Inaccuracies in the Use of Magnification Markers in Digital Hip Radiographs.

BACKGROUND: With the ubiquity of digital radiographs, the use of digital templating for arthroplasty has become commonplace. Although improved accuracy with digital radiographs and magnification markers is assumed, it has not been shown. QUESTIONS/PURPOSES: We wanted to (1) evaluate the accuracy of magnification markers in estimating the magnification of the true hip and (2) determine if the use of magnification markers improves on older techniques of assuming a magnification of 20% for all patients. METHODS: Between April 2013 and September 2013 we collected 100 AP pelvis radiographs of patients who had a THA prosthesis in situ and a magnification marker placed per the manufacturer's instructions. Radiographs seen during our standard radiographic review process, which met our inclusion criteria (AP pelvic view that included a well-positioned and observed magnification marker, and a prior total hip replacement with a known femoral head size), were included in the analysis. We then used OrthoView(TM) software program to calculate magnification of the radiograph using the magnification marker (measured magnification) and the femoral head of known size (true magnification). RESULTS: The mean true magnification using the femoral head was 21% (SD, 2%). The mean magnification using the marker was 15% (SD, 5%). The 95% CI for the mean difference between the two measurements was 6% to 7% (p < 0.001). The use of a magnification marker to estimate magnification at the level of the hip using standard radiographic techniques was shown in this study to routinely underestimate the magnification of the radiograph using an arthroplasty femoral head of known diameter as the reference. If we assume a magnification of 20%, this more closely approximated the true magnification routinely. With this assumption, we were within 2% magnification in 64 of the 100 hips and off by 4% or more in only four hips. In contrast, using the magnification marker we were within 2% of true magnification in only 20 hips and were off by 4% or more in 59 hips. CONCLUSION: We found the use of a magnification marker with digital radiographs for preoperative templating to be generally inaccurate, with a mean error of 6% and range from -5% to 15%. Additionally, these data suggest that the use of a magnification marker while taking preoperative radiographs of the hip may be unnecessary, as simply setting the software to assume a 20% magnification actually was more accurate. LEVEL OF EVIDENCE: Level III, diagnostic study.

Structural polymorphism analysis of Chinese Mongolian ethnic group revealed by a new STR panel: genetic relationship to other groups.

Mongolian is the eighth largest ethnic minority on Chinese population data according to the 2010 census. In the present study, we presented the first report about the allelic frequencies and forensic statistical parameters at the 21 new STRs and analyzed linkage disequilibrium of pairwise loci in the Mongolian ethnic minority, China. Hardy-Weinberg equilibrium tests demonstrated no significant deviations except for the D1S1627 locus. The cumulative power of discrimination and power of exclusion of all the loci are 0.9999999999999999992576 and 0.9999997528, respectively. The results of analysis of molecular variance showed that significant differences between the Mongolian and the other eight populations were found at 1-9 STR loci. In population genetics, the results of principal component analysis, structure analysis, and phylogenetic reconstruction analysis indicated shorter genetic distance between the Mongolian group and the Ningxia Han. All the results suggest that the 21 new STR loci will contribute to Chinese population genetics and forensic caseworks in the Mongolian group.

Studies of cardiovascular risk factors in polycystic ovary syndrome patients combined with subclinical hypothyroidism.

OBJECTIVE: To investigate cardiovascular risk factors in women with polycystic ovary syndrome (PCOS) combined with subclinical hypothyroidism (SCH). PATIENTS: A place-controlled study was performed. Group 1: 29 patients with PCOS and SCH; Group II: 35 patients with PCOS and normal thyroid function; and Group III: 34 healthy women with normal thyroid function. MAIN MEASURE INDEXES: Total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), Carotid Arterial Intima-Media Thickness (CIMT), free triiodothyronine 3 (FT3), free triiodothyronine 4 (FT4), thyroid stimulating hormone (TSH), fasting glucose, 1-hour oral glucose tolerance test (OGTT1), 2-hour oral glucose tolerance test (OGTT2), fasting insulin, insulin after 1 hour oral glucose (INS1), insulin after 2 h oral glucose (INS2), HOM-IR = (fasting glucose × fasting insulin)/22.5. RESULTS: TG, TC FIN, INS1, and HOM-IR levels were significantly higher, but the mean HDL level was significantly lower in Group I than in Group II (p < 0.05). LDL cholesterol, FGOGTT1, OGTT2, and insulin after 2 h oral glucose were not significantly higher in Group I than in Group II (p > 0.05). TG, TC, FIN and INS contents 2 h meal, HOM-IR levels were significantly higher, and the mean HDL cholesterol level was significantly lower in Group I than in Group III (p < 0.05). Blood glucose levels after 1 and 2 h were not significantly higher in Group I than in the Group III (p > 0.05). Carotid Arterial Intima-Media Thickness (CIMT) was significantly thicker in Group I than other two groups. CONCLUSIONS: The PCOS patients combined with SCH have higher risk of cardiovascular risk factors than in controls or in patients with PCOS.

Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels.

Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17ß-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation.

GPER: a novel target for non-genomic estrogen action in the cardiovascular system.

A key to harnessing the enormous therapeutic potential of estrogens is understanding the diversity of estrogen receptors and their signaling mechanisms. In addition to the classic nuclear estrogen receptors (i.e., ERα and ERß), over the past decade a novel G-protein-coupled estrogen receptor (GPER) has been discovered in cancer and other cell types. More recently, this non-genomic signaling mechanism has been found in blood vessels, and mediates vasodilatory responses to estrogen and estrogen-like agents; however, downstream signaling events involved acute estrogen action remain unclear. The purpose of this review is to discuss the latest knowledge concerning GPER modulation of cardiovascular function, with a particular emphasis upon how activation of this receptor could mediate acute estrogen effects in the heart and blood vessels (i.e., vascular tone, cell growth and differentiation, apoptosis, endothelial function, myocardial protection). Understanding the role of GPER in estrogen signaling may help resolve some of the controversies associated with estrogen and cardiovascular function. Moreover, a more thorough understanding of GPER function could also open significant opportunities for the development of new pharmacological strategies that would provide the cardiovascular benefits of estrogen while limiting the potentially dangerous side effects.

Lessons learned from managing a prospective, private practice joint replacement registry: a 25-year experience.

BACKGROUND: In 1984, we developed a private practice joint replacement registry (JRR) to prospectively follow patients undergoing THA and TKA to assess clinical and radiographic outcomes, complications, and implant survival. Little has been reported in the literature regarding management of this type of database, and it is unclear whether and how the information can be useful for addressing longer-term questions. QUESTIONS/PURPOSES: We answered the following questions: (1) What is the rate of followup for THA and TKA in our JRR? (2) What factors affect followup? (3) How successful is this JRR model in capturing data and what areas of improvement are identified? And (4) what costs are associated with maintaining this JRR? METHODS: We collected clinical data on all 12,047 patients having primary THA and TKA since 1984. Clinical and radiographic data were collected at routine followup intervals and entered into a prospective database. We searched this database to assess the rate of successful followup and data collection and to compare the effect of patient variables on followup. Costs related to database management were evaluated. RESULTS: Followup was poor at every time interval after surgery, with a tendency for worsening over time. Patients with a complication and those younger than 70 years tended to followup with greater frequency. There were difficulties with data capture and substantial expenses related to managing the database. CONCLUSIONS: Our findings highlight the difficulties in managing a JRR. Followup is poor and data collection is often incomplete. Newer technologies that allow easier tracking of patients and facilitate data capture may streamline this process and control costs.

Total hip arthroplasty after failed internal fixation of proximal femoral fractures.

Between February 1987 and October 2008, we performed 102 total hip arthroplasties (THAs) after failed internal fixation of a prior hip fracture. There were 39 intertrochanteric fractures and 63 femoral neck fractures. Etiology of failure included 35 cases of osteonecrosis, 32 cases of arthritis, 25 cases of early failure of fixation, and 10 cases of nonunion. There were 12 patients who had early surgical complications related to the procedure (11.8%, 12/102). These included 5 patients who had dislocations (4.9%), 4 periprosthetic fractures (3.9%), 2 hematomas (2.0%), and 1 infection (1%). Of these 102 THAs, 50 were available for at least 2 years of follow-up (mean, 3.2 years). At a minimum 2-year follow-up, THA after failed internal fixation of hip fracture in these patients was clinically successful with an elevated risk of periprosthetic fracture and dislocation.

Bundled payments for care improvement initiative: the next evolution of payment formulations: AAHKS Bundled Payment Task Force.

The Patient Protection and Affordable Care Act contains a number of provision for improving the delivery of healthcare in the United States, among the most impactful of which may be the call for modifications in the packaging of and payment for care that is bundled into episodes. The move away from fee for service payment models to payment for coordinated care delivered as comprehensive episodes is heralded as having great potential to enhance quality and reduce cost, thereby increasing the value of the care delivered. This effort builds on the prior experience around delivering care for arthroplasty under the Acute Care Episode Project and offers extensions and opportunities to modify the experience moving forward. Total hip and knee arthroplasties are viewed as ideal treatments to test the effectiveness of this payment model. Providers must learn the nuances of these modified care delivery concepts and evaluate whether their environment is conducive to success in this arena. This fundamental shift in payment for care offers both considerable risk and tremendous opportunity for physicians. Acquiring an understanding of the recent experience and the determinants of future success will best position orthopaedic surgeons to thrive in this new environment. Although this will remain a dynamic exercise for some time, early experience may enhance the chances for long term success, and physicians can rightfully lead the care delivery redesign process.

Testosterone-induced relaxation of coronary arteries: activation of BKCa channels via the cGMP-dependent protein kinase.

Androgens are reported to have both beneficial and detrimental effects on human cardiovascular health. The aim of this study was to characterize nongenomic signaling mechanisms in coronary artery smooth muscle (CASM) and define the ionic basis of testosterone (TES) action. TES-induced relaxation of endothelium-denuded porcine coronary arteries was nearly abolished by 20 nM iberiotoxin, a highly specific inhibitor of large-conductance, calcium-activated potassium (BK(Ca)) channels. Molecular patch-clamp studies confirmed that nanomolar concentrations of TES stimulated BK(Ca) channel activity by ∼100-fold and that inhibition of nitric oxide synthase (NOS) activity by N(G)-monomethyl-L-arginine nearly abolished this effect. Inhibition of nitric oxide (NO) synthesis or guanylyl cyclase activity also attenuated TES-induced coronary artery relaxation but did not alter relaxation due to 8-bromo-cGMP. Furthermore, we detected TES-stimulated NO production in porcine coronary arteries and in human CASM cells via stimulation of the type 1 neuronal NOS isoform. Inhibition of the cGMP-dependent protein kinase (PKG) attenuated TES-stimulated BK(Ca) channel activity, and direct assay determined that TES increased activity of PKG in a concentration-dependent fashion. Last, the stimulatory effect of TES on BK(Ca) channel activity was mimicked by addition of purified PKG to the cytoplasmic surface of a cell-free membrane patch from CASM myocytes (∼100-fold increase). These findings indicate that TES-induced relaxation of endothelium-denuded coronary arteries is mediated, at least in part, by enhanced NO production, leading to cGMP synthesis and PKG activation, which, in turn, opens BK(Ca) channels. These findings provide a molecular mechanism that could help explain why androgens have been reported to relax coronary arteries and relieve angina pectoris.

Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle.

Estrogens can either relax or contract arteries via rapid, nongenomic mechanisms involving classic estrogen receptors (ER). In addition to ERα and ERß, estrogen may also stimulate G protein-coupled estrogen receptor 1 (GPER) in nonvascular tissue; however, a potential role for GPER in coronary arteries is unclear. The purpose of this study was to determine how GPER activity influenced coronary artery reactivity. In vitro isometric force recordings were performed on endothelium-denuded porcine arteries. These studies were augmented by RT-PCR and single-cell patch-clamp experiments. RT-PCR and immunoblot studies confirmed expression of GPER mRNA and protein, respectively, in smooth muscle from either porcine or human coronary arteries. G-1, a selective GPER agonist, produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro. This response was attenuated by G15, a GPER-selective antagonist, or by inhibiting large-conductance calcium-activated potassium (BK(Ca)) channels with iberiotoxin, but not by inhibiting NO signaling. Last, single-channel patch-clamp studies demonstrated that G-1 stimulates BK(Ca) channel activity in intact smooth muscle cells from either porcine or human coronary arteries but had no effect on channels isolated in excised membrane patches. In summary, GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BK(Ca) channels and requires an intact cellular signaling mechanism. This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens.

Expression of GPR30, ERα and ERß in endometrium during window of implantation in patients with polycystic ovary syndrome: a pilot study.

Women with polycystic ovary syndrome (PCOS) exhibit a lower pregnancy rate, which may be related to decreased estrogen receptor (ER) expression or endometrial receptivity. We measured expression of ERα, ERß and the novel G protein-coupled ER (GPR30) in endometrium during window of implantation (WOI) in PCOS patients. Fifteen Chinese women with PCOS were compared to 15 normal subjects. Serial trans-vaginal ultrasonic scanner (TVUS) examinations detected follicular development, and endometrial thickness and pattern were assessed via TVUS on the day of ovulation. GPR30 expression was detected in the cytoplasm of endometrial epithelial cells, and was significantly lower in the PCOS group (p < 0.05). ERα and ERß expression was lower in the PCOS group, and was detected mainly in the nucleus of endometrial epithelial cells. There was no significant difference in endometrium thickness (p > 0.05), but there was a significant difference in the ultrasonic pattern (p < 0.05). Endometrial expression of GPR30, ERα and ERß was decreased during WOI in PCOS patients, and was accompanied by poor endometrial receptivity, low pregnancy rate and higher spontaneous abortions. We propose that restored receptor expression might improve endometrial receptivity and help lower infertility associated with PCOS.

A comparison of two implant systems in restoration of hip geometry in arthroplasty.

BACKGROUND: Restoration of hip offset and leg length during THA is often limited by available implant geometries. The recent introduction of femoral components with a modular junction at the base of the neck (two modular junction components) has expanded the options to restore femoral offset and leg length. QUESTIONS/PURPOSES: We asked (1) whether a femoral component with two modular junctions would predict by templating more frequent restoration of preoperative offset and leg length abnormalities than one with single modular junctions; and (2) how our use of these options compared with national sales data. PATIENTS AND METHODS: We retrospectively reviewed the preoperative templating data in 100 primary THAs using single modular junction implants with only a neutral version stem and 100 THAs using two modular junction implants. We compared the frequency with which the desired leg length and offset were completely restored by preoperative templating in the two groups. RESULTS: Offset and leg lengths were restored to within 1 mm in 85% of cases with two modular junction implants and 60% of cases with single modular junction implants. An anteverted or a retroverted neck was used in 25% of cases with the two modular junction stems. The national sales data revealed femoral neck components with version were used in 28% of cases. CONCLUSIONS: The use of a femoral component with two modular junctions resulted in more frequent ability to restore femoral offset and leg length than a single modular junction. The advantage of clinical flexibility should be tempered by the potential concerns of prosthetic mechanical failure (which has been reported in another implant system with two modular junctions), increased third-body wear and corrosive debris, and increased prosthetic cost. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Mutation of protein kinase C phosphorylation site S1076 on alpha-subunits affects BK(Ca) channel activity in HEK-293 cells.

Large conductance, calcium- and voltage-activated potassium (BK(Ca)) channels are important modulators of pulmonary vascular smooth muscle membrane potential, and phosphorylation of BK(Ca) channels by protein kinases regulates pulmonary arterial smooth muscle function. However, little is known about the effect of phosphorylating specific channel subunits on BK(Ca) channel activity. The present study was done to determine the effect of mutating protein kinase C (PKC) phosphorylation site serine 1076 (S1076) on transfected human BK(Ca) channel alpha-subunits in human embryonic kidney (HEK-293) cells, a heterologous expression system devoid of endogenous BK(Ca) channels. Results showed that mutating S1076 altered the effect of PKC activation on BK(Ca) channels in HEK-293 cells. Specifically, the phospho-deficient mutation BK(Ca)-alpha(S1076A)/beta(1) attenuated the excitatory effect of the PKC activator phorbol myristate acetate (PMA) on BK(Ca) channels, whereas the phospho-mimetic mutation BK(Ca)-alpha(S1076E)/beta(1) increased the excitatory effect of PMA on BK(Ca) channels. In addition, the phospho-null mutation S1076A blocked the activating effect of cGMP-dependent protein kinase G (PKG) on BK(Ca) channels. Collectively, these results suggest that specific putative PKC phosphorylation site(s) on human BK(Ca) channel alpha-subunits influences BK(Ca) channel activity, which may subsequently alter pulmonary vascular smooth muscle function and tone.

Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle.

Under normal physiological conditions, estrogen is a coronary vasodilator, and this response involves production of NO from endothelial cells. In addition, estrogen also stimulates NO production in coronary artery smooth muscle (CASM); however, the molecular basis for this nongenomic effect of estrogen is unclear. The purpose of this study was to investigate a potential role for the 90-kDa heat shock protein (Hsp90) in estrogen-stimulated neuronal nitric-oxide synthase (nNOS) activity in coronary artery smooth muscle. 17Beta-estradiol produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro, and this response was attenuated by inhibiting Hsp90 function with 1 microM geldanamycin (GA) or 100 microg/ml radicicol (RAD). These inhibitors also prevented estrogen-stimulated NO production in human CASM cells and reversed the stimulatory effect of estrogen on calcium-activated potassium (BK(Ca)) channels. These functional studies indicated a role for Hsp90 in coupling estrogen receptor activation to NOS stimulation in CASM. Furthermore, coimmunoprecipitation studies demonstrated that estrogen stimulates bimolecular interaction of immunoprecipitated nNOS with Hsp90 and that either GA or RAD could inhibit this association. Blocking estrogen receptors with ICI182780 (fulvestrant) also prevented this association. These findings indicate an essential role for Hsp90 in nongenomic estrogen signaling in CASM and further suggest that Hsp90 might represent a prospective therapeutic target to enhance estrogen-stimulated cardiovascular protection.

Acetabular loosening using an extended offset polyethylene liner.

UNLABELLED: The use of extended offset femoral components and acetabular liners helps restore preoperative offset during hip arthroplasty. We report a relatively high acetabular component aseptic loosening rate with the use of offset polyethylene liners. We reviewed 1919 primary and 346 revision total hip arthroplasties (THAs). A 7-mm offset acetabular liner was used in 120 of the primary and 100 of the revision THAs. The aseptic loosening rate in the primary THA group was 0.12% in the standard offset and 4.2% in the extended offset groups at a minimum of 2 years (mean, 3.6 years; range, 2-9 years) followup. The aseptic loosening rate in the revision group was 1.7% in the standard and 7% in the extended offset groups at a mean of 4 years (range, 2-9 years) followup. Although extended offset acetabular liners help restore hip offset, torsional force applied to the implant-bone interface may have a detrimental effect on fixation. We found a relatively high failure rate in our primary and revision acetabular components used with an offset liner. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Polyethylene exchange in a second-generation cementless acetabular component.

Some have suggested that isolated polyethylene exchange in a well-fixed Harris-Galante II acetabular component (Zimmer, Warsaw, Ind) necessitates cementing the liner or complete revision because the locking mechanism is suboptimal. We reviewed 29 hip revisions during which the polyethylene was exchanged using the native locking mechanism. Mean follow-up was 5.1 years (2-13 years). Of the 29 patients, one had a disengagement of the revision polyethylene at 2.5 years. At the time of this patient's original revision, one of the tines was fractured, but a direct exchange was performed. There were 4 other revisions (one for loosening and 3 for instability). There were no other complications attributable to the direct polyethylene exchange and no further reoperations. This series suggests that polyethylene exchange with the Harris-Galante II prosthesis can be performed safely using the native locking mechanism in the absence of fractured tines.

Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.

UNLABELLED: A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. PERSPECTIVE: Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.

Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation.

Epoxyeicosatrienoic acids (EETs) are considered to be endothelium-derived hyperpolarizing factors, and are potent activators of the large-conductance, Ca(2+)-activated K(+) (BK(Ca)) channel in vascular smooth muscle. Here, we investigate the signal transduction pathway involved in the activation of BK(Ca) channels by 11,12-EET and 11,12-EET stable analogs in rat mesenteric vascular smooth muscle cells. 11,12-EET and the 11,12-EET analogs, 11-nonyloxy-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE), 11-(9-hydroxy-nonyloxy)-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE-OH) and 11,12-trans-oxidoeicosa-8(Z)-enoic acid (11,12-tetra-EET-8-ZE), caused vasorelaxation of mesenteric resistance arteries. Mesenteric myocyte whole-cell (perforated-patch) currents were substantially (approximately 150%) increased by 11,12-EET and 11,12-EET analogs. Single-channel recordings were conducted to identify the target for 11,12-EET. 11,12-EET and 11,12-EET analogs also increased mesenteric myocyte BK(Ca) channel activity in cell-attached patches. Similar results were obtained in cell-free patches. Baseline mesenteric myocyte BK(Ca) channel activity (NPo) in cell-free patches averaged less than 0.001 at +50 mV and 11,12-EET (1 micromol/L) increased NPo to 0.03+/-0.02 and 11,12-EET analogs (1 micromol/L) increased NPo to 0.09+/-0.006. Inhibition of protein phosphatase 2A (PP2A) activity with okadaic acid (10 nmol/L) completely reversed 11,12-EET stimulated BK(Ca) channel activity and greatly attenuated 11,12-ether-EET-8-ZE mesenteric resistance artery vasorelaxation. 11,12-EET and 11,12-EET analogs increased mesenteric myocyte PP2A activity by 3.5-fold. Okadaic acid and the EET inhibitor, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) inhibited the 11,12-EET mediated increase in PP2A activity. These findings provide initial evidence that PP2A activity contributes to 11,12-EET and 11,12-EET analog activation of mesenteric resistant artery BK(Ca) channels and vasorelaxation.

The Importance of Economic Perspective and Quantitative Approaches in Oncology Value Frameworks of Drug Selection and Shared Decision Making.

The debate around value in oncology drug selection has been prominent in recent years, and several professional bodies have furthered this debate by advocating for so-called value frameworks. Herein, we provide a viewpoint on these value frameworks, emphasizing the need to consider 4 key aspects: (1) the economic underpinnings of value; (2) the importance of the perspective adopted in the valuation; (3) the importance of the difference between absolute and relative measures of risk and measuring patient preferences; and (4) the recognition of multiple quality-of-life (QoL) domains, and the aggregation and valuation of those domains, through utilities within a multicriteria decision analysis, may allow prioritization of QoL above the tallying of safety events, particularly in a value framework focusing on the individual patient. While several frameworks exist, they incorporate different attributes and-importantly-assess value from alternative perspectives, including those of patients, regulators, payers, and society. The various perspectives necessarily lead to potentially different, if not sometimes divergent, conclusions about the valuation. We show that the perspective of the valuation affects the framing of the risk/benefit question and the methodology to measure the individual patient choice, or preference, as opposed to the collective, or population, choice. We focus specifically on the American Society of Clinical Oncology (ASCO) Value Framework. We argue that its laudable intent to assist in shared clinician-patient decision making can be augmented by more formally adopting methodology underpinned by micro- and health economic concepts, as well as application of formal quantitative approaches. Our recommendations for value frameworks focusing on the individual patient, such as the ASCO Value Framework, are 3-fold: (1) ensure that stakeholders understand the importance of the adopted (economic) perspective; (2) consider using exclusively absolute measures of risk and formal patient-preference methodology; and (3) consider foregoing safety parameters for higher-order utility considerations. DISCLOSURES: No funding was received for conceptualizing, writing, and/or editing this manuscript. Waldeck and White are employees of, and received stock option grants from, Celldex Therapeutics. Van Hout and Botteman are employees and shareholders of Pharmerit International. Pharmerit International is a research contractor for Celldex. All authors have retained editorial control of the content of the manuscript. Conceptualization of this viewpoint article was contributed primarily by Waldeck, along with Botteman, White, and van Hout. Data analysis and revision of the manuscript was contributed equally by all the authors. The manuscript was written by Waldeck, Botteman, van Hout, and White.