subcellular localized analyzed by FISH. Lentivirus were used to interfere the expression of LncRNA XIST, and CCK8 was used to detect the proliferation of naive CD4+ T cells in PBC patients. Finally, naive CD4+ T cells were co-cultured with the bile duct epithelial cells (BECs), and the effects of LncRNA XIST on the typing of naive CD4+ T cells and related cytokines were determined by qRT-PCR and ELISA.ResultsThe expression levels of LncRNA XIST in NKs and CD4+ T cells in PBC patients were significantly higher than those in HC, and were primarily located at the nucleus. LncRNA XIST could promote the proliferation of naive CD4+ T cells. When naive CD4+ T cells were co-cultured with BECs, the expressions of IFN-γ, IL-17, T-bet and RORγt in naive CD4+ T cells were decreased.ConclusionLncRNA XIST was associated with lymphocyte abnormalities in patients with PBC. The high expression of LncRNA XIST could stimulate proliferation and differentiation of naive CD4+ T cells, which might account for the high occurrence of PBC in female.

Abstract Background Anticoagulation for preventing stroke in atrial fibrillation is under-utilised despite evidence supporting its use, resulting in avoidable death and disability. We aimed to evaluate an intervention to improve the uptake of anticoagulation. Methods We carried out a national, cluster randomised controlled trial in the Australian primary health care setting. General practitioners received an educational session, delivered via telephone by a medical peer and provided information about their patients selected either because they were not receiving anticoagulation or for whom anticoagulation was considered challenging. General practitioners were randomised to receive feedback from a medical specialist about the cases (expert decisional support) either before or after completing a post-test audit. The primary outcome was the proportion of patients reported as receiving oral anticoagulation. A secondary outcome assessed antithrombotic treatment as appropriate against guideline recommendations. Results One hundred and seventy-nine general practitioners participated in the trial, contributing information about 590 cases. At post-test, 152 general practitioners (84.9%) completed data collection on 497 cases (84.2%). A 4.6% (Adjusted Relative Risk = 1.11, 95% CI = 0.86–1.43) difference in the post-test utilization of anticoagulation between groups was not statistically significant (p = 0.42). Sixty-one percent of patients in both groups received appropriate antithrombotic management according to evidence-based guidelines at post-test (Adjusted Relative Risk = 1.0; 95% CI = 0.85 to 1.19) (p = 0.97). Conclusions Specialist feed-back in addition to an educational session did not increase the uptake of anticoagulation in patients with AF. Trial registration ANZCTRN12611000076976 Retrospectively registered.

Histone ubiquitination plays a critical role in the DNA damage response pathway. Here the authors reveal how RNF168 ubiquitinates the H2A family including noncanonical variants, H2AZ and macroH2A1/2, at the divergent N-terminal tail lysine residue.

Abstract Background This study is to elucidate the disinfection effect of ozone producing low-pressure Hg vapor lamps against human pathogens. Ozone producing low-pressure Hg vapor lamps emit mainly 254 nm ultraviolet light C (UVC) with about 10% power of Vacuum-ultraviolet (VUV) light at 185 nm. The combination of UVC and VUV can inactivate airborne pathogens by disrupting the genetic materials or generation of reactive oxygen species, respectively. In this study, inactivation of common bacteria including Escherichia coli ATCC25922 (E. coli), Extended Spectrum Beta-Lactamase-producing E. coli (ESBL), Methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis (MTB), and that of influenza A viruses H1N1 and H3N2 under the radiation from ozone producing low-pressure Hg vapor lamps was examined. Log reduction values at different treatment durations were determined. Methods In vitro tests were carried out. Various bacterium and virus suspensions were added onto nitrocellulose filter papers and subjected to the illumination from ozone producing low-pressure Hg vapor lamps. The extents of pathogen inactivation at different illumination times were investigated by conducting a series of experiments with increasing duration of illumination. log10 reduction in CFU/ml and reduction at log10(TCID50) were respectively measured for bacteria and viruses. The disinfection effectiveness of this type of lamps against the pathogens under the environment with a moderate barrier to light was therefore evaluated. Results Ozone producing low-pressure Hg vapor lamp successfully inactivated these human pathogens. Nevertheless, among these pathogens, disinfection of MTB required more intense treatment. In the best tested situation, 3-log10 inactivation of pathogens can be achieved with ≤10 min of VUV treatment except MTB which needed about 20 min. This demonstrated the high resistance against UV disinfection of MTB. Conclusions Following the criteria that valid germicidal results can be reflected with 3-log10 inactivation for bacteria, 4-log10 inactivation for viruses and 5-log10 inactivation for MTB, most of the bacteria required ≤10 min of VUV treatment, 20 min for the influenza viruses while MTB needed about 30 min VUV treatment. This indicated that VUV light is an effective approach against different environmental microorganisms.

We report a girl with drug-resistant seizures, progressive behavioral changes, and cognitive decline. Investigations showed abnormal EEG with frequent high-voltage bifrontotemporal sharp and slow waves, especially during sleep. Seizures were difficult to control, despite the usage of various antiepileptic drugs. Perampanel as an add-on antiepileptic drug appeared efficacious. Due to the recognizable pattern of seizures and EEG findings, a karyotype study was performed which revealed 46 chromosomes with a ring 20 chromosome mosaicism. Ring 20 chromosome is associated with drug-resistant refractory seizures, cognitive decline, and behavioral problems. This case highlights the difficulty and challenge faced in managing drug-resistant refractory seizures associated with ring 20 chromosome. While ring 20 chromosome is often underdiagnosed, one should have a high index of awareness and suspicion of such rare epilepsy syndrome, so that an early diagnosis can be made.

We search for gravitational-wave (GW) transients associated with fast radio bursts (FRBs) detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project, during the first part of the third observing run of Advanced LIGO and Advanced Virgo (2019 April 1 15:00 UTC–2019 October 1 15:00 UTC). Triggers from 22 FRBs were analyzed with a search that targets both binary neutron star (BNS) and neutron star–black hole (NSBH) mergers. A targeted search for generic GW transients was conducted on 40 FRBs. We find no significant evidence for a GW association in either search. Given the large uncertainties in the distances of our FRB sample, we are unable to exclude the possibility of a GW association. Assessing the volumetric event rates of both FRB and binary mergers, an association is limited to 15% of the FRB population for BNS mergers or 1% for NSBH mergers. We report 90% confidence lower bounds on the distance to each FRB for a range of GW progenitor models and set upper limits on the energy emitted through GWs for a range of emission scenarios. We find values of order 10 ^51 –10 ^57 erg for models with central GW frequencies in the range 70–3560 Hz. At the sensitivity of this search, we find these limits to be above the predicted GW emissions for the models considered. We also find no significant coincident detection of GWs with the repeater, FRB 20200120E, which is the closest known extragalactic FRB.

Fast radio bursts (FRBs) display a confounding variety of burst properties and host-galaxy associations. Repeating FRBs offer insight into the FRB population by enabling spectral, temporal, and polarimetric properties to be tracked over time. Here, we report on the polarized observations of 12 repeating sources using multiyear monitoring with the Canadian Hydrogen Intensity Mapping Experiment (CHIME) over 400–800 MHz. We observe significant rotation measure (RM) variations from many sources in our sample, including RM changes of several hundred radians per square meter over month timescales from FRBs 20181119A, 20190303A, and 20190417A, and more modest RM variability (ΔRM ≲ few tens of radians per square meter) from FRBs 20181030A, 20190208A, 20190213B, and 20190117A over equivalent timescales. Several repeaters display a frequency-dependent degree of linear polarization that is consistent with depolarization via scattering. Combining our measurements of RM variations with equivalent constraints on DM variability, we estimate the average line-of-sight magnetic field strength in the local environment of each repeater. In general, repeating FRBs display RM variations that are more prevalent and/or extreme than those seen from radio pulsars in the Milky Way and the Magellanic Clouds, suggesting repeating FRBs and pulsars occupy distinct magnetoionic environments.

Fast radio burst (FRB) source FRB 20180916B exhibits a 16.33-day periodicity in its burst activity. It is as of yet unclear what proposed mechanism produces the activity, but polarization information is a key diagnostic. Here we report on the polarization properties of 44 bursts from FRB 20180916B detected between 2018 December and 2021 December by CHIME/FRB, the FRB project on the Canadian Hydrogen Intensity Mapping Experiment. In contrast to previous observations, we find significant variations in the Faraday rotation measure (RM) of FRB 20180916B. Over the 9-month period 2021 April and 2021 December we observe an apparent secular increase in RM of ∼50 rad m ^−2 (a fractional change of over 40%) that is accompanied by a possible drift of the emitting band to lower frequencies. This interval displays very little variation in the dispersion measure (ΔDM ≲ 0.8 pc cm ^−3 ), which indicates that the observed RM evolution is likely produced from coherent changes in the Faraday-active medium’s magnetic field. Burst-to-burst RM variations appear unrelated to the activity cycle phase. The degree of linear polarization of our burst sample (≳80%) is consistent with the negligible depolarization expected for this source in the 400–800 MHz bandpass of CHIME. FRB 20180916B joins other repeating FRBs in displaying substantial RM evolution. This is consistent with the notion that repeater progenitors may be associated with young stellar populations by their preferential occupation of dynamic magnetized environments commonly found in supernova remnants, in pulsar wind nebulae, or near high-mass stellar companions.

Electrical impedance myography (EIM) is a sensitive assessment for neuromuscular diseases to detect muscle inherent properties, whereas surface electromyography (sEMG) is a common technique for monitoring muscle activation. However, the application of EIM in detecting training effects on stroke survivors is relatively few. This study aimed to evaluate the muscle inherent properties and muscle activation alteration after functional electrical stimulation (FES)-assisted cycling training to chronic stroke survivors. Fifteen people with chronic stroke were recruited for 20 sessions of FES-assisted cycling training (40 min/session, 3–5 sessions/week). The periodically stimulated and assessed muscle groups were quadriceps (QC), tibialis anterior (TA), hamstrings (HS), and medial head of gastrocnemius (MG) on the paretic lower extremity. EIM parameters [resistance (R), reactance (X), phase angle (θ), and anisotropy ratio (AR)], clinical scales (Fugl-Meyer Lower Extremity (FMA-LE), Berg Balance Scale (BBS), and 6-min walking test (6MWT)] and sEMG parameters [including root-mean square (RMS) and co-contraction index (CI) value] were collected and computed before and after the training. Linear correlation analysis was conducted between EIM and clinical scales as well as between sEMG and clinical scales. The results showed that motor function of the lower extremity, balance, and walking performance of subjects improved after the training. After training, θ value of TA (P = 0.014) and MG (P = 0.017) significantly increased, and AR of X (P = 0.004) value and AR of θ value (P = 0.041) significantly increased on TA. The RMS value of TA decreased (P = 0.022) and a significant reduction of CI was revealed on TA/MG muscle pair (P < 0.001). Significant correlation was found between EIM and clinical assessments (AR of X value of TA and FMA-LE: r = 0.54, P = 0.046; X value of TA and BBS score: 0.628, P = 0.016), and between sEMG and clinical scores (RMS of TA and BBS score: r = −0.582, P = 0.029). This study demonstrated that FES-assisted cycling training improved lower limb function by developing coordinated muscle activation and facilitating an orderly myofiber arrangement. The current study also indicated that EIM can jointly evaluate lower extremity function alteration with sEMG after rehabilitation training.Clinical Trail Registration: The study was registered on the Clinical Trial Registry (trial registration number: NCT 03208439, https://clinicaltrials.gov/ct2/show/NCT03208439).

Background and AimsPrimary Biliary Cholangitis (PBC) is an organ-specific autoimmune liver disease. Mononuclear phagocytes (MNPs), comprise of monocyte, dendritic cells and monocyte-derived macrophages, constitute major arm of the innate immune system known to be involved in the pathogenesis of autoimmune disorders. MNPs were shown to accumulate around intra-hepatic bile ducts in livers of PBC patients. Interleukin 23 (IL-23) is a pro-inflammatory cytokine. IL-23-positive cells were detected in livers of patients with advanced stage PBC and IL-23 serum levels found to be in correlation with PBC disease severity. Our overall goal was to assess the importance of IL-23 derived from MNPs in PBC pathogenesis.MethodsWe utilized an inducible murine model of PBC and took advantage of transgenic mice targeting expression of IL-23 by specific MNP populations. Analysis included liver histology assessment, flow cytometry of hepatic immune cells and hepatic cytokine profile evaluation. Specific MNPs sub-populations were sorted and assessed for IL-23 expression levels.ResultsFlow cytometry analysis of non-parenchymal liver cells in autoimmune cholangitis revealed massive infiltration of the liver by MNPs and neutrophils and a decrease in Kupffer cells numbers. In addition, a 4-fold increase in the incidence of hepatic IL-17A producing CD4+ T cells was found to be associated with an increase in hepatic IL23-p19 and IL17A expression levels. Disease severity was significantly ameliorated in both CD11ccreP19flox/flox and CX3CR1creP19 flox/flox mice as assessed by reduced portal inflammation and decreased hepatic expression of various inflammatory cytokines. Amelioration of disease severity was associated with reduction in IL-17A producing CD4+ T cells percentages and decreased hepatic IL23-p19 and IL17A expression levels. qRT-PCR analysis of sorted hepatic MNPs demonstrated high expression levels of IL-23 mRNA specifically by CX3CR1hiCD11c+ monocyte-derived macrophages.ConclusionOur results indicate a major role for IL-23 produced by hepatic monocyte-derived macrophages in the pathogenesis of PBC. These results may pave the road for the development of new immune-based and cell specific therapeutic modalities for PBC patients not responding to current therapies.

Size and shape of bones are important for height and body shape. Here, Styrkarsdottir et al identify 12 loci in a GWAS for bone area derived from DXA scans and show that these loci associate with other bone-related phenotypes including osteoarthritis, height, bone mineral density and risk of hip fracture.

Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc1 complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc1. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian’s equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Qi sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc1 with improved antimalarial properties.