Percentage Of Fibrosis Research Articles

Abstract 10380: Differences in Cardiac Magnetic Resonance Native T1 Values Demonstrate Utility in Identifying Acute Cellular Rejection and Assessing Graft Health

Introduction: Cardiac Magnetic Resonance (CMR) is an emerging tool for cardiac graft assessment in heart transplant recipients, with native T1 mapping directed at identifying both rejection and graft fibrosis to predict and guide management of graft dysfunction. Hypothesis: CMR native T1 values may identify acute rejection, predict graft dysfunction, and in secondary analysis, correlate with fibrosis percentage from right ventricle (RV) endomyocardial biopsy (EMB). Methods: Pediatric subjects (n=34, age 12.4±4.9 y, graft age 5.4±4.3 y, LVEF 62.9±5.6%) underwent simultaneous EMB and 1.5T CMR with breath-held T1 mapping via Modified Look-Locker Inversion recovery in 8 short-axis slices, from which global mean and peak native T1 values were quantified. EMB analyzed for histopathological fibrosis% using digital analysis of Maisson’s trichrome stained slides. Patients were stratified into three groups by decision to treat: acute rejection with new treatment initiated, ongoing treatment modified, or no change in treatment. In patients without acute rejection, linear regression was used to compare T1 values with clinical markers of right atrial (RA) mean pressure and brain natriuretic peptide (BNP). Results: Mean T1 values were higher in patients with acute rejection compared to those without, with stratified groups demonstrating a monotonic trend; peak T1 values trended towards significance. In patients without acute rejection, peak T1 values correlated with BNP (r=0.53, p=0.004) and RA mean pressure (r=0.39, p=0.046). Fibrosis% from random RV EMB did not correlate with native T1 values or clinical markers of graft dysfunction. Conclusion: In pediatric heart transplant patients, T1 values from comprehensive CMR identified acute rejection requiring initiation of treatment and graft dysfunction, with regional analysis key to capturing correlation with clinical markers. CMR shows promise as an important tool for evaluation of graft health in children.

Quantification of myocardial fibrosis using noninvasive T2-mapping magnetic resonance imaging: Preclinical models of aging and pressure overload.

Noninvasive imaging of cardiac fibrosis is important for early diagnosis and intervention in chronic heart diseases. Here, we investigated whether noninvasive, contrast agent-free MRI T2 -mapping can quantify myocardial fibrosis in preclinical models of aging and pressure overload. Myocardial fibrosis and remodeling were analyzed in two animal models: (i) aging (15-month-old male CF-1 mice vs. young 6- to 8-week-old mice), and (ii) pressure overload (PO; by transverse aortic constriction in 4- to 5-month-old male C57BL/6 mice vs. sham-operated for 14 days). In vivo T2 -mapping was performed by acquiring data during the isovolumic and early diastolic phases, with a modified respiratory and ECG-triggered multiecho TurboRARE sequence on a 7-T MRI. Cine MRI provided cardiac morphology and function. A quantitative segmentation method was developed to analyze the in vivo T2 -maps of hearts at midventricle, apex, and basal regions. The cardiac fibrosis area was analyzed ex vivo by picro sirius red (PSR) staining. Both aged and pressure-overloaded hearts developed significant myocardial contractile dysfunction, cardiac hypertrophy, and interstitial fibrosis. The aged mice had two phenotypes, fibrotic and mild-fibrotic. Notably, the aged fibrotic subgroup and the PO mice showed a marked decrease in T2 relaxation times (25.3 ± 0.6in aged vs. 29.9 ± 0.7ms in young mice, p = 0.002; and 24.3 ± 1.7in PO vs. 28.7 ± 0.7ms in shams, p = 0.05). However, no significant difference in T2 was detected between the aged mild-fibrotic subgroup and the young mice. Accordingly, an inverse correlation between myocardial fibrosis percentage (FP) and T2 relaxation time was derived (R2 = 0.98): T2 (ms)=30.45 - 1.05× FP. Thus, these results demonstrate a statistical agreement between T2 -map-quantified fibrosis and PSR staining in two different clinically relevant animal models. In conclusion, T2 -mapping MRI is a promising noninvasive contrast agent-free quantitative technique to characterize myocardial fibrosis.

Physical Training as a Blood Pressure Reducer and a Remodeler of Cardiac Fibers in Spontaneously Hypertensive Rats (SHR)

Background: Hypertension is the most prevalent of all cardiovascular diseases, reaching target organs such as the heart. Blood pressure control is critical for preventing organ damage induced by hypertension.
 Objective: To analyze blood pressure, heart rate, left ventricular thickness, the percentage of cardiac fibrosis and the percentage of type III collagen in Spontaneously Hypertensive Rats (SHR) submitted to swimming physical training.
 Methods: The experimental groups were composed of male Wistar Kyoto (WKY) rats (309-311g), which were divided into: 1) Normotensive Sedentary group (SN) (n = 6); 2) Trained Normotensive group (TN) (n = 6); 3) Sedentary Hypertensive group (SH) (n = 6); 4) Trained Hypertensive group (TH) (n = 6). After the end of the protocol, the animals were initially anesthetized to measure blood pressure.
 Results: Physical training was responsible for decreasing blood pressure (F = 16,968; p <0.001) and heart rate (F = 10.710; p = 0.004) in the trained groups (normotensive and hypertensive). Moreover, training was responsible for providing an increase in the thickness of the left ventricle (F = 7,254; p = 0.014) and a reduction in the percentage of cardiac fibrosis (F = 16,081; p <0.001). Furthermore, it was observed that the trained group had lower values of type III collagen (F = 13,166; p = 0.002).
 Conclusions: Physical swimming training triggered a decrease in blood pressure, heart rate, the percentage of fibrosis and the percentage of type III collagen. In addition, there was also a cardiac remodeling due to the increase in left ventricular hypertrophy.

The NLRP3 inhibitor dapansutrile attenuates folic acid induced nephrotoxicity via inhibiting inflammasome/caspase-1/IL axis and regulating autophagy/proliferation

AimsChemical renal toxicity is common and has limited therapeutic interventions. The NLRP3 inhibitor dapansutrile (DAPA) undergoes clinical phase II trials and it shows promising beneficial effects in various inflammatory diseases. The current study aims at evaluating the effect of DAPA on folic acid (FA) induced acute kidney injury (AKI) and its possible transition to chronic injury. Materials and methodsTwo treatment protocols were studied depending on DAPA injection timing. A prophylactic protocol involving the injection of DAPA (0.2 mg/kg) daily for seven days before FA challenge and a therapeutic protocol where DAPA was injected after FA. Each protocol included four groups of rats: control group, DAPA group, FA group and DAPA+FA group. Serum creatinine, urea and uric acid were measured. Also, kidney injury, necrosis and fibrosis percentage in addition to infiltration of CD68 positive cells were evaluated. Activation markers of inflammasome and the expression of Ki-67 and LC-3 were measured. Key findingsResults showed an improvement in renal tissue integrity and a significant decrease in kidney function biomarkers, caspase-1, IL-1β and IL-18 by DAPA injection (p < 0.05). In addition, DAPA decreased the proliferation marker Ki-67 and the autophagic marker LC-3 (p < 0.01). SignificanceDAPA potentially alleviates FA induced nephrotoxicity through targeting inflammasome/caspase-1/IL axis. Moreover, it shows a regulatory effect on renal regeneration and autophagy.

ALT Levels in Treatment-Naive, Chronic Hepatitis B Patients with Concurrent Fatty Liver Disease: A US Nationwide Study

Introduction: Treatment criteria for chronic hepatitis B (CHB) relies on ALT, which can be impacted by concurrent nonalcoholic fatty liver disease (NAFLD), but ALT data on patients with CHB and NAFLD are limited. We aimed to characterize ALT distribution in untreated CHB patients with NAFLD. Methods: We retrospectively analyzed untreated US adults with CHB (533 with NAFLD, 3,172 without NAFLD) using the Clinformatics^™ Data Mart Database (2003–2019). The main outcome was ALT elevation (>1× upper limit of normal, 35/25 U/L for men/women, respectively). Secondary outcomes were advanced fibrosis (via FIB-4 index) and factors associated with fibrosis. Results: The majority of patients were Asian (61.0%) and hepatitis B e-antigen (HBeAg)-negative (90.4%). Patients with CHB and NAFLD were older (57.2 vs. 49.5 years, p < 0.001), more likely male (59.3% vs. 46.2%, p < 0.001), with higher percentages of advanced fibrosis (3.6% vs. 2.6%, p < 0.001) than those with CHB alone. CHB-NAFLD patients were more likely to have elevated ALT than those with CHB only, but this difference was only significant among those with low hepatitis B virus (HBV) DNA (38.1% vs. 25.6%, p < 0.001), not those with higher HBV DNA (>2,000 IU/mL). After adjusting for HBeAg, HBV DNA, and diabetes, NAFLD was not independently associated with advanced fibrosis (odds ratio 1.18, 95% confidence interval: 0.30–4.59, p = 0.81). Discussion: CHB-NAFLD patients with HBV DNA below treatment threshold were more likely to have elevated ALT but not those with higher HBV DNA, suggesting that ALT threshold does not need to be raised for antiviral eligibility for CHB with NAFLD.

Abatacept in rheumatoid arthritis-associated interstitial lung disease: short-term outcomes and predictors of progression

IntroductionInterstitial lung disease in rheumatoid arthritis (RA-ILD) is an extra-articular involvement that impairs the prognosis and for which there is still no well-coded treatment. The aim of this study was to evaluate abatacept (ABA) effectiveness and safety in patients with RA-ILD.MethodsRA-ILD patients who started ABA treatment were consecutively enrolled. Chest high-resolution computed tomography (HRCT), clinical, laboratory and respiratory function variables were collected at baseline and after 18 months of ABA treatment. HRCT abnormalities were evaluated using a computer-aided method (CaM). ABA response was established based on the change in the percentage of fibrosis evaluated at HRCT-CaM, dividing patients into “worsened” (progression ≥ 15%), “improved” (reduction ≥ 15%), and “stable” (changes within the 15% range). The multivariate regression model was used to assess the associations between RA characteristics and ABA response.ResultsForty-four patients (81% women, mean age 59.1 ± 8.0, mean disease duration of 7.5 ± 3.1 years) were studied. Five patients (11.4%) showed RA-ILD progression, 32 patients (72.6%) were considered stable, and 7 patients (16.0%) showed an RA-ILD improvement. The proportion of current smokers was significantly different between “worsened” patients, respect to those defined as "improved/stable” (p = 0.01). Current smoking habit (p = 0.005) and concomitant methotrexate treatment (p = 0.0078) were the two variables related to RA-ILD progression in multivariate regression analysis.ConclusionTreatment with ABA is associated with a RA-ILD stability or improvement in the 88.6% of patients. Current smoking habit and concomitant treatment with methotrexate are the modifiable factors associated with RA-ILD worsening.Key Points• Abatacept plays a favourable role in the control of RA-ILD, with a significant worsening in only 11.4% of patients during a 18-month follow-up period.• The predictive variables related to RA-ILD progression during abatacept therapy are the concomitant treatment with methotrexate and current smoking habit.

B-PO02-177 INCREASED SUBSTRATE HETEROGENEITY ASSESSED BY LGE-CMR IS ASSOCIATED WITH VENTRICULAR ARRHYTHMIAS AND MORTALITY IN PATIENTS WITH CARDIAC SARCOIDOSIS

Patients with cardiac sarcoidosis (CS) are at risk for life-threatening ventricular arrhythmias (VA). Current risk stratification approaches have limited predictive value. Analysis of substrate heterogeneity on LGE-CMR is an emerging technique for prognostication in cardiomyopathy patients. To assess the utility of spatial dispersion analysis of LGE-CMR, as a quantitative measure of substrate heterogeneity, in risk stratifying patients with CS for VA and death. 62 patients with CS had LGE-CMR. We generated biventricular dispersion maps: We categorized each pixel based on signal intensity (SI) as abnormal, intermediate, or normal (SI ≥3SD, SI 1-3 SD, or SI <1SD above the mean respectively); we assigned to each pixel a value of 0-8 based on the number of adjacent pixels of a different category. We calculated average dispersion score (DS, Fig A). The primary endpoint was VA and the secondary endpoint was the composite of VA or death. During 4.7 ± 3.5 years of follow up, 6 patients had VA and 5 non arrhythmic death. DS was significantly higher in patients with VA or events versus those without. Patients at the highest tertile of DS had a higher incidence of VA (HR 11.73, 95%CI: 1.33-103.2, Fig B) and the combination of VA or mortality (HR 5.78, 95%CI: 1.48-22.55, Fig C). DS had a better predictive value compared to percent fibrosis (Harrel’s C: 0.71 and 0.74 vs 0.67 and 0.63 for the primary and secondary endpoints, respectively). Increased substrate heterogeneity, quantified by spatial dispersion analysis of LGE-CMR, may be helpful in risk-stratifying patients with CS for adverse events, including life-threatening arrhythmias.

The Protein-Independent Role of Phosphate in the Progression of Chronic Kidney Disease.

Several factors contribute to renal-function decline in CKD patients, and the role of phosphate content in the diet is still a matter of debate. This study aims to analyze the mechanism by which phosphate, independent of protein, is associated with the progression of CKD. Adult Munich-Wistar rats were submitted to 5/6 nephrectomy (Nx), fed with a low-protein diet, and divided into two groups. Only phosphate content (low phosphate, LoP, 0.2%; high phosphate, HiP, 0.95%) differentiated diets. After sixty days, biochemical parameters and kidney histology were analyzed. The HiP group presented worse renal function, with higher levels of PTH, FGF-23, and fractional excretion of phosphate. In the histological analysis of the kidney tissue, they also showed a higher percentage of interstitial fibrosis, expression of α-actin, PCNA, and renal infiltration by macrophages. The LoP group presented higher expression of beclin-1 in renal tubule cells, a marker of autophagic flux, when compared to the HiP group. Our findings highlight the action of phosphate in the induction of kidney interstitial inflammation and fibrosis, contributing to the progression of renal disease. A possible effect of phosphate on the dysregulation of the renal cell autophagy mechanism needs further investigation with clinical studies.

Protective effect of valsartan against doxorubicin-induced cardiotoxicity: Histopathology and metabolomics in vivo study.

Doxorubicin (DOX) treatment has been associated with cardiotoxicity. Therefore, it is crucial to search for a therapeutic that can effectively mitigate DOX-induced cardiotoxicity. This study was conducted to investigate the protective effects of valsartan (VAL) against DOX-induced cardiotoxicity. Sprague-Dawley rats were divided into four treatment groups: Group I: Control, Group II: VAL (30 mg/kg, ip), Group III: DOX (15 mg/kg, ip), and Group IV: VAL + DOX (30 + 15 mg/kg, ip). All groups were treated every other day for 14 days. Blood was isolated for biochemical and metabolomics studies, and sections of the heart were also analyzed for histopathological and immunohistochemical alterations to detect changes in P53, BAX, BCL-2, and P62 expression. The combination of VAL + DOX resulted in a marked decrease in cardiac biomarker enzymes (aminotransferase and creatine phosphokinase) compared to DOX monotherapy. In addition, the histopathological examination of the VAL + DOX combination revealed a low percentage of fibrosis and inflammation. Immunohistochemical expression of p53 and BAX was significantly reduced, whereas BCL-2 expression was significantly increased in the VAL + DOX treatment group compared to DOX monotherapy. Also, the combination of VAL + DOX reverses the negative effect of DOX on nuclear p62 expression. Analysis of serum metabolites showed that DOX monotherapy reduced the number of several amino acids, whereas the combination of VAL + DOX restored these metabolic pathways. This study revealed the potential cardioprotective effect of VAL, which may provide novel and promising approaches for managing cardiotoxicity induced by DOX.

Pancreatic Fibrosis (Early Chronic Pancreatitis) as Emerging Diagnosis in Structural Causes of Dyspepsia: Evidence from Endoscopic Ultrasonography and Shear Wave Elastography.

A new concept for the diagnosis and management of non-functional dyspepsia in guidelines was lacking in the past decade. Medical advancement has proven pancreatic fibrosis (essential image evidence of early chronic pancreatitis) to be a cause of dyspepsia and related to pancreatic exocrine dysfunction. This study aimed to analyze the clinical picture, biomarker, and percentage of pancreatic fibrosis in the dyspeptic population. A total of 141 consecutive patients were retrospectively enrolled. They were diagnosed with peptic ulcer disease, 9.2% (n = 13); pancreatic fibrosis, 17% (n = 24); pure Helicobacter pylori infection, 19.9% (n = 28); functional dyspepsia, 53.2% (n = 75); and chronic pancreatitis, 0.7% (n = 1). Among those with pancreatic fibrosis, (n = 24), 11 were diagnosed on the basis of a pancreatic acoustic radiation force impulse exceeding 1.4 m/s, and the remaining 13 were diagnosed with early chronic pancreatitis with at least three of the Japanese endoscopic ultrasonography criteria. The anatomic distribution of parenchymal criteria of early chronic pancreatitis was head, 53%; body, 38%; and tail, 9%. There were 17 cases (71%, 17/24) without Helicobacter pylori and whose dyspepsia improved after pancreatic enzyme replacement with a ratio of 82.3% (14/17). Of the 141 cases, 19 received gastric emptying scintigraphy and Western blot analysis of chromogranin-A in duodenal mucosa. Delayed gastric emptying was more common in functional dyspepsia and chromogranin-A was expressed more in pancreatic fibrosis. In conclusion, pancreatic fibrosis (including early chronic pancreatitis) outnumbered peptic ulcer disease in the dyspeptic population and pancreatic enzyme therapy was effective for 82% of cases. In early chronic pancreatitis, pancreatic fibrosis is dominant in the head location, and duodenum mucosa chromogranin-A is a potential biomarker with increased expression in an age-matched manner.

Morphological Features of Testicular Biopsies in Infertile Males at a Tertiary Hospital, Southwest Nigeria

Background Male Infertility accounts for 30-40% of all cases of infertility and its evaluation requires a good history, thorough physical examination, and several investigations to include testicular biopsy which might be used to further categorize infertile males for proper management and prognostication. This study aims to determine the predominant histopathological patterns of testicular biopsies in infertile males and to compare the findings with previous studies. Methods A retrospective cross-sectional study of 225 selected cases of testicular biopsies reviewed for the evaluation of male infertility in the Pathology department, of a tertiary hospital, Southwest, Nigeria, between 1987 and 2012. Relevant clinical and histopathological information was extracted from the departmental records. All histologic cases were reviewed, and a classification based on histological patterns of spermatogenesis was utilized to group the cases into normal findings, hypo spermatogenesis, maturation arrest, Sertoli cell-only syndrome, peritubular hyalinization/ tubular fibrosis and mixed patterns. The data obtained were analysed using descriptive and inferential statistics at a 5% level of significance. Results Among the 225 cases reviewed with a mean age of 37.7 years (SD - 8.61), 82.7% had primary infertility of which 92.9% were azoospermic, while 7.1% had oligospermia. The histological patterns included 34.2% of Hypospermatogenesis, 32% of Peritubular hyalinization/ tubular fibrosis, 14.2% had maturation arrest and Sertoli cell-only syndrome was found in 6.7% of cases, only 0.9% had normal histologic pattern while the mixed histologic pattern was seen in 12% of cases. Conclusion The commonest morphological pattern was Hypospermatogenesis, which is similar to some of the previous local and international studies. A high percentage of peritubular fibrosis was noted with few tubules containing scanty late spermatids or spermatozoa when proper sampling and evaluation were made. Multiple patterns within a biopsy were seen with careful review, especially in non-obstructive azoospermic cases. This is significant in male infertility patient management in our environment because it suggests greater chances of successful sperm extraction for Assisted Reproduction Technique in such patients.

Histological and immunohistochemical features suggesting aetiological differences in lymph node and (muco)cutaneous feline tuberculosis lesions.

To identify and describe histological and immunohistochemical criteria that may differentiate between skin and lymph node lesions associated with Mycobacterium (M.) bovis and M. microti in a diagnostic pathology setting. Archived skin and lymph node biopsies of tuberculous lesions were stained with haematoxylin and eosin, Ziehl-Neelsen and Masson's Trichrome. Immunohistochemistry was performed to detect the expression of calprotectin, CD3 and Pax5. Samples were scored for histological parameters (i.e. granulomas with central necrosis versus small granulomas without central necrosis, percentage necrosis and/or multinucleated giant cells), number of acid-fast bacilli (bacterial index) and lesion percentage of fibrosis and positive immunohistochemical staining. Twenty-two samples were examined (M. bovis n=11, M. microti n=11). When controlling for age, gender and tissue, feline M. bovis-associated lesions more often featured large multi-layered granulomas with central necrosis. Conversely, this presentation was infrequent in feline M. microti-associated lesions, where small granulomas without central necrosis predominated. The presence of an outer fibrous capsule was variable in both groups, as was the bacterial index. There were no differences in intralesional expression of immunohistochemical markers. Differences in the histological appearance of skin and lymph node lesions may help to infer feline infection with either M. bovis or M. microti at an earlier stage when investigating these cases, informing clinicians of the potential zoonotic risk. Importantly, cases of tuberculosis can present with numerous acid-fast bacilli. This implies that a high bacterial index does not infer infection with non-zoonotic non-tuberculous mycobacteria.

Application of the ANCA Renal Risk Score in the United States: A Single-Center Experience

Application of the ANCA Renal Risk Score in the United States: A Single-Center Experience

MO282EARLY RENAL RECOVERY AFTER A FIRST FLARE OF PAUCI IMMUNE GLOMERULONEPHRITIS

Abstract Background and Aims Renal involvement is a severe manifestation of ANCA-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after a first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in eGFR between diagnosis and follow-up at 3 months (ΔeGFRM0–M3) in a cohort of patients with a first flare of pauci-immune glomerulonephritis. Methods This was a retrospective study over the period 2003–2018 of incident patients in the Nord-Pas-de-Calais (France). Patients were recruited if they had a first histologically-proven flare of pauci immune glomerulonephritis with at least 1 year of follow up. Kidney function was estimated with MDRD-equation and analysed at diagnosis, 3rd, 6th and 12th months. The primary outcome was ΔeGFRM0–M3. Factors evaluated were histological (Berden classification, interstitial fibrosis, percentage of crescents), clinical (extra-renal manifestations, sex, age) or biological (severity of acute kidney injury, dialysis, ANCA subtype). Results One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs 28 ± 26 ml/min/1.73 m2, p &amp;lt; 0.001), with a ΔeGFRM0–M3 of 12 ± 19 ml/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs 40 ± 24 ml/min/1.73m2, p = 0.003). The factors significantly associated with ΔeGFRM0–M3 in univariate analysis were: sclerotic class according to Berden classification, percentage of interstitial fibrosis, percentage of cellular crescents, acute tubular necrosis, neurological involvement. The factors associated with ΔeGFRM0–M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in eGFR was 2.90 ± 0.06 ml/min/1.73m2 for every 10-point gain in the percentage of cellular crescents. ΔeGFRM0–M3 was not associated with the risks of end-stage renal disease or death in long-term follow-up. Conclusions Early renal recovery after a first flare of pauci-immune glomerulonephritis occurred mainly in the first three months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery.

Atrial tissue characterization by cardiac magnetic resonance and high-density mapping in patients with atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Left atrial fibrosis is a marker of atrial disease and it has an important role in the pathophysiology of atrial fibrillation (AF). Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) is an emerging tool to detect left atrial fibrosis. However, data on the correlation between LGE-CMR detected fibrosis and low voltage areas to define fibrotic tissue is scarce. PURPOSE To assess the correlation and degree of concordance between LGE-CMR and high-density bipolar voltage mapping for the identification of left atrial abnormal tissue. METHODS Seven patients scheduled for AF ablation (including first and redo procedures) underwent a preprocedural 1.5 Tesla LGE-CMR including left atrial 3D inversion-recovery steady-state free precession sequence (ECG and respiratory triggering) 20 minutes after the injection of 0.2 mmol/kg of gadobutrol. A high-density electroanatomical voltage mapping was acquired with a 16-electrode grid configuration mapping catheter during sinus rhythm. LGE-CMR studies were analyzed off-line with an advanced image post-processing tool (ADAS 3D). Atrial wall intensity was normalized to blood pool, obtaining an image intensity ratio (IIR) value for each CMR point of the 3D model. High-density bipolar voltage maps and LGE-CMR 3D left atrial reconstruction were merged (figure, panel A). Voltage points were projected to the LGE-CMR left atrial 3D model, allowing point-by-point correlation analysis between voltage (log transformed due to non-normal distribution) with IIR. Left atrial fibrosis area and percentage were quantified using the standard cut-off values (bipolar voltage &amp;lt;0.5mV and IIR &amp;gt;1.2). We assessed the degree of concordance for normal and abnormal (fibrosis) tissue classification between the two techniques using different cut-off values (&amp;lt; 0.5mV and &amp;lt;1mV for bipolar voltage and &amp;gt;0.9, &amp;gt;1, &amp;gt;1.1 and &amp;gt;1.2 for IIR). RESULTS The average fibrosis area detected with LGE-CMR was lower than that detected with high-density bipolar voltage, using standard cut-off values (18.6 ± 5.7 cm2 vs. 40.6 ± 12.5 cm2, p = 0.13 respectively). There was a poor global point-by-point correlation between log-transformed voltage and IIR was r=-0.093, p &amp;lt; 0.001 (figure, panel B). The best concordance was obtained when using bipolar voltage and IIR of 0.5mV and 1.2, respectively (64.7 %; Kappa 0.101). However, the highest kappa index (0.142) for concordance was achieved with cutoff values of bipolar voltage &amp;lt;1mV and IIR &amp;gt;1, with an agreement percentage of 54.6%. CONCLUSIONS Left atrial tissue characterization between LGE-CMR and high-density bipolar voltage mapping showed significant but poor point-by-point correlation. Although the highest concordance was obtained using standard cutoff values, the Kappa index was best when applying non-standard cutoffs (1mV for bipolar voltage and &amp;gt;1 for IIR). Abstract Figure.

Adipose tissue fibrosis assessed by high resolution ex vivo MRI as a hallmark of tissue alteration in morbid obesity.

To determine whether magnetic resonance imaging (MRI) when used in an optimal ex vivo setting can help detecting and quantifying the 3D fibrosis fraction in human subcutaneous adipose tissue (SAT) samples, as compared to histology. This prospective observational study was approved by our institutional review board 3D MRI acquisitions were performed at 4.0 T (Bruker) on XX human SAT samples (around 1 cm3) collected from biopsy in morbidly obese patients. Such acquisitions included saturation-recovery T1 mapping (spatial resolution: 200 µm, acquisition time: ~16 minutes) and DIXON imaging (spatial resolution: 200 µm, acquisition time: ~20 minutes). After MRI, histological quantification of fibrosis was performed using picrosirius staining. T1 maps were clustered based on a k-means algorithm allowing quantification of fibrosis within the adipose tissue and percentage of fibrosis over the entire sample volume was calculated. Fat maps were computed from DIXON in-phase and out-of-phase images. The 3D MRI fibrosis percentage within the SAT samples were comprised between 6% and 15%. Excellent correlations and levels of agreement were observed between single slice MRI and histology (r=0.9, P=0.08) and between 3D MRI and histology in terms fibrosis percentages within SAT samples (r=0.9, P=0.01). High Field ex vivo MRI was able to quantify fibrosis in human SAT samples with high agreement with histology and moreover to provide 3D SAT fibrosis quantification avoiding histological sampling errors.

Direct-acting antiviral treatments display excellent outcomes even in older HCV-infected patients at increased risk of fibrosis.

BackgroundThis study compared the efficacy and tolerability of available direct-acting antiviral (DAA) regimens between individuals aged 60 years and older and younger patients in a real-life setting. Specifically, we aimed to provide evidence of the efficacy and safety of DAAs in the treatment of older adults in Tianjin, China.MethodsIn this retrospective observational cohort study, patients with chronic hepatitis C virus (HCV) were enrolled between April 2018 and December 2019 at 2 tertiary hospitals in Tianjin, China. We assessed the sustained virologic response (SVR) 12 weeks (SVR12) after DAA treatment, and adverse events in two groups using age stratification by comparing older adults (≥60 years) and younger adults (<60 years). Logistic regression analyses were performed to explore the risk factors associated with the SVR12.ResultsOf 1,106 patients, 440 (39.8%) were ≥60 years of age. The overall SVR12 rate was 97.8% in the entire cohort. In the older adult group, the SVR12 rate was 98.0% (431/440) compared to 97.7% (651/666) in the younger adult group. A multivariate analysis showed that (I) age was not predictive of SVR; and (II) the variables of treatment-experience [adjusted odds ratio (aOR) =27.53; 95% confidence interval (CI) =3.35–226.08; P=0.002] and aspartate aminotransferase (AST) (aOR =1.02; 95% CI =1.01–1.04; P=0.027) were independently associated with the SVR12 in the older adult group. All of the available DAA regimens were well-tolerated in older adult group.ConclusionsChinese older adults with chronic HCV infection showed a significantly higher percentage of fibrosis; however, the available different DAA regimens were safe, well-tolerated, and achieved high rates of SVR in all age subgroups. Our observations suggest that DAA treatment should not be withheld even from older patients suffering from chronic HCV.

Gene Expression Classifier Reveals Prognostic Osteosarcoma Microenvironment Molecular Subtypes.

Osteosarcoma (OSA) is the most common bone malignancy and displays high heterogeneity of molecular phenotypes. This study aimed to characterize the molecular features of OSA by developing a classification system based on the gene expression profile of the tumor microenvironment. Integrative analysis was performed using specimens and clinical information for OSA patients from the TARGET program. Using a matrix factorization method, we identified two molecular subtypes significantly associated with prognosis, S1 (infiltration type) and S2 (escape type). Both subtypes displayed unique features of functional significance features and cellular infiltration characteristics. We determined that immune and stromal infiltrates were abundant in subtype S1 compare to that in subtype S2. Furthermore, higher expression of immune checkpoint PDCD1LG2 and HAVCR2 was associated with improved prognosis, while a preferable chemotherapeutic response was associated with FAP-positive fibroblasts in subtype S1. Alternatively, subtype S2 is characterized by a lack of effective cytotoxic responses and loss of major histocompatibility complex class I molecule expression. A gene classifier was ultimately generated to enable OSA classification and the results were confirmed using the GSE21257 validation set. Correlations between the percentage of fibroblasts and/or fibrosis and CD8+ cells, and their clinical responses to chemotherapy were assessed and verified based on 47 OSA primary tumors. This study established a new OSA classification system for stratifying OSA patient risk, thereby further defining the genetic diversity of OSA and allowing for improved efficiency of personalized therapy.

Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model

PurposeLow free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model.MethodsMale rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson’s trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining.ResultsCompared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions.ConclusionsHistological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia.

Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: (a) animals raised in ambient air for 6 weeks (n = 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution (n = 10), or (c) MSC-EVs (n = 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings further support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodeling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.