EASL position paper on clinical follow-up after HCV cure.

Following the advent of direct-acting antivirals (DAAs), hepatitis C virus (HCV) infection can be cured in almost all infected patients. This has led to a number of clinical questions regarding the optimal management of the millions of patients cured of HCV. This position statement provides specific guidance on the appropriate follow-up after a sustained virological response in patients without advanced fibrosis, those with compensated advanced chronic liver disease, and those with decompensated cirrhosis. Guidance on hepatocellular carcinoma risk assessment and the management of extrahepatic manifestations of HCV is also provided. Finally, guidance is provided on the monitoring and treatment of reinfection in at-risk patients. The recommendations are based on the best available evidence and are intended to help healthcare professionals involved in the management of patients after treatment for HCV.

Peer support for people living with hepatitis B virus-A foundation for treatment expansion.

Chronic hepatitis B infection (CHB) affects 300 million people worldwide and is being targeted by the United Nations 2030 Sustainable Development Goals (SDGs) and the World Health Organisation (WHO), working towards elimination of hepatitis B virus (HBV) as a public health threat. In this piece, we explore the evidence and potential impact of peer support to enhance and promote interventions for people living with CHB. Peer support workers (PSWs) are those with lived experience of an infection, condition or situation who work to provide support for others, aiming to improve education, prevention, treatment and other clinical interventions and to reduce the physical, psychological and social impacts of disease. Peer support has been shown to be a valuable tool for improving health outcomes for people living with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), but to date has not been widely available for communities affected by HBV. HBV disproportionately affects vulnerable and marginalised populations, who could benefit from PSWs to help them navigate complicated systems and provide advocacy, tackle stigma, improve education and representation, and optimise access to treatment and continuity of care. The scale up of peer support must provide structured and supportive career pathways for PSWs, account for social and cultural needs of different communities, adapt to differing healthcare systems and provide flexibility in approaches to care. Investment in peer support for people living with CHB could increase diagnosis, improve retention in care, and support design and roll out of interventions that can contribute to global elimination goals.

Rate and determinants of antiviral treatment initiation for patients with HBeAg-negative chronic hepatitis B.

Most clinic attenders with chronic hepatitis B (CHB) are serum HBeAg-negative, and a minority will require suppressive antiviral treatment. Expert guidelines propose schedules for the monitoring of untreated patients, but the recommended frequency of patient review does not reflect recognised demographic determinants of HBeAg-negative chronic hepatitis. Also, the impact of patient ethnicity on risk has not been defined. The aim of our study was to determine the rates and determinants of antiviral treatment initiation in a large multi-ethnic cohort of CHB patients attending a single centre. We undertook a retrospective study using entirely electronic sources of patient information. Treatment initiation dates were identified from electronic pharmacy records. Crude and time-dependent statistical analyses were undertaken to identify rate and risk factors for treatment initiation. Treatment was initiated for 232/1256 (18.5%) patients with rates of 23.2% and 33.2% at 5 and 10 years. An increased risk of treatment was associated with male sex (RR 1.803), older age at presentation (RR 1.027 per year increase) and with non-Black ethnicity (RR 1.654). Patient sex, baseline age and ethnicity also determined risk for treatment in the subset of patients with normal serum ALT and low HBV DNA at baseline, though overall treatment rate in this group was low (only 2% per annum). Thus, patient demographics permit risk stratification for treatment initiation and could determine to a significant extent the frequency of review required for untreated HBeAg-negative patients. Black ethnicity is associated with a significant reduction in risk of treatment initiation.

Impaired lower limb muscle mass, quality and function in end stage liver disease: A cross-sectional study.

NEW FINDINGS: What is the central question of this study? To what extent does musculoskeletal impairment occur (i.e., muscle mass, quality and function) in patients with end stage liver disease (ESLD) by comparison to a healthy age/sex-matched control group? What is the main finding and its importance? Muscle mass, quality and function are impaired in patients with ESLD (compared to age/sex matched controls). Importantly, greater impairments were seen in lower limb compared to arm and trunk muscle groups. These findings may suggest that there should be greater consideration of muscle health in functionally relevant lower limb muscle groups. ABSTRACT: Sarcopenia is associated with reduced quality of life and increased mortality in patients with end stage liver disease (ESLD). Historically, sarcopenia identification in ESLD utilised L3 skeletal muscle index (SMI). There are few data on muscle quality and function within lower limb muscle groups with high functional relevance. The aim of this prospective case-control study was to evaluate the quadriceps muscle in patients with ESLD. Muscle mass and quality were evaluated using MRI (quadriceps anatomical cross sectional area (ACSA), quadriceps volume index, L3 SMI, quadriceps intermuscular adipose tissue (IMAT)), mid-arm muscle circumference (MAMC) and ultrasonography (vastus lateralis (VL) thickness and quadriceps ACSA). Muscle strength/function was assessed by handgrip strength, peak quadriceps isokinetic torque and chair rise time. Thirty-nine patients with ESLD (55 years, 61% male, 48% alcoholic related liver disease (ArLD), 71% Child-Pugh B/C) and 18 age/sex-matched healthy control participants (HC) were studied. Quadriceps mass was significantly reduced in ESLD versus HC (-17%), but L3 SMI and MAMC were unchanged. Quadriceps IMAT percentage was increased in ESLD (+103%). Handgrip strength (-15%), peak isokinetic torque (-29%), and chair rise time (+56%) were impaired in ESLD. Ultrasound measures of VL thickness (r = 0.56, r = 0.57, r = 0.42) and quadriceps ACSA (r = 0.98, r = 0.86, r = 0.67) correlated to MRI quadriceps ACSA, quadriceps volume and L3 SMI, respectively. Quadriceps muscle mass, quality, and function were impaired in patients with ESLD, whereas conventional assessments of muscle (L3 SMI and MAMC) highlighted no differences between ESLD and HC. Full evaluation of lower limb muscle health is essential in ESLD in order to accurately assess sarcopenia and target future interventions.

Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions.

HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.

Hepatitis B e antigen and e antibody in a multi-ethnic cohort of adult chronic hepatitis B virus patients followed at a single liver unit for a period of 20 years.

Hepatitis B virus e antigen (HBeAg) loss and the appearance of antibodies to HBeAg (anti-HBe) are favourable events in the history of chronic hepatitis B virus (CHB) infection. Most CHB patients have the HBeAg/anti-HBe profiles +/- or -/+, and little is published on the derivation or fate of the +/+ and -/- profiles. We have used electronically accessible patient data to study the HBeAg and anti-HBe profiles of a multi-ethnic cohort of adult HBV patients seen at a single centre over a period of more than 20 years. 3594 HBsAg-positive patients were identified and patients with viral coinfection or acute HBV infection were excluded. Cross-sectional and longitudinal analyses of HBeAg/anti-HBe status were undertaken. Compared with White or Black patients, Chinese and Asian patients are more likely to be HBeAg positive during child-bearing years. Patients with +/+ profile are likely to undergo HBeAg loss and seroconversion during relatively short follow-up. Chinese patients have a relatively increased rate of seroconversion. For HBeAg-positive patients, the risk of seroconversion diminishes with advancing age. Despite HBeAg loss, seroconversion is seldom observed after age 60 years. The proportion of HBV patients with -/- increases with age, and most acquire this profile by HBeAg loss but without antecedent seroconversion. -/- patients can lose HBsAg and develop anti-HBs. It was not possible to demonstrate a favourable impact of antiviral treatment on the rate of HBeAg seroconversion.

A UWB-Based Lighter-Than-Air Indoor Robot for User-Centered Interactive Applications.

Features such as safety and longer flight times render lighter-than-air robots strong candidates for indoor navigation applications involving people. However, the existing interactive mobility solutions using such robots lack the capability to follow a long-distance user in a relatively larger indoor space. At the same time, the tracking data delivered to these robots are sensitive to uncertainties in indoor environments such as varying intensities of light and electromagnetic field disturbances. Regarding the above shortcomings, we proposed an ultra-wideband (UWB)-based lighter-than-air indoor robot for user-centered interactive applications. We developed the data processing scheme over a robot operating system (ROS) framework to accommodate the robot's integration needs for a user-centered interactive application. In order to explore the user interaction with the robot at a long-distance, the dual interactions (i.e., user footprint following and user intention recognition) were proposed by equipping the user with a hand-held UWB sensor. Finally, experiments were conducted inside a professional arena to validate the robot's pose tracking in which 3D positioning was compared with the 3D laser sensor, and to reveal the applicability of the user-centered autonomous following of the robot according to the dual interactions.

Sarcopenia in chronic liver disease: mechanisms and countermeasures.

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with cirrhosis and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and posttransplant complications. In chronic liver disease (CLD), sarcopenia is most commonly defined through the measurement of the skeletal muscle index of the third lumbar spine. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover, which likely occurs due to a decrease in muscle protein synthesis and an elevation in muscle protein breakdown. This imbalance is assumed to arise due to several factors including accelerated starvation, hyperammonemia, amino acid deprivation, chronic inflammation, excessive alcohol intake, and physical inactivity. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to mitochondrial dysfunction and an increase in myostatin expression. Currently, the use of nutritional interventions such as late-evening snacks, branched-chain amino acid supplementation, and physical activity have been proposed to help the management and treatment of sarcopenia. However, little evidence exists to comprehensively support their use in clinical settings. Several new pharmacological strategies, including myostatin inhibition and the nutraceutical Urolithin A, have recently been proposed to treat age-related sarcopenia and may also be of use in CLD. This review highlights the potential molecular mechanisms contributing to sarcopenia in CLD alongside a discussion of existing and potential new treatment strategies.

Persistent Hepatitis E virus infection across England and Wales 2009-2017: Demography, virology and outcomes.

The first clinical case of persistent HEV infection in England was reported in 2009. We describe the demography, virology and outcomes of patients identified with persistent HEV infection in England and Wales between 2009 and 2017. A series of 94 patients with persistent HEV infection, defined by HEV viraemia of more than 12 weeks, was identified through routine reference laboratory testing. Virology, serology and clinical data were recorded through an approved PHE Enhanced Surveillance System. Sixty-six cases (70.2%) were transplant recipients, 16 (17.0%) had an underlying haematological malignancy without stem cell transplantation, six (6.4%) had advanced HIV infection, five (5.3%) were otherwise immunosuppressed, and one patient (1.1%) had no identified immunosuppression. Retrospective analysis of 46 patients demonstrated a median 38 weeks of viraemia before diagnostic HEV testing. At initial diagnosis, 16 patients (17.0%) had no detectable anti-HEV serological response. Of 65 patients treated with ribavirin monotherapy, 11 (16.9%) suffered virological relapse despite undetectable RNA in plasma or stool at treatment cessation. Persistent HEV infection remains a rare diagnosis, but we demonstrate that a broad range of immunocompromised patients are susceptible. Both lack of awareness and the pauci-symptomatic nature of persistent HEV infection likely contribute to significant delays in diagnosis. Diagnosis should rely on molecular testing since anti-HEV serology is insufficient to exclude persistent HEV infection. Finally, despite treatment with ribavirin, relapses occur even after cessation of detectable faecal shedding of HEV RNA, further emphasising the requirement to demonstrate sustained virological responses to treatment.

Reinforced Aortic Root Reconstruction in Type A Aortic Dissection: A Prospective Study.

BACKGROUND: Type A aortic dissection is a challenging surgical emergency associated with high morbidity and mortality. Many techniques have evolved to repair the dissected sinus segments and restore aortic valve dynamics. Herein, we evaluate the early outcome of a novel technique for reconstruction of dissected aortic root. METHODS: A prospective study was conducted on 300 patients to evaluate the early results of repair of dissected root in type A aortic dissection. The mean age was 59.65±8.52 years, and 76% of patients were males. All patients had four standard steps for aortic reconstruction: 1) commissural resuspension; 2) right coronary sinus reinforcement with pericardial and Dacron bands; 3) non-coronary sinus reinforcement using external Dacron patch; 4) circumferential inversion of adventitial layer of the root. Patients were followed up clinically, echocardiographically, and by CT scan. RESULTS: The in-hospital mortality was 8%. The mean cross-clamp time was 120±30 minutes, and circulatory arrest time was 25+10 minutes. Twenty-seven patients (9%) experienced postoperative complications, including bleeding and acute kidney injury. During a mean follow-up time of 48±12 months, there were no recurrent aortic dissection, aortic dilatation, pseudoaneurysm, or progression of aortic regurgitation during the entire study period. CONCLUSIONS: This reconstructive technique technically is undemanding, feasible, safe, and durable with good early results. A larger cohort of patients with longer period of follow up should generate a more powerful evaluation of this technique.

How to Interact with a Fully Autonomous Vehicle: Naturalistic Ways for Drivers to Intervene in the Vehicle System While Performing Non-Driving Related Tasks.

Autonomous vehicle technology increasingly allows drivers to turn their primary attention to secondary tasks (e.g., eating or working). This dramatic behavior change thus requires new input modalities to support driver-vehicle interaction, which must match the driver's in-vehicle activities and the interaction situation. Prior studies that addressed this question did not consider how acceptance for inputs was affected by the physical and cognitive levels experienced by drivers engaged in Non-driving Related Tasks (NDRTs) or how their acceptance varies according to the interaction situation. This study investigates naturalistic interactions with a fully autonomous vehicle system in different intervention scenarios while drivers perform NDRTs. We presented an online methodology to 360 participants showing four NDRTs with different physical and cognitive engagement levels, and tested the six most common intervention scenarios (24 cases). Participants evaluated our proposed seven natural input interactions for each case: touch, voice, hand gesture, and their combinations. Results show that NDRTs influence the driver's input interaction more than intervention scenario categories. In contrast, variation of physical load has more influence on input selection than variation of cognitive load. We also present a decision-making model of driver preferences to determine the most natural inputs and help User Experience designers better meet drivers' needs.

Lipreading Architecture Based on Multiple Convolutional Neural Networks for Sentence-Level Visual Speech Recognition.

In visual speech recognition (VSR), speech is transcribed using only visual information to interpret tongue and teeth movements. Recently, deep learning has shown outstanding performance in VSR, with accuracy exceeding that of lipreaders on benchmark datasets. However, several problems still exist when using VSR systems. A major challenge is the distinction of words with similar pronunciation, called homophones; these lead to word ambiguity. Another technical limitation of traditional VSR systems is that visual information does not provide sufficient data for learning words such as "a", "an", "eight", and "bin" because their lengths are shorter than 0.02 s. This report proposes a novel lipreading architecture that combines three different convolutional neural networks (CNNs; a 3D CNN, a densely connected 3D CNN, and a multi-layer feature fusion 3D CNN), which are followed by a two-layer bi-directional gated recurrent unit. The entire network was trained using connectionist temporal classification. The results of the standard automatic speech recognition evaluation metrics show that the proposed architecture reduced the character and word error rates of the baseline model by 5.681% and 11.282%, respectively, for the unseen-speaker dataset. Our proposed architecture exhibits improved performance even when visual ambiguity arises, thereby increasing VSR reliability for practical applications.

Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.

BACKGROUND: Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. METHODS: Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months. RESULTS: After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. CONCLUSIONS: This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.

Description and Impact of a Comprehensive Multispecialty Multidisciplinary Intervention to Decrease Opioid Prescribing in Surgery.

INTRODUCTION: Diversion of excess prescription opioids contributes to the opioid epidemic. We sought to describe and study the impact of a comprehensive departmental initiative to decrease opioid prescribing in surgery. METHODS: A multispecialty multidisciplinary initiative was designed to change the culture of postoperative opioid prescribing, including: consensus-built opioid guidelines for 42 procedures from 11 specialties, provider-focused posters displayed in all surgical units, patient opioid/pain brochures setting expectations, and educational seminars to residents, advanced practice providers, residents and nurses. Pre- (April 2016-March 2017) versu post-initiative (April 2017-May 2018) analyses of opioid prescribing at discharge [median oral morphine equivalent (OME)] were performed at the specialty, prescriber, patient, and procedure levels. Refill prescriptions within 3 months were also studied. RESULTS: A total of 23,298 patients were included (11,983 pre-; 11,315 post-initiative). Post-initiative, the median OME significantly decreased for 10 specialties (all P values < 0.001), the percentage of patients discharged without opioids increased from 35.7% to 52.5% (P < 0.001), and there was no change in opioids refills (0.07% vs 0.08%, P = 0.9). Similar significant decreases in OME were observed when the analyses were performed at the provider and individual procedure levels. Patient-level analyses showed that the preinitiative race/sex disparities in opioid-prescribing disappeared post-initiative. CONCLUSION: We describe a comprehensive multi-specialty intervention that successfully reduced prescribed opioids without increase in refills and decreased sex/race prescription disparities.

Home-Based Exercise in Patients Awaiting Liver Transplantation: A Feasibility Study.

Frailty is associated with increased mortality both before and after liver transplantation (LT). There are no standardized exercise programs, in particular home-based exercise programs (HBEPs), for patients awaiting LT. The aim was to investigate the feasibility of such a program in patients awaiting LT. Patients were randomly selected from the Birmingham LT waiting list and provided with a 12-week HBEP, including average daily step (ADS) targets and twice-weekly resistance exercises. Feasibility was based on patient eligibility (≥66% of waiting list), target recruitment (≥90% of n = 20), safety (no related serious adverse events), and adherence (≥66% adherence to 6-week HBEP). Measures of aerobic (incremental shuttle walk test [ISWT], ADS), functional capacity (short physical performance battery test [SPPBT]), and health-related quality of life (EuroQol 5-Dimension 5-Level (EQ-5D-5L) and hospital anxiety and depression score [HADS]) were taken at baseline and at 6 and 12 weeks. 18 patients (50% male; median age, 55 years) were recruited. All domains of the study feasibility criteria were met. ISWT improved after 6 weeks (50 m; P ≤ 0.01) and 12 weeks (210 m; P ≤ 0.01), despite withdrawal of the telephone health calls. Similarly, improvements were seen in ADS (2700/day; P ≤ 0.01) and the SPPBT (2.5; P = 0.02) after 12 weeks. There was no difference in HADS (median difference [MD] -3; P = 0.69), but EQ-5D-5L after 12 weeks (17.5%; P = 0.04). In conclusion, a 12-week HBEP, incorporating both easy-to-apply resistance and aerobic exercises, is safe and feasible in patients awaiting LT. Measures of aerobic and functional capacity demonstrate trends toward improvement that warrant further investigation in a randomized controlled trial.

Aortic conduit aneurysm and enteric fistula formation in a post-liver transplant patient: A potential causative role for cytomegalovirus?

Hepatic arterial aortic conduits can be used as an alternative means of revascularizing the donor liver when the native recipient hepatic artery (HA) cannot be used. Cytomegalovirus (CMV) is a common Herpesviridae infection in patients who have undergone solid organ transplants. It can be asymptomatic but may cause fever and invasive disease affecting any organ system. Here we describe the first case in the literature of an aortic conduit aneurysm and concurrent CMV viremia following liver transplantation. We speculate on a causative role for CMV in the development of the aneurysm.

The Micro-Elimination Approach to Eliminating Hepatitis C: Strategic and Operational Considerations.

The introduction of efficacious new hepatitis C virus (HCV) treatments galvanized the World Health Organization to define ambitious targets for eliminating HCV as a public health threat by 2030. Formidable obstacles to reaching this goal can best be overcome through a micro-elimination approach, which entails pursuing elimination goals in discrete populations through multi-stakeholder initiatives that tailor interventions to the needs of these populations. Micro-elimination is less daunting, less complex, and less costly than full-scale, country-level initiatives to eliminate HCV, and it can build momentum by producing small victories that inspire more ambitious efforts. The micro-elimination approach encourages stakeholders who are most knowledgeable about specific populations to engage with each other and also promotes the uptake of new models of care. Examples of micro-elimination target populations include medical patients, people who inject drugs, migrants, and prisoners, although candidate populations can be expected to vary greatly in different countries and subnational areas.

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

Identification of occult active infection using PET-CT in a combined liver-kidney transplant candidate.

This case describes a patient being considered for combined liver-kidney transplantation for Caroli's disease with a failed renal transplant. A chronic septic focus could not be located with standard imaging techniques, such as ultrasonography and computed tomography. This case report highlights the observation that a retained non-functioning transplant can be the cause of fever of unknown origin and PET-CT can be useful in diagnosing these challenging cases.