Population Median Value Research Articles

Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA.

The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described. Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored. A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target. Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

Artificial Intelligence and Machine Learning with Moment Generating Functions to Enhance Biological Count Data Analysis

This research presents artificial intelligence with supervised machine learning to determine the median count given training data from biological laboratory experimentation. After determining the central moment of the median, machine learning is then used to predict the population median value. When computer programs learn they access available data, then autonomously analyze the information to make informed, data-driven decisions. Moment generating function restrictions identify a parameter of interest by restricting the expected value of the moment generating function. This research proposes a theoretical foundation for achieving such predictions. A summary of the key elements underlying the statistical power of the Mann– Whitney test, a nonparametric hypothesis test for the median of count data, is also presented. A nonparametric approach allows for accurate predictions while relaxing distributional assumptions such as normality.

Abstract 12139: Left Ventricular Myocardial Work in Patients With Chagas Disease From a Quaternary Hospital in Brazil

Background: Left ventricular (LV) function assessment in patients (pts) with Chagas disease (ChD) is challenging. LV ejection fraction (LVEF) as a marker of myocardial contractility in these pts has issues, and alterations in myocardial deformation (MD) may occur in early stages of cardiac disease (CD) before the decline of LVEF. LV global longitudinal strain (GLS) is a good parameter to evaluate LV MD, but is dependent on afterload. LV myocardial work (MW) is a technique which integrates afterload to the calculation of GLS Purpose: To analyze LV function using MW in pts with ChD Methods: 39 pts with positive serology for ChD, (74,4% women, age 68,8 ± 9,7) followed in a quaternary Brazilian hospital, were divided in groups of stages of CD: G1 - normal Echocardiography (Echo) and ECG, G2 - alterations in ECG a/o Echo, normal LVEF, G3 - reduced LVEF. LV MW was measured integrating GLS with non-invasive blood pressure as an afterload index, for generation of pressure-strain loops by specific software(fig.1). Global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE) were measured. Results: 11 pts (28,2%) were in G1, 14 (35,9%) in G2, and 14 (35,9%) in G3. In overall population median values of MW were within normal ranges: GWI = 1760mmHg% (>968), GCW = 2046mmHg% (>1550), GWW= 178mmHg% (<331), GWE = 92 (>83). Values of GWI, GCW and GWE were significantly lower and GWW was higher in G3, compared to G1 and G2, translating into less LV mechanical efficiency (ME) in these pts with more advanced CD (table 1). Despite LVEF and GLS similar between G1 and G2, values of GCW were 12% lower in G2 compared to G1, which could point to a tendency of early alterations in these pts, although not reaching statistical significance (p > 0,05). Conclusion: In pts with advanced stages with Chagas CD (G3) there were significant alterations in parameters that evaluate ME, with reduced values of GWI, GCW and GWE, with higher GWW

ВЛИЯНИЕ ВОЗРАСТА И ПОЛА НА СПИРОМЕТРИЧЕСКИЕ ПАРАМЕТРЫ У ПОДРОСТКОВ С БРОНХИАЛЬНОЙ АСТМОЙ

Peculiarities of the course of bronchial asthma (BA) in adolescents from the standpoint of the influence of age and gender on it cannot be considered fully studied as yet. Materials and methods used: the data were obtained from 367 patients’ records of atopic BA aged 10 to 17 years old (73,6% boys) who were treated for atopic BA at the Nizhny Novgorod City Children’s Clinical Hospital No. 1 (Nizhny Novgorod, Russia). The patients were divided into two age groups: early adolescence (EA, 10 to 14 y/o, 239 patients) and middle adolescence (MA, 15 to 17 y/o, 128). All patients underwent spirometric studies with an assessment of the forced vital capacity of the lungs (FVC), the ratio of forced expiratory volume in one second (FEV1) to FVC (FEV1/FVC), the average volume velocity of forced exhalation, averaged in the exhalation interval from 25 to 75% FVC (FEF25-75). Spirometric parameters were evaluated using the z-criteria of the Global Lung Initiative. Results: in the general group of patients, the zFVC index was statistically significantly lower in MA compared to EA (p=0,001), and the indicators of zFEV1/FVC and zFEF25-75 were statistically significantly higher in MA (p=0,020, p=0,022 respectively). In the cohort of boys, there were similar differences in spirometric parameters in EA and MA (p=0,009, p=0,002, p=0,002, respectively). In girls, the values of FVC in MA were statistically significantly lower than in EA (p=0,0310, as in the general cohort and the cohort of boys). At the same time, in girls, the indicators of zFEV1/FVC and zFEF25-75, reflecting bronchial permeability, were slightly lower in MA than in EA, but the differences were not statistically significant. Conclusion: in boys, but not in girls, the spirometric parameters reflecting bronchial patency in MA were statistically significantly higher than in EA. At the same time, in both boys and girls, the indicators of FVC decrease in MA compared to EA, remaining above the population median values of indicators.

Prognostic implications of left ventricular inward displacement assessed by cardiac magnetic resonance imaging in patients with myocardial infarction.

Risk stratification of patients with ischemic heart disease (IHD) still depends mainly on the left ventricular ejection fraction (LVEF). LV inward displacement (InD) is a novel parameter of LV systolic function, derived from feature tracking cardiac magnetic resonance (CMR) imaging. We aimed to investigate the prognostic impact of InD in patients with IHD and prior myocardial infarction. A total of 111 patients (mean age 57 ± 10, 86% male) with a history of myocardial infarction who underwent CMR were included. LV InD was quantified by measuring the displacement of endocardially tracked points towards the centreline of the LV during systole with feature tracking CMR. The endpoint was a composite of all-cause mortality, heart failure hospitalization and arrhythmic events. During a median follow-up of 142 (IQR 107-159) months, 31 (27.9%) combined events occurred. Kaplan-Meier analysis demonstrated that patients with LV InD below the study population median value (23.0%) had a significantly lower event-free survival (P < 0.001). LV InD remained independently associated with outcomes (HR 0.90, 95% CI 0.84-0.98, P = 0.010) on multivariate Cox regression analysis. InD also provided incremental prognostic value to LVEF, LV global radial strain and CMR scar burden. LV InD, measured with feature tracking CMR, was independently associated with outcomes in patients with IHD and prior myocardial infarction. LV InD also provided incremental prognostic value, in addition to LVEF and LV global radial strain. LV InD holds promise as a pragmatic imaging biomarker for post-infarct risk stratification.

A Complement Type to SRS-Schwab Adult Spinal Deformity Classification: The Failure of Pelvic Compensation

Retrospective review. To determine characteristics of patients with adult spinal deformity (ASD) who showed failed pelvic compensation even with significant sagittal imbalance. Patients who show failed pelvic compensation despite significant sagittal imbalance reportedly present distinct clinical outcomes. However, to our knowledge, no study has clearly defined or characterized this subgroup of patients with ASD. We examined 126 patients who underwent reconstructive spinal surgery for ASD between September 2016 and September 2020. Radiographic spinopelvic parameters were assessed. The patients were divided into four quadrant groups based on the two axes of pelvic tilt/pelvic incidence (PT/PI) and the sagittal vertical axis (SVA) with reference to the population median values (0.68 and 147.5mm, respectively). Patients with low PT/PI and high SVA were considered to have failed pelvic compensation, and they were compared with other patient groups. Patients with failed pelvic compensation (low PT/PI and high SVA) had worse clinical outcomes than those with successful pelvic compensation (high PT/PI and high SVA) at one year after surgery. Regarding radiographic outcomes, patients with failed pelvic compensation showed a significantly larger postoperative SVA even after correcting the PI-lumbar lordosis mismatch was corrected to a comparable range with the group of successful pelvic compensation. Notably, patients with failed pelvic compensation showed larger cross-sectional areas of the psoas and back extensor muscles than those with successful pelvic compensation. This suggests that failure of pelvic compensation did not occur because of back muscle weakness, which implies another underlying pathophysiology, including neurological origin. Compared with patients with successful pelvic compensation, those with failed pelvic compensation showed lower postoperative improvements in clinical and radiographic outcomes. Therefore, it is important to consider pelvic compensation when planning surgical correction of deformities. Distinct surgical approaches, including overcorrection of the PI-lumbar lordosis mismatch or global sagittal alignment, should be attempted to ensure postoperative symptom improvement.

On calcium fluorophore’s impact in platelet signaling studies

Observation of calcium signaling in platelets - blood cells designed to be involved in stopping bleeding and forming blood clots - is an important part of fundamental research in hemostasis. However, such a study is possible only with the use of calcium fluorophores - small molecules that penetrate the platelet membrane due to their hydrophobic -AM part, which is then hydrolyzed by cytosol esterases. In this work, we consider the phenomenon of inhomogeneous loading of calcium fluorophores into platelets.We used platelets from healthy adult donors loaded with various fluorescent probes (CalBryte590, DiOC6 (3), Fura Red, Fluo-4 and CellTracker Violet BMQC) and immobilized on antibodies to CD31 in parallel plane flow chambers. Total internal reflection fluorescence (TIRF) microscopy was used for observations.We demonstrated that all studied probes are loaded heterogeneously, with 30% platelets being loaded with a probe 2-6 times higher than the population median value. Using the CalBryte590 probe as an example, we have shown that a decrease in the incubation temperature, the addition of Pluronic 127 to the incubation medium, or membrane cholesterol depletion significantly reduces the heterogeneity of the probe distribution in the population. By looking at platelet activation from the surface, we have shown that the probability of experiencing strong activation, as measured by the intensity of calcium oscillations, correlates with the amount of probe in the platelet.Thus, we conclude that the type of fluorophore used and the conditions of its loading into platelets can significantly affect the results of experiments on the observation of calcium signaling in platelets.

Serum soluble tumor necrosis factor receptor (sTNFR) 1 and 2 in STEMI

Tumor necrosis factor-α (TNF-α) interacts with two soluble receptors: TNFR1 and TNFR2. Little is known about the role of sTNFR1 and sTNFR2 in patients with acute ST-segment elevation myocardial infarction (STEMI). Our hypothesis was that the serum levels of sTNFR1 and sTNFR2 might be a marker of the severity of STEMI. We prospectively enrolled 230 consecutive STEMI patients who underwent PCI revascularization in our hospital into a prospective cohort. Blood samples were collected at 5 time points: admission, 4, 24, 48 hours and 1 month after admission (H4, H24, H48, M1). sTNFR1 and sTNFR2 serum levels were assessed using an ELISA assay. Patients underwent cardiac magnetic resonance imaging at M1. Clinical outcomes were recorded over 18 months after STEMI. Mean age of the study population was 59 ± 12 years and 48.5% patients exhibited anterior STEMI. sTNFR1 level significantly increased at H24 with a median of 601.2 pg/mL (interquartile range [IQR] [397.1–896.7]). sTNFR2 level significantly increased at H48 with a median of 2262.3 pg/mL (IQR [1659.6–2862.4]). Patients with sTNFR1 and sTNFR2 peak levels greater than the population median value displayed significantly larger final infarct size and lower LVEF. Patients with peak levels of sTNFR1 and sTNFR2 higher than the population median value were more likely to have an adverse clinical event (MI, stroke, hospitalization for heart failure and all-cause death) during the first 18 months after STEMI (hazard ratio [HR] at 9.0 [3.7–22.2], P = 0.0003 for sTNFR1 and 5.5 [2.1–14.3], P = 0.002 for sTNFR2). Patients with high level of both sTNRF1 and sTNFR2 were at higher risk of adverse clinical event compared to patients with low level (HR = 13.1 [4.4–38.7], P = 0.0005). High levels of circulating sTNFR1 and sTNFR2 were associated with larger infarct size, impaired recovery of LVEF and adverse clinical event in STEMI patients. sTNFR1 and 2 might be useful prognosis markers.

Prediagnostic Immune Cell Profiles and Breast Cancer

Higher overall leukocyte counts in women may be associated with increased risk of breast cancer, but the association of specific leukocyte subtypes with breast cancer risk remains unknown. To determine associations between circulating leukocyte subtypes and risk of breast cancer. Between 2003 and 2009, the Sister Study enrolled 50 884 women who had a sister previously diagnosed with breast cancer but were themselves breast cancer free. A case-cohort subsample was selected in July 2014 from the full Sister Study cohort. Blood samples were obtained at baseline, and women were followed up through October 2016. Data analysis was performed in April 2019. The main outcome was the development of breast cancer in women. Whole-blood DNA methylation was measured, and methylation values were deconvoluted using the Houseman method to estimate proportions of 6 leukocyte subtypes (B cells, natural killer cells, CD8+ and CD4+ T cells, monocytes, and granulocytes). Leukocyte subtype proportions were dichotomized at their population median value, and Cox proportional hazard models were used to estimate associations with breast cancer. Among 2774 non-Hispanic white women included in the analysis (mean [SD] age at enrollment, 56.6 [8.8] years), 1295 women were randomly selected from the full cohort (of whom 91 developed breast cancer) along with an additional 1479 women who developed breast cancer during follow-up (mean [SD] time to diagnosis, 3.9 [2.2] years). Circulating proportions of B cells were positively associated with later breast cancer (hazard ratio [HR], 1.17; 95% CI, 1.01-1.36; P = .04). Among women who were premenopausal at blood collection, the association between B cells and breast cancer was significant (HR, 1.38; 95% CI, 1.05-1.82; P = .02), and an inverse association for circulating proportions of monocytes was found (HR, 0.75; 95% CI, 0.57-0.99; P = .05). Among all women, associations between leukocyte subtypes and breast cancer were time dependent: higher monocyte proportions were associated with decreased near-term risk (within 1 year of blood collection, HR, 0.62; 95% CI, 0.43-0.89; P = .01), whereas higher B cell proportions were associated with increased risk 4 or more years after blood collection (HR, 1.38; 95% CI, 1.15-1.67; P = .001). Circulating leukocyte profiles may be altered before clinical diagnoses of breast cancer and may be time-dependent markers for breast cancer risk, particularly among premenopausal women.

Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas.

The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P=0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population's median value (OR, 2.63; 95% CI, 1.07 to 6.46; P=0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P=0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH.

Abstract P3-05-02: Quantitative ERα measurements in TNBC from the I-SPY 2 TRIAL correlate with HER2-EGFR co-activation and heterodimerization

Abstract Background: We have previously described that TNBC patients whose tumors have both HER2 Y1248 phosphorylation (pHER2) “high” and phospho-EGFR Y1173 (pEGFR) “high” have increased response (pCR) to neratinib in the I-SPY2 TRIAL. We hypothesize that the paradoxical finding of a response prediction signature comprised of HER2 activation in a HER2 IHC/FISH-negative population means there must be a ligand-driven biochemical event responsible for the HER2 phosphorylation because HER2 mutations were also not found to be significant. Exploratory analysis of additional cellular signaling events and protein expression levels in pre-treatment, LCM-purified tumor epithelium by reverse phase protein microarray (RPPA) included semi-quantitative measurement of total levels of estrogen receptor alpha (ERα), which has been previously shown to be able to act as a membrane non-genomic signaling molecule through direct interaction with various tyrosine kinases including EGFR and HER2. Since ERα has been previously shown to act as a ligand and co-stimulate (activate) HER2 and EGFR when present at low levels, we investigated whether or not RPPA-measured ERα levels in the TNBC cohort analyzed to date were higher in tumors with both pHER2 “high” and pEGFR “high” levels and thus provide evidence explaining how HER2-EGFR activation is occurring in TNBC. Methods: Using RPPA analysis, we measured 118 analytes in lysates of LCM tumor epithelium obtained from the pre-treatment biopsy samples of 86 TNBC (Allred=0) patients in the I-SPY2 TRIAL analyzed to date. Cutpoints for pEGFR and pHER2 were determined previously by ROC analysis for pCR correlation in the neratinib treated TNBC population, and used here to dichotomize the pHER2 and pEGFR data in the larger TNBC population. Wilcoxon Rank Sum testing was performed using the continuous variable total ERα data and compared the TNBC that were both pHER2 and pEGFR “high” (N=39) to the rest of the TNBC population (N=47). Total ERα values were then divided into “high” and “low” groups based on the TNBC population median value in order to determine frequency/percentages within each class. Our study is exploratory with no claims for generalizability of the data, and calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Results: Total ERα values were obtained in 84/86 TNBC tumors analyzed. Total levels of ERα were higher (p&amp;lt; 0.006) in TNBC tumors with pHER2 and pEGFR “high” levels. 68% (26/38) of tumors in the pHER2 and pEGFR “high” group had ERα levels above the population median compared to 35% (16/46) in the rest of the TNBC population. Conclusion: Our exploratory analysis reveals that ERα levels are significantly higher in TNBC with pHER2 and pEGFR activation and may be behaving as a direct signaling ligand in TNBC and driving HER2-EGFR signaling. This ERα-pHER2/pEGFR association was missed by current ER and HER2 clinical laboratory testing techniques, and if validated in larger independent study sets could suggest that utilization of new protein-based techniques defining ER more quantitatively could be helpful to understand tumor biology and therapeutic response prediction, especially in the context of TNBC that are ostensibly ER negative. Citation Format: Gallagher RI, Yau C, Wolf DM, Dong T, Hirst G, Brown-Swigart L, ISPY-2 TRIAL Investigators, Buxton M, DeMichele A, van't Veer L, Yee D, Paoloni M, Esserman L, Berry D, Park J, Petricoin EF, Wulfkuhle JD. Quantitative ERα measurements in TNBC from the I-SPY 2 TRIAL correlate with HER2-EGFR co-activation and heterodimerization [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-05-02.

The Mayak Worker Dosimetry System (MWDS-2013): Plutonium Binding in the Lungs-An Analysis of Mayak Workers.

Estimates of plutonium lung doses from urine bioassay are highly dependent on the rate of absorption from the lungs to blood assumed for the inhaled aerosol. Absorption occurs by dissolution of particles in lung fluid followed by uptake to blood. The latter may occur either rapidly or dissolved ions may first become temporarily bound within airway tissue. The presence of long-term binding can greatly increase lung doses, particularly if it occurs in the bronchial and bronchiolar regions. Analyses of autopsy data from Beagle dogs and USTUR Case 0269, obtained following exposure to plutonium nitrate, suggest that a small fraction of 0.2-1.1 and 0.4-0.7%, respectively, of plutonium becomes permanently bound within the lungs. The present work performs a further analysis using autopsy data of former plutonium workers of the Mayak Production Association to determine values of the bound fraction that are supported by these data. The results suggest a bound fraction value of 0-0.3%. The results also indicate that the Mayak worker population median values of the particle transport clearance parameters from the alveolar-interstitial region are largely consistent with expected values, but suggest the rate from the alveolar region to the interstitium may be lower than initially thought.

Validity of a Job-Exposure Matrix for Psychosocial Job Stressors: Results from the Household Income and Labour Dynamics in Australia Survey.

IntroductionA Job Exposure Matrix (JEM) for psychosocial job stressors allows assessment of these exposures at a population level. JEMs are particularly useful in situations when information on psychosocial job stressors were not collected individually and can help eliminate the biases that may be present in individual self-report accounts. This research paper describes the development of a JEM in the Australian context.MethodsThe Household Income Labour Dynamics in Australia (HILDA) survey was used to construct a JEM for job control, job demands and complexity, job insecurity, and fairness of pay. Population median values of these variables for all employed people (n = 20,428) were used to define individual exposures across the period 2001 to 2012. The JEM was calculated for the Australian and New Zealand Standard Classification of Occupations (ANZSCO) at the four-digit level, which represents 358 occupations. Both continuous and binary exposures to job stressors were calculated at the 4-digit level. We assessed concordance between the JEM-assigned and individually-reported exposures using the Kappa statistic, sensitivity and specificity assessments. We conducted regression analysis using mental health as an outcome measure.ResultsKappa statistics indicate good agreement between individually-reported and JEM-assigned dichotomous measures for job demands and control, and moderate agreement for job insecurity and fairness of pay. Job control, job demands and security had the highest sensitivity, while specificity was relatively high for the four exposures. Regression analysis shows that most individually reported and JEM measures were significantly associated with mental health, and individually-reported exposures produced much stronger effects on mental health than the JEM-assigned exposures.DiscussionThese JEM-based estimates of stressors exposure provide a conservative proxy for individual-level data, and can be applied to a range of health and organisational outcomes.

Locoregional Control of Non-Small Cell Lung Cancer in Relation to Automated Early Assessment of Tumor Regression on Cone Beam Computed Tomography

Large interindividual variations in volume regression of non-small cell lung cancer (NSCLC) are observable on standard cone beam computed tomography (CBCT) during fractionated radiation therapy. Here, a method for automated assessment of tumor volume regression is presented and its potential use in response adapted personalized radiation therapy is evaluated empirically. Automated deformable registration with calculation of the Jacobian determinant was applied to serial CBCT scans in a series of 99 patients with NSCLC. Tumor volume at the end of treatment was estimated on the basis of the first one third and two thirds of the scans. The concordance between estimated and actual relative volume at the end of radiation therapy was quantified by Pearson's correlation coefficient. On the basis of the estimated relative volume, the patients were stratified into 2 groups having volume regressions below or above the population median value. Kaplan-Meier plots of locoregional disease-free rate and overall survival in the 2 groups were used to evaluate the predictive value of tumor regression during treatment. Cox proportional hazards model was used to adjust for other clinical characteristics. Automatic measurement of the tumor regression from standard CBCT images was feasible. Pearson's correlation coefficient between manual and automatic measurement was 0.86 in a sample of 9 patients. Most patients experienced tumor volume regression, and this could be quantified early into the treatment course. Interestingly, patients with pronounced volume regression had worse locoregional tumor control and overall survival. This was significant on patient with non-adenocarcinoma histology. Evaluation of routinely acquired CBCT images during radiation therapy provides biological information on the specific tumor. This could potentially form the basis for personalized response adaptive therapy.

Structural Equation Modeling in a Near-Highway Exposure Study: Ultrafine Particles and Association with Cardiovascular Disease Risk

Background: Structural equation modeling (SEM) is a statistical method that has not been used widely in epidemiological studies of ambient air pollution. Aims: Assess the association between individually-calculated exposure to UFP (&lt;100 nm, estimated as particle number concentration or PNC) and cardiovascular disease risk. Methods: Air pollution data based on 55 days of mobile monitoring was used to build a regression model for assigning residential ambient hourly PNC for participants of the Community Assessment of Freeway Exposure and Health (CAFEH) study (N=140, a subset of CAFEH). Participants completed questionnaires on residential and occupational exposure, income, education, smoking, diet, physical activity and stress. Blood samples were analyzed for C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-? receptor II (TNF?); fibrinogen. Ankle brachial pressure index (ABI) as well as systolic, diastolic and pulse pressures were also measured. SEM was conducted using Proc Calis in SAS to determine path loadings, p-values between latent variables, and the individual variables contributing to the latent variables. Results: CRP, IL-6 and TNF? were not normally distributed and had population median values of 1.62mg/L for CRP; 1.61pg/mL for IL-6; and 2256pg/mL for TNF?. Fibrinogen was normally distributed with a mean of 475mg/dL. Initial SEM model development for the dependent latent variable construct cardiovascular disease risk produced the largest standardized estimates with the indicator variables CRP, TNF?, BMI, hypertension, and IL-6. PNC and the independent latent variable construct other combustion exposures displayed a positive association with cardiovascular disease risk, while and socio-economic status displayed a negative association. Conclusion: Initial analysis indicates that our model may have one endogenous latent variable, cardiovascular disease risk, and two or more exogenous latent variables related to air pollution and lifestyle.

Assessment of clinical performance without adequate analytical validation: A prescription for confusion

Objectives Lp-PLA2 is a biomarker with promise for predicting cardiac risk. The lack of reproducible results has limited its use. In evaluating a new reagent kit, we investigated conditions for optimal reproducibility. Methods The Auto-PLAC reagents were evaluated on the Cobas instrument. Performance characteristics, stability, and population ranges were determined. Results Analytical performance characteristics replicated manufacturer's claims. The stability profile of the analyte was unusual, with increasing results observed with storage at 4 °C or − 20 °C. Only storage at − 70 °C gave acceptable stability. Population median values with properly preserved samples were much lower than the cut off previously validated for increased risk. Conclusions It is postulated that variability in specimen handling was a major contributor to the lack of traceability of the current reagents to the earlier clinical studies demonstrating its utility. We are now unsure how to identify reliable criteria for result interpretation.

TAS2R38 bitter taste genetics, dietary vitamin C, and both natural and synthetic dietary folic acid predict folate status, a key micronutrient in the pathoaetiology of adenomatous polyps

Taste perception may influence dietary preferences and nutrient intakes contributing to diet-related disease susceptibility. This study examined bitter taste genetics and whether variation in the TAS2R38 gene at three polymorphic loci (A49P, V262A and I296V) could alter dietary and systemic folate levels and dietary vitamin C intake, and whether a nutrigenetic circuit existed that might link bitter taste, folate/antioxidant status and risk for a colonic adenomatous polyp. TAS2R38 diplotype predicted bitter taste (PROP) phenotype (p value <0.00001) and red cell folate status (p=0.0179) consistent with the diplotype that has the broadest range of bitter perception (AVI/PAV) also possessing the highest average red cell folate value. However, TAS2R38 diplotype did not predict dietary intake of methylfolic acid, pteroylmonoglutamic acid or total folic acid. Neither did it predict dietary intake of vitamin C. Despite this, intake of dietary folate predicts red cell folate with analysis pointing to a key nutrient-nutrient interaction between vitamin C intake and systemic folate status. Analysis of 38 patients with an adenomatous polyp and 164 controls showed that individually, dietary nutrient intake, nutrient status and taste diplotype did not influence polyp risk. However, red cell folate status (in individuals below the population median value) did interact with bitter taste diplotype (AVI/PAV) to predict polyp risk (p=0.0145). Furthermore, synthetic folic acid (below median intake) was statistically associated with adenoma occurrence (p=0.0215); individuals with adenomatous polyps had a 1.77× higher intake than controls. Additionally, stepwise regression taking account of all dietary nutrients showed a tight relationship between methylfolic acid (but not pteroylmonoglutamic acid) intake and red cell folate level in those with a low folate status and occurrence of an adenomatous polyp (p=0.0039). These findings point to a role for folate in the pathoaetiology of adenomatous polyps, with the natural and synthetic vitamers not necessarily having the same biological effect.

Personal exposures to VOC in the upper end of the distribution—relationships to indoor, outdoor and workplace concentrations

Abstract Evaluation of relationships between median residential indoor, indoor workplace and population exposures may obscure potential strategies for exposure reduction. Evaluation of participants with personal exposures above median levels in the EXPOLIS study in Athens, Helsinki, Oxford and Prague illustrated that these participants frequently showed a different relationship to indoor and workplace levels than that shown by the population median. Thus, prioritization of environments for control measures based on median exposures may exclude important areas where effectively focused control measures are possible, and may therefore have little impact on the highest and most harmful exposures. Further, personal exposures at the upper end of the distribution may exceed the US EPA inhalation reference concentration (Rfc), illustrated here using hexane, naphthalene and benzene. For example upper 90th percentile personal exposures to benzene in Athens and Prague were 64 and 27 μg m−3 with peak exposures of 217 and 38 μg m−3, respectively for non-ETS exposed participants relative to an Rfc of 30 μg m−3. Strategies to reduce exposures to individual compounds, therefore, may benefit from focus on the high end of the distribution to identify activities and behaviors that result in elevated exposures. Control strategies targeting activities that lead to exposures in the upper end of the distribution would reduce the variability associated with population median values by bringing the upper end of the exposure distribution closer to median values. Thus, compliance with health-based standards would be more protective of the higher exposed fraction of the population, in whom health effects would be more expected.

Adaptive ventilator FiO 2 advisor: use of non-invasive estimations of shunt

A non-invasive and simple method of parameter estimation has been developed for the model-based decision support of the artificial ventilation in intensive care units. The parameter concerned was the respiratory shunt. Originally, the shunt had to be estimated using a numerical algorithm, which was slow and unreliable. The estimation process also required the knowledge of other parameters, whose values could only be obtained using invasive monitoring equipment. In this paper, the respiratory index is used for the shunt estimation. A linear regression model and a non-linear adaptive neuro-fuzzy inference system (ANFIS) model were used to describe the relationship between the respiratory index and the shunt. The shunts estimated using these models were then used to calculate the fractional inspired oxygen needed to attain the target arterial oxygen level of the model patient. The advisor also utilises population median values of the cardiac index and oxygen consumption index. This alleviates the need for invasive monitoring. In a simulation study, the mean squared error of the control using the ANFIS model was 0.75 kPa 2 compared to 2.06 kPa 2 using the linear regression model. Therefore, the performance of the FiO 2 advisor was better when the shunt was estimated using the non-linear ANFIS model.

Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia

Thiopurine methyltransferase deficiency, inherited as an autosomal codominant trait, is associated with aberrant mercaptopurine metabolism leading to excessive cellular accumulation of 6-thioguanine nucleotides, the active metabolites of mercaptopurine. We describe a case of severe thiopurine methyltransferase deficiency (activity less than 1 U/8 x 10(8) erythrocytes) in a young girl with acute lymphocytic leukemia. The level of 6-thioguanine nucleotide in the patient's erythrocytes was seven times the population median value, and she had intolerable hematologic toxic effects during postremission therapy with a standard dosage of mercaptopurine (75 mg/m2 per day). Subsequent therapy with 6% of this dosage (10 mg/m2 three times weekly) yielded erythrocytic 6-thioguanine nucleotide concentrations consistently above the population median but not associated with prohibitively toxic effects. This case demonstrates that thiopurine methyltransferase deficiency does not absolutely contraindicate mercaptopurine therapy, and it also provides insight into the mechanism of excessive toxic effects of mercaptopurine sometimes observed in children with acute lymphocytic leukemia.