Correlation of creatinine‐ and specific gravity‐normalized free and glucuronidated urine cannabinoid concentrations following smoked,vaporized, and oral cannabis in frequent and occasional cannabis users

Variability in urine dilution complicates urine cannabinoid test interpretation. Normalizing urine cannabinoid concentrations to specific gravity (SG) or creatinine was proposed to account for donors' hydration states. In this study, all urine voids were individually collected from eight frequent and eight occasional cannabis users for up to 85 hours after each received on separate occasions 50.6 mg Δ9‐tetrahydrocannabinol (THC) by smoking, vaporization, and oral ingestion in a randomized, within‐subject, double‐blind, double‐dummy, placebo‐controlled protocol. Each urine void was analyzed for 11 cannabinoids and phase I and II metabolites by liquid chromatography?tandem mass spectrometry (LC–MS/MS), SG, and creatinine. Normalized urine concentrations were log₁₀ transformed to create normal distributions, and Pearson correlation coefficients determined the degree of association between the two normalization methods. Repeated‐measures linear regression determined if the degree of association differed by frequent or occasional cannabis use, or route of administration after adjusting for gender and time since dosing. Of 1880 urine samples examined, only 11‐nor‐9‐carboxy‐THC (THCCOOH), THCCOOH‐glucuronide, THC‐glucuronide, and 11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabivarin (THCVCOOH) were greater than the method's limits of quantification (LOQs). Associations between SG‐ and creatinine‐normalized concentrations exceeded 0.90. Repeated‐measures regression analysis found small but statistically significant differences in the degree of association between normalization methods for THCCOOH and THCCOOH‐glucuronide in frequent vs occasional smokers, and in THCVCOOH and THC‐glucuronide by route of administration. For the first time, SG‐ and creatinine‐normalized urine cannabinoid concentrations were evaluated in frequent and occasional cannabis users and following oral, smoked, and inhaled cannabis. Both normalization methods reduced variability, improving the interpretation of urine cannabinoid concentrations and methods were strongly correlated.     

Differences in cardiovascular safety with non‐steroidal anti‐inflammatory drug therapy—A nationwide study in patients with osteoarthritis

Osteoarthritis (OA) and the non‐steroidal anti‐inflammatory drugs (NSAIDs) used to relieve OA‐associated pain have been linked independently to increased cardiovascular risk. We examined the risk of cardiovascular events associated with NSAID use in patients with OA. We employed linked nationwide administrative registers to examine NSAID use between 1996 and 2015 by Danish patients with OA aged ≥18 years. Using adjusted Cox proportional hazard analyses, we calculated the risk of the composite outcome of cardiovascular death, non‐fatal myocardial infarction and non‐fatal ischaemic stroke/TIA, and of each outcome separately, up to 5 years after OA diagnosis. Of 533 502 patients included, 64.3% received NSAIDs and 38 226 (7.2%) experienced a cardiovascular event during follow‐up. Compared with non‐use, all NSAIDs were associated with increased risk of the composite outcome: hazard ratio (HR) for rofecoxib, 1.90 (95% confidence interval, 1.74‐2.08); celecoxib, 1.47 (1.34‐1.62); diclofenac, 1.44 (1.36‐1.54); ibuprofen, 1.20 (1.15‐1.25); and naproxen, 1.20 (1.04‐1.39). Similar results were seen for each outcome separately. When celecoxib was used as reference, ibuprofen (HRs: 0.81 [CI: 0.74‐0.90]) and naproxen (HRs: 0.81 [0.68‐0.97]) exhibited a lower cardiovascular risk, even when low doses were compared. Low‐dose naproxen and ibuprofen were associated with the lowest risks of the composite outcome compared to no NSAID use: HRs: 1.12 (1.07‐1.19) and 1.16 (0.92‐1.42), respectively. In patients with OA, we found significant differences in cardiovascular risk among NSAIDs. Naproxen and ibuprofen appeared to be safer compared to celecoxib, also when we examined equivalent low doses. In terms of cardiovascular safety, naproxen and ibuprofen, at the lowest effective doses, may be the preferred first choices among patients with OA needing pain relief.     

Timescales of developmental toxicity impacting on research and needs for intervention

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision‐making must be weighed against the costs and necessary duration of research, as well as the long‐term costs to human health because of delayed protection of vulnerable early‐life stages of human development and, possibly, future generations. Although two‐generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY‐BPA‐type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.     

Impaired participation of potassium channels and Na+/K+‐ATPase in vasodilatation due to reduced nitric oxide bioavailability in rats exposed to mercury

Mercury intoxication is a public health risk factor due to its hazardous effect to several organs, including the cardiovascular system. There is evidence of endothelial dysfunction after exposure to mercury, but the effects on endothelium‐dependent vasodilatation are still unknown. In the present study, we aimed to evaluate the chronic effects of high HgCl₂ doses on the mechanisms of vasodilatation. Wistar rats were injected with HgCl₂ (1st dose 10.86 μg/kg, and daily doses 0.014 μg/kg for 30 days i.m.), and saline was used as control. Mercury exposure reduced the acetylcholine‐induced vasodilatation in aortic rings, which was restored by incubation with antioxidant tiron. Inhibition of the NO synthase, Na⁺/K⁺‐ATPase and K⁺ channels indicates reduced participation of these factors. In the mercury group, there were an increased local anion superoxide and a reduced NO. The vasodilatation to exogenous NO was partially inhibited by co‐incubation with TEA plus tiron, suggesting that reduced NO bioavailability is the responsible to that decreased the participation of K⁺ channels. Moreover, there was an increased participation of the Na⁺/K⁺‐ATPase associated with an up‐regulation of its alpha‐1 subunit. In conclusion, reduced NO bioavailability plays a major role in the impaired participation of K⁺ channels and Na⁺/K⁺‐ATPase in the acetylcholine‐mediated relaxation, although sodium pump is up‐regulated probably as a compensatory mechanism.     

Experimental model standardizing polyvinyl alcohol hydrogel to simulate endoscopic ultrasound and endoscopic ultrasound-elastography

BACKGROUND Endoscopic ultrasound(EUS) and endoscopic ultrasound elastography(EUS-E) simulation lessens the learning curve; however, models lack realism, diminishing competitiveness.AIM To standardize the mechanical properties of polyvinyl alcohol(PVA) hydrogel for simulating organs and digestive lesions.METHODS PVA hydrogel(Sigma Aldrich, degree of hydrolysis 99%) for simulating EUS/EUS-E lesions was investigated in Unidad de Investigación y Desarrollo Tecnológico at Hospital General de México "Dr. Eduardo Liceaga", Mexico City. We evaluated physical, contrast, elasticity and deformation coefficient characteristics in lesions, applying Kappa's concordance and satisfaction questionnaire(Likert 4-points).RESULTS PVA hydrogel showed stable mechanical properties. Density depended on molecular weight(MW) and concentration(C). PVA bblocks with the greatest density showed lowest tensile strength(r =-0.8, P = 0.01). Lesions were EUSgraphically visible. Homogeneous and heterogeneous examples were created from PVA blocks or PVA phantoms, exceeding(MW_2 = 146000-186000, C_9 = 15% and C_(10) = 20%) with a density under(MW_1 = 85000-124000, C_1 = 7% and C_2 = 9%). We calculated elasticity and deformation parameters of solid(blue) areas, contrasting with the norm(Kappa = 0.8; high degree of satisfaction).CONCLUSION PVA hydrogels were appropriate for simulating organs and digestive lesions using EUS/EUS-E, facilitating practice and reducing risk. Repetition amplified skills, while reducing the learning curve.     

A multicentre observational study of the effectiveness,safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice

International Journal of Clinical Pharmacy - Background Immunotherapy has become a standard treatment for lung cancer; however, the high cost makes it necessary to assess health outcomes. Objective...     

Is peracetic acid suitable for the cleaning step of reprocessing flexible endoscopes?

The bioburden(blood, protein, pathogens and biofilm) on flexible endoscopes after use is often high and its removal is essential to allow effective disinfection, es-pecially in the case of peracetic acid-based disinfect-ants, which are easily inactivated by organic material. Cleaning processes using conventional cleaners remove a variable but often sufficient amount of the biobur-den. Some formulations based on peracetic acid are recommended by manufacturers for the cleaning step. We performed a systematic literature search and re-viewed the available evidence to clarify the suitability of peracetic acid-based formulations for cleaning flex-ible endoscopes. A total of 243 studies were evaluated. No studies have yet demonstrated that peracetic acid-based cleaners are as effective as conventional clean-ers. Some peracetic acid-based formulations have dem-onstrated some biofilm-cleaning effects and no biofilm-fixation potential, while others have a limited cleaning effect and a clear biofilm-fixation potential. All published data demonstrated a limited blood cleaning effect and a substantial blood and nerve tissue fixation potential of peracetic acid. No evidence-based guidelines on reproc-essing flexible endoscopes currently recommend using cleaners containing peracetic acid, but some guidelines clearly recommend not using them because of their fixa-tion potential. Evidence from some outbreaks, especially those involving highly multidrug-resistant gram-negative pathogens, indicated that disinfection using peracetic acid may be insufficient if the preceding cleaning step is not performed adequately. Based on this review we conclude that peracetic acid-based formulations should not be used for cleaning flexible endoscopes.     

Lack of Evidence to Support Thromboprophylaxis in Hospitalized Medical Patients with Cancer

Background

The administration of anticoagulant thromboprophylaxis for all patients with cancer who are hospitalized for acute medical illness is considered standard practice and strongly recommended in clinical guidelines. These recommendations are extrapolated from randomized controlled prophylaxis trials not specifically conducted in cancer cohorts. Because hospitalized patients with cancer constitute a unique population with increased risk of venous thromboembolic events and major hemorrhage, validation of the efficacy and safety of primary thromboprophylaxis in this population is critical. We sought to summarize the rates of venous thromboembolic events and major bleeding episodes among hospitalized patients with cancer who were receiving anticoagulant therapy compared with placebo.

Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. Two reviewers independently extracted data onto standardized forms. The primary end points were all venous thromboembolic events. Secondary end points included major bleeding episodes and symptomatic venous thromboembolic events. Pooled analysis with relative risk using a random effect model was used as the primary measurement.

Results

A total of 242 citations were identified by the literature search. Of these, 3 placebo-controlled randomized trials included venous thromboembolic events as a primary outcome and were analyzed according to cancer subgroups. The pooled relative risk of venous thromboembolic events was 0.91 (95% confidence interval, 0.21-4.0; I²: 68%) among hospitalized patients with cancer who were receiving thromboprophylaxis compared with placebo. None of the trials reported the rates of symptomatic venous thromboembolic events or major bleeding episodes according to cancer status.

Conclusions

The risks and benefits of primary thromboprophylaxis with anticoagulant therapy in hospitalized patients with cancer are not known. This is especially relevant because numerous Medicare-type pay-for-performance incentives mandate prophylaxis specifically in patients with cancer.     

Lifestyle Modification for Metabolic Syndrome: A Systematic Review

Background

All 5 components of metabolic syndrome have been shown to improve with lifestyle and diet modification. New strategies for achieving adherence to meaningful lifestyle change are needed to optimize atherosclerotic cardiovascular risk reduction. We performed a systematic literature review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework (PRISMA), investigating optimal methods for achieving lifestyle change in metabolic syndrome.

Methods

We submitted standardized search terms to the PubMed Central, CINAHL, Web of Science, and Ovid databases. Within those results, we selected randomized controlled trials (RCTs) presenting unique methods of achieving lifestyle change in patients with one or more components of the metabolic syndrome. Data extraction using the population, intervention, comparator, outcome, and risk of bias framework (PICO) was used to compare the following endpoints: prevalence of metabolic syndrome, prevalence of individual metabolic syndrome components, mean number of metabolic syndrome components, and amount of weight loss achieved.

Results

Twenty-eight RCTs (6372 patients) were included. Eight RCTs demonstrated improvement in metabolic syndrome risk factors after 1 year. Team-based, interactive approaches with high-frequency contact with patients who are motivated made the largest and most lasting impact. Technology was found to be a useful tool in achieving lifestyle change, but ineffective when compared with personal contact.

Conclusion

Patient motivation leading to improved lifestyle adherence is a key factor in achieving reduction in metabolic syndrome components. These elements can be enhanced via frequent encounters with the health care system. Use of technologies such as mobile and Internet-based communication can increase the effectiveness of lifestyle change in metabolic syndrome, but should not replace personal contact as the cornerstone of therapy. Our ability to derive quantitative conclusions is limited by inconsistent outcome measures across studies, low power and homogeneity of individual studies, largely motivated study populations, short follow-up periods, loss to follow-up, and lack of or incomplete blinding.