Warfarin Pharmacogenomics in a Hispanic Population: A Candidate SNP Study

Background: Warfarin remains one of the most widely prescribed anticoagulants but is also a leading cause of adverse drug reactions. Genotype-guided warfarin dosing algorithms enable accurate dose estimation, potentially leading to improved safety and efficacy. However, genotype-guided dosing algorithms were developed primarily in populations of European descent and limited data are available regarding single nucleotide polymorphisms (SNPs) that significantly influence warfarin dose in Hispanic populations. Research Aim: The objective of this study was to determine whether clinical factors and SNPs previously associated with stable warfarin dose variability in populations of European and Hispanic descent accurately predicted warfarin stable dose in a Hispanic population. Study Design: Self-reported Hispanic and Latino patients on stable warfarin dose (defined as the same dose for at least two clinic visits separated by at least two weeks) were recruited. Methods: Candidate SNPs, including CYP2C9*2/*3, VKORC1-1639G>A, CYP4F2*3, and NQO1*2, were genotyped and clinical data were collected using a survey and the electronic medical record. Stepwise linear regression was performed to determine variables that significantly predicted square root of weekly warfarin dose. Results: A total of 76 patients of primarily Mexican American ancestry participated. All SNPs were within Hardy-Weinberg Equilibrium. The final stepwise regression model incorporated six variables, which explained 71% of the variability in warfarin weekly dose requirements. Significant predictors included weight (R2=0.287, p<0.0001), age (R2=0.143, p<0.0001), amiodarone use (R2=0.067, p=0.0005), and prior stroke (R2=0.025, p=0.02). Significant SNPs included VKORC1-1639A (R2=0.152, p<0.0001), and CYP2C9*2/*3 (R2=0.032, p=0.02). CYP4F2*3 and NQO1*2 did not significantly impact warfarin dose requirements despite previously published associations in Hispanic populations. Conclusion: These findings suggest that clinical and genetic predictors of warfarin weekly dose requirements are similar among populations of European descent and Hispanic populations with Mexican American ancestry. These results require replication and validation in independent cohorts with similar ethnicity, but advance our understanding of influences on warfarin dose variability among different race/ethnic groups

Pharmacological Advances in Opioid Therapy: A Review of the Role of Oliceridine in Pain Management

Problems with the treatment of acute pain may arise when a patient is opioid-tolerant, such as those on chronic therapy with opioids or opiate replacement therapy, those who misuse opioids, and those who are in recovery. While some of the adverse effects of opioid medications are well known, it is also important to recognize the roles of tolerance and hyperalgesia. Oliceridine can target and modulate a novel μ-receptor pathway. The G protein-biased agonism of oliceridine allows for effective re-sensitization and desensitization of the mu-opioid receptor, which decreases the formation of opioid tolerance in patients. Oliceridine has been demonstrated to be an effective and relatively safe intravenous analgesic for the treatment of postoperative pain and is generally well tolerated with a favorable side effect profile when compared to morphine. As the prevalence of pain increases, it is becoming increasingly important to find safe and effective analgesics

The effect of right ventricular apical and non-apical pacing on the short- and long-term changes in left ventricular ejection fraction: a systematic review and meta-analysis of randomized-controlled trials

BACKGROUND The right ventricular apex (RVA) is the traditional lead site for chronic pacing but in some patients may cause impaired left ventricular (LV) systolic function over time. Comparisons with non-apical (RVNA) pacing sites have generated inconsistent results and recent meta-analyses have demonstrated unclear benefit due to heterogeneity across studies. METHODS AND RESULTS A systematic search for randomized controlled trials that compared LVEF outcomes between RVNA and RVA pacing was performed up to October 2014. Twenty four studies (n = 1628 patients) met the inclusion criteria. To avoid between study heterogeneity two homogenous groups were created; group one where studies reported a difference (in favor of RVNA pacing) and group two where studies reported no difference between pacing sites. For group one weighted mean difference (WMD) between RVNA and RVA pacing in terms of LVEF at follow-up was 5.40% (95% CI: 3.94 to 6.87), related in part to group one's RVA arm demonstrating a significant reduction (mean loss -3.31%; 95% CI: -6.19 to -0.43) in LVEF between study baseline and end of follow-up. Neither of these finding were seen in group two. Weighted regression modeling demonstrated that inclusion of poor baseline LVEF (<40%) in combination with greater than 12 months follow-up was three times more common in group one compared to group two (weighted RR 2.82; 95% CI 1.03 - 7.72; P = 0.043). CONCLUSIONS In patients requiring chronic right ventricular pacing where there is inclusion of impaired baseline LVEF (<40%), RVA pacing is associated with deterioration in LV function relative to RVNA pacing. This article is protected by copyright. All rights reserved

Advice to clinicians on communication from adolescents and young adults with cancer and parents of children with cancer

Effective communication is integral to patient and family-centered care in pediatric and adolescent and young adult (AYA) oncology and improving healthcare delivery and outcomes. There is limited knowledge about whether AYAs and parents have similar communication preferences and needs. By eliciting and comparing communication advice from AYAs and parents, we can identify salient guidance for how clinicians can better communicate. We performed secondary analysis of semi-structured interviews from 2 qualitative communication studies. In one study, 80 parents of children with cancer during treatment, survivorship, or bereavement were interviewed. In the second study, AYAs with cancer during treatment or survivorship were interviewed. We asked AYAs and parents to provide communication advice for oncology clinicians. Using thematic analysis, we identified categories of advice related to three overarching themes: interpersonal relationships, informational preferences, and delivery of treatment, resources, and medical care. AYAs and parents provided similar advice about the need for compassion, strong connections, hopefulness, commitment, and transparent honesty However, AYAs placed additional emphasis on clinicians maintaining a calm demeanor

Cardiac Substrate Utilization and Relationship to Invasive Exercise Hemodynamic Parameters in HFpEF

We conducted transcardiac blood sampling in healthy subjects and subjects with heart failure with preserved ejection fraction (HFpEF) to compare cardiac metabolite and lipid substrate use. We demonstrate that fatty acids are less used by HFpEF hearts and that lipid extraction is influenced by hemodynamic factors including pulmonary pressures and cardiac index. The release of many products of protein catabolism is apparent in HFpEF compared to healthy myocardium. In subgroup analyses, differences in energy substrate use between female and male hearts were identified

Review of Interventional Therapies for Refractory Pediatric Migraine.

This is a review of the latest and seminal evidence in pediatric migraine. It covers the etiology and pathophysiology known today, and then will review treatment options, efficacy and safety, quality of data and indications. Though migraine is usually regarded as an infliction in adults, it is not uncommon in the pediatric population and affects up to 8% of children. Children may experience migraine differently than adults, and present not only with headache but also frequent gastrointestinal symptoms. They are frequently shorter in duration than in adults. Traditional migraine treatment in adults is less effective in children. In this population, adjunct therapies - such as interventional techniques - should be considered when traditional treatment fails, including Botulinum Toxin A (BTA) injections, peripheral nerve and ganglion blocks. BTA injections are FDA approved for migraine prophylaxis in adults, but currently not in children; however, recent evidence shows efficacy and safety in pediatric migraine management. Nerve blocks stop nociceptive afferent fibers through injection of local anesthetics, and it may be associated with the local injection of corticosteroids. Although more common in adults, recent data suggests they are safe and effective in children and adolescents. Blocking the sphenopalatine ganglion can be achieved through nasal approach, and achieves a similar action by blocking the entire ganglion. Interventional techniques may provide a key component in the alleviation of this otherwise debilitating chronic migraine pain. Though most studies have been performed in adults, new studies provide encouraging results for treatment in children

The Zwicky Transient Facility Camera

The Zwicky Transient Facility Camera (ZTFC) is a key element of the ZTF Observing System, the integrated system of optoelectromechanical instrumentation tasked to acquire the wide-field, high-cadence time-domain astronomical data at the heart of the Zwicky Transient Facility. The ZTFC consists of a compact cryostat with large vacuum window protecting a mosaic of 16 large, wafer-scale science CCDs and 4 smaller guide/focus CCDs, a sophisticated vacuum interface board which carries data as electrical signals out of the cryostat, an electromechanical window frame for securing externally inserted optical filter selections, and associated cryo-thermal/vacuum system support elements. The ZTFC provides an instantaneous 47 deg^2 field of view, limited by primary mirror vignetting in its Schmidt telescope prime focus configuration. We report here on the design and performance of the ZTF CCD camera cryostat and report results from extensive Joule-Thompson cryocooler tests that may be of broad interest to the instrumentation community

The Keck Cosmic Web Imager Integral Field Spectrograph

We report on the design and performance of the Keck Cosmic Web Imager (KCWI), a general purpose optical integral field spectrograph that has been installed at the Nasmyth port of the 10 m Keck II telescope on Maunakea, Hawaii. The novel design provides blue-optimized seeing-limited imaging from 350–560 nm with configurable spectral resolution from 1000–20,000 in a field of view up to 20'' × 33''. Selectable volume phase holographic (VPH) gratings and high-performance dielectric, multilayer silver, and enhanced-aluminum coatings provide end-to-end peak efficiency in excess of 45% while accommodating the future addition of a red channel that will extend wavelength coverage to 1 micron. KCWI takes full advantage of the excellent seeing and dark sky above Maunakea with an available nod-and-shuffle observing mode. The instrument is optimized for observations of faint, diffuse objects such as the intergalactic medium or cosmic web. In this paper, a detailed description of the instrument design is provided with measured performance results from the laboratory test program and 10 nights of on-sky commissioning during the spring of 2017. The KCWI team is lead by Caltech and JPL (project management, design, and implementation) in partnership with the University of California at Santa Cruz (camera optical and mechanical design) and the W. M. Keck Observatory (observatory interfaces)

Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity

Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii . The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities. Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactam-resistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations. Results: Despite achieving colistin steady-state targets of an AUC 0-24 >60 mg·h/L and C avg of >2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam eradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth. Conclusions: To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise