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Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have declined in recent decades. In contrast, there has been a steady increase in the incidence of CRC in individuals under 50 years of age. Hereditary syndromes contribute disproportionately to early onset CRC (EOCRC). These include microsatellite instability high (MSI+) tumors arising in patients with Lynch Syndrome. However, most EOCRCs are not associated with familial syndromes or MSI+ genotypes. Comprehensive genomic profiling has provided the basis of improved more personalized treatments for older CRC patients. However, less is known about the basis of sporadic EOCRC. To define the genomic landscape of EOCRC we used DNA content flow sorting to isolate diploid and aneuploid tumor fractions from 21 non-hereditary cases. We then generated whole exome mutational profiles for each case and whole genome copy number, telomere length, and EGFR immunohistochemistry (IHC) analyses on subsets of samples. These results discriminate the molecular features of diploid and aneuploid EOCRC and provide a basis for larger population-based studies and the development of effective strategies to monitor and treat this emerging disease. [ABSTRACT FROM AUTHOR]

With heightened concerns on carbon dioxide (CO2) emissions from coal power plants, there has been a major emphasis in recent years on development of safe and economical geological carbon sequestration (GCS) technology. However, the detailed multiphase fluid dynamics and processes of GCS are not fully understood because various CO2 trapping mechanisms in geological formations have large variations in both spatial and temporal scales. As a result, there remain many uncertainties in determining the sequestration capacity of the reservoir and the safety of sequestered CO2 due to leakage. Furthermore, the sequestration efficiency is highly dependent on the CO2 injection strategy, which includes injection rate, injection pressure, and type of injection well, and its orientation, etc. The goal of GCS is to maximize the sequestration capacity and minimize the plume migration by optimizing the GCS operation. In this paper, first the basic fluid dynamics and trapping mechanisms for CO2 sequestration are briefly discussed. They are followed by a brief summary of current GCS projects worldwide with special emphasis on those in the United States. Majority of the paper is devoted to the numerical modeling, simulation, and optimization of CO2 sequestration in saline aquifers at macro spatial scales of a few to hundreds of kilometers and macro temporal scales of a few to hundreds of years. Examples of numerical simulations of a few large industrial scale projects are presented. The optimization studies include the investigation of various injection and well placement strategies to determine the optimal approach for maximizing the storage and minimizing the plume migration. [ABSTRACT FROM AUTHOR]

The FASB has asserted, without proof, that information about an enterprise's earnings based on accrual accounting generally provides a better indication of a company's ability to generate favorable cash flows than information about cash flows themselves. This study tests that assertion, empirically. The test results provide empirical evidence supporting the FASB's contention. [ABSTRACT FROM AUTHOR]

Background: TAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan.Methods: CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count < 1500/mm(3)). Patients had confirmed mCRC that was refractory to standard therapies. Patient demographics and clinical characteristics were compared between patients with CIN-1-month (CIN-1-month positive) versus those who did not have CIN-1-month (CIN-1-month negative); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test.Results: Our cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1-month mark. Patients who developed ≥ grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P-value = 0.01), as well as OS (14.0 versus 5.6 months; Log-rank P-value < 0.0001). Only CIN-1-month (adjusted HR: 0.21 (95 % CI: 0.11-0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95 % CI: 1.22-3.35) were noted to be independent predictors of OS. Furthermore, the CIN-1-month was noted to be a statistically significantly predictor of OS over a wide range of cutoffs.Conclusions: Our observations are novel and hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. It can be postulated that the dosage of TAS-102 potentially may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Further pharmacologic investigations should help elucidate these issues. [ABSTRACT FROM AUTHOR]

This study examines the unintended effects of a pre-Reg FD practice that gave a broad group of sophisticated market participants 15-minute earlier access to all corporate press releases than the general public. We find that roughly one-eighth of the price discovery to earnings announcements issued during regular trading hours was due to privileged access to information in earnings press releases, with the 15-minute priority dissemination contributing to just over 50 percent of price discovery from all privileged access. In addition, we find that transient institutions benefited from priority dissemination, especially when the earnings contained good news. Finally, consistent with economic theory, we find that intraday bid-ask spreads decreased post-Reg FD for firms that had sufficient market liquidity to allow trading opportunities during the 15-minute window. Our study has implications for current discussions on whether preferential information distribution by firms and information intermediaries creates an uneven playing field among investors. [ABSTRACT FROM AUTHOR]

Using data from the EDGAR era, we find a significant market reaction surrounding quarterly periodic reports only when their filing coincides with the first public disclosure of earnings, although that for 10-K reports is not subsumed by earnings releases. However, after eliminating incidence of concurrent earnings releases, the 10-K market reaction is restricted to a quarter of the reports that are filed around calendar quarter-ends. The calendar quarter-end price and volume effects are unrelated to the filing of periodic reports and are not explained by self-selection. However, while the quarter-end volume reaction is indistinguishable between filers and non-filers, we find an incremental price reaction to 10-K filings at calendar quarter-ends in recent times. We provide evidence that the calendar-time effect is partially due to an intra-industry information transfer that is a function of the incidence of 10-K reports at quarter-ends. Finally, equity analyst reactions are muted around periodic filings, with no evidence that they contribute to quarter-end information transfer. [ABSTRACT FROM AUTHOR]

New agents for the treatment of metastatic colorectal cancer have extended median overall survival to more than 20 months, an increase that has changed the view of advanced colorectal cancer from an acute to a chronic condition. This article proposes a shift in treatment strategy from the concept of successive "lines" of therapy, in which chemotherapy is continued until disease progression, to that of a continuum of care, in which the use of chemotherapy is tailored to the clinical setting and includes switching chemotherapy prior to disease progression, maintenance therapy, drug "holidays," and surgical resection of metastases in selected patients. In this approach, the distinction between lines of therapy is no longer absolute. This represents a paradigm shift in the management of metastatic colorectal cancer to that of a continuum of care approach that includes individualized planning, in which patients are given the opportunity to benefit from exposure to all active agents and modalities while minimizing unnecessary treatment and toxicity, with the ultimate goal of improving survival as well as quality of life. [ABSTRACT FROM AUTHOR]

The article presents a discussion paper focusing on reports issued by associations such as the International Accounting Standards Board (IASB) concerning financial accounting and reporting standards. The discussion paper was authored by the American Accounting Association's Financial Accounting Standards Committee. The report points out that in many IASB countries public and private firms are subject to the same accounting standards. In the United States however, private firms are not subject to the Generally Accepted Accounting Principles (GAAP) that public firms must comply with. The authors question whether it is necessary for private firms to use something other than GAAP, arguing that GAAP would be useful for private firms as well. The authors leave open the possibility of another standards setting body creating rules for private firms.

This article discusses a theory of vehicle and nonvehicle currency trade in the U.S. Vehicle and nonvehicle currencies are two types of currencies in the pricing of internationally traded goods. When the currency of the exporter or the importer is used, non-vehicle currency pricing occurs while vehicle currency pricing occurs if a third currency is used. In fact, the dollar is not even a major nonvehicle currency for the U.S. trade with some of its developed country trading partners. Major-minor currency pricing relationships occur among countries with strong and weak currencies, respectively, while symmetric currency pricing occurs for countries with convertible currencies and equal inflation risk. The dollar is considered as an important vehicle role or standard of value in certain product markets. The vehicle role of the dollar as a standard of deferred payment has been emphasized. In effect, the contribution of the change in an exporter's output price to the variance of a firm's cash flow is more than equivalent variance in an importer's purchasing costs. The exchange risk is shifted to importers due to differential preference of exporters for contracting in their home currency.

To study the dividend payouts of private firms we extend the agency cost/external financing cost trade-off model of dividend payouts to include the accumulated earnings tax (AET). The firm's optimal dividend policy trades off the benefits from lower agency costs against external financing costs and the AET. Information from tax court records reveals that private firms' payouts are influenced by both agency costs and the AET. [ABSTRACT FROM AUTHOR]

The evaluation of historical water use in the Upper Rio Grande Basin (URGB), United States and Mexico, using Landsat-derived actual evapotranspiration (ETa) from 1986 to 2015 is presented here as the first study of its kind to apply satellite observations to quantify long-term, basin-wide crop consumptive use in a large basin. The rich archive of Landsat imagery combined with the Operational Simplified Surface Energy Balance (SSEBop) model was used to estimate and map ETa across the basin and over irrigated fields for historical characterization of water-use dynamics. Monthly ETa estimates were evaluated using six eddy-covariance (EC) flux towers showing strong correspondence (r2 > 0.80) with reasonable error rates (root mean square error between 6 and 19 mm/month). Detailed spatiotemporal analysis using peak growing season (June–August) ETa over irrigated areas revealed declining regional crop water-use patterns throughout the basin, a trend reinforced through comparisons with gridded ETa from the Max Planck Institute (MPI). The interrelationships among seven agro-hydroclimatic variables (ETa, Normalized Difference Vegetation Index (NDVI), land surface temperature (LST), maximum air temperature (Ta), potential ET (ETo), precipitation, and runoff) are all summarized to support the assessment and context of historical water-use dynamics over 30 years in the URGB. [ABSTRACT FROM AUTHOR]

Presents a personal computer-based analysis system for turbomachinery vibration from Virginia Tech University in Blacksburg, Virginia. Background on rotor dynamics; Features of the system.

Background: Emergency medical services (EMS) often serve as the first medical contact for ill or injured patients, representing a critical access point to the health care delivery continuum. While a growing body of literature suggests inequities in care within hospitals and emergency departments, limited research has comprehensively explored disparities related to patient demographic characteristics in prehospital care., Objective: We aimed to summarize the existing literature on disparities in prehospital care delivery for patients identifying as members of an underrepresented race, ethnicity, sex, gender, or sexual orientation group., Methods: We conducted a scoping review of peer-reviewed and non-peer-reviewed (gray) literature. We searched PubMed, CINAHL, Web of Science, Proquest Dissertations, Scopus, Google, and professional websites for studies set in the U.S. between 1960 and 2021. Each abstract and full-text article was screened by two reviewers. Studies written in English that addressed the underrepresented groups of interest and investigated EMS-related encounters were included. Studies were excluded if a disparity was noted incidentally but was not a stated objective or discussed. Data extraction was conducted using a standardized electronic form. Results were summarized qualitatively using an inductive approach., Results: One hundred forty-five full-text articles from the peer-reviewed literature and two articles from the gray literature met inclusion criteria: 25 studies investigated sex/gender, 61 studies investigated race/ethnicity, and 58 studies investigated both. One study investigated sexual orientation. The most common health conditions evaluated were out-of-hospital cardiac arrest (n = 50), acute coronary syndrome (n = 36), and stroke (n = 31). The phases of EMS care investigated included access (n = 55), pre-arrival care (n = 46), diagnosis/treatment (n = 42), and response/transport (n = 40), with several studies covering multiple phases. Disparities were identified related to all phases of EMS care for underrepresented groups, including symptom recognition, pain management, and stroke identification. The gray literature identified public perceptions of EMS clinicians' cultural competency and the ability to appropriately care for transgender patients in the prehospital setting., Conclusions: Existing research highlights health disparities in EMS care delivery throughout multiple health outcomes and phases of EMS care. Future research is needed to identify structured mechanisms to eliminate disparities, address clinician bias, and provide high-quality equitable care for all patient populations.

Purpose of Review: The regulatory framework set by the Organ Procurement and Transplantation Network (OPTN) and Center for Medicare and Medicaid Services (CMS) for practice of liver transplantation in US is periodically updated and risk adjusted. Therefore, it is prudent for transplant centers to know the rules of engagement as it pertains to their practice., Recent Findings: OPTN besides providing the regulatory oversight for safe and continued practice of transplant centers, provides necessary tools like: advanced statistical models and technological platforms to aid, and guide transplant centers including the necessary safeguards for high-quality transplant care.CMS regulations although had different thresholds to flag underperformance, often covered common grounds similar to the OPTN, therefore considered duplicative and unnecessary. But with much deliberation and consideration CMS undertook a major overhaul to the final rule for re-approval applications, a giant leap in the positive direction for transplant innovation and growth., Summary: The duplicative regulatory framework of OPTN and CMS has although achieved the goal of improving 1-year patient outcomes, it has proven costly in terms of slowing innovation, increasing organ discard and stunting growth of transplant volume. But the new updates in effect and also in the pipeline are a long-awaited opportunity for waiting transplant patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Recent studies have demonstrated that racial differences can influence breast cancer incidence and survival rate. African American (AA) women are at two to three fold higher risk for breast cancer than other ethnic groups. AA women with aggressive breast cancers show worse prognoses and higher mortality rates relative to Caucasian (CA) women. Over the last few years, effective treatment strategies have reduced mortality from breast cancer. Unfortunately, the breast cancer mortality rate among AA women remains higher compared to their CA counterparts. The focus of this review is to underscore the racial differences and differential regulation/expression of genetic signatures in CA and AA women with breast cancer. Moreover, immune cell infiltration significantly affects the clinical outcome of breast cancer. Here, we have reviewed recent findings on immune cell recruitment in the tumor microenvironment (TME) and documented its association with breast cancer racial disparity. In addition, we have extensively discussed the role of cytokines, chemokines, and other cell signaling molecules among AA and CA breast cancer patients. Furthermore, we have also reviewed the distinct genetic and epigenetic changes in AA and CA patients. Overall, this review article encompasses various molecular and cellular factors associated with breast cancer disparity that affects mortality and clinical outcome.

Recombinant drug products successfully treat many life-threatening and chronic diseases. The high cost of these drugs makes them inaccessible to the patients particularly in developing countries. Patent expiration of innovator recombinant drug products has led to the development of biosimilars or similar biologics by several manufacturers. Unlike generics, these are not identical to their innovator products because of the differences in the manufacturing process; however, they are similar in quality characteristics, biological activity, safety, and efficacy. The regulatory procedures used for generic drugs cannot be applied for biosimilars as they are large complex structures produced from living cells and can produce potential risk of immune-based adverse reactions. Out of several safety issues related to biosimilars, two main safety concerns are variable potency and immunogenicity, for which a robust long-term pharmacovigilance system is needed. Various guidelines have been issued for the regulatory approval and pharmacovigilance of biosimilars by USFDA, EU, and pharma-emerging countries like China and India. The article includes the pharmacovigilance plan of biosimilars in these countries, discusses the challenges and opportunities in pharmacovigilance through spontaneous reporting systems, and suggests amendments in the existing suspected adverse event reporting form of the Pharmacovigilance Programme of India.

Community-associated acquisition of extended-spectrum beta-lactamase- (ESBL) and carbapenemase-producing Enterobacteriaceae has significantly increased in recent years, necessitating greater inquiry into potential exposure routes, including food and water sources. In high-income countries, drinking water is often neglected as a possible source of community exposure to antibiotic-resistant organisms. We screened coliform-positive tap water samples (n = 483) from public and private water systems in six states of the United States for bla CTX-M , bla SHV , bla TEM , bla KPC , bla NDM , and bla OXA-48 -type genes by multiplex PCR. Positive samples were subcultured to isolate organisms harboring ESBL or carbapenemase genes. Thirty-one samples (6.4%) were positive for bla CTX-M , ESBL-type bla SHV or bla TEM , or bla OXA-48 -type carbapenemase genes, including at least one positive sample from each state. ESBL and bla OXA-48 -type Enterobacteriaceae isolates included E. coli, Kluyvera, Providencia, Klebsiella, and Citrobacter species. The bla OXA-48 -type genes were also found in non-fermenting Gram-negative species, including Shewanella, Pseudomonas and Acinetobacter. Multiple isolates were phenotypically non-susceptible to third-generation cephalosporin or carbapenem antibiotics. These findings suggest that tap water in high income countries could serve as an important source of community exposure to ESBL and carbapenemase genes, and that these genes may be disseminated by non-Enterobacteriaceae that are not detected as part of standard microbiological water quality testing.

Central obesity is a known cardiovascular risk factor and measures of visceral obesity are known to predict atherosclerosis. This study sought to explore the association between various anthropometric measures and markers of subclinical atherosclerosis (MoSCA) among low risk healthy individuals. Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of Caucasian (38%), Afro-American (28%), Chinese (22%) and Hispanic (12%) subjects, aged 45-84 years, free from clinical cardiovascular disease. We performed a post hoc analysis of the limited access dataset of MESA subjects to evaluate the association between carotid intima media thickness and coronary artery calcium score (CACS), as MoSCA and various measures of obesity. Multivariable regression analyses adjusted for traditional cardiovascular risk factors, ethnicity and C-reactive protein were performed. Each unit increase in waist-hip ratio was strongly associated with increase in both common and internal carotid intima media thickness (beta: 0.12, 95% confidence interval (CI): 0.06 to 0.18, p < 0.001 and beta: 0.23, 95% CI: 0.03 to 0.43, p = 0.021, respectively). Measures of central obesity were superior to body mass index as demonstrated by their consistent association with each category of CACS when compared to the reference category (CACS = 0). Compared to body mass index, measures of visceral obesity were significantly associated with MoSCA in this multiethnic healthy population. Waist-hip ratio seems to be more consistent in its association with various MoSCA compared to other anthropometric measures.

Background: For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine., Methods: Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m(2)doses×3, plus gemcitabine, weekly 200 mg/m(2) doses×4 starting 1 week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated., Results: Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1 year., Conclusions: Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic adenocarcinoma, even when resectable, remains highly lethal. Although surgical outcomes have improved considerably, median overall survival after surgery and adjuvant therapy such as single-agent gemcitabine remains less than 2 years. We discuss preclinical and clinical data supporting the contention that even early-stage pancreatic cancer is a systemic disease. Autopsy series reveal that 70% to 85% of patients die of systemic recurrence, rather than local disease, after pancreatic cancer resection. Preclinical studies using genomics and mouse models reveal evidence of metastatic spread even before histopathologic evidence of a pancreatic tumor. Analogous to breast cancer, we propose that the Halstedian approach of treating pancreatic cancer as a local, surgical problem should be replaced by Fisher's alternative hypothesis of cancer as a systemic disease. Newer multiagent chemotherapy regimens have shown meaningful response rates and improvement in overall survival in the metastatic setting and, for the first time, offer investigators an opportunity to use effective systemic therapy. We emphasize that a surgery-first approach is not resonant with our current understanding of pancreatic adenocarcinoma biology and that an upfront systemic approach for even resectable pancreatic cancer warrants testing in clinical trials.

Introduction: We sought to evaluate the ability of various metabolic syndrome definitions in predicting primary cardiovascular disease (CVD) outcomes in a vast multiethnic U.S. cohort., Methods: This study included 6,814 self-identified men and women aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) study. Gender-stratified analyses were performed to calculate hazard ratios of CVD, stroke, and mortality associated with various metabolic syndrome definitions and their individual constructs., Results: The hazard ratios [95% confidence interval (CI)] for all-cause CVD in men were 2.90 (2.18-3.85), 2.64 (1.98-3.51), 2.16 (1.62-2.88), 2.56 (1.91-3.44), 1.82 (1.35-2.46), and 2.92 (2.15-3.95) for the National Cholesterol Education Program (NCEP), American Heart Association (AHA), World Health Organization (WHO), International Diabetes Federation (IDF), European Group for the Study of Insulin Resistance (EGIR), and the newly defined consensus criteria. Hazard ratios in women were 2.11 (1.41-3.15), 2.17 (1.45-3.27), 2.04 (1.37-3.06), 1.91 (1.27-2.88), 1.85 (1.23-2.79), and 2.08 (1.37-3.14), respectively. Metabolic syndrome was strongly associated with stroke risk only in males. In men, all constitutive metabolic syndrome components were continuously and strongly associated with CVD. In women, high-density lipoprotein and triglycerides did not appear to be associated with short term CVD risk., Conclusion: We found the newly defined consensus criteria for metabolic syndrome to be similarly predictive of cardiovascular events when compared to existing definitions. Significant gender differences exist in the association between metabolic syndrome, its individual components, and CVD.

Background: Metabolic syndrome poses a significant risk for cardiovascular disease. Recently, glycosylated hemoglobin (HbA1c) has been included in the diagnostic criteria for diabetes mellitus and prediabetes. We sought to determine if HbA1c is associated with prevalent metabolic syndrome in nondiabetic U.S. adults., Methods: A total of 9,022 nondiabetic participants of National Health and Nutrition Examination Surveys 1999-2008 (age, 47.5 ± 18.3 years, 51% females) were divided into quintiles (Q) of HbA1c: Q1 (reference), ≤5%; Q2, 5.1%-5.3%; Q3, 5.4%-5.5%; Q4, 5.6%-5.7%; and Q5, ≥5.8%. Modified National Cholesterol Education Program Adult Treatment Panel III criteria were used to identify metabolic syndrome (n=2,821; 31.3%). Unadjusted and adjusted multivariate logistic regression analysis was performed to assess the risk of metabolic syndrome., Results: A graded increase in odds of having prevalent metabolic syndrome with increase from each quintile of HbA1c compared to Q1 was observed after adjusting for age, sex, race, body mass index (BMI), total cholesterol, lipid-lowering therapy, current smoking, family history of diabetes, C-reactive protein, and fasting insulin. Stratified analysis based on gender, ethnicity, and BMI showed similar results. The HbA1c value of ≥5.4% remained appropriate cutoff for predicting metabolic syndrome in Caucasians and Hispanics, whereas ≥5.6% provided the best accuracy for African Americans based on receiver operating characteristics analysis., Conclusion: HbA1c much below the level for prediabetes was associated with prevalence of the metabolic syndrome in a cohort of nondiabetic U.S. adults. HbA1c can be considered as a surrogate marker for metabolic syndrome in nondiabetics.

Realistic modeling of the interaction between surgical instruments and organs has been recognized as a key requirement in the development of high-fidelity surgical simulators. For a nonlinear model, the well-known Poynting effect developed during shearing of the tissue results in normal forces not seen in a linear elastic model. It is demonstrated that the difference in force magnitude for myocardial tissue is larger than the just noticeable difference for contact force discrimination thresholds published in the psychophysics literature. This work also proposes the validation of simulators by careful examination of relevant simulator design parameters that relate to final simulator behaviors affecting clinical outcomes.

CYP3A4-V, an A to G promoter variant associated with prostate cancer in African Americans, exhibits large differences in allele frequency between populations. Given that the African American population is genetically heterogeneous because of its African ancestry and subsequent admixture with European Americans, case-control studies with African Americans are highly susceptible to spurious associations. To test for association with prostate cancer, we genotyped CYP3A4-V in 1376 (2 N) chromosomes from prostate cancer patients and age- and ethnicity-matched controls representing African Americans, Nigerians, and European Americans. To detect population stratification among the African American samples, 10 unlinked genetic markers were genotyped. To correct for the stratification, the uncorrected association statistic was divided by the average of association statistics across the 10 unlinked markers. Sharp differences in CYP3A4-V frequencies were observed between Nigerian and European American controls (0.87 and 0.10, respectively; P<0.0001). African Americans were intermediate (0.66). An association uncorrected for stratification was observed between CYP3A4-V and prostate cancer in African Americans (P=0.007). A nominal association was also observed among European Americans (P=0.02) but not Nigerians. In addition, the unlinked genetic marker test provided strong evidence of population stratification among African Americans. Because of the high level of stratification, the corrected P-value was not significant (P=0.25). Follow-up studies on a larger dataset will be needed to confirm whether the association is indeed spurious; however, these results reveal the potential for confounding of association studies by using African Americans and the need for study designs that take into account substructure caused by differences in ancestral proportions between cases and controls.