Sensitive Screening Research Articles

Zero Background Visualizing Phosphorescence Lateral Flow Immunoassay of Cardiac Troponin I for Rapid and Accurate Diagnosis of Myocardial Infarction.

Fluorescence lateral flow immunoassays (FL-LFIA) have attracted considerable attention in clinical diagnosis due to their outstanding merits of affordable, sensitive, on-site, and quick detection. However, they are still plagued by significant signal interference, such as autofluorescence and scattered light. The development of high-performance and robust phosphors, i.e., label probes featuring with the character of low/no optical background, remains a great challenge. Herein, we report a novel visualized phosphorescence LFIA (Phos-LFIA), where the composite microspheres, i.e., carbon dots (CDs) covalently embedded in dendritic mesoporous silicon nanoparticles (DMSNs), were designed and selected as the report probes. The obtained CDs@DMSNs revealed uniform morphologies and particle sizes, as well as ultralong (lifetime: 1.14 s, visible for over 8 s to naked eyes) room temperature phosphorescence (RTP) in aqueous solution. As competitive nanotags, CDs@DMSNs were designed for an ultralong phosphorescence-based time-gated LFIA for cardiac troponin I (cTnI) without optical interference. The fabricated Phos-LFIA test strips demonstrated zero-background signal and were applied for highly sensitive cTnI detection in both buffer and a complex serum matrix, with corresponding limits of detection (LODs) of 0.19 and 0.21 ng/mL, respectively. For a clinical validation, the proposed Phos-LFIA revealed an excellent clinical analytical performance (sensitivity: 95.45%, specificity: 88.9%, κ value: 0.85), demonstrating its potential for rapid and accurate diagnosis of myocardial infarction. This work provided a promising background-free probe for FL-LFIA, and it would also open an opportunity for developing highly sensitive screening platforms for other targets through modifying different recognition ligands onto CDs@DMSNs.

Circulating microRNA panels for multi-cancer detection and gastric cancer screening: leveraging a network biology approach

BackgroundScreening tests, particularly liquid biopsy with circulating miRNAs, hold significant potential for non-invasive cancer detection before symptoms manifest.MethodsThis study aimed to identify biomarkers with high sensitivity and specificity for multiple and specific cancer screening. 972 Serum miRNA profiles were compared across thirteen cancer types and healthy individuals using weighted miRNA co-expression network analysis. To prioritize miRNAs, module membership measure and miRNA trait significance were employed. Subsequently, for specific cancer screening, gastric cancer was focused on, using a similar strategy and a further step of preservation analysis. Machine learning techniques were then applied to evaluate two distinct miRNA panels: one for multi-cancer screening and another for gastric cancer classification.ResultsThe first panel (hsa-miR-8073, hsa-miR-614, hsa-miR-548ah-5p, hsa-miR-1258) achieved 96.1% accuracy, 96% specificity, and 98.6% sensitivity in multi-cancer screening. The second panel (hsa-miR-1228-5p, hsa-miR-1343-3p, hsa-miR-6765-5p, hsa-miR-6787-5p) showed promise in detecting gastric cancer with 87% accuracy, 90% specificity, and 89% sensitivity.ConclusionsBoth panels exhibit potential for patient classification in diagnostic and prognostic applications, highlighting the significance of liquid biopsy in advancing cancer screening methodologies.

Quantifying Cognitive Function in Diabetes: Relationships Between AD8 Scores, HbA1c Levels, and Other Diabetic Comorbidities

Background/Objectives: Dementia associated with diabetes mellitus (DM) has been well documented in the literature, but studies utilizing early screening tools to target populations with mild cognitive dysfunction remain limited. This study aimed to investigate early cognitive decline by studying the relationships between “Ascertain Dementia 8” (AD8) questionnaire scores and glycemic control, lipid profiles, estimated glomerular filtration rate (eGFR), and the complications of diabetes. Methods: This case–control, cross-sectional, observational study was conducted at a medical center and an affiliated regional hospital in southern Taiwan from 30 June 2021 to 30 June 2023. Patients diagnosed with type 2 diabetes mellitus aged ≥40 years were recruited. Their past medical history, biochemical data, and AD8 score were collected at the same time. Results: The patients with glycated hemoglobin (HbA1c) levels of ≥7% had a higher risk of cognitive impairment than those with HbA1c levels of <7% (p < 0.001). The participants whose eGFR was <60 mL/min/1.73 m2 had a higher mean AD8 score compared to those with an eGFR of ≥60 mL/min/1.73 m2 (p = 0.008). The patients with a medical history of peripheral artery disease and diabetic neuropathy were also associated with a higher mean AD8 score (p < 0.001 and p = 0.017, respectively). Conclusions: By employing the AD8 questionnaire as a sensitive screening tool, our study suggests that early cognitive decline is significantly associated with poorer glycemic control, a lower glomerular filtration rate, peripheral artery disease, and diabetic neuropathy. Early detection of these risk factors may facilitate timely interventions and tailored treatment strategies to treat or prevent cognitive dysfunction.

MSH2, MSH6, MLH1, and PMS2 immunohistochemistry as highly sensitive screening method for DNA mismatch repair deficiency syndromes in pediatric high-grade glioma

Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients’ families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.

Performance of artificial intelligence for diagnosing cervical intraepithelial neoplasia and cervical cancer: a systematic review and meta-analysis

Cervical cytology screening and colposcopy play crucial roles in cervical intraepithelial neoplasia (CIN) and cervical cancer prevention. Previous studies have provided evidence that artificial intelligence (AI) has remarkable diagnostic accuracy in these procedures. With this systematic review and meta-analysis, we aimed to examine the pooled accuracy, sensitivity, and specificity of AI-assisted cervical cytology screening and colposcopy for cervical intraepithelial neoplasia and cervical cancer screening. In this systematic review and meta-analysis, we searched the PubMed, Embase, and Cochrane Library databases for studies published between January 1, 1986 and August 31, 2024. Studies investigating the sensitivity and specificity of AI-assisted cervical cytology screening and colposcopy for histologically verified cervical intraepithelial neoplasia and cervical cancer and a minimum of five cases were included. The performance of AI and experienced colposcopists was assessed via the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) through random effect models. Additionally, subgroup analyses of multiple diagnostic performance metrics in developed and developing countries were conducted. This study was registered with PROSPERO (CRD42024534049). Seventy-seven studies met the eligibility criteria for inclusion in this study. The pooled diagnostic parameters of AI-assisted cervical cytology via Papanicolaou (Pap) smears were as follows: accuracy, 94% (95% CI 92-96); sensitivity, 95% (95% CI 91-98); specificity, 94% (95% CI 89-97); PPV, 88% (95% CI 78-96); and NPV, 95% (95% CI 89-99). The pooled accuracy, sensitivity, specificity, PPV, and NPV of AI-assisted cervical cytology via ThinPrep cytologic test (TCT) were 90% (95% CI 85-94), 97% (95% CI 95-99), 94% (95% CI 85-98), 84% (95% CI 64-98), and 96% (95% CI 94-98), respectively. Subgroup analysis revealed that, for AI-assisted cervical cytology diagnosis, certain performance indicators were superior in developed countries compared to developing countries. Compared with experienced colposcopists, AI demonstrated superior accuracy in colposcopic examinations (odds ratio (OR) 1.75; 95% CI 1.33-2.31; P<0.0001; I2=93%). These results underscore the potential and practical value of AI in preventing and enabling early diagnosis of cervical cancer. Further research should support the development of AI for cervical cancer screening, including in low- and middle-income countries with limited resources. This study was supported by the National Natural Science Foundation of China (No. 81901493) and the Shanghai Pujiang Program (No. 21PJD006).

The Turkish validity and reliability of Addenbrooke's Cognitive Examination III.

Addenbrooke's Cognitive Examination III (ACE-III) was developed as a screening tool for cognitive disorders. Many countries have proven the cultural adaptation, reliability and validity of ACE-III. To make cultural adaptations of ACE-III for the Turkish population and to examine its validity and reliability. First, ACE-III was translated and adapted into Turkish (ACE-III-TR), then its validity and reliability were examined. The study included 234 people: 93 with dementia (78 Alzheimer's disease (AD) and 15 frontotemporal dementia (FTD)), 46 with mild cognitive impairment (MCI) and 95 healthy. Two blinded speech and language therapists rated the ACE-III-TR simultaneously for interrater validity. The same practitioner retested the same participants 2 weeks later for test-retest reliability. The construct validity of the culturally adapted test was assessed by analysing subsection correlations with the ACE-III-TR total score. The association between the Mini-Mental State Examination (MMSE) total score, relevant subsections and ACE-III-TR total score was examined for criterion validity. Intergroup differences for healthy, MCI and dementia were studied for ACE-III-TR subsections and total score, and cut-off scores were calculated for total score with sensitivity and specificity in differential diagnosis. Attention, memory and ACE-III-TR total scores showed a statistically significant difference between the three groups of dementia, MCI and healthy (p<0.001). Statistically significant positive correlations ranging from 0.571 to 0.929 were found between ACE-III-TR subsections and total scores (p<0.05). A highly significant positive correlation was found between MMSE total score and ACE-III-TR total score (r=0.870). Between the second and first measurements, positive, moderately significant correlations were found for all subsections and ACE-III-TR total (ICC=0.508-0.784, r=0.477-0.646). A high level of agreement was found between two raters for all ACE-III-TR subsections and the ACE-III-TR total score (alpha=0.9296-0.99995). The total ACE-III-TR cut-off score was 79.5 for healthy and MCI and 69.5 for MCI and mild stage dementia. This study found that ACE-III-TR is a sensitive and specific screening test for the diagnosis of MCI and dementia that has high validity and reliability. ACE-III-TR was found to be a valid and reliable tool in dementia, including AD and FTD, and in mild, moderate and advanced dementia. By providing a more comprehensive assessment of a person's cognitive profile, it can help the clinician make a differential diagnosis of MCI and dementia. ACE-III-TR may be useful in monitoring the progression of cognitive deficits in clinical practice, research studies and therapy follow-up processes. What is already known on the subject ACE was used as a screening tool to detect MCI and to differentiate AD from FTD. ACE was revised by Hsieh etal. in 2013 and updated as ACE-III, which has the advantages of assessing five cognitive domains, not requiring the use of additional materials, and providing an effective and sensitive measurement in a short time. However, the validity and reliability study of the ACE-III in Turkish has not been conducted. What this study adds to the existing knowledge This study demonstrates the validity and reliability of the Turkish ACE-III (ACE-III-TR), which is a sensitive and specific screening test for the diagnosis of MCI and dementia. What are the practical and clinical implications of this work? The ACE-III-TR can provide clinicians and patients with a quick and brief general cognitive screening, indicating both the patient's overall cognitive profile and the measures of each of the assessed domains. By providing a more comprehensive assessment of a person's cognitive profile, it can help the clinician make a differential diagnosis of MCI and dementia. ACE-III-TR may be useful in monitoring the progression of cognitive deficits in clinical practice, research studies and therapy follow-up processes.

Qualitative confirmation of 30 phencyclidine analogs in human blood and urine using GC-HRMS and a self-built library search.

Phencyclidine, a dissociative anesthetic with hallucinogenic effects, is commonly abused as a recreational drug. Phencyclidine analogs are compounds produced by substitutions of the phenyl and piperidine rings of phencyclidine. Illegal use of phencyclidine and its analogs has symptoms such as addiction, confusion, and increased tendencies toward violence. In this study, a novel high-throughput screening method was applied for GC-HRMS identification of 30 phencyclidine analogs in human blood and urine. After a simple extraction with ethyl ether and buffer, followed by centrifugation, the supernatant was injected into the system. Analytes were identified using a self-built library and searching against reference spectra. Phencyclopiperidine analogs in the samples were identified, and isomers were differentiated using the exact molecular mass and retention time (RT) of the characteristic fragment ions. The method was fully validated, no exogenous or endogenous interferences were observed, and recovery ranged from 30% to 123%. The more than 100% recovery of DMXE, HXE, ketamine, and Cl-634 may be due to matrix-induced response enhancement. The limits of detection ranged from 0.05 to 5ng/mL. The analytical method was successfully applied for separation of three groups of isomers: 2-FDCK and 4-FDCK; 3-MeO-PCP, 4-MeO-PCP and 4-MeOH-PCP; and PCMPA and PCEEA. This analytical approach was successfully applied for the identification of phencyclidine analogs in blood and urine samples from 800 authentic forensic cases. Four phencyclidine analogs were detected-2-F-2-oxo-PCE, 3-MeO-PCE, O-PCE, and 2-FDCK-demonstrating the method's suitability for sensitive and fast high-throughput screening of drugs in human blood and urine samples.

Performance of a blood-based screening test for the early detection of colorectal cancer.

232 Background: While the clinical benefit of highly sensitive screening tools for colorectal cancer (CRC) has been established, adherence rates remain low. The convenience and familiarity of blood-based testing may reduce disease burden through greater access and compliance to regular and recommended asymptomatic screening. We report on preliminary findings from a minimally invasive blood-based early cancer detection (ECD) screening test for CRC. Methods: Plasma samples from healthy individuals and CRC patients sourced from biobanks were included. A targeted panel composed of differentially methylated genomic regions was developed. Using an independent cohort of plasma samples, a machine-learning model was trained to classify patient samples into cancer-free and CRC based on observed differential methylation patterns in circulating cell-free DNA (cfDNA). The assay performance was calculated based on concordance with clinical diagnosis (CRC, cancer-free). Results: The test set included 440 individuals: 127 with a confirmed CRC diagnosis (47% stage I/II, mean age 65±12 years, male 46%) and 313 without cancer (mean age 56±10 years, male 41%). Overall sensitivity was 95% (95% CI: 88-100%), and specificity was 91% (95% CI: 84-98%). Among patients with stage I disease, sensitivity was 92% overall, and 88% in screen-detected individuals. Sensitivity was 100% (n=14/14) in microsatellite-high tumors and 95% (n=107/113) in microsatellite-stable tumors. Multivariate analysis demonstrated associations between methylation signal and tumor size, cancer stage, and sex. Compared with a tumor-informed, variant-based circulating tumor DNA (ctDNA) test (Signatera), we observed a PPA (positive percent agreement) of 100%. Moreover, the differentially methylated allele fraction (DMAF) across target regions strongly correlated with variant allele frequencies (VAFs) from the tumor-informed test (Spearman’s correlation coefficient, 0.85). Conclusions: Using epigenetic markers specific for CRC, we developed a sensitive and specific blood-based test to detect cfDNA from early-stage and asymptomatic disease. The methylation signal strongly correlated with ctDNA VAFs from a clinically validated tumor-informed test and increased with cancer stage and disease burden. This test could serve as a means to increase patient adherence rates for CRC screening, thereby improving patient outcomes.

Comparison of screening outcomes associated with advanced precancerous lesion versus colorectal cancer sensitivity for a blood-based test: A simulation study.

89 Background: With estimates of over 150,000 incident and 50,000 fatal colorectal cancer (CRC) cases in 2024, efforts are ongoing to improve the national screening performance and engagement in the US. The Centers for Medicare &amp; Medicaid Services (CMS) have established criteria for covering new blood-based CRC screening tests if minimum CRC sensitivity and specificity thresholds are met. However, the current blood-based tests are challenged by their relative inability to detect advanced precancerous lesions (APLs). At present, the importance of APL versus CRC sensitivity on screening outcomes remains undetermined. To address this knowledge gap, we conducted a simulation study to compare the screening effectiveness and outcomes of a hypothetical blood-based test across a range of sensitivities for CRC and APL detection. Methods: Outcomes were simulated using the CRC-AIM microsimulation model, which has been previously calibrated and validated. Predicted outcomes were calculated for average-risk individuals screened triennially with a blood-based test between ages 45-75 years, assuming perfect adherence. Base-case screening sensitivity and specificity inputs were based on CMS minimum thresholds (74% CRC sensitivity, 90% specificity) with assumed 10% APL sensitivity. Additional scenarios considered an increase in either APL or CRC sensitivity. Outcomes of interest included life years-gained (LYG), CRC incidence, and mortality reductions. Results: Compared to the CMS minimum performance (Table), increasing APL sensitivity by 1% (from 10% to 11%) resulted in a similar increase in LYG as compared to increasing CRC sensitivity by 11% (from 74% to 85%). Additionally, increasing APL sensitivity by 1% resulted in greater reductions in CRC cases and deaths (3% decrease) as compared to increasing CRC sensitivity by 11% (0% and 1% reductions, respectively). Conclusions: Data from this study show that increased APL sensitivity is a key determinant of screening-related outcomes, such as LYG, derived from a blood-based strategy, and that similar results would require much larger increases in CRC sensitivity. With the current CMS minimum performance threshold, blood-based tests that are designed to have high APL sensitivity can outperform tests with higher CRC sensitivity and little to no APL sensitivity. Comparison of CRC screening health outcomes with CMS proposed minimum threshold blood-test versus hypothetical tests with either increased APL and CRC sensitivity. APL Sensitivity CRC Sensitivity CRC Specificity Follow-up Colonoscopies CRC Cases (% reduction) CRC Deaths (% reduction) Life-Years Gained (LYG) (% increase) 10% 74% 90% 809 50 (ref) 18 (ref) 220 (ref) 11% 74% 90% 813 48 (-3%) 17 (-3%) 226 (3%) 10% 85% 90% 809 50 (0%) 18 (-1%) 227 (3%) APL: Advanced precancerous lesions; CRC: Colorectal cancer.

IMMUNOLOGICAL DETECTION METHODS, CYTOKINES TEST AND C-REACTIVE PROTEIN TEST IN WOMEN INFECTED WITH TRICHOMONAS VAGINALIS

Trichomonas vaginalis is the most prevalent non-viral sexually transmitted infection, Nucleic acid amplification tests and point-of-care tests are newly available diagnostic methods that can be conducted on a variety of specimens, potentially allowing highly sensitive testing and screening of both women and men at risk for infection, The most commonly used method of diagnosis is a direct microscopic. We developed an indirect enzyme-linked immune sorbent assay (ELISA) for the detection of Trichomonas vaginalis which is both rapid and sensitive (detection limit of approximately 100 trichomonads per ml). that the ELISA is a significant improvement over the wet mount method for the diagnosis of trichomoniasis.as well as immunological staining of fixed specimens, Is a technique that permits visualization of virtually many components in any given tissue or cell type. This broad capability is achieved through combinations of specific antibodies tagged with fluorophores. Assays for anti trichomonad antibodies in either serum or vaginal secretions, and indirect immunofluorescence also was important as well as the cytokines test they allow your immune system to mount a defense if germs or other substances that can make you sick enter your body.And CRP test measures the level of C-reactive protein in a sample of your blood.

P-2181. Cardiac MRI Identifies Heart Disease Risk in Individuals with Hepatitis C Regardless of Myocardial Damage Markers or Fibrosis Stage

Abstract Background Infection with hepatitis C virus (HCV) increases the risk of extrahepatic manifestations, including cardiovascular disease (CVD). Cardiac magnetic resonance (CMR) remains the gold standard test for non-invasive structural and functional assessment of the heart and can be used to detect CVD. We sought to determine the CVD risk in patients with HCV prior to therapy using CMR.Table 1.Baseline Demographic Features of HCV CMR Cohort Methods Individuals with chronic HCV infection were prospectively enrolled in the CHROME study (NCT 03823911). A subset of 10 HCV-infected individuals were enrolled in the MRI sub-study from March to September 2019. HCV antibody and RNA, liver fibrosis score, and markers of inflammation and myocardial damage were obtained. CMR was performed prior to the initiation of DAA treatment. ECV fraction was calculated using the equation: ECV = 100% x (1-hematocrit) x [(1/T1myocardium post) – (1/T1myocardium pre)]/[(1/T1blood post) – (1/T1 blood pre)]. An ECV fraction &amp;gt; 30% was considered abnormally increased. 10 age-matched, HCV-negative volunteers were included in the analysis so that T-test was used to compare ECV fraction in both groups.Figure 1.Extracellular Volume (ECV) of HCV-infected individuals and Healthy Volunteers. ECV fraction in the HCV-infected individuals was significantly increased (0.30 ±0.03 vs. 0.26±0.03, p=0.0036). Results Demographics are shown in Table 1. CMR showed that 8 of 10 HCV-infected individuals had an abnormal ECV fraction ( &amp;gt;30%)7 (average=0.30, range 29-38%). When compared with age-matched normal volunteers, ECV fraction in the HCV-infected individuals was significantly increased (0.30 ±0.03 vs. 0.26±0.03, p=0.0036) (Figure 1). Three of 10 HCV-infected individuals had non-ischemic patterns of gadolinium enhancement on the LGE images (Figure 2). For HCV-infected individuals, markers of inflammation and myocardial damage were within laboratory reference range for all subjects in the CMR cohort, and ECV fraction was elevated regardless of myocardial damage markers or liver fibrosis stage.Figure 2.A) Short axis late gadolinium enhancement image shows a midwall pattern of enhancement within the basal septal wall (arrow), compatible with an area of midwall fibrosis. B) Native T1 map and C) post contrast T1 map show a corresponding area of abnormal T1 measurements within the basal septum (arrows). Conclusion Our findings suggest that myocardial changes secondary to HCV infection can occur without measurable changes in inflammatory or myocardial biomarkers, and ECV fraction via CMR may be a sensitive screening tool to detect these changes. This has important implications for the necessity of early HCV treatment, since cardiovascular changes can precede the development of advanced liver fibrosis in HCV-infected individuals. Disclosures All Authors: No reported disclosures

Incorporating an Elevated Perfusion Index in the Right Hand Enhanced Screening Sensitivity for Critical Aortic Arch Obstruction in Newborn Infants.

Newborn infants with critical aortic arch obstruction are often undiagnosed at discharge, despite screening. This study investigated if adding the perfusion index improved early detection. We retrospectively studied 38 newborn infants with critical aortic arch obstruction, who were routinely screened in 2014-2019 by 13 Swedish hospitals using pulse oximetry and the perfusion index. They were identified through surgery records and national mortality databases. The controls were 512 healthy newborn infants from one hospital. Optimal perfusion index cut-offs were determined using frequency distribution analysis. The groups had similar median gestational ages and birth weight. No infants with critical aortic arch obstruction were diagnosed just because of a positive perfusion index result. However, the right-hand perfusion index was significantly higher in the cases than in controls (p < 0.001). A perfusion index of > 3%, or positive pulse oximetry or positive physical examination, yielded 76% sensitivity and 85% specificity, with an area under the receiver operating characteristic curve of 0.81 (range 0.73-0.89, p < 0.0001). Pulse oximetry and just neonatal physical examinations had a lower sensitivity (45%, p = 0.009). A high perfusion index in the right hand enhanced critical aortic arch obstruction screening and repeated measurements should be explored to minimise false positives.

IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening.

T-cell prolymphocytic leukemia (T-PLL) is an aggressive lymphoid malignancy with limited treatment options. To discover new treatment targets for T-PLL, we performed high-throughput drug sensitivity screening on 30 primary patient samples ex-vivo. After screening over 2'800 unique compounds, we found T-PLL to be more resistant to most drug classes, including chemotherapeutics, compared to other blood cancers. Furthermore, we discovered previously not reported vulnerabilities of T-PLL. T-PLL cells exhibited a particular sensitivity to drugs targeting autophagy (thapsigargin, bafilomycin A1), nuclear export (selinexor), and inhibitor of apoptosis proteins (IAPs) (birinapant), sensitivities that were also shared by other T-cell malignancies. Through bulk and single-cell RNA-Sequencing we found these compounds to activate the toll-like-receptor (TLR) (bafilomycin A1), p53 (selinexor), and TNF-ɑ/NFκB signaling pathways (birinapant) in T-PLL cells. Focussing on birinapant for its potential in drug repurposing, we uncovered that IAP inhibitor-induced cell death was primarily necroptotic and dependent on TNF-ɑ. Through spectral flow cytometry we confirmed the absence of cleaved caspase-3 in IAP inhibitor treated T-PLL cells and show that IAP inhibition reduces the proliferation of T-PLL cells stimulated ex-vivo, while showing only a limited effect on non-malignant T-cells. In summary, our study maps the drug sensitivity of T-PLL across a broad range of targets and identifies new therapeutic approaches for T-PLL by targeting IAPs, XPO1 and autophagy, highlighting potential candidates for drug repurposing and novel treatment strategies.

The evolution of cell-free fetal DNA testing: expanded non-invasive prenatal testing and its effect on target populations.

To evaluate the clinical performance of expanded non-invasive prenatal testing (NIPT-plus) in screening for fetal chromosome aneuploidy and copy number variations (CNVs) among pregnant women with different risk factors to investigate how the target population of cell-free fetal DNA may change in NIPT-plus. The clinical data, test results, confirmatory invasive testing outcomes, and follow-up results of 6,220 pregnant women who underwent NIPT-plus were re-viewed. The performance indicators of the positive predictive value (PPV), positive rate (PR), specificity, and sensitivity in screening for common trisomies, sex chromosomal abnormalities (SCAs), rare autosomal aneuploidies (RAAs), and CNVs were calculated. The PR or PPV of NIPT-plus for screening chromosome aneuploidy and CNVs in women of varying ages, risk factors, and clinical indications were determined. The PRs of common trisomies, SCAs, RAAs, and CNVs in NIPT-plus were 0.71, 0.45, 0.32, and 0.59%, respectively, with 100% sensitivity and specificities ranging from 99.69 to 99.87%. The PPVs were 80.95, 30.77, 13.33, and 44.12%, respectively. The high-risk group had higher PRs and PPVs for chromosome aneuploidy, with no significant difference in screening for CNVs. NIPT-plus showed greater PR for aneuploidy in the older age group than in the younger age group, with no significant differences in CNVs screening. NIPT-plus was able to effectively screen for chromosome aneuploidy and CNVs. The performance of CNVs screening was not significantly different among different risk factors and age groups. The target population for NIPT-plus should include all pregnant women, not just those at high risk.

Clostridioides difficile infection diagnosis

Clostridioides difficile is a Gram-positive, spore-forming anaerobic enteropathogen responsible for a wide spectrum of clinical diseases ranging from mild diarrhoea to pseudomembranous colitis. It is the first cause of healthcare-associated diarrhoeas, but community-associated Clostridioides difficile infections (CDI) are increasingly reported in patients without the common risk factors (age > 65 years, previous antibiotic treatment). The main C. difficile virulence factors are toxins A (TcdA) and B (TcdB), and in some cases the binary toxin. The CDI incidence has increased in Europe since the early 2000s, then decreased to reach approximately 4 cases/10,000 patients/days. C. difficile should be tested only in diarrheal stools. Children less than 3 years old are frequently colonized, therefore CDI diagnosis should be carried out only in specific cases (outbreak, Hirschsprung disease). No stand-alone method can be used for the CDI diagnosis. The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) recommends a two-step algorithm with a sensitive screening test (molecular assay or glutamate dehydrogenase immunochromatographic assay). If the screening test is negative, the CDI diagnosis can be ruled out. If the screening test is positive, a second highly specific test should be used, such as toxin A/B immunochromatographic assay.

Diagnostic accuracy of combined screening algorithm for early detection of congenital heart disease among term newborns in India.

To determine the validity of a screening algorithm based on combination of clinical examination and pulse oximetry, for early detection of congenital heart disease (CHD) in term newborns. CHD is the most frequent major congenital anomaly, with prevalence of 6-12 per 1000 live births. Clinical examination alone may fail to detect CHD in more than 50% of affected newborns. Recent studies have concluded that pulse oximetry has a high sensitivity and specificity as a screening tool for critical CHD. JSS Hospital, Mysuru, Karnataka, India. In this prospective observational study, all term neonates delivered at the hospital were included. The screening algorithm consisted of seven clinical parameters and pulse oximetry screening guidelines recommended by the American Academy of Paediatrics. Term newborns with the presence of any one of the above parameters in the algorithm were considered screen-positive. Echocardiography was done in all screen positives. Newborns were classified into those with and without CHD, based on echocardiography findings at birth and clinical examination and echocardiography findings at follow-up at 6 weeks. Among 1009 term neonates included in the study, CHD was detected in 57 (5.6%) with cyanotic CHD in 12. The sensitivity and specificity of combined screening to detect CHD was 71.93% and 95.8%, respectively. The positive predictive value was 50.62% and the negative predictive value was 98.28%. Screening for CHD with a simple comprehensive algorithm, integrating clinical evaluation and pulse oximetry, has moderate sensitivity and high specificity in detecting CHD in term newborns. Further work is needed to evaluate this form of screening.

Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease characterized by the presence of autoantibodies, including those targeting O-phosphoseryl-tRNA:selenocysteine-tRNA synthase (SepSecS), also known as soluble liver antigen (SLA). Anti-SepSecS antibodies have been associated with a more severe phenotype, suggesting a key role for the SepSecS autoantigen in AIH. To analyze the immune response to SepSecS in patients with AIH at the clonal level, we combined sensitive high-throughput screening assays with the isolation of monoclonal antibodies (mAbs) and T cell clones. The anti-SepSecS mAbs isolated were primarily IgG1, affinity-matured compared with their germline versions, and recognized at least 3 nonoverlapping epitopes. SepSecS-specific CD4+ T cell clones were found in patients with AIH who were anti-SLA-positive and anti-SLA-negative,and, to a lesser extent, in patients with non-AIH liver diseases and in healthy individuals. SepSecS-specific T cell clones from patients with AIH produced IFN-γ, IL-4, and IL-10, targeted multiple SepSecS epitopes, and, in one patient, were clonally expanded in both blood and liver biopsy. Finally, SepSecS-specific B cell clones, but not those of unrelated specificities, were able to present soluble SepSecS to specific T cells. Collectively, our study provides the first detailed analysis of B and T cell repertoires targeting SepSecS in patients with AIH, offering a rationale for improved targeted therapies.

Non-Destructive Detection of Silage pH Based on Colorimetric Sensor Array Using Extended Color Components and Novel Sensitive Dye Screening Method

Non-destructive detection of maize silage quality is essential. The aim is to propose a fast and non-destructive silage pH detection method based on a colorimetric sensor array (CSA). Extended color components, a novel sensitive dye screening method, and a feature screening method were integrated and applied to enhance pH detection. Fifty color components were constructed from five color spaces and used to extract information about the response of CSA to silage. Forward and backward stepwise selection and support vector regression (SVR) were combined to create a sensitive dye screening method, which was used to determine the optimal sensitive dye. The variable combination population analysis–iteratively retains informative variables algorithm was iterated to optimize effective features. Consequently, six hundred variables were extracted from the twelve dyes, which were able to comprehensively and finely characterize the CSA response. Four sensitive dyes were screened out from the twelve dyes, which were sensitive to silage volatile compounds and accurately reflected the odor changes. Twenty-eight effective features were preferred, based on which the SVR model had Rp2, RMSEP and RPD scores of 0.9533, 0.4186, and 4.4186, respectively; the pH prediction performance was substantially improved. This study provides technical support for the scientific evaluation of silage quality.

Early screening of lung function by electrical impedance tomography in people with normal spirometry reveals unrecognized pathological features

Early detection of lung function impairment is crucial. However, the sensitivity of spirometry in detecting early lung function deterioration is limited. In this study, lungs of 3180 healthy participants scheduled for annual health check were screened. Electrical impedance tomography measurements were conducted in 130 participants with normal spirometry for concept establishment phase and 105 for validation phase. A follow-up CT examination was suggested for participants with abnormal regional time constant or tobacco consumption ≥10 pack-years. Using CT as reference, the sensitivity and specificity of electrical impedance tomography-based screening were 81.3% and 50.0%, respectively in the concept establishment phase. In the validation phase, the sensitivity and specificity were 77.9% and 50.0%. In this study we show that conventional spirometry may not capture early changes that occur at a regional level. The regional time constant based on electrical impedance tomography can be a promising tool for early screening of lung function impairment. Clinical trial registration: ChiCTR2300076673, www.chictr.org.cn.

Bearing Fault Feature Extraction Method Based on Adaptive Time-Varying Filtering Empirical Mode Decomposition and Singular Value Decomposition Denoising

Aiming to address the difficulty in extracting the early weak fault features of bearings under complex operating conditions, a fault diagnosis method is proposed based on the adaptive fusion of time-varying filtering empirical mode decomposition (TVF-EMD) modal components and singular value decomposition (SVD) noise reduction. First, the snake optimization (SO) technique is used to optimize the TVF-EMD algorithm in order to determine the optimal parameters that match the input signal. Then, the bearing signal is divided into a number of intrinsic mode functions (IMFs) using TVF-EMD in order to reduce the nonlinearity and non-stationary characteristics of the fault signal. An index for the envelope fault information energy ratio (EFIER) is created to overcome the drawback of there being too many IMF components after TVF-EMD decomposition. The IMF components are ranked in descending order according to the EFIER, and they are fused according to the maximum principle of the energy ratio of envelope fault information until the optimal fusion component is determined. Finally, the fault feature is extracted when the optimal fusion component is denoised using SVD. Two measured bearing fault signals and simulation signals are used to validate the performance of the proposed method. The experimental findings demonstrate that the approach has good sensitive feature screening, fusion, and noise reduction capabilities. The proposed method can more precisely extract the early fault features of bearings and accurately identify fault types.