BACKGROUND: Molecular testing with gene-expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used in the surveillance for acute cellular rejection (ACR) after heart transplant. However, the performance of dual testing over each test individually has not been established. Further, the impact of dual noninvasive surveillance on clinical decision-making has not been widely investigated.
METHODS: We evaluated 2,077 subjects from the Surveillance HeartCare Outcomes Registry registry who were enrolled between 2018 and 2021 and had verified biopsy data and were categorized as dual negative, GEP positive/dd-cfDNA negative, GEP negative/dd-cfDNA positive, or dual positive. The incidence of ACR and follow-up testing rates for each group were evaluated. Positive likelihood ratios (LRs+) were calculated, and biopsy rates over time were analyzed.
RESULTS: The incidence of ACR was 1.5% for dual negative, 1.9% for GEP positive/dd-cfDNA negative, 4.3% for GEP negative/dd-cfDNA positive, and 9.2% for dual-positive groups. Follow-up biopsies were performed after 8.8% for dual negative, 14.2% for GEP positive/dd-cfDNA negative, 22.8% for GEP negative/dd-cfDNA positive, and 35.4% for dual-positive results. The LR+ for ACR was 1.37, 2.91, and 3.90 for GEP positive, dd-cfDNA positive, and dual-positive testing, respectively. From 2018 to 2021, biopsies performed between 2 and 12-months post-transplant declined from 5.9 to 5.3 biopsies/patient, and second-year biopsy rates declined from 1.5 to 0.9 biopsies/patient. At 2 years, survival was 94.9%, and only 2.7% had graft dysfunction.
CONCLUSIONS: Dual molecular testing demonstrated improved performance for ACR surveillance compared to single molecular testing. The use of dual noninvasive testing was associated with lower biopsy rates over time, excellent survival, and low incidence of graft dysfunction.

Hereditary transthyretin (ATTRv) amyloidosis is a rare and autosomal dominant disorder associated with mutations in the transthyretin gene. Patients present with diverse symptoms related to sensory, motor, and autonomic neuropathy, as well as gastrointestinal, ocular, cardiac, renal and orthopedic symptoms, resulting from the deposition of transthyretin amyloid fibrils in multiple organs. The progressive nature of ATTRv amyloidosis necessitates pre- and post-onset monitoring of the disease. This review article is primarily based on a collation of discussions from a medical advisory board meeting in August 2021. In this article, we summarize the best practices in amyloidosis centers in three major endemic countries for ATTRv amyloidosis (Japan, Brazil, and Portugal), where most patients carry the Val30Met mutation in the transthyretin gene and the patients\' genetic background was proven to be the same. The discussions highlighted the similarities and differences in the management of asymptomatic gene mutation carriers among the three countries in terms of the use of noninvasive tests and tissue biopsies and timing of starting the investigations. In addition, this article discusses a set of practical tests and examinations for monitoring disease progression applicable to neurologists working in diverse medical settings and generalizable in non-endemic countries and areas. This set of assessments consists of periodic (every 6 to 12 months) evaluations of patients\' nutritional status and autonomic, renal, cardiac, ophthalmologic, and neurological functions. Physical examinations and patient-reported outcome assessments should be also scheduled every 6 to 12 months. Programs for monitoring gene mutation carriers and robust referral networks can aid in appropriate patient management in pre- to post-onset stages. For pre- and post-symptom onset testing for ATTRv amyloidosis, various noninvasive techniques are available; however, their applicability differs depending on the medical setting in each country and region, and the optimal option should be selected in view of the clinical settings, medical environment, and available healthcare resources in each region.

Until recently, coronary revascularization with coronary artery bypass grafting or percutaneous coronary intervention has been regarded as the standard choice for stable coronary artery disease (CAD), particularly for patients with a significant burden of ischemia. However, in conjunction with remarkable advances in adjunctive medical therapy and a deeper understanding of its long-term prognosis from recent large-scale clinical trials, including ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), the approach to stable CAD has changed drastically. Although the updated evidence from recent randomized clinical trials will likely modify the recommendations for future clinical practice guidelines, there are still unresolved and unmet issues in Asia, where prevalence and practice patterns are markedly different from those in Western countries. Herein, the authors discuss perspectives on: 1) assessing the diagnostic probability of patients with stable CAD; 2) application of noninvasive imaging tests; 3) initiation and titration of medical therapy; and 4) evolution of revascularization procedures in the modern era.

Colorectal cancer is a leading cause of mortality worldwide. The high incidence and the acceleration of incidence in younger people reinforces the need for better techniques of early detection. The use of noninvasive biomarkers has potential to more accurately inform how patients are prioritised for clinical investigation, which, in turn, may ultimately translate into improved survival for those subsequently found to have curable-stage CRC. This review surveys a wide range of CRC biomarkers that may (alone or in combination) identify symptomatic patients presenting in primary care who should be progressed for clinical investigation.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) is managed predominately in primary care, however, there is uncertainty regarding how to best identify patients for specialist referral. We examined the accuracy of noninvasive tests as screening tools for the prediction of outcomes in MAFLD patients referred from primary care.
METHODS: Patients with MAFLD referred by primary care for specialist review to Sir Charles Gairdner Hospital (cohort 1, n = 626) or tertiary centers within Western Australia (cohort 2, n = 246) were examined. Hepascore, aspartate aminotransferase to platelet ratio, Fibrosis-4 (FIB-4), and nonalcoholic fatty liver disease fibrosis score performed at baseline were examined for their accuracy in predicting liver-related death (LRD), decompensation, and hepatocellular carcinoma. Outcomes were collected from hospital records and data linkage.
RESULTS: The median follow-up period was 5.0 years (range, 0.1-13.0 y) and 3.8 years (range, 0.1-10.0 y) in cohorts 1 and 2, respectively. In both cohorts, Hepascore and FIB-4 had the highest area under the curve for the prediction of LRD (0.90-0.95 and 0.83-0.94, respectively), decompensation (0.86-0.91 and 0.86-0.87, respectively), and hepatocellular carcinoma (0.75-0.90 and 0.67-0.85, respectively). The sensitivity and negative predictive values were high (>90%) for Hepascore (cut-off value, 0.60), FIB-4 (cut-off value, 1.30), and nonalcoholic fatty liver disease fibrosis score (cut-off value, -1.455) for all outcomes in cohort 1, and for predicting LRD in cohort 2. Hepascore had the highest specificity, classified the greatest proportion of patients as low risk, and was favored by decision curve analysis as providing the greatest net benefit.
CONCLUSIONS: Serum noninvasive tests accurately stratify risk of liver-related outcomes in MAFLD patients and can be used as a screening tool for patients referred for specialist review by primary care.

In the mid-1970s, a group of clinicians and bioengineers at the University of Washington, under the direction of Dr D Eugene Strandness, Jr, built a prototype duplex scanner that combined B-mode imaging and pulsed Doppler flow detection in a single instrument. At that time, I was a general surgery resident with an interest in vascular disease, and arrangements were made for me to spend a year in the Strandness laboratory. The prototype duplex system was just being completed when I arrived in 1978, and I immediately became involved in a series of validation studies in which patients with carotid disease were scanned and spectral waveform parameters were correlated with independently read contrast arteriograms. This work resulted in the University of Washington duplex criteria for carotid artery disease, which have been widely adopted and modified. Subsequent advances in ultrasound technology expanded the applications of duplex scanning to the peripheral arteries and veins, as well as the abdominal vessels. In 1984, I joined Dr Strandness on the faculty in the Department of Surgery at the University of Washington where I have remained throughout my career. Over the years, I have had the opportunity to participate in many important developments, described in this article, that have helped to make the vascular laboratory the essential clinical resource that it is today.

OBJECTIVE: The fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) are noninvasive and accessible methods for assessing advanced liver fibrosis risk in primary care. We evaluated the distribution of FIB-4 and NFS scores in primary care patients with clinical signals for nonalcoholic fatty liver disease (NAFLD).
METHODS: This retrospective cohort study of electronic record data between 2007 and 2018 included adults with at least one abnormal aminotransferase and no known (non-NAFLD) liver disease. We calculated patient-level FIB-4 and NFS scores, the proportion of patients with mean values exceeding advanced fibrosis thresholds (indeterminate risk: FIB-4 > 1.3, NFS > -1.455; high-risk: FIB-4 > 2.67, NFS > 0.676), and the proportion of patients with a NAFLD International Classification of Diseases-9/10 code. Logistic regression models evaluated the associations of metabolic syndrome (MetS) components with elevated FIB-4 and NFS scores.
RESULTS: The cohort included 6506 patients with a median of 6 (interquartile range: 3-13) FIB-4 and NFS scores per patient. Of these patients, 81% had at least two components of MetS, 29% had mean FIB-4 and NFS scores for indeterminate fibrosis risk, and 11% had either mean FIB-4 or NFS scores exceeding the high advanced fibrosis risk thresholds. Regression models identified associations of low high-density lipoprotein, hyperglycemia, Black race and male gender with high-risk FIB-4 and NFS values. Only 5% of patients had existing diagnoses for NAFLD identified.
CONCLUSIONS: Many primary care patients have FIB-4 and NFS scores concerning for advanced fibrosis, but rarely a diagnosis of NAFLD. Elevated FIB-4 and NFS scores may provide signals for further clinical evaluation of liver disease in primary care settings.

Surveillance of allograft health after transplantation has traditionally relied on biopsy procedures that enable pathologic assessment for acute rejection. Noninvasive methods to assess for graft injury have been developed and tested over the past decade, and now offer a convenient way to reduce reliance on invasive testing and improve patient satisfaction. Emerging evidence suggests that detection of allograft injury via donor-derived cell-free DNA (dd-cfDNA) may, in fact, have better sensitivity compared to traditional biopsy-based strategies. This state-of-the-art review describes the development, testing, and current use of dd-cfDNA assays for acute rejection monitoring after heart transplantation, and discusses innovative ways that such assays can be used for personalized patient management.

UNASSIGNED: Nonalcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence of 25% in the general population. Given the epidemic increase, regulatory agencies have defined an unmet medical need and implemented initiatives to expedite the development of drugs for NASH treatment.
UNASSIGNED: Literature search in Medline and worldwide web was accessed latest in 23.01.2021. In recent years new drugs acting on various pathophysiological processes in NASH have entered clinical development. These drugs combine beneficial metabolic effects with anti-inflammatory and anti-fibrotic effects to treat NASH. Current drug classes being investigated for NASH treatment are agonists of nuclear receptors such as FXR agonists (including FGF19), PPAR agonists, chemokine receptor inhibitors, thyroid hormone receptor-ß agonists and analogues of enterohepatic hormones including GLP-1 and FGF21 or SGLT2 inhibitors.
UNASSIGNED: Obeticholic acid is the only drug with significant benefit in the phase 3 interim results and remains the candidate for first conditional approval as a NASH therapeutic. However, monotherapy with these drugs leads to a histological resolution of NASH in less than one-third of patients in recent trials. Therefore, the future of NASH therapy will putatively be a combination therapy of two different drug classes with complementary effects.

Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. These malignancies derive from melanocytes in the uveal tract or conjunctiva. The genetic profiles of these different entities differ from each other. In uveal melanoma, GNAQ and GNA11 gene mutations are frequently found and prognosis is based on mutation status of BAP1, SF3B1 and EIF1AX genes. Iris melanoma, also originating from the uvea, has similarities to the genetic makeups of both posterior uveal melanoma (UM) and conjunctival melanoma since mutations in GNAQ and GNA11 are less common and genes involved in conjunctival melanoma such as BRAF have been described. The genetic spectrum of conjunctival melanoma, however, includes frequent mutations in the BRAF, NRAS and TERT promoter genes, which are found in cutaneous melanoma as well. The BRAF status of the tumor is not correlated to prognosis, whereas the TERT promoter gene mutations are. Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma. Tissue material is needed to classify ocular melanoma in the different subgroups, which creates a need for the use of noninvasive techniques to prognosticate patients who underwent eye preserving treatment.