Automatic Diagnosis of Pathological Myopia from Heterogeneous Biomedical Data

10.1371/journal.pone.0065736PLoS ONE86

Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial

Background: Hereditary transthyretin (ATTRm) amyloidosis is a rare, progressive and fatal disease with a range of clinical manifestations.Objective: This study comprehensively evaluates disease characteristics in a large, diverse cohort of patients with ATTRm amyloidosis.Methods: Adult patients (N = 172) with Stage 1 or Stage 2 ATTRm amyloidosis who had polyneuropathy were screened and enrolled across 24 investigative sites and 10 countries in the NEURO-TTR trial (www.clinicaltrials.gov, NCT01737398). Medical and disease history, quality of life, laboratory data, and clinical assessments were analyzed.Results: The NEURO-TTR patient population was diverse in age, disease severity, TTR mutation, and organ involvement. Twenty-seven different TTR mutations were present, with Val30Met being the most common (52%). One third of patients reported early onset disease (before age 50) and the average duration of neuropathy symptoms was 5.3 years. Symptoms affected multiple organs and systems, with nearly 70% of patients exhibiting broad involvement of weakness, sensory loss, and autonomic disturbance. Over 60% of patients had cardiomyopathy, with highest prevalence in the United States (72%) and lowest in South America/Australasia (33%). Cardiac biomarker NT-proBNP correlated with left ventricular wall thickness (p<.001). Quality of life, measured by Norfolk QoL-DN and SF-36 patient-reported questionnaires, was significantly impaired and correlated with disease severity.Conclusions: Baseline data from the NEURO-TTR trial demonstrates ATTRm amyloidosis as a systemic disease with deficits in multiple organs and body systems, leading to decreased quality of life. We report concomitant presentation of polyneuropathy and cardiomyopathy in most patients, and early involvement of multiple body systems

An exploration of patient-reported symptoms in systemic lupus erythematosus and the relationship to health-related quality of life

Objective: The aim of this study was to explore the most distressing symptoms of systemic lupus erythematosus (SLE) and determine how these relate to health-related quality of life (HRQoL), anxiety/depression, patient demographics and disease characteristics (duration, activity, organ damage). Methods: In a cross-sectional study, patients with SLE (n=324, age 18-84 years) gave written responses regarding which SLE-related symptoms they experienced as most difficult. Their responses were categorized. Within each category, patients reporting a specific symptom were compared with non-reporters and analyzed for patient demographics, disease duration, results from the questionnaires: Medical Outcomes Study Short-Form 36, Hospital Anxiety and Depression Scale, Systemic Lupus Activity Measure, SLE disease activity index and the Systemic Lupus International Collaboration Clinics/American College of Rheumatology damage index. Results: 23 symptom categories were identified. Fatigue (51%), Pain (50%) and Musculoskeletal distress (46%) were most frequently reported. Compared with non-reporters, only patients reporting Fatigue showed statistically significant impact on both mental and physical components of HRQoL.. Patients with no present symptoms (10%) had higher HRQoL (p<0.001) and lower levels of depression (p<0.001), anxiety (p<0.01) and disease activity (SLAM) (p<0.001). Conclusion: Fatigue, pain or musculoskeletal distress dominated the reported symptoms in approximately half of the patients. Only patients reporting Fatigue scored lower on both mental and physical aspects of HRQoL. Our results emphasize the need for further support and interventions to ease the symptom load and improve HRQoL in patients with SLE. Our findings further indicate that this need is particularly urgent for patients with symptoms of pain or fatigue

A systematic review of the relationship between subchondral bone features, pain and structural pathology in peripheral joint osteoarthritis

Introduction: Bone is an integral part of the osteoarthritis (OA) process. We conducted a systematic literature review in order to understand the relationship between non-conventional radiographic imaging of subchondral bone, pain, structural pathology and joint replacement in peripheral joint OA. Methods: A search of the Medline, EMBASE and Cochrane library databases was performed for original articles reporting association between non-conventional radiographic imaging-assessed subchondral bone pathologies and joint replacement, pain or structural progression in knee, hip, hand, ankle and foot OA. Each association was qualitatively characterised by a synthesis of the data from each analysis based upon study design, adequacy of covariate adjustment and quality scoring. Results: In total 2456 abstracts were screened and 139 papers were included (70 cross-sectional, 71 longitudinal analyses; 116 knee, 15 hip, six hand, two ankle and involved 113 MRI, eight DXA, four CT, eight scintigraphic and eight 2D shape analyses). BMLs, osteophytes and bone shape were independently associated with structural progression or joint replacement. BMLs and bone shape were independently associated with longitudinal change in pain and incident frequent knee pain respectively. Conclusion: Subchondral bone features have independent associations with structural progression, pain and joint replacement in peripheral OA in the hip and hand but especially in the knee. For peripheral OA sites other than the knee, there are fewer associations and independent associations of bone pathologies with these important OA outcomes which may reflect fewer studies; for example the foot and ankle were poorly studied. Subchondral OA bone appears to be a relevant therapeutic target. Systematic review: PROSPERO registration number: CRD 4201300500

Social & psychological factors associated with oral analgesic use in knee osteoarthritis management

Objective: Determine modifiable social and psychological health factors that are associated with use of oral opioid and non-opioid medications for OA. Methods: Patients were categorized based on use of the following oral medications: opioids (with/without other oral analgesic treatments), non-opioid analgesics, and no oral analgesic treatment. We used multinomial logistic regression models to estimate adjusted relative risk ratios (RRRs) of using an opioid or a non-opioid analgesic (vs. no oral analgesic treatment), comparing patients by levels of social support (Medical Outcomes Study scale), health literacy ("How confident are you filling out medical forms by yourself?"), and depressive symptoms (Patient Health Questionnaire-8). Models were adjusted for demographic and clinical characteristics. Results: In this sample (mean age 64.2 years, 23.6% women), 30.6% (n = 110) reported taking opioid analgesics for OA, 54.2% (n = 195) reported non-opioid use, and 15.3% (n = 55) reported no oral analgesic use. Opioid users had lower mean social support scores (10.0 vs 10.5 vs 11.9, P = 0.007) and were more likely to have moderate-severe depressive symptoms (42.7% vs 24.1% vs 14.5%, P < 0.001). Health literacy did not differ by treatment group type. Having moderate-severe depression was associated with higher risk of opioid analgesic use compared to no oral analgesic use (RRR 2.96, 95% CI 1.08-8.07) when adjusted for sociodemographic and clinical factors. Neither social support nor health literacy was associated with opioid or non-opioid oral analgesic use in fully adjusted models. Conclusions: Knee OA patients with more severe depression symptoms, compared to those without, were more likely to report using opioid analgesics for OA. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.Veterans Health Administration Health Services Research and Development Service [IIR13-080]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [K23AR067226]; NIAMS [K24AR055259]12 month embargo; available online 1 February 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Gene, Environment and Methylation (GEM): a tool suite to efficiently navigate large scale epigenome wide association studies and integrate genotype and interaction between genotype and environment

BACKGROUND: The interplay among genetic, environment and epigenetic variation is not fully understood. Advances in high-throughput genotyping methods, high-density DNA methylation detection and well-characterized sample collections, enable epigenetic association studies at the genomic and population levels (EWAS). The field has extended to interrogate the interaction of environmental and genetic (GxE) influences on epigenetic variation. Also, the detection of methylation quantitative trait loci (methQTLs) and their association with health status has enhanced our knowledge of epigenetic mechanisms in disease trajectory. However analysis of this type of data brings computational challenges and there are few practical solutions to enable large scale studies in standard computational environments. RESULTS: GEM is a highly efficient R tool suite for performing epigenome wide association studies (EWAS). GEM provides three major functions named GEM_Emodel, GEM_Gmodel and GEM_GxEmodel to study the interplay of Gene, Environment and Methylation (GEM). Within GEM, the pre-existing “Matrix eQTL” package is utilized and extended to study methylation quantitative trait loci (methQTL) and the interaction of genotype and environment (GxE) to determine DNA methylation variation, using matrix based iterative correlation and memory-efficient data analysis. Benchmarking presented here on a publicly available dataset, demonstrated that GEM can facilitate reliable genome-wide methQTL and GxE analysis on a standard laptop computer within minutes. CONCLUSIONS: The GEM package facilitates efficient EWAS study in large cohorts. It is written in R code and can be freely downloaded from Bioconductor at https://www.bioconductor.org/packages/GEM/

Prevalence of MRI-detected mediopatellar plica in subjects with knee pain and the association with MRI-detected patellofemoral cartilage damage and bone marrow lesions: Data from the Joints on Glucosamine study

Background: The mediopatellar plica is a synovial fold representing an embryonic remnant from the developmental process of the synovial cavity formation in the knee. We aimed to examine the frequency of MRI-detected mediopatellar plica and its cross-sectional association with MRI-detected cartilage damage and bone marrow lesions (BMLs) in the patellofemoral joint (PFJ) in a cohort of subjects with knee pain. Methods. 342 knees with chronic frequent knee pain were evaluated for MRI-detected mediopatellar plica (type A, B or C according to the modified Sakakibara classification). Cartilage damage (scored 0 to 6) and BMLs (scored 0 to 3) were semiquantitatively assessed in four subregions of the PFJ on MRI. Hoffa-synovitis and effusion-synovitis were graded 0 to 3. Patellar length ratio (PLR), lateral patellar tilt angle (LPTA), bisect offset (BO), and sulcus angle (SA) were measured on MRI. The presence of mediopatellar plica and its association with cartilage damage and BMLs in the PFJ was assessed using logistic regression after adjusting for age, gender, body mass index, PLR, LPTA, BO, SA, and Hoffa- and effusion-synovitis. Results: 163 (47.7%) knees exhibited mediopatellar plica (76 (22.2%) type A, 69 (20.2%) type B, and 18 (5.3%) type C) on MRI. Significant cross-sectional associations of MRI-detected mediopatellar plica and cartilage damage were observed for the medial patella (adjusted odds ratio (aOR) 2.12, 95% CI 1.23-3.64 for all types combined, and aOR 4.20, 95% CI 1.92-9.19 for type B lesion), but not for the anterior medial femur or the lateral PFJ. No associations were found between the presence of MRI-detected mediopatellar plica and BMLs in any patellofemoral subregion. Conclusion: On MRI, types A and B mediopatellar plicae were commonly observed in this cohort of subjects with knee pain. MRI-detected mediopatellar plica was cross-sectionally associated with higher likelihood of the presence of MRI-detected medial patellar cartilage damage after adjustment for confounders. © 2013 Hayashi et al.; licensee BioMed Central Ltd

Long-Term Efficacy and Safety of Inotersen for Hereditary Transthyretin Amyloidosis: NEURO-TTR Open-Label Extension 2-Year Update (S27.008)

Objective: To provide an update on the long-term efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of transthyretin protein production, in patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy. Background: Patients with hATTR, a rare protein misfolding disorder, experience progressive and debilitating polyneuropathy. A randomized, controlled phase 3 trial (NEURO-TTR; NCT01737398) demonstrated efficacy and safety of inotersen treatment in patients with hATTR polyneuropathy (Benson 2018 NEJM). Design/Methods: Patients who completed NEURO-TTR were eligible to enroll in the ongoing open-label extension (OLE) study (NCT02175004). Assessments included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7), Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN), and adverse events. Results: Of 139 patients who completed NEURO-TTR, 135 (97.1%) enrolled in the OLE. As of 9/15/17, 134 patients had received ≥1 dose of inotersen. Patients were predominantly white (93.3%) and male (69.4%), and 88/134 (65.7%) had both polyneuropathy and cardiac involvement. At OLE baseline, 83/134 (61.9%) patients were ambulatory without assistance, 47/134 (35.1%) required walking aid(s), and 4/134 (3.0%) were unable to walk. Patients who initiated inotersen in the OLE demonstrated slowing of neurologic disease progression by mNIS+7 and Norfolk QoL-DN within 6 months, and patients who had received inotersen for 27 months (15 months in NEURO-TTR + 12 months in the OLE) continued to show benefit. Greater benefit in mNIS+7 and Norfolk QoL-DN was observed in patients treated earlier with inotersen. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure, and no new safety concerns have been identified. This presentation will be updated with data from 2 years of follow-up in the OLE. Conclusions: In the OLE, inotersen treatment slowed hATTR polyneuropathy progression, with greater stabilization observed in patients who initiated inotersen earlier. Disclosure: Dr. Brannagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols, Ionis, Alnylam, and CSL Behring. Dr. Brannagan has received research support from Ionis, Alnyalm, Viromed, Catalyst, Pharnext, Novartis, Grifols. Dr. Waddington Cruz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc., Genzyme/Sanofi, and Pfizer. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. Dr. Polydefkis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis, Alnylam, Vertex, Chromocell. Dr. Polydefkis has received compensation for serving on the Board of Directors of Travel-Ionis and Pfizer. Dr. Polydefkis has received research support from Pfizer, Ionis, and Alnylam . Dr. Dyck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam and Ionis. Dr. Khella has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics and Alnylam Pharmaceuticals. Dr. Khella has received research support from Akcea Therapeutics. Dr. Plante-Bordeneuve has nothing to disclose. Dr. Berk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea, Alnylam. Dr. Barroso has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Barroso has received research support from Alnylam. Dr. Merlini has nothing to disclose. Dr. Conceicao has nothing to disclose. Dr. Hughes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals Inc. Dr. Kwoh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Jung, PhD has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Guthrie has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Pollock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Benson has nothing to disclose. Dr. Gertz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc., Alnylam Pharmaceuticals, and Prothena. Dr. Coelho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam and Biogen. Dr. Coelho has received research support from Pfizer, Ionis and Alnylam.Fil: Brannagan, Thomas. Columbia University Medical Center; Estados Unidos.Fil: Waddington Cruz, Marcia. Federal University of Rio de Janeiro; Brasil. University Hospital Rio de Janeiro; Brasil.Fil: Wang, Annabel K. University of California; Estados Unidos.Fil: Polydefkis, Michael J. Johns Hopkins University; Estados Unidos.Fil: Dyck, Peter J. Mayo Clinic; Estados Unidos.Fil: Khella, Sami. University of Pennsylvania; Estados Unidos.Fil: Plante-Bordeneuve, Violaine. CHU Henri Mondor Creteil; Francia.Fil: Berk, John L. Boston University Boston; Estados Unidos.Fil: Barroso, Fabio Adrián. Fleni. Departamento de Neurología. Sección de Enfermedades Neuromusculares; Argentina.Fil: Merlini, Giampaolo. Amyloidosis Center, IRCCS Policlinico San Matteo; Italia. University of Pavia Pavia; Italia.Fil: Conceição, Isabel. CHLN Hospital de Santa Maria Lisbon; Portugal.Fil: Hughes, Steven G. Ionis Pharmaceuticals Inc; Estados Unidos.Fil: Kwoh, Jesse. Akcea Therapeutics; Estados Unidos.Fil: Jung, Shiangtung. Indiana University School of Medicine; Estados Unidos.Fil: Guthrie, Spencer. Akcea Therapeutics; Estados Unidos.Fil: Pollock, Michael. Akcea Therapeutics; Estados Unidos.Fil: Benson, Merrill D. Indiana University School of Medicine; Estados Unidos.Fil: Gertz, Morie. Mayo Clinic; Estados Unidos.Fil: Coelho, Teresa. Centro Hospitalar do Porto Porto; Portugal