Long-term survival in venous thromboembolic disease: rivaroxaban vs. warfarin - propensity score matching study.

BACKGROUND: Venous thromboembolic disease (VTE) is characterized by obstruction of venous blood flow by a thrombus. Survival data, frequency of disease recurrence, and bleeding rate in patients on anticoagulant therapy with warfarin compared to rivaroxaban in the Latin American population are limited in VTE. METHODS: A retrospective cohort study with propensity score matching analysis was conducted in patients with pulmonary embolism and/or deep vein thrombosis anticoagulated with warfarin or rivaroxaban treated. Survival analysis was performed using a Kaplan-Meier curve for each of the intervention groups, and it was compared using a Log Rank test. RESULTS: Of 2193 potentially eligible patients with a suspected diagnosis of VTE, 505 patients entered the analysis; of these, 285 subjects were managed with warfarin and 220 anticoagulated with rivaroxaban. Major bleeding at 12 months occurred in 2.7% (6/220) of patients treated with Rivaroxaban, compared to 10.2% (29/285) in the Warfarin group in the unmatched population (p = 0.001). In the matched population, bleeding at 12 months occurred in 2.9% (6/209) of patients on Rivaroxaban and in 11.0% (23/209) of patients on Warfarin (p = 0.001). The survival rates at 6 months were 97.1% for Rivaroxaban and 97.6% for Warfarin (p = 0.76). At 12 months, the survival rates were 94.7% for Rivaroxaban and 95.7% for Warfarin (p = 0.61). CONCLUSION: In the treatment of VTE, there is no differences on 6 and 12-month survival or a reduction in the occurrence of new thromboembolic events when comparing rivaroxaban to warfarin. However, a lower risk of major bleeding is observed at 12 months with Rivaroxaban.

Automated fluorescence quantification of extracellular vesicles collected from blood plasma using dielectrophoresis.

Tumor-secreted exosomes and other extracellular vesicles (EVs) in circulation contain valuable biomarkers for early cancer detection and screening. We have previously demonstrated collection of cancer-derived nanoparticles (NPs) directly from whole blood and plasma with a chip-based technique that uses a microelectrode array to generate dielectrophoretic (DEP) forces. This technique enables direct recovery of NPs from whole blood and plasma. The biomarker payloads associated with collected particles can be detected and quantified with immunostaining. Accurately separating the fluorescence intensity of stained biomarkers from background (BG) levels becomes a challenge when analyzing the blood from early-stage cancer patients in which biomarker concentrations are low. To address this challenge, we developed two complementary techniques to standardize the quantification of fluorescently immunolabeled biomarkers collected and concentrated at predictable locations within microfluidic chips. The first technique was an automated algorithm for the quantitative analysis of fluorescence intensity at collection regions within the chip compared to levels at adjacent regions. The algorithm used predictable locations of particle collection within the chip geometry to differentiate regions of collection and BG. We successfully automated the identification and removal of optical artifacts from quantitative calculations. We demonstrated that the automated system performs nearly the same as a human user following a standard protocol for manual artifact removal with Pearson's r-values of 0.999 and 0.998 for two different biomarkers (n = 36 patients). We defined a usable dynamic range of fluorescence intensities corresponding to 1 to 2000 arbitrary units (a.u.). Fluorescence intensities within the dynamic range increased linearly with respect to exposure time and particle concentration. The second technique was the implementation of an internal standard to adjust levels of biomarker fluorescence based on the relative collection efficiency of the chip. Use of the internal standard reduced variability in measured biomarker levels due to differences in chip-to-chip collection efficiency, especially at low biomarker concentrations. The internal standard did not affect linear trends between fluorescence intensity and exposure time. Adjustments using the internal standard improved linear trends between fluorescence intensity and particle concentration. The optical quantification techniques described in this paper can be easily adapted for other lab-on-a-chip platforms that have predefined regions of biomarker or particle collection and that rely on fluorescence detection.

Identification of Multiple High-Risk Human Papillomavirus Infections in a Rural Population of Canatlan, Durango, Mexico.

Background: The human papillomavirus (HPV) is the most frequent etiological agent driving development of cervical cancer (CC); therefore typing and classifying the status of these infections are of great importance for treatment. The frequency of the various HPV types may change in relation to low-grade lesions and have the potential to cause more severe lesions. Objective: The purpose of this study was the identification and typing of HPV in a rural population in Mexico. Methods: Detection and typing were determined by PCR-RFLPs and confirmed by viral DNA sequencing. Results: HPV was detected in 17.28% of the samples, this was 3.58% higher than had been determined in a rural population in Central Mexico. Viral types 16, 18 and 52 were found most frequently. Analysis of all HPV-positive samples revealed that 14.3% had a single infection; 57.1% had a double infection; and 28.6% had a triple infection. Thus, 85.7% of positive cases presented with multiple infections with HPV16 being the most prevalent. Only the lifetime number of sexual partners was found to have an association with the colposcopic diagnoses (OR = 7.08; 95% CI: 1.68-29.8; p > 0.008). Conclusion: A higher frequency of multiple HPV infections was found among our test population compared to other rural populations in Durango and Central Mexico. HPV type 16 was the most frequent infection.

OCULAR ADVERSE EVENTS ASSOCIATED WITH MEK INHIBITORS.

PURPOSE: Mitogen-activates protein kinase (MAPK) inhibitors, particularly MEK inhibitors, have shifted the treatment paradigm for metastatic BRAF-mutant cutaneous melanoma; however, oncologists, ophthalmologists, and patients have noticed different toxicities of variable importance. This review aims to provide an update of the ocular adverse events (OAEs), especially retinal toxicity, associated with the use of MEK inhibitors. METHODS: We conducted a scientific literature search using the PubMed database up to July 2018 with the terms "MEK inhibitors" with a "review" filter and "MEK inhibitors" with a "clinical trials" filter. Phase I-III experimental studies and reviews were selected. Current principles and techniques for diagnosing and managing MEK inhibitor retinopathy and other OAEs are discussed. RESULTS: In patients treated with MEK inhibitors, including asymptomatic patients, OAEs occur with an incidence of up to 90%. Mild to severe ophthalmic toxicities are described, including visual disturbances, a 2-line decrease in Snellen visual acuity, dry eye symptoms, ocular adnexal abnormalities, visual field defects, panuveitis, and retinal toxicities, such as different degrees of MEK-associated retinopathy, vascular injury, and retinal vein occlusion. CONCLUSION: MEK inhibitors can lead to different degrees of retinal, uveal, and adnexal OAE, causing visual disturbances or discomfort. One of the most relevant OAE of MEK therapy is MEK inhibitor-associated retinopathy (MEKAR), which is usually mild, self-limited, and may subside after continuous use of the drug for weeks or months, or discontinuation, thereby restoring the normal visual function of the retina, with some exceptions. Ocular adverse events are often associated with other systemic adverse effects that can modify the dosage of treatment, so the communication with the oncologist is fundamental.

Wettability control of droplet durotaxis.

Durotaxis refers to cell motion directed by stiffness gradients of an underlying substrate. Recent work has shown that droplets also move spontaneously along stiffness gradients through a process reminiscent of durotaxis. Wetting droplets, however, move toward softer substrates, an observation seemingly at odds with cell motion. Here, we extend our understanding of this phenomenon, and show that wettability of the substrate plays a critical role: while wetting droplets move in the direction of lower stiffness, nonwetting liquids reverse droplet durotaxis. Our numerical experiments also reveal that Laplace pressure can be used to determine the direction of motion of liquid slugs in confined environments. Our results suggest new ways of controlling droplet dynamics at small scales, which can open the door to enhanced bubble and droplet logic in microfluidic platforms.

Screening pulmonary arteriovenous malformations in a large cohort of Spanish patients with hemorrhagic hereditary telangiectasia.

BACKGROUND AND OBJECTIVES: Because of the serious nature of potential complications, screening for pulmonary arteriovenous malformations is required in patients with hereditary hemorrhagic telangiectasia. The aim of this study was to evaluate the utility of contrast echocardiography and compare the performance of two contrast agents: agitated saline and Gelofusine. MATERIAL AND METHODS: Two hundred and five patients screened for PAVMs using TTCE and computed tomography (CT) performed with an interval of less than 180days. Contrast echocardiography studies were graded on a 4-point semiquantitative scale based on the amount of microbubbles seen in left heart chambers. RESULTS: Positive TTCE findings were seen in 137 (66.8%) patients, whereas CT confirmed PAVMs in 59 (43.1%). Two of 67 grade 1 patients; 18 of 42 grade 2; 17 of 22 grade 3 and all grade 4 had PAVMs on CT. Embolotherapy was feasible in 38.9% patients in grade 2 and 82.3% and 95.2% in grades 3-4. No patients in grade 1 were embolized. The mean cardiac cycle in which bubbles were first seen in the left heart in patients without and with PAVMs on CT was 6.1 and 3.9 (p<0.0001). Compared to saline, Gelofusine produced an overall increase in grade. CONCLUSIONS: No grade 1 patients had treatable PAVMs. There is a need for improvement in the selection of patients for CT in grade 2, where less than half have PAVMs on CT. The cardiac cycle may help to differentiate between patients with and without PAVMs. Gelofusine was not better than saline for PAVM screening.

Brain clock driven by neuropeptides and second messengers.

The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles.

A simple negative interaction in the positive transcriptional feedback of a single gene is sufficient to produce reliable oscillations.

Negative and positive transcriptional feedback loops are present in natural and synthetic genetic oscillators. A single gene with negative transcriptional feedback needs a time delay and sufficiently strong nonlinearity in the transmission of the feedback signal in order to produce biochemical rhythms. A single gene with only positive transcriptional feedback does not produce oscillations. Here, we demonstrate that this single-gene network in conjunction with a simple negative interaction can also easily produce rhythms. We examine a model comprised of two well-differentiated parts. The first is a positive feedback created by a protein that binds to the promoter of its own gene and activates the transcription. The second is a negative interaction in which a repressor molecule prevents this protein from binding to its promoter. A stochastic study shows that the system is robust to noise. A deterministic study identifies that the dynamics of the oscillator are mainly driven by two types of biomolecules: the protein, and the complex formed by the repressor and this protein. The main conclusion of this paper is that a simple and usual negative interaction, such as degradation, sequestration or inhibition, acting on the positive transcriptional feedback of a single gene is a sufficient condition to produce reliable oscillations. One gene is enough and the positive transcriptional feedback signal does not need to activate a second repressor gene. This means that at the genetic level an explicit negative feedback loop is not necessary. The model needs neither cooperative binding reactions nor the formation of protein multimers. Therefore, our findings could help to clarify the design principles of cellular clocks and constitute a new efficient tool for engineering synthetic genetic oscillators.

The molecular and supramolecular structures of the isomeric compounds 5,7-dimethoxyimidazo[1,2-c]pyrimidine and 7-methoxy-1-methylimidazo[1,2-a]pyrimidin-5(1H)-one.

The supramolecular structures of the isomeric compounds 5,7-dimethoxyimidazo[1,2-c]pyrimidine, C(8)H(9)N(3)O(2), (I), and 7-methoxy-1-methylimidazo[1,2-a]pyrimidin-5(1H)-one, C(8)H(9)N(3)O(2), (II), are determined by weak C-H.N and C-H.O hydrogen bonds in (I), which generate alternating linked centrosymmetric R(2)(2)(8) and R(2)(2)(10) rings that form a ribbon running parallel to the c axis, and by C-H.O bonds in (II), which link the molecules into sheets comprising centrosymmetric R(2)(2)(10) and R(4)(4)(22) rings.