Percentage Of Fibrosis Research Articles

P0393 Radiological healing in perianal fistulising Crohn’s disease: MRI predictors and disease course

Abstract Background Perianal fistulising Crohn’s disease (CD) is a disabling condition affecting up to 30% of patients. Studies suggest that greater fibrosis in the fistula tract is linked to improved clinical outcomes. This study aims to describe the natural history of perianal fistulising CD, including MRI parameters, and to identify clinical and radiological predictors of relapse and radiological healing Methods Pelvic MRIs for perianal fistula performed at CHU Liège, Belgium, from 2018 to 2023 were collected. MRI protocols used 1.5T [Siemens Aera/Sola] or 3T [Siemens Vida] machines, with sequences including T2 TSE, T2 TSE FS, and T1 TSE FS before and after gadolinium injection. The MAGNIFI-CD and modified Van Assche (VA) indices were assessed for each patient. Two blinded radiologists evaluated fistula tract fibrosis. For patients with perianal flare, only the first MRI was analysed (MRI 1). For others, the first and last MRI (MRI 2) within the study period were assessed. Perianal flare was defined as abscess drainage or stoma creation for active perianal CD, and radiological healing as ≥80% fistula fibrosis or a MAGNIFI-CD score of 0. Results A total of 102 pelvic MRIs from 84 patients were included. The median patient age was 39 years (31–51), with 40% female. The median duration of perianal CD was 52 months (2–144); 26% had a seton at MRI 1, 7% had a stoma, and 41% were on anti-TNF therapy. During follow-up, 22% required abscess drainage. No clinical factors were associated with perianal flare. Univariate analysis identified several MRI 1 radiologic predictors of flare: fibrosis percentage (OR=0.72, p=0.033), VA hyperintensity T2 (OR=3.22, p=0.028), VA rectal involvement (OR=1.75, p=0.040), VA inflammatory mass (OR=1.42, p=0.022), VA T1 post-contrast hyperintensity (OR=3.68, p=0.045), MAGNIFI-CD score (OR=1.13, p=0.022), MAGNIFI T1 post-contrast hyperintensity (OR=1.77, p=0.031), and MAGNIFI inflammatory mass (OR=1.40, p=0.033). In multivariate analysis, only MAGNIFI T1 post-contrast hyperintensity remained significant (OR=1.77, p=0.031). Radiological healing was achieved in 30% at MRI 1 (25/84) and 44% at MRI 2 (8/18). No factors at MRI 1 predicted healing at MRI 2, though T1 post-contrast hyperintensity at MRI 1 showed a trend towards predicting lack of healing (OR=0.11, p=0.071). Conclusion One-fifth of patients experienced perianal flare during follow-up. Clinical and therapeutic factors did not predict outcomes; only persistent MRI inflammation and low fistula fibrosis were linked to future abscess drainage. Specific MRI features may serve as therapeutic targets in perianal CD management, pending validation in a prospective cohort.

Heterogeneity in response to neoadjuvant radiotherapy between soft tissue sarcoma histotypes: associations between radiology and pathology findings.

To investigate imaging biomarkers of tumour response by describing changes in imaging and pathology findings after neoadjuvant radiotherapy (nRT) and exploring their correlations. Tumour diameter, volume, and tumour-to-muscle signal intensity (SI) ratio were collected before and after radiotherapy in a cohort of 107 patients with intermediate/high-grade STS and were correlated with post-radiotherapy pathology findings (percentage of necrosis, viable cells, and fibrosis) using Spearman Rank test. Pathological complete response (pCR) was defined as no residual viable cells present, whereas the presence of < 10% viable cells was defined as near-complete pathologic response (near-pCR). Median amount of necrosis, viable cells, and fibrosis after nRT were 10%, 30%, and 25%, respectively. 7% of patients achieved pCR and 22% near-pCR. No changes in tumour volume were found except for subtypes myxoid liposarcoma (mLPS) -Δ54.47%, undifferentiated pleomorphic sarcoma (UPS) +Δ24.22% and dedifferentiated liposarcoma (dLPS) +Δ35.91%. The median change of tumour-to-muscle SI ratio was -19.7% for the entire population, whereas it was -19.55% and -36.26% for UPS and mLPS, respectively. Correlations (positive and negative) were found between change in volume and the presence of necrosis or fibrosis (rs = 0.44; rs = -0.44), as well as between tumour-to-muscle SI ratio and viable cells (rs = 0.33) or fibrosis (rs = -0.28). STS displays extensive heterogeneity in response patterns after nRT. In some subgroups, particularly UPS and mLPS, tumour size changes or tumour-to-muscle SI ratio are significantly linked with the percentage of viable cells, fibrosis, or necrosis. Question How do primary soft tissue sarcomas (STS) respond to neoadjuvant therapy, and what correlations exist between pathological findings and imaging characteristics in assessing treatment response? Findings mLPS shrank post-nRT; undifferentiated pleomorphic and dLPSs enlarged. Volume increase correlated with higher necrosis and lower fibrosis; tumour-to-muscle intensity ratio correlated with viable cells. Clinical relevance These findings emphasise the extensive heterogeneity in STS response to nRT across different subtypes. Preoperative correlations between tumour volume and SI changes with necrosis, fibrosis, and viable cells can aid in more precise treatment assessment and prognostication.

Does the modified shuttle test exhibit a ceiling effect in healthy and cystic fibrosis children and adolescents?

The modified shuttle test-15 (MST-15) is a valid alternative for assessing exercise capacity when a cardiopulmonary exercise testing is not feasible. This study aims to describe the percentage of healthy and cystic fibrosis (CF) children and adolescents reaching the MST-15 ceiling. Additionally, it examines associations between MST-15 distance and demographic, anthropometric, and lung function data. This retrospective cross-sectional study involved 286 healthy volunteers (11.5 ± 3.3 years) and 70 CF patients (11.9 ± 4.4 years). Data on age, gender, weight, height, body mass index, lung function, and MST-15 were collected. The ceiling effect was determined by the absolute and relative number of participants reaching the 15th level. Univariate linear regression and correlation analyses were conducted to explore associations with MST-15 distance. A ceiling effect for the MST-15 was found in 19 healthy participants (6.6%) and 1 CF patient (1.4%). The ceiling effect was correlated with age (r = 0.777 for healthy; r = 0.538 for CF), with no cases under 10 years and reaching 25% in healthy participants aged 17-19. Regression analysis showed significant associations between age and MST-15 distance in healthy participants (β = 53.6) and CF patients (β = 32.1). Additionally, sex was significantly associated with MST-15 distance in healthy participants (β = 107.0), and FEV1 with MST-15 distance in CF patients (β = 31.0). The ceiling effect on the MST-15 is age-dependent, with no occurrences observed in children under 10 years and a gradual increase in incidence as participants age.

The histological grading of fibrosis in Budd-Chiari syndrome: A chronic liver disease, different from others.

Budd-Chiari syndrome (BCS) is an uncommon disease caused by hepatic venous outflow obstruction. They can result in centrilobular fibrosis, nodular regenerative hyperplasia and cirrhosis. Assessing liver fibrosis is crucial for determining the stage of BCS, predicting disease progression and guiding treatment decisions. Although this pathology has been known for decades, no useful grading system was assigned. This study aims to introduce a histologic fibrosis grading system for BCS patients. All patients from 2017 to 2022 (Sanjay Gandhi Postgraduate Institute of Medical Sciences [SGPGIMS]), Lucknow diagnosed with BCS for whom liver biopsy was performed were included in the study. The Budd-Chiari syndrome-Hepatic Fibrosis system (BCS-HFS) was implemented to grade fibrosis. The fibrosis grade was compared with the fibrosis percentage area and a correlation was found with the hemodynamic variables (hepatic venous pressure gradient[HVPG])and the prognostic scores. There were 56 patients with BCS. The median age was 27years, with a male-female ratio of 1.8:1. There was a significant difference in the fibrosis percentage, hemorrhage percentage and model for end-stage liver disease (MELD) score among the BCS-HFS grades (p < 0.05). There was a significant correlation between BCS-HFS and HVPG (ρ = 0.699, p < 0.001) and the MELD prognostic score (ρ = 0.474, p < 0.001). BCS-HFS is applicable for grading fibrosis in BCS. It can help in uniform histopathology reporting and for further prospective and comparative studies.

Abstract 4135080: Relation of focal and diffuse myocardial fibrosis to left bundle branch block in patients with dilated cardiomyopathy and structurally normal heart

The role of fibrosis in etiology of left bundle branch block (LBBB) in still not defined. The aim of this study was to assess the relation of focal and diffuse LV fibrosis to LBBB in patients with dilated cardiomyopathy (DCM) and in patients with structurally normal heart. Materials and methods: 60 DCM with LBBB (DCM-LBBB group, 46.7% male, mean age 57[50;63] years), 50 non-LBBB DCM (78% male, mean age 43[32.3;54] years), 15 patients (53.3% male, mean age 39[28;50] years) with LBBB and no signs of structural heart disease and 10 healthy volunteers (HV) were included in the study. Endomyocardial biopsy (EMB) was performed in 15(24,6%) LBBB-DCM and 16(32%) non-LBBB DCM patients and allowed the quantification of collagen volume fraction (CVF, Fig.1A-D). All patients and HV underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) analysis. Obtained LGE LV images were post-proceed for core scar (CS) and gray zone (GZ) calculation and 3D reconstruction. Diffuse LV interstitial fibrosis was estimated on all LGE-CMR images with the novel introduced marker - diffuse intensity ratio (DIR). Results: DIR was validated on EMB samples: the percentage of CVF (8.2[4.6;10.8]%) correlated with the DIR value (0.71 ± 0.13) in the same segment (r=0.66, p&lt;0.001, Fig.1E-F). The value of CVF (Fig1A-D) and LGE presence in the septum in both DCM groups (Fig2) was comparable (8.2[4.6; 10.3] versus 7.6[6.1;15.3]%, p=0.82 and 19 (31.7%) versus 17 (34%) patients in non-LBBB DCM group respectively, p=0.8) Moreover, the presence of LGE and midwall fibrosis in septum was not related to the QRS duration (p=0.93 and 0.59). In non-LBBB DCM patients the percentage of CS was significantly higher (4.0[1.55; 11.68]% versus 1.4[0.05;8.5]% in LBBB-DCM patients, p=0.047), whereas percentage of GZ and total fibrosis in both DCM groups was comparable (Fig.3A,B). DIR value was higher in patients with idiopathic LBBB than in HV (0.54±0.09 versus 0.34±0.1, p&lt;0.001) while the percentage of GZ and CS was extremely low and did not differ from its amount in HV (Fig.3C,D). Conclusion: Neither focal (including midwall striae) nor interstitial fibrosis is associated with LBBB in patients with DCM. Diffuse inflammation in LBBB-DCM patients may contribute to the progression of systolic dysfunction but is not the reason for LBBB. The increased value of interstitial fibrosis in patients with LBBB may reflect latent diffuse process in myocardium inexorably leading to DCM development.

Abstract 4136863: Diffuse Functional and Structural Abnormalities in Fibrosis: Potential Structural Basis for Sustaining Atrial Fibrillation

Background: Structural remodeling is associated with atrial fibrillation (AF), but detailed structural and functional characteristics is not well defined. Goal: Using a novel transgenic goat model with cardiac-specific overexpression of TGF-β1 leading to increased cardiac fibrosis, we evaluated detailed structural and functional differences between fibrotic and healthy regions of the atria. Methods: Ex-vivo MRI and histology were used to evaluate fibrosis, fiber disarray, and structural anisotropy. Ex-vivo MRI intensity values were scaled to standard deviations around the mean. The functional analysis examined conduction speeds and direction heterogeneity. Conduction anisotropy was measured along the fiber direction obtained with diffusion tensor imaging. Results: The transgenic goats (n=12) had, on average, 21% of the left atria labeled as fibrotic determined from ex-vivo MRI. The histology samples taken from the labeled fibrotic regions had an increase in fibrosis percentage compared to labeled healthy regions (7.78±3.76% vs 2.80±1.86%, p&lt;0.01). The structural anisotropy was lower in fibrotic regions (0.196±0.002 vs 0.244±0.002, p&lt;0.01). Fiber disarray was greater in the fibrotic regions (20.3±0.2° vs 19.2±0.1°, p&lt;0.01). The fibrotic regions had slower conduction speeds (0.78±0.02 m/s vs 1.12±0.02 m/s, p&lt;0.01) and more aligned conduction directions (30.5±0.2° vs 31.6±0.1°, p&lt;0.01), potentially developing unidirectional conduction block. Conduction anisotropy, measured on the fiber directions, was found to be lower in the fibrotic regions (1.86±0.05 vs 2.10±0.02, p=0.04). As scaled MRI intensity increased, the conduction speed, heterogeneity, and anisotropy all decreased. Conclusions: Functional and structural differences exist between fibrotic and healthy regions of the atria. Though statistically significant, the changes are not discrete. The correlation showed gradual functional abnormalities with MRI intensities. Fibrotic regions tended to have increased fiber disarray, slower conduction, and more unidirectional propagation with lower conduction and structural anisotropy. Diffuse functional and structural abnormalities may allow fibrotic regions to serve as a substrate to sustain AF.

Diffuse functional and structural abnormalities in fibrosis: Potential structural basis for sustaining atrial fibrillation

BackgroundStructural remodeling has been associated with increased incidence of atrial fibrillation, but how fibrotic regions allow atrial fibrillation to be sustained remains unclear. ObjectiveWith a novel transgenic goat model, we evaluated structural and functional differences between structurally remodeled and healthy regions of the atria. MethodsA novel transgenic goat model with cardiac-specific overexpression of transforming growth factor β1 was used. Ex vivo cardiac magnetic resonance imaging and histology were used to evaluate differences in fibrosis, fiber disarray, and structural anisotropy. Functional analysis examined conduction speeds and direction heterogeneity. By use of underlying fiber orientation obtained with diffusion tensor imaging, conduction anisotropy was calculated. ResultsThe transgenic goats had on average 21% of the left atria labeled fibrotic, determined from ex vivo cardiac magnetic resonance imaging. The histology samples within the labeled fibrotic regions showed an increase in fibrosis percentage. Fractional anisotropy, a measurement of structural anisotropy, was lower, whereas fiber direction heterogeneity, a measurement of the angle difference of the fiber from its neighbors, was greater, indicating increased fiber disarray in fibrotic regions. The fibrotic regions had slower conduction speeds and more aligned conduction directions, potentially allowing unidirectional conduction block to develop. Conduction anisotropy, measured on the underlying fiber directions, was found to be lower in the fibrotic regions. ConclusionFibrotic regions had slower conduction, and propagation tended to flow more unidirectionally. The direction of propagation differs from the underlying fiber direction, leading to lower conduction anisotropy. Functional and structural abnormalities of the fibrotic tissue may allow fibrotic regions to serve as a substrate for an arrhythmia to develop and to be sustained.

The impact of pulmonary fibrosis on cardiac function in chronic obstructive pulmonary disease

Abstract Background Emerging evidence indicates the coexistence pulmonary fibrosis and emphysema in patients with Chronic Obstructive Pulmonary Disease (COPD). The effect of pulmonary fibrosis on cardiac structure and function in COPD patients remains unclear. Purpose This study aimed to examine the association between the degree of pulmonary fibrosis identified on Computed Tomographic (CT) imaging and echocardiographic measures of cardiac structure and function in individuals with COPD. Methods The study included 456 individuals with COPD, participating in a large prospective cohort study. Patients with available CT scans and echocardiograms were included. Local histogram-based assessments of lung density were utilized to determine the percentage of fibrosis. Fibrosis was defined based on the CT attenuation within the range of -600 and -250 Hounsfield units. The association between percent fibrosis and measures of cardiac structure and function were investigated by univariable and multivariable linear regression models. Multivariable adjustments included age, sex, body mass index (BMI), and smoking. In addition, restricted cubic splines were generated to visually present the relationship between the percentage of fibrosis and specific echocardiographic parameters. Results The mean age was 71 (± 8 years), 48% were female, and the median BMI was 27 kg/m2 (IQR: 22; 30kg/m2). The mean forced expiratory volume in 1 second as a percentage of the predicted value (FEV1pp) was 47% (±18%). The mean forced vital capacity of predicted value was 71% (± 19%). The median percentage of fibrosis in the cohort was 4.9% (IQR: 3.9; 6.0%). Patients were stratified into tertiles based upon fibrosis percentage. BMI, frequency of diabetes, and FEV1pp were increasingly positively associated with fibrosis. Furthermore, significant trends for echocardiographic measures found that the patients with the most extensive fibrosis were seen to have impaired left ventricular (LV) ejection fraction (LVEF), lower absolute global longitudinal strain (GLS), increased left atrial (LA) volume index (LAVi), and higher LV mass as compared to those with less significant fibrosis. There were no significant differences between tertiles of fibrosis and age or sex. In univariable linear regression, significant inverse associations between the percentage of fibrosis, LVEF, GLS, and tricuspid annular plane systolic excursion (TAPSE) were seen (Table). For LV mass index and LAVi, significant direct associations were found (Table). After adjusting for potential confounding factors, only GLS and LAVi remained associated with pulmonary fibrosis (Figure). Conclusion This study found that GLS and LA volume were significantly associated with the degree of pulmonary fibrosis, even after adjusting for confounding variables. This may suggest that fibrosis is primarily linked with impaired left-sided measures of cardiac structure and function.Linear Regression ModelsCubic Spline Curves

Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.

Quantifying measurement uncertainty in renal transplant biopsy assessment.

Renal transplant biopsies provide insights into graft health and support decision making. The current evidence on links between biopsy scores and transplant outcomes suggests there may be numerous factors affecting biopsy scores. Here we adopt measurement science approach to investigate the sources of uncertainty in biopsy assessment and suggest techniques to improve its robustness. Histological assessments, Remuzzi scores, biopsy processing and clinical variables are obtained from 144 repeat biopsies originating from 16 deceased-donor kidneys. We conducted sensitivity analysis to find the morphometric features with highest discriminating power and studied the dependencies of these features on biopsy and stain type. The analysis results formed a basis for recommendations on reducing the assessment variability. Most morphometric variables are influenced by the biopsy and stain types. The variables with the highest discriminatory power are sclerotic glomeruli counts, healthy glomeruli counts per unit area, percentages of interstitial fibrosis and tubular atrophy as well as diameter and lumen of the worst artery. A revised glomeruli adequacy score is proposed to improve the robustness of the glomeruli statistics, whereby a minimum of 104 µm2 of cortex tissue is recommended to keep type 1 and type 2 error probabilities below 0.15 and 0.2. The findings are transferable to several biopsy scoring systems. We hope that this work will help practitioners to understand the sources of statistical uncertainty and improve the utility of renal biopsy.

Influence of Physical Exercise on the Rehabilitation of Volumetric Muscle Loss Injury Reconstructed with Autologous Adipose Tissue.

In volumetric muscle loss (VML) injuries, spontaneous muscle regeneration capacity is limited. The implantation of autologous adipose tissue in the affected area is an option to treat these lesions; however, the effectiveness of this therapy alone is insufficient for a complete recovery of the damaged muscle. This study examined the influence of treadmill exercise on the rehabilitation of VML injuries reconstructed with autologous adipose tissue, as a strategy to counteract the limitations of spontaneous regeneration observed in these injuries. Forty adult male Wistar rats were divided into eight groups of five individuals each: normal control (NC), regenerative control (RC), VML control (VML), VML injury reconstructed with fresh autologous adipose tissue (FAT), exercise-rehabilitated control (RNC), exercise-rehabilitated regenerative control (RRC), exercise-rehabilitated VML injury (RVML), and exercise-rehabilitated VML injury reconstructed with fresh autologous adipose tissue (RFAT). Histological and histochemical staining techniques were used for the analysis of structural features and histomorphometric parameters of the tibialis anterior muscle. Grip strength tests were conducted to assess muscle force. Exercise rehabilitation decreased the proportion of disoriented fibers in RFAT vs. FAT group. The percentage of fibrosis was significantly higher in FAT and RFAT groups versus NC and RNC groups but did not vary significantly between FAT and RFAT groups. Overall, muscle grip strength and fiber size increased significantly in the exercise-rehabilitated groups compared to control groups. To conclude, rehabilitation with physical exercise tended to normalize the process of muscle repair in a model of VML injury reconstructed with fresh autologous adipose tissue, but it did not reduce the intense fibrosis associated with these injuries.

Comparison of cardiac morphological and functional changes according to magnetic resonance imaging with the genetic testing data in patients with hypertrophic cardiomyopathy

Aim. To analyze the data of cardiac magnetic resonance imaging (MRI) of patients with hypertrophic cardiomyopathy (HCM) depending on the results of genetic testing.Material and methods. The study included 83 patients with a diagnosis of HCM (39 men, 44 women, mean age 50,4±14,9 years) who had no contraindications to MRI. Cardiac MRI was performed on 1,5 T and 3 T MRI systems using a standard protocol. T1 and T2 mapping was performed in 41 patients, and the extracellular volume fraction was estimated. All patients underwent genetic testing with assessment of sarcomeric genes, two non-sarcomeric genes associated with HCM, and genes of syndromic diseases (HCM phenocopies).Results. Positive results of genetic testing were obtained in 49 (59%) of 83 patients: MYBPC3 29%, MYH7 17%, TPM1 5%, FLNC 4%, MYL2 2%, TNNC1 1%, TNNI3 1% (genotype-positive group (G+)). Negative results of genetic testing were obtained in 34 (41%) patients (genotype-negative group (G-)). In the G-group, patients were significantly older than in G+ (57,7±12,9 vs 45,3±14,2 years, p&lt;0,05), with a smaller left ventricular (LV) wall thickness (18,9±4,2 vs 21,3±5,9 mm, p&lt;0,05), and a higher LV ejection fraction (70,5±10,7 vs 64,7±10,4%, p&lt;0,05). Comparison of myocardial fibrosis parameters between the groups showed a significantly lower incidence of delayed contrast enhancement in the G-group, and in its presence, the fibrosis severity, which was assessed as the fibrosis percentage from the total LV mass, was significantly lower than in the G+ group (71% vs 92%; 5,0±8,0% vs 11,4±9,0%, respectively, p&lt;0,05). When analyzing G+ patients depending on the identified mutations, no significant difference in the severity of fibrosis was found between the groups.Conclusion. In patients with HCM, a positive genetic analysis, regardless of the affected gene, is associated with a greater severity of fibrosis according to MRI data, which indicates a less favorable prognosis.

The role of strain wave elastography in the evaluation of renal fibrosis in patients with kidney diseases

BackgroundA renal biopsy represents the gold standard in the diagnosis, prognosis and management of patients with chronic kidney disease and glomerulonephritis. Strain wave elastography (SE) is a developing technique to assess tissue elasticity. The aim of this study was to correlate between the strain index value of renal parenchyma and degree of renal fibrosis detected with renal biopsy. MethodFor 68 patients who were referred for a kidney biopsy, SE test was performed. The Banff scoring system was utilized to classify the IFTA grading of kidney fibrosis that assigns a severity level of mild, moderate, or severe. Receiver operating characteristic curve (ROC) was utilized to correlate between the severity of renal fibrosis and the grade of renal elasticity determined by SE. ResultsIn total, 38 males and 30 females, the echogenicity, qualitative and semiquantitative elastography showed significant positive correlation with serum creatinine, percentage of fibrosis, G score and tubular atrophy and significant negative correlation with eGFR. ROC curve of SE for diagnosis of interstitial fibrosis shown that echogenicity has sensitivity 100.0%, specificity 62.5%, positive predictive value (PPV) 75.0%, negative predictive value (NPV) 100.0% with area under curve (AUC) 0.906, while qualitative elastography has sensitivity 77.8%, specificity 75.0%, PPV 77.8%, NPV 75.0%, AUC 0.833, semi quantitative elastography has sensitivity 83.3%, specificity 93.8%, PPV 93.8%, NPV 83.3% with AUC 0.915. ConclusionSE approach is simple to use, and can differentiate between varying stages of renal fibrosis. However, further research is required before it can be frequently used in clinical practice.

Role of Digital Image Analyser in Evaluation of Chronicity Index for Lupus Nephritis

Abstract Introduction Lupus nephritis is the most important cause of morbidity and mortality in systemic lupus erythematosus. Lupus nephritis patients with high chronicity index especially with moderate to severe tubular atrophy and interstitial fibrosis detected in renal biopsy are at much higher risk of developing end stage renal disease and death. The assessment of glomerular sclerosis and fibrous crescent percentages can be easily done without inter-observer variability, On the other hand, the assessment of the percentages of tubular atrophy and interstitial fibrosis is routinely done by visual assessment, that is subjective and might lack accuracy or interobserver agreement. The challenge is to quantify the interstitial fibrosis and tubular atrophy with accuracy and to minimize the inter-observer variability. Digital image analysis is an easily used objective tool with more accurate measurements, which can be used in conjunction with visual assessment. Material &amp; Methods The study included renal biopsy stained sections of 50 cases with lupus nephritis having chronic lesions. Tubular atrophy and interstitial fibrosis (IFTA)were evaluated in Masson Trichrome and PAS stained sections. IFTA was graded on a scale from I to III through visual assessment according to the percentage of IFTA of the cortex(&amp;lt;25%, 25-50% and &amp;gt;50% respectively). Sequential imaging of the whole renal cores was done by microscopic camera and the IFTA score was evaluated using a software image analyser digitally as a percentage of the total cortical area. The results of the same cases obtained by the two methods were compared and statistically analyzed. Results The study included 15 cases ISN/RPS class III (A/C), 23 cases ISN/RPS class IV (A/C), 10 cases ISN/RPS class V (4 cases combined with class III, 2 cases combined with class IV and 4 cases were pure class V) and 2 cases ISN/RPS class VI. The NIH activity indices ranged from 2-21out of 24 and the chronicity indices ranged from 2-9 out of 12. The IFTA scores evaluated by subjective visual assessment were classified into three grades. 34 cases were grade I (68%), 14 cases were grade II (28%) and 2 cases were grade III (4%). Regarding digital image analysis results, the cortical area of studied cases ranged from 296801µm²to1809799µm² (mean=670643.92 ± SD 216343.94). The Sum of areas of IFTA in studied cases ranged from 45987µm² to 656231 µm² (mean=222409.30 ± SD 152016.67). The Percentage (Sum of areas of IFTA / Cortical area) ranged from 6.08% to 74.02% (mean=30.56 ± SD 17.13). The grades of IFTA calculated by digital image analysis were: 26 cases grade I (52%), 15 cases grade II (30%) and 9 cases grade III (15%). Comparing the visually assessed IFTA grades with the image analyzer results revealed that in grade I IFTA, 23 cases were also graded I by digital image analysis (concordant in 67.65%), while 11 cases were upgraded to grade II by digital image analysis (32.35%). In IFTA grade II, 4 cases were also graded II by digital image analysis (concordant in 28.57), while 7 cases were upgraded to grade III (50%), and 3 cases were downgraded to grade I (21.43%) by digital image analysis. All cases with IFTA grade III by visual assessment were also graded III by digital image analysis (concordant in 100%). There was a fair agreement between the two methods (weighted Kappa measure for agreement = 0.40) with an overall concordance 58%, over grading in 36% and under grading in 6%. Any change (either increase or decrease) in cortical area had no significant correlation with IFTA score (P value 0.94). As regard the validity of visual assessment of IFTA grade compared to digital image analyser in different IFTA grades, in IFTA grade I, the accuracy was 72%, the sensitivity and specificity were 67.6% and 81.3% respectively, PPV 88.5%and NPV 54.2%. IFTA grade II has shown less accuracy 58%, less sensitivity and specificity (28.6% and 69.4%) respectively, with a lower PPV 26.7% and a higher NPV 71.4%. On the other hand, IFTA grade III has shown the highest accuracy 86%, highest sensitivity and specificity 100% and 85.4% respectively. The highest NPV100% and the least PPV 22.2%. This means that the severe IFTA grade can’t be missed by visual assessment, also the very low IFTA grade can also be easily identified by the visual assessment, but between the two extremes, the precise determination of the involved area will be difficult to assess without the help of digital image analyser. Conclusion Digital image analysis is an easily used tool that can improve the accuracy of measurement of chronicity index in lupus nephritis which has a great impact on treatment strategies and prognosis in these patients. Preferably it is recommended to be widely used in assessment of renal biopsy in lupus nephritis as well as different renal lesions

CGS-21680 defers cisplatin-induced AKI-CKD transition in C57/BL6 mice

Acute kidney injury (AKI), with a high mortality and morbidity, is known as a risk factor for developing progressive chronic kidney disease (CKD). Targeting transition of AKI to CKD displays an excellent therapeutic potential. This study aims at investigating the role of CGS-21680, selective A2AR agonist, in deferring Cis-induced AKI-CKD transition. The AKI-CKD transition model was induced in C57/BL6 mice by repeated low doses of Cis (2.5 mg/kg i.p for 5 consecutive days in two cycles with a recovery phase of 16 days between two cycles). CGS-21680 was administered daily for 6 weeks (0.1 mg/kg, i.p). Urine, blood, and kidney were collected at three different time points to track the disease progression. CGS-21680 administration preserved kidney function and attenuated tubular damage as evidenced by hematoxylin-eosin (H&E) histopathology. CGS-21680 significantly restored oxidative status as reflected by reduced malondialdehyde (MDA) content and increased total antioxidant capacity (TAC). CGS-21680 showed anti-inflammatory effect as indicated by decreased TNF-α and iNOS. Additionally, CGS-21680 ameliorated endothelial dysfunction and enhanced renal vasodilation as evidenced by upregulation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) expression and down regulation of endothelin-1 (ET-1) and its receptor endothelin-A (ET-A) receptor expression. CGS-21680 also attenuated renal fibrosis as reflected by the reduction of percentage of fibrosis in Masson's trichome-stained renal sections and down regulation of transforming growth factor beta1 (TGF-β1) protein expression in IHC-stained renal sections. In conclusion, CGS-21680 could defer Cis-induced AKI-CKD transition via its vasodilatory, antioxidant, anti-inflammatory, and anti-fibrotic effects.

Histological Changes in Skin and Subcutaneous Cellular Tissue in Patients with Massive Weight Loss After Bariatric Surgery.

Morbid obesity is a public health problem with high social and economic impact. Due to failure in its treatment with traditional weight loss strategies, surgical interventions are usually required, which give rise to massive weight loss. Until now, the studies made are inconclusive regarding the histological changes in the skin caused by massive weight loss, which may later generate post-surgical complications. Therefore, the objective of this study is to evaluate the cutaneous histological changes before and after bariatric surgery. Two skin biopsies were taken from nine different patients who underwent bariatric surgery. The first biopsy was taken before the surgical intervention, and the second biopsy was taken a year after the surgery and massive weight loss. Histological analysis was performed using haematoxylin & eosin staining, Weigert's Resorcin-Fuchsin, and Masson's trichrome stain to analyse the percentage of collagen fibres, percentage of fibrosis, percentage of vascularity, vascular layer involvement and adipocyte population. The differences between the biopsies were evaluated with the Student's T test and Mann-Whitney U test, with a p-value of <0.05. Biopsies from post-bariatric patients with MWL showed an increase in fibrosis percentage, and a decrease in collagen fibres, elastic fibres of the dermis, adipocyte population, as well as reduced vascular proliferation. MWL after bariatric surgery gives rise to changes in the skin and subcutaneous cellular tissue. Skin shows an increased fibrosis percentage after massive weight loss. Elastic and collagen fibres become disorganized after massive weight loss. Vascular proliferation is decreased after massive weight loss. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Ramipril After Transcatheter Aortic Valve Implantation in Patients Without Reduced Ejection Fraction: The RASTAVI Randomized Clinical Trial.

Patients with aortic stenosis may continue to have an increased risk of heart failure, arrhythmias, and death after successful transcatheter aortic valve implantation. Renin-angiotensin system inhibitors may be beneficial in this setting. We aimed to explore whether ramipril improves the outcomes of patients with aortic stenosis after transcatheter aortic valve implantation. PROBE (Prospective Randomized Open, Blinded Endpoint) was a multicenter trial comparing ramipril with standard care (control) following successful transcatheter aortic valve implantation in patients with left ventricular ejection fraction >40%. The primary end point was the composite of cardiac mortality, heart failure readmission, and stroke at 1-year follow-up. Secondary end points included left ventricular remodeling and fibrosis. A total of 186 patients with median age 83 years (range 79-86), 58.1% women, and EuroSCORE-II 3.75% (range 3.08-4.97) were randomized to receive either ramipril (n=94) or standard treatment (n=92). There were no significant baseline, procedural, or in-hospital differences. The primary end point occurred in 10.6% in the ramipril group versus 12% in the control group (P=0.776), with no differences in cardiac mortality (ramipril 1.1% versus control group 2.2%, P=0.619) but lower rate of heart failure readmissions in the ramipril group (3.2% versus 10.9%, P=0.040). Cardiac magnetic resonance analysis demonstrated better remodeling in the ramipril compared with the control group, with greater reduction in end-systolic and end-diastolic left ventricular volumes, but nonsignificant differences were found in the percentage of myocardial fibrosis. Ramipril administration after transcatheter aortic valve implantation in patients with preserved left ventricular function did not meet the primary end point but was associated with a reduction in heart failure re-admissions at 1-year follow-up. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03201185.

Whole-Heart Histological and Electroanatomic Assessment of Postinfarction Cardiac Magnetic Resonance Imaging Scar and Conducting Channels.

Cardiac magnetic resonance imaging (CMR)-defined ventricular scar and anatomic conduction channels (CMR-CCs) offer promise in delineating ventricular tachycardia substrate. No studies have validated channels with coregistered histology, nor have they ascertained the histological characteristics of deceleration zones (DZs) within these channels. We aimed to validate CMR scar and CMR-CCs with whole-heart histology and electroanatomic mapping in a postinfarction model. Five sheep underwent anteroseptal infarction. CMR (116±20 days post infarct) was postprocessed using ADAS-3D, varying pixel intensity thresholds (5545, 6040, 6535, and 7030). DZs were identified by electroanatomic mapping (129±12 days post infarct). Explanted hearts were sectioned and stained with Picrosirius red, and whole-heart histopathologic shells were generated. Scar topography as well as percentage fibrosis, adiposity, and remaining viable myocardium within 3 mm histological biopsies and within CMR-CCs were determined. Using the standard 6040 thresholding, CMR had 83.8% accuracy for identifying histological scar in the endocardium (κ, 0.666) and 61.4% in the epicardium (κ, 0.276). Thirty-seven CMR-CCs were identified by varying thresholding; 23 (62%) were unique. DZs colocalized to 19 of 23 (83%) CMR-CCs. Twenty (87%) CMR-CCs were histologically confirmed. Within-channel histological fibrosis did not differ by the presence of DZs (P=0.242). Within-channel histological adiposity was significantly higher at sites with versus without DZs (24.1% versus 8.3%; P<0.001). Postprocessed CMR-derived scars and channels were validated by histology and electroanatomic mapping. Regions of CMR-CCs at sites of DZs had higher adiposity but similar fibrosis than regions without DZs, suggesting that lipomatous metaplasia may contribute to arrhythmogenicity of postinfarction scar.

Application of adipose tissue-derived stem cell therapy with a clinically relevant dose does not significantly affect atherosclerotic plaque characteristics in a streptozotocin-induced hyperglycaemia mouse model

AimsDiabetes mellitus (DM) induces increased inflammation of atherosclerotic plaques, resulting in elevated plaque instability. Mesenchymal stem cell (MSC) therapy was shown to decrease plaque size and increase stability in non-DM animal models. We now studied the effect of MSC therapy in a streptozotocin-induced hyperglycaemia mouse model using a clinically relevant dose of adipose tissue-derived MSCs (ASCs). MethodsHyperglycaemia was induced in male C57BL/6 ApoE−/− mice (n=24) via intraperitoneal streptozotocin (STZ) injection (0.05 mg/g bodyweight) for 5 consecutive days. 16 weeks after the first STZ injection, the mice received either 100,000 ASCs (n=9) or vehicle (n=14) intravenously. The effects of ASC treatment on the size and stability of aortic root atherosclerotic plaques were determined 4 weeks post-treatment via (immuno)histochemical analyses. Furthermore, plasma monocyte subsets within 3 days pre- and 3 days post-treatment, and 4 weeks post-treatment, were studied. ResultsASC treatment did not significantly affect atherosclerotic plaque size or intra-plaque inflammation. Although ASC-treated mice had a higher percentage of intra-plaque fibrosis (42.5±3.3%) compared to vehicle-treated mice (37.6±6.8%, p=0.07), this did not reach significance. Additionally, although differences in the percentages of circulating pro- and anti-inflammatory monocytes were observed after ASC treatment compared to pre-treatment (p=0.005), their levels did not differ significantly at any time point compared to vehicle-treated mice. ConclusionsASC treatment with a clinically relevant dose did not significantly affect atherosclerotic plaque size or intra-plaque inflammation in a hyperglycaemia mouse model. Despite a borderline significant improvement in intraplaque fibrotic content, the potential of ASC treatment on atherosclerotic plaque stability in a diabetic environment remains to be determined.

Attenuated angiogenesis and macrophage infiltration during adipose tissue regeneration in a megavolume human fat grafting nude mouse model.

Survival and regeneration mechanisms of large (>250 mL) fat grafts remain incompletely understood. In fat grafts from volunteers with megavolume fat transfer breast augmentation, neovascularization and inflammatory cell infiltration decreased within 7 days according to histological analysis. We further investigated this phenomenon using a nude mouse model. To simulate clinical contexts, chambers containing 1 mL human fat were implanted into nude mice. Chambers allowed selective transfer of tissue fluid from recipient nude mice into chambers, but not capillaries or macrophages. Seven days later, fat was removed from the chamber and reimplanted into a new nude mouse in the open-chambered fat group (OCFG, n=45). Adipose samples from volunteers and explanted grafts from OCFG were subjected to histological analyses. Graft weight, vascularization, and immune response were also compared between the OCFG and conventional direct fat grafting (control group (CG)). Percent tissue integrity, percent fibrosis, adipocyte viability, and neovascularization did not significantly differ between volunteer samples and OCFG grafts at day 7. On day 90, OCFG retention rate was decreased relative to CG and the fibrosis area was larger in the OCFG than in the CG. However, the macrophage and capillary counts were lower in the OCFG group relative to CG at days 7 and 14 after transplantation. The present study provides histological analyses of megavolume fat grafts sampled from clinical breast augmentation tissues and a xenograft nude mouse model. However, these preliminary results in a small clinical cohort should be further assessed in large allogeneic animal models.