Nevin Manimala

ESMO Open. 2021 Dec 14;7(1):100338. doi: 10.1016/j.esmoop.2021.100338. Online ahead of print.

ABSTRACT

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment and burdened by cardiovascular toxicity. The majority of data come from clinical trials, thus in selected populations. The aim of our study is to evaluate the cardiotoxicity profile of VEGFR-targeted TKIs and the impact of cardiovascular risk factors in a real-life population.

PATIENTS AND METHODS: In this cohort, population-based study, patients treated with VEGFR-targeted TKIs, bevacizumab and trastuzumab between 2009 and 2014 were analyzed. A multi-source strategy for data retrieval through hospital, pharmaceutical and administrative databases of the Lombardy region, Italy, has been adopted. The primary endpoint was to determine the incidence and type of major adverse cardiovascular events (MACEs) along with their temporal trend. The secondary endpoint was to define the impact of cardiovascular risk factors in the occurrence of MACEs.

RESULTS: A total of 829 patients were treated with VEGFR-targeted TKIs. Eighty-one MACEs occurred in the first year of follow-up [crude cumulative incidence (CCI): 9.79%] mainly consisting of arterial thrombotic events (ATEs, 31 events, CCI: 3.99%), followed by rhythm disorders (22 events, CCI: 2.66%), pulmonary embolisms and heart failures (13 events each, CCI: 1.57%). While the incidence of most MACEs showed a plateau after 6 months, ATEs kept increasing along the year of follow-up. Hypertension and dyslipidemia were associated with an increase in risk of ATEs [relative risk difference (RRD) +209.8% and +156.2%, respectively], while the presence of previous MACEs correlated with a higher risk of all MACEs in multivariate analysis (RRD 151.1%, 95% confidence interval 53.6% to 310.3%, P < 0.001).

CONCLUSIONS: MACEs occur in a clinically significant proportion of patients treated with VEGFR-targeted TKIs, with ATEs being predominant, mainly associated with hypertension and dyslipidemia. A clinical algorithm for effective proactive management of these patients is warranted.

PMID:34920290 | DOI:10.1016/j.esmoop.2021.100338

J Environ Manage. 2021 Dec 14;304:114236. doi: 10.1016/j.jenvman.2021.114236. Online ahead of print.

ABSTRACT

In the present work, a suitable experimental setup was developed to successfully apply advanced oxidation processes (AOP) to real groundwater matrices. This setup combines an O₃-bubble column reactor with a carrier-bound TiO₂/UV-system. The degradation of various chlorinated ethene and methane derivatives commonly found of chlorinated volatile organic compound polluted regional groundwater samples was investigated. Because of known issues within water remediation using AOP such as toxification by transformation products, this study aimed at complete mineralization of the contained organic micropollutants. Moreover, the influences of variable process parameters such as flow rate, ozone concentration, and radiation dose on process performance were statistically evaluated and discussed. Parameter optimization using a Box-Behnken experimental design resulted in very promising degradation rates. It was thus possible to achieve a degradation rate of at least 98% for cis-dichloroethene, trichloroethene and tetrachloroethene and 85% for trichloromethane without formation of transformation products. The results of this work open up the possibility of developing innovative technologies based on AOP, which can be universally applied even to challenging matrices such as groundwater.

PMID:34920281 | DOI:10.1016/j.jenvman.2021.114236

Environ Int. 2021 Dec 14;159:107046. doi: 10.1016/j.envint.2021.107046. Online ahead of print.

ABSTRACT

Single nucleotide polymorphisms (SNPs) of cytochrome P450 (CYPs) and UDP-glucuronosyltransferase (UGTs) genes have been proposed to influence phthalates and 1,2-cyclo-hexanedicarboxylic acid diisononyl ester (DINCH) biotransformation but have not been investigated on a populational level. We investigated the role of SNPs in CYP2C9, CYP2C19, CYP2D6, UGT2B15, and UGT1A7 genes in the biotransformation of phthalates (DEHP, DEP, DiBP, DnBP, BBzP, DiNP, DidP) and DINCH by determining their urine metabolites. From the Slovenian study population of 274 men and 289 lactating primiparous women we obtained data on phthalate and DINCH urine metabolite levels (MEHP, 5OH-MEHP, 5oxo-MEHP, 5cx-MEPP, MEP, MiBP, MnBP, MBzP, cx-MINP, OH-MiDP, MCHP, MnPeP, MnOP, 5OH-MINCH, 5oxo-MINCH), SNP genotypes (rs1057910 = CYP2C9*3, rs1799853 = CYP2C9*2, rs4244285 = CYP2C19*2, rs12248560 = CYP2C19*17, rs3892097 = CYP2D6*4, rs1902023 = UGT2B15*2, and rs11692021 = UGT1A7*3) and questionnaires. Associations of SNPs with levels of metabolites and their ratios were assessed by multiple linear regression and ordinary logistic regression analyses. Significant associations were observed for CYP2C9*2, CYP2C9*3, CYP2C19*17, and UGT1A7*3 SNPs. The most pronounced was the influence of CYP2C9*2 and *3 on the reduced DEHP biotransformation, with lower levels of metabolites and their ratios in men and women. In contrast, carriers of CYP2C19*17 showed higher urine levels of DEHP metabolites in both genders, and in women also in higher DiNP, DiDP, and DINCH metabolite levels. The presence of UGT1A7*3 was associated with increased metabolite levels of DINCH in men and of DiBP and DBzP in women. Statistical models explained up to 27% of variability in metabolite levels or their ratios. Our observations confirm the effect of CYP2C9*2 and *3 SNPs towards reduced DEHP biotransformation. We show that CYP2C9*2, CYP2C9*3, CYP2C19*17, and UGT1A7*3 SNPs might represent biomarkers of susceptibility or resilience in phthalates and DINCH exposure that have been so far unrecognised.

PMID:34920277 | DOI:10.1016/j.envint.2021.107046

Talanta. 2021 Dec 8;239:123131. doi: 10.1016/j.talanta.2021.123131. Online ahead of print.

ABSTRACT

Developing a sensitive portable sensor for the screening of illicit drugs is always challenging. Due to the importance of pethidine (PTD) tracking in addiction diagnosis, many demands have recently increased for a selective and real-time sensor. Herein, a simple electrochemical sensor has been developed based on conductive carbon cloth (CC) modified with carbon selenide nanofilms (CSe₂NF) to provide a CSe₂NF/CC electrode as a novel PTD sensing tool. Profiting from the ingenious design of doping strategy during the synthesis process, Se was doped in the carbonaceous skeleton of the CC. Thus, the active surface area of the CSe₂NF (4.61 cm²) increased respect to the unmodified CC (0.094 cm²) to embed a suitable sensing interface in the fast PTD assay. By optimizing some effective experimental parameters such as pH, supporting electrolyte, Se powder amount, scan rate and accumulation time, the sensor catalyzed efficiently the oxidation reaction of PTD at 0.97 V. Based on peak current variations, the PTD was measured over a broad concentration range from 29 nM up to 181.8 μM with a limit of detection (LOD) as low as 19.3 nM compared to the other reported PTD sensors. The developed flexible sensor recognized the spiked PTD concentrations in some biofluids, including human blood, urine and saliva. The results of PTD analysis in the non-spiked and spiked blood, urine and saliva samples as the real samples by the developed sensor were validated by HPLC analysis as the reference method using t-test statistical method at confidence level of 5%. This sensing strategy based on the binder-free electrode could be promising for designing some sizable wearable sensors at a low cost. The high sensitivity of the sensor, which is a bonus for the rapid and on-site measurement of PTD, may open up a route for noninvasive routine analysis in clinical samples.

PMID:34920261 | DOI:10.1016/j.talanta.2021.123131

Talanta. 2021 Dec 10;239:123140. doi: 10.1016/j.talanta.2021.123140. Online ahead of print.

ABSTRACT

In this study, a new approach for PLS modelling for low-correlated multiple responses, called Common-Subset-of-Independent-Variables Partial-Least-Squares, denoted as CSIV-PLS1, is proposed and evaluated. In CSIV-PLS1, for each response vector, individual PLS1 models with individual model complexities are developed, based on one common set of independent variables, obtained after variable selection by the Final Complexity Adapted Models method, using the absolute values of the PLS regression coefficients, denoted as FCAM-REG. CSIV-PLS1 combines a common variable set for all response vectors, which is a characteristic of PLS2, with the individual model complexity for each response, which is a characteristic of PLS1. These characteristics make CSIV-PLS1 more flexible than PLS2. The selective and predictive abilities of the proposed CSIV-PLS1 method are investigated using one simulated and four real data sets with low-correlated multiple responses from different sources. The simulated data set is used to test the general applicability of the CSIV-PLS1 method. The predictive abilities, measured by the RMSEP values, resulting from CSIV-PLS1 models, are statistically compared with those of the corresponding PLS1 and PLS2 models, using one-tailed paired t-tests. The selective ability of the CSIV-PLS1 method is good, because mostly variables with an informative meaning to the responses are selected. The RMSEP values resulting from the CSIV-PLS1 method are (i) significantly lower at the 95% confidence level than those of the corresponding PLS2 method, and (ii) borderline significantly lower at the 90-95% confidence level than those of the corresponding PLS1 methods. In case of low-correlated multiple responses, the predictive ability of the CSIV-PLS1 method is significantly better than that of the PLS2 method, and borderline significantly better than those of the corresponding PLS1 methods. Therefore, CSIV-PLS1 modelling may be an alternative for PLS1 or PLS2.

PMID:34920253 | DOI:10.1016/j.talanta.2021.123140

J Equine Vet Sci. 2021 Oct 29;109:103798. doi: 10.1016/j.jevs.2021.103798. Online ahead of print.

ABSTRACT

The study investigated between-rider differences in pelvic roll and pitch motion during horseback riding as the horse walked around circles without rein contact (walk on long reins), with rein contact, and with moderate collection. Ten horses were ridden by five riders on left and right 10 m circles, in a partly crossed design, yielding 14 trials. Each trial included each of the three walk variations in both directions. Riders wore an inertial measurement unit (IMU), logging at 100 Hz, dorsally on the pelvis. Pelvic roll and pitch data were split into strides based on data from IMU-sensors on the horse’s hind cannons. Data were analyzed using signal decomposition into the fundamental frequency (the stride frequency) and its first two harmonics. Mixed models accounting for the type of walk were used to analyze how riders differed in roll and pitch pelvic motion in two ways: comparing amplitudes of the frequency components and comparing whole stride mean data. Graphically pelvic pitch showed substantial timing and amplitude differences between riders, and this was confirmed statistically. Pelvic roll timing was similar, but amplitude varied between the riders, both graphically and statistically. Individual rider patterns tended to persist across different horses and all exercises. These results suggest that exercises at walk can be ridden with different pelvis pitch timing, a fact that has so far not been discussed in the equestrian literature. Whether pelvic pitch timing affects the horse’s performance remains to be investigated.

PMID:34920247 | DOI:10.1016/j.jevs.2021.103798

J Thromb Haemost. 2021 Dec 17. doi: 10.1111/jth.15623. Online ahead of print.

ABSTRACT

INTRODUCTION: Patients with lower-leg cast immobilization and patients undergoing knee arthroscopy have an increased risk of venous thrombosis (VT). Guidelines are ambiguous about thromboprophylaxis use and individual risk factors for developing VT are often ignored. To assist in VT risk stratification and guide thromboprophylaxis use, various prediction models have been developed. These models depend largely on clinical factors and provide reasonably good C-statistics of around 70%. We explored using protein levels in blood plasma measured by multiplexed quantitative targeted proteomics to predict VT. Our aim was to assess whether a VT risk prediction model based on absolute plasma protein quantification is possible.

METHODS: We used internal standards to quantify proteins in less than 10 μL plasma. We measured 270 proteins in samples from patients scheduled for knee arthroscopy or with lower-leg cast immobilization. The two prospective POT-(K)CAST trails allow complementary views of VT signature in blood, namely pre and post trauma, respectively. From approximately 3,000 patients, 31 patients developed VT who were included and matched with double the number of controls.

RESULTS: Top discriminating proteins between cases and controls included APOC3, APOC4, APOC2, ATRN, F13B, and F2 in knee arthroscopy patients and APOE, SERPINF2, B2M, F13B, AFM, and C1QC in patients with lower-leg cast. A logistic regression model with cross-validation resulted in C-statistics of 88.1% (95%CI: 85.7-90.6%) and 79.6% (95% CI: 77.2-82.0%) for knee arthroscopy and cast immobilization groups respectively.

CONCLUSIONS: Promising C-statistics merit further exploration of the value of proteomic tests for predicting VT risk upon additional validation.

PMID:34919779 | DOI:10.1111/jth.15623

Epilepsia. 2021 Dec 16. doi: 10.1111/epi.17145. Online ahead of print.

ABSTRACT

OBJECTIVE: The integration of high-frequency oscillations (HFOs; ripples [80-250 Hz], fast ripples [250-500 Hz]) in epilepsy evaluation is hampered by physiological HFOs, which cannot be reliably differentiated from pathological HFOs. We evaluated whether defining abnormal HFO rates by statistical comparison to region-specific physiological HFO rates observed in the healthy brain improves identification of the epileptic focus and surgical outcome prediction.

METHODS: We detected HFOs in 151 consecutive patients who underwent stereo-electroencephalography and subsequent resective epilepsy surgery at two tertiary epilepsy centers. We compared how HFOs identified the resection cavity and predicted seizure-free outcome using two thresholds from the literature (HFO rate > 1/min; 50% of the total number of a patient’s HFOs) and three thresholds based on normative rates from the Montreal Neurological Institute Open iEEG Atlas (https://mni-open-ieegatlas.

RESEARCH: mcgill.ca/): global Atlas threshold, regional Atlas threshold, and regional + 10% threshold after regional Atlas correction.

RESULTS: Using ripples, the regional + 10% threshold performed best for focus identification (77.3% accuracy, 27% sensitivity, 97.1% specificity, 80.6% positive predictive value [PPV], 78.2% negative predictive value [NPV]) and outcome prediction (69.5% accuracy, 58.6% sensitivity, 76.3% specificity, 60.7% PPV, 74.7% NPV). This was an improvement for focus identification (+1.1% accuracy, +17.0% PPV; p < .001) and outcome prediction (+12.0% sensitivity, +1.0% PPV; p = .05) compared to the 50% threshold. The improvement was particularly marked for foci in cortex, where physiological ripples are frequent (outcome: +35.3% sensitivity, +5.3% PPV; p = .014). In these cases, the regional + 10% threshold outperformed fast ripple rate > 1/min (+3.6% accuracy, +26.5% sensitivity, +21.6% PPV; p < .001) and seizure onset zone (+13.5% accuracy, +29.4% sensitivity, +17.0% PPV; p < .05-.01) for outcome prediction. Normalization did not improve the performance of fast ripples.

SIGNIFICANCE: Defining abnormal HFO rates by statistical comparison to rates in healthy tissue overcomes an important weakness in the clinical use of ripples. It improves focus identification and outcome prediction compared to standard HFO measures, increasing their clinical applicability.

PMID:34919741 | DOI:10.1111/epi.17145

J Clin Lab Anal. 2021 Dec 17:e24180. doi: 10.1002/jcla.24180. Online ahead of print.

ABSTRACT

OBJECTIVES: This study is to explore the clinical significance of folate receptor-positive circulating tumor cells (FR⁺ CTC) in the early diagnosis and disease progress in patients with breast cancer.

METHODS: Folate receptor-positive circulating tumor cells was enriched from peripheral blood of the patients with immunomagnetic separation method and quantitated by folate receptor on the CTC with the ligand-targeted PCR.

RESULTS: The levels of FR⁺ CTC were significantly higher in breast cancer patients compared with healthy controls. Detective rate of FR⁺ CTC was decreased in 19 of 27 patients underwent the surgery in 2 weeks post-operation compared with pre-operation; statistical analysis showed the difference was significant. We also found that the combination of FR⁺ CTC, CEA, CA125, and CA153 can significantly improve the diagnostic efficiency for breast cancer.

CONCLUSIONS: This study showed the detective rate of FR⁺ CTC is significantly increased in the patients with breast cancer, and the detective level is associated with disease progress.

PMID:34919735 | DOI:10.1002/jcla.24180

Oper Dent. 2021 Dec 17. doi: 10.2341/20-059-LIT. Online ahead of print.

ABSTRACT

PURPOSE: The following PICO (Patient/Population, Intervention, Comparison, and Outcomes) question was proposed: “Are retention rates of composite resin restorations in noncarious cervical lesions (NCCLs) when using adhesives considered “gold standard” (OptiBond FL and Clearfil SE Bond) higher than those obtained with other adhesives brands”?

METHODS: A search was performed in February 2019 (updated in November 2019) in the PubMed/MEDLINE, EMBASE, LILACS, BBO, Web of Science, Cochrane Library, Grey Literature, and IADR abstracts (1990-2018); unpublished and ongoing trial registries, dissertations, and theses were also searched. Only randomized clinical trials (RCTs) conducted in NCCLs that compared either OptiBond FL or Clearfil SE Bond adhesive with other commercially available adhesives were included. The risk of bias (RoB) was applied by using the Cochrane Collaboration tool. A meta-analysis was performed for retention rates at different follow-up times using a random effects model for both the adhesives. Heterogeneity was assessed with the Cochran Q test and I2 statistics. Grading of Recommendations: Assessment, Development and Evaluation (GRADE) assessed the quality of evidence.

RESULTS: After removal of duplicates and noneligible articles, 25 studies remained for qualitative synthesis, as one study was common to the two adhesives, of which 9 studies were used for the OptiBond FL meta-analysis and 14 for the Clearfil SE Bond meta-analysis. No significant differences were observed for retention rates in follow-up periods of 12-24 months (p=0.97), 36-48 months (p=0.72), or 108-156 months (p=0.73) for OptiBond FL; and for 12-24 months (p=0.10) and 36-48 months (p=0.17) for Clearfil SE Bond. A significant difference was only found for OptiBond FL at 60-96 months (p=0.02), but only three studies were included in this meta-analysis.

CONCLUSIONS: The evidence from available RCTs conducted in NCCLs that compared OptiBond FL or Clearfil SE Bond does not support the widespread concept that these adhesives are better than any other competitive brands available in the dental market.

PMID:34919728 | DOI:10.2341/20-059-LIT