Clinical Use Research Articles

Development, validation and visualization of a web-based nomogram for predicting risk of new-onset diabetes after percutaneous coronary intervention

Simple and practical tools for screening high-risk new-onset diabetes after percutaneous coronary intervention (PCI) (NODAP) are urgently needed to improve post-PCI prognosis. We aimed to evaluate the risk factors for NODAP and develop an online prediction tool using conventional variables based on a multicenter database. China evidence-based Chinese medicine database consisted of 249, 987 patients from 4 hospitals in mainland China. Patients ≥ 18 years with implanted coronary stents for acute coronary syndromes and did not have diabetes before PCI were enrolled in this study. According to the occurrence of new-onset diabetes mellitus after PCI, the patients were divided into NODAP and Non-NODAP. After least absolute shrinkage and selection operator regression and logistic regression, the model features were selected and then the nomogram was developed and plotted. Model performance was evaluated by the receiver operating characteristic curve, calibration curve, Hosmer–Lemeshow test and decision curve analysis. The nomogram was also externally validated at a different hospital. Subsequently, we developed an online visualization tool and a corresponding risk stratification system to predict the risk of developing NODAP after PCI based on the model. A total of 2698 patients after PCI (1255 NODAP and 1443 non-NODAP) were included in the final analysis based on the multicenter database. Five predictors were identified after screening: fasting plasma glucose, low-density lipoprotein cholesterol, hypertension, family history of diabetes and use of diuretics. And then we developed a web-based nomogram (https://mr.cscps.com.cn/wscoringtool/index.html) incorporating the above conventional factors for predicting patients at high risk for NODAP. The nomogram showed good discrimination, calibration and clinical utility and could accurately stratify patients into different NODAP risks. We developed a simple and practical web-based nomogram based on multicenter database to screen for NODAP risk, which can assist clinicians in accurately identifying patients at high risk of NODAP and developing post-PCI management strategies to improved patient prognosis.

Phosphoproteomic profiling of early rheumatoid arthritis synovium reveals active signalling pathways and differentiates inflammatory pathotypes

BackgroundKinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level.MethodsWe validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics.ResultsDifferential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis.ConclusionsSpecific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.

Desktop 3D printed anatomic models for minimally invasive direct coronary artery bypass

BackgroundThree-dimensional (3D) printing technology has impacted many clinical applications across medicine. However, 3D printing for Minimally Invasive Direct Coronary Artery Bypass (MIDCAB) has not yet been reported in the peer-reviewed literature. The current observational cohort study aimed to evaluate the impact of half scaled (50% scale) 3D printed (3DP) anatomic models in the pre-procedural planning of MIDCAB.MethodsRetrospective analysis included 12 patients who underwent MIDCAB using 50% scale 3D printing between March and July 2020 (10 males, 2 females). Distances measured from CT scans and 3DP anatomic models were correlated with Operating Room (OR) measurements. The measurements were compared statistically using Tukey’s test. The correspondence between the predicted (3DP & CT) and observed best InterCostal Space (ICS) in the OR was recorded. Likert surveys from the 3D printing registry were provided to the surgeon to assess the utility of the model. The OR time saved by planning the procedure using 3DP anatomic models was estimated subjectively by the cardiothoracic surgeon.ResultsAll 12 patients were successfully grafted. The 3DP model predicted the optimal ICS in all cases (100%). The distances measured on the 3DP model corresponded well to the distances measured in the OR. The measurements were significantly different between the CT and 3DP (p < 0.05) as well as CT and OR (p < 0.05) groups, but not between the 3DP and OR group. The Likert responses suggested high clinical utility of 3D printing. The mean subjectively estimated OR time saved was 40 min.ConclusionThe 50% scaled 3DP anatomic models demonstrated high utility for MIDCAB and saved OR time while being resource efficient. The subjective benefits over routine care that used 3D visualization for surgical planning warrants further investigation.

CHK1 inhibitor induced PARylation by targeting PARG causes excessive replication and metabolic stress and overcomes chemoresistance in ovarian cancer

Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated in mediating therapeutic resistance. DNA damage checkpoint kinase 1 (CHK1) integrates cell cycle and DNA repair in replicating cells, and its inhibition causes replication stress, repair deficiency and cell cycle dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) of proteins (PARylation) and subsequent decrease in cellular NAD+ levels in OC cells treated with the CHK1 inhibitor prexasertib, indicating activation of NAD+ dependent DNA repair enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are in clinical use in treating OC, tumor resistance to these drugs is highly imminent. We reasoned that inhibition of dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt metabolic and DNA repair crosstalk to overcome chemoresistance. Although PARG inhibition (PARGi) trapped PARylation of the proteins and activated CHK1, it did not cause any significant OC cell death. However, OC cells deficient in CHK1 were hypersensitive to PARGi, suggesting a role for metabolic and DNA repair crosstalk in protection of OC cells. Correspondingly, OC cells treated with a combination of CHK1 and PARG inhibitors exhibited excessive replication stress-mediated DNA lesions, cell cycle dysregulation, and mitotic catastrophe compared to individual drugs. Interestingly, increased PARylation observed in combination treatment resulted in depletion of NAD+ levels. These decreased NAD+ levels were also paralleled with reduced aldehyde dehydrogenase (ALDH) activity, which requires NAD+ to maintain cancer stem cells. Furthermore, prexasertib and PARGi combinations exhibited synergistic cell death in OC cells, including an isogenic chemoresistant cell line and 3D organoid models of primary patient-derived OC cell lines. Collectively, our data highlight a novel crosstalk between metabolism and DNA repair involving replication stress and NAD+-dependent PARylation, and suggest a novel combination therapy of CHK1 and PARG inhibitors to overcome chemoresistance in OC.

Safety and efficacy of Holmium-166 selective internal radiotherapy of primary and secondary liver cancer confirmed by real-world data.

Holmium-166 has emerged as a promising option for selective internal radiotherapy (SIRT) for hepatic malignancies, but data on routine clinical use are lacking. The purpose of this study was to describe the safety and effectiveness of Holmium-166 SIRT in real-world practice through retrospective analysis of a multicenter registry. Retrospective analysis was conducted on Holmium-166 SIRT procedures performed between July 15, 2019, and July 15, 2021, across seven European centers. Treatment planning, treatment realization and post-treatment follow-up were conducted according to routine local practice. Safety and effectiveness data were extracted from the patients' health records. Primary endpoint analysis was assessed for the entire study population with separate analysis for subgroups with hepatocellular carcinoma, metastatic colorectal cancer and intrahepatic cholangiocarcinoma. A total of 167 SIRT procedures in 146 patients (mean age 66 ± 11 years, 68% male) were retrospectively evaluated. Most common tumor entities were hepatocellular carcinoma (n=55), metastatic colorectal cancer (n=35), intrahepatic cholangiocarcinoma (n=19) and metastatic neuroendocrine tumors (n=10). Nine adverse events grade ≥ 3 according to Common Terminology Criteria for Adverse Events were recorded, including one fatal case of radioembolization-induced liver disease. Response rates and median overall survival for the above mentioned subgroups were comparable to results from previous Holmium-166 trials as well as to results from Yttrium-90 registries. This study confirms that the safety and effectiveness of Holmium-166 SIRT derived from prospective trials also applies in routine clinical practice, reinforcing its potential as a viable treatment option for primary and secondary liver cancer.

Development and validation of a LASSO prediction model for cisplatin induced nephrotoxicity: a case-control study in China

BackgroundEarly identification of high-risk individuals with cisplatin-induced nephrotoxicity (CIN) is crucial for avoiding CIN and improving prognosis. In this study, we developed and validated a CIN prediction model based on general clinical data, laboratory indications, and genetic features of lung cancer patients before chemotherapy.MethodsWe retrospectively included 696 lung cancer patients using platinum chemotherapy regimens from June 2019 to June 2021 as the traing set to construct a predictive model using Absolute shrinkage and selection operator (LASSO) regression, cross validation, and Akaike’s information criterion (AIC) to select important variables. We prospectively selected 283 independent lung cancer patients from July 2021 to December 2022 as the test set to evaluate the model’s performance.ResultsThe prediction model showed good discrimination and calibration, with AUCs of 0.9217 and 0.8288, sensitivity of 79.89% and 45.07%, specificity of 94.48% and 94.81%, in the training and test sets respectively. Clinical decision curve analysis suggested that the model has value for clinical use when the risk threshold ranges between 0.1 and 0.9. Precision-Recall (PR) curve shown in recall interval from 0.5 to 0.75: precision gradually declines with increasing Recall, up to 0.9.ConclusionsPredictive models based on laboratory and demographic variables can serve as a beneficial complementary tool for identifying high-risk populations with CIN.

Paying attention to safety of posterior chamber phakic intraocular lens implantation

Posterior chamber phakic intraocular lens implantation is a type of intraocular surgery. With advancements in implant materials and design, this procedure has seen rapid adoption and widespread use in ophthalmology clinics in recent years. However, the changes in surgical techniques and the occurrence of postoperative complications have raised safety concerns that require significant attention in clinical practice. This paper aims to address the key factors influencing the safety of posterior chamber phakic intraocular lens implantation, exploring relevant characteristics, mechanisms, and current challenges. By emphasizing the importance of this surgery and proposing effective measures, it aims to provide guidance for clinical practice, enhance the safety of posterior chamber phakic intraocular lens implantation, and foster the healthy advancement of this surgical technique.

Targeting S. aureus Extracellular Vesicles: A New Putative Strategy to Counteract Their Pathogenic Potential.

Long-term inflammatory skin disease atopic dermatitis is characterized by dry skin, itching, and eczematous lesions. During inflammation skin barrier protein impairment promotes S. aureus colonisation in the inflamed skin, worsening AD patient's clinical condition. Proteomic analysis revealed the presence of several immune evasion proteins and virulence factors in S. aureus extracellular vesicles (EVs), suggesting a possible role for these proteins in the pathophysiology of atopic dermatitis. The objective of this study is to assess the efficacy of a wall fragment obtained from a patented strain of C. acnes DSM28251 (c40) and its combination with a mucopolysaccharide carrier (HAc40) in counteract the pathogenic potential of EVs produced by S. aureus ATCC 14458. Results obtained from in vitro studies on HaCaT keratinocyte cells showed that HAc40 and c40 treatment significantly altered the size and pathogenicity of S. aureus EVs. Specifically, EVs grew larger, potentially reducing their ability to interact with the target cells and decreasing cytotoxicity. Additionally, the overexpression of the tight junctions mRNA zona occludens 1 (ZO1) and claudin 1 (CLDN1) following EVs exposure was decreased by HAc40 and c40 treatment, indicating a protective effect on the epidermal barrier's function. These findings demonstrate how Hac40 and c40 may mitigate the harmful effects of S. aureus EVs. Further investigation is needed to elucidate the exact mechanisms underlying this interaction and explore the potential clinical utility of c40 and its mucopolysaccharide carrier conjugate HAc40 in managing atopic dermatitis.

Plasma proteomics in the UK Biobank reveals youthful brains and immune systems promote healthspan and longevity.

Organ-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer's disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements. Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.

The Analysis of Utilization of Voluntary Counseling and Testing (VCT) Clinics by Men Who Have Sex with Men Living with HIV/AIDS

Men Who Have Sex with Men (MSM) are a high-risk group for HIV/AIDS transmission due to their tendency to have multiple partners and engage in anal sex. This study aims to determine the factors influencing the utilization of VCT clinics by MSM living with HIV/AIDS in the VCT clinic at Kendari City General Hospital. This research method is quantitative with an analytical cross-sectional design, conducted in March 2024 at the VCT Clinic of Kendari City General Hospital with a population of 428 MSM who visited the VCT clinic until March. Sampling was done using simple random sampling. The data obtained were processed using SPSS software by conducting chi-square tests, then presented in tabular form accompanied by narration. The research results showed that 74.4% utilized the VCT Clinic well, while 25.6% underutilized the VCT clinic. Based on bivariate analysis, it was found that there is an influence between knowledge (p = 0.000), peer support (p = 0.004) on the utilization of VCT clinics. The researchers suggest that local authorities conduct socialization and disseminate information about HIV/AIDS and VCT clinics through mass media, print, electronic media, optimize mobile VCT, and develop comfortable VCT clinic facilities Keywords: Knowledge, Attitude, Behavior, Family Support, Peer Support, VCT, Men Who Have Sex with Men

Choline Phosphate-Grafted Nanozymes as Universal Extracellular Vesicle Probes for Bladder Cancer Detection.

Urinary extracellular vesicles (uEVs) are regarded as highly promising liquid-biopsy biomarkers for the early diagnosis and prognosis of bladder cancer (BC). However, detection of uEVs remains technically challenging owing to their huge heterogeneity and ultralow abundance in real samples. We herein present a choline phosphate-grafted platinum nanozyme (Pt@CP) that acts as a universal EV probe for the construction of a high-throughput and high-sensitivity immunoassay, which allowed multiplex profiling of uEV protein markers for BC detection. With the Pt@CP-based immunoassays, three uEV protein markers (MUC-1, CCDC25, and GLUT1) were identified for BC, by which the BC cases (n = 48), cystitis patients (n = 27), and healthy donors (n = 24) were discriminated with high clinical sensitivity and specificity (area under curve = 98.3%). For the BC cases (n = 9) after surgery, the Pt@CP-based immunoassay could report the postoperative residual tumor that cannot be observed by cystoscopy, which is clinically significant for assessing BC recurrence. This work provides generally high sensitivity for EV detection, facilitating the discovery and clinical use of EV-based biomarkers.

Abstract IA009: Single strand DNA GAP accumulation as a functional biomarker for DNA Repair Inhibitors

Abstract Deficiency of homologous recombination (HR)-mediated DNA repair occurs through genetic or epigenetic inactivation of the BRCA1 and BRCA2 (BRCA1/2) genes. HR-deficiency also provides unique opportunities for targeted therapy, through the mechanism of synthetic lethality, as exemplified by the hypersensitivity of BRCA1/2-mutated tumors to PARP inhibitors (PARPi). To date, several PARP inhibitors have been approved for clinical use. The promising clinical response of patients with germline BRCA1/2-mutations prompted the use of PARPi for patients with somatic BRCA1/2 mutations as well. In addition, these results extended the use of PARPi for various types of ovarian, breast, pancreatic, and prostate tumors with HR defects. PARPi resistance is emerging as the major obstacle to clinical effectiveness in patients with HR-deficient tumors. PARPi resistance results from several independent mechanisms, leading to the restoration of Homologous Recombination and/or Replication Fork stabilization. The absence of alternative options for patients with tumors with innate or acquired resistance underlines the urgency to develop additional therapeutics. More recent studies have identified new synthetic lethal opportunities for BRCA1/2 deficient tumors. Knockout of the genes for POLQ (DNA polymerase theta) or for USP1 (Ubiquitin Specific Protease 1) results in killing of these tumors, and inhibitors of these enzymes are emerging as promising agents for HR-deficient tumors. POLQ and USP1 expression is particularly high in subtypes of breast and ovarian tumors with defects in HR. As a result, POLQi or USP1i in HR-deficient tumors induces cell death. POLQi or USP1i can synergize with PARPi in killing HR-deficient tumors or PARPi-resistant tumors. BRCA1/2 deficient tumors have an increase in single strand DNA gaps (ssGAPs) near replication forks. Treatment with PARPi results in an increase in the size and number for these ssGAPs, ultimately leading to DSBs and cell death. Interestingly, PARPi resistance results, at least in part, from the ability of resistant cells to close the ssGAPs through enhanced POLQ and USP1 activity, thereby providing a rationale for the combination of PARP1, POLQi, and USP1 in HR-deficient cancers. USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. Moreover, this synergy was observed in a set of patient-derived ovarian cancer organoids (PDOs), thus confirming the sensitivity of BRCA1-deficient cells to inhibition by these agents. The accumulation of ssDNA gaps after treatment with a USP1i, PARP, or POLQi correlated with the sensitivity to these drugs in all models tested. Ovarian cancer PDOs provide a powerful tool for detecting drug synergy and for rapid in vitro sensitivity testing. The detection of ssDNA gap accumulation may be a useful predictive biomarker for response to DNA Repair inhibitors as monotherapy or in combination in ongoing clinical trials. Citation Format: Alan D. D'Andrea. Single strand DNA GAP accumulation as a functional biomarker for DNA Repair Inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA009.

The current landscape of machine learning-based radiomics in arteriovenous malformations: a systematic review and radiomics quality score assessment.

Arteriovenous malformations (AVMs) are rare vascular anomalies involving a disorganization of arteries and veins with no intervening capillaries. In the past 10 years, radiomics and machine learning (ML) models became increasingly popular for analyzing diagnostic medical images. The goal of this review was to provide a comprehensive summary of current radiomic models being employed for the diagnostic, therapeutic, prognostic, and predictive outcomes in AVM management. A systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, in which the PubMed and Embase databases were searched using the following terms: (cerebral OR brain OR intracranial OR central nervous system OR spine OR spinal) AND (AVM OR arteriovenous malformation OR arteriovenous malformations) AND (radiomics OR radiogenomics OR machine learning OR artificial intelligence OR deep learning OR computer-aided detection OR computer-aided prediction OR computer-aided treatment decision). A radiomics quality score (RQS) was calculated for all included studies. Thirteen studies were included, which were all retrospective in nature. Three studies (23%) dealt with AVM diagnosis and grading, 1 study (8%) gauged treatment response, 8 (62%) predicted outcomes, and the last one (8%) addressed prognosis. No radiomics model had undergone external validation. The mean RQS was 15.92 (range: 10-18). We demonstrated that radiomics is currently being studied in different facets of AVM management. While not ready for clinical use, radiomics is a rapidly emerging field expected to play a significant future role in medical imaging. More prospective studies are warranted to determine the role of radiomics in the diagnosis, prediction of comorbidities, and treatment selection in AVM management.

Expert Panel Recommendations for a Standardized Ambulatory Glucose Profile Report for Connected Insulin Pens.

Connected insulin pens capture data on insulin dosing/timing and can integrate with continuous glucose monitoring (CGM) devices with essential insulin and glucose metrics into a single platform. Standardization of connected insulin pen reports is desirable to enhance clinical utility with a single report. An international expert panel was convened to develop a standardized connected insulin pen report incorporating insulin and glucose metrics into a single, clinically useful report. An extensive literature review and identification of examples of current connected insulin pen reports was performed serving as the basis for creation of a draft of a standardized connected insulin pen report. The expert panel participated in three virtual standardization meetings and online surveys. The AGP Report: Connected Insulin Pen brings all clinically relevant CGM-derived glucose and connected insulin pen metrics into a single simplified two-page report. The first page contains the time in ranges bar, summary of key insulin and glucose metrics, the ambulatory glucose profile (AGP) curve, and detailed basal (long-acting) insulin assessment. The second page contains the bolus (mealtime and correction) insulin assessment periods with information on meal timing, insulin-to-carbohydrate ratio (ICR), average bolus insulin dose and number of days with bolus doses recorded. The report's second page contains daily glucose profiles with an overlay of the timing and amount of basal and bolus insulin administered. The AGP Report: Connected Insulin Pen is a standardized clinically useful report that should be considered by companies developing connected pen technology as part of their system reporting/output.

Specification for the clinical application of non fiber-optic transmission technology Er:YAG laser in dentistry

Non fiber-optic transmission technology Er:YAG laser is becoming more widely used in clinical applications, whose therapeutic effects have been recognized by domestic and international researches. However, there is no standardized application for non fiber-optic transmission technology Er:YAG laser in oral medicine. Domestic multidisciplinary dental experts have been organized by Oral Health Branch Association of China Association of Gerontology and Geriatrics to discuss and formulate this standard comprising its application requirements in specialties of dentistry, aiming to promote the standardization of non fiber-optic transmission technology Er:YAG laser clinical use, which could help to better utilize the advantages of laser in oral treatment and to improve the effectiveness of disease treatment.

Evaluation of clinical characters and use of alternative medicines in the management of headache and predictors of treatment satisfaction among Saudi adults – A community-based study in Saudi Arabia

Background and objectiveThe use of alternative medicine (AM) is rising globally. Hence this study aimed to assess the Use of and Satisfaction with Alternative Medicine in the management of headache and Related Factors in Individuals, living in Saudi Arabia. MethodsA cross-sectional study was conducted from July to December 2023 using an online questionnaire in Riyadh Saudi Arabia. The data was collected using a series, of prevalidated questionnaires aimed to assess the utilization and satisfaction of AM for the headache. Convenience sampling was applied for data collection. ResultsA response rate of 93.1 % (n = 550) was obtained. Among the respondents, 78.7 % reported having headaches, while 69.2 % had a history of using AMs for headaches. However, among the users of AMs, 65.9 % of them were satisfied with the results of AMs, of those who were satisfied, 33.7 % said that AMs helped to prevent headache attacks, and 53.8 % reported that AMs use reduced pain intensity. The regression results demonstrated that there was a significant relationship between the satisfaction of AM for the headache and age (p < 0.004), and Active in sports (p < 0.019) and severity of the headache pain (p < 0.081) ConclusionThe findings reported that relatively high prevalence of AMs used to manage headaches, while 65.9% of the users were satisfied with the outcomes, the satisfaction was found to have a significant relationship with age, activity in sports and severity of pain. To avoid negative effects of AM, it is recommended to use under the qualified healthcare professionals.

Clonal Dynamics and Relapse Risk Revealed by High-Sensitivity FLT3-Internal Tandem Duplication Detection in Acute Myeloid Leukemia

The ability to detect low-level disease is key to our understanding of clonal heterogeneity in acute myeloid leukemia (AML) and residual disease that elude conventional assays and seed relapse. We developed a high-sensitivity next-generation sequencing (HS-NGS) clinical assay, able to reliably detect low levels (1 × 10−5) of FLT3-ITD, a frequent, therapeutically targetable and prognostically relevant mutation in AML. By applying this assay to 289 longitudinal samples from 62 patients at initial diagnosis and/or clinical follow-up (mean follow-up of 22 months), we revealed the frequent occurrence of FLT3-ITD subclones at diagnosis and demonstrated a significantly decreased relapse risk when FLT3-ITD is cleared after induction or thereafter. We perform pairwise sequencing of diagnosis and relapse samples from 23 patients to uncover more detailed patterns of FLT3-ITD clonal evolution at relapse than is detectable by less-sensitive assays. Finally, we show that rising ITD level during consecutive biopsies is a harbinger of impending relapse. Our findings corroborate the emerging clinical utility of high-sensitivity FLT3-ITD testing and expands our understanding of clonal dynamics in FLT3-ITD–positive AML.

Development of a nomogram for predicting liver transplantation prognosis in hepatocellular carcinoma

BACKGROUND At present, liver transplantation (LT) is one of the best treatments for hepatocellular carcinoma (HCC). Accurately predicting the survival status after LT can significantly improve the survival rate after LT, and ensure the best way to make rational use of liver organs. AIM To develop a model for predicting prognosis after LT in patients with HCC. METHODS Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated. The expression levels of alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, Golgi protein 73, cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer. The best cutoff value of biomarkers was determined using the Youden index. Cox regression analysis was used to identify the independent risk factors. A forest model was constructed using the random forest method. We evaluated the accuracy of the nomogram using the area under the curve, using the calibration curve to assess consistency. A decision curve analysis (DCA) was used to evaluate the clinical utility of the nomograms. RESULTS The total tumor diameter (TTD), vascular invasion (VI), AFP, and cytokeratin-18 epitopes M30 (CK18-M30) were identified as important risk factors for outcome after LT. The nomogram had a higher predictive accuracy than the Milan, University of California, San Francisco, and Hangzhou criteria. The calibration curve analyses indicated a good fit. The survival and recurrence-free survival (RFS) of high-risk groups were significantly lower than those of low- and middle-risk groups (P &lt; 0.001). The DCA shows that the model has better clinical practicability. CONCLUSION The study developed a predictive nomogram based on TTD, VI, AFP, and CK18-M30 that could accurately predict overall survival and RFS after LT. It can screen for patients with better postoperative prognosis, and improve long-term survival for LT patients.

PAX1 methylation as a robust predictor: developing and validating a nomogram for assessing endocervical curettage (ECC) necessity in human papillomavirus16/18-positive women undergoing colposcopy

ObjectiveThe major challenge in routine endocervical curettage (ECC) among Human Papillomavirus (HPV) 16/18-positive patients is that only a small fraction benefit. Nevertheless, current reported models often overestimate the validity and necessity of ECC, making it difficult to improve benefits for patients. This research hypothesized that assessing paired boxed gene 1 methylation levels (PAX1m) and clinical characteristics could enhance the predictive accuracy of detecting additional high-grade squamous intraepithelial lesions or worse (HSIL +) through ECC that were not identified by colposcopy-directed biopsy (CDB).MethodsData from 134 women with HPV16/18 positivity undergoing CDB and ECC between April 2018 and April 2022 were collected and analyzed. Quantitative methylation-specific polymerase chain reaction (qMSP) was utilized to measure PAX1m, expressed as ΔCp. Univariate and multivariate regression analyses were conducted to screen variables and select predictive factors. A nomogram was constructed using multivariate logistic regression to predict additional HSIL + detected by ECC. The discrimination, calibration, and clinical utility of the nomogram were evaluated using receiver operating characteristic curves (ROC) and the calibration plot.ResultsAge (odds ratio [OR], 5.654; 95% confidence interval [CI], 1.131–37.700), cytology (OR, 24.978; 95% CI, 3.085–540.236), and PAX1 methylation levels by grade (PAX1m grade) (OR, 7.801; 95% CI, 1.548–44.828) were independent predictive factors for additional detection of HSIL + by ECC. In HPV16/18-positive women, the likelihood of additional detection of HSIL + through ECC increased with the severity of cytological abnormalities, peaking at 43.8% for high-grade cytological lesions. Moreover, when cytological findings indicated low-grade lesions, PAX1 methylation levels were positively correlated with the additional detection of HSIL + by ECC (P value < 0.001). A nomogram prediction model was developed (area under curve (AUC) = 0.946; 95% CI, 0.901–0.991), demonstrating high sensitivity (90.9%) and specificity (90.5%) at the optimal cutoff point of 107. Calibration analysis confirmed the model’s strong agreement between predicted and observed probabilities.ConclusionThe clinical nomogram presented promising predictive performance for the additional detection of HSIL + through ECC among women with HPV16/18 infection. PAX1 methylation level could serve as a valuable tool in guiding individualized clinical decisions regarding ECC for patients with HPV 16/18 infection, particularly in cases of low-grade cytological findings.

Point-of-care high-sensitivity cardiac troponin in suspected acute myocardial infarction assessed at baseline and 2 h.

Strategies to assess patients with suspected acute myocardial infarction (AMI) using a point-of-care (POC) high-sensitivity cardiac troponin I (hs-cTnI) assay may expedite emergency care. A 2-h POC hs-cTnI strategy for emergency patients with suspected AMI was derived and validated. In two international, multi-centre, prospective, observational studies of adult emergency patients (1486 derivation cohort and 1796 validation cohort) with suspected AMI, hs-cTnI (Siemens Atellica® VTLi) was measured at admission and 2 h later. Adjudicated final diagnoses utilized the hs-cTn assay in clinical use. A risk stratification algorithm was derived and validated. The primary diagnostic outcome was index AMI (Types 1 and 2). The primary safety outcome was 30-day major adverse cardiac events incorporating AMI and cardiac death. Overall, 81 (5.5%) and 88 (4.9%) patients in the derivation and validation cohorts, respectively, had AMI. The 2-h algorithm defined 66.1% as low risk with a sensitivity of 98.8% [95% confidence interval (CI) 89.3%-99.9%] and a negative predictive value of 99.9 (95% CI 99.2%-100%) for index AMI in the derivation cohort. In the validation cohort, 53.3% were low risk with a sensitivity of 98.9% (95% CI 92.4%-99.8%) and a negative predictive value of 99.9% (95% CI 99.3%-100%) for index AMI. The high-risk metrics identified 5.4% of patients with a specificity of 98.5% (95% CI 96.6%-99.4%) and a positive predictive value of 74.5% (95% CI 62.7%-83.6%) for index AMI. A 2-h algorithm using a POC hs-cTnI concentration enables safe and efficient risk assessment of patients with suspected AMI. The short turnaround time of POC testing may support significant efficiencies in the management of the large proportion of emergency patients with suspected AMI.