Use of whole-genome sequence data and novel genomic selection strategies to improve selection for age at puberty in tropically-adapted beef heifers.

BACKGROUND: In tropically-adapted beef heifers, application of genomic prediction for age at puberty has been limited due to low prediction accuracies. Our aim was to investigate novel methods of pre-selecting whole-genome sequence (WGS) variants and alternative analysis methodologies; including genomic best linear unbiased prediction (GBLUP) with multiple genomic relationship matrices (MGRM) and Bayesian (BayesR) analyses, to determine if prediction accuracy for age at puberty can be improved. METHODS: Genotypes and phenotypes were obtained from two research herds. In total, 868 Brahman and 960 Tropical Composite heifers were recorded in the first population and 3695 Brahman, Santa Gertrudis and Droughtmaster heifers were recorded in the second population. Genotypes were imputed to 23 million whole-genome sequence variants. Eight strategies were used to pre-select variants from genome-wide association study (GWAS) results using conditional or joint (COJO) analyses. Pre-selected variants were included in three models, GBLUP with a single genomic relationship matrix (SGRM), GBLUP MGRM and BayesR. Five-way cross-validation was used to test the effect of marker panel density (6 K, 50 K and 800 K), analysis model, and inclusion of pre-selected WGS variants on prediction accuracy. RESULTS: In all tested scenarios, prediction accuracies for age at puberty were highest in BayesR analyses. The addition of pre-selected WGS variants had little effect on the accuracy of prediction when BayesR was used. The inclusion of WGS variants that were pre-selected using a meta-analysis with COJO analyses by chromosome, fitted in a MGRM model, had the highest prediction accuracies in the GBLUP analyses, regardless of marker density. When the low-density (6 K) panel was used, the prediction accuracy of GBLUP was equal (0.42) to that with the high-density panel when only six additional sequence variants (identified using meta-analysis COJO by chromosome) were included. CONCLUSIONS: While BayesR consistently outperforms other methods in terms of prediction accuracies, reasonable improvements in accuracy can be achieved when using GBLUP and low-density panels with the inclusion of a relatively small number of highly relevant WGS variants.

Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group.

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.

Globular and Fibrous Proteins Modified with Deep Eutectic Solvents: Materials for Drug Delivery.

Proteinaceous materials have numerous structures, many of which aid in the roles they perform. Some need to impart strength while others need elasticity or toughness. This study is the first to investigate the modification of both globular and fibrous protein, namely, zein, soy protein and gelatin, using deep eutectic solvents (DES) to form bioplastics, which may have application in drug delivery systems. The effects of DES content on the thermal and mechanical properties of the material were determined. Zein and soy are globular proteins, which both showed a significant change in the properties by the addition of DES. Both of these materials were, however, weaker and less ductile than the starch based materials previously reported in the literature. The material made from gelatin, a fibrous protein, showed variable properties depending on how long they were in contact with each other before pressing. Conductivity and NMR measurements indicate the existence of a continuous liquid phase, which are useful in the demonstrated application of transdermal drug delivery systems. It is shown that pharmaceutical DESs can be gelled with gelatin and this method is three times faster at delivering a pharmaceutical active ingredient across the skin barrier than from a corresponding solid formulation.

The effect of smoking on open carpal tunnel release recovery.

INTRODUCTION: This study examines the relationship between smoking status and surgical outcomes in open carpal tunnel release. Smoking status has previously been correlated with orthopedic surgical complications unless smoking cessation occurs at least 4 weeks prior to surgery; however, the effect of smoking on open carpal tunnel release has not been specifically examined. METHODS: This study is a retrospective review of patient charts over the last 5 years (n = 131). Smoking status was determined at the time of carpal tunnel release from the patients' charts. Patients were dichotomized as smokers (n = 58) or non-smokers (n = 73). Data comprised preoperative pain, postoperative pain at 2 and 6 weeks, postoperative wrist stiffness, wound healing time, and infection status. Data were compared on chi square, Fisher exact, and one-sided Fisher exact tests. RESULTS: Infection rates were significantly higher in smokers. Postoperative numbness and wrist stiffness were also significantly higher in smokers. Smokers reported higher postoperative pain scores at 2 and 6 weeks. Non-smokers were also significantly more likely to report complete pain resolution at 6 weeks. DISCUSSION: In the present study smoking was associated with surgical outcome complications in open carpal tunnel release. This could be attributed to immune system suppression or to poor wound healing, both of which are known side-effects of smoking. Pain scores 6 weeks post-surgery were significantly higher in smokers than in non-smokers. Smokers undergoing open carpal tunnel release need to understand the risk of surgical complications and should consider smoking cessation to optimize their chances of successful surgery. CONCLUSION: Patients who were active smokers showed poorer recovery from open carpal tunnel surgery than non-smoking patients.

The Effects of Ultrasound-Guided Percutaneous Tenotomy on Patients' Pain and Satisfaction Levels.

INTRODUCTION: Tendinopathy is a common pathology with numerous treatment options. Ultrasound-guided percutaneous tenotomy is a newer procedure to treat chronic tendinopathy. It reduces costs and risks compared to other treatments, such as open surgery and platelet-rich plasma (PRP) injections. The goal of percutaneous tenotomy is to induce an acute inflammatory response that recruits clotting and growth factors, induces bleeding, and transforms scar tissue and diseased tendons into a healing state. METHODS: A tenotomy was performed in 57 patients for elbow epicondylitis (13), supraspinatus tendonitis (4), gluteal tendinopathy (34), and patellar tendinopathy (5). The survey was created and sent electronically to all 57 patients, yielding 46 respondents. Each patient was surveyed postoperatively to determine their pain levels on a numeric scale from 1 to 10 prior to and following the procedure. We also asked patients about their satisfaction with the procedure, whether they would recommend it to a friend, and how long it took them to recover completely. RESULTS: Forty-six of 57 patients responded to the survey. The average healing time was 58 days, and no patients required further surgery. Pain scores significantly improved after tenotomies in the shoulder, elbow, and hip. About 74% of patients were completely satisfied with the procedure, and 80% received enough benefit to recommend it to a friend. CONCLUSIONS: Ultrasonic tenotomy provides significant relief for tendinopathy in the shoulder, elbow, and hip for the majority of patients. The knee pain scores were not significantly reduced, likely due to the small sample size of four patients. Some patients did not experience complete relief and benefited from a PRP injection after tenotomy. Some patients did not benefit, likely due to additional pathology, arthritis, and referred pain. Some limitations to our study include the lack of a control group and each procedure was performed by the same physician, which limits its generalizability. The survey responses were subjective, and the sample size was variable between each body region. More high-quality research is needed to establish the efficacy of tenotomy between different tendons and compare it to other treatment methods.

State Variation in Medicare Reimbursement for the Top 100 Cardiothoracic Surgery Procedures, 2013-2022.

Objective We analyzed changes in reimbursement rates for cardiothoracic surgery procedures from 2013 to 2022 to identify interstate variance and compare changes in reimbursement between procedural groups. Methods The Center for Medicare and Medicaid Services database was analyzed to find the 100 highest-grossing cardiothoracic surgery CPT codes from 2013 to 2022. Medicare Administrative Contractor codes were utilized to identify reimbursement for each state. The payments were adjusted for inflation utilizing the consumer price index. Procedures were weighted according to revenue, and an average yearly, inflation-adjusted percent change in reimbursement was generated for each U.S. state. Procedural groups were compared using single-factor ANOVA and post-hoc tests. Results Since 2013, the inflation-adjusted Medicare reimbursement for the top cardiothoracic surgery procedures for all U.S. states and territories decreased by a yearly average of 2.67%. Puerto Rico (-0.33%), Louisiana (-1.84%), and Alabama (-1.85%) showed the smallest change. Illinois (-3.62%), Kansas (-3.40%), and Wyoming (-3.22%) had the greatest decrease in reimbursement throughout the observed period. Pacemaker and defibrillator (mean: -20.85), valvular (-22.07%), and coronary artery bypass graft (CABG) surgery (-21.99%) procedural groups demonstrated significant differences between valvular (p=0.01) or CABG (p=0.02) and pacemaker and defibrillator. Conclusions Our study confirms that reimbursement patterns vary by geographical area. Second, geographic variation suggests an incentive for physicians to practice in states with higher Medicare reimbursement. Certain procedural groups have been affected more than others. New lobbying strategies may be needed to mitigate diminishing reimbursement so that quality of care is not impacted for Medicare beneficiaries in low reimbursement states.

Changes in Medicare Reimbursement for Top Burn Surgery Procedures by State Between 2011 and 2022.

This study analyzed the geographic variation in annual Medicare reimbursement changes for common burn surgery procedures from 2011 to 2022 to clarify trends in reimbursement. The Center for Medicare and Medicaid Services' Physician fee schedule database was analyzed to find state-by-state reimbursement rates for the most common burn surgery procedures. Physician reimbursement was adjusted for inflation utilizing the consumer price index. Procedures were weighted according to frequency, and an inflation-adjusted percent change was identified for each state. Since 2011, the inflation-adjusted Medicare reimbursement for the top burn surgery procedures for all U.S. states decreased by a yearly average of 2.67%. Washington (-2.17%), New York (-2.31%), Oregon (-2.33%), and the District of Columbia (-2.35%) showed the smallest annual percent change. Illinois (-3.34%), Mississippi (-3.04%), Idaho (-2.99%), and Michigan (-2.96%) were the states with the greatest annual decrease. The most common procedures included initial treatment of burns (16000), burn dressing and debridement (16020, 16025, 16030), and burn eschar incision (16035). Medicare reimbursement for burn surgery procedures decreased from 2011 to 2022. The geographic variance in reimbursement patterns may incentivize physicians to pursue other surgical specialties or practice in certain areas which could limit access to care in low reimbursement areas. Further research is needed to examine disparities that may have arisen due to decreasing reimbursement over the last decade. New action is also needed to moderate diminishing burn surgery reimbursement to ensure quality care for Medicare beneficiaries in low-reimbursement states.

Influence of colourants on environmental degradation of plastic litter.

Plastic degradation and the resultant production of microplastics has an important effect on the environment and fauna across the world. This paper shows that the colourant incorporated into plastic formulations has a significant effect on the stability of plastics. A static experimental exposure of differently coloured polypropylene bottle tops from the same manufacturer to a moderate climate over 3 years showed that black, white and silver plastics were almost unaffected whereas the specific blue, green and especially red pigments used in this study were significantly degraded. The second part of the study collected littered HDPE plastic containers from a remote South African beach and analysed their condition as a function of the given manufacturing date stamp. Most items were black or white and samples up to 45 years old were found with relatively little environmental degradation other than mild abrasion. It appears that carbon and titanium dioxide colourants protect the HDPE polymer from photolytic degradation. While anthraquinone, phthalocyanine and diketopyrrolopyrrole pigments were found to enable UV light to degrade the polymer leading to brittle plastics, promoting the formation of microplastics, it is likely that other pigments that do not strongly absorb in the UV will result in similar degradation.

The Effect of Body Mass Index on Open Carpal Tunnel Release Recovery.

Purpose: The purpose of this study was to determine whether a relationship exists between body mass index (BMI), specifically obesity, and surgical outcomes for open carpal tunnel release. Obesity is correlated with increased incidence of carpal tunnel syndrome; however, the effect of obesity on after release recovery has not been examined. Methods: This study used a retrospective review of patient charts (n = 142). BMI was calculated based on height and weight measurements, and patients were grouped based on their BMI into the following categories: healthy BMI (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obesity class one (30-34.9 kg/m2) (OB1), obesity class (2 35-39.9 kg/m2) (OB2), or obesity class three (40+ kg/m2) (OB3). Data were then complied on surgical outcomes by assessing preoperative pain, postoperative pain at 2 and 6 weeks, postoperative joint stiffness, wound healing time, and infection status. Data were analyzed using chi-square analyses and multivariable logistic regression to assess the differences in treatment outcomes while controlling for possible confounding variables. Results: Age at the time of release was found to be inversely correlated with BMI. Healthy BMI patients (n = 19) underwent release at an average age of 59.1 years, whereas OB3 (n = 30) underwent release at an average age of 46.9 years. The odds of improvement in pain were significantly lower in all three obesity groups when compared with healthy BMI at both 2 and 6 weeks after operation. Conclusions: Our results indicate that obesity may be positively correlated with earlier incidence of carpal tunnel syndrome requiring surgical intervention. These data also indicate the increased rates of postoperative complications in obese patients, particularly patients with OB3. Patients with OB3 need to understand these risks before undergoing open release. Further study should examine the impact of type 2 diabetes on carpal tunnel release recovery. Clinical relevance: The information included in this study may be used to guide surgeons and patients when considering the effect and potential improvement in outcomes that may come from addressing patient BMI before open carpal tunnel surgery.

Fully-modelled blood-focused variable inversion times for 3D late gadolinium-enhanced imaging.

PURPOSE: Variable heart rate during single-cycle inversion-recovery Late Gadolinium-Enhanced (LGE) scanning degrades image quality, which can be mitigated using Variable Inversion Times (VTIs) in real-time response to R-R interval changes. We investigate in vivo and in simulations an extension of a single-cycle VTI method previously applied in 3D LGE imaging, that now fully models the longitudinal magnetisation (fmVTI). METHODS: The VTI and fmVTI methods were used to perform 3D LGE scans for 28 3D LGE patients, with qualitative image quality scores assigned for left atrial wall clarity and total ghosting. Accompanying simulations of numerical phantom images were assessed in terms of ghosting of normal myocardium, blood, and myocardial scar. RESULTS: The numerical simulations for fmVTI showed a significant decrease in blood ghosting (VTI: 410 ± 710, fmVTI: 68 ± 40, p < 0.0005) and scar ghosting (VTI: 830 ± 1300, fmVTI: 510 ± 730, p < 0.02). Despite this, there was no significant change in qualitative image quality scores, either for left atrial wall clarity (VTI: 2.0 ± 1.0, fmVTI: 1.8 ± 1.0, p > 0.1) or for total ghosting (VTI: 1.9 ± 1.0, fmVTI: 2.0 ± 1.0, p > 0.7). CONCLUSIONS: Simulations indicated reduced ghosting with the fmVTI method, due to reduced Mz variability in the blood signal. However, other sources of phase-encode ghosting and blurring appeared to dominate and obscure this finding in the patient studies available.

Treatment of chytridiomycosis with reduced-dose itraconazole.

Effective treatment methods to eliminate infection with Batrachochytrium dendrobatidis (Bd) are required for development of sustainable captive survival assurance populations of amphibians and to reduce the risk of introducing Bd to new locations as part of amphibian trade or reintroduction programs. Treatment with itraconazole baths at 100 mg l-1 is commonly used in captive amphibians, but side effects are observed in some amphibian species and life stages. Naturally occurring outbreaks of chytridiomycosis in Wyoming toads Anaxyrus baxteri and White's tree frogs Litoria caerulea were treated with lower-dose itraconazole baths (e.g. 50 mg l-1 for White's tree frogs) and followed post-treatment with serial Taqman PCR testing to confirm elimination of Bd infection. Post-treatment PCR tests were consistently negative for the presence of Bd and treatment was deemed successful. Although this was not a controlled clinical trial, results suggest that lower doses of itraconazole may be effective for treatment of chytridiomycosis with resulting cost savings to amphibian conservation programs and a potential for a reduction in dose-related side effects from itraconazole treatment. Prospective clinical trials of alternative itraconazole treatment protocols are encouraged.

Ca2+ Sensors Assemble: Function of the MCU Complex in the Pancreatic Beta Cell.

The Mitochondrial Calcium Uniporter Complex (MCU Complex) is essential for ß-cell function due to its role in sustaining insulin secretion. The MCU complex regulates mitochondrial Ca2+ influx, which is necessary for increased ATP production following cellular glucose uptake, keeps the cell membrane K+ channels closed following initial insulin release, and ultimately results in sustained insulin granule exocytosis. Dysfunction in Ca2+ regulation results in an inability to sustain insulin secretion. This review defines the functions, structure, and mutations associated with the MCU complex members mitochondrial calcium uniporter protein (MCU), essential MCU regulator (EMRE), mitochondrial calcium uptake 1 (MICU1), mitochondrial calcium uptake 2 (MICU2), and mitochondrial calcium uptake 3 (MICU3) in the pancreatic ß-cell. This review provides a framework for further evaluation of the MCU complex in ß-cell function and insulin secretion.

Surgery by a minimally invasive approach is associated with improved textbook outcomes in oesophageal and gastric cancer.

INTRODUCTION: Textbook outcome (TBO) is a composite measure of a number of peri-operative and clinical outcomes in oesophagogastric malignancy. It has previously been shown that TBOs are associated with improved overall survival in both oesophageal and gastric cancer. The influence of a minimally invasive approach (MIA) on TBO is not well defined. The purpose of this study is to validate TBO in our population, examine the influence of a MIA on achieving a TBO, and the impact of TBO on long-term survival. METHODS: 269 patients undergoing oesophagectomy and 258 patients undergoing subtotal or total gastrectomy were included in this study. Demographic, clinical and pathological differences between patients with and without a TBO were compared using univariable and multivariable analysis. Overall survival for those with and without a TBO was examined. The influence of MIA on overall survival and TBO was determined using Cox proportional hazard models. RESULTS: Patients undergoing oesophagectomy and gastrectomy were significantly more likely to achieve a TBO when MIA was used (p = 0.01 and 0.001 respectively). When MIA is included as an outcome measure patients achieving a TBO show improved overall survival in both oesophageal and gastric cancer. MIA, clear resection margins and no unplanned admission to critical care are the strongest predictors of overall survival from the putative bundle of TBO parameters. CONCLUSION: Minimally invasive surgery is associated with improved TBO. Completion of a minimally invasive approach should be considered for inclusion as a textbook parameter.

Are We Cutting Enough? A Five-Year Audit of Melanoma Excision Margins in the South East of Ireland.

AIM: Malignant melanoma is the fifth commonest invasive cancer in Ireland. The British Association of Dermatology (BAD) guidelines are currently the recognized standard for melanoma related surgery. The aim was to examine adherence to BAD guidelines and establish contributing factors resulting in non-adherence to guidelines in a group of melanoma patients in the South East Region of Ireland. METHODS: A retrospective review of a prospectively maintained melanoma registry of all patients undergoing surgery in the South East Region of Ireland from January 2011 to 2016 was performed. Data were analyzed using SPSS statistical software. Univariate analysis using logistic regression was performed to examine factors associated with not meeting the BAD margin excision guidelines Data with a p < 0.05 was analyzed using a multivariate logistic regression model. RESULTS: 459 patients underwent surgery for invasive cutaneous melanoma. 314 (68.4%) surgeries had excision margins adequately recorded and of these 234(74.5%) fulfilled the BAD guidelines. 267(58.2%) patients (2011-2016 inclusive) qualified for sentinel lymph node biopsy (SNLB) with a cancer staging of pT1b or higher. Of these patients 100(37%) agreed to proceed to a SNLB following informed discussion. 33 had a positive sentinel node. On multivariate analysis inadequate margins were independently associated with tumor thickness 2.01-4.00 mm (p = 0.0001) and >4.00 mm (p = 0.0001) and head and neck location (p < 0.0001). CONCLUSIONS: Adherence to BAD guidelines in the South East is good but requires optimization since centralization of melanoma treatment in 2013 to a single specialized center. It is important that Clinicians are fully aware of the implications of not achieving adequate excision margins in surgery. Improvements in melanoma data management is needed to fully evaluate current practices in Ireland.

Anatomic Reinforced Medial Meniscal Root Reconstruction With Gracilis Autograft.

Meniscal root tears, left untreated, result in accelerated progression of arthritis. Numerous techniques to repair medial meniscus posterior root tears have been presented in the literature. Direct repair of the meniscus to bone without reconstructive tissue may result in a nonanatomic and biologically weak construct with a significant number of structural repair failures. Re-creation of the ligament-like structures that fix the meniscal root to bone is critical to restoring normal knee biomechanics. We present an arthroscopic reconstructive technique using gracilis autograft with suture reinforcement for medial meniscus posterior root tears.

Towards multi-breed genomic evaluations for female fertility of tropical beef cattle.

Developing accurate genomic evaluations of fertility for tropical beef cattle must deal with at least two major challenges (i) recording cow fertility traits in extensive production systems on large numbers of cows and (ii) the genomic evaluations should work across the breeds, crossbreds, and composites used in tropical beef production. Here, we assess accuracy of genomic evaluations for a trait which can be collected on a large scale in extensive conditions, corpus luteum score (CLscore), which is 1 if ovarian scanning indicates a heifer has cycled by 600 d and 0 if not, in a multi-breed population. A total of 3,696 heifers, including 979 Brahmans, 914 Droughtmasters, and 1,803 Santa Gertrudis in seven herds across 3-yr cohorts with CLscores, were genotyped for 24,211 SNPs. Genotypes were imputed to 728,785 SNPs. GBLUP and BayesR were used to predict GEBV. Accuracy of GEBV was evaluated with two validation strategies. In the first strategy, the last year cohort of heifers from each herd was used for validation, such that every herd had heifers in both reference and validation populations. In the second validation strategy, each herd in turn was removed in its entirety from the reference population, and was used for validation. For both validation strategies, accuracy of GEBV for single breed and multi-breed reference populations was assessed. For the first validation strategy, accuracy of GEBV ranged from 0.2 for Brahmans to 0.4 for Droughtmasters. Increasing marker density from 24K SNPs to 728K SNPs resulted in a small increase in accuracy, and including multiple-breeds in the reference did not help improve accuracy. These results suggest that provided a herd has animals in the reference population, the accuracy of the GEBV is largely determined by within herd (linkage) information. The situation was very different when entire herds were predicted in the second validation. In this case accuracy of GEBV using only 24K SNPs and only a within breed reference was close to zero for all breeds. Accuracy increased substantially when 728K SNPs, BayesR, and a multi-breed reference were used, from 0.15 for Brahmans to 0.35 for Santa Gertrudis. Given the second validation strategy is more likely to reflect the situation for many herds in tropical beef production (no animals in the reference), genomic evaluations for fertility in tropical beef cattle should be based on high-density markers (728K SNPs) and should be multi-breed.

Statistical shape modeling of the left ventricle: myocardial infarct classification challenge.

Statistical shape modeling is a powerful tool for visualizing and quantifying geometric and functional patterns of the heart. After myocardial infarction (MI), the left ventricle typically remodels in response to physiological challenges. Several methods have been proposed in the literature to describe statistical shape changes. Which method best characterizes left ventricular remodeling after MI is an open research question. A better descriptor of remodeling is expected to provide a more accurate evaluation of disease status in MI patients. We therefore designed a challenge to test shape characterization in MI given a set of three-dimensional left ventricular surface points. The training set comprised 100 MI patients, and 100 asymptomatic volunteers (AV). The challenge was initiated in 2015 at the Statistical Atlases and Computational Models of the Heart workshop, in conjunction with the MICCAI conference. The training set with labels was provided to participants, who were asked to submit the likelihood of MI from a different (validation) set of 200 cases (100 AV and 100 MI). Sensitivity, specificity, accuracy and area under the receiver operating characteristic curve were used as the outcome measures. The goals of this challenge were to (1) establish a common dataset for evaluating statistical shape modeling algorithms in MI, and (2) test whether statistical shape modeling provides additional information characterizing MI patients over standard clinical measures. Eleven groups with a wide variety of classification and feature extraction approaches participated in this challenge. All methods achieved excellent classification results with accuracy ranges from 0.83 to 0.98. The areas under the receiver operating characteristic curves were all above 0.90. Four methods showed significantly higher performance than standard clinical measures. The dataset and software for evaluation are available from the Cardiac Atlas Project website1.

Oral eosinophilic granulomas in tigers (Panthera tigris)--a collection of 16 cases.

Oral eosinophilic granulomas were diagnosed in 16 tigers (Panthera tigris). All lesions were located on the hard or soft palate and typically consisted of flat or slightly raised circular ulcers. Histologic features of these lesions were essentially identical to those seen in oral eosinophilic granulomas of domestic cats and dogs. No clinical signs were noted in eight cases, though various degrees of inappetence, excessive salivation, and dysphagia were noted in the other eight tigers. Six cases were not treated. Treatment for the remaining 10 cases centered on corticosteroids and additional treatments included surgical removal, cryotherapy, antibiotics, and chlorpheniramine. Treatment with corticosteroids did appear to be effective in some cases, though lesions would worsen after cessation of therapy and no cases were cured. In addition, three cases developed complications possibly related to this corticosteroid therapy. The etiology of these lesions remains unknown, though an underlying allergic condition is likely.

N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor.

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.

Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src.

Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.