Masks: A Viable Option for the Modern Stage

It is the position of this paper that masks have a viable place on the stage today. As we look at the historical usage and at the present views of masks, we will see the mystical effect of masks has not changed. Although our technology has improved, masks still create a mystical illusion for the audience and for the actor. Learning of the many techniques and approaches to mask-making has been a delightful experience. I must thank Niki Juncker for the many times she has cleared my muddled thinking. Without her guidance I am sure this project would not have been completed. I must also acknowledge the encouragement I found in the writings of E. G. Craig in his book on the Art of the Theatre. Did you think when the longing came upon you and when you told your family that you must go upon the stage that such a great longing was to be soon satisfied? Is satisfaction so small a thing? Is desire a thing of nothing that a five years\u27 quest can make a parody of it? But of course not . Your whole life is not too long, and then only at the very end will some small atom of what you have desired come to you. And so you will be still young when you are full of years (p . 8)

A Physiologic approach to the pharmacogenomics of hypertension

Hypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered

Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment

Introduction: Increasing clinical evidence supports the implementation of genotyping for anti-hypertensive drug dosing and selection. Despite robust evidence gleaned from clinical trials, the translation of genotype guided therapy into clinical practice faces significant challenges. Challenges to implementation include the small effect size of individual variants and the polygenetic nature of antihypertensive drug response, a lack of expert consensus on dosing guidelines even without genetic information, and proper definition of major antihypertensive drug toxicities. Balancing clinical benefit with cost, while overcoming these challenges, remains crucial. Areas covered: This review presents the most impactful clinical trials and cohorts which continue to inform and guide future investigation. Variants were selected from among those identified in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR), the Genetic Epidemiology of Responses to Antihypertensives study (GERA), the Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study, the SOPHIA study, the Milan Hypertension Pharmacogenomics of hydro-chlorothiazide (MIHYPHCTZ), the Campania Salute Network, the International Verapamil SR Trandolapril Study (INVEST), the Nordic Diltiazem (NORDIL) Study, GenHAT, and others. Expert Commentary: The polygenic nature of antihypertensive drug response is a major barrier to clinical implementation. Further studies examining clinical effectiveness are required to support broad-based implementation of genotype-based prescribing in medical practice

Five-Year Weight Loss Experience of Outpatients Receiving Laparoscopic Adjustable Gastric Band Surgery

BACKGROUND: This study evaluated the efficacy and safety of laparoscopic adjustable gastric banding (LAGB) in a large cohort of morbidly obese patients followed for up to 5 years. METHODS: Morbidly obese patients, ≥16 years of age, who underwent LAGB surgery at the Surgical Weight Loss Clinic in Ontario, Canada, between May 2005 and January 2011 were eligible for this retrospective chart review. Electronic files were searched to identify all patients who met the inclusion/exclusion criteria. Demographics, weights at baseline and follow-up visits (up to 60 months following surgery), and post-operative complications were documented. As follow-up visits occurred at unevenly spaced intervals within and across patients, modeling methods were used to more accurately assess mean % weight loss (WL) and % excess weight loss (EWL) over time. RESULTS: This study included 2,815 patients (82 % female, mean age 43 years, mean baseline BMI 44.6 kg/m(2)) followed for a mean of 21.8 ± 15.4 months. Complications developed in 238 patients (8.5 %), the most frequent being prolapse/slippage (4.2 %), tubing/access port problems (1.2 %), and explantation (1.2 %). Mean %WL and %EWL progressed continuously over the first 2.5 years post-LAGB, plateauing at 20 and 49 %, respectively, for up to 5 years of follow up. Factors associated with increased weight loss were time since surgery, greater baseline weight (excess weight), older age at time of surgery, and male gender. CONCLUSIONS: Weight loss was maintained for up to 5 years in our population of patients who underwent LAGB for the treatment of morbid obesity

Pharmacometabolomics reveals racial differences in response to atenolol treatment.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug

Tolvaptan in ADPKD Patients With Very Low Kidney Function

Introduction: Tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) in TEMPO 3:4 and REPRISE trials. Tolvaptan effects in subjects with eGFR 15 to 24 ml/min per 1.73 m2 were not investigated. This post hoc analysis retrospectively investigated eGFR decline in REPRISE versus an open-label, phase 3b extension trial (open-label extension [OLE] NCT02251275) in subjects who received placebo in REPRISE and tolvaptan in OLE with eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2, respectively. Methods: One data subset comprised subjects with OLE baseline eGFR 15 to 29 ml/min per 1.73 m2 who had received placebo in REPRISE and began tolvaptan in OLE. The second comprised subjects who had received tolvaptan in REPRISE and were matched to REPRISE placebo-treated subjects for REPRISE baseline characteristics. Annualized eGFR slopes in REPRISE versus OLE were compared within the REPRISE placebo (i.e., placebo vs. tolvaptan treatment) and tolvaptan (i.e., 2 periods of tolvaptan treatment) subsets. Results: Mean annualized eGFR slopes (ml/min per 1.73 m2) during tolvaptan treatment in OLE versus placebo treatment in REPRISE were -3.4 versus -5.2 for subjects with OLE baseline eGFR 15 to 29 (difference, 1.7; P < 0.001), -3.6 versus -5.4 with baseline eGFR 15 to 24 (difference, 1.8; P < 0.001), and -3.3 versus -4.9 with baseline eGFR 25 to 29 (difference, 1.6; P < 0.001). In REPRISE tolvaptan subjects who continued tolvaptan in OLE, treatment effect was maintained (no difference between mean annualized eGFR slopes). Conclusion: Initiating or maintaining tolvaptan therapy significantly delayed eGFR decline in subjects with baseline eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2

Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy

Hypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments (CLIA)-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy

Renal structure and hypertension in autosomal dominant polycystic kidney disease

Renal structure and hypertension in autosomal dominant polycystic kidney disease. Hypertension has been reported to occur in 50 to 75 percent of subjects with autosomal dominant polycystic kidney disease (ADPKD) prior to the onset of marked renal insufficiency but concurrent with cystic deformation of the renal parenchyma. The present study was undertaken to examine whether the renal structural abnormalities are greater in hypertensive (HBP) versus normotensive (NBP) male and female patients with ADPKD who were matched within gender groups for age, body surface area, serum creatinine concentration (males HBP 1.2 ± 0.02 vs. NBP 1.1 ± 0.03 mg/dl, NS; females HBP 0.9 ± 0.03 vs. NBP 0.9 ± 0.02 mg/dl, NS) and creatinine clearance (males HBP 100 ± 3 vs. NBP 108 ± 3 ml/min/1.73 m2, NS; females HBP 97 ± 3 vs. NBP 96 ± 2 ml/min/1.73 m2, NS). Renal volume was significantly greater in the HBP compared to the NBP group (males HBP 624 ± 47 vs. NBP 390 ± 43 cm3, P < 0.0005; females HBP 466 ± 32 vs. NBP 338 ± 24 cm3, P < 0.002). Since increased renal volume is due to increased cysts, the results indicate that the early high incidence of hypertension in ADPKD correlates with the renal structural abnormalities in this disorder