Disease Cohort Research Articles

Validation and development of a scoring system for comprehensively evaluating arterial damage in the elderly chinese

Abstract Background and aims Existing assessments on arterial damage focus on specific segments of arterial system (e.g., carotid artery), lacking a comprehensive index to evaluate overall arterial health. We aimed to integrate existing assessments for arterial damage and develop a new score, named Arterial Damage Index (ADI), to comprehensively evaluate arterial health status of the whole-body arterial system. Methods A total of 3075 community-dwelling elderly Chinese (age ≥65 years) from the North Shanghai Study (2014–2022) were included. Assessments on arteries including ankle-brachial index (ABI), pulse wave velocity (PWV), carotid intima-media thickness (CIMT) and plaques, pulse pressure (PP), and inter-arm (IASBPD) and -leg (ILSBPD) systolic blood pressure difference were included for screening. Cox proportional hazards regressions of MACEs (non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality) were conducted to acquire the ADI algorithm. Internal and external validation on ADI were also performed. Results Over a median follow-up period of 6.4 years, 316 individuals (10.3%) experienced an incident of MACE. After screening, PWV, ABI, PP, CIMT, and carotid plaque were included for ADI scoring system. Survival analysis revealed a significant difference in the rates of composite events across different ADI stratifications (p for trend < .05). ADI showed superior discriminative performance (C-index 0.65±0.02) compared to any individual arterial-related indicator. Calibration curve shows the predictive model showed that the predicted and actual probabilities were broadly consistent. Additionally, ADI provided better incremental value when added to the base model (net reclassification improvement, 36.2% [95% CI, 15.3%-52.1%]; p < .05, integrated discrimination improvement, 7.9% [95% CI, 4.9%-11.0%]; p < .05) compared to any individual arterial-related indicator. These findings were confirmed in internal validation sets (p for DeLong tests >0.05), and was externally validated in 2155 participants from a community-based cardiovascular disease cohort among residents in Beijing, China. Conclusion ADI can comprehensively assess arterial damage and provide a valuable tool for further assessment of future cardiovascular risk.central illustration

Association between PCSK9 inhibitor with cause-specific morality amongst cancer survivors

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has emerged as a novel pharmacotherapy for dyslipidemia and been shown to be effective in reducing the risks of atherosclerotic cardiovascular diseases. PCSK9 is aberrantly expressed in a broad spectrum of cancers and has been demonstrated to contribute to cancer prognosis. However, no prior study has investigated the associations between PCSK9 inhibitors (PCSK9i) with cardiovascular and cancer mortality amongst cancer survivors. Purpose This study investigated the effects of PCSK9i on cause-specific mortality amongst cancer survivors. Methods This retrospective study used data from the Tianjin Coronary Artery Disease Cohort, which included medical data from 71 secondary or tertiary hospitals in Tianjin, China. Adult patients with coronary artery disease (CAD) diagnosed with incident cancer between 2017 and 2023 were enrolled in this study. Propensity score matching with a 1:3 ratio for PCSK9i users versus non-users was performed. The primary outcomes included all-cause mortality, cardiovascular mortality, and cancer mortality. Multivariable Cox regression was used to test associations between PCSK9i with outcomes, adjusting for age, gender, cardiovascular and non-cardiovascular comorbidities, lipid-lowing agents and other medication use, lipid level, as well as cancer characteristics. Multivariable competing risk analysis was used as sensitivity analysis. Results A total of 62,341 incident cancer patients were identified. After matching, 424 PCSK9i users and 1,272 non-users were included in this study. During a median follow-up of 1,009 days, 315 patients died, among which 98 died due to cardiovascular cause, 146 died due to cancer cause. Compared to non-users, cancer patients treated with PCSK9i presented with significantly lower risk of all-cause mortality (hazard ratio [HR], 0.33; 95% confidence interval [CI] 0.23-0.47; p <0.001), after adjusting for potential confounders. In addition, PCSK9i therapy was associated with a 63% lower risk of cardiovascular mortality (HR, 0.37; 95%CI 0.20-0.69; p=0.002) and a 75% lower risk of cancer-related mortality (HR, 0.25; 95%CI 0.14-0.45; p<0.001), in relation to non-PCSK9i group. Sensitivity analysis using multivariable competing risk model also suggested a significant association between PCSK9i treatment with reduced risk of cardiovascular mortality (HR, 0.41; 95%CI 0.22-0.76; p=0.005) and cancer mortality (HR, 0.26; 95%CI 0.15-0.48; p<0.001) among cancer survivors. Conclusion The use of PCSK9i was associated lower risks of all-cause, cardiovascular-related, and cancer-related mortality amongst cancer survivors. These findings potentially indicate benefits of PCSK9i beyond adverse cardiovascular events related to atherosclerosis.

International dietary quality index and its association with diabetes in RaNCD cohort study

Diabetes and its complications pose a significant threat to global health. Various factors contribute to the development of diabetes, with diet being an important trigger. The Dietary Quality Index-International (DQI-I) serves as an indicator of changes in diet and its association with chronic diseases, including diabetes. The aim of this study is to examine the association between DQI-I and diabetes in adults. Data from the first phase of the Ravansar Non-Communicable Disease Cohort Study (RaNCD) were used for this cross-sectional study. The study included individuals from western Iran aged between 35 and 65 years. The DQI-I was used to assess diet quality and the essential aspects of a healthy diet. Multiple logistic regression analyses were performed to compare DQI-I total score and diabetes. A total of 7,079 individuals were included, including 608 diabetic and 6,471 healthy individuals. The mean DQI-I score was 60.51 ± 8.47 in healthy individuals and 63.12 ± 8.64 in diabetics. The odds of developing diabetes were higher in individuals with a higher DQI-I (adjusted odds ratio: 1.49, 95% CI: 1.30–1.73). The variety was 13.43 ± 4.47 in diabetics and 12.59 ± 4.79 in healthy individuals. Adequacy was 33.23 ± 3.71 in diabetics and 33.79 ± 3.37 in healthy individuals. Moderation was 13.27 ± 6.05 in diabetics and 11.79 ± 5.47 in healthy individuals. The overall balance was 2.88 ± 2.21 in the healthy group and 2.61 ± 2.13 in the diabetics. The macronutrient ratio was 2.15 ± 1.88 in the healthy group and 2.04 ± 1.84 in the diabetics. The fatty acid ratio was 0.72 ± 1.29 in the healthy group and 0.56 ± 1.17 in the diabetic group. The overall balance score was higher in the healthy subjects. The DQI-I total score was higher in diabetics, indicating a positive association between diabetes and the DQI-I. Therefore, the importance of continuous dietary management and education of diabetic patients should be emphasized.

Serum peroxiredoxin-4, a biomarker of oxidative stress, associates with new-onset chronic kidney disease: A population-based cohort study

BackgroundChronic Kidney Disease (CKD), is often detected late due to its asymptomatic nature in the early stage of the disease. Overproduction of reactive oxygen species contributes to various pathological processes through oxidative stress (OS), impacting on cellular structures and functions with previous studies suggesting a link between OS and CKD progression. This study investigated the association between serum peroxiredoxin-4 (Prx4), a biomarker of oxidative stress, and the development of CKD in the general population. MethodsThis study featured data from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, involving 5341 participants without CKD at baseline who underwent extensive prospective health evaluations. Serum Prx4 levels were quantified using an immunoluminometric assay. The primary outcome was new-onset CKD as defined by the composite of urinary albumin excretion (UAE) > 30 mg/24-h, an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, or both. ResultsBaseline median Prx4 level was 0.65 [interquartile range (IQR): 0.42–1.04] U/L, median eGFR was 98 [IQR: 87–108] mL/min/1.73 m2, and median UAE was 8.1 [IQR: 6.0–12.1] mg/L. During a median follow-up of 10.4 [IQR: 6.3–11.4] years, 867 (16.2 %) patients developed new-onset CKD. Higher Prx4 levels were significantly associated with an increased risk of CKD (hazard ratio (HR) per doubling: 1.29 [95 % confidence interval (CI): 1.21–1.37], p < 0.001), also after adjustment for risk factors including sex, smoking status, systolic blood pressure, high-sensitive C-reactive protein, chronic heart failure, diabetes mellitus and dyslipidemia (HR per doubling: 1.16 [1.06–1.24], p < 0.001). Sensitivity analyses confirmed the robustness of these findings. ConclusionsThis study supports the hypothesis that systemic oxidative stress, reflected by higher serum Prx4 levels, is significantly associated with the risk of developing CKD in the general population. These findings suggest that Prx4 could be a valuable biomarker for early risk stratification and prevention strategies in CKD management.

A qualitative exploratory study into medical, nursing and allied health professional experiences of elective withdrawal of non-invasive ventilation in a motor neurone disease cohort.

With absence of a cure, the mainstay of management for patients with motor neurone disease (MND) is holistic supportive care and symptom control. Non-invasive ventilation (NIV) can provide relief from distressing dyspnoea which often accompanies progressive respiratory muscle weakness. Some patients using NIV will become dependent on it, with a small proportion of these patients going on to request withdrawal. Despite being legal in the UK, elective withdrawal of NIV can be emotionally and ethically challenging for the staff involved. To guide the process of symptom-controlled withdrawal, in 2015 the Association for Palliative Medicine (APM) released clinical guidance. The aim of this study is to explore the experiences of the multi-disciplinary team (MDT) involved in elective withdrawal of NIV in an MND cohort following the publication of this guidance. A qualitative, semi-structured interview study of eight NHS qualified staff members (three Doctors, four Nurses, one Allied Health Professional). Clinicians were asked questions relating to their experiences of the withdrawals. After full transcription, data was analysed thematically. Four main themes were identified, offering insight into how the withdrawals affected staff's well-being and summarised via an 'enablers and barriers' model. The setting was important, as was the depth and longevity of the clinician's investment in the patient. Positive influences on staff's well-being arose from the sense of fulfilling the patient's wishes, good teamwork, presence of an experienced clinician and awareness of the APM (2015) Guidance. Conversely, barriers to well-being were expressed through the unpredictability of each scenario, moral and ethical uncertainties, external pressures on time, mismatched expectations, poor communication and the emotional intensity of the act. Elective withdrawal is highly emotive, simultaneously positively and negatively influencing staff well-being. By addressing the potential mitigating factors, the overall impact on staff's mental health and well-being maybe improved and thus, subsequently, patient care.

Eleven Years of Change: Disease Progression in Biomarker-Defined Sporadic Parkinson's Disease.

Long-term longitudinal data on outcomes in sporadic Parkinson's Disease are limited, especially from cohorts with extensive biological characterization. Recent advances in biomarkers characterization of Parkinson's Disease necessitate an updated examination of long-term progression within contemporary cohorts like the Parkinson's Progression Markers Initiative, which enrolled individuals within 2 years of clinical diagnosis of Parkinson's Disease. Our study leverages the Neuronal Synuclein Disease framework, which defines the disease based on biomarker assessed presence of neuronal alpha-synuclein and dopamine deficit, rather than based on conventional clinical diagnostic criteria. In this study we aimed to provide a comprehensive long-term description of disease progression using the integrated biological and clinical staging system framework. We analyzed data from 344 participants from the sporadic Parkinson's Disease cohort in the Parkinson's Progression Markers Initiative, who met Neuronal Synuclein Disease criteria. We assessed 11-year progression in a spectrum of clinical measures. We used Cox proportional hazards models to assess the association between baseline stage and time to key outcomes, including survival, postural instability (Hoehn & Yahr ≥ 3), loss of independence (Schwab & England < 80%), cognitive decline, and domain-based milestones such as walking and balance, motor complications, autonomic dysfunction, and activities of daily living. Additional analyses were completed to account for death and participant dropout. Biomarker analysis included dopamine transporter binding measures, as well as serum urate, neurofilament light chain and CSF amyloid-beta, phosphorylated tau and total tau. At baseline, despite the cohort consisting of individuals within 2 years of clinical diagnosis, there was clear separation of participants in Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). At 11 years, data were available for 153 participants; 35 participants had died over the follow up period. Of retained participants, 59% presented normal cognition, 24% had evidence of postural instability and mean Schwab & England score was 78.5. Serum neurofilament light chain consistently increased over time. No other biofluids had a consistent change in trajectory. Of importance, baseline Neuronal Synuclein Disease Stage predicted progression to clinically meaningful milestones. This study provides data on longitudinal, 11-year progression in Neuronal Synuclein Disease participants within 2 years of clinical diagnosis. We observed better long-term outcomes in this contemporary observational study cohort. It highlights the heterogeneity in the early Parkinson's Disease population as defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functionally based inclusion criteria in the design of new clinical trials.

Experts consensus on standard items of the cohort construction and quality control of temporomandibular joint diseases (2024)

Temporomandibular joint (TMJ) diseases are common clinical conditions. The number of patients with TMJ diseases is large, and the etiology, epidemiology, disease spectrum, and treatment of the disease remain controversial and unknown. To understand and master the current situation of the occurrence, development and prevention of TMJ diseases, as well as to identify the patterns in etiology, incidence, drug sensitivity, and prognosis is crucial for alleviating patients'suffering.This will facilitate in-depth medical research, effective disease prevention measures, and the formulation of corresponding health policies. Cohort construction and research has an irreplaceable role in precise disease prevention and significant improvement in diagnosis and treatment levels. Large-scale cohort studies are needed to explore the relationship between potential risk factors and outcomes of TMJ diseases, and to observe disease prognoses through long-term follw-ups. The consensus aims to establish a standard conceptual frame work for a cohort study on patients with TMJ disease while providing ideas for cohort data standards to this condition. TMJ disease cohort data consists of both common data standards applicable to all specific disease cohorts as well as disease-specific data standards. Common data were available for each specific disease cohort. By integrating different cohort research resources, standard problems or study variables can be unified. Long-term follow-up can be performed using consistent definitions and criteria across different projects for better core data collection. It is hoped that this consensus will be facilitate the development cohort studies of TMJ diseases.

A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT

AbstractBronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial, adult participants with BOS were treated with ruxolitinib 10 mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared with enrollment. The primary end point differed according to cohort (cohort A, improvement, defined as ≥10% increase in FEV1; cohort B, stabilization, defined as an absence of ≥10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting the criteria for BOS were enrolled and treated (cohort A, n = 36; cohort B, n = 13). The primary end point was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 National Institutes of Health Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response and 18.4% partial response), with most responses occurring in mild or moderate disease. Noninfectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03674047.

Identification of key proteins in early-onset Alzheimer's disease based on WGCNA.

Early-onset Alzheimer's disease (EOAD) is sporadic, highly heterogeneous, and its underlying pathogenic mechanisms remain largely elusive. Proteomics research aims to uncover the biological processes and key proteins involved in disease progression. However, no proteomic studies to date have specifically focused on EOAD brain tissue. We integrated proteomic data from brain tissues of two Alzheimer's disease (AD) cohorts and constructed a protein co-expression network using weighted gene co-expression network analysis (WGCNA). We identified modules associated with EOAD, conducted functional enrichment analysis to understand the biological processes involved in EOAD, and pinpointed potential key proteins within the core modules most closely linked to AD pathology. In this study, we identified a total of 2,749 proteins associated with EOAD. Through protein co-expression network analysis, we discovered 41 distinct co-expression modules. Notably, the proteins within the core module most closely linked to AD pathology were significantly enriched in neutrophil degranulation. Additionally, we identified two potential key proteins within this core module that have not been previously reported in AD and validated their expression levels in 5xFAD mice. In summary, through a protein co-expression network analysis, we identified EOAD-related biological processes and molecular pathways, and screened and validated two key proteins, ERBB2IP and LSP1. These proteins may play an important role in the progression of EOAD, suggesting they could serve as potential therapeutic targets for the disease.

Employment and its Associations in an International Cohort of Myelin Oligodendrocyte Glycoprotein Antibody Disease

Employment and its Associations in an International Cohort of Myelin Oligodendrocyte Glycoprotein Antibody Disease

A prospective cohort study investigating the association between type 2 diabetes and subsequent cardiovascular events in patients with different blood pressure, HbA1c, and lipid levels.

Globally, there has been a steady increase in the prevalence of type 2 diabetes, and the risk of cardiovascular disease has increased. The relationship between diabetes and the incidence of cardiovascular disease (CVD) at different blood pressure, glycated haemoglobin A1c (HbA1c), and lipid levels remains uncertain. This study aimed to investigate these associations within a population-based cohort. We analysed data from the Guiyang subcentre of the China Cardiometabolic Disease and Cancer Cohort Study, which enrolled participants aged 40 years and older between 2011 and 2012. Subsequently, a follow-up visit was conducted during 2014-2016 to assess incident CVD events. The analysis included a cohort of 7197 adults, of whom 590 were diagnosed with diabetes. Among all the participants, the CVD events linked to diabetes had a multivariable adjusted hazard ratio of 2.37 [95% confidence intervals (CI): 1.38-4.08]. Patients with diabetes had a greater risk of experiencing CVD events if they had high blood pressure [hazard ratios (HR): 1.24, 95% CI: 1.39-4.21] and high lipid levels (HR: 2.19, 95% CI: 1.29-3.70) compared to people with normal blood pressure (HR: 1.23, 95% CI: 0.54-2.82) and lipid levels (HR: 1.26, 95% CI: 0.47-3.41). Our analysis revealed a significant association between diabetes and an increased risk of subsequent CVD events, which can be mitigated through optimal management of the metabolic profile of cardiovascular risk factors.

7179 Efficacy of radioactive iodine for the treatment of thyrotoxicosis in a prospective cohort in Aotearoa/New Zealand

Abstract Disclosure: J. Tamatea: None. S. Nottingham: None. V. Boyle: None. M.S. Elston: None. Background – The outcome following treatment of thyrotoxicosis with a single fixed-dose radioiodine (RAI) can be difficult to predict and has been shown to have a lower success rate in Māori vs. non-Māori (1).Aim – the aim of this prospective study was to compare RAI treatment outcomes between Māori and non-Māori, identify factors that are associated with RAI treatment failure in thyrotoxicosis and whether these factors affect the difference in ethnicity outcomes seen.Method – all patients over the age of 16 years referred to Waikato Hospital (Hamilton, New Zealand) for the treatment of thyrotoxicosis with RAI between March 2013 and February 2015 were invited to participate in this study. Demographic information was collected with a questionnaire prior to treatment. Aetiology and severity of thyrotoxicosis at time of diagnosis was retrospectively collected. Laboratory investigations, ultrasound thyroid volume and thyroid pertechnetate uptake were carried out prior to RAI treatment. Participants were followed up for12 months after RAI to assess outcome to treatment. Univariate analysis of variables were carried out for the full cohort and for Graves’ Disease (GD) cohort. Logistic regression analysis was carried out including ethnicity and additional variables of age, gender, diagnosis, thyroid volume, smoking status, and BMI.Results – a total of 162 participants were included: 71 identified as Māori and 91 as non-Māori. At 12 months follow up, 146 participants (90.1%) had a successful treatment outcome follow a single dose of RAI. Successful outcome was achieved in 85.9% of Māori vs 93.4% of non-Māori (p = .113), however when only looking at the GD cohort, Māori were less likely to have successful outcome than non-Māori (68.75% vs 89.4% p = .022). Following regression analysis ethnicity was no longer a variable associated with treatment failure. When controlling for other variables, factors found to increase the risk of failing RAI were diagnosis of TMNG/STA (OR 0.03; 95%CI 0.002-0.035), larger thyroid volumes (OR 1.04; 95%CI 1.01 - 1.07 per mL of thyroid volume) and smoking (OR 6.71; 95%CI 1.2 - 37.4 for current smokers).Conclusion - RAI is an effective definitive treatment option for thyrotoxicosis. Factors found to be associated with treatment outcome are aetiology of thyrotoxicosis, thyroid volume, and smoking status. These factors likely explain the ethnicity difference in treatment outcome following RAI in Māori vs non-Māori.References – 1. Tamatea JAU, Conaglen JV, Elston MS. Response to Radioiodine Therapy for Thyrotoxicosis: Disparate Outcomes for an Indigenous Population. International Journal of Endocrinology. 2016;2016:7863867. Presentation: 6/2/2024

Health Care Usage During the COVID-19 Pandemic and the Adoption of Telemedicine: Retrospective Study of Chronic Disease Cohorts.

The COVID-19 pandemic accelerated telehealth adoption across disease cohorts of patients. For many patients, routine medical care was no longer an option, and others chose not to visit medical offices in order to minimize COVID-19 exposure. In this study, we take a comprehensive multidisease approach in studying the impact of the COVID-19 pandemic on health care usage and the adoption of telemedicine through the first 12 months of the COVID-19 pandemic. We studied the impact of the COVID-19 pandemic on in-person health care usage and telehealth adoption across chronic diseases to understand differences in telehealth adoption across disease cohorts and patient demographics (such as the Social Vulnerability Index [SVI]). We conducted a retrospective cohort study of 6 different disease cohorts (anxiety: n=67,578; depression: n=45,570; diabetes: n=81,885; kidney failure: n=29,284; heart failure: n=21,152; and cancer: n=35,460). We used summary statistics to characterize changes in usage and regression analysis to study how patient characteristics relate to in-person health care and telehealth adoption and usage during the first 12 months of the pandemic. We observed a reduction in in-person health care usage across disease cohorts (ranging from 10% to 24%). For most diseases we study, telehealth appointments offset the reduction in in-person visits. Furthermore, for anxiety and depression, the increase in telehealth usage exceeds the reduction in in-person visits (by up to 5%). We observed that younger patients and men have higher telehealth usage after accounting for other covariates. Patients from higher SVI areas are less likely to use telehealth; however, if they do, they have a higher number of telehealth visits, after accounting for other covariates. The COVID-19 pandemic affected health care usage across diseases, and the role of telehealth in replacing in-person visits varies by disease cohort. Understanding these differences can inform current practices and provides opportunities to further guide modalities of in-person and telehealth visits. Critically, further study is needed to understand barriers to telehealth service usage for patients in higher SVI areas. A better understanding of the role of social determinants of health may lead to more support for patients and help individual health care providers improve access to care for patients with chronic conditions.

Quantitative Blood Serum IVDr NMR Spectroscopy in Clinical Metabolomics of Cancer, Neurodegeneration, and Internal Medicine.

Despite more than two decades of metabolomics having joined the "omics" scenery, to date only a few novel blood metabolite biomarkers have found their way into the clinic. This is changing now by massive large-scale population metabolic phenotyping for both healthy and disease cohorts. Here, nuclear magnetic resonance (NMR) spectroscopy is a method of choice, as typical blood serum markers can be easily quantified and by knowledge of precise reference concentrations, more and more NMR-amenable biomarkers are established, moving NMR from research to clinical application. Besides customized approaches, to date two major commercial platforms have evolved based on either 600MHz (14.1 Tesla) or 500MHz (11.7 Tesla) high-field NMR systems. This chapter provides an introduction into the field of quantitative in vitro diagnostics research (IVDr) NMR at 600 MHzand its application within clinical research of cancer, neurodegeneration, and internal medicine.

B-080 Development and Validation of a GQ1b IgG ELISA as a Diagnostic Aid for Subacute Demyelinating Polyneuropathies

Abstract Background Autoimmunity targeting GQ1b is associated with group of disorders that includes Miller-Fisher Syndrome (MFS), Bickerstaff Brainstem Encephalitis (BBE) and classic Guillain Barre Syndrome (GBS) with ophthalmoplegia. Collectively these are referred to as GQ1B-IgG related syndromes. The prevalence of GQ1b-IgG in this population of patients is high and has been reported to be &amp;gt;80% in well-defined clinical cohorts. Clinical phenotypic presentation is diverse and requires highly accurate antibody testing. The objective of this study was to evaluate a newly developed custom GQ1b-IgG assay, using a semi-quantitative ELISA-based method. Methods A GQ1b-IgG ELISA was developed and validated. Patient sera along with assay controls and a single-point calibrator are diluted and incubated in duplicate wells in a 96-well plate coated with GQ1b antigen. The plate is washed and incubated with anti-human-IgG secondary antibody conjugated with HRP. After a colorimetric reaction, optical densities (OD) are read. The OD of patient samples are compared against the calibrator, generating a cut-off index (COI). Samples ≥1.0 COI are considered positive. During the validation phase, analytical and clinical performance characteristics were evaluated. Studies included assessment of imprecision at multiple concentrations of GQ1b-IgG, accuracy using method comparison, analytical sensitivity and specificity, reference range, common interferences, plate drift, and clinical performance in relevant disease and control cohorts. Results Intra-assay imprecision (coefficient of variation; %CV) ranged from 1.0 - 16% across all concentrations of GQ1b-IgG. Inter-assay imprecision (%CV) ranged from 12.4 - 44.5% but was &amp;lt;20% at or above the assay cut-off. We found perfect qualitative agreement with an independent ELISA reference method (20 positive and 20 negative samples selected based on reference method results [reference interval &amp;lt;1:100]). Limit of detection (LOD) was calculated at a COI of 0.22. To assess analytical specificity, 40 samples with high concentrations of immunoglobulins (hypergammaglobulinemia [N=15], IgG M-protein [N=15] and systemic lupus erythematosus [N=10] were tested and all were negative. A reference interval study was performed on 140 healthy donor serums, all were negative. Interference studies were conducted on 2 positive and 2 negative serum samples, spiked for highly hemolytic (1000 mg/dL), lipemic (2000 mg/dL) and icteric (60 mg/dL) conditions. There was no impact on the assay even with high levels of a given interferent. Plate drift on 2 distinct patient pools tested across the plate (COI range 0.7 - 1.3) had overall plate CV’s ≤10%. ROC analysis was performed on a cohort of 278 patient samples (15 MFS cases and 263 controls [suspected demyelinating neuropathy or disease mimics]). A cut-off value of 1.0 (COI) was selected based on the Youden index. At this cut-off, clinical sensitivity for MFS was 87% while clinical specificity was 99.2%. Conclusions The observed performance of the GQ1b-IgG ELISA was acceptable for clinical laboratory implementation. A COI of ≥ 1.0 was selected for clinical use.

B-249 Assessing Targeted Mass Spectrometry Assay Performance for Putative Biomarker Proteins on a New Hybrid Nominal Mass Instrument

Abstract Background The development of targeted mass spectrometry-based proteomics assays that monitor biomedically relevant proteins is an important step in bridging discovery experiments to highly multi-analyte clinical studies. Targeted assays are currently unable to scale to thousands of peptide targets from hundreds of proteins, requiring extensive refinement down assays for the minimum useful analytes. Large parallel reaction monitoring (PRM) assays are now possible with a new hybrid nominal-mass instrument. The scale of assay is achievable with this instrument by using real-time alignment, while being sensitive and fast enough to handle many concurrent targets. To assess the performance of this new instrument we constructed a large scale PRM assay for proposed neurodegenerative disease marker proteins, and an assay for proteins associated with amyloid tissue typing. Methods To evaluate the performance of this instrument on proteins of interest in cerebrospinal fluid, we performed an analysis on a pool from individuals diagnosed as Alzheimer’s, Parkinson’s, or cognitively normal. A calibration curve of cerebrospinal fluid diluted into chicken serum at 14 dilutions and individual human cerebrospinal fluid were digested with a protein aggregation and capture based digestion protocol. CSF peptides were separated by 60 minute gradient on C18 IonOpticks column, and amyloid tissue peptides separated by 30 minute gradient on C18 PepMap column with a Vanquish Neo UHPLC and analyzed by data-independent acquisition (DIA) and PRM with a new hybrid nominal mass instrument designed for targeted tandem mass spectrometry (tMS2). Scheduled methods were generated using a Skyline external tool, transitions were refined to minimize interference and maximize the LLOQ. DIA data was searched, and data extracted and analyzed in Skyline. PRM data was extracted and quantified with Skyline; CSF calibration curve LLOQ is calculated by bilinear fit. Results For the large scale cerebrospinal fluid (CSF) assay the selection of protein targets was based on literature from neurodegenerative disease cohort studies. We target 1065 peptides from 104 proteins, including proteins currently measured by ELISA in clinical research, e.g.: APP, TAU, and APOE. Sensitivity and reproducibility of the assay is assessed using figures of merit from replicate matched-matrix calibration curves. Over 80% of proteins have at least one peptide with a LLOQ below 30% dilution in the matched matrix, and of all targeted peptides over 55% had a LLOQ below 30% dilution. To demonstrate the application of the real-time alignment on the new instrument we constructed an assay for samples where not every analyte is shared. An assay for amyloidosis associated proteins was constructed for a total of 180 peptides mapping to 52 proteins. This includes 11 proteins most commonly associated with amyloid deposition; APCS, APOA4, APOE, CLU, LECT2, IGKC, IGLC2/4/7, SAA1, TTR, and VTN. From the preliminary set of 12 previously typed samples we observe peptide abundances consistent with the assigned type. Conclusions This novel instrument provides a new approach for building large targeted mass spectrometry assays. We demonstrate the ability of the real-time alignment to adjust scheduled retention time windows, ensuring that chromatographic shifts do not lead to a loss of peptide detection and quantification.

Genetic Analysis of Neurite Outgrowth Inhibitor-Associated Genes in Parkinson's Disease: A Cross-Sectional Cohort Study.

Parkinson's disease (PD) is a neurodegenerative disease caused by a combination of aging, environmental, and genetic factors. Previous research has implicated both causative and susceptibility genes in PD development. Nogo-A, a neurite outgrowth inhibitor, has been shown to impact axon growth through ligand-receptor interactions negatively, thereby involved in the deterioration of dopaminergic neurons. However, rare genetic studies have identified the relationship between neurite outgrowth inhibitor (Nogo)-associated genes and PD from a signaling pathway perspective. We enrolled 3959 PD patients and 2931 healthy controls, categorized into two cohorts based on their family history and age at onset: sporadic early Parkinson's disease & familial Parkinson's disease (sEOPD & FPD) cohort and sporadic late Parkinson's disease (sLOPD) cohort. We selected 17 Nogo-associated genes and stratified them into three groups via their function, respectively, ligand, receptors, and signaling pathway groups. Additionally, we conducted the burden analysis in rare variants, the logistic regression analysis in common variants, and the genotype-phenotype association analysis. Last, bioinformatics analysis and functional experiments were conducted to identify the role of the MTOR gene in PD. Our findings demonstrated that the missense variants in the MTOR gene might increase PD risk, while the deleterious variants in the receptor subtype of Nogo-associated genes might mitigate PD risk. However, common variants of Nogo-associated genes showed no association with PD development in two cohorts. Furthermore, genotype-phenotype association analysis suggested that PD patients with MTOR gene variants exhibited relatively milder motor symptoms but were more susceptible developing dyskinesia. Additionally, bioinformatics analysis results showed MTOR gene was significantly decreased in PD, indicating a potential negative role of the mTOR in PD pathogenesis. Experimental data further demonstrated that MHY1485, a mTOR agonist, could rescue MPP+-induced axon inhibition, further implicating the involvement of mTOR protein in PD by regulating cell growth and axon growth. Our preliminary investigation highlights the association of Nogo-associated genes with PD onset in the Chinese mainland population and hints at the potential role of the MTOR gene in PD. Further research is warranted to elucidate the mechanistic pathways underlying these associations and their therapeutic implications.

Healthy beverage index is associated with metabolic syndrome: insights from the Ravansar non-communicable disease (RaNCD) cohort study

BackgroundDietary patterns play a crucial role in the development and management of metabolic syndrome (MetS). The Healthy Beverage Index (HBI) is a novel tool that assesses the quality of beverage choices in the diet and provides insights into their potential impact on metabolic health. The aim of this study was to investigate the association between the HBI and the MetS.MethodsThis cross-sectional study was conducted using data collected at baseline from the Ravansar Noncommunicable Disease Cohort Study. A total of 9,025 participants aged 35 to 65 years were included in the analysis. HBI was calculated using food items from the Food Frequency Questionnaire (FFQ). MetS status was defined according to established criteria, and logistic regression analysis was performed to assess the association between HBI scores and MetS, adjusting for potential confounding variables.ResultsIn our study, 41.13% of the population was found to have MetS, with a significant association between MetS and tertiles of HBI. Furthermore, the logistic regression model showed a significant inverse association between HBI scores and the odds of developing a MetS (OR = 0.90; 95% CI: 0.86, 0.94), even after adjusting for confounding factors, emphasizing the potential protective effect of higher HBI scores.ConclusionIncreased HBI scores were associated with lower risk of MetS, emphasizing the importance of choosing health-promoting beverages in controlling MetS. These findings support the association between dietary habits and metabolic health and provide practical guidance for individuals and public health initiatives aimed at improving metabolic outcomes.

Performance of an envelope glycoprotein-based multiplex immunoassay for Ebola virus antibody detection in a cohort of Ebola virus disease survivors

Serological surveillance in animal and human hosts can be a cost-effective strategy for orthoebolavirus detection, but is challenged by accurate estimates of seroprevalence, potential pauci-symptomatic disease presentation, and antigenic cross-reactivity. Here, we describe the use of an envelope glycoprotein (GP)-based multiplex microsphere immunoassay, consisting of nine filovirus GP antigens, for the detection of anti-Ebola virus (EBOV) antibodies in a well-characterized cohort of Guinean Ebola virus disease (EVD) survivors and contacts from the 2013 – 2016 West African EVD outbreak. We examined sensitivity and specificity for the detection of anti-EBOV antibodies by GP expressed as recombinant trimeric ectodomains, yielding an assay performance of 95.96% sensitivity and 98.61% specificity. Additionally, agreement between the multiplex test and a whole virus ELISA and virus neutralization test showed strong correlations. The results demonstrate this filovirus multiplex test is a sensitive tool for high-throughput serosurveillance

10 Years of C3 Glomerulopathy in the Netherlands: A Large Cohort of a Rare Kidney Disease

10 Years of C3 Glomerulopathy in the Netherlands: A Large Cohort of a Rare Kidney Disease