Beta-amyloid deposition around hepatic bile ducts is a novel pathobiological and diagnostic feature of biliary atresia.

BACKGROUND AND AIMS: Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aimed to investigate the underlying pathogenesis and molecular signatures associated with BA. METHODS: We combined organoid and transcriptomic analysis to gain new insights into BA pathobiology using patient samples and a mouse model of BA. RESULTS: Liver organoids derived from patients with BA and a rhesus rotavirus A-infected mouse model of BA, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids. CONCLUSION: The novel observation that beta-amyloid accumulates around bile ducts in the livers of patients with BA has important pathobiological implications, as well as diagnostic potential. LAY SUMMARY: Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition - the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy - around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.

Natural history and risk factors for rupture of thoracic aortic arch aneurysms.

OBJECTIVE: The management of degenerative aneurysms of the aortic arch requires careful selection of patients, taking into consideration risk of rupture and operative risks, which is more relevant with the emergence of hybrid debranching and branched and fenestrated endovascular options. The natural history of true arch aneurysms has not been previously studied. We aimed to determine the expansion rate of thoracic aortic arch aneurysm and to identify predictors for rupture. METHODS: Consecutive patients with known true thoracic aortic arch aneurysms monitored with serial computed tomography from 2000 to 2014 were retrospectively reviewed. Thoracoabdominal aneurysms and aneurysms due to aortic dissection and connective tissue diseases were excluded. Variables studied included patient demographics, aneurysm morphology, and ascending aorta diameter. A size expansion curve for each patient was plotted with serial computed tomography scan data, and the slope obtained by linear interpolation was taken as the expansion rate. Multiple logistic regression analysis was performed to identify independent predictors of rupture. Average yearly risks of rupture for overall and expansion rate substrata were calculated from life-table analysis. RESULTS: A total of 45 arch aneurysms were followed up for a mean of 36.6 months (3-104). Aneurysm growth was largely linear, with an average rate of 2.5 mm/y (0-16). During surveillance, 10 aneurysms ruptured (22%) and 8 patients died. There was one additional arch aneurysm-related death during follow-up, whereas 14 patients (31%) died of other causes. Aneurysms expanding at >5.5 mm/y have a 67% likelihood of rupture compared with 8.3% of those expanding at <5.5 mm/y. Aneurysm size >6.5 cm (P = .0001) and hyperlipidemia (P = .0321) were positively correlated with fast expansion. On univariate analysis, only aneurysm size and expansion rate were significant predictors of rupture. On multivariate analysis, aneurysm expansion rate was the sole independent risk factor of aneurysm rupture (odds ratio, 1.43; 95% confidence interval, 1.06-1.92; P = .018). CONCLUSIONS: Aneurysm expansion rate >5.5 mm/y is a significant rupture predictor in addition to size compared with aneurysm morphology and other demographic factors. Aneurysm size >6.5 mm and hyperlipidemia are determining factors of expansion rate. These may have implications in selection of patients for surgery. Better control of hyperlipidemia may alleviate the risk of rupture.

Allan-Herndon-Dudley syndrome in Hong Kong: Implication for newborn screening.

BACKGROUND: Allan-Herndon-Dudley syndrome (MCT 8 deficiency) is an X-linked recessive condition caused by hemizygous pathogenic variants in SLC16A2 encoding the monocarboxylate transporter 8 (MCT8). Patients present with global developmental delay and neurological impairment, and abnormal serum thyroid function tests. The drug, 3,3',5 triiodothyroacetic acid (TRIAC), was recently demonstrated to improve the endocrinological profile. Improvement in diagnostic approach is key to earlier start of treatment. PATIENT FINDINGS: We described four Chinese patients with MCT8 deficiency undergoing different diagnostic odysseys. Their initial presentation included global developmental delay and dystonia. Patient 2 also had epilepsy. Patients 1 and 2 presented with two novel variants: (1)hemizygous NM_006517.4(SLC16A2):c.1170 + 2 T > A; p.(?), and (2)hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17) respectively. Patients 3 and 4 were biological brothers harboring hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17), which was first reported in 2004. We obtained the measurement of triiodothyronine (T3) and reverse T3 (rT3) from dried blood spot samples collected on Day 1 of life from Patient 1 and studied the biomarkers (rT3 and T3/rT3 ratio) proposed by Iwayama et al. for the detection of MCT8 deficiency at birth. Our data verified the significantly reduced rT3 level in Patient 1, compared with healthy newborns, although low T3 level and comparable T3/rT3 ratio with controls were detected. SUMMARY: Patients with MCT8 deficiency often undergo diagnostic odysseys. An early diagnosis could be missed by a normal newborn thyroid function screening result based on biochemical measurement of TSH and/or T4/fT4. Early detection of rT3 is key to improving current diagnostic approach. CONCLUSION: We recommend that full thyroid function profile (TSH, T4/fT4, T3/fT3, rT3) be considered early for all pediatric patients presenting with unexplained developmental delay and/or dystonia. The potential inclusion of rT3 measurement in newborn screening may prove promising.

Current and Future Perspectives on Microfluidic Tear Analytic Devices.

Most current invasive analytic devices for disease diagnosis and monitoring require the collection of blood, which causes great discomfort for patients and may potentially cause infection. This explains the great need for noninvasive devices that utilize other bodily fluids like sweat, saliva, tears, or urine. Among them, eye tears are easily accessible, less complex in composition, and less susceptible to dilution. Tears also contain valuable clinical information for the diagnosis of ocular and systemic diseases as the tear analyte level shows great correlation with the blood analyte level. These unique advantages make tears a promising platform for use in clinical settings. As the volume of tear film and the rate of tear flow are only microliters in size, the use of microfluidic technology in analytic devices allows minimal sample consumption. Hence, more and more microfluidic tear analytic devices have been proposed, and their working mechanisms can be broadly categorized into four main types: (a) electrochemical, (b) photonic crystals, (c) fluorescence, and (d) colorimetry. These devices are being developed toward the application of point-of-care tests with rapid yet accurate results. This review aims to provide a general overview of the recent developmental trend of microfluidic devices for tear analysis. Moreover, the fundamental principle behind each type of device along with their strengths and weaknesses will be discussed, especially in terms of their abilities and potential in being used in point-of-care settings.

Virtual reality and augmented reality- emerging screening and diagnostic techniques in ophthalmology: A systematic review.

In health care, virtual reality (VR) and augmented reality (AR) have been applied extensively for many purposes. Similar to other technologies such as telemedicine and artificial intelligence, VR and AR may improve clinical diagnosis and screening services in ophthalmology by alleviating current problems, including workforce shortage, diagnostic error, and underdiagnosis. In the past decade a number of studies and products have used VR and AR concepts to build clinical tests for ophthalmology, but comprehensive reviews on these studies are limited. Therefore, we conducted a systematic review on the use of VR and AR as a diagnostic and screening tool in ophthalmology. We identified 26 studies that implemented a variety of VR and AR tests on different conditions, including VR cover tests for binocular vision disorder, VR perimetry for glaucoma, and AR slit lamp biomicroscopy for retinal diseases. In general, while VR and AR tools can become standardized, automated, and cost-effective tests with good user experience, several weaknesses, including unsatisfactory accuracy, weak validation, and hardware limitations, have prevented these VR and AR tools from having wider clinical application. Also, a comparison between VR and AR is made to explain why studies have predominantly used VR rather than AR.

Treatment of large, chronic and persistent macular hole with internal limiting membrane transposition and tuck technique.

BACKGROUND: Large, chronic full thickness macular holes which failed previous treatments are difficult to manage and even left untreated due to poor prognosis. A retrospective review of consecutive cases with chronic (at least 1 year) full thickness macular holes and internal limiting membrane (ILM) free flap transposition with tuck technique, after previously failed vitrectomy. METHODS: This was a retrospective and interventional study conducted in a single centre by a single surgeon. Patients with full thickness macular hole for at least 1 year and at least one previously failed vitrectomy with ILM peeling were recruited. A 25G vitrectomy with ILM free flap transposition was done without assistance of PFCL, viscoelastic or autologous blood. The free flap was manually tucked into the macular hole free space and gas fluid exchange was performed with 20% SF6 as tamponade. The patients were postured prone for 2 weeks postoperatively. Best corrected visual acuity, macular hole duration, previous surgeries, optical coherence tomography (OCT) appearance, hole size and closure rate were recorded. RESULTS: 8 consecutive patients were included from May 2016 to Feb 2018. Transposition surgery was performed an average of 1481 days (SD 1096) after diagnosis of macular hole and average of 1226 days (SD 1242) after first vitrectomy. Macular hole mean size was 821 µm (SD 361.3), preoperative VA was logMAR 1.038 (SD 0.19), postoperative VA was logMAR 0.69 (SD 0.19) at 3 months. There were 1.13 lines gained and a significant improvement of logMAR 0.33 (p = 0.0084) at 6 months. Hole closure was seen in 7 out of 8 eyes (87.5%). The OCT with failed closure showed ILM flap within a flat hole, however no overlying neurosensory layers was seen. The duration from diagnosis to surgery was 2349 days in this case. CONCLUSION: Free flap ILM transposition tuck without the use of additional intraoperative tamponade is an effective technique in treating large chronic macular holes with previously failed primary macular hole surgeries.Trial registration (IRB of the Hong Kong University and Hospital Authority Hong Kong West Cluster, ref UW19-440), June 17, 2019.

Fatty corner lesions in T1-weighted magnetic resonance imaging as an alternative to sacroiliitis for diagnosis of axial spondyloarthritis.

BACKGROUND: A fatty corner lesion (FCL) is a well-demarcated fat infiltration in the corner of a vertebral body on T1 magnetic resonance imaging (MRI) sequence. It has been reported to be useful in the diagnosis of axial spondyloarthritis (axSpA). Our objective is to systematically evaluate the diagnostic accuracy of FCLs in tertiary centre patients with chronic back pain. METHOD: Two hundred and thirty eight axSpA patients and 62 non-axSpA patients with back pain were recruited from five rheumatology centres. Clinical, biochemical, and radiological parameters were collected and all patients underwent a MRI of the spine and sacroiliac (SI) joints. FCLs in vertebral bodies from C4 to L5 were scored. The number and location of FCLs were clustered together to determine an optimal combination for diagnosis. Results were compared with expert diagnosis as the "gold standard". RESULTS: FCLs of the anterior whole spine (AUC 0.62; p = 0.003) and anterior thoracic spine (AUC 0.64; p = 0.001) had diagnostic significance. Incorporating at least 5 whole spine FCLs into the imaging criteria of the Assessment of SpondyloArthritis international Society (ASAS) criteria for axSpA yielded a sensitivity of 91.6% and specificity of 91.9%. Similarly, applying at least 3 anterior thoracic FCLs to the imaging criteria of the ASAS axial SpA criteria yielded a sensitivity of 92.0% and specificity of 93.5%. CONCLUSION: FCLs could be used to diagnose axial SpA. The presence of at least 3 anterior thoracic FCLs in T1-weighted MRI spine suggests a diagnosis of axial SpA without additional MRI of the SI joints. TRIAL REGISTRATION: The cohort has been registered in the clinical trial registry of the University of Hong Kong (HKUCTR-2087).

Cholangiopathies - Towards a molecular understanding.

Liver diseases constitute an important medical problem, and a number of these diseases, termed cholangiopathies, affect the biliary system of the liver. In this review, we describe the current understanding of the causes of cholangiopathies, which can be genetic, viral or environmental, and the few treatment options that are currently available beyond liver transplantation. We then discuss recent rapid progress in a number of areas relevant for decoding the disease mechanisms for cholangiopathies. This includes novel data from analysis of transgenic mouse models and organoid systems, and we outline how this information can be used for disease modeling and potential development of novel therapy concepts. We also describe recent advances in genomic and transcriptomic analyses and the importance of such studies for improving diagnosis and determining whether certain cholangiopathies should be viewed as distinct or overlapping disease entities.