Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR improves hepatic and cardiac dysfunction of NASH mice.

A2AR-disrupted mice is characterized by severe systemic and visceral adipose tissue (VAT) inflammation. Increasing adenosine cyclase (AC), cAMP, and protein kinase A (PKA) formation through A2AR activation suppress systemic/VAT inflammation in obese mice. This study explores the effects of 4 wk A2AR agonist PSB0777 treatment on the VAT-driven pathogenic signals in hepatic and cardiac dysfunction of nonalcoholic steatohepatitis (NASH) obese mice. Among NASH mice with cardiac dysfunction, simultaneous decrease in the A2AR, AC, cAMP, and PKA levels were observed in VAT, liver, and heart. PSB0777 treatment significantly restores AC, cAMP, PKA, and hormone-sensitive lipase (HSL) levels, decreased SREBP-1/FASN, MCP-1, and CD68 levels, reduces infiltrated CD11b+ F4/80+ cells and adipogenesis in VAT of NASH + PSB0777 mice. The changes in VAT were accompanied by the suppression of hepatic and cardiac lipogenic/inflammatory/injury/apoptotic/fibrotic markers, the normalization of cardiac contractile [sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2)] marker, and cardiac dysfunction. The in vitro approach revealed that conditioned media (CM) of VAT of NASH mice (CMnash) trigger palmitic acid (PA)-like lipotoxic (lipogenic/inflammatory/apoptotic/fibrotic) effects in AML-12 and H9c2 cell systems. Significantly, A2AR agonist pretreatment-related normalization of A2AR-AC-cAMP-PKA levels was associated with the attenuation of CMnash-related upregulation of lipotoxic markers and the normalization of lipolytic (AML-12 cells) or contractile (H9C2 cells) marker/contraction. The in vivo and in vitro experiments revealed that A2AR agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflammation, injury, apoptosis, fibrosis, hypocontractility, and subsequently improve hepatic and cardiac dysfunction in NASH mice.NEW & NOTEWORTHY Protective role of adenosine A2AR receptor (A2AR) and AC-cAMP-PKA signaling against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) possibly via its actions on adipocytes is well known in the past decade. Thus, this study evaluates pharmacological activities of A2AR agonist PSB0777, which has already demonstrated to treat NASH. In this study, the inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR with A2AR agonist PSB0777 improves the hepatic and cardiac dysfunction of high-fat diet (HFD)-induced NASH mice.

Negative effects on medical students' scores for clinical performance during the COVID-19 pandemic in Taiwan: a comparative study.

PURPOSE: Coronavirus disease 2019 (COVID-19) has heavily impacted medical clinical education in Taiwan. Medical curricula have been altered to minimize exposure and limit transmission. This study investigated the effect of COVID-19 on Taiwanese medical students' clinical performance using online standardized evaluation systems and explored the factors influencing medical education during the pandemic. METHODS: Medical students were scored from 0 to 100 based on their clinical performance from 1/1/2018 to 6/31/2021. The students were placed into pre-COVID-19 (before 2/1/2020) and midst-COVID-19 (on and after 2/1/2020) groups. Each group was further categorized into COVID-19-affected specialties (pulmonary, infectious, and emergency medicine) and other specialties. Generalized estimating equations (GEEs) were used to compare and examine the effects of relevant variables on student performance. RESULTS: In total, 16,944 clinical scores were obtained for COVID-19-affected specialties and other specialties. For the COVID-19-affected specialties, the midst-COVID-19 score (88.513.52) was significantly lower than the pre-COVID-19 score (90.143.55) (P<0.0001). For the other specialties, the midst-COVID-19 score (88.323.68) was also significantly lower than the pre-COVID-19 score (90.063.58) (P<0.0001). There were 1,322 students (837 males and 485 females). Male students had significantly lower scores than female students (89.333.68 vs. 89.993.66, P=0.0017). GEE analysis revealed that the COVID-19 pandemic (unstandardized beta coefficient=-1.99, standard error [SE]=0.13, P<0.0001), COVID-19-affected specialties (B=0.26, SE=0.11, P=0.0184), female students (B=1.10, SE=0.20, P<0.0001), and female attending physicians (B=-0.19, SE=0.08, P=0.0145) were independently associated with students' scores. CONCLUSION: COVID-19 negatively impacted medical students' clinical performance, regardless of their specialty. Female students outperformed male students, irrespective of the pandemic.

Preservation of vascular endothelial glycocalyx and barrier by activation of adenosine A2A receptor (A2AR) improved renal dysfunction in cirrhotic rats.

Cirrhosis-related hepatic and renal endothelial dysfunction is characterized by macrophage-endothelium adhesion-mediated inflammation, glycocalyx/barrier damage, and impaired vasodilation. Activation of adenosine A2A receptor (A2AR) protects cirrhotic rats from impairment of hepatic microcirculation post hepatectomy. This study evaluates the effects of A2AR activation on the cirrhosis-related hepatic and renal endothelial dysfunction in biliary cirrhotic rats receiving two weeks of A2AR agonist PSB0777 [bile duct ligated (BDL)+PSB0777] treatment. Endothelial dysfunction in cirrhotic liver, renal vessels, and kidney is characterized by downregulation of the A2AR expressions, decreased vascular endothelial vasodilatory (p-eNOS)/anti-inflammatory (IL-10/IL-10R)/barrier [VE-cadherin (CDH5) and ß-catenin (CTNNB1)]/glycocalyx [syndecan-1 (SDC1) and hyaluronan synthase-2 (HAS2)] markers, and increased leukocyte-endothelium adhesion molecules (F4/80, CD68, ICAM-1, and VCAM-1). In BDL rats, PSB0777 treatment improves hepatic and renal endothelial dysfunction, ameliorates portal hypertension, and attenuates renal hypoperfusion by restoring of the vascular endothelial anti-inflammatory, barrier, glycocalyx markers and vasodilatory response as well as inhibiting the leukocyte-endothelium adhesion. In an in vitro study, conditioned medium (CM) of bone marrow-derived macrophage (BMDM) of BDL rats [BMDM-CM (BDL)] induced barrier/glycocalyx damage, which was reversed by the PSB0777 pre-treatment. The A2AR agonist is a potential agent that can simultaneously correct cirrhosis-related hepatic and renal endothelial dysfunction, portal hypertension, renal hypoperfusion, and renal dysfunction.

Lessons learned from a novel 3-year longitudinal stepwise "Residents-as-Teachers" program.

BACKGROUND: Most residents-as-teachers (RaT) programs are delivered over days to weeks without comprehensive evaluation, and stepwise approaches have rarely been applied to RaT activities. This study aimed to depict the implementation experience and evaluate the effectiveness of a novel longitudinal 3-year, stepwise RaT program. METHODS: The longitudinal RaT program included three once yearly face-to-face courses according to the different teaching roles of the residents. To evaluate the effectiveness of the new longitudinal program, we designed a randomized controlled study for first-year residents of all specialties in one medical center. The effectiveness was evaluated by the objective structured teaching exercise (OSTE), feedback from participants and medical students, and evaluation of clinical practice performance by program directors. RESULTS: A total of 35 (37.6%) of 93 residents participated in this study, and 13 (37.1%) of all enrolled residents completed all 3-year courses, including seven for the longitudinal program and six for the traditional. The serial OSTE revealed significantly higher scores in the longitudinal group in the second and third years (13.43 vs 9.50, p = 0.001 and 14.29 vs 10.33, p = 0.015). Satisfaction was higher when advanced topics were taught in the second and third years compared with those taught in the first year (4.43 vs 3.89, p = 0.02). The feedback from medical students was similar between the two groups, and the evaluation from program directors revealed insignificantly better clinical performance among the longitudinal course participants. CONCLUSION: It is challenging to conduct a multi-year longitudinal RaT program on young residents. Nevertheless, this longitudinal program was potentially associated with better learning retention and higher satisfaction and worthy to be promoted.

Low lymphocyte-to-monocyte ratio, calcitriol level, and CD206 level predict the development of acute-on-chronic liver failure in patients cirrhosis with acute decompensation.

BACKGROUND: Cirrhosis-related acute-on-chronic liver failure (ACLF) is associated with high morbidity and mortality rates. Prognostic models of ACLF have been developed; however, few studies have focused on the occurrence of ACLF. This study aimed to identify the factors that predict the development of ACLF, hepatic encephalopathy (HE), and infection in patients with cirrhosis. METHODS: Patients with cirrhosis were enrolled, and the serum levels of calcitriol, Cluster of Differentiation 26 (CD206), and macrophage-inducible lectin receptor (Mincle) were measured, and lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio were calculated; all the patients were tracked for 6 months. A generalized estimating equation (GEE) was used to assess the factors associated with ACLF development, HE, and infection. The aforementioned model was derived based on immunological markers, and receiver operating characteristic analysis with area under the curve (AUC) was adopted to evaluate accuracy. RESULTS: After screening 325 patients with cirrhosis, 65 patients were eligible. In the GEE model, low levels of calcitriol (odds ratio [OR] = 3.259; 95% confidence interval [CI] = 1.118-8.929) and CD206 (OR = 2.666; 95% CI = 1.082-6.567) were associated with the development of ACLF, and the LMR was a protective factor (OR = 0.356; 95% CI = 0.147-0.861). Low calcitriol levels were a risk factor for HE (OR = 3.827) and infection (OR = 2.489). LMR was found to be a protective factor against HE (OR = 0.388). An immunological model for the discrimination of ACLF development within 6 months was proposed, with an AUC of 0.734 (95% CI = 0.598-0.869). CONCLUSION: Single and combined immunological markers, including low LMR and low levels of calcitriol and CD206, were promising for early prediction of the development of ACLF, HE, and infection in patients with cirrhosis.

Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice.

BACKGROUND: Suppression of cardiac iinflammasome, which can be inhibited by Farnesoid X receptor (FXR) agonist, can ameliorate cardiac inflammation and fibrosis. Increased cardiac inflammasome decrease the abundance of regulatory T (Treg) cells and exacerbate cardiac dysfunction. Interaction between cardiomyocytes and Treg cells is involved in the development of nonalcoholic steatohepatitis (NASH)-related cardiac dysfunction. AIMS: This study evaluates whether the FXR agonist obeticholic acid (OCA) treatment improves NASH-associated cardiac dysfunction. METHODS: The in vivo and in vitro mechanisms and effects of two weeks of OCA treatment on inflammasome and Treg dysregulation-related cardiac dysfunction in NASH mice (NASH-OCA) at systemic, tissue and cellular levels were investigated. RESULTS: The OCA treatment suppressed the serum and cardiac inflammasome levels, reduced the cardiac infiltrated CD3+ T cells, increased the cardiac Treg-represented anti-inflammatory cytokines (IL-10/IL-10R) and improved cardiac inflammation, fibrosis and function [decreased left ventricle (LV) mass and increased fractional shortening (FS)] in NASH-OCA mice. The percentages of OCA-decreased cardiac fibrosis and OCA-increased FS were positively correlated with the percentage of OCA-increased levels of cardiac FXR and IL-10/IL-10R. In the Treg cells from NASH-OCA mice spleen, in comparison with the Treg cells of the NASH group, higher intracellular FXR but lower inflammasome levels, and more proliferative/active and less apoptotic cells were observed. Incubation of H9c2 cardiomyoblasts with Treg-NASHcm [supernatant of Treg from NASH mice as condition medium (cm)], increased inflammasome levels, decreased the proliferative/active cells, suppressed the intracellular FXR, and downregulated differentiation/contraction marker. The Treg-NASHcm-induced hypocontractility of H9c2 can be attenuated by co-incubation with OCA, and the OCA-related effects were abolished by siIL-10R pretreatment. CONCLUSIONS: Chronic FXR activation with OCA is a potential strategy for activating IL-10/IL-10R signalling, reversing cardiac regulatory T cell dysfunction, and improving inflammasome-mediated NASH-related cardiac dysfunction.

Equal Z standard-setting method to estimate the minimum number of panelists for a medical school's objective structured clinical examination in Taiwan: a simulation study

PURPOSE: Undertaking a standard-setting exercise is a common method for setting pass/fail cut scores for high-stakes examinations. The recently introduced equal Z standard-setting method (EZ method) has been found to be a valid and effective alternative for the commonly used Angoff and Hofstee methods and their variants. The current study aims to estimate the minimum number of panelists required for obtaining acceptable and reliable cut scores using the EZ method. METHODS: The primary data were extracted from 31 panelists who used the EZ method for setting cut scores for a 12-station of medical school's final objective structured clinical examination (OSCE) in Taiwan. For this study, a new data set composed of 1,000 random samples of different panel sizes, ranging from 5 to 25 panelists, was established and analyzed. Analysis of variance was performed to measure the differences in the cut scores set by the sampled groups, across all sizes within each station. RESULTS: On average, a panel of 10 experts or more yielded cut scores with confidence more than or equal to 90% and 15 experts yielded cut scores with confidence more than or equal to 95%. No significant differences in cut scores associated with panel size were identified for panels of 5 or more experts. CONCLUSION: The EZ method was found to be valid and feasible. Less than an hour was required for 12 panelists to assess 12 OSCE stations. Calculating the cut scores required only basic statistical skills.

Medical school grades may predict future clinical competence.

BACKGROUND: In real-world medical education, there is a lack of reliable predictors of future clinical competencies. Hence, we aim to identify the factors associated with clinical competencies and construct a prediction model to identify "improvement required" trainees. METHODS: We analyzed data from medical students who graduated from National Yang-Ming University with clerkship training and participated in the postgraduate year (PGY) interview at Taipei Veterans General Hospital. Clinical competencies were evaluated using grades of national objective structured clinical examination (OSCEs). This study used data from medical students who graduated in July 2018 as the derivation cohort (N = 50) and those who graduated in July 2020 (n = 56) for validation. RESULTS: Medical school grades were associated with the performance of national OSCEs (Pearson r = 0.34, p = 0.017), but the grades of the structured PGY interviews were marginally associated with the national OSCE (Pearson r = 0.268, p = 0.06). A prediction model was constructed to identify "improvement required" trainees, defined: trainees with the lowest 25% of scores in the national OSCEs. According to this model, trainees with the lowest 25% medical school grades predicted a higher risk of the "improvement required" clinical performance (Q1-Q3 vs Q4 = 15% vs 60%, odds ratio = 8.5 [95% confidence interval = 1.8-39.4], p = 0.029). In the validation cohort, our prediction model could accurately classify 76.7% "improvement required" and "nonimprovement required" students. CONCLUSION: Our study suggests that interventions for students with unsatisfactory medical school grades are warranted to improve their clinical competencies.

Cytomegalovirus viral interleukin-10 in patients with Aspergillus infection and effects on clinical outcome.

BACKGROUND: Human cytomegalovirus (CMV) is associated with aspergillosis, but the simultaneous presence of CMV viral interleukin-10 (cmvIL-10) and aspergillosis has never been investigated. CmvIL-10 is produced by CMV-infected cells and acts as an immune modulator during CMV infection. The aim of this study was to evaluate cmvIL-10 levels in peripheral blood and its influence on the clinical outcomes of Aspergillus infection. METHODS: Patients who visited or were admitted to the hospital with suspected Aspergillus infection, including invasive aspergillosis (IA) and chronic pulmonary aspergillosis (CPA), were prospectively enrolled. The cmvIL-10, human IL-10 (hIL-10), IL-1B, IL-6, IL-8, IFN-γ, and TNF-α levels in peripheral blood were measured. RESULTS: Patients with Aspergillus infection had a higher level of cmvIL-10 than the control group (158 ± 305 vs 27.9 ± 30.4 pg/ml, p < .05). The level of cmvIL-10 was not correlated with CMV viremia or end-organ disease. The cmvIL-10 but not hIL-10 level was positively correlated with the IFN-γ level (p < .05) and marginally negatively correlated with IL-1B and IL-8 levels (p < .1). In patients with CPA, a high level of cmvIL-10 (≥100 pg/ml) was a poor prognostic factor for long-term survival (p < .05). In contrast, CMV viremia or end-organ disease was associated with poor survival in patients with IA (p = .05). CONCLUSIONS: Aspergillus infection was associated with CMV coinfection with cmvIL-10 in blood. A cmvIL-10 concentration ≥100 pg/ml was a predictor for unfavourable outcome in CPA patients.

Developing a competency-based framework for resident-as-teacher.

BACKGROUND/PURPOSE: Residents play an important role as teachers of junior colleagues and medical students. Clinical teaching also helps residents in clinical learning. However, the skills required for residents to be competent teachers are rarely described systemically. Beyond the widely adopted six core competencies for postgraduate training by the Accreditation Council for Graduate Medical Education (ACGME), the teaching competencies should be further developed, and the milestones should be clearly defined to serve as better references for resident training programs. METHODS: Twenty members, including five experts from major teaching hospitals across Taiwan and 15 from a public medical center, were invited to a workgroup to collaboratively develop a competency-based framework. The development process was similar to that suggested by the ACGME. The teaching competencies framework were drafted by an experienced physician educator. The draft was sent to each group member, and feedback was collected. Two workgroup meetings were held for consensus formation. The contents of the teaching competencies of residents were confirmed after two rounds of revision. The outline of the framework was also reported at an international meeting in September 2019. RESULTS: Two core competencies, instruction and assessment, with three sub-competencies and 37 milestones, were adopted in the final edition of resident-as-teacher competencies. The sub-competencies were "dissemination of knowledge" and "teaching of procedural skills" for instruction, and "direct observation and feedback" for assessment. CONCLUSION: A competency-based framework for resident-as-teacher was developed. The framework can be applied in combination with other existing competencies for holistic postgraduate training programs.

Enhancing the learning and transfer of preprocedural communication skills during clerkship using audio-visual material: a prospective case-controlled study over 2 years.

OBJECTIVE/DESIGN/SETTING: This study aims to develop preprocedural communication-specific framework that emphasises the use of audiovisual materials and compares its acceptability by trainees with a regular module. TRAINEES: Between October 2018 and July 2021, 96 medical clerks were enrolled and randomly divided into regular and intervention groups. Another 48 trainees whose did not join the framework-based training but complete self-assessments were enrolled as the control group. INTERVENTIONS: In the intervention training module, the key steps of preprocedural communication-specific skills were structuralised into a framework using the acronym of OSCAR. PRIMARY AND SECONDARY OUTCOME MEASURES: This study compared the acceptability of trainees for two modules by measuring the degree of increase in the end-of-rotation and follow up (4 weeks later) competency from baseline by trainees' self-assessments and physician assessments after serial trainings. RESULTS: In comparison with regular group trainees, greater degree of improvements (framework-1 statement: 111%±13% vs 27%±5%, p<0.001; framework-2 statement: 77%±9% vs 48%±2%, p<0.05; skill-1 statement: 105%±9% vs 48%±3%, p<0.001); skill-2 statement: 71%±11% vs 50%±9%, p<0.05) were noted in the framework-related and skill-related statement 1-2 (the familiarity and confidence to use the framework and skills) than those of intervention group. At the end-of-rotation stage, the trainees ability to use the 'A-step: using audiovisual materials' of the OSCAR was significantly improved (229%±13%, p<0.001), compared with other steps. In the intervention group, the degree of improvement of the end-of-rotation data of trainees' self-assessment from baseline was significantly correlated with the degree of the improvement in physicians' assessment data in the aspects of skills, framework and steps in framework (R=0.872, p<0.01; R=0.813, p<0.001; R=0.914, p<0.001). CONCLUSIONS: The OSCAR framework-based intervention module is well accepted by medical clerks and motivates them to integrate the acquired skills in clinical practice, which leads to trainees' primary care patients being satisfied with their preprocedural communication.

Comparison of OSCE performance between 6- and 7-year medical school curricula in Taiwan.

BACKGROUND: The year 2013 marks a watershed in the history of medical education in Taiwan. Following Taiwan's Taskforce of Medical School Curriculum Reform recommendations, the medical school curriculum was reduced from 7 to 6 years. This study aimed to analyze the impact of medical school curriculum reform on medical students' performance in objective structured clinical examinations (OSCEs). METHODS: We retrospectively analyzed the OSCE records at Taipei Veterans General Hospital (Taipei VGH), one of Taiwan's largest tertiary medical centers, between November 2016 and July 2020. The eligibility criteria were medical students receiving a full one-year clinical sub-internship training at Taipei VGH and in their last year of medical school. All medical students received a mock OSCE-1 at the beginning of their sub-internship, a mock OSCE-2 after six months of training, and a national OSCE at the end of their sub-internship. The parameters for performance in OSCEs included "percentage of scores above the qualification standard" and "percentage of qualified stations." RESULTS: Between November 2016 and July 2020, 361 undergraduates underwent clinical sub-internship training at Taipei VGH. Among them, 218 were taught under the 7-year curriculum, and 143 were instructed under the 6-year curriculum. Based on baseline-adjusted ANCOVA results, medical students under the 7-year curriculum had a higher percentage of scores above the qualification standard than those under the 6-year curriculum at the mock OSCE-1 (7-year curriculum vs. 6-year curriculum: 33.8% [95% CI 32.0-35.7] vs. 28.2% [95% CI 25.9-30.4], p < 0.001), and mock OSCE-2 (7-year curriculum vs. 6-year curriculum: 89.4% [95% CI 87.4-91.4] vs. 84.0% [95% CI 81.5-86.4], p = 0.001). Moreover, medical students in the 7-year curriculum had a higher percentage of qualified stations in mock OSCE-1 (7-year curriculum vs. 6-year curriculum: 89.4% [95% CI 87.4-91.4] vs. 84.0% [95% CI 81.5-86.4], p = 0.001) and mock OSCE-2 (7-year curriculum vs. 6-year curriculum: 91.9% [95% CI 90.1-93.8] vs. 86.1% [95% CI 83.8-88.3], p = 0.001). After clinical sub-internship training, there were no differences in the percentage of scores above the qualification standard (7-year curriculum vs. 6-year curriculum: 33.5% [95% CI 32.2-34.9] vs. 34.6 [95% CI 32.9-36.3], p = 0.328) and percentage of qualified stations (7-year curriculum vs. 6-year curriculum: 89.4% [95% CI 88.1-90.7] vs. 90.2% [95% CI 88.6-91.8], p = 0.492). CONCLUSIONS: At the beginning of the sub-internship, medical students under the 7-year curriculum had better OSCE performance than those under the 6-year curriculum. After the clinical sub-internship training in Taipei VGH, there was no difference in the national OSCE score between the 6- and 7-year curricula. Our study suggests that clinical sub-internship is crucial for the development of clinical skills and performance in the national OSCE.

Immersive virtual reality (VR) training increases the self-efficacy of in-hospital healthcare providers and patient families regarding tracheostomy-related knowledge and care skills: A prospective pre-post study.

BACKGROUND: Virtual reality (VR)-based simulation in hospital settings facilitates the acquisition of skills without compromising patient safety. Despite regular text-based training, a baseline survey of randomly selected healthcare providers revealed deficiencies in their knowledge, confidence, comfort, and care skills regarding tracheostomy. This prospective pre-post study compared the effectiveness of regular text- and VR-based intervention modules in training healthcare providers' self-efficacy in tracheostomy care skills. METHODS: Between January 2018 and January 2020, 60 healthcare providers, including physicians, nurses, and respiratory therapists, were enrolled. For the intervention, a newly developed head-mounted display (HMD) and web VR materials were implemented in training and clinical services. Subsequently, in-hospital healthcare providers were trained using either text or head-mounted display virtual reality (HMD-VR) materials in the regular and intervention modules, respectively. For tracheostomy care skills, preceptors directly audited the performance of trainees and provided feedback. RESULTS: At baseline, the degree of trainees' agreement with the self-efficacy-related statements, including the aspects of familiarity, confidence, and anxiety about tracheostomy-related knowledge and care skills, were not different between the control and intervention groups. At follow-up stage, compared with the regular group, a higher percentage of intervention group' trainees reported that they are "strongly agree" or "somewhat agree" that the HMD-VR simulation increases their self-efficacy, including the aspects of familiarity and confidence, and reduced their anxiety about tracheostomy-related knowledge and care skills. After implementation, a higher degree of trainees' average satisfaction with VR-based training and VR materials was observed in the intervention group than in the regular group. Most reported that VR materials enabled accurate messaging and decreased anxiety. The increasing trend of the average written test and hands-on tracheostomy care skills scores among the intervention group trainees was significant compared to those in the regular group. The benefits of HMD-VR simulations and web-VR material-based clinical services for in-hospital healthcare providers and patient families persisted until 3 to 4 weeks later. CONCLUSION: The current study suggests that VR materials significantly enhance trainees' self-efficacy (increased familiarity, increased confidence, and reduced anxiety) and their satisfaction with the training, while motivating them to use acquired knowledge and skills in clinical practice.

Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats.

Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.

Chronic Pulmonary Aspergillosis: Disease Severity Using Image Analysis and Correlation with Systemic Proinflammation and Predictors of Clinical Outcome.

(1) Background: The presentation of chronic pulmonary aspergillosis (CPA) ranges from single granuloma to fibrosis in the affected lung. CPA can be divided into five categories according to European Respirology Society (ERS) guidance but is usually assessed by clinical physicians. Computer-based quantitative lung parenchyma analysis in CPA and its correlation with clinical manifestations, systemic inflammation, and angiogenesis have never been investigated. (2) Method: Forty-nine patients with CPA and 36 controls were prospectively enrolled. Pulmonary function tests (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FCV) and biomarkers in the peripheral blood (the chemokines interleukin (IL)-1B, IL-6, IL-10, IL-8, CRP, ESR, MMP1, MMP7, MMP8, TNF-α, calprotectin, SDF-1α, and VEGFA) were measured before antifungal treatment. The disease severity was categorized into mild, moderate, and severe based on chest computed tomography (CT) images. The oxygen demand and overall mortality until the end of the study were recorded. Quantitative parenchyma analysis was performed using the free software 3Dslicer. (3) Results: The results of quantitative parenchyma analysis concorded with the visual severity from the chest CT, oxygen demand, FVC, and FEV1 in the study subjects. The decrease in kurtosis and skewness of the lung density histograms on CT, increase in high attenuation area (HAA), and reduced lung volume were significantly correlated with increases in the PMN %, CRP, IL-1B, SDF-1α, MMP1, and Calprotectin in peripheral blood in the multivariable regression analysis. TNF-α and IL-1B at study entry and the CPA severity from either a visual method or computer-based evaluation were predictors of long-term mortality. (4) Conclusion: The computer-based parenchyma analysis in CPA agreed with the categorization on a visual basis and was associated with the clinical outcomes, chemokines, and systemic proinflammation profiles.

Deletion of intestinal SIRT1 exacerbated muscle wasting in cirrhotic mice by decreasing the intestinal concentration of short-chain fatty acids and inflammation.

Systemic sirtuin 1 (SIRT1) activation alleviates muscle wasting and improves muscle function by downregulation of myotropic and proteolytic markers. In this study, we evaluated the effects of the intestinal Sirt1 deletion on the dysregulated gutmuscle axis in cirrhotic mice. Cirrhosis-related muscle wasting was induced by common bile duct ligated (BDL) in either wild-type (WT) or intestine-specific Sirt1-deleted (Sirt1IEC-KO) mice, including WT-BDL, WT-sham, Sirt1IEC-KO-BDL and Sirt1IEC-KO-sham mice. Compared with WT-BDL mice, Sirt1IEC-KO-BDL mice showed worsened low lean mass, exacerbated muscle wasting, increased expression of myotropic markers, increased muscular protein degradation, and decreased expression of myogenic markers through aggravation of intestinal inflammation (as evidenced by increased fecal calprotectin/lipocalin-2 levels, increased intestinal macrophage infiltration, and increased intestinal TNFα/IL-6 levels), decrease in abundance of short-chain fatty acid (SCFA)-producing bacteria, decrease in levels of intestinal SCFAs (with anti-inflammatory effects), and downregulation of SCFA receptor GPR43. In biliary cirrhotic mice, a decrease in the abundance of SCFA-producing bacteria and an increase in the levels of intestinal/muscular inflammatory markers are involved in the pathogenesis of dysregulated gut-muscle axis-related muscle wasting, and intestinal deletion of Sirt1 exacerbated these changes.

Roles and mechanisms of circulating CEACAM1 in the cirrhosis-related intestinal hyperpermeability: in vitro approach.

BACKGROUND: Cirrhosis-related intestinal hyperpermeability and endotoxemia are characterized by intestinal epithelial cell apoptosis, impaired restitution (proliferation and migration), decreased tight junction protein levels, and subsequent barrier dysfunction. In addition to endotoxin and tumor necrosis factor-α (TNFα), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) plays crucial roles in the regulation of apoptosis, restitution, tight junction protein-maintained barrier function of intestinal epithelial cells. METHODS: This study aims to explore the roles and underlying mechanisms of CEACAM1 in cirrhosis-related intestinal hyperpermeability through in vitro approach. RESULTS: In cirrhotic patients, high serum levels of intestinal hyperpermeability (zonulin and endotoxin) markers were accompanied by elevated serum levels of TNFα and soluble CEACAM1. In in vitro experiments, we evaluated the individual and interacted roles of TNFα and human recombinant CEACAM1 (hrCEACAM1) in LC-sera (sera of cirrhotic patients)-induced intestinal hyperpermeability-related pathogenic signals. In the cell Line human from human colon (Caucasian colon adenocarcinoma) (Caco-2) cell culture, LC-sera, TNFα, and hrCEACAM1 increased apoptosis (measured by Terminal deoxynucleotidyl transferase [TdT] dUTP nick end labeling+/annexin-5+propidium iodide+ cells and caspase-3 activity), decreased restitution capacity (proliferation and migration), and disrupted tight junction protein-maintained barrier function in Caco-2 cells. The pathogenic changes mentioned above were accompanied by an increase in intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase release, and endoplasmic reticulum stress-related signals in the LC-sera or TNFα-pretreated Caco-2 cells. Concomitant incubation of Caco-2 cells with anti-CEACAM1 suppressed these LC-sera or TNFα-induced negative effects on restitution, barrier function, and cell viability. CONCLUSION: This study demonstrated that sera from cirrhotic patients contain soluble CEACAM1, which is involved in the pathogenesis of intestinal hyperpermeability. Accordingly, it is noteworthy to explore the potential use of anti-CEACAM1 treatment for cirrhosis-related intestinal hyperpermeability and endotoxemia.

Non-Selective Beta-Blockers Decrease Infection, Acute Kidney Injury Episodes, and Ameliorate Sarcopenic Changes in Patients with Cirrhosis: A Propensity-Score Matching Tertiary-Center Cohort Study.

BACKGROUND: Cirrhotic complications resulting from portal hypertension can be considerably reduced by non-selective beta-blockers (NSBBs); however, scarce studies have investigated therapeutic agents for other complications. We aimed to investigate the effects of NSBBs on common cirrhotic complications of infection, acute kidney injury (AKI), chronic renal function declination, and sarcopenic changes. METHODS: Medical records of hospitalization for cirrhosis with at least a 4-year follow-up were analyzed and selected using propensity-score matching (PSM). Generalized estimating equation (GEE) was applied to assess the association of NSBBs with infection requiring hospitalization and AKI. Chronic renal function declination was evaluated by slope of regression lines derived from reciprocal of the serum creatinine level. The covariates of CT-measured skeletal muscle index (SMI) alterations were analyzed by generalized linear mixed model. RESULTS: Among the 4946 reviewed individuals, 166 (83 NSBB group, 83 non-NSBB group) were eligible. Using GEE, Charlson comorbidity index, Child-Pugh score and non-NSBB were risk factors for infection; non-NSBB group revealed a robust trend toward AKI, showed no significant difference with chronic renal function declination of NSBB group, and was negatively associated with SMI alteration. CONCLUSION: Chronic NSBB use lowered the episodes of infection requiring hospitalization and AKIs, whereas non-NSBB was associated with sarcopenic changes.

Effects of a simulation-based blended training model on nurses' treatment decision-related knowledge about oral cancer in Taiwan: a pilot survey.

The present study aimed to evaluate the effects of virtual reality (VR) simulations combined with bedside assignments on nurses' self-efficacy in providing pre-treatment educational services. Between March 2019 and November 2020, we conducted a study of VR educational materials that were developed to cover information about the treatment of oral cancers. The effects of the VR simulation, the thinking-path tracking map method, and bedside assignments on the nurses' treatment decision-related knowledge were evaluated in a ward for oral cancer patients at Taipei Veterans General Hospital, Taipei, Taiwan. The blended training model significantly increased nurses' familiarity (P<0.01) and confidence (P<0.03) regarding their knowledge of treatments and treatment decision-related knowledge. This model also significantly increased their confidence in their skills in bedside pre-treatment education for admitted oral cancer patients (P<0.002). Oral cancer-specific VR materials enhanced the effectiveness of skills training among nurses in the oral cancer ward.

Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice.

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.