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The goal of this study was to determine demographic factors associated with reported safety behavior by studying 2250 Iowa junior high and high school students via a self-administered questionnaire. Students attending rural schools used front seat belts and helmets less frequently than urban students. Seat belt and helmet use and swim safety decreased dramatically with age. Occurrences of driving or riding while drunk or high increased with age. Boys were less likely than girls to wear back seat belts and moped helmets and to check water depth before diving. Possession of a driver's license was not independently associated with any of the safety behaviors. [ABSTRACT FROM AUTHOR]

ObjectiveThis study aimed to compare the relative physical recovery and symptoms after SARS-CoV-2 infection between groups confirmed positive or negative to early strains of COVID-19.MethodsA prospective, longitudinal cohort study compared outcomes of metropolitan adults polymerase chain reaction-tested for COVID-19 between March and November 2020 in Western Australia. Control matching was attempted: inpatients (gender, age) and ambulatory clinic (gender, age, asthma, chronic pulmonary disease). One-year follow-up involved three repeated measures: physical function (grip strength and 1-min sit-to-stand) and patient-reported outcomes (Fatigue Severity Scale, modified Medical Research Council dyspnoea scale and Euroqol-5D-5L).ResultsThree hundred and forty-four participants were recruited (154 COVID+, age 54±18years, 75 females [49%]); 190 COVID-, age 52±16years, 67 females [35%]) prior to national vaccination roll-out. No between-group differences in physical function measures were evident at any time point. Fatigue (OR 6.62, 95% CI 2.74-15.97) and dyspnoea (OR 2.21, 95% CI 1.14-4.30) were higher in the COVID+ group at second assessment (T2). On Euroqol-5D-5L, no between-group differences were evident in the physical function domains of self-care, mobility or usual activities at any time point. However, COVID+ participants were less likely to report an absence of anxiety or depression symptoms at T2 (OR 0.41, 95% CI 0.19-0.89).ConclusionsNeither statistical nor clinically meaningful differences in physical function were evident between COVID+ and COVID- participants to 12-months after acute illness. Symptoms of fatigue, dyspnoea, anxiety or depression were more prevalent in the COVID+ group til ~8months after illness with between-group differences no longer evident at 1 year.

Background: Mental capacity for treatment decisions in psychiatry inpatients is an important ethical and legal concern, especially in light of changes in mental capacity legislation in many jurisdictions., Aims: To conduct a systematic review of literature examining the prevalence of mental capacity for treatment decisions among voluntary and involuntary psychiatry inpatients, and to assess any correlations between research tools used to measure mental capacity and binary judgements using criteria such as those in capacity legislation., Method: We searched PsycINFO, Ovid MEDLINE and EMBASE for studies assessing mental capacity for treatment decisions in people admitted voluntarily and involuntarily to psychiatric hospitals., Results: Forty-five papers emanating from 33 studies were identified. There was huge variability in study methods and often selective populations, but the prevalence of decision-making capacity varied between 5% and 83.7%. These figures resulted from studies using cut-off scores or categorical criteria only. The prevalence of decision-making capacity among involuntary patients ranged from 7.7% to 42%, and among voluntary patients ranged from 29% to 97.9%. Two papers showed positive correlations between clinicians' judgement of decision-making capacity and scores on the MacArthur Competence Assessment Tool for Treatment; two papers showed no such correlation., Conclusions: Not all voluntary psychiatry inpatients possess mental capacity and many involuntary patients do. This paradox needs to be clarified and resolved in mental health legislation; supported decision-making can help with this task.Key PointsLegislative changes for mental capacity are taking place in many jurisdictions.This is an important human rights issue for many people, including psychiatry inpatients.In our review, we found the prevalence of decision-making capacity varies between 5% and 83.7% in psychiatry inpatients.Not all voluntary inpatients have decision-making capacity.Many involuntary inpatients have mental capacity to make decisions.Supported decision-making can help those with impairments in their mental capacity.

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 ( 43 ), and a backup clinical candidate, BMS-986141 ( 49 ). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

Background: In adults hospitalized with community-acquired pneumonia (CAP), increasing ward-based walking may reduce length of stay (LOS). There are few data to describe ward-based walking in this population. In adults hospitalized with CAP, we aimed to report variables of walking and non-walking time, to determine whether demographic or clinical variables influenced daily step count, and to determine whether daily step count influenced LOS., Methods: Following admission, daily step count and variables related to walking and non-walking time were quantified using the StepWatch Activity Monitor. Details regarding demographics, clinical characteristics, clinical care, and LOS were extracted from the medical records and hospital electronic data systems. Frailty was calculated via the 7-point Clinical Frailty Scale; disease severity was measured via the CURB-65 score. Health care utilization at 30 d following discharge was measured via telephone interview., Results: Two hundred participants completed the study, of whom 121 contributed ≥ 24 h of data from the StepWatch Activity Monitor. The median (interquartile range (IQR)) number of daily steps was 926 (457-1706). These were accumulated over 66 (41-121) min/d, with a usual bout duration of 3 (2-4) min and 1-min peak cadence of 56 (43-74) steps/min. An average of 93% (89-96) of waking hours was spent in non-walking time. In the multivariable model, increased frailty was retained as a predictor of lower step count (incidence rate ratio [IRR] 0.59, 95% CI 0.41-0.85). For every increase in 500 steps/d, LOS reduced by 11% (IRR 0.89, 95% CI 0.80-0.99)., Conclusions: Subjects hospitalized with CAP did very little walking, most of which was accumulated in short bouts at a low intensity. Compared with subjects with mild frailty, those with moderate to severe frailty took 59% fewer steps per day. Those with a higher daily step count had a shorter LOS., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

Evaluation expertise to assist with identifying improvements, sourcing relevant literature and facilitating learning from project implementation is not routinely available or accessible to not-for-profit organisations. The right information, at the right time and in an appropriate format, is not routinely available to program managers. Program management team members who were implementing The Fred Hollows Foundation's Indigenous Australia Program's Trachoma Elimination Program required information about what was working well and what required improvement. This article describes a way of working where the program management team and an external evaluation consultancy collaboratively designed and implemented an utilisation-focused evaluation, informed by a developmental evaluation approach. Additionally, principles of knowledge translation were embedded in this process, thereby supporting the evaluation to translate knowledge into practice. The lessons learned were that combining external information and practice-based knowledge with local knowledge and experience is invaluable; it is useful to incorporate evaluative information from inception and for the duration of a program; a collaborative working relationship can result in higher quality information being produced and it is important to communicate findings to different audiences in different formats.

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651 , in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651 . UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

A 22-year-old woman presented to her local district hospital with left-sided abdominal pain. She denied any urinary or gastrointestinal symptoms. She had a CT scan of her abdomen which showed a probable 8×5×8 cm left-sided adrenal mass. Functional tests for hormone excess were negative. She was referred to a tertiary referral centre and given the size of the adrenal mass; she consented for laparoscopic left adrenalectomy. During the operation, the mass was grossly adherent to the celiac axis, left renal pedicle and DJ flexure. A small nodule posterior to the renal vein was also identified. The operation was completed laparoscopically and she made an uneventful recovery. The specimen was reported as a poorly differentiated neuroblastoma. She had a postoperative MIBG scan which was negative for residual or metastatic disease. She was commenced on platinum-based chemotherapy with a plan for further radiological follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Adrenal metastases can arise from different primary sites. Surgical resection of the adrenal gland in patients with isolated metastases may offer improved survival in many of these patients. However, the benefit of surgery in this heterogenous group is often disputed. The aim of this study was to identify patients undergoing adrenalectomy for isolated metastases and to describe survival outcomes based on origin of the primary malignancy., Methods: Patients undergoing surgery for isolated adrenal metastases were retrospectively analysed from a prospectively kept database. Data collected included the age of the patient, gender, size and functional status of the tumour and the site of the primary malignancy. Overall survival and survival based on the primary tumour were calculated using Kaplan-Meier survival analyses., Results: 42 patients were included for analysis. The median tumour size was 40 mm. 91% (n = 38) of operations were performed laparoscopically. Metastases were from the following primary organs: kidney (n = 22), lung (n = 11), breast (n = 2), gastric (n = 1), skin (n = 3), liver (n = 2) and neuroendocrine (n = 1). Overall median survival was 56 (19-93) months with 95% of patients followed up for >6 months. There was a significant difference in median survival between primary organs of origin: 83(42-123), 14(9-18), 15 and 12(3-20) months (p < 0.05) for kidney, lung, breast and skin respectively., Conclusion: There is a potential survival benefit for patients undergoing surgery for isolated adrenal metastases; however this survival benefit is greater in patients undergoing resection for metastases arising from kidney primaries. A selective approach should be adopted to identify patients that will clearly benefit from surgery., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background: Little is known about available guidelines that can be used to evaluate health systems' Doctor of Nursing Practice (DNP) capstone projects., Objectives: The twofold purpose of this study was to identify the scope of nurse executive leadership practices, as demonstrated in final health systems' DNP Projects and propose a framework to guide evaluating health systems' DNP capstone projects., Methods: This qualitative study used content analysis to evaluate DNP project posters of 10 health systems' DNP students graduating from one Midwestern college of nursing. Students were engaged in activities pertinent to managerial and executive-level nurse leaders., Results: Students were engaged in activities pertinent to both managerial and executive level nurse leaders and followed AONE competencies. Leadership styles were operational and transformational. Six types of activities were identified. Leadership activities and themes were organized into a framework for action that can guide curriculum., Conclusions: The Framework for Action themes can be used to coach students in nurse manager or executive roles and identify developmental needs of students., Implications for Nursing: A specific new competency on impact is indicated. Use of simulation techniques is an opportunity in health systems education., (© 2018 Springer Publishing Company, LLC.)

A 32-year-old man was referred to our surgical unit with a left adrenal lesion. He was previously diagnosed with Birt-Hogg-Dube syndrome after presenting with a left pneumothorax and an incidental finding of a right apical lung mass. This syndrome is characterised commonly by benign skin hamartomas, recurrent pneumothoraces and an increased risk of renal tumours. He was unable to tolerate a biopsy of his lung lesion, however, this lung lesion was thought to be benign. Given the size of his adrenal lesion and radiological appearances, we performed a laparoscopic left adrenalectomy. Pathology confirmed that based on morphological appearances and immunohistochemical staining, this may represent an oncocytic tumour of the adrenal gland. This is only the third published case of an oncocytic tumour of the adrenal gland in a patient with Birt-Hogg-Dube syndrome., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited [2018]. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and aims Sublingual glyceryl trinitrate has been used as an aid to cannulate the Sphincter of Oddi during endoscopic retrograde cholangiopancreatography. Its role in terminal ileal intubation during colonoscopy is unknown. This study examines the role of sublingual glyceryl trinitrate in terminal ileal intubation during colonoscopy. Methods A triple-blind randomized controlled trial comparing sublingual glyceryl trinitrate (800 µg) vs. placebo (saline) in relation to terminal ileal intubation during colonoscopy was performed. Following caecal intubation, participants received sublingual glyceryl trinitrate/placebo followed by a 2-min observation period before intubation was attempted. Data on time to intubate the terminal ileum and intubation rate were collected. Results A total of 110 patients (age: 58 years (18-75)) were recruited and randomised as per protocol: 54 received sublingual glyceryl trinitrate. Terminal ileal intubation was successful in all patients receiving sublingual glyceryl trinitrate and in 53 (94.6%) of those receiving saline ( p = 0.243: Fischer's exact). The median time taken for ileal intubation after application of spray was 72.5 (7-900) s in the glyceryl trinitrate group compared with 125 (5-900) s in the placebo group ( p = 0.150: Mann-Whitney). There were no major adverse events reported in either group. Conclusions Terminal ileal intubation rates and timing were very good in both groups. Routine sublingual glyceryl trinitrate was not proven to be beneficial in improving terminal ileal intubation or intubation success rates in the hands of experienced colonoscopists. However, trends in this small study might suggest that glyceryl trinitrate could be useful in the hands of less experienced colonoscopists or in difficult terminal ileal intubation cases.

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care., (Copyright © 2017, American Association for the Advancement of Science.)

Adenosine diphosphate directly induces platelet aggregation via the G-protein coupled P2Y1 and P2Y12 receptors. P2Y12, but not P2Y1, receptor antagonists are available in the clinic. The relevance of the P2Y1 receptor as an antiplatelet target has been studied in rodents, but not in higher species. We therefore examined effects of the pharmacological blockade of the P2Y1 receptor with its selective antagonist MRS2500 in monkey models of electrolytic-mediated arterial thrombosis (ECAT) and kidney bleeding time (KBT). Abciximab, a GPIIb-IIIa antagonist, and cangrelor, a P2Y12 antagonist, were utilized to validate these monkey models. Compounds were given IV at 15-60 min before thrombosis initiation in anesthetized monkeys. Scanning electron microscopy showed the luminal surface of thrombotic artery covered with platelet aggregates and fibrin network. Administration of abciximab at 0.25 and 0.7 mg/kg IV significantly reduced thrombus weight by 71 ± 1 and 100 ± 0 %, and increased KBT by 10.0 ± 0.1- and 10.1 ± 0-fold, respectively (n = 3/dose). Likewise, cangrelor at 0.6 and 2 mg/kg/h IV significantly reduced thrombus weight significantly by 72 ± 9 % and 100 ± 0 % and increased KBT by 2.1 ± 0.1- and 9.8 ± 0.2-fold, respectively (n = 3/dose). MRS2500 [mg/kg + mg/kg/h IV] at 0.09 + 0.14 and 0.45 + 0.68 significantly reduced thrombus weight by 57 ± 1 % and 88 ± 1 % and increased KBT by 2.1 ± 0.3- and 4.9 ± 0.6-fold, respectively (n = 4/dose). In summary, MRS2500 prevented occlusive arterial thrombosis at a dose that moderately prolonged KBT, indicating a role of P2Y1 receptors in arterial thrombosis and hemostasis in monkeys. Thus P2Y1 receptor antagonism provides a suitable target for drug discovery.

Background: Currently, no doctoral guidelines to teach innovation exist. Using Christensen's theory of disruptive innovation, the five discovery skills used by disruptive innovators provide the framework for designing a leadership development approach to enable and support a mindset to innovate., Method: Executive leadership students were provided with didactic content on innovation, were assigned to non-healthcare settings for an anthropological dig to uncover innovative activities, and were provided with reflective prompts to enable a new context for innovation. Faculty collaborated with other fields and took risks to provide new contexts to innovate., Results: Students identified and proposed innovations for current health care issues. Some of the innovations included processes, evaluation methods, data analytics for care design, and patient engagement solutions., Conclusion: Faculty crossed borders for field experiences, as well as disciplinary borders. This collaborative seminar demonstrated that it is possible to develop executive nurse leaders to innovate., (Copyright 2016, SLACK Incorporated.)

BMS-654457 ((+) 3'-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5'-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of BMS-654457 and its in vivo activities in rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Kinetic studies conducted in vitro with a chromogenic substrate demonstrated that BMS-654457 is a reversible and competitive inhibitor for FXIa. BMS-654457 increased activated partial thromboplastin time (aPTT) without changing prothrombin time. It was equipotent in prolonging the plasma aPTT in human and rabbit, and less potent in rat and dog. It did not alter platelet aggregation to ADP, arachidonic acid and collagen. In vivo, BMS-654457 or vehicle was given IV prior to initiation of thrombosis or cuticle transection. Preservation of integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of antithrombotic efficacy. BMS-654457 at 0.37 mg/kg + 0.27 mg/kg/h produced almost 90 % preservation of iCBF compared to its vehicle (87 ± 10 and 16 ± 3 %, respectively, n = 6 per group) and increased BT by 1.2 ± 0.04-fold (P < 0.05). At a higher dose (1.1 mg/kg + 0.8 mg/kg/h), BMS-654457 increased BT by 1.33 ± 0.08-fold. This compares favorably to equivalent antithrombotic doses of reference anticoagulants (warfarin and dabigatran) and antiplatelet agents (clopidogrel and prasugrel) which produced four- to six-fold BT increases in the same model. In summary, BMS-654457 was effective in the prevention of arterial thrombosis in rabbits with limited effects on BT. This study supports inhibition of FXIa, with a small-molecule, reversible and direct inhibitor as a promising antithrombotic therapy with a wide therapeutic window.

Many children have difficulty producing movements well enough to improve in perceptuo-motor learning. We have developed a training method that supports active movement generation to allow improvement in a 3D tracing task requiring good compliance control. We previously tested 7-8 year old children who exhibited poor performance and performance differences before training. After training, performance was significantly improved and performance differences were eliminated. According to the Dynamic Systems Theory of development, appropriate support can enable younger children to acquire the ability to perform like older children. In the present study, we compared 7-8 and 10-12 year old school children and predicted that younger children would show reduced performance that was nonetheless amenable to training. Indeed, the pre-training performance of the 7-8 year olds was worse than that of the 10-12 year olds, but post-training performance was equally good for both groups. This was similar to previous results found using this training method for children with DCD and age-matched typically developing children. We also found in a previous study of 7-8 year old school children that training in the 3D tracing task transferred to a 2D drawing task. We now found similar transfer for the 10-12 year olds., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.

Theodore Millon was a brilliant man: erudite, thoughtful, confident, deliberate, and curious. He was an integrative thinker. It is widely known how these characteristics manifested themselves in his landmark work in the areas of personality theory, personality development, and personality assessment. What is likely less well known is that he displayed these same characteristics in and to the world of business; in particular, his relationships with those who published and distributed his assessment measures. This article traces those relationships. Various components are explored, ranging from product development to product marketing, from the protection of intellectual property to the development and execution of contracts, from deciding how and when to revise a test to ensuring that his legacy continues long into the future. Although the primary dynamic of these relationships was commercial, the reasons for their success were personal. Common goals, clarity of communication, persistence, respect, and trust allowed these relationships to develop, prosper, evolve, and endure.

Prevention and treatment of injection drug use remains a public health concern. We used data from the 2005 Centers for Disease Control and prevention National HIV Behavioral Surveillance system to assess substance abuse treatment utilization, risk behaviors, and recruitment processes in a respondent driven sample of suburban injectors. Twelve service utilization and injection risk variables were analyzed using latent class analysis. Three latent classes were identified: low use, low risk; low use, high risk; and high use, moderate/high risk. In multivariate analysis, annual income <$15,000 (adjusted odds ratio (aOR) = 8.19 [95 % confidence interval (CI), 3.83-17.51]) and self-reported hepatitis C virus infection (aOR = 4.32, 95 % CI (1.84-10.17)) were significantly associated with class membership. Homophily, a measure of preferential recruitment showed that injectors with recent treatment utilization appear a more cohesive group than out-of-treatment injectors. Preferentially reaching injection drug users with high risk behaviors and no recent drug treatment history via respondent driven sampling will require future research.

Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Sphingosine kinase is an enzyme that catalyses the phosphorylation of sphingosine to form sphingosine 1-phosphate. Sphingosine 1-phosphate is a bioactive lipid, which has been shown to have an important role in promoting the survival, growth and invasiveness of cancer cells. Sphingosine 1-phosphate binds to five different plasma membrane sphingosine 1-phosphate receptors (S1P(1-5) ) and can regulate intracellular target proteins. We have used immunohistochemical analysis to determine the concurrent expression levels of sphingosine kinase 1 or S1P receptors and other signaling proteins in estrogen receptor-positive breast cancer tumors and have then assessed the impact of these combinations on clinical outcome. This approach has enabled identification of (i) novel biomarkers and (ii) several spatially controlled associations between either sphingosine kinase 1 or S1P(1-3) and other signaling proteins whose combination affect prognosis. For instance, the translocation of sphingosine kinase 1 to the plasma membrane has been shown to be a critical determinant in cancer progression. However, our findings identify an additional novel role for the nuclear localization of sphingosine kinase 1 combined with either ERK-1/2 or SFK or LYN or AKT or NF-κB, which significantly shortens disease-specific survival and/or recurrence. We also demonstrate that nuclear S1P(2) receptor and c-SRC are associated with improved prognosis and this is linked with a reduction in the nuclear localization of sphingosine kinase 1. These findings identify potential novel biomarker associations, which might serve as new targets for drug intervention designed to improve treatment of estrogen receptor-positive breast cancer., (Copyright © 2012 UICC.)

BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 μM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose-dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold-increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 ± 0.04 and 1.52 ± 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy.

Various studies in cell lines have previously demonstrated that sphingosine kinase 1 (SK1) and extracellular signal-regulated kinase 1/2 (ERK-1/2) interact in an estrogen receptor (ER)-dependent manner to influence both breast cancer cell growth and migration. A cohort of 304 ER-positive breast cancer patients was used to investigate the prognostic significance of sphingosine 1-phosphate (S1P) receptors 1, 2, and 3 (ie, S1P1, S1P2, and S1P3), SK1, and ERK-1/2 expression levels. Expression levels of both SK1 and ERK-1/2 were already available for the cohort, and S1P1, S1P2, and S1P3 levels were established by immunohistochemical analysis. High membrane S1P1 expression was associated with shorter time to recurrence (P=0.008). High cytoplasmic S1P1 and S1P3 expression levels were also associated with shorter disease-specific survival times (P=0.036 and P=0.019, respectively). Those patients with tumors that expressed high levels of both cytoplasmic SK1 and ERK-1/2 had significantly shorter recurrence times than those that expressed low levels of cytoplasmic SK1 and cytoplasmic ERK-1/2 (P=0.00008), with a difference in recurrence time of 10.5 years. Similarly, high cytoplasmic S1P1 and cytoplasmic ERK-1/2 expression levels (P=0.004) and high cytoplasmic S1P3 expression and cytoplasmic ERK-1/2 expression levels (P=0.004) were associated with shorter recurrence times. These results support a model in which the interaction between SK1, S1P1, and/or S1P3 and ERK-1/2 might drive breast cancer progression, and these findings, therefore, warrant further investigation.

Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to ADP, gamma-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 +/- 5% increase in blood flow), addition of razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding.

Objective: Pulmonary rehabilitation in patients with COPD has been shown to be beneficial but the optimal setting is not known. In the present study, the efficacy of a short-term community-based exercise programme was compared with a standard hospital outpatient programme. Additionally, the usefulness of community or home programmes in maintaining improvements in the longer term was studied., Methodology: Forty-three patients with moderate to severe COPD were randomized to one of the following three groups: a 3-month hospital programme then a 9 month home programme (Hospital/Home); a 3-month hospital programme then a 9-month community programme (Hospital/Community); or a 12-month community programme (Community/Community). The initial 3-month programme was analysed by comparing the Hospital group (Hospital/Home plus Hospital/Community) with the Community group (Community/Community). Six-minute walking distance (6MWD), quality of life (Guyatt chronic respiratory disease questionnaire, CRQ) and lung function were measured at 0, 3, 6 and 12 months and results were analysed using the Wilcoxon rank sum test., Results: At 3 months, there was a significant improvement from baseline in 6MWD in the Hospital group (81.3 +/- 18.3 m, P < 0.05, anova) but not the Community group (14.4 +/- 28.5 m, not significant). The difference between the groups was not significant (P = 0.058). At 3 months, there was a significant improvement in quality of life in the Hospital group (CRQ +16.3 +/- 3.1, P < 0.01, anova) and in the Community group (CRQ +10.2 +/- 4.9, P < 0.05, anova) but the difference between the groups was not significant. Following the initial 3-month programme, the dropout rate was high overall (73% by 12 months), and therefore data from the maintenance programme could not be analysed., Conclusions: A 3-month community-based exercise programme for patients with COPD did not improve 6MWD. The long-term retention rates in the programmes were poor.

Clinical information systems are proven to enhance workflow and outcomes, and yet hospitals often face staff resistance when systems are installed. This roundtable discussion explores how nurses and physicians can collaborate on developing IT systems.