Diagnosis Of Fibrosis Research Articles

Potential role of SIRT-1 and SIRT-3 as biomarkers for the diagnosis and prognosis of idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a debilitating and progressive lung disease of unknown aetiology, characterized by the relentless deposition of fibrotic tissue. Biomarkers may play a pivotal role as indicators of disease presence, progression, and treatment response. Sirtuins, a family of enzymes with ADP ribosyltransferase or deacetylase activity, have been implicated in several diseases, including pulmonary fibrosis.MethodsA cross-sectional, prospective, observational single-center study was conducted to investigate the potential role of serum SIRTs levels as biomarkers in patients with IPF. Demographic, clinical, and functional data and serological samples were collected from 34 patients with IPF followed at the Interstital Lung and Rare Diseases Outpatient Clinic of the Vanvitelli Pneumology Clinic, Monaldi Hospital, Naples, Italy and from 19 age-matched controls.ResultsSerum SIRT-1 levels were significantly reduced in IPF patients compared to controls (median IPF 667 [435–858] pg/mL versus controls 925 [794–1173] pg/mL; p < 0.001 ). In contrast, serum SIRT-3 levels were significantly increased in IPF patients compared to controls (median IPF 338 [230–500] pg/mL versus controls 154 [99.8–246] pg/mL; p < 0.001). There were no statistically significant differences in serum SIRT-6 and SIRT-7 levels between IPF and controls. In addition, we found a significant positive correlation between SIRT-1 and lung function parameters such as FEV1% (ϱ=0.417;p = 0.016), FVC% (ϱ=0.449;p = 0.009) and DLCO% (ϱ=0.393;p = 0.024), while a significant negative correlation was demonstrated between SIR-1 and GAP score, demonstrating a significant reduction in SIRT-1 in advanced Gender-Age-Physiology (GAP) stages 2–3 compared to GAP stage 1 (p = 0.008).ConclusionsThis prospective, cross-sectional study showed that SIRT-1 was associated with lung function and IPF severity and that both SIRT-1 and SIRT-3 could be considered as potential biomarkers of IPF, whereas SIRT-6 and SIRT-7 were not associated with IPF.

Perioperative cardiovascular and cerebrovascular outcomes in recipients of ECMO bridge to lung transplant

BackgroundThe use of ECMO as bridge to lung transplant (BTT) has increased over time. While one-year and overall survival have been reported to be similar with non-ECMO transplant recipients, there are limited data major adverse cardiovascular and cerebrovascular events (MACCE) and clinically relevant bleeding (CRB) events. In this study we sought to evaluate the incidence of perioperative MACCE and CRB in lung transplant recipients who underwent ECMO BTT. MethodsUsing the National Inpatient Sample from 2008 to 2019, we identified 5,254 lung transplant recipients who either received or did not require pre-transplant ECMO. Perioperative MACCE and CRB were compared between the two cohorts. ResultsPatients with ECMO BTT had a higher incidence of MACCE compared to non-ECMO patients (35% vs. 13.3%, p <0.0001) and CRB (34.5% vs 12.9%, p <0.0001). Recipients of pre-transplant ECMO for double lung transplant (n=158) were more likely to have perioperative MACCE and CRB as opposed to patients without pre-transplant ECMO (n=3,584) (adjusted odds ratio 2.69, p <0.0001; 95% CI 1.86-3.80). The ECMO BTT cohort were notably younger with less cardiac comorbidities and higher diagnoses of cystic fibrosis and ILD. ConclusionOur data indicate that lung transplant recipients who required ECMO BTT are at significantly higher risk of MACCE and bleeding events despite being younger with less comorbidities as opposed to those who did not require ECMO.

Continuous Shear Wave Elastography for Liver Using Frame-to-Frame Equalization of Complex Amplitude.

This study addresses a crucial necessity in the field of noninvasive liver fibrosis diagnosis by introducing the concept of continuous shear wave elastography (C-SWE), utilizing an external vibration source and color Doppler imaging. However, an application of C-SWE to assess liver elasticity, a deep region within the human body, arises an issue of signal instability in the obtained data. To tackle this challenge, this work proposes a method involving the acquisition of multiple frames of datasets, which are subsequently compressed. Furthermore, the proposed frame-to-frame equalization method compensates discrepancies in the initial phase that might exist among multiple-frame datasets, thereby significantly enhancing signal stability. The experimental validation of this approach encompasses both phantom tests and in vivo experiments. In the phantom tests, the proposed technique is validated through a comparison with the established shear wave elastography (SWE) technique. The results demonstrate a remarkable agreement, with an error in shear wave velocity of less than 4.2%. Additionally, the efficacy of the proposed method is confirmed through in vivo tests. As a result, the stabilization of observed shear waves using the frame-to-frame equalization technique exhibits promising potential for accurately assessing human liver elasticity. These findings collectively underscore the viability of C-SWE as a potential diagnostic instrument for liver fibrosis.

Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis

BackgroundHuman epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). MethodsSerum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th–75th percentile). ResultsSerum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15–139.08) vs 73.50 (59.88–82.00) vs 48.75 (43.38–52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child–Pugh class C patients compared with Child–Pugh class B patients and Child–Pugh class A patients [106.50 (83.46–151.25) vs 110.00 (73.83–166.75) vs 77.03 (72.35–83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412–54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146–0.946). ConclusionsSerum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.

Racial inequities and rare CFTR variants: Impact on cystic fibrosis diagnosis and treatment

Cystic fibrosis (CF) has been traditionally viewed as a disease that affects White individuals. However, CF occurs among all races, ethnicities, and geographic ancestries. The disorder results from mutations in the CF transmembrane conductance regulator (CFTR). Varying incidence of CF is reported among Black, Indigenous, and People of Color (BIPOC), who typically exhibit worse clinical outcomes. These populations are more likely to carry rare CFTR variants omitted from newborn screening panels, leading to disparities in care such as delayed diagnosis and treatment. In this study, we present a case-in-point describing an individual of Gambian descent identified with CF. Patient genotype includes a premature termination codon (PTC) (c.2353C>T) and previously undescribed single nucleotide deletion (c.1970delG), arguing against effectiveness of currently available CFTR modulator-based interventions. Strategies for overcoming these two variants will likely include combinations of PTC suppressors, nonsense mediated decay inhibitors, and/or alternative approaches (e.g. gene therapy). Investigations such as the present study establish a foundation from which therapeutic treatments may be developed. Importantly, c.2353C>T and c.1970delG were not detected in the patient by traditional CFTR screening panels, which include an implicit racial and ethnic diagnostic bias as these tests are comprised of mutations largely observed in people of European ancestry. We suggest that next-generation sequencing of CFTR should be utilized to confirm or exclude a CF diagnosis, in order to equitably serve BIPOC individuals. Additional epidemiologic data, basic science investigations, and translational work are imperative for improving understanding of disease prevalence and progression, CFTR variant frequency, genotype-phenotype correlation, pharmacologic responsiveness, and personalized medicine approaches for patients with African ancestry and other historically understudied geographic lineages.

A Machine Learning System to Indicate Diagnosis of Idiopathic Pulmonary Fibrosis Non-Invasively in Challenging Cases.

Radiologic usual interstitial pneumonia (UIP) patterns and concordant clinical characteristics define a diagnosis of idiopathic pulmonary fibrosis (IPF). However, limited expert access and high inter-clinician variability challenge early and pre-invasive diagnostic sensitivity and differentiation of IPF from other interstitial lung diseases (ILDs). We investigated a machine learning-driven software system, Fibresolve, to indicate IPF diagnosis in a heterogeneous group of 300 patients with interstitial lung disease work-up in a retrospective analysis of previously and prospectively collected registry data from two US clinical sites. Fibresolve analyzed cases at the initial pre-invasive assessment. An Expert Clinical Panel (ECP) and three panels of clinicians with varying experience analyzed the cases for comparison. Ground Truth was defined by separate multi-disciplinary discussion (MDD) with the benefit of surgical pathology results and follow-up. Fibresolve met both pre-specified co-primary endpoints of sensitivity superior to ECP and significantly greater specificity (p = 0.0007) than the non-inferior boundary of 80.0%. In the key subgroup of cases with thin-slice CT and atypical UIP patterns (n = 124), Fibresolve's diagnostic yield was 53.1% [CI: 41.3-64.9] (versus 0% pre-invasive clinician diagnostic yield in this group), and its specificity was 85.9% [CI: 76.7-92.6%]. Overall, Fibresolve was found to increase the sensitivity and diagnostic yield for IPF among cases of patients undergoing ILD work-up. These results demonstrate that in combination with standard clinical assessment, Fibresolve may serve as an adjunct in the diagnosis of IPF in a pre-invasive setting.

Automatic breathing phase identification based on the second derivative of the recorded lung sounds

This paper presents a new method for automatic identification of the inspiratory and expiratory breathing phases in lung sound recordings. Adventitious lung sounds (wheezes and crackles), superimposed on the breath sounds, are generally an early indication of the disease, and their timing in the breathing cycle (early/mid/late inspiratory or expiratory) has clinical significance for monitoring or diagnosing disease. Therefore, the identification of the phases of the breathing cycle is an essential step for clinical interpretation of pulmonary auscultation. The proposed algorithm is designed to be robust in the presence of adventitious lung sounds or where the breath sounds may be noisy compared to healthy lung sounds. The algorithm uses the Savitzky & Golay (SG) filter to estimate the second derivative of the lung sound signal then calculates its normalized absolute value. A threshold value is used to clip any large amplitude peaks and, following low-pas filtering, the breathing phases are visible in the plotted signal. A rule-based approach to locating peaks and troughs is then used to identify inspirations and expirations. The performance of the method is evaluated using four different datasets: (a) a longitudinal dataset recorded from 19 subjects with a diagnosis of idiopathic pulmonary fibrosis (IPF), (b) a cross-sectional dataset recorded from 55 subjects who were referred for high-resolution computed tomography (HRCT) scan of the chest for various clinical indications, (c) a longitudinal dataset recorded from 10 healthy subjects, and (d) an open access lung sounds dataset containing recordings from 41 subjects with wheeze (9 with chronic obstructive pulmonary fibrosis and 32 with asthma). On average for inspiratory phase identification the algorithm had a sensitivity of (mean (standard deviation)) 92.84 (12.88)%, positive predictive value of 90.64(15.96)%, and F1-score of 90.67 (12.53)%. For identification of the expiratory phase, the algorithm had an average sensitivity of 92.19 (13.44)%, an average positive predictive value of 91.55 (15.23)%, and an average F1-score of 90.89 (12.45)%. The method shows good potential for automatic identification of breathing phases in recorded lung sounds.

The effect of antifibrotic agents on acute respiratory failure in COVID-19 patients: a retrospective cohort study from TriNetX US collaborative networks

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on global health and economies, resulting in millions of infections and deaths. This retrospective cohort study aimed to investigate the effect of antifibrotic agents (nintedanib and pirfenidone) on 1-year mortality in COVID-19 patients with acute respiratory failure.MethodsData from 61 healthcare organizations in the TriNetX database were analyzed. Adult patients with COVID-19 and acute respiratory failure were included. Patients with a pre-existing diagnosis of idiopathic pulmonary fibrosis before their COVID-19 diagnosis were excluded. The study population was divided into an antifibrotic group and a control group. Propensity score matching was used to compare outcomes, and hazard ratios (HR) for 1-year mortality were calculated.ResultsThe antifibrotic group exhibited a significantly lower 1-year mortality rate compared to the control group. The survival probability at the end of the study was 84.42% in the antifibrotic group and 69.87% in the control group. The Log-Rank test yielded a p-value of less than 0.001. The hazard ratio was 0.434 (95% CI: 0.264–0.712), indicating a significant reduction in 1-year mortality in the antifibrotic group. Subgroup analysis demonstrated significantly improved 1-year survival in patients receiving nintedanib treatment and during periods when the Wuhan strain was predominant.DiscussionThis study is the first to demonstrate a survival benefit of antifibrotic agents in COVID-19 patients with acute respiratory failure. Further research and clinical trials are needed to confirm the efficacy of these antifibrotic agents in the context of COVID-19 and acute respiratory failure.

Advances in the Study of Non-Coding RNA in the Signaling Pathway of Pulmonary Fibrosis.

Pulmonary fibrosis is a group of chronic, progressive, and irreversible interstitial lung diseases, which are common to most end-stage lung diseases and are one of the most difficult diseases of the respiratory system. In recent years, due to the frequent occurrence of air pollution and smog, the incidence of pulmonary fibrosis in China has increased year by year, the morbidity and mortality rates of pulmonary fibrosis have gradually increased and the age of the disease tends to be younger. However, the pathogenesis of pulmonary fibrosis is not yet fully understood and is needed to further explore new drug targets. Studies have shown that non-coding RNAs play an important role in regulating the process of pulmonary fibrosis, non-coding RNAs and their specifically expressed can promote or inhibit the process. Here, we review the role of some in the regulation of pulmonary fibrosis signaling pathways and provide new ideas for the clinical diagnosis and treatment of pulmonary fibrosis.

Diagnosis of Cystic Fibrosis Beyond Childhood in India

Abstract Cystic fibrosis (CF) is a life-limiting genetic condition with multisystemic manifestations. However, there are vast phenotypic as well as genotypic variations. This contributes to delay in diagnosis, especially in pancreatic-sufficient patients who may not manifest typical symptomatology. The last decade has witnessed significant breakthroughs in CF therapeutics. This in combination with early diagnosis through newborn screening, and aggressive supportive care can offer near-normal life expectancy for a majority of patients with CF (pwCF) worldwide. Even while addressing disparities in CF care around the world, it is crucial to train medical professionals to suspect and diagnose CF in children as well as in adults. Here, we share our experience of pwCF diagnosed beyond 16 years of age with an aim to highlight the clinical presentations in young adults, the need for screening family members of a newly diagnosed pwCF, and the negative effects of late diagnosis of CF.

International disparities in diagnosis and treatment access for cystic fibrosis.

Elexacaftor/tezacaftor/ivacaftor (ETI) has revolutionized cystic fibrosis (CF) treatment. However, previous research has demonstrated profound global disparities in diagnosis and treatment access. If unaddressed, these threaten to widen existing health inequities. Therefore, in this analysis we aimed to reappraise gaps and evaluate progress in diagnosis and treatment equity in high-income (HIC) versus low- and middle-income countries (LMICs). Estimates of the global CF population were made in 158 countries using patient registries, systematic literature searches, and an international survey of 14 CF experts. Estimates of the global burden of undiagnosed CF were made using epidemiological studies identified in literature searches and registry coverage data. The proportion of people receiving ETI was estimated using publicly available revenue data and a survey of 23 national drug pricing databases. 188,336 (163,421-209,204) people are estimated to have CF in 96 countries. Of these, 111,767 (59%) were diagnosed and 51,322 (27%) received ETI. The undiagnosed patient burden is estimated to be 76,569 people, with 82% in LMICs. ETI is reimbursed in 35 HICs, but only one LMIC. Four years after approval, there are 13,723 people diagnosed with CF who live in a country where ETI is inaccessible. This increases to 76,199 when including the estimated undiagnosed population. Equitable access to CFTR modulators must become a top priority for the international CF community. ETI costs up to $322,000 per year but could be manufactured for $5000 to allow access under a voluntary license. Given the extent of disparities, other mechanisms to improve access that circumvent the manufacturer should also be considered.

Economic evaluation of non-invasive liver tests for the diagnosis of liver fibrosis in chronic liver diseases: a systematic review protocol.

The objective of this review is to determine the costs and benefits of non-invasive liver tests vs liver biopsy in patients with chronic liver diseases. Hepatic diseases can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. In the past, liver biopsy was the only option for diagnosing fibrosis degree. Liver biopsy is an invasive procedure that depends on the sample size to be able to deliver an accurate diagnosis. In recent years, non-invasive liver tests have been increasingly used to estimate liver fibrosis degree; however, there is a lack of economic assessments of technology implementation outcomes. This review will include partial (cost studies) and complete economic evaluation studies on hepatitis B, hepatitis C, alcoholic liver disease, and non-alcoholic fatty liver disease that compare non-invasive liver tests with liver biopsies. Studies published in English, French, Spanish, German, Italian, or Portuguese will be included. No date limits will be applied to the search. This review will identify published and unpublished studies. Published studies will be identified using MEDLINE (PubMed), Cochrane Library (CENTRAL), Embase, Web of Science, Scopus, and LILACS. Sources of unpublished studies and gray literature will include sources from health technology assessment agencies, clinical practice guidelines, regulatory approvals, advisories and warnings, and clinical trial registries, as well as Google Scholar. Two independent reviewers will screen and assess studies, and extract and critically appraise the data. Data extracted from the included studies will be analyzed and summarized to address the review objective using narrative text, and the JBI dominance ranking matrix. PROSPERO CRD42023404278.

The diagnostic utility of FIB-4 as a non-invasive tool for liver fibrosis scoring among NAFLD patients: a retrospective cross-sectional study.

Liver biopsy is the gold standard method to evaluate patients with non-alcoholic fatty liver disease (NAFLD). However, due to its several limitations and complications, a reliable and non-invasive marker is required to assess liver fibrosis. In this study, we compared the performance of the FIB-4 index [based on age, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels and platelets count] with the Scheuer scoring system of liver biopsies to evaluate the diagnostic utility of FIB-4 among NAFLD patients with different liver fibrosis severities. A cross-sectional study was conducted at An-Najah National University Hospital (NNUH) in Palestine. The FIB-4 index was calculated using laboratory data for 128 NAFLD patients who underwent liver biopsies between November 2014 and July 2022. The results of FIB-4 were compared with the Scheuer scoring system of liver biopsies (using F0, F1+F2, F3+F4) to determine the sensitivity and specificity of FIB-4 in detecting and staging liver fibrosis. Out of 128 patients involved in our study, 49 of them had advanced fibrosis according to liver biopsy (F3+F4), where their FIB-4 indices showed 87% sensitivity at 1.45 cut off point and 87% specificity at 3.25 cut off point. The FIB-4 index may be used as a screening tool in the primary care setting. To raise awareness of liver diseases, this non-invasive, inexpensive, simple, and quick marker could identify people in need of further liver fibrosis evaluation and diagnosis.

Family case of cystic fibrosis

Cystic fibrosis is an autosomal recessively inherited monogenic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on the long arm of chromosome 7 (7q31.2). This mutation results in a disruption in the transport of sodium and chloride ions between intercellular fluid and the epithelial cells of the excretory ducts of the exocrine glands. This paper presents the description of a family case of cystic fibrosis involving two patients who have been under observation since birth and are sisters (patient A – 4 years 10 months, patient B – 1 year 11 months). In both patients, neonatal screening and sequential diagnosis of cystic fibrosis identified the DF508/CFTRdele2.3(21kb) mutation, the most prevalent among the Caucasian population in the Russian Federation. The primary concern in managing both patients is the correction of nutritional status and minimization of exacerbations of chronic bronchopulmonary inflammation. To determine the management strategy for these patients, a consultation was held with Dr. E.I. Kondratyeva, a leading cystic fibrosis expert and professor at the MGSC Institute, who serves as the head of the Scientific and Clinical Department of Cystic Fibrosis and the Department of Genetics of Respiratory System Diseases, an expert of the European Society for Cystic Fibrosis Committee on Diagnostics and Registry, and Deputy Chief for Scientific Work of Research Clinical Institute of Childhood of the Ministry of Health of the Moscow Region. The peculiarity of the presented clinical cases lies in the fact that within one family, with an interval of 3 years, two girls with severe disease were born. Early diagnosis was performed for both, which has allowed for the slowing down of the pathology's progression.

Prevalence and disparities in influenza vaccination among patients with COPD: A French nationwide population study

IntroductionDespite concordant international recommendations, many surveys found disappointing rates of influenza vaccination in at-risk populations, ranging from 23% in overall COPD population to more than 70% in more severe COPD subjects. Therefore, we assessed the proportion of French COPD patients non-vaccinated for influenza and their clinical and socio-demographic factors. Materiel and methodsThis was a national retrospective study based on the French health insurance database. We identified “diagnosed COPD”, defined as subjects hospitalized at least once in 2017 with a principal or associated diagnosis of COPD, and “suspected COPD” as those who were prescribed at least thrice long-acting bronchodilators (LAB), after exclusion of patients with a principal diagnosis or secondary associated diagnosis of asthma or cystic fibrosis, patients deceased before the influenza season and patients hospitalized in long-term or in palliative care unit. Multivariate logistic regression was used to assess the association between patients’ characteristics and the lack of influenza vaccination. ResultsFrom the national database, 1 474 396 subjects were identified as “suspected COPD” of whom 528 114 were excluded because of previous diagnosis of asthma or cystic fibrosis, and 350 566 as “diagnosed COPD”. Among the 1 296 848 patients included, 646 687 patients (53.3%) were vaccinated against influenza. Non-vaccinated subjects were significantly younger (62.1 vs 71.6 years old), more often women (47.9% vs 43.1%) and had fewer comorbidities assessed by Charlson's index (3.0 ± 2.2 vs 4.3 ± 2.1). Lack of vaccination was also associated with a lower LAB usage. Also, non-vaccinated subjects neither had severe exacerbation during the study period. Besides there was a significant heterogeneity in vaccination rate by geographic region, from 47% to 57%. In multivariate analysis, variables independently associated with the lack of influenza vaccination were female gender, younger age, fewer comorbidities and lower socio-economic level. ConclusionsThis study using the French exhaustive health insurance database shows that influenza vaccination among COPD patients remains dramatically low and must become a high-priority public-health strategy.

Abstract 1018: Characteristics and outcomes of patients with cystic fibrosis and pancreatic cancer: A population-based comparative analysis

Abstract Introduction: Advancements in diagnosis and treatment of cystic fibrosis (CF) has allowed improvement in overall survival which also in part explains the increasing incidence of malignancies among these patients, particularly, gastrointestinal cancers. Existing data related to the characteristics and outcomes of patients with CF and pancreatic cancer (PC) are limited to small case series. We sought to investigate the same using a large population-based database. Methods: We used TriNetX, a national database comprising approximately 74 million patients across 54 healthcare organizations in the United States. We retrospectively identified patients with CF who also had a diagnosis of PC (using ICD-10 codes). We then performed an age, sex and race-matched analysis to compare patients with CF+PC to patients with CF alone. To study the impact of CF diagnosis on PC-related outcomes, we performed a propensity matched analysis between cohorts of patients with CF+PC and patients with PC alone. Kaplan Meier estimates were used for survival analysis. A p-value of &amp;lt;0.05 was considered statistically significant. Results: We identified a total of 41,655 patients with CF, out of which 198 patients had a diagnosis of PC (0.48 %). A total of 180 patients were included in the propensity matched comparative analysis. Patients with CF and PC had a significantly higher prevalence of type 2 diabetes mellitus (42.8% vs 5.6%, p&amp;lt;0.001), hypertension (58.3% vs 5.6%, p&amp;lt;0.001) and hyperlipidemia (40% vs 5.6%, p&amp;lt;0.001) than patients with CF with no PC. No differences in the prevalence of liver cirrhosis were noted (8.9% vs 5.6%, p=0.22). Patients with PC and CF had a significantly lower prevalence of bronchiectasis (15.8% vs 28.7%, p=0.004). In a propensity matched analysis between patients with CF and PC and PC alone, CF did not impact survival among patients with resectable [HR=1.042 (0.35-3.11), p=0.79] or unresectable/advanced PC [HR=1.17 (0.62-2.22), p=0.09]. Conclusion: To our knowledge, this is the largest analysis investigating the characteristics and outcomes of patients with CF and PC. The prevalence of PC in patients with CF is higher than reported prevalence among general population. We found a significantly higher prevalence of diabetes, hypertension and hyperlipidemia and a significantly lower prevalence of bronchiectasis among patients with CF and PC. CF does not appear to impact overall survival among patients with resectable or unresectable or advanced PC. Our findings may inform risk prediction models for PC among patients with CF. Citation Format: Srija Manchkanti, Shiva J. Gaddam, Udhayvir S. Grewal. Characteristics and outcomes of patients with cystic fibrosis and pancreatic cancer: A population-based comparative analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1018.

Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences

BackgroundLimited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF.MethodsWe analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes.ResultsWe detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p < 0.05].ConclusionsWe leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Serum biomarkers associated with liver fibrosis in patients with type 2 diabetes

BACKGROUND: The diagnosis of liver fibrosis is an important task in the management of patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The currently used diagnostic methods have a number of disadvantages such as invasiveness and high cost, or insufficient sensitivity and specificity. Therefore, the search for new non-invasive markers of liver fibrosis remains an actual challenge.AIM: To assess a diagnostic value of serum growth differentiation factor-15 (GDF-15), microfibril-associated glycoprotein 4 (MFAP-4), collagen type IV alpha1 (COL4alpha1), Mac-2 binding protein (M2BPGI) and chitinase-3-like protein 1 (YKL-40) as markers of liver fibrosis in patients with type 2 diabetes and NAFLD.MATERIALS AND METHODS: A single center cross-sectional observational study was performed. The study included 74 patients, 23 men and 51 women, aged 18 to 74 years. Liver elastography was used as reference method for the fibrosis evaluation. APRI and fib-4, non-invasive fibrosis indices, were assessed. Serum concentrations of GDF-15, MFAP-4, COL4alpha1, M2BPGI, and YKL-40 were determined by ELISA. ROC analysis was used to evaluate the sensitivity and specificity of serum markers for the diagnosis of the liver fibrosis.RESULTS: Liver fibrosis stage 1 was verified in 16 subjects, stage 2 in 12, stage 3 in 7, and stage 4 in 19. Patients with advanced liver fibrosis (stages 3–4), compared with those without severe fibrosis (stages 0–2), had higher levels of GDF-15 (p=0.003), COL4alpha1 (p=0.007), and YKL-40 (p=0.04). Patients with stage 1-2 liver fibrosis had higher levels of COL4alpha compared to those without any signs of fibrosis (p=0.02). There were no significant differences in the level of MFAP-4 and M2BPGI between patients with different severity of fibrosis. According to the ROC analysis, GDF-15, COL4alpha1 and YKL-40 have diagnostic value in the detection of severe liver fibrosis comparable to that of the APRI and fib-4 indices.CONCLUSION: GDF-15, COL4alpha1 and YKL-40 could be considered as promising non-invasive markers of liver fibrosis in patients with type 2 diabetes and NAFLD.

Validation of FIB-6 score in assessment of liver fibrosis in chronic hepatitis B.

We recently developed a simple novel index called fibrosis 6 (FIB-6) using machine learning data analysis. We aimed to evaluate its performance in the diagnosis of liver fibrosis and cirrhosis in chronic hepatitis B (CHB). A retrospective observational analysis of data was obtained from seven countries (Egypt, Kingdom of Saudi Arabia (KSA), Turkey, Greece, Oman, Qatar, and Jordan) of CHB patients. The inclusion criteria were receiving an adequate liver biopsy and a complete biochemical and hematological data. The diagnostic performance analysis of the FIB-6 index was conducted and compared with other non-invasive scores. A total of 603 patients were included for the analysis; the area under the receiver operating characteristic curve (AUROC) of FIB-6 for the discrimination of patients with cirrhosis (F4), compensated advanced chronic liver disease (cACLD) (F3 and F4), and significant fibrosis (F2-F4) was 0.854, 0.812, and 0.745, respectively. The analysis using the optimal cut-offs of FIB-6 showed a sensitivity of 70.9%, specificity of 84.1%, positive predictive value (PPV) of 40.3%, and negative predictive value (NPV) of 95.0% for the diagnosis of cirrhosis. For the diagnosis of cACLD, the results were 71.5%, 69.3%, 40.8%, and 89.2%, respectively, while for the diagnosis of significant fibrosis, the results were 68.3%, 67.5%, 59.9%, and 75.0%, respectively. When compared to those of fibrosis 4 (FIB-4) index, aspartate aminotransferase (AST)-to-platelet ratio index (APRI), and AST-to-alanine aminotransferase (ALT) ratio (AAR), the AUROC for the performance of FIB-6 was higher than that of FIB-4, APRI, and AAR in all fibrosis stages. FIB-6 gave the highest sensitivity and NPV (89.1% and 92.4%) in ruling out cACLD and cirrhosis, as compared to FIB-4 (63.8% and 83.0%), APRI (53.9% and 86.6%), and AAR (47.5% and 82.3%), respectively. The FIB-6 index could be used in ruling out cACLD, fibrosis, and cirrhosis with good reliability.