Blinded Cohort Research Articles

Diagnosis and Biomarker Screening of Endometrial Cancer Enabled by a Versatile Exosome Metabolic Fingerprint Platform.

Exosomes have emerged as a revolutionary tool for liquid biopsy (LB), as they carry specific cargo from cells. Profiling the metabolites of exosomes is crucial for cancer diagnosis and biomarker discovery. Herein, we propose a versatile platform for exosomal metabolite assay of endometrial cancer (EC). The platform is based on a nanostructured composite material comprising gold nanoparticle-coated magnetic COF with aptamer modification (Fe3O4@COF@Au-Apt). The unique design and novel synthesis strategy of Fe3O4@COF@Au-Apt provide the material with a large specific surface area, enabling the efficient and specific isolation of exosomes. The exosomes captured Fe3O4@COF@Au-Apt can be directly used as the laser desorption/ionization mass spectrometry (LDI-MS) matrix for rapid exosomal metabolic patterns. By integrating these functionalities into a single platform, the analytical process is simplified, eliminating the need for additional elution steps and minimizing potential sample loss, resulting in large-scale exosomal metabolic fingerprints. Combining with machine learning algorithms on the metabolic patterns, accurate discrimination between endometrial patients (EGs) and benign controls (CGs) was achieved, and the area under the receiver operating characteristic curve of the blind test cohort was 0.924. Confusion matrix analysis of important metabolic fingerprint features further demonstrates the high accuracy of the proposed approach toward EC diagnosis, with an overall accuracy of 94.1%. Moreover, four metabolites, namely, hydroxychalcone, l-acetylcarnitine, elaidic acid, and glutathione, have been identified as potential biomarkers of EC. These results highlight the great value of the integrated exosome metabolic fingerprint platform in facilitating low-cost and high-throughput characterization of exosomal metabolites for cancer diagnosis and biomarker discovery.

Post-surgery sequelae unrelated to disease progression and chemotherapy revealed in follow-up of patients with stage III colon cancer

We studied the poorly-known dynamics of circulating DNA (cir-nDNA), as monitored prospectively over an extended post-surgery period, in patients with cancer. On patients with stage III colon cancer (N=120), using personalised molecular tags we carried out the prospective, multicenter, blinded cohort study of the post-surgery serial analysis of cir-nDNA concentration. 74 patients were included and 357 plasma samples tested. During post-operative follow-up, the patients' median cir-nDNA concentration was greater (P<0.0001 in the [43-364 days range]) than both the median value in healthy individuals and the pre-surgery value. These cir-nDNA levels were highly associated with NETs markers (P-value associating MPO and cir-nDNA, and NE and cir-nDNA are 6.6 x 10-17, and 1.9 x 10-7), in accordance with previous reports which indicate that cir-nDNA are NETs by-products. Unexpectedly, in 34 out of 50 patients we found that NETs continued to be formed for an extended duration post-surgery, even in patients without disease progression. Given that this phenomenon was observed in patients without adjuvant CT, and in patients >18 months post-surgery, the data suggest that the persistence of NETs formation is not due to the adjuvant CT. (1), Given the inter-patient heterogeneity, the post-surgery cir-nDNA level cannot be considered a reliable value, and caution must be exercised when determining mutation allele frequency or the mutation status; and (2), specific studies must be undertaken to investigate the possible clinical impact of the persistent, low-grade inflammation resulting from elevated NETs levels, such as observed in these post-surgery patients, given that such levels are known to potentially induce adverse cardiovascular or thrombotic events. This work was supported by the H2020 European ERA-NET grant on Translational Cancer Research (TRANSCAN-2).

Identification potential biomarkers for diagnosis, and progress of breast cancer by using high-pressure photon ionization time-of-flight mass spectrometry

BackgroundIn this study, exhaled breath testing has been considered a promising method for the detection and monitoring of breast cancer (BC). MethodsA high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) platform was used to detect volatile organic compounds (VOCs) in breath samples. Then, machine learning (ML) models were constructed on VOCs for the diagnosis of BC and its progression monitoring. Ultimately, 1981 women with useable breath samples were included in the study, of whom 937 (47.3 %) had been diagnosed with BC. VOC panels were used for ML model construction for BC detection and progression monitoring. ResultsOn the blinded testing cohort, this VOC-based model successfully differentiated patients with and without BC with sensitivity, specificity, and area under receiver operator characteristic curve (AUC) values of 85.9 %, 90.4 %, and 0.946. The corresponding AUC values when differentiating between patients with and without lymph node metastasis (LNM) or between patients with tumor-node-metastasis (TNM) stage 0/I/II or III/IV disease were 0.840 and 0.708, respectively. While developed VOC-based models exhibited poor performance when attempting to differentiate between patients based on pathological patterns (Ductal carcinoma in situ (DCIS) vs Invasive BC (IBC)) or molecular subtypes (Luminal vs Human epidermal growth factor receptor 2 (HER2+) vs Triple-negative BC (TNBC)) of BC. ConclusionCollectively, the HPPI-TOFMS-based breathomics approaches may offer value for the detection and progression monitoring of BC. Additional research is necessary to explore the fundamental mechanisms of the identified VOCs.

P-166 An artificial intelligence-powered tool to score fresh donor oocytes and predict blastulation: interim analysis of a prospective investigation conducted at 3 laboratories

Abstract Study question Is the Magenta-score associated with fresh donor oocytes’ blastulation competence, and can it be used to predict blastocyst rates per cohort of inseminated oocytes (BRpC)? Summary answer Developmentally-competent fresh donor oocytes showed significantly higher Magenta-score, although the number of blastocysts obtained was within the predicted range in only 63% of the cycles. What is known already Currently, many couples undergo donor oocyte treatments. However, despite donors being theoretically fertile, not all oocytes are developmentally competent, and many do not reach the blastocyst stage. Even if subjective and ineffective to predict oocyte competence, visual oocyte morphological assessment is still routinely used to evaluate oocytes. Lately, the rise of artificial intelligence (AI) resulted in promising tools to assess oocytes more objectively in a standardized method, possibly providing novel insights into the prediction of their competence. In this context, Magenta-score (Future Fertility), an AI-based image analysis tool, can potentially prove useful to optimize the management of oocyte donation treatments. Study design, size, duration A Blinded cohort study (June-2023/December-2023) was conducted to assess the primary outcome: association between fresh donor-oocytes’ Magenta-Score and their subsequent blastocyst development (assumed to be 50%). A sample size of 779 achieves 80%-power to detect the difference between the null-hypothesis point-biserial-correlation of 0 and the alternative hypothesis of 0.1 using a two-sided test with 5%-significance. Secondary outcomes were differences (i) predicted - true BRpCs, and (ii) predicted - true numbers of blastocysts obtained. Participants/materials, setting, methods Interim-analysis of 514 fresh-oocytes obtained from 63 donors at 3 centers and allocated (7.7±3, range:3-18) to 67 recipients. Pictures of denuded mature oocytes were acquired before ICSI. Magenta-scores were generated blindly (providing only donor age and total number of mature oocytes in cohort to the software). The software also estimated BRpCs and range of blastocysts obtainable from each cohort. Donors’ characteristics, ovarian stimulation/treatment cycle parameters, and sperm analyses were tested as confounders. Main results and the role of chance The only visual oocyte anomaly associated with lower Magenta-score was irregular shape (N = 484,5.4±2.2 vs N = 30,3.3±2.1, Mann-Whitney-U&amp;lt;0.01). Oocytes that developed into blastocysts (N = 194) had significantly higher Magenta-scores versus oocytes that did not reach this milestone (N = 320) (5.8±2.1 vs 4.9±2.3, Mann-Whitney-U&amp;lt;0.01; Odds-Ratio adjusted for sperm motility and incubator [standard/time-lapse]=1.26, 95%CI:1.13-1.34, p &amp;lt; 0.01; power=99.6%). No association was noted with day of blastulation or morphological quality. Data were concordant across centers. The average predicted-BRpC was 39.4±11.4% versus a true-BRpC of 40.6±22.6% (Person’s correlation: -0.24; mean difference: -1.1±27.6%, 95%CI from -7.8% to + 5.6%, p = 0.74). The average predicted number of blastocysts per oocyte cohort was 3.3±1.6 versus a true average of 2.9±1.7 (Person’s correlation: 0.25; mean difference: +0.4±2.0, 95%CI from -0.04 to + 0.9, p = 0.07). In 21% (N = 14) and 31% (N = 21) of cycles, the tool predicted an equal or lower number of blastocysts, respectively. In 5 cycles, no blastocyst was obtained, but the tool did not predict this unexpected outcome. When testing the predicted range of blastocysts obtained, the true number was within the range in 63% (N = 42) of cases and higher than the maximum predicted number in 13% (N = 9) of cases. No confounder was identified on the BRpC in this population of fresh donor cycles. Limitations, reasons for caution Of note, this is an interim analysis of an ongoing study. Not all mature oocytes recovered from a donor were utilized, thus not all oocytes in a cohort were imaged and included in analysis. Other putative confounders on BRpC should be considered in future studies with a larger sample size. Wider implications of the findings Effective management of an oocyte donation program is critical to comply with expected high success rates while minimizing the number of surplus blastocysts produced. The integration of genomic data, recipient couples’ characteristics, and the benefits of objective standardized AI-powered oocyte scoring is the most promising workflow to optimize this task. Trial registration number Not applicable

Ultrasound Guided Bilateral Erector Spinae Plane Block vs Intravenous Patient-Controlled Analgesia for Pain after Total Laparoscopic Hysterectomy

Abstract Background Pain is an everyday challenge during all surgeries and it is a chief postoperative complication, so pain management is a corner stone in anesthetic practice. Total Laparoscopic Hysterectomy (TLH) is a minimally invasive procedure, it has certain advantages over an open abdominal hysterectomy, such as reduced pain, less incidences of wound infection, a rapid recovery, a shorter hospital stay and lower complication Aim of the Work The present study was designed to assess the analgesic efficacy and safety of ultrasound guided ESPB done at lower thoracic transverse process level in patients undergoing TLH for postoperative analgesia versus intravenous patient-controlled analgesia. Patients and Methods This study is as Prospective double blinded cohort study, it was performed on Patients undergoing elective Total laparoscopic hysterectomy (TLH) in the hospital of gynecology of Ain Shams university hospitals over a period of six months. Patients who fulfilled the inclusion criteria and agreed to participate in the study were randomly divided into two groups using computer-generated randomized list such that group A for ESPB and group B for PCA. Results The main finding in this study was that ultrasound guided ESPB at level of thoracic process provided a good analgesic effect in patients undergoing TLH also reduced the need for rescue analgesia and the total amount of postoperative opioid consumption in comparison to PCA group, Prolonged the time to first request of analgesia (duration of analgesia), Provided early mobilization, Increase patient satisfaction in 1st 24 hour and Decrease incidence of nausea and vomiting due to decrease opioids intake. Conclusion Ultrasound-guided erector spinae plane block was found statistically efficient in reducing postoperative opioid consumption, alleviating postoperative pain scores and improving patients’ satisfaction in the first 24 hours after TLH, without associated adverse effects or complications like nausea and vomiting, nerve injury, respiratory depression and hematoma formation.

Unveiling the secrets of gastrointestinal mucous adenocarcinoma survival after surgery with artificial intelligence: A population-based study.

Research on gastrointestinal mucosal adenocarcinoma (GMA) is limited and controversial, and there is no reference tool for predicting postoperative survival. To investigate the prognosis of GMA and develop predictive model. From the Surveillance, Epidemiology, and End Results database, we collected clinical information on patients with GMA. After random sampling, the patients were divided into the discovery (70% of the total, for model training), validation (20%, for model evaluation), and completely blind test cohorts (10%, for further model evaluation). The main assessment metric was the area under the receiver operating characteristic curve (AUC). All collected clinical features were used for Cox proportional hazard regression analysis to determine factors influencing GMA's prognosis. This model had an AUC of 0.7433 [95% confidence intervals (95%CI): 0.7424-0.7442] in the discovery cohort, 0.7244 (GMA: 0.7234-0.7254) in the validation cohort, and 0.7388 (95%CI: 0.7378-0.7398) in the test cohort. We packaged it into Windows software for doctors' use and uploaded it. Mucinous gastric adenocarcinoma had the worst prognosis, and these were protective factors of GMA: Regional nodes examined [hazard ratio (HR): 0.98, 95%CI: 0.97-0.98, P < 0.001)] and chemotherapy (HR: 0.62, 95%CI: 0.58-0.66, P < 0.001). The deep learning-based tool developed can accurately predict the overall survival of patients with GMA postoperatively. Combining surgery, chemotherapy, and adequate lymph node dissection during surgery can improve patient outcomes.

Non-technical skills of Norwegian medical students at different training sites: a comparative, observational cohort study

PurposeMastering non-technical skills (NTS) is a fundamental part of the training of new physicians to perform effectively and safely in the medical practice environment. Ideally, they learn these skills during medical school. Decentralized medical education is being implemented increasingly worldwide. Two of the three training sites studied, Bodø (a regional hospital) and Finnmark (a rural local hospital), implemented decentralized medical education. The third training site was the main campus in Tromsø, located at an urban university hospital. The training in Finnmark emphasised training in non-technical skills using simulation to a larger extent than the two other university campuses. This study aimed to compare the NTS performance of medical students in their last year of education at three different training sites of the same university.MethodsThis blinded cohort study included students from the three training sites who participated in identical multi-professional simulations over a six-year period. Eight raters evaluated the video recordings of eight students from each training site using the Norwegian Medical Students Non-Technical Skills (NorMS-NTS) tool. The NorMS-NTS tool, which comprises four categories and 13 elements, assesses the NTS of Norwegian medical students and assigns an overall global score. Pairwise significant differences in the NTS performance levels between the training sites studied were assessed using Tukey’s test.ResultsThe overall NTS performance levels of the medical students from Finnmark (mean 4.5) were significantly higher than those of the students from Tromsø (mean 3.8) and Bodø (mean 3.5). Similarly, the NTS performance levels at category-level of the students in Finnmark were significantly higher than those of the students from Bodø and Tromsø. Except for one category, no significant differences were observed between the students from Bodø and Tromsø in terms of the overall or category-level NTS performance.ConclusionThe NTS performance levels of the medical students from Finnmark, which implements rural, decentralized medical education, were significantly higher than those of the students from Tromsø and Bodø.

Association of combination tumor texture and vessel tortuosity with progression free survival across PD-L1 subgroups in durvalumab treated non-small cell lung cancer (NSCLC): Blinded validation results from CP1108.

8600 Background: Immunotherapy (IO) has shown a durable response with minimal toxicity in the treatment of metastatic NSCLC. However, only 30-50% of these patients (pts) actually respond. Despite initial optimism surrounding PD-L1 expression as a potential biomarker, IO provides benefit across PD-L1 low (&lt;25%) and high (≥25%) status. This highlights a critical need for more effective biomarkers to guide treatment decisions. Here, we present blinded validation results of a CT-based biomarker of change in quantitative vessel tortuosity (1) (Δ-QVT) and texture radiomics (2) (Δ-Rad) between baseline (B) and 6 weeks post-treatment (TP1) for predicting response, overall survival (OS) and progression free survival (PFS) in CP1108 (NCT01693562). Methods: CT scans at B and TP1 were retrospectively analyzed from two studies (a) a multi-center training set (Str, N=110) of metastatic NSCLC pts treated with first line IO and (b) a blinded NSCLC cohort of N = 151 pts treated with Durvalumab in CP1108 study (Sv). In Sv, N=75 pts were PD-L1 high (Sv+) whereas N=65 pts were PD-L1 low (Sv-). An in-house MATLAB based algorithm was used to extract intra-tumoral, peri-tumoral texture and QVT features from up to two largest measurable tumors in each CT. A classifier (MCombo) was trained on Str to predict best overall response defined as per the RECIST v1.1 criteria using combination of Δ-QVT and Δ-Rad features. Area under the receiver operating characteristic (AUC) was used to evaluate MCombo against RECIST response whereas univariable and multivariable Cox regression models with log-rank test, hazard ratio (HR) with confidence interval (CI) and concordance index (C-index) were used to study the association of MCombo with OS and PFS in Sv, Sv+, and Sv-. Results: MCombo predicted objective response with an AUC of 0.78 in Sv and was statistically significantly associated with PFS (Table) in Sv, Sv+, and Sv-. MCombo was associated with OS in Sv, Sv+, but not in Sv-. Multivariable analysis with PD-L1 status, histological subtype, ECOG status, liver metastasis, line of therapy and sex showed independent association of MCombo across OS and PFS. Conclusions: Our results indicate that combination of radiomics and vessel tortuosity biomarker from CT is independently prognostic of response and PFS across PD-L1 levels. Prospective validation of this biomarker is needed. 1. Alilou et al. Sci Adv 2022. 2. Khorrami et al. Cancer Immunol Res 2020. [Table: see text]

Altered serum metabolome as an indicator of paraneoplasia or concomitant cancer in patients with rheumatic disease

ObjectivesA timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both...

A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

Abstract 3746: Identification of cancer specific extracellular vesical biomarkers to aid in diagnosis of cancer

Abstract The limitations of serial tumor biopsies are well known, thus liquid biopsies which allow for repeated plasma-based biomarker analysis are urgently needed. Extracellular vesicles (EVs) represent an extremely stable and emerging proteomic substrate which allows for deep enrichment of biologically relevant signals from plasma, and broad analysis of tumor associated and host response proteins. To identify novel biomarkers, we performed proteomics analysis on EVs purified using size exclusion chromatography and a proprietary buffer system which increases EV and corona protein recovery. Initial DIA mass spectrometry (MS) analysis was performed on EVs from 125 patients (25 each from CRC, breast, NSCLC, ovarian, and normal patients). A subset of 25 normal and 25 ovarian was subjected to a second deeper analysis on a much more powerful DIA platform. Initial analysis identified 204 unique proteins differentially expressed in ovarian cancer patients (&amp;gt;2-fold change; p&amp;lt;0.05). Repeat analysis of the ovarian vs normal cohorts on the Biognosys TrueDiscovery™ platform identified 645 differentially expressed, a significant increase in depth of analysis. These cancer exosome associated proteins represent a broad range of host response signals. Taking ~20 of the top proteins, we extended our analysis using ELISAs to determine if the results by MS were reproducible in a simpler format. The ELISA analysis recapitulated the MS results. This confirms that the TrueDiscovery™ platform can easily be translated into a simple, quick and distributable ELISA platform. Extending these results, a blinded cohort of ovarian and normal EVs was analyzed using a predefined cutoff for a host immune response biomarker. This blinded analysis demonstrated sensitivity of 1.0 and specificity of 0.9, exceptionally high values for a single analyte assay, underscoring the potential value of analyzing the host/immune response proteins in the context of the EV microenvironmentKey biomarkers from cancer patient EVs suggests it is possible to track host immunosuppressive environment via antigen presenting cell and check point antagonist biomarkers. In both cases, highly significant differences are seen comparing EVs from normal patient plasma versus cancer patient plasma. Interestingly, when these biomarkers are evaluated in pre-EV enriched plasma, no significant differences are seen. This underscores the unique nature of the EV microenvironment, and suggests that host immune response and tumor microenvironment may be recapitulated in the EV/host response proteome using our unique methods. These data confirm that the EV microenvironment represents a unique oncological ecosystem with highly specific and sensitive disease biomarkers which are not dysregulated in complete plasma. This novel approach to assessing cancer proteomics has great promise for real time, longitudinal analysis of cancer patient tumor/host immune biology. Citation Format: Todd A. Hembrough, Zachary Opheim, Cheryl Bandoski, Issa Isaac, Martin Mehnert, Alan Ezrin. Identification of cancer specific extracellular vesical biomarkers to aid in diagnosis of cancer [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 3746.

A proteomic classifier panel for early screening of colorectal cancer: a case control study

BackgroundDiagnosis of colorectal cancer (CRC) during early stages can greatly improve patient outcome. Although technical advances in the field of genomics and proteomics have identified a number of candidate biomarkers for non-invasive screening and diagnosis, developing more sensitive and specific methods with improved cost-effectiveness and patient compliance has tremendous potential to help combat the disease.MethodsWe enrolled three cohorts of 479 subjects, including 226 CRC cases, 197 healthy controls, and 56 advanced precancerous lesions (APC). In the discovery cohort, we used quantitative mass spectrometry to measure the expression profile of plasma proteins and applied machine-learning to select candidate proteins. We then developed a targeted mass spectrometry assay to measure plasma concentrations of seven proteins and a logistic regression classifier to distinguish CRC from healthy subjects. The classifier was further validated using two independent cohorts.ResultsThe seven-protein panel consisted of leucine rich alpha-2-glycoprotein 1 (LRG1), complement C9 (C9), insulin-like growth factor binding protein 2 (IGFBP2), carnosine dipeptidase 1 (CNDP1), inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3), serpin family A member 1 (SERPINA1), and alpha-1-acid glycoprotein 1 (ORM1). The panel classified CRC and healthy subjects with high accuracy, since the area under curve (AUC) of the training and testing cohort reached 0.954 and 0.958. The AUC of the two independent validation cohorts was 0.905 and 0.909. In one validation cohort, the panel had an overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 89.9%, 81.8%, 89.2%, and 82.9%, respectively. In another blinded validation cohort, the panel classified CRC from healthy subjects with a sensitivity of 81.5%, specificity of 97.9%, and overall accuracy of 92.0%. Finally, the panel was able to detect APC with a sensitivity of 49%.ConclusionsThis seven-protein classifier is a clear improvement compared to previously published blood-based protein biomarkers for detecting early-stage CRC, and is of translational potential to develop into a clinically useful assay.

Evaluation of salivary glycopatterns based diagnostic models for prediction of diabetic vascular complications

Diabetic vascular complications (DVC) are the main cause of death in diabetic patients. However, there is a lack of effective biomarkers or convenient methods for early diagnosis of DVC. In this study, the salivary glycopatterns from 130 of healthy volunteers (HV), 139 patients with type 2 diabetes mellitus (T2DM) and 167 patients with DVC were case-by-case analyzed by using lectin microarrays. Subsequently, diagnostic models were developed using logistic regression and machine learning algorithms based on the data of lectin microarrays in training set. The performance of diagnostic models was evaluated in an independent blind cohort. The results of lectin microarrays indicated that the glycopatterns identified by 16 lectins (e.g. BS-I, PWM and EEL) were significantly altered in DVC patients compared with patients with T2DM, which suggested the alterations in salivary glycopatterns could reflect onset of DVC. Notably, K-Nearest Neighbor (KNN) model exhibited better performance for distinguishing DVC (accuracy: 0.939) than other models in blind cohort. The integrated classifier, which combined three machine learning models, exhibited a higher overall accuracy (≥ 0.933) than other models in blind cohort. Our study provided a cost-effective and non-invasive method for auxiliary diagnosis DVC based on the combination of salivary glycopatterns and machine learning algorithms.

Performance of fetal ultrasound and magnetic resonance imaging in predicting birthweight according to the test-to-delivery interval: A cohort study

ObjectiveTo assess the influence of the test-to-delivery interval (TDI) on the performance of ultrasound (US) and magnetic resonance imaging (MRI) for predicting birthweight (BW). Study designThis is a secondary analysis of a prospective, single center, blinded cohort study that compared MRI and US for the prediction of BW ≥ 95th percentile in singleton pregnancies. Patients that were included in the initial study underwent US and MRI for estimation of fetal weight between 36 + 0/7 and 36 + 6/7 weeks of gestation (WG). The primary outcome of the current study was to report the changes of US and MRI sensitivity and specificity in the prediction of BW > 95th percentile, BW > 90th percentile, BW < 10th percentile, and BW < 5th percentile, according to the TDI. The secondary outcome was to represent the performance of both tools in the prediction of BW > 90th percentile when TDI is<2 weeks, between 2 and 4 weeks, and>4 weeks. Receiver operating characteristic (ROC) curves were constructed accordingly. Results2378 patients were eligible for final analysis. For the prediction of BW > 95th or 90th percentile, the sensitivity of MRI remains high until 2 weeks, and it decreases slowly between 2 and 4 weeks, in contrast to the sensitivity of US which decreases rapidly 2 weeks after examination (p < 0.001). For the prediction of BW < 10th or 5th percentile, the sensitivity of both tools decreases in parallel between 1 and 2 weeks. The specificities of both tools remain high from examination till delivery. These findings are reproducible with the use of the antenatal customized and the postnatal national growth charts. ConclusionThe performance of MRI in the prediction of BW, especially in large-for-gestational age, is maximal when delivery occurs within two weeks of the examination, decreasing slightly thereafter, in contrast with the performance of US which decreases drastically over time.

Head-to-head comparison of [11C]methionine PET, [11C]choline PET, and 4-dimensional CT as second-line scans for detection of parathyroid adenomas in primary hyperparathyroidism.

Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6months after surgery were used as gold standard for curation of HPT. A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost-benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques.

Accuracy and Feasibility of Three-Dimensional Ultrasound Testing in Eye Clinic and Emergency Department Patients with Vision Complaints

BackgroundOcular emergencies comprise 2–3% of emergency department (ED) visits, with retinal detachment requiring emergency surgery. Two-dimensional ultrasound is a rapid bedside tool but is highly operator dependent. ObjectiveWe determined three-dimensional ultrasound (3DUS) feasibility, acceptability, and usability in eye pathology detection using the ophthalmologist examination as reference standard. MethodsWe performed a prospective, blinded cohort study of a 3DUS-enabling device in 30 eye clinic and ED patients with visual symptoms and calculated 3DUS performance characteristics. Two expert readers interpreted the 3DUS images for pathology. All participants completed surveys. Results3DUS sensitivity was 0.81, specificity 0.73, positive predictive value 0.54, negative predictive value 0.91, and likelihood ratio (LR)+/LR− 3.03 and 0.26, respectively. Novice and expert sonographers had “substantial” agreement in correct diagnosis of abnormal vs. normal (κ = 0.68, 95% confidence interval 0.48–0.88). Most patients indicated that 3DUS is fast, comfortable, helps them understand their problem, and improves provider interaction/care, and all sonographers agreed; 4/5 sonographers felt confident performing ultrasound. Expert readers correctly identified an abnormal eye in 83/120 scans (76%) and correct diagnosis in 72/120 scans (65%), with no statistical difference between novice (79%; 69%) and expert (72%; 61%) sonographers (p = 0.39, p = 0.55), suggesting reduced operator dependence. Reader diagnosis confidence and image quality varied widely. Image acquisition times were fast for novice (mean 225 ± 83 s) and expert (201 ± 51) sonographers, with fast expert reader interpretation times (225 ± 136). ConclusionsA 3DUS-enabling device demonstrates a sensitivity of 0.81 and specificity of 0.73 for disease detection, fast image acquisition, and may reduce operator dependence for detecting emergent retinal pathologies. Further technological development is needed to improve diagnostic accuracy in identifying and characterizing retinal pathology.

Spinal shock in severe SCI dogs and early implementation of intensive neurorehabilitation programs

Spinal shock is complex, paradoxical with sudden presentation, possibly leading to a guarded prognosis. Thus, it is suggested the need for early implementation of intensive neurorehabilitation. This prospective controlled blinded cohort study aims to understand the implication of spinal shock in neurorehabilitation of severe SCI dogs and the importance of its evaluation thought a spinal shock scale (SSS). 371 dogs were randomized by stratification according the presence of spinal shock in the SG (n = 245) or CG (n = 126). The SSS, a punctuation scale (0–7), was evaluated at admission and each 6 h for 3 days, each day for 15 days, each week for 6 weeks, each month until 3 months, followed by 3 monthly follow-ups. All dogs had similar land and underwater treadmill training with functional electrical stimulation. Observational dataset allowed an approximate level of power (1-β) of 0.90 and an α (Type I error) of 0.01, with a total of 11,088 SSS observations between two blinded observers and 18% of disagreement. 75% of the dogs were admitted in 24-48 h after injury, allowing early detection of spinal shock, and dogs admitted at 72 h with SSS ≥ 4 were not able to achieve ambulation. Regarding ambulation rate, there was a significant difference between groups, with 66.9% of ambulation in the SG and 97.6% in the CG. Also, there was a difference in regard to time until ambulation, with a mean of 31.57 days for the SG and 23.02 for the CG. The SSS estimated marginal means had an exponential decrease within the first 6 h, followed by a slower decrease, but always faster in spinal shock dogs diagnosed with non-compressive myelopathies. Thus, early intensive neurorehabilitation in dogs after severe SCI may benefit from SSS classifications at admission and during treatment to establish different therapeutic protocols according to each patient's needs, especially in deep pain negative dogs.

The Tissue Systems Pathology Test Outperforms Pathology Review in Risk Stratifying Patients With Low-Grade Dysplasia

Low-grade dysplasia (LGD) is associated with an increased risk of progression in Barrett's esophagus (BE); however, the diagnosis of LGD is limited by substantial interobserver variability. Multiple studies have shown that an objective tissue systems pathology test (TissueCypher Barrett's Esophagus Test, TSP-9), can effectively predict neoplastic progression in patients with BE. This study aimed to compare the risk stratification performance of the TSP-9 test vs benchmarks of generalist and expert pathology. A blinded cohort study was conducted in the screening cohort of a randomized controlled trial of patients with BE with community-based LGD. Biopsies from the first endoscopy with LGD were assessed by the TSP-9 test and independently reviewed by 30 pathologists from 5 countries per standard practice. The accuracy of the test and the diagnoses in predicting high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) were compared. A total of 154 patients with BE (122 men), mean age 60.9 ± 9.8 years were studied. Twenty-four patients progressed to HGD/EAC within 5 years (median time of 1.7 years) and 130 did not progress to HGD/EAC within 5 years (median 7.8 years follow-up). The TSP-9 test demonstrated higher sensitivity (71% vs mean 63%, range 33%-88% across 30 pathologists), than the pathology review in detecting patients who progressed (P=.01186). The TSP-9 test outperformed the pathologists in risk stratifying patients with BE with LGD. Care guided by the test can provide an effective solution to variable pathology review of LGD, improving health outcomes by upstaging care to therapeutic intervention for patients at high risk for progression, while reducing unnecessary interventions in low-risk patients.

How Does Oxymetazoline Change Nasal Aerodynamics and Symptomatology in Patients with Turbinate Hypertrophy?

Oxymetazoline relieves nasal obstructive symptoms via vasoconstriction, however, the changes in nasal structures and aerodynamics that impact symptoms the most remain unclear. This prospective, longitudinal, and single blinded cohort study applied Computational Fluid Dynamic (CFD) modeling based on CT scans at baseline and post-oxymetazoline on 13 consecutive patients with chronic nasal obstruction secondary to inferior turbinate hypertrophy from a tertiary medical center. To account for placebo effect, a sham saline spray was administered with subject blindfolded prior to oxymetazoline, with 30 min rest in between. Nasal Obstruction Symptom Evaluation (NOSE) and unilateral Visual Analogue Scale (VAS) scores of nasal obstructions were collected at baseline, after sham, and 30 min after oxymetazoline. Both VAS and NOSE scores significantly improved from baseline to post-oxymetazoline (NOSE: 62.3 ± 12.4 to 31.5 ± 22.5, p < 0.01; VAS: 5.27 ± 2.63 to 3.85 ± 2.59, p < 0.05), but not significantly from baseline to post-sham. The anatomical effects of oxymetazoline were observed broadly throughout the entire length of the inferior and middle turbinates (p < 0.05). Among many variables that changed significantly post-oxymetazoline, only decreased nasal resistance (spearman r = 0.4, p < 0.05), increased regional flow rates (r = -0.3 to -0.5, p < 0.05) and mucosal cooling heat flux (r = -0.42, p < 0.01) in the inferior but not middle turbinate regions, and nasal valve Wall Shear Stress (WSS r = -0.43, p < 0.05) strongly correlated with symptom improvement. Oxymetazoline broadly affects the inferior and middle turbinates, however, symptomatic improvement appears to be driven more by global nasal resistance and regional increases in airflow rate, mucosal cooling, and WSS, especially near the head of the inferior turbinate. 3: Well-designed, prospective, single blinded cohort trial. Laryngoscope, 134:1100-1106, 2024.

The impact of different growth charts on birthweight prediction: obstetrical ultrasound vs magnetic resonance imaging

The estimation of fetal weight (EFW) by fetal magnetic resonance imaging (MRI) is a simple and rapid method, with a high sensitivity to predict birthweight (BW) in comparison to ultrasound (US). Several national and international growth charts are currently in use but there is substantial heterogeneity among these charts due to: variations in the selected populations from which they were derived, different methodologies and statistical analysis of data. The purpose of this study was to compare the performance of MRI and US for the prediction of BW using three commonly used fetal growth charts: INTERGROWTH-21st (IG-21) project, World Health Organization (WHO), and Fetal Medicine Foundation (FMF). Data derived from a prospective, single center, blinded cohort study that compared the performance of MRI and US between 36+0/7 to 36+6/7 weeks of gestation (WG) for the prediction of BW ≥ 95th percentile was reanalyzed. EFW were categorized as > or < 5th, > or < 10th, > or < 90th, and > or < 95th percentile according to the three growth charts. BW was similarly categorized according to the BW standards of each chart. The performances of US and MRI for the prediction of BW < 5th, < 10th, > 90th, and > 95th percentile using the different growth charts were compared. Data were analysed with R software version 4.1.2. The comparison of sensitivity and specificity was done by McNemar and exact binomial tests. A p-value < 0.05 was considered as statistically significant. 2378 women were eligible for final analysis. US and MRI were performed at a median gestational age of 36+3/7 WG, delivery occurred at a median gestational age of 39+3/7 WG, and median BW was 3380 grams. The incidences of BW < 5th and < 10th percentiles were highest with the FMF chart and lowest with the IG-21 chart, whereas the incidences of BW > 90th and > 95th percentiles were lowest with the FMF chart and highest with the IG-21 chart. The sensitivity of MRI with an EFW > 95th percentile in the prediction of BW > 95th percentile was significantly higher than that of US across the three growth charts, however, its specificity was slightly lower than that of US. In contrast, the sensitivity of MRI with an EFW <10th percentile for predicting BW <10th percentile was significantly lower than US in the IG-21 and FMF charts, whereas the specificity and positive predictive value (PPV) of MRI were significantly higher than US for the three charts. Findings for the prediction of BW > 90th percentile were close to those of BW > 95th percentile, and findings for the prediction of BW < 5th percentile were close to those of BW < 10th percentile. The sensitivity of MRI is superior to US for the prediction of large for gestational age (LGA) fetuses and inferior to US for the prediction of small for gestational age (SGA) fetuses across the three different growth charts. The reverse is true for the specificity of MRI in comparison to the specificity of US.