Low Diagnostic Yield Research Articles

Exploring risk Indicators of atrial fibrillation in severe Obesity: Left atrial cardiomyopathy and premature atrial contractions

BackgroundAlthough obesity is a major risk factor for atrial fibrillation (AF), its mechanisms and the diagnostic yield of AF screening in severe obesity is unclear. This study aims to enhance our comprehension of AF susceptibility in severe obesity by investigating associations between left atrial (LA) cardiomyopathy and premature atrial contractions (PACs) and to explore the diagnostic yield of AF screening. MethodsThis cross-sectional study included a total of 192 subjects aged 35–65 years with a BMI ≥ 35 kg/m2, alongside 50 non-obese controls, both without known cardiac disease. Prolonged heart rhythm registration was done with either 24-hours (n = 147) or 7-day Holter monitoring (n = 75) or an implantable loop recorder (ILR) (n = 10). Furthermore, we performed conventional transthoracic echocardiography and strain analyses. ResultsIn the obese cohort, LA enlargement was independently associated with PAC frequency. Each SD increment (10 ml/m2) of LA volume index corresponded with a 46 % increase in PACs. An increase of each SD (10 %) LA reservoir strain was associated with a decrease of 16 % in PAC frequency. There was no association found between LA cardiomyopathy and PACs in the control group. AF was not detected in any subject. ConclusionLA enlargement was independently associated with more frequent PACs in severe obesity, a well-known AF precursor. There was a noticeable trend suggesting a relation between impaired LA function and PACs. Considering our observed low diagnostic yield of AF screening within this population, further investigation is needed to determine whether incorporating LA cardiomyopathy as an additional risk measure could improve AF screening strategies for individuals with severe obesity.

Abstract 4137204: Classifying Left Ventricular Hypertrophy from ECG in Overall Population and Bundle Branch Blocks: Machine Learning Models are Superior to Published ECG Criteria

Background: Published ECG criteria for left ventricular hypertrophy (LVH) have low diagnostic yield, esp. with right/left bundle branch block (RBBB/LBBB). Machine learning (ML) may improve LVH classification. Hypothesis: ML performs better than published LVH criteria to classify LVH from ECG in overall population, and subgroups of RBBB/LBBB. Methods: In addition to standard ECG features like rates, intervals, axis etc., R, S and overall QRS amplitudes, and voltage-time-integrals were extracted from standard 12 leads and reconstructed vectorcardiographic X, Y, Z lead representative beats. Further, a variational autoencoder was used to extract latent encodings from the representative beats. ML algorithms (logistic regression, random forest, light gradient boosted machine, multilayered perceptron, residual network, and convolutional neural network) were trained to predict LVH (LV mass index women >95, men >115 g/m 2 ) from ECG features on a training set of adult ECGs and echocardiogram within 45 days of each other (general population N=240,476, RBBB n=22,110, LBBB n=12,563). We obtained ROC AUCs in a separate validation set for LVH classification by (a) individual ECG variables, (b) published LVH criteria and (c) ML models. Results: As shown in Tables 1-2 and Figure 1 , for LVH classification among the validation sets, AUCs were highest for ML models, intermediate for univariable models and least for published criteria (best ML model vs. best criteria: general population women 0.77 vs. 0.63, men 0.78 vs. 0.63; RBBB women 0.70 vs. 0.57, men 0.77 vs. 0.57; LBBB women 0.71 vs. 0.55, men 0.72 vs. 0.54). Conclusions: ML models perform better than published LVH criteria at classifying LVH from ECG in overall population, RBBB and LBBB.

The Catheter Flushing Method Shows a Similar Diagnostic Yield to the Conventional Method in Brushing Cytology for Biliary Strictures

Background/Objectives: Endobiliary brushing is usually performed in the diagnosis of indeterminate biliary strictures; however, in this setting, brush cytology is limited by a low diagnostic yield and sensitivity. Here, we compared the catheter flushing method (CFM) with the conventional cytologic method (CCM) in terms of cellularity and diagnostic performance. Methods: Endobiliary brushings were obtained during endoscopic retrograde cholangiopancreatography (ERCP) from patients with biliary strictures enrolled at six tertiary hospitals. Additionally, the CFM was performed after brushing. Using liquid-based cytologic preparations of samples, we assessed the diagnostic performance of the CCM using Pap staining and the CFM using methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence staining. Results: From a total of 399 patients (malignant, 253; benign, 146), 374 CCM samples and 361 CFM samples contained adequate cells, with no significant difference in diagnostic yield (93.7% vs. 90.5%, respectively; p = 0.088). The sensitivity of the CFM (90.3%) was significantly higher than that of the CCM (75.1%; p < 0.001), with no significant difference in accuracy between methods (81.2% vs. 82.6%, respectively; p = 0.608). Conclusions: The diagnostic yield of the CFM was comparable to that of the CCM. Additionally, the diagnostic performance of the CFM was comparable to that of the CCM. These findings indicate that the CFM could be an additional brush cytology method for sample collection in patients with indeterminate biliary strictures. Incorporating both the CCM and CFM might be expected to improve the diagnostic yield of brush cytology in the biliary strictures. Further prospective comparative studies between the CCM and CFM using the same staining method are needed to validate these findings.

Additional Diagnostic Yield of the Rapid Drink Challenge in Chicago Classification Version 4.0 Compared With Version 3.0.

Chicago classification version 4.0 enhances the diagnosis of esophageal motility disorders using position change and provocative tests such as multiple rapid swallows and a rapid drink challenge. This study investigates the diagnostic role of the rapid drink challenge based on Chicago classification 4.0 using a functional luminal imaging probe to estimate the cutoff value. This study included 570 patients who underwent esophageal manometry with a rapid drink challenge between January 2019 and October 2022. The diagnostic flow was analyzed according to Chicago classification 4.0. Ninety-nine patients (38, achalasia; 11, esophagogastric junction outflow obstruction; 7, ineffective esophageal motility; 1, hypercontractile esophagus; and 42, normal esophageal function) failed the rapid drink challenge. Among the 453 participants, 50 and 86 were diagnosed with achalasia and esophagogastric junction outflow obstruction, respectively, using Chicago classification 4.0. In 249/453 (55.0%) patients initially diagnosed with esophagogastric junction outflow obstruction using Chicago classification 3.0, the diagnosis was changed to achalasia (n = 28), hypercontractile esophagus (n = 7), ineffective esophageal motility (n = 7), or normal esophageal function (n = 121) using Chicago classification 4.0. Rapid drink challenge-integrated relaxation pressure's diagnostic cutoff value was 19 mmHg. Nine patients had diagnoses changed after the rapid drink challenge, including 3 with panesophageal pressurization. Chicago classification 4.0 increased the diagnostic yield of the rapid drink challenge by 2.0% (9/453 patients). However, the rapid drink challenge had a failure rate of 17.9% (99/552 patients). Given the relatively low diagnostic yield and high failure rate of the rapid drink challenge, we recommend adopting an individualized approach to manometry.

Machine learning to classify left ventricular hypertrophy using ECG feature extraction by variational autoencoder.

Traditional ECG criteria for left ventricular hypertrophy (LVH) have low diagnostic yield. Machine learning (ML) can improve ECG classification. ECG summary features (rate, intervals, axis), R-wave, S-wave and overall-QRS amplitudes, and QRS/QRST voltage-time integrals (VTIs) were extracted from 12-lead, vectorcardiographic X-Y-Z-lead, and root-mean-square (3D) representative-beat ECGs. Latent features were extracted by variational autoencoder from X-Y-Z and 3D representative-beat ECGs. Logistic regression, random forest, light gradient boosted machine (LGBM), residual network (ResNet) and multilayer perceptron network (MLP) models using ECG features and sex, and a convolutional neural network (CNN) using ECG signals, were trained to predict LVH (left ventricular mass indexed in women >95 g/m², men >115 g/m²) on 225,333 adult ECG-echocardiogram (within 45 days) pairs. AUROCs for LVH classification were obtained in a separate test set for individual ECG variables, traditional criteria and ML models. In the test set (n=25,263), AUROC for LVH classification was higher for ML models using ECG features (LGBM 0.790, MLP 0.789, ResNet 0.788) as compared to the best individual variable (VTI QRS-3D 0.677), the best traditional criterion (Cornell voltage-duration product 0.647) and CNN using ECG signal (0.767). Among patients without LVH who had a follow-up echocardiogram >1 (closest to 5) years later, LGBM false positives, compared to true negatives, had a 2.63 (95% CI 2.01, 3.45)-fold higher risk for developing LVH (p<0.0001). ML models are superior to traditional ECG criteria to classify-and predict future-LVH. Models trained on extracted ECG features, including variational autoencoder latent variables, outperformed CNN directly trained on ECG signal.

Diagnostic yield of stains for infectious organisms in esophageal or gastroesophageal junction biopsies with esophagitis*

ABSTRACT Stains frequently performed to exclude infectious etiologies in esophagitis include Grocott methenamine silver (GMS) and periodic acid–Schiff (PAS) as well as immunohistochemistry (IHC) assays for cytomegalovirus (CMV) and herpes simplex virus (HSV). The diagnostic yield of these tests, in this situation, has not been well studied. We retrospectively reviewed 261 esophageal biopsies, which had one or more of the above tests performed. The diagnostic yield for GMS and PAS was 8%, while CMV and HSV immunohistochemistry had a diagnostic yield of 1% and 0%, respectively. Our study suggests that routine use of ancillary labeling techniques in esophagitis biopsies may be of limited utility and have low diagnostic yield.

Diagnostic Value and Safety of Addition of Transbronchial Needle Aspiration to Transbronchial Biopsy Through Endobronchial Ultrasonography Using a Guide Sheath Under Virtual Bronchoscopic Navigation for the Diagnosis of Peripheral Pulmonary Lesions.

The diagnostic yield of peripheral pulmonary lesions (PPLs) through endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) under virtual bronchoscopic navigation is unsatisfactory because radial EBUS probe is not always located within the lesion. Transbronchial needle aspiration with a guide sheath (GS-TBNA) has the potential to overcome the lower diagnostic yield by improving the relationship between the probe and the lesion and enabling repeated sampling while maintaining the location of a GS near the lesion. However, there are few data regarding the diagnostic yield and safety for diagnosing PPLs in this procedure. We retrospectively analyzed consecutive 363 lesions (83 lesions underwent GS-TBNA/EBUS-GS TBB and 280 lesions underwent EBUS-GS TBB) at our institution between April 1, 2019 and March 31, 2022. We investigated the diagnostic efficacy and complications of GS-TBNA/EBUS-GS TBB and compared them with those of EBUS-GS TBB. The lesion size, distance from the hilum, presence of bronchus leading to the lesion, and EBUS images during the examination differed significantly between the two procedures. Logistic regression analysis adjusted for these 4 covariates revealed that GS-TBNA/EBUS-GS TBB was a significant factor affecting the diagnostic success of PPLs compared with EBUS-GS TBB (odds ratio=2.43, 95% CI=1.16-5.07, P=0.018). Neither procedure differed significantly in terms of complications (6.0% vs. 5.7%, P>0.999). GS-TBNA performed in addition to EBUS-GS TBB might be a promising sampling method for improving the diagnostic yield for PPLs without increasing the incidence of complications.

X-ray imaging of multiple adjacent regions in paediatric patients: Potential utility for diagnosis and patient management

BackgroundIn emergency presentations, it is not uncommon for patients to present with imaging requests of multiple body regions to detect concurrent injury. While current literature explores diagnostic efficacy of adjacent imaging for forearm fractures, there is limited research on its effectiveness across all extremities. This paper explores the diagnostic yield of X-ray adjacent imaging of the upper and lower limb in paediatric patients. MethodsA retrospective audit was performed using information available on radiology request forms from paediatric patients (age <18 years) that had multiple X-rays of adjacent body regions over six months at two hospitals. The main or first X-ray was referred to as initial imaging, while all subsequent X-rays of adjacent regions was considered secondary imaging. Clinical history and radiologists’ findings were collected, categorised, and analysed using Chi square. ResultsThere were 661 X-rays performed across 277 patients. Initial imaging was significantly more likely to detect injuries or abnormalities (35 %) than X-rays of adjacent regions (1.6 %), with 94 % of all abnormalities detected on initial imaging overall (χ2(3) = 241.247, p < 0.001). X-ray request forms with no clinical symptoms were significantly more likely to have no findings detected (χ2(3) = 53.493, p < 0.001). ConclusionX-ray imaging of a body region adjacent to an injury has low diagnostic yield, suggesting the need for interventions to reduce unnecessary adjacent X-ray imaging. Clinical history information was often limited and concurrent injuries were low.

Feasibility and Safety of Transesophageal Mediastinal Cryobiopsy in the Diagnosis of Mediastinal Pathologies

Introduction: Endobronchial ultrasound-guided transbronchial needle aspiration remains the gold standard for the diagnosis of mediastinal pathologies. Its greatest limitation has been the low diagnostic yield in lymphoproliferative disorders as well as insufficient samples for molecular testing. Transesophageal examinations using an EBUS scope have helped increase the diagnostic yield by allowing for additional biopsies of paraesophageal and intra-abdominal lesions. Similarly, the novel approach of transbronchial mediastinal cryobiopsy has further increased the yield by providing larger and better-preserved biopsies. Both complimentary techniques have shown great individual feasibility and safety. However, the feasibility of transesophageal cryobiopsies in the evaluation of mediastinal pathologies remains a subject of debate. Aim: The aim of the study was to investigate the safety and feasibility of transesophageal EBUS-guided mediastinal cryobiopsies performed at our center. Methods: We conducted a retrospective review of 30 patients who underwent mediastinal cryobiopsy through the esophagus at our institution between October 2023 and March 2024. Data on patient demographics, diagnostic yield, and complications were collected and analyzed. Results: The mean patient age was 43 years, with a gender distribution of 60% male and 40% female. The primary indications included suspicion of lymphoproliferative disorders, suspected sarcoidosis, and malignancies with paraesophageal lesions. The overall diagnostic yield was 93%. No major complications were noted in any of the patients. Conclusion: Transesophageal mediastinal cryobiopsy appears to be a promising complimentary technique for mediastinal evaluation with a relatively high diagnostic yield and favorable safety profile. However, further studies with larger cohorts are warranted to validate the findings at our institution.

Role of new generation implantable loop recorders in managing undiagnosed pediatric cardiac symptoms

Pediatric cardiac symptoms such as palpitations, syncope, or seizure-like episodes pose diagnostic challenges for general pediatricians. These symptoms, though often benign, may reveal underlying arrhythmias or inherited cardiac conditions (ICCs), affecting the quality of life and limiting activity participation. The purpose of this study is to determine the effectiveness and safety of implantable loop recorders (ILRs) in diagnosing and managing arrhythmias in pediatric patients. A retrospective cohort study conducted over an 8-year period from January 2016 to December 2023 in a single pediatric cardiology center. A cohort of 155 pediatric patients (median age 11.4 years) who underwent ILR implantation were selected based on symptoms such as palpitations, chest pain, or syncope, and those with previously recorded arrhythmias or high-risk ICCs. The primary outcomes were the diagnostic yield of ILRs for arrhythmias and subsequent changes in patient management. Diagnostic yield was defined as the detection of relevant arrhythmias, such as pauses of 3 s or longer, high-degree AV block, sinus node dysfunction, supraventricular tachycardia, ventricular tachycardia, or inappropriate sinus tachycardia. The median follow-up period was 2.3 years (845 days). Diagnostic arrhythmias were recorded in 60% of patients with symptom-activated transmissions and 80% of device-activated transmissions. Sinus pauses (37.5%) and VT (30%) were the most common arrhythmias detected. In patients with syncope (n = 76), 30% had relevant arrhythmias. In the palpitations group (n = 20), 35% had relevant arrhythmias. Approximately 80% of patients with ILR-diagnosed arrhythmias underwent targeted management, including medication changes and additional procedures. No significant complications were observed; minor complications occurred in 2.5% of patients.Conclusions: New generation ILRs are effective and safe for diagnosing and managing pediatric arrhythmias, providing significant reassurance to patients and families. Further studies are needed to evaluate the impact of ILRs on quality of life and sports participation in high-risk young patients.What is Known:• Pediatric Cardiac Symptoms: Symptoms like palpitations, syncope, and seizure-like episodes in pediatric patients pose significant diagnostic challenges.• Diagnostic Tools: Traditional diagnostic tools such as ECG, Holter monitors, and external loop recorders often have low diagnostic yields due to the sporadic nature of symptoms.• Implantable Loop Recorders (ILRs): ILRs have been shown to improve the diagnostic yield for arrhythmias in adults and provide long-term rhythm monitoring.What is New:• Effectiveness in Pediatrics: This study demonstrates that new generation ILRs significantly enhance the diagnostic yield for arrhythmias in pediatric patients with undiagnosed cardiac symptoms.• Safety and Efficacy: The study confirms that ILRs are both safe and effective in the pediatric population, with minimal complications and high diagnostic accuracy.• Targeted Management: Findings show that ILR-diagnosed arrhythmias lead to targeted management changes in approximately 80% of cases, including medication adjustments and additional procedures.• Long-term Monitoring: ILRs provide continuous long-term monitoring, offering reassurance to patients and families, and potentially improving quality of life and participation in activities for high-risk young patients.

An explorative analysis on the optimal cryo-passes and freezing time of the ultrathin cryoprobe in endobronchial ultrasound-guided transbronchial mediastinal cryobiopsy

EBUS-guided transbronchial mediastinal cryobiopsy (TBMC) has emerged as a promising biopsy tool for diagnosing hilar and mediastinal pathologies. However, several fundamental technical aspects of TBMC remain unexplored. This study aims to determine the optimal number of cryo-passes and freezing time of the ultrathin cryoprobe in EBUS-TBMC concerning specimen size and procedural diagnostic yield. We conducted a retrospective chart review of patients with mediastinal and hilar lesions who underwent EBUS-TBMC between January 2021 and April 2023 across three hospitals in Malaysia. A total of 129 EBUS-TBMC procedures were successfully completed, achieving an overall diagnostic yield of 88.4%. Conclusive TBMC procedures were associated with larger specimen sizes (7.0 vs. 5.0 mm, p < 0.01). Specimen size demonstrated a positive correlation with diagnostic yield (p < 0.01), plateauing at specimen size of 4.1–6.0 mm. A significant positive correlation was also observed between the number of cryo-passes and both specimen size (p < 0.01) and diagnostic yield (p < 0.05). Diagnostic yield plateaued after 2–3 cryo-passes. In contrast, longer freezing times trended towards smaller specimens and lower diagnostic yield, though not reaching statistical significance. The highest diagnostic yield was recorded at the 3.1–4.0 s freezing time. The safety profile of TBMC remains favourable, with one case (0.8%) of pneumothorax and nine cases (7%) of self-limiting bleeding. In our cohort, TBMC performance with 2–3 cryo-passes and a 3.1–4.0 s freezing time to achieve a total aggregate specimen size of 4.1–6.0 mm appeared optimal. Further prospective studies are needed to validate these findings.

Prospective multicenter study to identify optimal target population for motorized spiral enteroscopy

Motorized spiral enteroscopy (MSE) enhances small bowel exploration, but the optimal target population for this technique is unknown. We aimed to identify the target population for MSE by evaluating its efficacy and safety, as well as detecting predictors of efficacy. A prospective multicenter observational study was conducted at 9 tertiary hospitals in Spain, enrolling patients between June 2020–2022. Analyzed data included demographics, indications for the procedure, exploration time, depth of maximum insertion (DMI), technical success, diagnostic yield, interventional yield, and adverse events (AE) up to 14 days from enteroscopy. Patients with prior gastrointestinal surgery, unsuccessful balloon enteroscopy and small bowel strictures were analyzed. A total of 326 enteroscopies (66.6% oral route) were performed in 294 patients (55.1% males, 65 years ± 21). Prior abdominal surgery was present in 50% of procedures (13.5% gastrointestinal surgery). Lower DMI (162 vs 275 cm, p = 0.037) and diagnostic yield (47.7 vs 67.5%, p = 0.016) were observed in patients with prior gastrointestinal surgery. MSE showed 92.2% technical success and 56.9% diagnostic yield after unsuccessful balloon enteroscopy (n = 51). In suspected small bowel strictures (n = 49), the finding was confirmed in 23 procedures (46.9%). The total AE rate was 10.7% (1.8% classified as major events) with no differences related to prior gastrointestinal/abdominal surgery, unsuccessful enteroscopy, or suspected small bowel strictures. The study demonstrates that MSE has a lower diagnostic yield and DMI in patients with prior gastrointestinal surgery but is feasible after unsuccessful balloon-enteroscopy and in suspected small bowel strictures without safety concerns.

Schwannoma masquerading as a thyroid nodule: A diagnostic delimma.

We present a case of a 70 years old female presenting with a long-standing neck swelling with a recent increase in size and new onset pain. It was initially diagnosed and operated on as a cold nodule of thyroid as her thyroid scan showed left cold nodule and FNAC was inconclusive. However, a final diagnosis of schwannoma with Antoni A structures was made on histopathological attributes. Schwannomas are benign peripheral nerve tumors which grow slowly on parent nerves. The mainstay of treatment is surgical excision. To avoid unnecessary or inappropriate interventions, thorough pre-operative assessment is required in case of thyroid or non-thyroidal lesions as most are hypoechogenic on ultrasonography and fine needle aspiration has low diagnostic yield. The key pre-operative investigations are ultrasound and ultrasound guided cytology and immunohistochemical staining (for example S-100, calcitonin, CEA, thyroglobulin, TTF-1, melan-A, HMB45 and Ki-67). MRI is also a good diagnostic tool in neck swellings where diagnosis is uncertain.

Diagnostic Performance of Cardiac Stress Testing Following Exclusion of Acute Myocardial Infarction with a 0/1-Hour, High-Sensitivity Cardiac Troponin Protocol

Background: Rapid exclusion of acute myocardial infarction (AMI) is critical for patients presenting to emergency departments (EDs) with chest pain or other anginal equivalents. High-sensitivity cardiac troponin (hs-cTn) protocols have been widely adopted in the United States for this purpose. These protocols allow for early identification and exclusion of patients with AMI using a 0 and 1-hour hs-cTn measurement. However, little is known about the use of cardiac stress testing in patients who ruled-out for AMI within 1 hour with very low hs-cTn values. This study analyzed the diagnostic performance of cardiac stress tests in this population. Methods: We performed a secondary analysis of the RACE-IT trial, a stepped-wedge cluster randomized trial performed across 9 EDs in a large metropolitan health system from July 2020 through March 2021. The eligibility criteria for the trial mirrored the real-world use of hs-cTn testing, including both patients complaining of chest pain and/or other anginal equivalents. All adults with a hs-cTnI and electrocardiogram (ECG) completed in the ED were enrolled, while patients with ST- segment elevation AMI, trauma, or pregnancy were excluded. In the interventional arm of the trial, AMI was excluded if hs-cTnI was &lt;4 ng/L at presentation or =4 ng/L at presentation with a 1-hour value &lt; 8 ng/L. The trial followed all patients through 30 days to assess for AMI or death and captured all cardiac testing. We compared stress testing results to invasive coronary imaging with or without revascularization. Results: 10,444 study patients (43.61%) ruled out for AMI in the ED within 1 hour and were included in this analysis. There were 320 (3.0%) patients who had a stress test within 30 days, with few ischemic findings (25, 0.24%) or revascularization procedures (5, 0.05%). The positive predictive value of stress testing in this population to identify the need for revascularization was 10.1% (95% CI 2.8% - 29.4%). Table 1 displays the proportion of ischemic stress tests and overall test performance in this population. The rate of 30-day death or AMI was low (17, 0.20%) among those discharged from the ED or placed in observation (n=8,553). Conclusions: Our study highlights the infrequent use and low diagnostic yield of stress testing in patients who have been ruled out for AMI within 1 hour using an accelerated hs-cTn protocol in the ED.

Neurological diagnostic tests for patients with and without delirium: a prospective observational study.

Since most of the precipitating factors of delirium are not due to neurological disorders, neurological diagnostic tests (NDTs) may be of limited value. We hypothesized that delirium has a high burden of NDTs with a low diagnostic yield. All patients admitted to the internal medicine wards of a single secondary teaching hospital between November 2019 and January 2020 were eligible. Within the first 48 h of their admission, they had a formal evaluation by a neuropsychologist to screen for presence of delirium. NDTs (brain MRI, brain CT, electroencephalography (EEG), and lumbar puncture) performed during the hospital stay were compared between patients with and without delirium using a logistic regression model stratified by a propensity score. The proportions of diagnostic yield (acute anomalies that changed the treatment management) provided by each type of examination were compared. Of 217 patients included, 19/32 patients (61%) with delirium had one or more NDTs, compared to 48/185 (26%) without delirium (adjusted OR 2.7; 95%CI 1.1-6.7; p = 0.027). The proportions of NDT results affecting management for patients with and without delirium were 13 and 20% for brain CT scans (p = 0.71), 29 and 38% for brain MRI (p = 0.99), and 20 and 10% for EEGs (p = 0.99), respectively. The higher proportion of NDTs performed on patients with delirium was associated with a low diagnostic yield, although not statistically different from those performed among inpatients without delirium. There is a need for restrictive, evidence-based guidelines to help with the work-up for patients with delirium.

Country-specific differences in the lung tumour microbiome.

e20044 Background: Sputum examination for the early detection of lung cancer continues to be explored ( Thunnissen 2003 ), however has so far resulted in a low diagnostic yield. An increasing number of studies have evidenced a mechanistic role of the lung microbiome in the induction of lung cancer ( Liu et al., 2020 ), and the presence of bacterial biomarkers in bronchoalveolar lavage and sputum have been proposed ( Cheng et al., 2020 ). It is currently unknown whether the sputum microbiome can appropriately capture the lung tumour microbiome. Given that the lung microbiome may vary by geography, this analysis was considered over two populations: China and Italy. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. Data from 9 studies was used. In total, 461 samples from lung cancer patients in China (250 sputum, 211 tumour) and 60 from Italy (34 sputum, 26 tumour) were considered. Shannon’s diversity was used to consider within-sample diversity, and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Results: All sample were checked to have a library size greater than 100, and more than 10 unique species. Only those species present in over 1% of samples were considered to reduce noise. In both China and Italy, tumour samples had a lower diversity than sputum samples (p = 0.00016 and p &lt; 2.2e-16, respectively). Samples from Italy had a lower diversity than samples from China (p &lt; 2.22e-16). In the MDS analysis, the tumour samples from China and Italy formed two distinct, non-overlapping clusters. A third cluster was formed from the union of sputum samples from both countries. These results were independent of any study-specific effects. Conclusions: These results indicate that the sputum microbiome is not representative of the tumour microbiome, and that the divergence of the tumour microbiome away from the sputum microbiome is country specific. The results of this analysis highlight that further work into differences in the lung tumour microbiome by country is warranted, especially in light of the growing body of evidence suggesting a causative role of the microbiome in lung cancer. It is also possible that lung cancer treatments may be impacted by the country-specific nature of the lung tumour microbiome.

Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

Comparison of The Results of Sponsored Genetic Testing Panels for Inherited Retinal Diseases.

Background/Objectives: Gene therapy's emergence has made molecular diagnosis for inherited retinal diseases clinically significant. Free genetic testing panels have improved testing access in clinical practice, yet the interpretation of results, especially variants of unknown significance (VUS), remains challenging and requires expertise. This study shares our experience in utilizing sponsored IRD panel tests by Invitae and Blueprint Genetics (BG), reporting their positivity rates, and comparing their reclassification of variants through amendments. Methods: This retrospective study analyzed genetic test reports from patients who underwent testing via Invitae or BG panels. A positive test was determined if there was a pathogenic mutation in an autosomal dominant gene, two pathogenic mutations in an autosomal recessive gene, or a pathogenic mutation in an X-linked gene in a male patient. Results: The testing positivity rates were 34.9% for Invitae (n = 109) and 42.1% for BG (n = 107). Invitae had more pathogenic variants per report (0.87 vs. 0.58 variants, p = 0.0038) and issued more amendments than BG (0.54 vs. 0.03 amendments; p < 0.01). Of the Invitae variant classification changes, 66.2% switched a VUS to benign. In the BG group, 75% of variant reclassifications changed a VUS to pathogenic. As a result of the Invitae amendments, 88% did not change the overall report result. Conclusions: While free-of-charge genetic testing panels offer valuable insights for diagnosing IRD, limitations such as low diagnostic yield and variant classification discrepancies persist between Invitae and BG. VUS should not be considered pathogenic in the clinical decision-making process. Careful interpretation of genetic testing is required.

Unfolding the transition ratio: insight into the diagnostic criteria for the diagnosis of the origin of outflow tract ventricular arrhythmias

Abstract Background algorithms for the diagnosis of the site of origin of ventricular outflow tract arrhythmias (OTVA) share the rationale that more posterior structures (LVOT) produce a greater vector approaching the precordial leads than anterior structures (RVOT), i.e. R waves in V1-V3 of greater amplitude and duration, a transition generally earlier than the QRS in sinus rhythm (SR), and vice-versa. Methods in a retrospective cohort of 45 patients (53.3% LVOT, 46.7% RVOT) with OTVA (left bundle branch block morphology, transition in lead V3, absence of conduction aberrancy in SR, who underwent successful catheter ablation were retrospectively analyzed, comparing the diagnostic yield of the main literature criteria. a) The V2 transition ratio, (TR) calculated with the formula [(R\R+S)PVC : (R\R+S)SR] (LVOT if &amp;gt; 0.6) [1]. b) The V1-V2 S-Rd, calculated as [(V1S + V2S) – (V1R + V2R)] (LVOT if &amp;lt; 1.625) [2]. c) The V2S\V3R amplitude ratio (LVOT if &amp;lt; 1.5) [3]. d) The transition zone index (TZI), obtained by subtracting the transition zone of the PVC with that of the SR (LVOT if &amp;lt; 0) [4]. We extended the use of these criteria to the precordial leads V1 to V3; for TR the equation was applied to amplitude as well as duration measurements. Results Comparison of PVC QRS morphology with that of SR. 1. The diagnostic accuracy of the TR showed incremental values moving from lead V1 to V3, both using amplitude and duration measurements; compared to the modest accuracy of the V2 TR (AUC 0.630, 0.727), the V3 TR (LVOT if &amp;gt; 1) showed an accuracy of 85.3% (AUC 0.804, 0.855). 2. Simplifying the complex TR equation, comparing R or S waves of the PVC with those of the SR, we again found incremental values of accuracy moving from lead V1 to V3, with better results for the SVT\SSR compared to the RVT\RRS; the V3 SVT\SRS) (LVOT if &amp;lt; 1) showed an accuracy of 86.6% (AUC 0.917). 3. The TZI showed in our series a lower diagnostic yield compared to that of the literature (AUC 0.748, accuracy 73.3%) Comparison of PVC QRS morphology between two contiguous leads: 4. Compared to the V1-V2 S-Rd (AUC 0.830), the V2-V3 S-Rd (AUC 0.855), calculated as [(V2S + V3S) – (V2R + V3R)] showed greater accuracy (82.2%). 5. Similarly, compared to the V1S\V2R amplitude ratio (AUC 0.774), the V2S\V3R (AUC 0.930) showed the greatest accuracy (88.8%, with a more balanced sensitivity and specificity moving the cut-off for the diagnosis of origin from LVOT to &amp;lt; 2), resulting the criterion with the highest diagnostic yield. Conclusions variables that compare the morphology of the QRS of the PVC of two contiguous leads have greater accuracy than those that compare the morphology of the QRS of the PVC with that of the SR, with greater diagnostic yield when applied from lead V1 to V3; the V2S\V3R ratio represents the best criterion, with high sensitivity, like the V3 transition ratio; the simple ratio (SVT\SSR) can virtually replace the more complex TR, with similar accuracy but high specificity.

Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India

BackgroundCurrent clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India.Results903 smMIPs were designed to target exon and exon–intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood.ConclusionWe developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.