Prospective validation of the EASL management algorithm for acute kidney injury in cirrhosis.

BACKGROUND & AIMS: The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm for the management of AKI, but this has never been validated. We aimed to prospectively evaluate this algorithm in clinical practice. METHODS: We performed a prospective cohort study in consecutive hospitalized patients with cirrhosis and AKI. The EASL management algorithm includes identification/treatment of precipitating factors, 2-day albumin infusion in patients with AKI ≥stage 1B, and treatment with terlipressin in patients with hepatorenal syndrome (HRS-AKI). The primary outcome was treatment response, which included both full and partial response. Secondary outcomes were survival and adverse events associated with terlipressin therapy. RESULTS: A total of 202 AKI episodes in 139 patients were included. Overall treatment response was 80%, while renal replacement therapy was required in only 8%. Response to albumin infusion was achieved in one-third of episodes. Of patients not responding to albumin, most (74%) did not meet the diagnostic criteria of HRS-AKI, with acute tubular necrosis (ATN) being the most common phenotype. The response rate in patients not meeting the criteria for HRS-AKI was 70%. Only 30 patients met the diagnostic criteria for HRS-AKI, and their response rate to terlipressin was 61%. Median time from AKI diagnosis to terlipressin initiation was only 2.5 days. While uNGAL (urinary neutrophil gelatinase-associated lipocalin) could differentiate ATN from other phenotypes (AUROC 0.78), it did not predict response to therapy in HRS-AKI. Ninety-day transplant-free survival was negatively associated with MELD-Na, ATN and HRS-AKI as well as uNGAL. Three patients treated with terlipressin developed pulmonary edema. CONCLUSIONS: The application of the EASL AKI algorithm is associated with very good response rates and does not significantly delay initiation of terlipressin therapy. IMPACT AND IMPLICATIONS: The occurrence of acute kidney injury (AKI) in patients with cirrhosis is associated with poor short-term mortality. Improving its rapid identification and prompt management was the focus of the recently proposed EASL AKI algorithm. This is the first prospective study demonstrating that high AKI response rates are achieved with the use of this algorithm, which includes identification of AKI, treatment of precipitating factors, a 2-day albumin challenge in patients with AKI ≥1B, and supportive therapy in patients with persistent AKI not meeting HRS-AKI criteria or terlipressin with albumin in those with HRS-AKI. These findings support the use of this algorithm in clinical practice.

Impact of the implementation of a telemedicine program on patients diagnosed with asthma.

BACKGROUND: Asthma is one of the most common respiratory ailments worldwide. Despite broad understanding of the illness and of the available therapeutic options for it, patients with serious asthma suffer poor monitoring of their illness in 50% of cases. AIM: To assess the impact of the implementation of a mobile application (ESTOI) to control asthma in patients diagnosed with the illness, their adherence to treatment, and their perceived quality of life. METHODOLOGY: Randomized clinical trial with 52 weeks' follow-up of patients with asthma seen in a specialized hospital for their treatment in Spain. Some 108 included patients will be divided into two groups. The intervention group will undergo more exhaustive follow-up than normal, including access to the ESTOI application, which will have various categories of attention: control of symptoms, health recommendations, current treatment and personalized action plan, PEF record, nutritional plan, and chat access with a medical team. The asthma control questionnaire ACT is the main assessment variable. Other variables to be studied include an adherence test for the use of inhalers (TAI), the number of exacerbations, maximum exhalation flow, exhaled nitric oxide test, hospital anxiety and depression scale, asthma quality-of-life questionnaire, forced spirometry parameters (FVC, FEV1, and PBD), and analytic parameters (eosinophilia and IGE). The data will be collected during outpatient visits. TRIAL REGISTRATION: This trial has registered at ClinicalTrials.gov (Identifier: NCT06116292).

Alcoholic Foamy Degeneration, an Entity Resembling Alcohol-Associated Hepatitis: Diagnosis, Prognosis, and Molecular Profiling.

BACKGROUND & AIMS: Alcoholic foamy degeneration (AFD) is a condition with similar clinical presentation to alcohol-associated hepatitis (AH), but with a specific histologic pattern. Information regarding the prevalence and prognosis of AFD is scarce and there are no tools for a noninvasive diagnosis. METHODS: A cohort of patients admitted to the Hospital Clinic of Barcelona for clinical suspicion of AH who underwent liver biopsy was included. Patients were classified as AFD, AH, or other findings, according to histology. Clinical features, histology, and genetic expression of liver biopsy specimens were analyzed. The accuracy of National Institute on Alcohol Abuse and Alcoholism criteria and laboratory parameters for differential diagnosis were investigated. RESULTS: Of 230 patients with a suspicion of AH, 18 (8%) met histologic criteria for AFD, 184 (80%) had definite AH, and 28 (12%) had other findings. In patients with AFD, massive steatosis was more frequent and the fibrosis stage was lower. AFD was characterized by down-regulation of liver fibrosis and inflammation genes and up-regulation of lipid metabolism and mitochondrial function genes. Patients with AFD had markedly better long-term survival (100% vs 57% in AFD vs AH; P = .002) despite not receiving corticosteroid treatment, even in a model for end-stage liver disease-matched sensitivity analysis. Serum triglyceride levels had an area under the receiver operating characteristic of 0.886 (95% CI, 0.807-0.964) for the diagnosis of AFD, whereas the National Institute on Alcohol Abuse and Alcoholism criteria performed poorly. A 1-step algorithm using triglyceride levels of 225 mg/dL (sensitivity, 0.77; specificity, 0.90; and Youden index, 0.67) is proposed for differential diagnosis. CONCLUSIONS: AFD in the setting of suspicion of AH is not uncommon. A differential diagnosis is important because prognosis and treatment differ largely. Triglyceride levels successfully identify most patients with AFD and may be helpful in decision making.

Telerehabilitation following fast-track total knee arthroplasty is effective and safe: a randomized controlled trial with the ReHub® platform.

PURPOSE: After a total knee arthroplasty (TKA), ensuring rehabilitation is continued at home is essential for a successful recovery. The aim of this randomized clinical trial (NCT04155957) was to demonstrate the safety and efficacy of an interactive telerehabilitation system (ReHub®) to guide and provide feedback during exercise in the postoperative period of a fast-track TKA program. METHODS: Fifty-two patients who underwent TKA were randomized to intervention (N = 26) or control (N = 26). Upon discharge, they followed a 4-week plan of 5 daily exercises and up to 10 physiotherapy home visits. The intervention group performed exercises with ReHub® autonomously, control did not use any auxiliary device. Data were collected 1) on the day of discharge, 2) after 2 weeks and 3) after 4 weeks. RESULTS: Telerehabilitation patients showed higher adherence to exercise (p = 0.002) and greater quadriceps strength (p = 0.028). No significant differences between groups were found in other outcomes. Only 1 adverse event was linked to ReHub®. Patients gave the platform high System Usability Scale scores (83/100). CONCLUSION: Interactive telerehabilitation with ReHub® during a post-TKA exercise program is effective, safe, and well-received by patients. It provides real-time performance feedback and ensures communication. Quadriceps strength and adherence to the exercise plan are improved with ReHub®.IMPLICATIONS FOR REHABILITATIONTelerehabilitation platforms can be introduced into fast-track total knee arthroplasty protocols to monitor home-based exercise programmes without compromising efficacy and safety.Telerehabilitation and remote patient monitoring contribute to obtaining high levels of adherence to exercise plans, which is a current challenge faced by rehabilitation professionals.Real-time biofeedback on exercise performance facilitates correct exercise performance and motivates the patient.This technology allows professionals to monitor and adjust the patient's therapy remotely and avoid unnecessary travel.

Construction of nursing knowledge in commodified contexts: Views and experiences of nurses regarding primary care.

The commodification of health care, particularly primary care, presents challenges to care and knowledge development. The purpose of this study is to examine how nurses perceive and develop their knowledge in a commodified context. A mixed-methods study was conducted that included a closed-question survey and in-depth interviews with nurses in public primary care in Catalonia. There were 104 valid responses to the questionnaire and 10 in-depth interviews. The main findings of the survey were related to workload and limited time for nursing care. Six themes emerged from the in-depth interviews: (1) limited time for nursing, (2) feelings of burnout, (3) awareness of patient and family satisfaction, (4) organizational factors that favor nurses' needs, (5) organizational factors that hinder nurses' needs, and finally (6) public administration requirements. Participants perceive excessive workload and time constraints and feel that this affects their nursing care and their physical and mental health. However, nurses purposefully use knowledge patterns to cope with the problems associated with commodification. Nurses have multidimensional, contextualized, and integrated knowledge that allows them to optimize their care based on the needs of their patients. This research examines many challenges related to nursing practice and the nursing discipline and opens the door for further research that encompasses all areas of nursing.

Nursing care for patients with cirrhosis.

Cirrhosis represents a major cause of morbidity and mortality, leading to a marked impairment in the quality of life of patients and their caregivers, and resulting in a major burden on healthcare systems. Currently, in most countries, nurses still play a limited role in the care of patients with cirrhosis, which is mainly restricted to the care of patients hospitalised for acute complications of the disease. The current manuscript reviews the established and potential new and innovative roles that nurses can play in the care of patients with cirrhosis. In the hospital setting, specialised nurses should become an integral part of interprofessional teams, helping to improve the quality of care and outcomes of patients with cirrhosis. In the primary care setting, nurses should play an important role in the care of patients with compensated cirrhosis and also facilitate early diagnosis of cirrhosis in those at risk of liver diseases. This review calls for an improved global liver disease education programme for nurses and increased awareness among all healthcare providers and policymakers of the positive impacts of advanced or specialist nursing practice in this domain.

Implementation of advanced triage in the Emergency Department of high complexity public hospital: Research protocol.

AIM: To evaluate the efficacy of advanced nurse triage based on the quality of care outcomes of patients attending the Emergency Department of a high-complexity hospital. To analyse the concept of advanced triage and the essential elements of the construct. DESIGN: Mixed longitudinal study, divided into 4 steps; which will include an initial qualitative step, two observational studies and finally, a quasi-experimental study. CLINICAL TRIAL REGISTRATION NUMBER: NCT05230108. METHODS: Step 1 will consist of a concept analysis. Step 2 will include a mapping of advanced practice protocol terminologies. Step 3 will analyse the opinion of health professionals on advanced triage. In step 4: in the retrospective phase (n = 1095), sociodemographic and clinical variables and quality indicators such as waiting time will be analysed. After that, in the prospective phase (n = 547), advanced triage will be implemented and the two cohorts will be compared. The whole study will be carried out from January 2022 to January 2024. DISCUSSION: Patients classified as low complexity at triage are more vulnerable to emergency department overcrowding. The implementation of advanced triage would make it possible to respond to patient needs by offering equitable and quality healthcare, facilitating accessibility, safety and humanization of the emergency department.

Autonomous competences and quality of professional life of paediatric nurses in primary care, their relationship and associated factors: A cross-sectional study.

AIMS AND OBJECTIVES: To identify the autonomous competences and quality of professional life of paediatric nurses in primary care, their relationship and possible associated factors. BACKGROUND: The autonomous competences of paediatric nurses vary among healthcare providers in Catalonia, Spain. Autonomy is related to quality of professional life, but little is known about autonomous competences and other factors contributing to paediatric nurses' quality of professional life. DESIGN: A cross-sectional study following the STROBE statement. METHODS: Data from 206 paediatric primary care nurses were analysed. A self-administered survey consisting of an ad hoc questionnaire and a validated instrument to measure quality of professional life (QPL-35 questionnaire) was conducted. Descriptive, bivariate and general multivariate regression analyses were used to identify the relationship between autonomous competences and quality of professional life, and its predicting factors. RESULTS: 47.6% nurses reported a medium level of autonomous competences, 46.6% a high level, and 5.8% a low level. Quality of professional life was medium-high for the domains perception of managerial support and global perception of workload and for the item disconnect from work after work shift, and very high and high values for the domain intrinsic motivation and for the item quality of work life, respectively. Autonomous competences and perceived autonomy were factors associated with quality of professional life. Other associated factors were academic background, specific training and being a paediatric nurse specialist. CONCLUSIONS: Paediatric nurses in primary care have a medium-high level of autonomous competences and they perceive a high level of autonomy. Autonomous competences and level of perceived autonomy are predictors of quality of professional life. RELEVANCE TO CLINICAL PRACTICE: Enhancing paediatric nurses' autonomous competences and academic background, receiving specific training and being paediatric nurse specialists might improve their quality of professional life, healthcare quality and outcomes for the child population.

LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries.

BACKGROUND: The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. METHODS: This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. DISCUSSION: This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country. TRIAL REGISTRATION: This study is registered on Clinicaltrials.gov ( NCT03789825 ).

Patterns of kidney dysfunction in acute-on-chronic liver failure: Relationship with kidney and patients' outcome.

Impairment of kidney function is common in acute-on-chronic liver failure (ACLF). Patterns of kidney dysfunction and their impact on kidney and patient outcomes are ill-defined. Aims of the current study were to investigate patterns of kidney dysfunction and their impact on kidney and patient outcomes in patients with acute decompensation (AD) of cirrhosis, with or without ACLF. This prospective study includes 639 admissions for AD (232 with ACLF; 407 without) in 518 patients. Data were collected at admission and during hospitalization, and patients were followed up for 3 months. Urine samples were analyzed for kidney biomarkers. Most patients with ACLF (92%) had associated acute kidney injury (AKI), in most cases without previous chronic kidney disease (CKD), whereas some had AKI-on-CKD (70% and 22%, respectively). Prevalence of AKI in patients without ACLF was 35% (p < 0.001 vs. ACLF). Frequency of CKD alone was low and similar in both groups (4% and 3%, respectively); only a few patients with ACLF (4%) had no kidney dysfunction. AKI in ACLF was associated with poor kidney and patient outcomes compared with no ACLF (AKI resolution: 54% vs. 89%; 3-month survival: 51% vs. 86%, respectively; p < 0.001 for both). Independent predictive factors of 3-month survival were Model for End-Stage Liver Disease-Sodium score, ACLF status, and urine neutrophil gelatinase-associated lipocalin (NGAL). AKI is almost universal in patients with ACLF, sometimes associated with CKD, whereas CKD alone is uncommon. Prognosis of AKI depends on ACLF status. AKI without ACLF has good prognosis. Best predictors of 3-month survival are MELD-Na, ACLF status, and urine NGAL.

Stigmatization is common in patients with non-alcoholic fatty liver disease and correlates with quality of life.

BACKGROUND AND AIMS: Stigmatization is a well-documented problem of some diseases. Perceived stigma is common in alcohol-related liver disease and hepatitis C, but little information exists on stigma in patients with non-alcoholic fatty liver disease (NAFLD). Aim of the study was to investigate frequency and characteristics of perceived stigma among patients with NAFLD. METHODS: One-hundred and ninety-seven patients seen at the liver clinic were included: a study group of 144 patients with NAFLD, 50 with cirrhosis (34 compensated, 16 decompensated), and a control group of 53 patients with alcohol-related cirrhosis. Demographic, clinical, and laboratory data were collected. Quality-of-life was assessed by chronic liver disease questionnaire (CLDQ). Perceived stigma was assessed using a specific questionnaire for patients with liver diseases categorized in 4 domains: stereotypes, discrimination, shame, and social isolation. RESULTS: Perceived stigma was common in patients with NAFLD (99 patients, 69%) and affected all 4 domains assessed. The frequency was slightly higher, yet not significant, in patients with NAFLD cirrhosis vs those without (72% vs 67%, respectively; p = 0.576). In patients without cirrhosis perceived stigma was unrelated to stage of disease, since frequency was similar in patients with no or mild fibrosis compared to those with moderate/severe fibrosis (66% vs 68%, respectively). There were no differences in perceived stigma between patients with compensated cirrhosis and these with decompensated cirrhosis. Among patients with cirrhosis, stigmatization was more common in alcohol-related vs NAFLD-cirrhosis, yet differences were only significant in two domains. In patients with NAFLD, perceived stigma correlated with poor quality-of-life, but not with demographic or clinical variables. CONCLUSIONS: Perceived stigmatization is common among patients with NAFLD independently of disease stage, is associated with impaired quality-of-life, and may be responsible for stereotypes, discrimination, shame, and social isolation, which may affect human and social rights of affected patients.

Population screening for liver fibrosis: Toward early diagnosis and intervention for chronic liver diseases.

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease and alcohol-related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18% to 27%-in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression.

Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Decompensated cirrhosis (DC) is associated with high mortality, mainly owing to the development of acute-on-chronic liver failure (ACLF). Identifying the patients with DC who are at high risk of mortality and ACLF development is an unmet clinical need. Liver fatty acid-binding protein (L-FABP) is expressed in several organs and correlates with liver and systemic inflammation. Herein, we aimed to assess the prognostic value of L-FABP in patients with DC. METHODS: A prospective series of 444 patients hospitalized for DC was divided into 2 cohorts: study cohort (305 patients) and validation cohort (139 patients). L-FABP was measured in urine and plasma samples collected at admission. Neutrophil gelatinase-associated lipocalin (NGAL) was also measured in urine samples for comparison. RESULTS: Urine but not plasma L-FABP correlated with 3-month survival on univariate analysis. On multivariate analysis, urine L-FABP and model for end-stage liver disease (MELD)-Na were the only independent predictors of prognosis. Urine L-FABP levels were higher in patients with ACLF than in those without and also predicted the development of ACLF, together with MELD-Na, during follow-up. In patients with ACLF, urine L-FABP correlated with liver, coagulation, and circulatory failure. Urine L-FABP levels were also increased in patients with acute kidney injury, particularly in those with acute tubular necrosis. The ability of urinary L-FABP to predict survival and ACLF development was confirmed in the validation cohort. Urine NGAL predicted outcome on univariate but not multivariate analysis. CONCLUSIONS: Urinary L-FABP levels are independently associated with the 3-month clinical course in patients with DC, in terms of mortality and ACLF development. Urinary L-FABP is a promising prognostic biomarker for patients with DC. LAY SUMMARY: Increased levels of liver fatty acid-binding protein (L-FABP), a protein related to lipid metabolism, have been associated with liver-related diseases. The present study analyzed urinary L-FABP levels in 2 independent groups of patients with decompensated cirrhosis and showed that higher urinary L-FABP levels correlated with increased mortality and risk of acute-on-chronic liver failure development. Therefore, urinary L-FABP levels could be useful as a new tool to predict complications in patients with decompensated cirrhosis.

Quality of professional life of primary healthcare nurses: A systematic review.

AIMS: To identify and critically appraise the available evidence on the overall quality of professional life of primary care nurses worldwide and its main influencing factors. BACKGROUND: Quality of professional life of healthcare workers is a keystone that influences the quality of healthcare services provided by healthcare organisations. Nurses have a key role as healthcare services providers given the growing shortage of doctors in primary care. DESIGN: A systematic review design in accordance with the PRISMA statement. METHODS: The search was conducted through MEDLINE (PubMed), CINAHL, SCOPUS, Scientific Electronic Library Online (SciELO) and Web of Science databases. The grey literature was reviewed at OpenGrey. The search was limited to human studies published from April 2010-April 2020. No limit of original language publication was applied. Three independent reviewers analysed the methodological quality of the studies. RESULTS: Ten studies were included from five countries. Five studies reported nurses were satisfied with their quality of professional life and the influencing factors identified were Workload, Job autonomy, Demographic variables, Management support, Recognition, Intrinsic motivation, Interpersonal relations, Compassion fatigue, Burnout, Turnover intention, and work was reported as a component of Quality of life. CONCLUSION: Primary healthcare nurses reported a high level of quality of professional life, but the scarce studies found do not provide solid consistency to assess the overall quality of professional life. Perception of high workload was the most frequently identified factor to negatively influence the quality of professional life of nurses. RELEVANCE TO CLINICAL PRACTICE: Quality of professional life of primary care nurses is a key issue because of nurses' important relation with patient's care and satisfaction. Healthcare organisations should strive to address primary care nurses' quality of professional life to enhance their well-being and consequently patients' safety and high-quality healthcare services.

Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population.

BACKGROUND & AIMS: Fibrosis-4 (FIB-4) and the nonalcoholic fatty liver disease fibrosis score (NFS) are the 2 most popular noninvasive blood-based serum tests proposed for widespread fibrosis screening. We therefore aimed to describe the accuracy of FIB-4 and NFS to detect elevated liver stiffness as an indicator of hepatic fibrosis in low-prevalence populations. METHODS: This study included a total of 5129 patients with concomitant measurement of FIB-4, NFS, and liver stiffness measurement (LSM) by Fibroscan (Echosens, France) from 5 independent population-based cohorts from Spain, Hong Kong, Denmark, England, and France; 3979 participants from the general population and 1150 from at-risk cohorts due to alcohol, diabetes, or obesity. We correlated LSM with FIB-4 and NFS, and calculated pre- and post-test predictive values of FIB-4 and NFS to detect elevated LSM at 8 kPa and 12 kPa cutoffs. The mean age was 53 ± 12 years, the mean body mass index was 27 ± 5 kg/m2, and 2439 (57%) were women. One in 10 patients (552; 11%) had liver stiffness ≥8 kPa, but 239 of those (43%) had a normal FIB-4, and 171 (31%) had normal NFS. The proportion of false-negatives was higher in at-risk patients than the general population. FIB-4 was false-negative in 11% of diabetic subjects, compared with 2.5% false-negatives with NFS. Waist circumference outperformed FIB-4 and NFS for detecting LSM ≥8 kPa in the general population. Almost one-third (28%-29%) of elevated FIB-4/NFS were false-positive in both the general population and at-risk cohorts. CONCLUSIONS: FIB-4 and NFS are suboptimal for screening purposes due to a high risk of overdiagnosis and a non-negligible percentage of false-negatives, especially in patients with risk factors for chronic liver disease. Waist circumference emerged as a potential first step to identify patients at risk for liver fibrosis in the general population.