Duration Of Untreated Disease Research Articles

Deep learning-based quantification of osteonecrosis using magnetic resonance images in Gaucher disease

Gaucher disease is one of the most common lysosomal storage disorders. Osteonecrosis is a principal clinical manifestation of Gaucher disease and often leads to joint collapse and fractures. T1-weighted (T1w) modality in MRI is widely used to monitor bone involvement in Gaucher disease and to diagnose osteonecrosis. However, objective and quantitative methods for characterizing osteonecrosis are still limited. In this work, we present a deep learning-based quantification approach for the segmentation of osteonecrosis and the extraction of characteristic parameters. We first constructed two independent U-net models to segment the osteonecrosis and bone marrow unaffected by osteonecrosis (UBM) in spine and femur respectively, based on T1w images from patients in the UK national Gaucherite study database. We manually delineated parcellation maps including osteonecrosis and UBM from 364 T1w images (176 for spine, 188 for femur) as the training datasets, and the trained models were subsequently applied to all the 917 T1w images in the database. To quantify the segmentation, we calculated morphological parameters including the volume of osteonecrosis, the volume of UBM, and the fraction of total marrow occupied by osteonecrosis. Then, we examined the correlation between calculated features and the bone marrow burden score for marrow infiltration of the corresponding image, and no strong correlation was found. In addition, we analyzed the influence of splenectomy and the interval between the age at first symptom and the age of onset of treatment on the quantitative measurements of osteonecrosis. The results are consistent with previous studies, showing that prior splenectomy is closely associated with the fractional volume of osteonecrosis, and there is a positive relationship between the duration of untreated disease and the quantifications of osteonecrosis. We propose this technique as an efficient and reliable tool for assessing the extent of osteonecrosis in MR images of patients and improving prediction of clinically important adverse events.

B Cell Lymphocytosis in Juvenile Dermatomyositis.

In this study, we determined if B lymphocytosis may serve as a JDM biomarker for disease activity. Children with untreated JDM were divided into two groups based on age-adjusted B cell percentage (determined through flow cytometry): 90 JDM in the normal B cell group and 45 in the high B cell group. We compared through T-testing the age, sex, ethnicity, duration of untreated disease (DUD), disease activity scores for skin (sDAS), muscle (mDAS), total (tDAS), CMAS, and neopterin between these two groups. The patients in the high B cell group had a higher tDAS (p = 0.009), mDAS (p = 0.021), and neopterin (p = 0.0365). Secondary analyses included B cell values over time and BAFF levels in matched patients with JM (juvenile myositis) and concurrent interstitial lung disease (ILD); JM alone and healthy controls Patient B cell percentage and number was significantly higher after 3-6 months of therapy and then significantly lower on completion of therapy (p =< 0.0001). The JM groups had higher BAFF levels than controls 1304 vs. 692 ng/mL (p = 0.0124). This study supports B cell lymphocytosis as a JDM disease-activity biomarker and bolsters the basis for B cell-directed therapies in JDM.

Clues to Disease Activity in Juvenile Dermatomyositis: Neopterin and Other Biomarkers.

Easily accessible biomarkers are urgently needed to evaluate immune activation in Juvenile Dermatomyositis (JDM). The goal of this retrospective study is to define immunological and clinical differences between untreated JDM patients with either normal or elevated (>10 mmol/L) levels of neopterin, a biomarker of macrophage activation. We included all JDM with neopterin data obtained before initiating medical therapy. We assessed T, B, NK cell populations, muscle enzymes, and disease activity scores for skin (sDAS), muscle (mDAS), total (tDAS), the duration of untreated disease, disease course, and myositis-specific antibody (MSA). Seventy-nine percent of 139 untreated JDM patients had elevated serum neopterin. The group with elevated neopterin had significantly more active disease: tDAS 11.9 vs. 8.1 (p < 0.0001), mDAS 5.8 vs. 3.1 (p < 0.0001), sDAS 6.1 vs. 4.9 (p = 0.0002), aldolase 24.0 vs. 7.6 U/L (p < 0.0001), von Willebrand factor antigen (p < 0.0001), and ESR 19.8 vs. 11.5 mm/hr (p = 0.01). The flow cytometry documented both reduced T cells (1494 vs. 2278/mm3, p = 0.008) and NK cells (145 vs. 240/mm3, p = 0.003). TNFα-308AA/AG polymorphism was more common in children with elevated neopterin than TNFα-308GG (p 0.05). We conclude that the availability of neopterin data will contribute to the rapid assessment of untreated JDM disease activity.

Epidemiology and Natural History of Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) has emerged over the past 2decades as a major cause of upper gastrointestinal morbidity. Over this time, the epidemiology of EoE has also rapidly evolved. EoE has transformed from a rare case-reportable condition to disease that is commonly encountered in the gastroenterology clinic, hospital emergency room, and endoscopy suite. The incidence and prevalence are increasing at rates that outpace increased disease recognition. Current incidence estimates range from 5 to 10 cases per 100,000, and current prevalence estimates range from 0.5 to 1 case per 1000. We review the data and potential reasons behind this increase, examine risk factors, and identify important areas for research into disease etiology. The article also discusses the progression of EoE from an inflammatory to fibrostenotic phenotype. An accurate view of the natural history of EoE is central to discussions with patients regarding disease prognosis anddecisions about long-term use of medical, endoscopic, and diet therapies. Progressive remodelling appears to begradual, but not universal, and the duration of untreated disease is the best predictor of stricture risk. Ultimately, prospective, long-term outcome studies focusing on multiple aspects of disease activity are needed to fully understand the natural history of EoE.

Endothelial progenitor cell number is not decreased in 34 children with Juvenile Dermatomyositis: a pilot study

ObjectiveA pilot study to determine endothelial progenitor cells (EPC) number in children with Juvenile Dermatomyositis (JDM).MethodsAfter obtaining informed consent, the EPC number from 34 fasting children with definite/probable JDM at various stages of therapy—initially untreated, active disease on medication and clinically inactive, off medication—was compared with 13 healthy fasting pediatric controls. The EPC number was determined by fluorescence activated cell sorting (FACS), CD34+/VEGFR2+/CD45dim−, and assessed in conjunction with clinical variables: disease activity scores (DAS), duration of untreated disease (DUD), TNF-α allelic polymorphism (A/G) at the promoter region of −308, number of nailfold capillary end row loop (ERL) and von Willebrand factor antigen (vWF:Ag). Correlations of the EPC numbers with the clinical and demographic variables, including DAS Skin (DAS SK), DAS Weakness (DAS WK), DAS Total Score, DUD, Cholesterol, triglycerides, High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL), and ERL were calculated using the Pearson correlation coefficient. Tests of associations of EPC with gender (boy vs girl), TNF-α-308A allele (GA/AA vs GG), vWF:Ag (categorized by specific ABO type) as normal/abnormal were performed, using two-sample T- tests.ResultsThe EPC number for JDM was not significantly different from the healthy controls and was not associated with any of the clinical or cardiovascular risk factors tested.ConclusionThe EPC for JDM were in the normal range, similar to adults with DM. These data support the concept that the normal EPC numbers in DM/JDM, irrespective of age, differs from adult PM, where they are decreased, perhaps reflecting a different pathophysiology.

MicroRNA-10a Regulation of Proinflammatory Mediators: An Important Component of Untreated Juvenile Dermatomyositis.

To identify differentially expressed microRNA (miRNA) in muscle biopsies (MBx) from 15 untreated children with juvenile dermatomyositis (JDM) compared with 5 controls. Following MBx miRNA profiling, differentially expressed miRNA and their protein targets were validated by quantitative real-time PCR (qRT-PCR) and immunological assay. The association of miRNA-10a and miRNA-10b with clinical data was evaluated, including Disease Activity Score (DAS), von Willebrand factor antigen (vWF:Ag), nailfold capillary end row loops, duration of untreated disease, and tumor necrosis factor (TNF)-α-308A allele. In JDM, 16/362 miRNA were significantly differentially expressed [false discovery rate (FDR) < 0.05]. Among these, miRNA-10a was the most downregulated miRNA in both FDR and ranking of fold change: miRNA-10a = -2.27-fold, miRNA-10b = -1.80-fold. Decreased miRNA-10a and miRNA-10b expressions were confirmed using q -4.16 and -2.59 fold, respectively. The qRT-PCR documented that decreased miRNA-10a expression was related to increased vascular cell adhesion molecule 1 in 13 of these JDM cases (correlation -0.67, p = 0.012), unlike miRNA-10b data (not significant). Concurrent JDM plasma contained increased levels of interleukin (IL) 6 (p = 0.0363), IL-8 (p = 0.0005), TNF-α (p = 0.0011), and monocyte chemoattractant proteins 1 (p = 0.0139). Decreased miRNA-10a, but not miRNA-10b, was associated with the TNF-α-308A allele (p = 0.015). In the 15 JDM, a trend of association of miRNA-10a (but not miRNA-10b) with vWF:Ag and DAS was observed. MiRNA-10a downregulation is an important element in untreated JDM muscle pathophysiology. We speculate that muscle miRNA expression in adult dermatomyositis differs from muscle miRNA expression in untreated childhood JDM.

Abstract 505: Young Adults With Juvenile Dermatomyositis Have Endothelial Dysfunction: Studies of Brachial Artery Reactivity and Oxidized Lipids

Objective: Older patients with Juvenile Dermatomyositis (JDM) have increased carotid wall thickness and decreased nailfold capillary end row loops (ERL). This study tested young adults with JDM and decreased ERL for brachial artery reactivity (BAR) and HDL antioxidant function. Methods: 20 adults, 14 F, mean age 21.8± 4.2 yrs; mean age at JDM onset 7.6 ± 3.7 years, mean duration of untreated disease (DUD) at diagnosis 5.4 ± 4.8 months, and mean total duration of disease 14.2 ±3.9 years. JDM adults had a mean Total Disease Activity Score (DAS) 1.9 ± 2.5 and were medication free. They were matched by age, race, sex and BMI with 20 healthy controls (mean age 23.8 ± 4.2 years). All subjects were tested for: BAR, ERL number, height and weight. The antioxidant function of HDL was evaluated by the change in fluorescence intensity caused by oxidation of dichlorfluorescein-diacetate by oxidized LDL ±HDL was measured (mean HDL function in healthy controls ranges from 0.44 - 0.66).For BAR, individuals were fasting and rested supine for 10 minutes before ultrasound imaging. Brachial artery diameter was measured at rest and one minute after 4.5 minutes of supra-systolic forearm occlusion. BAR was expressed as the percent diameter change from baseline in response to increased sheer stress [(post-deflation - baseline diameter)/baseline diameter] x100. Results: The # of ERL were significantly lower in the JDM group, 6.35 ± 1.29 vs the controls, 7.4±0.58, p=0.003. The TNF-α -308A allele in the JDM group was 40% vs. 15% in controls. JDM were shorter than their controls, for JDM women, 159.7 ±8.8cm vs. 165.6 ±5.4cm, p=0.048, and for JDM men, 172.7±3.6cm compared to controls, 181.5 ±4.6cm, p=0.0046, perhaps a consequence of steroid administration. BAR in JDM was 3.35±3.06%, and 5.22±3.07% in normal controls (p=0.068). After adjusting for height, age, sex, and BA diameter, the BAR in JDM adults was significantly lower than controls by 2.31% (p=0.04). There were no associations of BAR with ERL, DUD, or DAS or oxidized lipids. Conclusion: BAR is decreased in young adults off medication for JDM, indicating endothelial cell dysfunction. Larger studies in young adults with JDM are needed to validate this finding

Altered Cortical Thickness Related to Clinical Severity But Not the Untreated Disease Duration in Schizophrenia

Although previous studies have reported deficits in the gray matter volume of schizophrenic patients, it remains unclear whether these deficits occur at the onset of the disease, before treatment, and whether they are progressive over the duration of untreated disease. Furthermore, the gray matter volume represents the combinations of cortical thickness and surface area; these features are believed to be influenced by different genetic factors. However, cortical thickness and surface area in antipsychotic-naive first-episode schizophrenic patients have seldom been investigated. Here, the cortical thicknesses and surface areas of 128 antipsychotic-naive first-episode schizophrenic patients were compared with 128 healthy controls. The patients exhibited significantly lower cortical thickness, primarily in the bilateral prefrontal and parietal cortex, and increased thickness in the bilateral anterior temporal lobes, left medial orbitofrontal cortex, and left cuneus. Furthermore, decreased cortical thickness was related to positive schizophrenia symptoms but not to the severity of negative symptoms and the untreated disease duration. No significant difference of surface area was observed between the 2 groups. Thus, without the confounding factors of medication and illness progression, this study provides further evidence to support anatomical deficits in the prefrontal and parietal cortex early in course of the illness. The increased thicknesses of the bilateral anterior temporal lobes may represent a compensatory factor or may be an early-course neuronal pathology caused by preapoptotic osmotic changes or hypertrophy. Furthermore, these anatomical deficits are crucial to the pathogenesis of positive symptoms and relatively stable instead of progressing during the early stages of the disease.

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Delay in Diagnosis of Eosinophilic Esophagitis Increases Risk for Stricture Formation in a Time-Dependent Manner

Development of strictures is a major concern for patients with eosinophilic esophagitis (EoE). At diagnosis, EoE can present with an inflammatory phenotype (characterized by whitish exudates, furrows, and edema), a stricturing phenotype (characterized by rings and stenosis), or a combination of these. Little is known about progression of stricture formation; we evaluated stricture development over time in the absence of treatment and investigated risk factors for stricture formation. We performed a retrospective study using the Swiss EoE Database, collecting data on 200 patients with symptomatic EoE (153 men; mean age at diagnosis, 39 ± 15 years old). Stricture severity was graded based on the degree of difficulty associated with passing of the standard adult endoscope. The median delay in diagnosis of EoE was 6 years (interquartile range, 2-12 years). With increasing duration of delay in diagnosis, the prevalence of fibrotic features of EoE, based on endoscopy, increased from 46.5% (diagnostic delay, 0-2 years) to 87.5% (diagnostic delay, >20 years; P = .020). Similarly, the prevalence of esophageal strictures increased with duration of diagnostic delay, from 17.2% (diagnostic delay, 0-2 years) to 70.8% (diagnostic delay, >20 years; P < .001). Diagnostic delay was the only risk factor for strictures at the time of EoE diagnosis (odds ratio = 1.08; 95% confidence interval: 1.040-1.122; P < .001). The prevalence of esophageal strictures correlates with the duration of untreated disease. These findings indicate the need to minimize delay in diagnosis of EoE.

Persistent Association of Nailfold Capillaroscopy Changes and Skin Involvement Over Thirty-Six Months With Duration of Untreated Disease in Patients With Juvenile Dermatomyositis

Persistent Association of Nailfold Capillaroscopy Changes and Skin Involvement Over Thirty-Six Months With Duration of Untreated Disease in Patients With Juvenile Dermatomyositis

The role of aggressive corticosteroid therapy in patients with juvenile dermatomyositis: a propensity score analysis.

To compare outcomes at 36 months in patients newly diagnosed with juvenile dermatomyositis (DM) treated with aggressive versus standard therapy. At diagnosis, 139 untreated juvenile DM patients were given aggressive therapy (intravenous methylprednisolone or oral prednisone 5-30 mg/kg/day; n = 76) or standard therapy (1-2 mg/kg/day; n = 63) by the treating physician. Aggressive therapy patients were more ill at diagnosis. Matching was based on the propensity for aggressive therapy because propensity scoring can reduce confounding by indication. Logistic regression of the matched data determined predictors of outcomes, controlling for clinical confounders and propensity score. Outcomes comprised Disease Activity Score (DAS) for skin and muscle, range of motion (ROM), and calcification. Sex, race, and age were similar between groups, and initial DAS weakness and ROM significantly predicted the therapy chosen. Based on propensity scores, 42 patients from each group were well matched. In the matched pairs, there were no significant differences in outcomes. Methotrexate use (odds ratio [OR] 3.6, 95% confidence interval [95% CI] 1.15-11.5) and duration of untreated disease (OR 1.2, 95% CI 1-1.38) were associated with ROM loss, hydroxychloroquine use (OR 11.2, 95% CI 3.7-33) and calcification (OR 6.8, 95% CI 1.8-25.4) with persistent rash, abnormal baseline lactate dehydrogenase (OR 11.2, 95% CI 1.4-92) and age at onset (OR 1.3, 95% CI 1-1.4) with weakness, and duration of untreated disease (OR 1.2, 95% CI 1-1.39) with calcification. Using a retrospective, nonrandomized design with propensity score matching, there was little difference in efficacy outcomes between aggressive and standard therapy; however, the sickest patients were treated with aggressive therapy and were not included in the matched analysis. Comprehensive clinical studies are needed to determine therapeutic pathways to the best outcome.

RANKL:Osteoprotegerin ratio and bone mineral density in children with untreated juvenile dermatomyositis

To determine bone mineral density (BMD) in patients at the time of diagnosis of juvenile dermatomyositis (DM), to compare the RANKL:osteoprotegerin (OPG) ratio in patients with juvenile DM with that in healthy control subjects, and to evaluate whether BMD is associated with the RANKL:OPG ratio and the duration of untreated disease. Thirty-seven children with juvenile DM were enrolled. Dual x-ray absorptiometry (DXA) was performed before treatment, and Z scores for the lumbar spine (L1-L4) were determined. The duration of untreated disease was defined as the period of time from the onset of rash or weakness to the time at which DXA was performed. Serum specimens obtained at the time of DXA were analyzed for concentrations of RANKL and OPG, using enzyme-linked immunosorbent assay. The RANKL:OPG ratio was also determined in 44 age-matched healthy control subjects. At the time of diagnosis of juvenile DM, patients had a significantly increased RANKL:OPG ratio compared with that in healthy children (mean +/- SD 2.19 +/- 3.03 and 0.13 +/- 0.17, respectively; P < 0.0001). In patients with a lumbar spine BMD Z score of -1.5 or lower, the RANKL:OPG ratio was significantly higher than that in patients with a lumbar spine BMD Z score higher than -1.5 (P = 0.038). Lumbar spine BMD Z scores (mean +/- SD -0.13 +/- 1.19 [range -2.10 to 2.85]) were inversely associated with the duration of untreated disease (R = -0.50, P = 0.003). Children with juvenile DM have an elevated RANKL:OPG ratio at the time of diagnosis, resulting in expansion of the number of osteoclasts and activation of the bone resorptive function. This may lead to a lack of normal bone mineral accretion and a subsequent reduction in the lumbar spine BMD Z score. Patients with a longer duration of untreated juvenile DM have reduced lumbar spine BMD Z scores. These data suggest that early diagnosis could reduce the likelihood of reduced lumbar spine BMD in these patients by prompting intervention strategies at an early stage.

Expression of TNFalpha by muscle fibers in biopsies from children with untreated juvenile dermatomyositis: association with the TNFalpha-308A allele.

Juvenile dermatomyositis (JDM) is the most common pediatric inflammatory myopathy. In patients with JDM, the A --> G polymorphism in the tumor necrosis factor alpha (TNFalpha)-308 promoter region (TNFalpha-308A) is associated with prolonged disease course and increased production of TNFalpha by peripheral blood mononuclear cells (Arthritis Rheum. 43, 2368-2377, 2000). Magnetic resonance imaging directed biopsies from 21 white children with untreated JDM were evaluated for TNFalpha expression. Using monoclonal antibody to TNFalpha, fresh frozen sections were processed by the standard immunohistochemical technique. We investigated the association among the expression of TNFalpha by muscle fibers, disease activity, duration of untreated disease, and the TNFalpha-308 polymorphism. Untreated children with JDM who had the TNFalpha-308A allele had an increased number of TNFalpha stained muscle fibers than children with the TNFalpha-308G allele (P = 0.001). There was no association with disease activity or duration of untreated disease. We speculate that muscle fiber production of TNFalpha provides a microenvironment in which TNFalpha acts synergistically with other mediators to prolong muscle fiber damage.

Time-Dependent Hazard Ratio: Modeling and Hypothesis Testing with Application in Lupus Nephritis

Abstract We investigate the association between duration of untreated disease and survival in lupus nephritis, a rare rheumatologic disease. In this case, as in many other studies of survival, a priori considerations suggest that the effect of the predictor on hazard may change with increasing follow-up time. To accommodate such situations, we use regression splines to model the hazard ratio as a flexible function of time. We propose model-based tests of the hypotheses of hazards proportionality and of no association. We evaluate the accuracy of estimation and inference in simulations and also present analysis of a larger medical data set.

Wilson's disease clinical correlation with cranial computed tomography

Cranial computed tomograms of 12 patients with proven Wilson's disease were correlated with clinical disturbances. CT abnormalities occurred only in the eight patients with neurological manifestations. The presence of atrophy and low density lesions of the basal ganglia shown on CT correlated well with clinical signs of extrapyramidal dysfunction. Cerebral atrophy and cerebellar cortical atrophy were only moderately related to the degree of intellectual dysfunction and ataxia, respectively; there were no specific clinical signs in cases with brainstem involvement. Abnormalities may be marked in scans taken within a year of neuropsychiatric symptoms, but the most severely abnormal CT scans occurred in patients with a relatively longer duration of untreated disease. Computed tomography provides the opportunity to follow the response of the abnormalities of the brain to cupruresis and can give some assistance in management.