Definitive Test Research Articles

Translation and Validation of the Niigata PPPD Questionnaire into Tamil: A Tool to Assess Persistent Postural-Perceptual Dizziness.

PPPD is a chronic and functional disorder without diagnostic data and definitive laboratory tests. In such conditions, questionnaires are the easiest quantifiable measures to identify and rate the severity of individuals suffering from PPPD. The current study aimed to adapt the Niigata PPPD Questionnaire (NPQ) into Tamil language and analyze its psychometric properties. A conventional method of translation involving forward and backward translation was carried out, followed by subsequent content validation. The translated version was field tested in three groups, the controls, the dizzy group, and PPPD group, for further analysis. The final Tamil version of the questionnaire, NPQ-T, had good reliability and validity. This version was identified to have good sensitivity and specificity in discriminating the PPPD group from the dizzy group. The NPQ in Tamil (NPQ-T) is a valid tool for identifying individuals with PPPD and noting the severity of the exacerbating factors.

Canine Bacterial Endocarditis: A Text Mining and Topics Modeling Analysis as an Approach for a Systematic Review.

Bacterial endocarditis (BE) is a severe infection of the endocardium and cardiac valves caused by bacterial agents in dogs. Diagnosis of endocarditis is challenging due to the variety of clinical presentations and lack of definitive diagnostic tests in its early stages. This study aims to provide a research literature analysis on BE in dogs based on text mining (TM) and topic analysis (TA) identifying dominant topics, summarizing their temporal trend, and highlighting any possible research gaps. A literature search was performed utilizing the Scopus® database, employing keywords pertaining to BE to analyze papers published in English from 1990 to 2023. The investigation followed a systematic approach based on the PRISMA guidelines. A total of 86 records were selected for analysis following screening procedures and underwent descriptive statistics, TM, and TA. The findings revealed that the number of records published per year has increased in 2007 and 2021. TM identified the words with the highest term frequency-inverse document frequency (TF-IDF), and TA highlighted the main research areas, in the following order: causative agents, clinical findings and predisposing factors, case reports on endocarditis, outcomes and biomarkers, and infective endocarditis and bacterial isolation. The study confirms the increasing interest in BE but shows where further studies are needed.

Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies

Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible and reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin of tauopathies patients, we aimed to exploit the ultrasensitive seeding activity assay (SAA) to assess tau seeding activity in skin of patients with tauopathies. In this multicentric, case-control study, patients with tauopathies and synucleinopathies were consecutively recruited and sex-matched to healthy controls (HC). Subjects underwent a double 3 mm skin biopsy in cervical area and ankle. Skin tau-SAA, using TauK18 and TauK19 as reaction substrates for 4R and 3R isoforms, seeding score, clinical scales, biochemical and morphological characterization of SAA end-products were evaluated. We analyzed 58 subjects: 24 tauopathies (18 progressive supranuclear palsy, PSP, and 6 corticobasal degeneration, CBD), 20 synucleinopathies (14 Parkinson’s disease, PD, and 6 multiple system atrophy, MSA), and 14 HC. PSP and CBD showed higher tau seeding activity at both anatomical sites. A greater sensitivity of 4R-SAA than 3R-SAA was observed. 4R tau-SAA identified tauopathies with 71% sensitivity and 93% specificity. Accuracy was higher for PSP than CBD: PSP vs HC / PD (AUC 0.825), while CBD vs HC / PD (AUC 0.797), and PSP vs MSA (AU 0.778). SAA end-products showed differences in biochemical and morphological characterization according to the anatomical site. Skin tau-SAA identifies tauopathies with good accuracy and can be used to implement the in-vivo clinical diagnosis of patients with neurodegenerative diseases. Further characterization of peripheral tau seed in skin may elucidate the structure of tau deposits in brain.

Artificial intelligence approaches for phenotyping heart failure in U.S. Veterans Health Administration electronic health record.

Heart failure (HF) is a clinical syndrome with no definitive diagnostic tests. HF registries are often based on manual reviews of medical records of hospitalized HF patients identified using International Classification of Diseases (ICD) codes. However, most HF patients are not hospitalized, and manual review of big electronic health record (EHR) data is not practical. The US Department of Veterans Affairs (VA) has the largest integrated healthcare system in the nation, and an estimated 1.5 million patients have ICD codes for HF (HF ICD-code universe) in their VA EHR. The objective of our study was to develop artificial intelligence (AI) models to phenotype HF in these patients. The model development cohort (n=20000: training, 16000; validation 2000; testing, 2000) included 10000 patients with HF and 10000 without HF who were matched by age, sex, race, inpatient/outpatient status, hospital, and encounter date (within 60days). HF status was ascertained by manual chart reviews in VA's External Peer Review Program for HF (EPRP-HF) and non-HF status was ascertained by the absence of ICD codes for HF in VA EHR. Two clinicians annotated 1000 random snippets with HF-related keywords and labelled 436 as HF, which was then used to train and test a natural language processing (NLP) model to classify HF (positive predictive value or PPV, 0.81; sensitivity, 0.77). A machine learning (ML) model using linear support vector machine architecture was trained and tested to classify HF using EPRP-HF as cases (PPV, 0.86; sensitivity, 0.86). From the 'HF ICD-code universe', we randomly selected 200 patients (gold standard cohort) and two clinicians manually adjudicated HF (gold standard HF) in 145 of those patients by chart reviews. We calculated NLP, ML, and NLP+ML scores and used weighted F scores to derive their optimal threshold values for HF classification, which resulted in PPVs of 0.83, 0.77, and 0.85 and sensitivities of 0.86, 0.88, and 0.83, respectively. HF patients classified by the NLP+ML model were characteristically and prognostically similar to those with gold standard HF. All three models performed better than ICD code approaches: one principal hospital discharge diagnosis code for HF (PPV, 0.97; sensitivity, 0.21) or two primary outpatient encounter diagnosis codes for HF (PPV, 0.88; sensitivity, 0.54). These findings suggest that NLP and ML models are efficient AI tools to phenotype HF in big EHR data to create contemporary HF registries for clinical studies of effectiveness, quality improvement, and hypothesis generation.

Reduction of long COVID symptoms after stellate ganglion block: A retrospective chart review study

The SARS-CoV-2 pandemic has left millions of individuals with a host of post-viral symptoms that can be debilitating and persist indefinitely. To date there are no definitive tests or treatments for the collection of symptoms known as “Long COVID” or Post-acute sequelae of COVID-19 (PASC). Following our initial case report detailing improvement of Long COVID symptoms after sequential bilateral stellate ganglion blockade (SGB), we performed a retrospective chart analysis study on individuals treated with the same protocol over the course of six months (2021−2022) in our clinic. Patients self-reported symptoms on a 10-point scale as part of optional patient follow-up using an online survey. After one month or more following treatment, patients reported striking reductions in Fatigue, Worsening of Symptoms following Mental and Physical Activity, Memory Problems, Problems Concentrating, Sleep Problems, Anxiety, and Depression. Loss of Taste and Loss of Smell in some individuals did not respond to treatment, likely indicating structural damage following infection. This study suggests that neuromodulation may provide relief of Long COVID symptoms for at least a subset of individuals, and provides support for prospective studies of this potential treatment.

A Hidden Cause of Hypertransaminasemia: Liver Toxicity Caused by Chelidonium Majus L.: Report of Two Cases of Herb-Induced Liver Injury and Literature Review.

In instances where individuals manifest elevated transaminase levels without a clearly discernible cause, a comprehensive patient history proves invaluable in unveiling latent triggers. In this report, we present 2 cases of herb-induced liver injury (HILI) characterized by severe hypertransaminasemia attributed to the consumption of Chelidonium majus L. (also known as greater celandine [GC]), an agent considered an alternative therapeutic remedy. Exploring the occurrence and range of clinical manifestations in HILI linked to Chelidonium majus L., while also investigating the potential triggers and predisposing factors for hepatotoxic reactions post Chelidonium majus L. usage, remains challenging due to the absence of definitive laboratory tests to identify the causative agent. Two case reports were detailed, and a systematic literature review using PubMed was conducted including published literature till March 2023. Moreover, a manual search of reference lists of pertinent articles was performed to identify any additional relevant missed publications. In the first case, a 64-year-old woman presented with jaundice, revealing a 1-month history of using GC capsules to manage gallstones. Diagnostic assessment identified HILI, gallstones, and choledocolithiasis, with transaminase levels exceeding 1000 IU/L. After discontinuing GC and receiving intravenous therapy with amino acids and phospholipids, the patient's condition significantly improved. Subsequently, she underwent endoscopic common bile duct stone removal and cholecystectomy. In the second case, a 66-year-old woman presented with elevated liver function test results discovered incidentally during musculoskeletal pain evaluation. Upon further questioning, the patient disclosed regular consumption of GC tea for "health promotion." Following intravenous therapy using amino acids and phospholipids, her transaminase levels returned to normal. The literature review identified 38 cases of HILI associated with GC preparations, primarily in adult women aged 27-77 years, with a predominant reporting location in Germany. Various forms of GC were used, with treatment durations ranging from 1 week to a year. Discontinuation of GC generally led to recovery in these cases. Chelidonium majus L., a potent herb often used in alternative medicine, has significant hepatotoxic potential, requiring physicians to be vigilant in cases of unexplained liver injury.

Adrenal insufficiency in pediatric kidney transplantation recipients.

Immunosuppression of pediatric kidney transplant (PKT) recipients often includes corticosteroids. Prolonged corticosteroid exposure has been associated with secondary adrenal insufficiency (AI); however, little is known about its impact on PKT recipients. This was a retrospective cohort review of PKT recipients to evaluate AI prevalence, risk factors, and adverse effects. AI risk was assessed using morning cortisol (MC) and diagnosis confirmed by an ACTH stimulation test. Potential risk factors and adverse effects were tested for associations with MC levels and AI diagnosis. Fifty-one patients (60.8% male, age 7.4 (IQR 3.8, 13.1) years; 1 patient counted twice for repeat transplant) were included. Patients at risk for AI (MC < 240 nmol/L) underwent definitive ACTH stimulation testing, confirming AI in 13/51 (25.5%) patients. Identified risk factors for AI included current prednisone dosage (p = .001), 6-month prednisone exposure (p = .02), daily prednisone administration (p = .002), and rejection episodes since transplant (p = .001). MC level (2.5 years (IQR 1.1, 5.1) post-transplant) was associated with current prednisone dosage (p < .001), 6-month prednisone exposure (p = .001), daily prednisone administration (p = .006), rejection episodes since transplant (p = .003), greater number of medications (β = -16.3, p < .001), 6-month hospitalization days (β = -3.3, p = .013), creatinine variability (β = -2.4, p = .025), and occurrence of acute kidney injury (β = -70.6, p = .01). Greater corticosteroid exposure was associated with a lower MC level and confirmatory diagnosis of AI noted with an ACTH stimulation test. Adverse clinical findings with AI included greater medical complexity and kidney function lability. These data support systematic clinical surveillance for AI in PKT recipients treated with corticosteroids.

AntiMicro.ai: An Artificial Intelligence powered web application for predicting antibacterial/antifungal susceptibility and constructing personalized machine learning models

Background To train and develop machine learning models on the Pfizer antibacterial and antifungal datasets with subsequent deployment to an interactive Web Application. Methods We utilized R version 4.3.1 to perform descriptive analysis to obtain features/predictors. Python 3.10 libraries NumPy, Pandas, Scikit learn, Pycaret were used to train machine learning models. All these models were scored using area under the curve, recall, precision, F1, Kappa and the Mathews correlation coefficient. The best performing model was then deployed into a web application built on Streamlit after which deployment was done using GitHub and Streamlit cloud. A prototype android app was also developed using GoNative. Results The exploratory data analysis, S Aureus (17.2%) was the most common species however in the sub group analysis of the isolates with genotypic values, K Pneumoniae(48.2%) and E Coli (36.9%) were dominant. Amongst the fungi, Candida albicans (38.3%) and Candida glabrata (15.5%) were dominant. Feature selection was done using Shapley additive explanation plots. Using Extreme Gradient Boosting (XGBoost), we were able to achieve 99% and 97.8% AUC in the prediction of antibacterial and antifungal susceptibility respectively with minimal overfitting. Conclusions Decision tree based methods are a viable options of predicting antibacterial and antifungal drug resistance. When presented in visually appealing modes like web applications and android apps, it can be a useful guide to clinicians on initial treatment while awaiting definitive phenotypic testing. It can also be a surveillance tool that can craft antimicrobial resistance strategies.

Enhancing Pragmatic Language skills for Young children with Social communication difficulties (E-PLAYS-2) trial: study protocol for a cluster-randomised controlled trial evaluating a computerised intervention to promote communicative development and collaborative skills in young children

BackgroundA number of children experience difficulties with social communication and this has long-term deleterious effects on their mental health, social development and education. The E-PLAYS-2 study will test an intervention (‘E-PLAYS’) aimed at supporting such children. E-PLAYS uses a dyadic computer game to develop collaborative and communication skills. Preliminary studies by the authors show that E-PLAYS can produce improvements in children with social communication difficulties on communication test scores and observed collaborative behaviours. The study described here is a definitive trial to test the effectiveness and cost-effectiveness of E-PLAYS delivered by teaching assistants in schools.MethodsThe aim of the E-PLAYS-2 trial is to establish the effectiveness and cost-effectiveness of care as usual plus the E-PLAYS programme, delivered in primary schools, compared to care as usual. Cluster-randomisation will take place at school level to avoid contamination. The E-PLAYS intervention will be delivered by schools’ teaching assistants. Teachers will select suitable children (ages 5–7 years old) from their schools using guidelines provided by the research team. Assessments will include blinded language measures and observations (conducted by the research team), non-blinded teacher-reported measures of peer relations and classroom behaviour and parent-reported use of resources and quality of life. A process evaluation will also include interviews with parents, children and teaching assistants, observations of intervention delivery and a survey of care as usual.The primary analysis will compare pragmatic language scores for children who received the E-PLAYS intervention versus those who did not at 40 weeks post-randomisation. Secondary analyses will assess cost-effectiveness and a mixed methods process evaluation will provide richer data on the delivery of E-PLAYS.DiscussionThe aim of this study is to undertake a final, definitive test of the effectiveness of E-PLAYS when delivered by teaching assistants within schools. The use of technology in game form is a novel approach in an area where there are currently few available interventions. Should E-PLAYS prove to be effective at the end of this trial, we believe it is likely to be welcomed by schools, parents and children.Trial registrationISRCTN 17561417, registration date 19th December 2022.Protocol version: v1.1 19th June 2023.

P074 Diagnostic Journeys of Patients with Hypophosphatasia

Abstract Background/Aims Hypophosphatasia (HPP) is an ultra-rare genetic disorder characterised by low activity of tissue non-specific alkaline phosphatase (TNAP). Due to heterogeneity of clinical presentation and lack of definitive biochemical testing, misdiagnosis and diagnostic delay are common. Methods We used information reported by HPP patients to the Rare and Undiagnosed Diseases Study (RUDY) online registry (www.rudystudy.org). We included patients with a self-reported diagnosis of HPP and information on at least one of our outcomes. We described their diagnostic journey, including diagnostic delays, initial symptoms, incorrect diagnoses and healthcare professionals seen. Results 16 participants with a self-reported diagnosis of HPP were included in the analysis with 14/16 female. Of those reporting the date of initial symptom onset, 9/14 participants had symptom onset before the age of 18, whereas five had symptom onset in adulthood. The median time from symptom onset to HPP final diagnosis was 26.5 years (N = 8, IQR 11.2 to 34.6). From the first GP visit related HPP to final diagnosis the median time was 9.5 years (N = 6, IQR 6.2 to 11.1), and from the first hospital visit related to HPP, the median time to final diagnosis was 3.9 years (N = 10, IQR 0.8 to 10.5). Among participants reporting initial symptoms (N = 13), 16 categories of initial symptom were reported, with a median of two initial symptom categories per participant (IQR 1 to 2). The most prevalent initial symptom was pain (10/13, 77%). Of these 10 participants, four had lower limb pain, one had upper limb pain, one had back pain, and five had pain of unspecified location. Skeletal deformity at birth, dental manifestations, joint swelling, and infantile feeding problems were each present in 2/13 participants (15%). Among participants reporting whether they had received other diagnoses prior to that of HPP (N = 13), nine participants (75%) received at least one other diagnosis, with diagnoses of 10 different conditions reported across the cohort. The most common other diagnosis was fibromyalgia (4/13, 31%), followed by hypermobility (2/13, 15%). 21 different types of healthcare professionals were seen prior to final diagnosis. General Practitioners were the most commonly consulted (9/14, 64%). This was followed by allied health professionals (8/14, 57%). Of the eight participants seeing allied health professionals, all eight saw physiotherapists, and 4 (29% of total) also saw at least one other allied health professional. Other types of healthcare professional seen by multiple responders included orthopaedic surgeons (5/14, 36%), rheumatologists (5/14, 36%), geneticists (4/14, 29%), endocrinologists (3/14, 21%), metabolic specialists (3/14, 21%) and dentists (2/14, 14%). Conclusion Patients typically present with a cluster of symptoms, often including pain, and are often seen by general practitioners and physiotherapists before diagnosis. Increasing awareness of HPP in these professions may improve early recognition of the disease. Disclosure D. Marsden: None. R. Ridley: None.

Clinician Ordering and Management Patterns of Urine Toxicology Results at a Cancer Center

ContextOpioid therapy is a cornerstone for treatment of cancer-related pain, but standardized management practices for patients with cancer and aberrant urine drug test (UDT) results are lacking. ObjectivesTo identify the prevalence of UDT ordering (both screening and definitive testing) in the oncology setting and to examine clinician management practices for patients with cancer on opioid therapy with aberrant definitive UDT results. MethodsWe conducted a retrospective chart review of patients with cancer on opioid therapy at an academic cancer center in the United States. Outcomes included UDT ordering patterns and clinician management practices in response to aberrant definitive UDT results. ResultsOur study revealed an overall UDT ordering rate of 3.7% among 10,371 patients with cancer on opioid therapy. Among 143 patients for whom definitive UDTs were ordered, oncologists only ordered 14 (9.8%) UDTs, while palliative care ordered the majority (n = 129; 90.2%). Fifty-five (38.5%) patients had aberrant results, and the most common aberrancy was presence of illicit drugs 22 [15.4%]. Clinicians rarely made medication changes (20 [36.4%]) when UDT results were aberrant, and in the setting of possible fentanyl use (n = 8), only 3 (37.5%) patients were started/switched to methadone, and none were started/switched to buprenorphine. ConclusionOverall UDT ordering was infrequent for patients with cancer on opioid therapy, especially by oncologists, and clinicians rarely made prescribing changes when definitive UDT results were aberrant. More definitive guidance related to UDT ordering and opioid management are needed for patients with cancer and aberrant UDT results.

Can We Predict Renal Function Recovery After Pyeloplasty in Pediatrics with Ureteropelvic Junction Obstruction? A Systematic Review.

Chronic unilateral renal obstruction, primarily caused by ureteropelvic junction obstruction (UPJO), poses challenges in determining the optimal timing for corrective surgery. The goal is to preserve renal function and alleviate symptoms, but there is no definitive diagnostic test to reliably predict the outcomes of surgery. This systematic review aimed to identify predictors for renal function recovery after pyeloplasty in order to guide effective treatment options. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A literature search was performed on PubMed, Embase, and Scopus using keywords related to renal function, pyeloplasty, and predictors. The search was conducted on March 10, 2022. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Out of 344 potentially relevant articles, 11 met the eligibility criteria for this study. These included 6 retrospective and 5 prospective studies, with a total of 925 participants. Most studies evaluated renal function using differential renal function (DRF). The overall quality of the included studies was considered average. The findings indicated that age at the time of surgery and gender did not significantly influence functional recovery after pyeloplasty. However, preoperative DRF consistently emerged as a critical predictor. Preoperative DRF can serve as the most common predictors used for renal function recovery following pyeloplasty. These findings contribute to understanding effective treatment options for chronic unilateral renal obstruction. However, further research for each predictor is needed to validate these predictors and their clinical utility. Cite this article as: Siregar S, Mustafa A, Steven S. Can we predict renal function recovery after pyeloplasty in pediatrics with ureteropelvic junction obstruction? A systematic review. Urol Res Pract. Published online March 31, 2024. DOI:10.5152/tud.2024.23220.

Behçet's Disease, Pathogenesis, Clinical Features, and Treatment Approaches: A Comprehensive Review.

Behçet's disease is a systemic inflammatory disorder of unknown etiology. The disease manifests with diverse clinical symptoms, most commonly recurrent oral and genital ulcers, skin lesions, and uveitis, though it can affect multiple organ systems. Diagnosis is primarily clinical due to the lack of a definitive diagnostic test, and management involves a multidisciplinary approach to control inflammation and manage symptoms. Current treatment strategies involve corticosteroids, immunosuppressive agents, and, increasingly, biological therapies. Behçet's disease exhibits a higher prevalence along the Silk Road, suggesting a role of environmental and genetic factors. Despite significant progress in understanding its clinical characteristics and treatment approaches, gaps remain in our understanding of its pathogenesis. Future research is needed to elucidate the disease's pathophysiology and optimize treatment strategies.

Epidemiología, clínica y prevención de la Viruela Símica. Revisión bibliográfica

Introduction: Monkeypox, or monkeypox, is a zoonosis endemic in the rural jungle areas of central and western Africa, in humans the first occurrence was in 1970 in the Democratic Republic of Congo. It is caused by a virus belonging to the genus Orthopoxvirus of the Poxviridae family. Objective: To determine the causes and predisposing factors to the outbreak of monkeypox, transmission routes, clinical manifestations, evolution, complications, diagnosis, therapeutic management, prevention and control of infection.Material and methods: A systematic review was carried out in the Medscape, Pubmed, Science Direct and Scielo databases. Thirty-one papers were used.Results: Monkeypox was discovered in 1958 in the city of Copenhagen, capital of Denmark, in monkeys used for research. In 1970, the first case of monkeypox in humans was reported in a child in the Democratic Republic of Congo. Once the diagnostic suspicion is determined, sampling is indicated to confirm infection by nucleic acid amplification test (NAAT) or real-time PCR. PCR is the definitive diagnostic test, can be alone or followed by restriction fragment length polymorphism (RFLP) analysis or sequencing, has high sensitivity and specificity; and a rapid turnaround time of about one day or less. Monkeypox is usually mild and most people recover without treatment.Conclusions: So far in Ecuador 421 cases of monkeypox have been reported, so it is important that public health officials and health care personnel receive training on the risk of the disease, recognition, treatment and isolation of cases. It is important that the country has sufficient PCR tests in public facilities for the confirmation of cases and as a method of prevention, citizens should maintain the biosecurity measures announced by the MSP.

Abstract 3012: Characterizing the functional significance of "variant of uncertain significance" of the tumour suppressor CDH1

Abstract We aim to develop a new approach to systematically characterize the functional significance of “variant of uncertain significance (VUS),” focusing on the tumor suppressor gene CDH1. Genetic testing is a powerful clinical tool for identifying individuals at risk of developing inherited or familial cancers. If a potential cancer-causing genetic variant (mutation) is found, clinicians can begin managing the patient’s risk early by initiating surveillance or prophylactic treatment. For an aggressive form of inherited stomach cancer called hereditary diffuse gastric cancer (HDGC), the most commonly mutated gene is CDH1, which encodes the tumor suppressor E-Cadherin. However, due to insufficient clinical evidence, over 50% of all publicly reported CDH1 variants either have conflicting interpretations or cannot be classified, thus are not actionable. Consequently, almost 1 in 2 patients who undergo genetic testing for HDGC will not have a definitive test result and cannot benefit from early screening, causing strain on the healthcare system and psychological burden for the patients. To overcome this challenge, we developed a single-cell screening system to accurately classify CDH1 variants using a combination of functional assays, machine learning, and deep learning. Our hypothesis, now supported by preliminary data, is that pathogenic variants will disrupt normal E-Cadherin’s ability to control its signaling partner beta-catenin. Thus, loss-of-function (LoF) CDH1 variants would cause protein mislocalization and altered signaling which lead to abnormal proliferation, an early indicator for carcinogenesis. We express CDH1 variants in human cell lines and use multiplexed high-content imaging to visualize E-Cadherin and beta-catenin. Next, our deep learning pipeline extracts single-cell phenotypic profiles, and our classifier then classifies variants as functional or LoF. Initial analysis of prioritized variants show that our pipeline can accurately separate clinically pathogenic and benign variants based on their functional status as predicted by our pipeline. The outcomes of this project will contribute to a systematic approach to reclassify VUS. Citation Format: Jasmine Wen, Ajay Singh, David Nguyen, Kaitlynn Meier-Ross, Ben Martin, Vedanta Khan, Kiran Dhami, Jesse Chao. Characterizing the functional significance of "variant of uncertain significance" of the tumour suppressor CDH1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3012.

Usefulness of serial testing for the diagnosis of malaria in cases of fever upon return from travel.

When malaria is suspected in case of fever after travel in endemic areas, the current recommendation is to repeat the malaria test at 24-hour intervals, with up to two additional tests, as long as the test result is negative. A retrospective analysis was conducted to investigate the appropriateness of this recommendation by determining the proportion of tests with negative result at first and subsequently with a positive one at second or third attempt. A retrospective study was conducted at the Centre for Primary Care and Public Health, Lausanne, covering a period of 15years. All patients tested once for malaria were included. Testing included microscopy thick and thin films as well as malaria rapid diagnostic test used in combination. The main outcome measure was the proportion of patients with a first negative test result, subsequently positive on second or third test over the total patients with suspected malaria assessed. Demographic, travel, clinical, and laboratory variables were collected from patients' records to identify potential predictors of an initially negative and then positive test result. Four thousand nine hundred seventy-two patients were included. Of those, 4557 (91.7%) had definitive negative test results, and 415 (8.3%) had a positive result on the first test [332/415 (80%) Plasmodium falciparum, 40/415 (9.6%) P. vivax, 21/415 (5.1%) P. ovale, 12/415 (2.9%) P. vivax/ovale, 9/415 (2.2%) P. malariae and 1/415 (0.2%) P. knowlesi], and 3/4972 (0.06%) had a positive result on the second test after a first negative result, 1/4972(0.02%) had a positive test result after 2 negative results, all with P. falciparum. One of the four patients that were positive after their initial negative test was pregnant. The very small number of patients with an initially negative test result and secondarily positive did not allow for risk factor analysis. The current recommendation of serial malaria testing is not supported by the present study, a fortiori for those who do not present with a strong clinical or laboratory predictor of malaria.

Potential Metabolite Biomarkers of Multiple Sclerosis from Multiple Biofluids.

Multiple sclerosis (MS) is a chronic and progressive neurological disorder without a cure, but early intervention can slow disease progression and improve the quality of life for MS patients. Obtaining an accurate diagnosis for MS is an arduous and error-prone task that requires a combination of a detailed medical history, a comprehensive neurological exam, clinical tests such as magnetic resonance imaging, and the exclusion of other possible diseases. A simple and definitive biofluid test for MS does not exist, but is highly desirable. To address this need, we employed NMR-based metabolomics to identify potentially unique metabolite biomarkers of MS from a cohort of age and sex-matched samples of cerebrospinal fluid (CSF), serum, and urine from 206 progressive MS (PMS) patients, 46 relapsing-remitting MS (RRMS) patients, and 99 healthy volunteers without a MS diagnosis. We identified 32 metabolites in CSF that varied between the control and PMS patients. Utilizing patient-matched serum samples, we were able to further identify 31 serum metabolites that may serve as biomarkers for PMS patients. Lastly, we identified 14 urine metabolites associated with PMS. All potential biomarkers are associated with metabolic processes linked to the pathology of MS, such as demyelination and neuronal damage. Four metabolites with identical profiles across all three biofluids were discovered, which demonstrate their potential value as cross-biofluid markers of PMS. We further present a case for using metabolic profiles from PMS patients to delineate biomarkers of RRMS. Specifically, three metabolites exhibited a variation from healthy volunteers without MS through RRMS and PMS patients. The consistency of metabolite changes across multiple biofluids, combined with the reliability of a receiver operating characteristic classification, may provide a rapid diagnostic test for MS.

Autoimmune inner ear disease associated with antiphospholipid antibodies.

The percentage of autoimmune diseases in Western countries is approximately 8% of the total population. Despite numerous studies indicating an increase in prevalence and incidence over the past two decades, autoimmune vestibular disorders seem to be underdiagnosed, primarily due to the lack of a definitive test capable of identifying the specific antigen of the inner ear. Autoimmune inner ear disease (AIED) is defined as a rapidly progressive and often fluctuating bilateral neurosensorial hearing loss that develops over a period of weeks or months. AIED can affect only the inner ear or be part of systemic diseases such as granulomatosis with polyangiitis, Cogan's syndrome, systemic lupus erythematosus, polyarteritis nodosa, or relapsing polychondritis, among others. Our main objective was to conduct a study on the presence of antiphospholipid antibodies (aPL) in patients with AIED seen in a specialised clinic. We designed an observational retrospective study in which we selected patients from a total group of 55 with AIED referred to the Autoimmune Diseases Clinic, those with confirmed positivity for antiphospholipid antibodies, and described their clinical, analytical, and epidemiological characteristics. We found a prevalence of 29% positivity for antiphospholipid antibodies, with lupus anticoagulant (LA) being the most frequently detected, followed by anticardiolipin (aCL) and anti-beta2 glycoprotein (anti-B2GP). Double positivity was observed in 25% of patients. The main clinical manifestations were bilateral hearing loss, vestibular symptoms, and tinnitus. Only 25% of patients experienced audiometric improvement during the course of the disease. We emphasise the importance of identifying the presence of aPL in AIED, enabling the establishment of appropriate and specific therapeutic management to prevent audiometric deterioration.

A81 GASTROINTESTINAL (GI) FEATURES OF HYPERMOBILE EHLERS-DANLOS SYNDROME (HEDS) AND HYPERMOBILITY SPECTRUM DISORDER (HSD): A SCOPING REVIEW

Abstract Background Ehlers-Danlos syndromes (EDS) are a varied group of hereditable connective tissue disorders (HCTD) typified by skin, joint and vascular features, along with less well-recognized features of chronic pain, immunological dysfunction and chronic GI symptoms. The latest EDS classification (2017) lists 13 EDS types and 19 genetic factors but there is no identified genetic basis for hEDS, the most common type and the most-commonly associated with GI symptoms. There is a need for robust data on the prevalence of GI symptoms and diagnoses in hEDS and HSD. Aims To investigate the extent of evidence on GI symptom prevalence and methods used to establish GI diagnoses in patients with hEDS and HSD. Methods Following the JBI (Joanna Briggs Institute) guide for scoping reviews, a systematic search of Ovid Medline, Embase and Cochrane Library retrieved scoping and systematic reviews, published in English (1974 – Sept 2023), reporting GI symptom prevalence, assessment and complications in EDS or HSD. Abstracts of identified papers were reviewed by NC &amp; DB and discrepancies resolved by YY &amp; DA. As a scoping review, it required no statistical comparisons. Results Duplicate screening of 410 abstracts yielded 10 papers that met inclusion criteria: 1 scoping and 9 systematic reviews. Four systematic reviews reported GI surgical issues related to vascular EDS; none was evaluated further. Two papers reported, specifically, on GI symptoms in patients with postural tachycardia syndrome or eating disorders, some of whom had hEDS or HSD and two papers reported on multiple GI and non-GI symptoms associated with fibromyalgia or functional somatic symptoms. The final 2 papers reported on multiple GI and non-GI symptoms in patients with HSD or multiple EDS types, limited in the latter case to papers published after the latest EDS classification (2017). In general, GI symptoms were characterised as IBS-like symptoms (Rome III or Rome IV) or as typical GI symptoms but without using a validated symptom questionnaire. Conclusions There are few data on GI symptom prevalence in hEDS or HSD and no standardised methods for identifying or characterizing GI symptoms or function in hEDS. The evaluation of GI function and symptoms in EDS is hampered by the absence of a definitive genetic or diagnostic test for hEDS or HSD and by changes in EDS classification over the last 50 years. There is a need for targeted systematic reviews of the prevalence of various GI symptoms in hEDS individuals and of relevant diagnostic methods, to guide further research into the causes of GI dysfunction in hEDS or HSD. Funding Agencies None

Rapid Tetra-Primer Amplification Refractory Mutation System-Polymerase Chain Reaction Protocol for Detection of Y132F Mutation in Fluconazole Resistant Candida parapsilosis.

There is an emerging fluconazole resistance in Candida parapsilosis in recent years. The leading mechanism causing azole resistance in C. parapsilosis is the Y132F codon alteration in the ERG11 gene which encodes the target enzyme of azole drugs. In this study, we evaluated the sensitivity, compatibility, and specificity of a novel tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method for rapid detection of the Y132F mutation in fluconazole nonsusceptible C. parapsilosis. Antifungal susceptibility tests for detection of fluconazole resistance were performed by broth microdilution according to the CLSI guidelines. All susceptible and nonsusceptible C. parapsilosis isolates were analyzed for ERG11 mutations with Sanger sequencing. T-ARMS-PCR was fully concordant with the Sanger sequencing (100% of sensitivity and specificity) for detection of Y132F mutations. T-ARMS-PCR method could be a rapid, simple, accurate, and economical assay in the early detection of the most common cause of fluconazole resistance in C. parapsilosis isolates. In routine laboratories with high C. parapsilosis isolation rates, performing the T-ARMS-PCR for early detection of the most common reason of fluconazole resistance in C. parapsilosis, could be a life-saving approach for directing antifungal therapy before obtaining the definitive antifungal susceptibility tests results.