Precise Cutoff Research Articles

Improving CYP2C19 phenotyping using stereoselective omeprazole and 5-hydroxy-omeprazole metabolic ratios.

Omeprazole (OME) is a CYP2C19 phenotyping probe, marketed as a racemic (S)/(R) mixture or as an S-enantiomer. Both CYP2C19 and CYP3A4 enzymes mediate (R)-OME hydroxylation to (R)-5-hydroxyomeprazole, while (S)-OME is exclusively hydroxylated via CYP2C19. This study investigates OME and its 5-hydroxymetabolite enantiomers' pharmacokinetics using data from two studies involving healthy volunteers. In Study A, volunteers received OME alone in Session 1, OME combined with voriconazole and fluvoxamine in Session 2 and finally OME with rifampicin in Session 3. In Study B, volunteers received OME alone in Session 1, OME combined with voriconazole in Session 2 and finally OME with fluvoxamine in Session 3. Despite low metabolic ratio values of (S)-OME, detectable modulation of CYP2C19 activity suggests both (R)- and (S)-OME isomers could effectively assess CYP2C19 activity. Further research is needed for precise cut-offs in different phenotype groups.

NanoRidge filters: Fabrication strategies and performance optimization for nano-scale microfluidic particle filtration.

Filters with high throughput, minimal dead volume, and greater sensitivity to particle size are needed, which traditional benchtop filtration cannot provide. Leveraging microfabrication techniques developed by the electronics and optics industries, the filters presented here feature a unique serpentine "NanoRidge" structure, offering a continuous filtration gap spanning over three meters on a compact 4 × 14.5 mm2 footprint. This design provides more precise size filtration cut-offs and consistent flow paths compared to traditional membrane filtration systems. Despite challenges associated with glass substrate deformation impacting uniform filter gap sizes, the study provides valuable insights into the development of NanoRidge filters (NRFs) for enhancing filtration efficiency in preparatory techniques and sample analysis. This study describes the fabrication and testing of these new filter types and directly compares the performance to traditional membrane filters using the metrics of particle size cut-off (the smallest difference in particle size which can be filtered vs passed) and particle loss. The NanoRidge filters were characterized using imaging (during fabrication, post-fabrication and use, fluorescent particles captured and small molecule dye), pressure and flow measurements, and a series of particle sizes "filter or pass" studies. Particle capacity (100-250 nm) ranged from 5 × 108 to 7 × 109 in 1 ml samples at a flow rate of 100 μl/min with backpressure in the range of 1-3 Bar. The optimized fabrication procedure for the 150 nm NRF yielded a small particle recovery of 95% while also achieving a large particle filtration of 73%. High filtration efficiency was also proven in the final 60 and 80 nm NRF fabrication procedures at 96% and 91%, respectively.

Unveiling fairness in scoring: a thorough method for precise cutoff score calculation in education assessment

PurposeThe purpose of this research is to address the need for a robust system to accurately determine a cutoff score by using the Angoff method and leveraging the Rasch infit and outfit statistics of item response theory by detecting and removing misfitting items in a test.Design/methodology/approachResearchers in educational evaluation support the use of grades as a complete measure to evaluate students’ overall academic performance. In higher education, determining cutoff scores is crucial for assessing academic progress and achievement. Higher education institutions worldwide set predefined minimal standards of success, sometimes referred to as cutoff thresholds. These thresholds serve as benchmarks for assessing performance quality and determining eligibility for academic credit or advancement.FindingsThe proposed approach combines the Angoff method with Rasch item fit statistics to precisely determine the cutoff score by excluding items that do not fit well (misfitting items) in a test. This methodology holds the potential to enhance the fairness and accuracy of grading practices, ensuring that assessments align with educational objectives and provide meaningful feedback to students.Originality/valueThe value of this research extends to various fields where cutoff scores are used for decision-making purposes. By using Rasch item fit statistics and the Angoff method, practitioners and researchers can enhance the quality and validity of their assessments.

Evaluation of Laparoscopic Colorectal Resection Among Elderly Individuals With Colorectal Malignancy: A Single-center Retrospective Analysis.

The purpose of the current study was to statistically clarify the precise risk age in elderly patients undergoing colorectal surgery and to evaluate the safety and efficacy of laparoscopic colorectal resection in these patients. Patients' clinical variables were extracted from the database of the Gastrointestinal Surgery Centre, Third Affiliated Hospital of Sun Yat-sen University, from 2015 to 2019. Logistic regression was conducted to identify independent risk factors of postoperative complications and ORs for each age. Curves of odds ratios (ORs) and CIs for each age were fitted by using a locally weighted scatterplot smoother, and a structural breakpoint was determined by the Chow test to identify a precise cutoff risk age for elderly patients. Comparison and subgroup analysis were conducted between surgical approach groups using the Student t test and χ 2 analysis. Locally weighted scatterplot smoother OR analysis manifested that patients aged 69 years old or older suffered a higher possibility of postoperative complications and should be defined as high-risk age. Comparison according to the high-risk age revealed laparoscopic colorectal surgery is better than laparotomic surgery for elderly individuals in terms of hospital stay (9.46 ± 5.96 vs 15.01 ± 6.34, P < 0.05), the incidence of intensive care unit transfer (4 vs 20, P < 0.05), and incidence of surgical site infection (15 vs 20, P < 0.05). Patients who underwent laparotomic surgery had a greater prevalence of Clavien-Dindo II/III complications ( P < 0.05). These findings remained stable even after propensity matching. Furthermore, such superiority was proved especially significant for patients who underwent left-side colorectal resection. In addition, overall survival was improved in the laparoscopic surgery group, whereas no differences were observed in disease-free survival. In our study population, age 69 or older was a cutoff point age suggests a higher possibility of postoperative morbidity after colorectal surgery. Laparoscopic colorectal resection should be regarded as a superior therapeutic choice for these elderly individuals, especially for left-side colorectal surgeries.

The iPREFACE score is useful for predicting fetal acidemia: A retrospective cohort study of 113 patients who underwent emergency cesarean section for non-reassuring fetal status during labor

The iPREFACE score may aid in predicting fetal acidemia and neonatal asphyxia in emergency cesarean and vaginal deliveries, which may improve labor management precision in the future. This study aimed to assess the score use of the iPREFACE as an objective indicator of the need for rapid delivery in cases of repeated abnormal waveforms without concurrent indications for immediate medical intervention during labor. This retrospective cohort study was conducted among term (37+ 0 days to 41+6 days) singleton pregnant women who underwent emergency cesarean delivery owing to a nonreassuring fetal status. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-decision of emergency cesarean delivery score, calculated from a 30-minute cardiotocography waveform before the decision to perform emergency cesarean delivery, and the integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography transducer score, calculated from a 30-minute cardiotocography waveform before cardiotocography transducer removal, were employed. The primary outcome was the assessment of the predictive ability of these scores for fetal acidemia, whereas the secondary outcomes were differences in umbilical artery blood gas findings and postnatal outcomes between the 2 groups, divided by the cutoff values of the integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography score. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-decision of emergency cesarean delivery and integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography transducer scores demonstrated the capability to predict an umbilical artery blood pH of <7.2. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-decision of emergency cesarean delivery and -removal of cardiotocography transducer score, with cutoff values of 37 and 46 points, respectively, exhibited an area under the receiver operating characteristic curve of 0.82 and 0.87, respectively. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography transducer group with ≥46 points had higher incidence rates of an umbilical cord artery blood pH of <7.2, <7.1, and <7.0 and neonatal intensive care unit admissions for neonatal asphyxia. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring, derived from cardiotocography during an emergency cesarean delivery, may enable clinicians to predict fetal acidemia in cases of nonreassuring fetal status. Improved prediction of fetal acidemia and facilitation of timely intervention hold promise for enhancing the outcomes of mothers and newborns during childbirth. Prospective studies are warranted to establish precise cutoff values and to validate the clinical application of these scores.

A unique circulating microRNA pairs signature serves as a superior tool for early diagnosis of pan-cancer

Cancer remains a major burden globally and the critical role of early diagnosis is self-evident. Although various miRNA-based signatures have been developed in past decades, clinical utilization is limited due to a lack of precise cutoff value. Here, we innovatively developed a signature based on pairwise expression of miRNAs (miRPs) for pan-cancer diagnosis using machine learning approach. We analyzed miRNA spectrum of 15832 patients, who were divided into training, validation, test, and external test sets, with 13 different cancers from 10 cohorts. Five different machine-learning (ML) algorithms (XGBoost, SVM, RandomForest, LASSO, and Logistic) were adopted for signature construction. The best ML algorithm and the optimal number of miRPs included were identified using area under the curve (AUC) and youden index in validation set. The AUC of the best model was compared to previously published 25 signatures. Overall, Random Forest approach including 31 miRPs (31-miRP) was developed, proving highly efficient in cancer diagnosis across different datasets and cancer types (AUC range: 0.980–1.000). Regarding diagnosis of cancers at early stage, 31-miRP also exhibited high capacities, with AUC ranging from 0.961 to 0.998. Moreover, 31-miRP exhibited advantages in differentiating cancers from normal tissues (AUC range: 0.976–0.998) as well as differentiating cancers from corresponding benign lesions. Encouragingly, comparing to previously published 25 different signatures, 31-miRP also demonstrated clear advantages. In conclusion, 31-miRP acts as a powerful model for cancer diagnosis, characterized by high specificity and sensitivity as well as a clear cutoff value, thereby holding potential as a reliable tool for cancer diagnosis at early stage.

MarrowCellDLD: a microfluidic method for label-free retrieval of fragile bone marrow-derived cells

Functional bone marrow studies have focused primarily on hematopoietic progenitors, leaving limited knowledge about other fragile populations, such as bone marrow adipocytes (BMAds) and megakaryocytes. The isolation of these cells is challenging due to rupture susceptibility and large size. We introduce here a label-free cytometry microsystem, MarrowCellDLD, based on deterministic lateral displacement. MarrowCellDLD enables the isolation of large, fragile BM-derived cells based on intrinsic size properties while preserving their viability and functionality. Bone marrow adipocytes, obtained from mouse and human stromal line differentiation, as well as megakaryocytes, from primary human CD34+ hematopoietic stem and progenitor cells, were used for validation. Precise micrometer-range separation cutoffs were adapted for each cell type. Cells were sorted directly in culture media, without pre-labeling steps, and with real-time imaging for quality control. At least 106 cells were retrieved intact per sorting round. Our method outperformed two FACS instruments in purity and yield, particularly for large cell size fractions. MarrowCellDLD represents a non-destructive sorting tool for large, fragile BM-derived cells, facilitating the separation of pure populations of BMAds and megakaryocytes to further investigate their physiological and pathological roles.

A molecular sieve with ultrafast adsorption kinetics for propylene separation

The design of molecular sieves is vital for gas separation, but it suffers from a long-standing issue of slow adsorption kinetics due to the intrinsic contradiction between molecular sieving and diffusion within restricted nanopores. We report a molecular sieve ZU-609 with local sieving channels that feature molecular sieving gates and rapid diffusion channels. The precise cross-sectional cutoff of molecular sieving gates enables the exclusion of propane from propylene. The coexisting large channels constituted by sulfonic anions and helically arranged metal-organic architectures allow the fast adsorption kinetics of propylene, and the measured propylene diffusion coefficient in ZU-609 is one to two orders of magnitude higher than previous molecular sieves. Propylene with 99.9% purity is obtained through breakthrough experiments with a productivity of 32.2 L kg −1 .

A perspective of randomness in a clinical test of olfactory performance

Random walks describe stochastic processes characterized by a sequence of unpredictable changes in a random variable with no correlation to past changes. This report describes the random walk component of a clinical sensory test of olfactory performance. The precise definition of this stochastic process allows the establishment of precise diagnostic cut-offs for the identification of olfactory loss. Within the Sniffin`Sticks olfactory test battery, odor discrimination (D) and odor identification (I) are assessed by four- and three-alternative forced-choice designs, respectively. Meanwhile, the odor threshold (T) test integrates a three-alternative forced-choice paradigm within a staircase paradigm with seven turning points. We explored this paradigm through computer simulations and provided a formal description. The odor threshold assessment test consists of two sequential components, the first of which sets the starting point for the second. Both parts can be characterized as biased random walks with significantly different probabilities of moving to higher (11%) or lower (89%) values. The initial odor concentration step for the first phase of the test and the length of the subsequent random walk in the second phase significantly affect the probability of randomly achieving high test scores. Changing the odor concentration from where the starting point determination for the second test part begins has raised the current cut-off for anosmia, represented as T + D + I < 16, from the 87th quantile of random test scores to the 97th quantile. Analogous findings are likely applicable to other sensory tests that use the staircase paradigm characterized as random walk.

Long-term prognosis of low language proficiency in children

Objectives This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: Primary objectives Population Children between four and eight years of age, diagnosed with a language disorder, or determined to have low language proficiency before age eight. Intervention Not applicable, this is a review of observational studies and will not include active interventions. Comparator The comparison group will be peers or siblings with typically developing language skills, that is, no identified language disorder or low language proficiency. Outcome We will include the following outcomes if measured when participants are at least 12 years old (adolescents and adults): Proximal outcomes in language and literacy (outcomes within the same domain as the original assessments: omnibus tests of expressive, receptive (including listening comprehension), total language, vocabulary, grammar, narrative or expository discourse, clinical markers, such as nonsense word repetition, sentence repetition, or both) World Health Organization quality of life outcomes across five domains: physical (including general health, sleep and energy, sexual health); psychological (including mental health, self‐esteem, memory, learning, and concentration); independence (including activities of daily living, occupational outcomes, dependence on medicinal and non‐medicinal drugs and supports, independent living); social relationships (including friendships, romantic relationships, parenthood, peer problems, and anti‐social behaviour); environment (including academic outcomes, work satisfaction, financial resources, societal participation in leisure/community activities, safety). Timing Studies must have traced the individuals into adolescence, or transition to adulthood or adulthood, or both, thus, when participants are 12 years and older. Setting Identification, or assessment and diagnosis using standard diagnostic algorithms. Precise measures and cutoffs on standardised tests will vary from study to study. For instance, Tomblin 1997 used the diagnostic algorithm of < ‐1.25 standard deviations on two or more language composite scores; and in Norbury 2016, language disorder was defined as scores of −1.5 standard deviations or below on two of five language composites in the absence of intellectual disability, existing medical diagnosis, or both. Identification by speech‐language pathologists, educational psychology services, or in the context of research (population studies). Identification includes measures of language, such as vocabulary, grammar, morphosyntax, narrative. It can be expressive measure(s), receptive measure(s), or both. We will exclude identification made on the basis of tests of phonology/speech production, pragmatics, reading, or working memory only. We will include large‐scale population studies in which low language proficiency may be determined by a cut‐off of at least ‐1 standard deviation on at least one standard test of language to assess longitudinal relationships between single measures and quality of life outcomes in large community samples (Beitchman 2014; Caspi 2016; Thornton 2021). The main objective of this review is to assess the long‐term prognosis of an early language disorder or low language proficiency (LLP) for children aged four to eight years at baseline, and from age 12 years and up at follow‐up, in areas of language and literacy, and broad quality of life outcomes in physical, psychological, independence, social relationships, and environment outcomes. This will include measures of mental and physical health, academic outcome, employment status, financial resources, and societal participation. We will ask the following research questions: 1) To what extent do children with LLP age four to eight years show higher risk for persistent difficulties with language and literacy into adolescence and adulthood? 2) To what extent do children age four to eight years, with LLP, experience higher risk for poor quality of life across five domains of physical, psychological, independence, social relationships, and environment well‐being in adolescence, and adulthood (WHO 2012)? Secondary objectives Secondary objectives are: 1) to understand how severity of early language problems affects long‐term prognosis and quality of life, and 2) to identify gaps in the extant research. For instance, while the indicative sample of papers consistently report academic and employment outcomes, there is little evidence regarding physical or medical health outcomes. Investigation of sources of heterogeneity between studies We expect that there will be substantial heterogeneity between the included studies on the following variables: Diagnostic criteria Severity of language impairment Method of ascertainment (population study versus recruitment from special schools or clinics) Year of publication Age of outcome measurement Inclusiveness of non‐verbal IQ (Specific Language Impairment versus Developmental Language Disorder) Stability of schooling (e.g. special school consistently versus changing between special school and mainstream classrooms) Literacy skills

Do sleep disruptions promote social fragmentation?

Sleep changes predate shifts in mood/affect, thought processing, mental and physical health, civic engagement, and contextual circumstances, among other things. Theory predicts that these changes may lead to shifts in political and social beliefs. Do sleep disruptions shape how individuals see the world, the people around them, and themselves in relation to others? In this article, we use daily survey data from the 77 waves (N ≈ 460,000) of the University of California, Los Angeles's 2019-2021 Nationscape Survey-a nationally representative political survey-to examine the effect of an exogenous short-term sleep disruption on measures of political views, polarization, and discriminatory beliefs. Using this data set, we leverage the modest sleep disruption that occurs at the start (and end) of Daylight Saving Time (DST) and employ a regression discontinuity in time design around the precise DST cutoff (which we supplement with event study models). Despite strong theoretical expectations and correlational connection between measures of sleep and many outcomes related to social fragmentation, we find that the DST change has little to no causal effect on citizens' levels of polarization or their discriminatory attitudes. These effects are precise enough to rule out small effects, robust to a host of specification checks, and consistent across potential subgroups of interest. Our work adds to a small but growing body of research on the social and political effects of sleep disruptions.

The Role of Corrected Dlco in Predicting Relapse and Mortality Post Autologous Hematopoietic Cell Transplantation in Multiple Myeloma

Introduction: Autologous Hematopoietic Cell Transplantation (AHCT) remains the standard of care for multiple myeloma (MM) patients who achieve at least a partial response to prior chemotherapy. Survival post AHCT is associated with disease risk and patient comorbidities, including lung diseases indicated by pulmonary function. The corrected diffusing capacity for carbon monoxide (DLCOc) is usually assessed in transplant candidates in order to determine AHCT eligibility, although precise DLCOc cut-offs are yet to be standardized. Recent studies suggested that a DLCOc ≤60% possesses a prognostic value in predicting relapse and mortality post AHCT. Hence, we aimed to validate the role of DLCOc ≤60% in predicting post-AHCT outcomes at our institution. Methods: We did a retrospective review of MM patients who underwent AHCT at Cleveland Clinic between January 1st, 2011 and January 15th 2021. The patients were categorized based on their corrected DLCO into two groups: DLCOc ≤60% and DLCOc >60% of the predicted value. Baseline characteristics, including patient, disease, and transplant factors were compared between the two groups. The collected data were analyzed using SPSS and GraphPad Prim by means of Chi square, ANOVA, and Kaplan Meier survival analysis. Results: A total of 466 patients with available DLCOc data were included in our study, of which 38 patients had a DLCOc ≤60% and 428 had a DLCOc >60% of the predicted value. Our cohort had a median follow up of 31.9 months post-AHCT. Patient and disease characteristics were similar between the 2 groups, including age (median 59.1 vs 60.3 years, P= 0.407), sex (Males 65.8 vs 58.2%, P=0.361), standard risk (81.5 vs 66.4%) and high risk (18.5 vs 33.6%) cytogenetic profiles (P=0.107), as well as history of smoking (23 vs 38.2%, P=0.1). In addition, both groups had a similar distribution across the International Staging System (ISS) stages (37.9, 37.9, 24.2% vs 38.3, 38.9, 22.8% for stages I, II and III, P= 0.987) and received similar preparative regimens (92.1, 7.9, 0% vs 96.3, 3, 0.7% for Melphalan 200 mg/m2, Melphalan 140 mg/m2 and Busulfan + Cyclophosphamide, P=0.25). Kaplan-Meier survival analysis showed that the DLCOc ≤60% group survived for a significantly shorter period with median overall survival (mOS) of 27.3 vs 91.7 months (P<0.0001) (Fig 1A). In addition, the DLCOc ≤60% group had earlier relapses with median progression free survival (mPFS) of 21.2 vs 38.7 months (P=0.0115) (Fig 1B). Subgroup analysis confirmed that mOS was significantly shorter in the DLCOc ≤60% group irrespective of relapse, with mOS of 25.4 vs 79.6 months (P<0.0001) in relapsed MM of DLCOc ≤60% (n=18) and DLCOc >60% (n=193) patients, respectively. Similarly, non-relapse survival was also shorter (medians unreached) in the non-relapsed DLCOc ≤60% group (n=20) compared to the non-relapsed DLCOc >60% group (n=235) (P<0.0001). When selecting patients of standard risk cytogenetics from both groups, the significant difference in mOS and mPFS was retained with mOS 51.7 vs unreached months (P<0.0001) and mPFS 21.2 vs 67.7 months (P=0.0051) for DLCOc ≤60% group (n=22) and DLCOc >60% (n=225), respectively. Likewise, matching for melphalan 200 mg/m2 regimen patients further maintained the remarkable gap in mOS 25.4 vs 91.7 months (P<0.0001) and mPFS 20 vs 40 months (P=0.0013) for DLCOc ≤60% group (n=35) and DLCOc >60% (n=413), respectively. Conclusion: The pre-AHCT DLCOc level possesses a useful prognostic value that can predict disease relapse as well as both relapse- and non-relapse related mortality post AHCT. This was demonstrated when using a cut-off value of ≤60% vs >60%. Our findings were supported by the fact that both groups had similar clinical and cytogenetic characteristics, thus reducing the risk of confounding effects. Our findings were also validated when controlling for cytogenetic risks and melphalan dosage. Large, prospective trials are warranted to determine whether DLCOc ≤60% can serve AHCT eligibility criterion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictive value of inflammatory indices: a prospective study in critical oncological patients

The aim of this study was to evaluate the association of inflammatory indices and survival in critical cancer patients. This is a prospective, observational cohort study in which patients were followed up for 28 days after admission to the intensive care unit (ICU) of a reference hospital specialized in oncology. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), and modified Glasgow Prognostic Score (mGPS) were calculated within 24 hours of admission to the ICU. Spearman’s correlation, Kaplan-Meier survival curve, and Cox regression were used to associate the selected variables with survival. One hundred patients were selected, 78% of whom had active cancer, and 27 of whom died. Patients with mGPS 1 and 2 had a lower probability of 28-day survival and were 4.1 times more likely to die than the patients with mGPS 0. mGPS is a better predictor of survival than NLR, PLR, and MLR in critically ill patients diagnosed with solid tumors. Further studies are needed to establish the precise cutoff point for mGPS in relation to mortality and to assess its applicability in clinical practice.&#x0D; Keywords: inflammation; critical care; neoplasms; prognosis.

Predictive value of PSA density in the diagnosis of prostate cancer in lebanese men.

Being the second most common cancer in men, prostate cancer detection relies on laboratory tests, imaging, and surgical procedures, although biopsy remains the mainstay in diagnosis of prostate cancer. No clear cut-off of prostate specific antigen density (PSAD) for suspecting prostate cancer has been established in the Lebanese population. Our primary objective was to evaluate the diagnostic strength of the PSAD value versus total prostate specific antigen (tPSA) level in the Lebanese men in correlation with biopsy outcome to avoid unnecessary prostate biopsy. A retrospective study of 347 patients with history of prostate biopsy done for cancer suspicion included tPSA, prostate volume, and prostate density values and results of prostate biopsy. Data was collected from Bahman hospital and statistical analysis of the mean values of tPSA, prostate volume and PSAD in different age groups was done. Significance of the results was tested using. On average, patients with negative biopsies were younger and they had lower tPSA levels, lower PSAD values and larger prostate volume compared to patients with positive biopsies. A PSAD cutoff of 0.185 ng/ml2 revealed the highest predictive strength for prostate cancer (6 times risk) compared with other parameters. These findings were mainly referred to patients with PSA > 10 ng/ml. A multifactorial approach must be conducted including all parameters in order to decide upon the need for prostate biopsy. PSAD proved to be a good marker in favor or against a prostate biopsy with a cut-off of 0.185 ng/ml2, especially in patients with tPSA level higher to 10 ng/ml. A multicenter study was recommended for better and more reliable results and more precise cut-offs.

Clinical Validity of Circulating Tumor DNA as Prognostic and Predictive Marker for Personalized Colorectal Cancer Patient Management.

Simple SummaryCtDNA analysis is a promising tool in liquid biopsy for the detection of tumor recurrence and progression, and is increasingly adopted into clinical practice. Still, guidelines for the accurate clinical interpretation of ctDNA analysis results are largely lacking, especially for tumor mutant variants detected at very low frequencies. Here, we show that cutoff determination for the detection and quantification of low-frequency mutant variants enables the accurate prediction of residual disease, tumor recurrence and progression, even before clinical evidence. CtDNA analysis using these cutoffs outperformed cfDNA and CEA level measurements. With these findings, we highlight the need to thoroughly validate each liquid biopsy assay and define the assay-specific limit of blanks (LOB) and limit of quantifications (LOQ) of BRAF p.V600E and KRAS p.G12/p.G13 assays for clinical interpretation. Our approach enables accurate clinical interpretation to support clinical decision making.Circulating tumor DNA (ctDNA) is a promising liquid biopsy (LB) marker to support clinical decisions in precision medicine. For implementation into routine clinical practice, clinicians need precise ctDNA level cutoffs for reporting residual disease and monitoring tumor burden changes during therapy. We clinically validated the limit of blank (LOB) and the limit of quantification (LOQ) of assays for the clinically most relevant somatic variants BRAF p.V600E and KRAS p.G12/p.G13 in colorectal cancer (CRC) in a study cohort encompassing a total of 212 plasma samples. We prove that residual disease detection using the LOB as a clinically verified cutoff for ctDNA positivity is in concordance with clinical evidence of metastasis or recurrence. We further show that tumor burden changes during chemotherapy and the course of disease are correctly predicted using the LOQ as a cutoff for quantitative ctDNA changes. The high potential of LB using ctDNA for accurately predicting the course of disease was proven by direct comparison to the routinely used carcinoembryonic antigen (CEA) as well as the circulating free DNA (cfDNA) concentration. Our results show that LB using validated ctDNA assays outperforms CEA and cfDNA for residual disease detection and the prediction of tumor burden changes.

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease

ObjectiveTo investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.MethodsEstablished patients at New York University Langone...

Biomarkers in Asthma - Interpretation, and Utility in Current Asthma Management

Asthma is a complex and highly heterogeneous disorder, having many clinical phenotypes and underlining mechanisms, a broad spectrum of severity, and variable response to controller therapy. Intensive research has been focused on the identification and validation of the most appropriate biomarkers in the clinical management of asthma, mostly addressed to severe and refractory cases. The use of reliable biomarkers in severe asthma can contribute to a better understanding of disease biology, diagnosis and screening, by a refined characterization of particular phenotypes and endotypes, assessment of severity, control, and prognosis. There is an increasing interest to validate biomarkers able to indicate the adequate therapeutic choice from the class of biological agents, most of them targeting T2 inflammation. Using a reliable and validated biomarker, the clinician can monitor the response to initial therapy and early identify a severe phenotype. The aim of this paper is to review the clinical utility of relevant biomarkers currently used in asthma management. Indication for more advanced and efficient therapy, such as monoclonal antibodies and selection of the optimal molecule, is based on biomarkers and clinical criteria, according to the most recent experts’ recommendations. Peripheral blood eosinophils are considered an important biomarker for the selection and identification of responders to anti-eosinophil biological therapy. Real-life long-term studies to confirm the precise use and cutoffs of the already approved biomarkers for T2 phenotypes and to identify reliable biomarkers for non- T2 severe asthma are still unmet needs in asthma management.

Carbon hollow fiber membranes for a molecular sieve with precise-cutoff ultramicropores for superior hydrogen separation

Carbon molecular sieve (CMS) membranes with rigid and uniform pore structures are ideal candidates for high temperature- and pressure-demanded separations, such as hydrogen purification from the steam methane reforming process. Here, we report a facile and scalable method for the fabrication of cellulose-based asymmetric carbon hollow fiber membranes (CHFMs) with ultramicropores of 3–4 Å for superior H2 separation. The membrane fabrication process does not require complex pretreatments to avoid pore collapse before the carbonization of cellulose precursors. A H2/CO2 selectivity of 83.9 at 130 °C (H2/N2 selectivity of >800, H2/CH4 selectivity of >5700) demonstrates that the membrane provides a precise cutoff to discriminate between small gas molecules (H2) and larger gas molecules. In addition, the membrane exhibits superior mixed gas separation performances combined with water vapor- and high pressure-resistant stability. The present approach for the fabrication of high-performance CMS membranes derived from cellulose precursors opens a new avenue for H2-related separations.

Salivary LDH in oral cancer and potentially malignant disorders: A systematic review and meta-analysis.

To evaluate whether salivary lactate dehydrogenase (LDH) levels are increased in patients with oral cancer (OC) or oral potentially malignant disorders (OPMD) when compared to a healthy control group (CG). We conducted a comprehensive search of specialized databases (PubMed/MEDLINE, The Cochrane Library, Web of Science, Scopus, and OpenGrey), including observational analytical studies evaluating the salivary LDH levels (in UI/L or μ/L) in OC or OPMD patients and compared them with a CG. Thirteen case-control studies were included. A total of 755 patients were evaluated, including 303 OC cases, 149 OPMD cases, and 303 controls. The meta-analysis showed that LDH levels were higher within the OC group than the CG (SMD 9.49; 95% CI 6.97-12; p=.00001). Patients with oral leucoplakia (SMD 11.67; 95% CI 1.01-22.33; p=.03) and oral submucous fibrosis (SMD 25.83; 95% CI -1.74-53.40; p=.07) also presented higher levels than the CG. In addition, OC patients had higher salivary LDH levels than oral leucoplakia patients (SMD 5.62; 95% CI 2.14-9.11; p=.002). Heterogeneity was high across all the evaluated studies. The determination of salivary LDH may be a useful method for screening and tracking OC and OPMD, but new protocolized studies are required to establish precise cutoff values.

Subgroup Analysis Can Optimize the Relapse-Prediction Cutoff Value for WT1 Expression After Allogeneic Hematologic Stem Cell Transplantation in Acute Myeloid Leukemia

High WT1 expression after allogeneic hematologic stem cell transplantation (allo-HSCT) can strongly predict relapse in acute myeloid leukemia (AML). However, the cutoff values obtained have been inconsistent. Precise cutoff values may be optimized through subtype analysis; the RUNX1-RUNX1T1 fusion transcript provides an ideal reference. RUNX1-RUNX1T1 and WT1 transcript levels were simultaneously measured in 1299 bone marrow samples serially collected from 176 t(8;21) AML patients after allo-HSCT. The upper limit of the normal bone marrow WT1 level was 0.6%, which we previously reported to be the cutoff value for significant relapse prediction in AML as a whole. WT1 cutoff values of 0.6%, 1.2%, and 1.8% significantly differentiated patients in relapse after allo-HSCT. Nonetheless, patients with WT1 levels of 0.6% to 1.2% and those with levels of >1.2% and 1.8% after HSCT had rates of cumulative incidence of relapse similar to those with a continuous WT1 level of ≤0.6%, and both were significantly lower than that in patients with a WT1 level of >1.8%. WT1 expression was significantly related to RUNX1-RUNX1T1 transcript levels at WT1 levels of >1.8% but not at levels of 0.6% to 1.2% or >1.2% to 1.8%. Therefore, subgroup analysis can optimize the relapse-prediction cutoff value of WT1 expression. A cutoff level of 1.8% more accurately differentiates t(8;21) AML patients in relapse after allo-HSCT than does a cutoff level of 0.6%.