Assess Disease Progression Research Articles

Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19

ObjectiveThis was a post hoc analysis of the Edaravone Phase III Study MCI186-19 (‘Study 19’) to examine the utility of clinical staging systems as end points in clinical trials in...

Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer's Disease.

Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging - Alzheimer's Association (NIA-AA) research framework. Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models. 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = -.58, p < .001). Word List Delayed Recall (β = -.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = -1.13, p < .001) and 4 (β = -2.23, p < .001). We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.

Tandem Mass Tag-Based Serum Proteome Profiling for Biomarker Discovery in Young Duchenne Muscular Dystrophy Boys.

Blood-accessible molecular biomarkers are becoming highly attractive tools to assess disease progression and response to therapies in Duchenne muscular dystrophy (DMD) especially in very young patients for whom other outcome measures remain subjective and challenging. In this study, we have standardized a highly specific and reproducible multiplexing mass spectrometry method using the tandem mass tag (TMT) strategy in combination with depletion of abundant proteins from serum and high-pH reversed-phase peptide fractionation. Differential proteome profiling of 4 year-old DMD boys (n = 9) and age-matched healthy controls (n = 9) identified 38 elevated and 50 decreased serum proteins (adjusted P < 0.05, FDR <0.05) in the DMD group relative to the healthy control group. As expected, we confirmed previously reported biomarkers but also identified novel biomarkers. These included novel muscle injury-associated biomarkers such as telethonin, smoothelin-like protein 1, cofilin-1, and plectin, additional muscle-specific enzymes such as UTP–glucose-1-phosphate uridylyltransferase, aspartate aminotransferase, pyruvate kinase PKM, lactotransferrin, tissue alpha-l-fucosidase, pantetheinase, and ficolin-1, and some pro-inflammatory and cell adhesion-associated biomarkers such as leukosialin, macrophage receptor MARCO, vitronectin, galectin-3-binding protein, and ProSAAS. The workflow including serum depletion, sample processing, and mass spectrometry analysis was found to be reproducible and stable over time with CV < 20%. Furthermore, the method was found to be superior in terms of specificity compared to other multiplexing affinity-based methods. These findings demonstrate the specificity and reliability of TMT-based mass spectrometry methods in detection and identification of serum biomarkers in presymptomatic young DMD patients.

SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes.

Diabetic kidney disease (DKD) is a topic of increasing concern among clinicians involved in the management of type 2 diabetes mellitus (T2DM). It is a progressive and costly complication associated with increased risk of adverse cardiovascular (CV) and renal outcomes and mortality. Ongoing monitoring of the estimated glomerular filtration (eGFR) rate alongside the urine albumin:creatinine ratio (ACR) is recommended during regular T2DM reviews to enable a prompt DKD diagnosis or to assess disease progression, providing an understanding of adverse risk for each individual. Many people with DKD will progress to end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT), typically haemodialysis or kidney transplantation. A range of lifestyle and pharmacological interventions is recommended to help lower CV risk, slow the advancement of DKD and prevent or delay the need for RRT. Emerging evidence concerning sodium-glucose co-transporter-2 inhibitor (SGLT2i) agents suggests a role for these medicines in slowing eGFR decline, enabling regression of albuminuria and reducing progression to ESKD. Improvements in renal end points observed in SGLT2i CV outcome trials (CVOTs) highlighted the possible impact of these agents in the management of DKD. Data from the canagliflozin CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) have since demonstrated the effectiveness of this medicine in reducing the risk of kidney failure and CV events in a population comprising individuals with T2DM and renal disease. CREDENCE was the first SGLT2i study to examine renal outcomes as the primary end point. Real-world studies have reaffirmed these outcomes in routine clinical practice. This article summarises the evidence regarding the use of SGLT2i medicines in slowing the progression of DKD and examines the possible mechanisms underpinning the renoprotective effects of these agents. The relevant national and international guidance for monitoring and treatment of DKD is also highlighted to help clinicians working to support this vulnerable group.Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00930-x) contains supplementary material, which is available to authorized users.

Cost-effectiveness analysis of polycystic ovary syndrome management and the risk of gestational diabetes in pregnant women: a decision-tree model

ABSTRACT Background This study estimated the cost-effectiveness of metformin to reduce the risk of gestational diabetes mellitus (GDM) in pregnant women with polycystic ovary syndrome (PCOS) from the US health-care payer perspective. Methods A decision tree was developed to simulate the progression of PCOS in a hypothetical cohort of 10,000 pregnant women diagnosed with PCOS and two scenarios were tested. Normal glucose regulation without developing GDM, average cost-effectiveness ratios (ACER), and the incremental cost-effectiveness ratios (ICERs) were the outcome measures assessed through pregnancy. Evidence from randomized clinical trials and other published literature were used to assess disease progression and its associated health-care costs. Sensitivity analyses that varied key model parameters were conducted. Results Management of PCOS with metformin was associated with lowest ACER ($669.78 per normal glucose regulation without GDM) as compared to ‘no intervention’ strategy. Metformin use is the most cost-effective strategy to manage PCOS during pregnancy with average cost savings of $7,593,372.97 and an average effect gain of 2271 of normal glucose regulation without GDM among pregnant women with PCOS. Sensitivity analyses determined that the results are robust. Conclusions Management of PCOS during pregnancy may be a cost-effective strategy to reduce GDM risk and its associated complications.

Utilidad De La Radiografía De Tórax En El Contexto De La Pandemia Por SARS-CoV-2

In the current SARS-COV-2 pandemic, the choice of an imaging modality to aid diagnosis is based on the patient's clinical conditions, laboratory tests, and the availability of imaging equipment in health facilities. Tomography (CT) and chest radiography (CXR) are the most widely used imaging modalities; CXR, with less sensitivity than CT, is an accessible method, less expensive and less exposure to health personnel, its use is recommended in emergencies and in hospital services. The objective of the article is to guide decision-making to choose an imaging modality according to scenarios, taking into account its potential benefits and deepening in the description of the radiographic characteristics of suspected SARS-COV-2 infection that may serve in emergencies and we assess disease progression using a scoring system.

Viral load of SARS-CoV-2 across patients and compared to other respiratory viruses

RT-PCRs to detect SARS-CoV-2 RNA is key to manage the COVID-19 pandemic. We analyzed SARS-CoV-2 viral loads from 22′323 RT-PCR results according to samples types, gender, age, and health units. Viral load did not show any difference across age and appears to be a poor predictor of disease outcome. SARS-CoV-2 viral load showed similar high viral loads than the one observed for RSV and influenza B. The importance of viral load to predict contagiousness and to assess disease progression is discussed.

Detection of Monocyte/Macrophage and Microglia Activation in the TMEV Model of Chronic Demyelination Using USPIO-Enhanced Ultrahigh-Field Imaging.

Blood-derived monocytes/macrophages can be labeled with ultrasmall superparamagnetic iron oxides (USPIO) at periphery and subsequently migrate into areas of inflammation in the brain. We investigated temporal pattern of migration of peripheral immune cells in Theiler's murine encephalomyelitis virus (TMEV) model of chronic demyelination by USPIO-enhanced imaging. Fifteen SJL mice (Envigo, Indianapolis, IN) were injected with TMEV (n = 12) or saline (n = 3) at 7 weeks of age. Brain MRI of 9.4 T was performed at 3 months postinfection (mpi) (the peak of inflammatory phase), at 4, 5, and 7 mpi (throughout neurodegenerative phase) using T2*-weighted gradient echo MRI, and performed 24 hours after USPIO injection. Contrast enhancing lesion (CEL) number and volume were measured and development of brain atrophy was assessed across serial time points. Clinical disability scale and rotarod score assessed disease progression. CEL was detected in a total of eight (66.7%) TMEV-infected animals and none of the Controls. The CEL was present in four (33.3%) TMEV-infected animals at 3 mpi, two (16.7%) at 4 mpi, six (54.5%) at 5 mpi, and four (44.4%) at 7 mpi, respectively. In TMEV-infected animals, the CEL number and volume increased significantly from 3 to 7 mpi (P < .01 for both). The correlation between total CEL number and volume with clinical and MRI outcomes was trending (P < .05). On histopathology analysis, CEL showed increased density of Iba1 staining for microglia activity. Serial USPIO imaging is a promising biomarker for investigating the effect of therapeutic interventions on monocytes/macrophages and microglia activation and neurodegeneration in TMEV-infected animals.

Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease

This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson's disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson's disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson's disease and clinical scores of motor disability, cognition and mood/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson's disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra's morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson's disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification.

Influence of evolving HIV treatment guidance on CD4 counts and viral load monitoring: A mixed-methods study in three African countries

ABSTRACT Little is known about how CD4 and viral load testing have evolved following implementation of universal test and treat (UTT) in African settings. We reviewed World Health Organization (WHO) guidance from 2013 to 2018, and compared it against national HIV policies in Malawi, Tanzania and South Africa. Three surveys rounds were conducted in 2013, 2016 and 2017–2018 in 33 health facilities across the three settings to assess implementation of national policies on the use of biological markers. Qualitative interviews were conducted with 26 HIV policymakers or programme managers, 21 providers and 66 people living with HIV to explore understandings and experiences of these tests. Various factors influenced adoption and implementation of WHO guidance, including historical policies on CD4 counts, governance issues, supply chain challenges and funding mechanisms. Facility-level practices relating to the use of these tests often diverged from national policies. Patients and providers valued both tests, but did not always understand their roles. In addition to continued support for scaling-up viral load testing, renewed focus should be placed on the ongoing value of point-of-care CD4 tests in the UTT era, including its role in assessing disease progression and informing clinical management of cases to reduce HIV-related mortality.

Abstract CT161: Phase I clinical trials of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors

Abstract Carbonic anhydrase IX (CAIX) is a cell surface, HIF-1A-inducible enzyme that is highly expressed in many solid tumors, is considered to be an endogenous marker of hypoxia and is a prominent biomarker of poor patient prognosis. In contrast, CAIX expression in normal human normal tissue is highly restricted, making it an attractive therapeutic target and driving the development of CAIX-specific inhibitors. SLC-0111 is an ureido-substituted benzenesulfonamide small molecule inhibitor of CAIX. We have shown previously that targeting CAIX activity with SLC-0111, alone and in combination with chemotherapy or immune checkpoint blockade, results in anti-tumor efficacy in multiple solid tumor models in vivo. Here, we report the findings of a multi-center, open-label, first-in-human phase I clinical trial investigating the safety and tolerability of SLC-0111 in patients with previously treated, advanced solid tumors (NCT02215850). Using a 3+3 design, dose escalation started at 500 mg oral daily dosing of SLC-0111 in cohort 1 and increased to 1000 mg and 2000 mg in cohorts 2 and 3. Drug-related adverse events (AEs) were monitored to determine safety and tolerability. Pharmacokinetic analyses assessed plasma concentrations of single and repeated doses of SLC-0111. RECIST 1.1 criteria were used to assess disease progression. No DLTs were reported and patients dosed at 1000 mg and below exhibited fewer drug-related AEs ≥ grade 3 and fewer AEs such as nausea and vomiting, compared to the 2000 mg cohort. 41% of patients experienced dose interruptions or discontinuation and the majority (71%) of these occurred in the 2000 mg cohort. Mean Cmax and AUC(0-24) values for single doses were similar at the 1000 mg and 2000 mg dose levels. Mean Tmax and T1/2 values of SLC-0111 were similar after single and repeated dosing. Power-law analysis of Cmax and AUC(0-24) showed that exposure to SLC-0111 was generally dose proportional. No objective responses were observed, but stable disease greater than 24 weeks was observed in 2 patients. These data show that SLC-0111 is safe in patients and support 1000 mg/day as the recommended phase II dose (RP2D). Based on these encouraging results, a phase Ib clinical trial to evaluate SLC-0111 in combination with chemotherapy in a defined population of CAIX-positive pancreatic cancer patients (NCT03450018) is now open and future clinical development will include investigation of SLC-0111 in combination with chemotherapy in patients with glioblastoma. Citation Format: Paul C. McDonald, Stephen Chia, Philippe L. Bedard, Qunicy Chu, Michael Lyle, Liren Tang, Madhu Singh, Zaihui Zhang, Claudiu T. Supuran, Daniel J. Renouf, Shoukat Dedhar. Phase I clinical trials of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT161.

Serial MRI studies over 12\u2009months using manual and atlas-based region of interest in patients with amyotrophic lateral sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of upper and lower motor neurons. There is a need for an imaging biomarker to track disease progression. Previously, magnetic resonance imaging (MRI) has shown loss of grey and white matter in the brain of patients with ALS compared to controls. We performed serial diffusion tractography imaging (DTI) study of patients with ALS looking for changes over time.MethodsOn all subjects (n = 15), we performed three MRI studies at 6 month intervals. DTI changes were assessed with tract-based spatial statistics (TBSS) and region of interest (ROI) studies. Cortic-spinal tract (CST) was selected for our ROI at the upper level; the posterior limb of internal capsule (PLIC), and a lower level in the pons.ResultsThere was no significant change in DTI measures over 12 months of observation. Better correlation of manual and atlas-based ROI methods was found in the posterior limb of the internal capsule than the pons.ConclusionWhile previous DTI studies showed significant differences between ALS subjects and controls, within individual subjects there is little evidence of progression over 12 months. This suggests that DTI is not a suitable biomarker to assess disease progression in ALS.

Estimation of Salivary 8-Hydroxydeoxyguanosine (8-OHdG) as a Potential Biomarker in Assessing Progression towards Malignancy: A Case-Control Study.

Objective:Squamous Cell Carcinoma is almost always preceded by potentially malignant disorders in the oral cavity before malignant transformation. Characterization of 8-OHdG from the saliva offers a relatively non-invasive, simple and efficient methodology for monitoring oxidative stress in subjects of Premalignant oral disorders (PMOD) and Oral Squamous Cell Carcinoma (OSCC). Hence the aim of the current study is to estimate the levels of salivary 8-hydroxydeoxyguanosine (8-OHdG) as a potential DNA Damage Biomarker in OSMF and OSCC patients in comparison to healthy individuals to assess disease progression from potentially malignant oral disorder to frank malignancy. Materials and Methods:The study was conducted among 90 patients [Oral Squamous cell carcinoma (n=30) and Oral Submucous Fibrosis (n=30) and healthy gender and age matched controls (n=30)]. 4ml of unstimulated saliva was collected from each of the subjects and was subjected to Sandwich ELISA for the quantification of salivary 8-OHdG. Statistical analysis was done using ANOVA, and p value was set at ≤0.05. Results:The mean age of OSCC patients were 56.8±11.8 years. Smoking was the most prevalent adverse habit among this group (66.6%) followed by Smokeless tobacco chewers (40%). The mean age of OSMF patients was 46.2± 9.8 years. Smokeless tobacco was the most predominant habit among the OSMF patients (83.33%) followed by smoking (33.33%). The mean OHdG levels among the controls was 6.59±1.47 (ng/dl) and almost doubled in patients of OSMF 13.89±1.96(ng/dL) and further raised in OSCC patients 19.96 ± 2.11 (ng/dL). These levels showed a highly significant difference (p <0.0001) in mean on comparison by using one-way ANOVA. Pearson correlation between the groups were also statistically significant (p=0.000). Conclusion:There were significant differences in the concentration of salivary 8-OHdG between healthy controls, OSMF, and OSCC patients. Hence, 8-OHdG can be used as a novel biomarker of DNA damage to assess disease progression.

Clinical significance of anti-glycopeptidolipid-core IgA antibodies in patients newly diagnosed with Mycobacterium avium complex lung disease

BackgroundAlthough recent studies have identified anti-glycopeptidolipid (GPL)-core IgA antibodies as a serodiagnostic test for Mycobacterium avium complex lung disease (MAC-LD), this test shows insufficient sensitivity. This study aimed to determine the clinical utility of these antibodies in assessing disease progression and the clinical characteristics of MAC-LD patients with negative antibody results. MethodsWe retrospectively reviewed the medical records of consecutive newly diagnosed, untreated MAC-LD patients in two referral hospitals. We evaluated the association of anti-GPL-core IgA antibody results with disease progression requiring treatment and the factors associated with negative antibody results. ResultsIn total, 229 patients (161 females; median age, 71 years; 185 with nodular/bronchiectatic disease phenotype; 69 with cavitary lesions) were enrolled; 146 patients (64%) were anti-GPL-core IgA antibody-positive. Radiological severity scores were associated with anti-GPL-core IgA antibody titers. During the median 364-day follow-up, 114 patients (49.8%) required treatment. Multivariate Cox proportional hazards analysis showed that positive anti-GPL-core IgA antibody results, a younger age, the absence of malignancy, and the presence of cavitary lesions were associated with disease progression requiring treatment. Multivariate logistic analysis revealed that significant factors related to the negative antibody results included underlying pulmonary disease, lower radiological scores, chronic sinusitis, and macrolide monotherapy. ConclusionIn addition to cavitary lesions, anti-GPL-core IgA antibody positivity was associated with disease progression requiring treatment. Physicians should carefully use anti-GPL-core IgA antibody results for the diagnosis of patients with underlying pulmonary disease, chronic sinusitis, macrolide monotherapy, and lower radiological severity.

Utility of Optical Coherence Tomography in the Diagnosis and Management of Optic Neuropathy in Patients with Fibrous Dysplasia.

Optic neuropathy (ON) is a highly disabling complication of fibrous dysplasia (FD). The optimal test for identifying and monitoring ON in FD is unknown. Optical coherence tomography (OCT) is an imaging modality that detects retinal nerve fiber layer (RNFL) thinning, a sign of optic nerve atrophy. The purpose of this study was to (i) assess the ability of OCT RNFL thickness measurements to identify ON in FD; (ii) compare the performance of RNFL thickness to computed tomography measurements; and (iii) examine changes in RNFL thickness over time to assess disease progression. A retrospective cohort study was performed to assess subjects (n = 70) who underwent neuro-ophthalmologic examination, including OCT. The diagnostic utility of RNFL thickness was determined using receiver operator characteristic (ROC) curve analysis, and the accuracy was compared with computed tomography measurements. The relationship between RNFL thickness and age was assessed cross-sectionally, using generalized estimating equation methodology, and longitudinally, using a generalized mixed model. Eleven subjects were identified with ON. RNFL thickness identified ON (area under curve = 0.997, p < 0.0001) with sensitivity and specificity of 100% and 95%, respectively, when using the diagnostic criterion of ≤71 μm. RNFL thickness outperformed computed tomography measurements of optic canal narrowing and optic nerve stretch. Subjects with ON exhibited a greater decrease in RNFL thickness with each year of age (-0.70 μm/year, p < 0.001) than subjects with normal vision (-0.16 μm/year, p < 0.05). When assessed longitudinally, subjects with normal vision demonstrated an increase in RNFL thickness until approximately age 20 years that decreased thereafter. In contrast, subjects with ON exhibited an earlier decrease in RNFL thickness during adolescence. In conclusion, RNFL thickness of ≤71 μm accurately identified ON in this population. By establishing the difference in rate of RNFL thinning in patients with and without ON, clinicians may distinguish between patients at risk for ON and intervene before irreversible damage. © 2020 American Society for Bone and Mineral Research.

Comprehensive cardiopulmonary assessment in α mannosidosis.

α Mannosidosis is an extremely rare, progressive, and complex lysosomal storage disease, characterized by mental retardation, hearing impairment, coarse facial features, skeletal abnormalities, and pulmonary involvement. While bone marrow transplantation has been the only therapeutic option to date, nowadays new treatment options are being explored, which may affect pulmonary and exercise capacity. To assess cardiopulmonary involvement in patients with α mannosidosis by pulmonary function tests, cardiopulmonary exercise testing, and low irradiation chest computed tomography (CT). Five patients aged 11 to 28 years were followed in our Respiratory-Metabolic Clinic. All five had pulmonary symptoms and received inhaled therapy. Three patients underwent bone marrow transplantation. Parenchymal lung disease was evident in 3/5 chest CT tests. Pulmonary function tests were abnormal in all patients and showed obstructive/restrictive impairment with air trapping. All five patients showed reduced peak oxygen uptake (median 23.1; range 20.4-32.2 mL/minute/kg, median %predicted 62; range %predicted 59-79). Pulmonary involvement is a known complication in this rare disease. Comprehensive cardiopulmonary evaluation is feasible among these patients and may help in assessing disease progression and response to new treatment modalities.

2278-PUB: Longitudinal Progression of Diabetes Mellitus in Wolfram Syndrome

Wolfram Syndrome (WFS) is a rare, genetic, neurodegenerative disorder with associated features of diabetes mellitus (DM), diabetes insipidus, deafness, and optic atrophy. In order to design intervention studies, concrete markers of disease progression are required. DM in WFS is believed to be due to endoplasmic reticulum stress-induced failure of insulin secretion. Therefore, progressive loss of insulin production may be a viable marker of disease progression. The purpose of this study was to examine progression of DM, measured by beta-cell function, in WFS patients over time. N=44 (25F/19M) participants with genetically confirmed WFS attended the Washington University Wolfram Research Clinic from 2010-2019. A mixed meal tolerance test was administered to assess beta cell function (i.e., C-peptide). A hierarchical random coefficients model was used to relate C-peptide as a function of DM duration. Most patients (91%) had DM at time of study enrollment (N=39) or developed DM during the study (N=1). There was a significant association between C-peptide and DM duration, such that C-peptide decreased over time (F= 39.44, p=&amp;lt;0.0001). Given the high prevalence and easily dated onset of DM in WFS, deterioration in C-peptide could potentially be used as a biomarker to assess disease progression in intervention trials for WFS, particularly in those with duration of DM &amp;lt; 10 years as they may be less likely to experience a C-peptide floor effect. Disclosure M. Ray: None. T. Hershey: None. L. Chen: None. N.H. White: None. B.A. Marshall: None. Funding Washington University (HD070855, U54HD087011); Clinical and Translational Science Award (UL1RR024992); National Institute on Drug Abuse (5T32DA007261-27); Diabetes Research Center (DK020579); Snow Foundation, George Decker and Julio V. Santiago Pediatric Diabetes Research Fund; Mallinckrodt Institute of Radiology; McDonnell Center for Systems Neuroscience

Preclinical Assessment of a Cartridge-Based Flow-Through Assay for Determination of Adult CD4 T-Cell Count

Background: Despite the emphasis on viral load testing, current HIV testing guidelines consider CD4 T-cell count measurement as an important criterion for assessing disease progression, making decisions about anti-retroviral therapy regime changes, and treating HIV infected individuals with opportunistic infections. The CD4 counting by established methods (e.g., flow cytometry) presents challenges not only in resource-scarce settings due to cost and lack of skilled technicians but also in resource-rich areas where it is limited to centralized facilities. Objective: Current options for Point-Of-Care (POC) CD4 enumeration are few and labor-intensive, prompting the need for newer technological methods that can overcome the aforementioned challenges. Methods: The novel and patented flow-through cell counting assay (FTCA) described previously (Bystryak et al., 2019) was developed further into a point-of-care CD4 testing system using a disposable cartridge device and a portable imaging instrument. A pilot study with ~100 samples using this device was conducted to assess the validity of FTCA as a POC test for the measurement of CD4 count. Results: The FTCA signal was found to be linear over a wide range (17 - 1540 cells/μL) of CD4 T-cell concentration. The FTCA method also exhibits a strong agreement with flow cytometry, with very low bias (− 7 cells/μL) towards CD4 count measurement. Conclusion: The cartridge-based FTCA method has great potential to be a fully quantitative method with low complexity, portability, low-cost, and wide applicability in clinical practice.

Analysis of collateral lymphatic circulation in patients with lower limb lymphedema using magnetic resonance lymphangiography

ObjectiveAlthough the development of lymphatic collaterals is expected following lymphedema, little is known about the anatomic details of such compensatory pathways or their association with symptoms. Magnetic resonance lymphangiography (MRL) has been shown to be superior to lymphoscintigraphy and indocyanine green lymphography in visualizing lymphatics. This study aimed to analyze MRL images of lower limbs to elucidate the patterns of lymphatic collateral formation and their association with the clinical stages of lymphedema. MethodsWe enrolled 56 consecutive patients (112 lower limbs) with lymphedema who underwent MRL. Two radiologists performed a consensus reading of MRL images for the presence or absence of collateral lymphatic pathways, and the results were compared with the clinical stages. Furthermore, the frequency of abnormal MRL findings in 43 asymptomatic lower limbs of patients with unilateral lymphedema was analyzed and compared with that in the 69 symptomatic lower limbs of the patients. The imaging findings were also compared with the cause of lymphedema. ResultsAll three collateral pathways (anterolateral, deep, and posteromedial lymphatics) were visualized at a higher (P < .05) frequency in stage II than in stage 0 lower limbs. The frequency of visualization of the three collaterals was significantly higher in symptomatic (stages I-III) lower limbs than in asymptomatic (stage 0) lower limbs. Most (76.8%) of the symptomatic limbs exhibited at least one of these collaterals, and the frequency was significantly higher than in the asymptomatic limbs (P < .001). Most (81.4%) of the asymptomatic (stage 0) lower limbs had at least one abnormal finding in terms of lymphatic circulation, although this proportion was significantly lower compared with the symptomatic limbs (98.6%). The collaterals tended to appear less frequently in primary lymphedema than in secondary lymphedema, reaching statistical significance in the posteromedial lymphatics. ConclusionsThese results suggested that the two superficial lymphatic groups and the deep lymphatic system act as major collaterals of the lower limbs in patients with lymphedema. Furthermore, MRL of most patients with unilateral lymphedema demonstrated abnormal findings, including collateral formation, not only in the affected lower limb but also in the asymptomatic lower limb. In primary lymphedema, the collaterals may appear less frequently than in secondary lymphedema. Collaterals should be taken into consideration in planning the site of lymphaticovenous anastomosis and assessing disease progression. MRL can visualize preclinical alterations in lymphatic flow and compensatory pathways; therefore, we expect that it will be useful for the early diagnosis of lymphedema.

MON-LB75 Stratifying the Risk of Malignancy in Indeterminate Thyroid Nodules

Background Thyroid cancer is the most common endocrine cancer globally, and accounts for 3.4% of all new cancer cases in the US. Although several clinical guidelines to detect/manage thyroid nodules are available, a great deal of controversy still exists around the optimal approach for diagnosis. Approximately 20-30% of cytology results from thyroid fine-needle aspiration (FNA) fall into one of three indeterminate diagnostic categories. In recent years, a number of molecular and gene mutation diagnostic tests have been developed to diagnose the indeterminate thyroid nodules in FNA specimens. However, nearly half of patients recommended for surgery based on these tests were found to have a benign nodule. Therefore, there is a need for a more accurate predictive and prognostic test for thyroid cancer. In case of Euthyroid Hashimoto Thyroiditis condition (EHT), where patient required a partial thyroxin replacement dose, having about 48% risk of thyroid cancer. However, there is still not a very accurate predictive marker for early detection of thyroid cancer in EHT. Invention DescriptionResearchers at the University of Toledo have found that thyroid nodule microenvironment cell profiling can be used as a predictive and prognostic marker for thyroid cancer. This approach uniquely focuses on the phenotype, rather than the genotype, of the microenvironment. Recently described Double Negative (DN) T-cells were significantly more abundant in lymphocytic infiltrates of thyroid cancer. They were shown to downregulate proliferation and cytokine production of activated effector T cells present in the tumor microenvironment and contribute to tumor tolerance and active avoidance of tumor immunity. If the quantify of DN T cells exceeds the defined threshold, it indicates a likelihood of cancer presence. Aside from immune cell profiling, our approach further establishes an integration of the information derived from transcriptome/meta-analysis of the genome and cytokine/chemokine signal analysis all from thyroid FNA. Applications[[Unsupported Character - Symbol Font •]] Diagnosis of thyroid cancer from FNA samples[[Unsupported Character - Symbol Font •]] Predictive tool of severity of disease Advantages[[Unsupported Character - Symbol Font •]] Microenvironment profiling can provide a unique way to diagnose and assess disease progression[[Unsupported Character - Symbol Font •]] Sheds light on cellular cross-talk; more accurate diagnose; can prevent unnecessary surgery IP Status:​Patent Pending