Clinical use of rivaroxaban: pharmacokinetic and pharmacodynamic rationale for dosing regimens in different indications.

Target-specific oral anticoagulants have become increasingly available as alternatives to traditional agents for the management of a number of thromboembolic disorders. To date, the direct Factor Xa inhibitor rivaroxaban is the most widely approved of the new agents. The dosing of rivaroxaban varies and adheres to specific schedules in each of the clinical settings in which it has been investigated. These regimens were devised based on the results of phase II dose-finding studies and/or pharmacokinetic modeling, and were demonstrated to be successful in randomized, phase III studies. In most cases, the pharmacodynamic profile of rivaroxaban permits once-daily dosing. A once-daily dose is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery, the long-term prevention of stroke in patients with non-valvular atrial fibrillation, and the long-term secondary prevention of recurrent VTE. Twice-daily dosing is required in the acute phase of treatment in patients with VTE and in the combination of rivaroxaban with standard single or dual antiplatelet therapy for secondary prevention after acute coronary syndrome events. This article reviews the empirical and clinical rationale supporting the dose regimens of rivaroxaban in each clinical setting

Bicarbonate-based Purge Solution As A Bleeding Reduction Strategy in Patients on Impella Support

Study: The Impella Catheters require a heparin-containing purge solution to maintain proper pump function by reducing the risk of biomaterial deposition in the purge gaps. A bicarbonate-based purge solution (BBPS) has been proposed as an alternative to a heparin-based purge solution. We review performance in patients supported to date with a BBPS (heparin-induced thrombocytopenia patients were excluded from this analysis). Methods: This review includes patients (n=26) supported using sodium bicarbonate (25 mEq/1L of D5W) in the purge from September 2020 to February 2021. These patients were supported with BBPS post-operatively where heparin in the purge was not desired or were transitioned to BBPS because of bleeding issues. Case data were collected from an internal database to develop the clinical narrative and cross-referenced against Impella Controller data logs to assess purge trends and pump function. Results: All pumps were switched to BBPS in the purge if not started with BBPS (Figure 1A). The average time to initiating BBPS was 1.6 days (excluding n=3 outliers where time to switching was \u3e15 days). The average duration of support with BBPS was 5 days and a maximum duration of 22 days (Figure 1B). Figure 1C shows clinical indications for use. Purge pressure and purge flow remained stable while on BBPS (Figure 1D). In conclusion, this preliminary experience suggests the feasibility of using BBPS to maintain purge patency, ensure pump motor reliability, reduce bleeding risk, and simplify anticoagulation management. Use of a BBPS may be a safe and effective alternative to heparin in the purge for patients in which heparin is contraindicated or not feasible. More patient experience and analysis are needed to evaluate how bicarbonate compares to heparin in the purge for all patients

Bicarbonate Purge Solution to Support Impella Devices for Patients with Clinically Suspected or Confirmed Heparin-induced Thrombocytopenia

Study: The Impella catheter is a transvalvular, micro-axial left ventricular assist device that provides temporary mechanical circulatory support and requires a heparin-containing purge solution to reduce the risk of biomaterial deposition in the purge gaps and also maintain proper pump function. For patients with suspected or confirmed heparin-induced thrombocytopenia (HIT), direct thrombin inhibitors (DTI) have been proposed as an alternative to heparin in the purge, but have been associated with pump failure requiring temporary tPA in the purge solution to normalize pump function. In this report, we review HIT patients supported with a sodium bicarbonate-based purge solution (BBPS). Methods: Patients with suspected or confirmed HIT on Impella support using sodium bicarbonate (25 mEq in 1L D5W solution) in the purge from September 2020 to January 2021 were reviewed. Case data were obtained from Impella Quality (IQ) database for those supported with a BBPS and clinically suspected or confirmed HIT. Purge pressures and purge flows were evaluated from the Automated Impella Controller (AIC). Results: Ten patients were supported with a BBPS during this period. Impella support was begun either with no anticoagulant (n=5), DTI (n=2), or heparin (n=3) and then switched to BBPS. Impella run time using a BBPS ranged from 1-14 days; five pumps had a run time with a BBPS \u3e 10 days (Figure 1). Systemic DTI use was used in five cases along with a BBPS. No purge pathway thrombosis or bleeding events were observed, along with no changes in purge flow or purge pressures observed. In conclusion, preliminary experience suggests the use of BBPS in the setting suspected or confirmed HIT patients supported with an Impella is safe and effective and may provide a useful therapeutic option for heparin intolerant patients. Future work should investigate mechanisms and purge reliability of BBPS in this setting

A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13).

BACKGROUND: Rhinovirus infection is a major cause of asthma exacerbations. OBJECTIVES: We studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations. METHODS: We used nasosorption on days 0, 2-5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n=28) and healthy non-atopic controls (n=11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay. RESULTS: Following rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P<0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0-7, all P<0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P<0.01) and levels increased by days 3 and 4 (P<0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P<0.05). CONCLUSIONS: Precision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation

Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population

Background: The ‘exposome’ represents the accumulation of all environmental exposures across a lifetime. Topdown strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an individual’s metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium. Methods: High-resolution 1H NMR spectroscopy (metabonomics) was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress. Results: Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4- deoxy-erythronic acid) or one-carbon metabolism (dimethylglycine, creatinine, creatine), were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels) was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction. Conclusions: This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental concentrations, paving the way for exposome research. Keywords: metabonomics, cadmium, environmental health, exposome, metabolomics, molecular epidemiolog

The relationship between microstructure and photocatalytic behavior in lanthanum-modified 2D TiO2 nanosheets upon annealing of a freeze-cast precursor

Titanium dioxide modified with 3 wt% La was prepared via a green freeze-casting method, and its photocatalytic activity was tested in terms of its ability to degrade 4-chlorophenol (4-CP) and remove total organic carbon (TOC). Under annealing conditions, the freeze-cast precursor was transformed into an La-modified anatase with a well-defined 2D TiO(2) nanosheet morphology. Rietveld refinement of the X-ray diffraction patterns confirmed the substitutional nature of the La cation that induced local structural variations and involved subtle ion displacement in the TiO(2) lattice due to the ionic size effect. Despite nearly identical tetragonal structures, replacement of Ti with La alters the photocatalytic activity through a reduction in band gap energies and an increase in charge carrier mobility. Material annealed at 650 °C exhibited the highest photocatalytic performance and achieved efficient TOC removal. Upon annealing at 800 °C, nanoscale lanthanum-enriched regions were generated due to the diffusive migration of La cations and phase transition from anatase to rutile. The La(3+) cation, acting as a structural promoter, supported 2D TiO(2) growth with well controlled crystallite size, surface area and porosity. La(3+) could be regarded as a potential electronic promoter that can reduce the band gap of 2D TiO(2) nanosheets and can provide a signature of the electron transfer and carrier charge separation. Both methods, kinetics of degradation of 4-CP and TOC, provided similar results, revealing that the photocatalytic activity under UV light irradiation increased in the order 950C < 500 °C < 800 °C < 650 °C < TiO(2)-P25

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Special Issue: NMR-Based Metabolomics

Nuclear magnetic resonance (NMR) spectroscopy remains one of the core analytical platforms for metabolomics, providing complementary chemical information to others, such as mass spectrometry, and offering particular advantages in some areas of research on account of its inherent robustness, reproducibility, and phenomenal dynamic range [...