Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis

BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Factors influencing willingness to participate in ophthalmic clinical trials and strategies for effective recruitment

AIM:To explore the factors influencing individuals’willingness to participate in ophthalmic clinical trials.METHODS:A questionnaire survey was conducted from January to April 2021 among patients and their family members at Zhongshan Ophthalmic Center,Sun Yat-sen University,in Guangzhou,China.The survey gathered data on respondents’willingness,demographic and socioeconomic profiles,as well as their reasons and concerns regarding engagement in clinical trials.RESULTS:Of the 1078 residents surveyed(mean age 31.2±13.1y;65.8%females)in Guangzhou,749(69.5%)expressed a willingness to participate in future ophthalmic clinical trials.Specific characteristics associated with greater willingness included a younger age,lower annual income,higher education,prior participation experience,previous ophthalmic treatment,and a better understanding of clinical trials.With the exception of age,these characteristics were significantly linked to a higher willingness.The primary barrier to participation,expressed by 64.8%of those willing and 54.4%of those unwilling,was“Uncertain efficacy”.In terms of motivations,the willing group ranked“Better therapeutic benefits”(35.0%),“Professional monitoring”(34.3%),and“Trust in healthcare professionals”(33.1%)as their top three reasons,whereas the unwilling participants indicated“Full comprehension of the protocol”(46.2%)as the key facilitator.CONCLUSION:This study reveals a substantial willingness to participate in ophthalmic clinical trials and demonstrates the predictive role of demographic and socioeconomic factors.Variations in motivators and concerns between willing and unwilling participants highlight the significance of tailored recruitment strategies.Importantly,the need for and trust in healthcare professionals stand out as powerful motivations,underscoring the importance of enhancing physician-patient relationships,adopting patient-centered communication approaches,and addressing individualized needs to improve accrual rates.

Modified stapled hemorrhoidopexy for lower postoperative stenosis: A five-year experience

BACKGROUND Stapled hemorrhoidopexy(SH)is currently a widely accepted method for treating the prolapse of internal hemorrhoids.Postoperative anal stenosis is a critical complication of SH.A remedy for this involves the removal of the circumferential staples of the anastomosis,followed by the creation of a hand-sewn anastomosis.Numerous studies have reported modified SH procedures to improve outcomes.We hypothesized that our modified SH technique may help reduce complications of anal stenosis after SH.AIM To compare outcomes of staple removal at the 3-and 9-o’clock positions during modified SH in patients with mixed hemorrhoids.METHODS This was a single-center,retrospective,observational study.Patients with grade III or IV hemorrhoids who underwent standard or modified SH at our colorectal center between January 1,2015,and January 1,2020,were included.The operation time,blood loss,length of hospital stay,and incidence of minor or major complic-ations were recorded.RESULTS Patients with grade III or IV hemorrhoids who underwent standard or modified SH at our colorectal center between January 1,2015 and January 1,2020,were included.Operation time,blood loss,length of hospital stay,and incidence of minor or major complications were recorded.We investigated 187 patients(mean age,50.9 years)who had undergone our modified SH and 313 patients(mean age,53.0 years)who had undergone standard SH.In the modified SH group,54%of patients had previously undergone surgical intervention for hemorrhoids,compared with the 40.3%of patients in the standard SH group.The modified SH group included five(2.7%)patients with anal stenosis,while 21(6.7%)patients in the standard SH group had complications of anal stenosis.There was a significant relationship between the rate of postoperative anal stenosis and the modified SH:0.251(0.085-0.741)and 0.211(0.069-0.641)in multiple regression analysis.The modified SH technique is a safe surgical method for advanced grade hemorrhoids and might result in a lower rate of postoperative anal stenosis than standard SH.CONCLUSION The modified SH technique is a safe surgical method for advanced grade hemorrhoids and might result in a lower rate of postoperative anal stenosis than standard SH.

3D MXene architectures as sulfur hosts for high-performance lithium-sulfur batteries

Lithium-sulfur batteries(LSBs)are one of the most promising energy storage devices because of their high theoretical energy density;however,inherent issues including poor electrical conductivity and severe dissolution of S and its discharged products hinder their practical applications.MXenes have metallic conductivity,ultra-thin two-dimensional(2D)structures,rich surface functional groups,and macrostructural adjustability and have been widely used to design advanced sulfur hosts.3D network structures assembled by 2D MXene nanosheets have shown superior performance for improving reaction kinetics,accommodating and dispersing sulfur at the micro-/nanoscale,and capturing polysulfides due to their porous interconnected structure.Herein,the applications of MXene architectures related to 2D layered structures,3D multilayered structures,and 3D spherical structures as sulfur hosts are reviewed.The structure-performance relationship,challenges for current designs,and opportunities for future 3D architectures for LSBs are also analyzed.

Special AT-rich sequence-binding protein 2 acts as a negative regulator of stemness in colorectal cancer cells

AIM To find the mechanisms by which special AT-rich sequence-binding protein 2(SATB2) influences colorectal cancer(CRC) metastasis.METHODS Cell growth assay, colony-forming assay, cell adhesion assay and cell migration assay were used to evaluate the biological characteristics of CRC cells with gain or loss of SATB2. Sphere formation assay was used to detect the self-renewal ability of CRC cells. The m RNA expression of stem cell markers in CRC cells with upregulated or downregulated SATB2 expression was detected by quantitative real-time polymerase chain reaction. Chromatin immunoprecipitation(Ch IP) was used to verify the binding loci of SATB2 on genomic sequences of stem cell markers. The Cancer Genome Atlas(TCGA) database and our clinical samples wereanalyzed to find the correlation between SATB2 and some key stem cell markers.RESULTS Downregulation of SATB2 led to an aggressive phenotype in SW480 and DLD-1 cells, which was characterized by increased migration and invasion abilities. Overexpression of SATB2 suppressed the migration and invasion abilities in SW480 and SW620 cells. Using sequential sphere formation assay to detect the selfrenewal abilities of CRC cells, we found more secondary sphere formation but not primary sphere formation in SW480 and DLD-1 cells after SATB2 expression was knocked down. Moreover, most markers for stem cells such as CD133, CD44, AXIN2, MEIS2 and NANOG were increased in cells with SATB2 knockdown and decreased in cells with SATB2 overexpression. Ch IP assay showed that SATB2 bound to regulatory elements of CD133, CD44, MEIS2 and AXIN2 genes. Using TCGA database and our clinical samples, we found that SATB2 was correlated with some key stem cell markers including CD44 and CD24 in clinical tissues of CRC patients.CONCLUSION SATB2 can directly bind to the regulatory elements in the genetic loci of several stem cell markers and consequently inhibit the progression of CRC by negatively regulating stemness of CRC cells.

Prolonged use of bedaquiline in two patients with pulmonary extensively drug-resistant tuberculosis: Two case reports

BACKGROUND Bedaquiline is among the prioritized drugs recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis(XDRTB).Many patients have not achieved better clinical improvement after bedaquiline is stopped at 24 wk.However,there is no recommendation or guideline on bedaquiline administration beyond 24 wk,which is an important consideration when balancing the benefit of prognosis for XDR-TB against the uncertain safety concerning the newer antibiotics.CASE SUMMARY This paper reported 2 patients with XDR-TB(a female of 58 years of age and a female of 18 years of age)who received bedaquiline for 36 wk,as local experience to be shared.The 2 cases had negative cultures after 24 wk of treatment,but lung imaging was still positive.After discussion among experts,the consensus was made to bedaquiline prolongation by another 12 wk.The 36-wk prolonged use of bedaquiline in both cases achieved a favorable response without increasing the risk of cardiac events or new safety signals.CONCLUSION Longer regimen,including 36-wk bedaquiline treatment,might be an option for patients with XDR-TB.More studies are needed to explore the effectiveness and safety of prolonged use of bedaquiline for 36 wk vs standard 24 wk in the treatment of multidrug-resistant/XDR-TB or to investigate further the biomarkers and criteria indicative for extension of bedaquline to facilitate clinical use of thisnovel drug.

No-Reference Image Quality Assessment Method Based on Visual Parameters

Recent studies on no-reference image quality assessment (NR-IQA) methods usually learn to evaluate the image quality by regressing from human subjective scores of the training samples. This study presented an NR-IQA method based on the basic image visual parameters without using human scored image databases in learning. We demonstrated that these features comprised the most basic characteristics for constructing an image and influencing the visual quality of an image. In this paper, the definitions, computational method, and relationships among these visual metrics were described. We subsequently proposed a no-reference assessment function, which was referred to as a visual parameter measurement index (VPMI), based on the integration of these visual metrics to assess image quality. It is established that the maximum of VPMI corresponds to the best quality of the color image. We verified this method using the popular assessment database—image quality assessment database (LIVE), and the results indicated that the proposed method matched better with the subjective assessment of human vision. Compared with other image quality assessment models, it is highly competitive. VPMI has low computational complexity, which makes it promising to implement in real-time image assessment systems.

Clinical efficacy of tocilizumab combined with leflunomide in the treatment of rheumatoid arthritis

Objective:To study the clinical efficacy of tocilizumab combined with leflunomide in the treatment of rheumatoid arthritis.Methods:114 patients with rheumatoid arthritis admitted from May 2015 to April 2018 were randomly divided into control group(n=57)and observation group(n=57).The control group was treated with leflunomide.On the basis of this,the observation group was treated with tocilizumab for 12 weeks.Functional indicators,erythrocyte sedimentation rate(ESR),rheumatoid factor and inflammatory factors were evaluated and adverse reactions were recorded.Results:The total treatment efficiency of the observation group(89.47%)was significantly higher than that of the control group(75.44%)(P<0.05).Morning stiffness time,joint pain score,joint swelling score,ESR,serum C-reactive protein(CRP),rheumatoid factor(RF),tumor necrosis factor(TNF-α),and interleukin-1 were observed in the observation group and the control group.The levels of IL-1),IL-6,IL-8 and other indicators were lower than those before treatment.The indexes of the observation group were significantly lower than those before treatment(P<0.05),and after treatment The morning stiffness time,joint pain score,joint swelling score,ESR,CRP,RF,TNF-α,IL-1,IL-6,IL-8 and other indicators in the observation group were significantly lower than those in the control group(P<0.05).The incidence of adverse reactions in the observation group was 14%,and the incidence of adverse reactions in the control group was 17.54%.Toltuzumab combined with leflunomide in the treatment of rheumatoid arthritis did not increase the probability of adverse reactions.Conclusion:The use of tocilizumab combined with leflunomide in the treatment of rheumatoid joints has good efficacy and safety.This may be related to a significant reduction in inflammatory factors TNF-α,IL-1,IL-6,IL-8 and the like.

Multiphase flow inside a four-strand continuous casting tundish using three types of ladle shrouds

Numerical and physical models have been built and validated to study the multiphase flow inside three ladle shrouds and a four-strand tundish.A conventional straight ladle shroud and two types of trumpet-shaped ladle shroud(TLS)have been comparatively investigated.The maximum velocity at ladle shroud outlet reduces from 1.3 to 0.5 m/s,which indicates a quieter tundish pool.It is demonstrated that the use of a TLS can also decrease the maximum surface velocity from 0.16 to 0.13 m/s,which reduces the tendency of forming tundish open eye.The flow pattern and mixing behavior are improved inside the tundish,especially in enlarging the plug volume from 6.61%to 9.04%.The difference between the near and far outlets is narrowed when the TLS is applied.A computational program was developed to calculate characteristic parameters of different ladle shroud designs,and a dimensionless index was proposed to evaluate their mass and inner volume.Plant trials have been carried out,and the results showed that TLS can reduce level fluctuation in the pouring zone,which is beneficial to promoting better protective performance from secondary contamination and heat loss during continuous casting.

Metatranscriptome of human lung microbial communities in a cohort of mechanically ventilated COVID-19 Omicron patients

The Omicron variant of the severe acute respiratory syndrome coronavirus 2(SARS‑CoV‑2)infected a substantial proportion of Chinese population,and understanding the factors underlying the severity of the disease and fatality is valuable for future prevention and clinical treatment.We recruited 64 patients with invasive ventilation for COVID-19 and performed metatranscriptomic sequencing to profile host transcriptomic profiles,plus viral,bacterial,and fungal content,as well as virulence factors and examined their relationships to 28-day mortality were examined.In addition,the bronchoalveolar lavage fluid(BALF)samples from invasive ventilated hospital/community-acquired pneumonia patients(HAP/CAP)sampled in 2019 were included for comparison.Genomic analysis revealed that all Omicron strains belong to BA.5 and BF.7 sub-lineages,with no difference in 28-day mortality between them.Compared to HAP/CAP cohort,invasive ventilated COVID-19 patients have distinct host transcriptomic and microbial signatures in the lower respiratory tract;and in the COVID-19 non-survivors,we found significantly lower gene expressions in pathways related viral processes and positive regulation of protein localization to plasma membrane,higher abundance of opportunistic pathogens including bacterial Alloprevotella,Caulobacter,Escherichia-Shigella,Ralstonia and fungal Aspergillus sydowii and Penicillium rubens.Correlational analysis further revealed significant associations between host immune responses and microbial compositions,besides synergy within viral,bacterial,and fungal pathogens.Our study presents the relationships of lower respiratory tract microbiome and transcriptome in invasive ventilated COVID-19 patients,providing the basis for future clinical treatment and reduction of fatality.

Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China:focus on the safety

Background:World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis(DR-TB)should develop and implement a system for active pharmacovigilance that allows for detection,reporting and management of adverse events.The aim of the study is to evaluate the frequency and severity of adverse events(AEs)of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant(MDR)/extensively drug-resistant(XDR)-TB based on active drug safety monitoring(aDSM)system of New Drug Introduction and Protection Program(NDIP).

Process evaluation of E-learning in continuing medical education:evidence from the China-Gates Foundation Tuberculosis Control Program

Background:E-learning is a growing phenomenon which provides a unique opportunity to address the challenges in continuing medical education(CME).The China-Gates Foundation Tuberculosis(TB)Control Program implemented online training forTB health workers in three provinces of China.We aim to evaluate the implementation of E-learning CME programs,analyse the barriers and facilitators during the implementation process,and to provide policy recommendations.

The effectiveness of E-learning in continuing medical education for tuberculosis health workers: a quasi-experiment from China

Background:Given the context of rapid technological cha nge and COIVD-19 pan demies,E-lear ning may provide a unique opportunity for addressing the challenges in traditional face-to-face continuing medical education(CME).However,the effectiveness of E-learning in CME interventions remains unclear.This study aims to evaluate whether E-learning training program can improve TB health personnel's knowledge and behaviour in China.

The China tuberculosis clinical trials consortium network:a model for international TB clinical trials capacity building

Background:With the second largest tuberculosis(TB)burden globally,China is committed to actively engage in international TB clinical trials to contribute to global TB research.However,lack of research capacity among local sites has been identified as a barrier.Main text:The China Tuberculosis Clinical Trials Consortium(CTCTC)was initiated by Beijing Chest Hospital with investment from the US National Institutes of Health and technical support from Family Health International 360 in 2013,as a nationwide collaborative clinical trial network to strengthen selected clinical site research capacity and attract TB clinical trials.The program aims to:1)recruit leading hospitals that care for TB patients;2)conduct on-site assessment to identify capacity gaps and needs for improvement;3)design and deliver capacity building activities;4)attract and deliver high quality results for TB clinical trials.A total of 24 sites have joined CTCTC,covering 20 provinces in China.Twenty-two sites have been accredited by the National Medical Products Administration(NMPA)to be qualified to conduct TB clinical trials.The onsite assessment,extensive trainings among the CTCTC sites and young investigators have resulted in better understanding and improvement of the site capacity in conducting TB clinical trials.The establishment and growth of the CTCTC network has benefited from the good leadership,effective international cooperation and local commitment.Issues in human resources,regulatory environment and sustainability have been challenging the network from continuing growth.Clinical researchers have full-time clinical responsibilities in China and it is thus important to build a cadre of other human resources to assist.The regulatory environment is becoming friendlier in China to introduce international clinical trials to the CTCTC network.Conclusions:The CTCTC,with mature management structure and sustainable development model,which are distilled five key lessons for other developing countries or investigators of interest.They are the respectively using assessment-based approach to design tailored training package,understanding the availability of clinical researchers,providing solutions to maintain sustainability,understanding local regulatory environments and working with an international organization with local on-site team,respectively.Although,the experiences and capacity of China’s TB hospitals in conducting clinical research vary.Considerable efforts to continue building the capacity are still needed,although the gap is smaller for a few top-tier hospitals.