Variants in the CDKN2A tumor suppressor are associated with Familial Melanoma (FM), although for many variants the linkage is weak. The effects of missense variants on protein function and pathogenicity are often uncl...
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Variants in the CDKN2A tumor suppressor are associated with Familial Melanoma (FM), although for many variants the linkage is weak. The effects of missense variants on protein function and pathogenicity are often unclear. Multiple methods (e. g., laboratory, computational, epidemiological) have been developed to analyze whether a missense variant is pathogenic or not. It is not yet clear how to integrate these data types into a strategy for variant classification. We studied 51 CDKN2A missense variants using a cell cycle arrest assay. There was a continuum of results ranging from full wild-type effect through partial activity to complete loss of arrest. A reproducible decrease of 30% of cell cycle arrest activity correlated with FM association. We analyzed missense CDKN2A germline variants using a Bayesian method to combine multiple data types and derive a probability of pathogenicity. When equal to or more than two data types could be evaluated with this method, 22 of 25 FM-associated variants and 8 of 15 variants of uncertain significance were classified as likely pathogenic with >95% probability. The other 10 variants were classified as uncertain (probability 5-95%). For most variants, there were insufficient data to draw a conclusion. The Bayesian model appears to be a sound method of classifying missense variants in cancer susceptibility genes. Hum Mutat 32:900-911, 2011. (C) 2011 Wiley-Liss, Inc.
Background/Aims: Biochemical tests and ultrasonography (US) are useful in the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C (CH-C);however histology remains the reference standard. Thi...
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Background/Aims: Biochemical tests and ultrasonography (US) are useful in the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C (CH-C);however histology remains the reference standard. This multicenter, cross-sectional cohort study evaluated the accuracy of APRI (AST-to-platelet-ratio-index) and liver surface ultrasound nodularity (LSN), singularly and sequentially combined in an algorithm, in diagnosing advanced fibrosis (i.e. METAVIR F3, F4), to derive a prediction rule to confirm or exclude F3, F4. Methods: Four hundred and thirty consecutive CH-C patients with elevated ALT, grouped into a first cohort (training set), and an internal and an external validation cohort, were studied. APRI and LSN were compared to liver biopsy and sequentially combined in order to obtain a predictive rule for advanced fibrosis METAVIR F3,F4. Results: LSN was negative and APRI <= 1 in 185/430 patients, whereas LSN was positive and APRI > 2 in 46/430 cases, with a 94% diagnostic accuracy for presence/absence of F3, F4, respectively. In a further 60/430 patients, F3,F4 was detected with an accuracy of 83%. In the remaining cases no classification was possible. Conclusions: An algorithm based on APRI and LSN confirms or excludes F3, F4 in 54% of CH-C patients with elevated ALT and suggests a highly probable diagnosis in a further one-sixth of patients, thus rendering liver biopsy unnecessary in these patients. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Avidin is a tetramer of 16-kDa subunits that have a high affinity for biotin. Proteolysis of native apoavidin by proteinase K results in a limited attack at the loop between beta-strands 3 and 4, involving amino acids...
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Avidin is a tetramer of 16-kDa subunits that have a high affinity for biotin. Proteolysis of native apoavidin by proteinase K results in a limited attack at the loop between beta-strands 3 and 4, involving amino acids 38-43. Specifically, sites of proteolysis are at Thr 40-Ser 41 and Asn 42-Glu 43. The limited proteolysis results in anl avidin product that remains otherwise intact and which has enhanced binding for 4'-hydroxyazobenzene-2-benzoic acid (HABA), a chromogenic reporter that can occupy the biotin-binding site. Saturation of the biotin-binding site with the natural ligand protects avidin from proteolysis, but saturation with HABA enhances the rate of proteolysis of the same site. Analysis of the three-dimensional structures of apoavidin and holoavidin reveals that the 3-4 loop is accessible to solvent and scores highly in an algorithm developed to identify sites of proteolytic attack. The structure df holoavidin is almost identical to the apoprotein. In particular, the 3-4 loop has the same structure in the apo and hole forms, yet there are marked differences in proteolytic susceptibility of this region. Evidence suggests that the 3-4 loop is rather mobile and flexible in the apoprotein, and that it becomes constrained upon ligand binding. In one crystal structure of the apoprotein, this loop appears constrained by contacts with symmetry-related molecules. Structural analyses suggest that the ''lid'' to the biotin-binding site, formed by the 3-4 loop, is displaced and made more accessible by HABA binding, thereby enhancing its proteolytic susceptibility.
Objective This study was performed to evaluate the capability of routine clinical indicators to predict the early outcome of embryos with cardiac activity in women with recurrent spontaneous abortion (RSA). Methods A ...
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Objective This study was performed to evaluate the capability of routine clinical indicators to predict the early outcome of embryos with cardiac activity in women with recurrent spontaneous abortion (RSA). Methods A retrospective cohort study of pregnant women with a history of RSA in a Chinese tertiary hospital was performed using unadjusted and multivariable logistic regression. Results Of 789 pregnant women with RSA, 625 (79.21%) had ongoing pregnancy, whereas 164 (20.79%) developed abortion before 20 full weeks of gestational age even after embryonic heart motion was detected. The final model had an area under the curve of 0.81 (95% confidence interval, 0.78-0.84) with a sensitivity of 74.39%, a specificity of 76.00%, and a false-positive rate of 52.32% at a fixed detection rate of 90%. Conclusions The combination of multiple routine clinical indicators was valuable in predicting the early outcome of embryos with cardiac activity in viable pregnancies with RSA. However, this model might result in a high false-positive rate with a fixed detection rate of 90%;other markers must be investigated to identify first-trimester RSA once positive embryonic heart motion is established.
Background and Objectives: We sought to summarize the study design, modelling strategies, and performance measures reported in studies on clinical prediction models developed using machine learning ***: We search PubM...
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Background and Objectives: We sought to summarize the study design, modelling strategies, and performance measures reported in studies on clinical prediction models developed using machine learning ***: We search PubMed for articles published between 01/01/2018 and 31/12/2019, describing the development or the development with external validation of a multivariable prediction model using any supervised machine learning technique. No restrictions were made based on study design, data source, or predicted patient-related health ***: We included 152 studies, 58 (38.2% [95% CI 30.8-46.1]) were diagnostic and 94 (61.8% [95% CI 53.9-69.2]) prognostic studies. Most studies reported only the development of prediction models (n = 133, 87.5% [95% CI 81.3-91.8]), focused on binary outcomes (n = 131, 86.2% [95% CI 79.8-90.8), and did not report a sample size calculation (n = 125, 82.2% [95% CI 75.4-87.5]). The most common algorithms used were support vector machine (n = 86/522, 16.5% [95% CI 13.5-19.9]) and random forest (n = 73/522, 14% [95% CI 11.3-17.2]). Values for area under the Receiver Operating Characteristic curve ranged from 0.45 to 1.00. Calibration metrics were often missed (n 5 494/522, 94.6% [95% CI 92.4-96.3]).Conclusion: Our review revealed that focus is required on handling of missing values, methods for internal validation, and reporting of calibration to improve the methodological conduct of studies on machine learning-based prediction *** review registration: PROSPERO, CRD42019161764. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://***/licenses/by/4.0/).
Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus....
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Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.
Background: Chronic obstructive pulmonary disease (COPD) is often associated with cardiovascular artery disease (CAD), representing a potential and independent risk factor for cardiovascular morbidity. Therefore, the ...
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Background: Chronic obstructive pulmonary disease (COPD) is often associated with cardiovascular artery disease (CAD), representing a potential and independent risk factor for cardiovascular morbidity. Therefore, the aim of this study was to identify an algorithm for predicting the risk of CAD in COPD patients. Methods: We analyzed data of patients afferent to the Cardiology ward and the Respiratory Diseases outpatient clinic of Tor Vergata University (2010-2012, 1596 records). The study population was clustered as training population (COPD patients undergoing coronary arteriography), control population (non-COPD patients undergoing coronary arteriography), test population (COPD patients whose records reported information on the coronary status). The predicting model was built via causal relationship between variables, stepwise binary logistic regression and Hosmer-Lemeshow analysis. The algorithm was validated via split-sample validation method and receiver operating characteristics (ROC) curve analysis. The diagnostic accuracy was assessed. Results: In training population the variables gender (men/women OR: 1.7, 95%Cl: 1.237-2.5, P < 0.05), dyslipidemia (OR: 1.8, 95%Cl: 1.2-2.5, P < 0.01) and smoking habit (OR: 1.5, 95%CI: 1.2-1.9, P < 0.001) were significantly associated with CAD in COPD patients, whereas in control population also age and diabetes were correlated. The stepwise binary logistic regressions permitted to build a well fitting predictive model for training population but not for control population. The predictive algorithm shown a diagnostic accuracy of 81.5% (95%Cl: 77.78-84.71) and an AUC of 0.81 (95%Cl: 0.78-0.85) for the validation set. Conclusions: The proposed algorithm is effective for predicting the risk of CAD in COPD patients via a rapid, inexpensive and non-invasive approach. 2015 Elsevier Ltd. All rights reserved.
Aims To predict worsening heart failure hospitalizations (WHFHs) in patients with implantable defibrillators and remote monitoring, the HeartInsight algorithm (Biotronik, Berlin, Germany) calculates a heart failure (H...
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Aims To predict worsening heart failure hospitalizations (WHFHs) in patients with implantable defibrillators and remote monitoring, the HeartInsight algorithm (Biotronik, Berlin, Germany) calculates a heart failure (HF) score combining seven physiologic parameters: 24 h heart rate (HR), nocturnal HR, HR variability, atrial tachyarrhythmia, ventricular extrasystoles, patient activity, and thoracic impedance. We compared temporal trends of the HF score and its components 12 weeks before a WHFH with 12-week trends in patients without WHFH, to assess whether trends indicate deteriorating HF regardless of alert status. Methods and results Data from nine clinical trials were pooled, including 2050 patients with a defibrillator capable of atrial sensing, ejection fraction <= 35%, NYHA class II/III, no long-standing atrial fibrillation, and 369 WHFH from 259 patients. The mean HF score was higher in the WHFH group than in the no WHFH group (42.3 +/- 26.1 vs. 30.7 +/- 20.6, P < 0.001) already at the beginning of 12 weeks. The mean HF score further increased to 51.6 +/- 26.8 until WHFH (+22% vs. no WHFH group, P = 0.003). As compared to the no WHFH group, the algorithm components either were already higher 12 weeks before WHFH (24 h HR, HR variability, thoracic impedance) or significantly increased until WHFH (nocturnal HR, atrial tachyarrhythmia, ventricular extrasystoles, patient activity). Conclusion The HF score was significantly higher at, and further increased during 12 weeks before WHFH, as compared to the no WHFH group, with seven components showing different behaviour and contribution. Temporal trends of HF score may serve as a quantitative estimate of HF condition and evolution prior to WHFH. [GRAPHICS] .
Aims Monitoring early signs of clinical deterioration could allow physicians to adjust medical treatment for patients at risk of acute heart failure decompensation. To date, several strategies using different surrogat...
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Aims Monitoring early signs of clinical deterioration could allow physicians to adjust medical treatment for patients at risk of acute heart failure decompensation. To date, several strategies using different surrogate measures of clinical status emerged, but none has yet been proven to predict clinical events. We hypothesized that the Physiological Diagnostic feature, which combines data from minute ventilation and physical activity sensors, predicts heart failure events in patients implanted with cardiac resynchronization therapy with defibrillation (CRT-D) devices. Methods and results The Clinical Evaluation of the Physiological Diagnostic feature in the PARADYM CRT device (CLEPSYDRA) trial is a multicentre, prospective, non-randomized, double-blind study comprising 521 CRT-D patients with heart failure [67.410.1years (mean +/- SD), 82% male, New York Heart Association class III/IV 85.0%/6.7%, QRS 155.3 +/- 26.6ms, left ventricular ejection fraction 25.7 +/- 7.7%]. The objective of the study was the sensitivity and false positive rate of the Physiological Diagnostic algorithm to predict heart failure events within the following month. After a mean follow-up of 17.0 +/- 8.7months, 130 (25.6%) patients experienced a heart failure event. The sensitivity of the algorithm to predict an event was 34% and the false positive rate was 2.4 per patient-year. Conclusion Thirty-four per cent of heart failure events occurring within a month were predicted by the Physiological Diagnostic algorithm, and 2.4 alerts per patient per year were not followed by an heart failure event within the subsequent month.
Fifty-eight patients undergoing continuous volume-controlled hemofiltration (CVHF) and extracorporeal lung assistance (ECLA) received drug therapy determined by use of a new predictive algorithm in a validation study....
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Fifty-eight patients undergoing continuous volume-controlled hemofiltration (CVHF) and extracorporeal lung assistance (ECLA) received drug therapy determined by use of a new predictive algorithm in a validation study. Amikacin, netilmicin, tobramycin, ceftriaxone, vancomycin, and teicoplanin doses were given as predicted from clinical parameters. Corrections were necessary in 15 cases (e.g., CVHF 68% and ECLA 82% precision). There were no statistical differences between predicted and monitored drug doses. The correlation coefficient gave r2 = 0.921. Preliminary results from not yet analyzed drugs (ceftriaxone, teicoplanin) fit well into the curve. Because of rapid intraindividual changes, toxic drugs should continue to be monitored.
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