Genetic and pharmacological relationship between P-Glycoprotein and increased cardiovascular risk associated with clarithromycin prescription:An Epidemiological and Genomic Population-Based Cohort Study in Scotland, UK

BackgroundThere are conflicting reports regarding the association of the macrolide antibiotic clarithromycin with cardiovascular (CV) events. A possible explanation may be that this risk is partly mediated through drug-drug interactions and only evident in at-risk populations. To the best of our knowledge, no studies have examined whether this association might be mediated via P-glycoprotein (P-gp), a major pathway for clarithromycin metabolism. The aim of this study was to examine CV risk following prescription of clarithromycin versus amoxicillin and in particular, the association with P-gp, a major pathway for clarithromycin metabolism.Methods and findingsWe conducted an observational cohort study of patients prescribed clarithromycin or amoxicillin in the community in Tayside, Scotland (population approximately 400,000) between 1 January 2004 and 31 December 2014 and a genomic observational cohort study evaluating genotyped patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study, a longitudinal cohort study of 18,306 individuals with and without type 2 diabetes recruited between 1 December 1988 and 31 December 2015. Two single-nucleotide polymorphisms associated with P-gp activity were evaluated (rs1045642 and rs1128503 -AA genotype associated with lowest P-gp activity). The primary outcome for both analyses was CV hospitalization following prescription of clarithromycin versus amoxicillin at 0-14 days, 15-30 days, and 30 days to 1 year. In the observational cohort study, we calculated hazard ratios (HRs) adjusted for likelihood of receiving clarithromycin using inverse proportion of treatment weighting as a covariate, whereas in the pharmacogenomic study, HRs were adjusted for age, sex, history of myocardial infarction, and history of chronic obstructive pulmonary disease. The observational cohort study included 48,026 individuals with 205,227 discrete antibiotic prescribing episodes (34,074 clarithromycin, mean age 73 years, 42% male; 171,153 amoxicillin, mean age 74 years, 45% male). Clarithromycin use was significantly associated with increased risk of CV hospitalization compared with amoxicillin at both 0-14 days (HR 1.31; 95% CI 1.17-1.46, p ConclusionsIn this study, we observed that the increased risk of CV events with clarithromycin compared with amoxicillin was associated with an interaction with P-glycoprotein

Racial disparities among patients with lung cancer who were recommended operative therapy.

HYPOTHESIS: Health care system and provider biases and differences in patient characteristics are thought to be prevailing factors underlying racial disparities. The influence of these factors on the receipt of care would likely be mitigated among patients who are recommended optimal therapy. We hypothesized that there would be no significant evidence of racial disparities among patients with early-stage lung cancer who are recommended surgical therapy. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of patients in the Surveillance, Epidemiology, and End Results-Medicare database who were diagnosed with stage I or II lung cancer between January 1, 1992, and December 31, 2002 (follow-up through December 31, 2005). MAIN OUTCOME MEASURES: Receipt of lung resection and overall survival. RESULTS: Among 17,739 patients who were recommended surgical therapy (mean [SD] age, 75 [5] years; 89% white, 6% black), black patients less frequently underwent resection compared with white patients (69% vs 83%, respectively; P < .001). After adjustment, black race was associated with lower odds of receiving surgical therapy (odds ratio = 0.43; 99% confidence interval, 0.36-0.52). Unadjusted 5-year survival rates were lower for black patients compared with white patients (36% vs 42%, respectively; P < .001). After adjustment, there was no significant association between race and death (hazard ratio = 1.03; 99% confidence interval, 0.92-1.14) despite a 14% difference in receipt of optimal therapy. CONCLUSIONS: Even among patients who were recommended surgical therapy, black patients underwent lung resection less often than white patients. Unexpectedly, racial differences in the receipt of optimal therapy did not appear to affect outcomes. These findings suggest that distrust, beliefs and perceptions about lung cancer and its treatment, and limited access to care (despite insurance) might have a more dominant role in perpetuating racial disparities than previously recognized

Epidural Hematoma Following Cervical Spine Surgery.

STUDY DESIGN: A multicentered retrospective case series. OBJECTIVE: To determine the incidence and circumstances surrounding the development of a symptomatic postoperative epidural hematoma in the cervical spine. METHODS: Patients who underwent cervical spine surgery between January 1, 2005, and December 31, 2011, at 23 institutions were reviewed, and all patients who developed an epidural hematoma were identified. RESULTS: A total of 16 582 cervical spine surgeries were identified, and 15 patients developed a postoperative epidural hematoma, for a total incidence of 0.090%. Substantial variation between institutions was noted, with 11 sites reporting no epidural hematomas, and 1 site reporting an incidence of 0.76%. All patients initially presented with a neurologic deficit. Nine patients had complete resolution of the neurologic deficit after hematoma evacuation; however 2 of the 3 patients (66%) who had a delay in the diagnosis of the epidural hematoma had residual neurologic deficits compared to only 4 of the 12 patients (33%) who had no delay in the diagnosis or treatment (P = .53). Additionally, the patients who experienced a postoperative epidural hematoma did not experience any significant improvement in health-related quality-of-life metrics as a result of the index procedure at final follow-up evaluation. CONCLUSION: This is the largest series to date to analyze the incidence of an epidural hematoma following cervical spine surgery, and this study suggest that an epidural hematoma occurs in approximately 1 out of 1000 cervical spine surgeries. Prompt diagnosis and treatment may improve the chance of making a complete neurologic recovery, but patients who develop this complication do not show improvements in the health-related quality-of-life measurements

C5 Palsy After Cervical Spine Surgery: A Multicenter Retrospective Review of 59 Cases.

STUDY DESIGN: A multicenter, retrospective review of C5 palsy after cervical spine surgery. OBJECTIVE: Postoperative C5 palsy is a known complication of cervical decompressive spinal surgery. The goal of this study was to review the incidence, patient characteristics, and outcome of C5 palsy in patients undergoing cervical spine surgery. METHODS: We conducted a multicenter, retrospective review of 13 946 patients across 21 centers who received cervical spine surgery (levels C2 to C7) between January 1, 2005, and December 31, 2011, inclusive. P values were calculated using 2-sample t test for continuous variables and χ(2) tests or Fisher exact tests for categorical variables. RESULTS: Of the 13 946 cases reviewed, 59 patients experienced a postoperative C5 palsy. The incidence rate across the 21 sites ranged from 0% to 2.5%. At most recent follow-up, 32 patients reported complete resolution of symptoms (54.2%), 15 had symptoms resolve with residual effects (25.4%), 10 patients did not recover (17.0%), and 2 were lost to follow-up (3.4%). CONCLUSION: C5 palsy occurred in all surgical approaches and across a variety of diagnoses. The majority of patients had full recovery or recovery with residual effects. This study represents the largest series of North American patients reviewed to date

Saccharomyces cerevisiae-based system for studying clustered DNA damages

DNA-damaging agents can induce clustered lesions or multiply damaged sites (MDSs) on the same or opposing DNA strands. In the latter, attempts to repair MDS can generate closely opposed single-strand break intermediates that may convert non-lethal or mutagenic base damage into double-strand breaks (DSBs). We constructed a diploid S. cerevisiae yeast strain with a chromosomal context targeted by integrative DNA fragments carrying different damages to determine whether closely opposed base damages are converted to DSBs following the outcomes of the homologous recombination repair pathway. As a model of MDS, we studied clustered uracil DNA damages with a known location and a defined distance separating the lesions. The system we describe might well be extended to assessing the repair of MDSs with different compositions, and to most of the complex DNA lesions induced by physical and chemical agents

The relationship of bottle feeding and other sucking behaviors with speech disorder in Patagonian preschoolers

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown that children's nonnutritive sucking habits may lead to delayed development of their oral anatomy and functioning. However, these findings were inconsistent. We investigated associations between use of bottles, pacifiers, and other sucking behaviors with speech disorders in children attending three preschools in Punta Arenas (Patagonia), Chile.</p> <p>Methods</p> <p>Information on infant feeding and sucking behaviors, age starting and stopping breast- and bottle-feeding, pacifier use, and other sucking behaviors, was collected from self-administered questionnaires completed by parents. Evaluation of speech problems was conducted at preschools with subsequent scoring by a licensed speech pathologist using age-normative standards.</p> <p>Results</p> <p>A total of 128 three- to five-year olds were assessed, 46% girls and 54% boys. Children were breastfed for an average of 25.2 (SD 9.6) months and used a bottle 24.4 (SD 15.2) months. Fifty-three children (41.7%) had or currently used a pacifier for an average of 11.4 (SD 17.3) months; 23 children (18.3%) were reported to have sucked their fingers. Delayed use of a bottle until after 9 months appeared to be protective for subsequent speech disorders. There was less than a one-third lower relative odds of subsequent speech disorders for children with a delayed use of a bottle compared to children without a delayed use of a bottle (OR: 0.32, 95% CI: 0.10-0.98). A three-fold increase in relative odds of speech disorder was found for finger-sucking behavior (OR: 2.99, 95% CI: 1.10-8.00) and for use of a pacifier for 3 or more years (OR: 3.42, 95% CI: 1.08-10.81).</p> <p>Conclusion</p> <p>The results suggest extended use of sucking outside of breastfeeding may have detrimental effects on speech development in young children.</p

Seasonality of isoprene emissions and oxidation products above the remote Amazon

The Amazon rainforest is the largest source of isoprene emissions to the atmosphere globally. Under low nitric oxide (NO) conditions (i.e. at NO mixing ratios less than about 40 pptv), isoprene reacts rapidly with hydroxyl (OH) to form isoprene-derived peroxy radicals (ISOPOO), which subsequently react with the hydroperoxyl radical (HO2) to form isoprene epoxydiols (IEPOX). IEPOX compounds are efficient precursors to the formation of secondary organic aerosols (SOA). Natural isoprene emissions, therefore, have the potential to influence cloudiness, rainfall, radiation balance and climate. Here, we present the first seasonal analysis of isoprene emissions and concentrations above the Amazon based on eddy covariance flux measurements made at a remote forest location. We reveal the forest to maintain a constant emission potential of isoprene throughout the year (6.9 mg m-2 h-1). The emission potential of isoprene is calculated by normalising the measured fluxes to a set of standard conditions (303 K and 1500 mmol m-2 s-1). During the wet season a factor of two reduction in absolute emissions was observed but this is explained entirely on the basis of meteorology and leaf area index, not by a change in isoprene emissions potential. Using an innovative analysis of the isoprene fluxes, in combination with measurements of its oxidation products and detailed chemical box-modelling, we explore whether concentrations of IEPOX follow the same seasonal cycle as the isoprene precursor. Our analysis implies that during the dry season (Sep–Jan) air pollution from regional biomass burning provides a modest increase in NO concentrations (indirectly inferred from a combination of other anthropogenic tracer measurements and box-modelling) which creates a competing oxidation pathway for ISOPOO; rather than forming IEPOX, alternative products are formed with less propensity to produce aerosol. This competition decreases IEPOX formation rates by a factor of two in the dry season compared with a scenario with no anthropogenic NO pollution, and by 30% throughout the year. The abundance of biogenic SOA precursors in the Amazon appears not to be dictated by the seasonality of natural isoprene emissions as previously thought, but is instead driven by regional anthropogenic pollution which modifies the atmospheric chemistry of isoprene

Expression Analysis of PAC1-R and PACAP Genes in Zebrafish Embryos

This study describes the expression of the pituitary adenylate cyclase-activating polypeptide (PACAP1 and PACAP2) and PAC1 receptor genes (PAC1a-R and PAC1b-R) in the brain of zebrafish (Danio rerio) during development. In situ hybridization of the 24- and 48-hpf embryos revealed that PACAP genes were expressed in the telencephalon, the diencephalon, the rhombencephalon, and the neurons in the dorsal part of the spinal cord. PACAP2 mRNA appears to be the most abundant form during brain development. The two PAC1-R subtypes showed a similar expression pattern: mRNAs were detected in the forebrain, the thalamus, and the rhombencephalon. However, in the tectum, only PAC1b-R gene was detected. These results suggest that, in fish, PACAP may play a role in brain development