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https://www.readbyqxmd.com/read/26819676/discovery-of-mk-8831-a-novel-spiro-proline-macrocycle-as-a-pan-genotypic-hcv-ns3-4a-protease-inhibitor
#1
Santhosh F Neelamkavil, Sony Agrawal, Thomas Bara, Chad Bennett, Sathesh Bhat, Dipshikha Biswas, Linda Brockunier, Nicole Buist, Duane Burnette, Mark Cartwright, Samuel Chackalamannil, Robert Chase, Mariappan Chelliah, Austin Chen, Martin Clasby, Vincent J Colandrea, Ian W Davies, Keith Eagen, Zhuyan Guo, Yongxin Han, John Howe, Charles Jayne, Hubert Josien, Stacia Kargman, Karen Marcantonio, Shouwu Miao, Randy Miller, Andrew Nolting, Patrick Pinto, Murali Rajagopalan, Rebecca T Ruck, Unmesh Shah, Aileen Soriano, Donald Sperbeck, Francisco Velazquez, Jin Wu, Yan Xia, Srikanth Venkatraman
We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing...
January 14, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/25734840/the-prevalence-of-traumatic-brain-injury-among-young-offenders-in-custody-a-systematic-review
#2
REVIEW
Nathan Hughes, W H Williams, Prathiba Chitsabesan, Rebecca C Walesby, Luke T A Mounce, Betony Clasby
OBJECTIVES: To examine the prevalence of traumatic brain injury (TBI) among young people in custody and to compare this with estimates within the general youth population. DESIGN: Systematic review of research from various national contexts. Included studies were assessed for the relevance of the definition of TBI and the research population, and the quality of the study design. RESULTS: Ten studies were identified for inclusion in the review...
March 2015: Journal of Head Trauma Rehabilitation
https://www.readbyqxmd.com/read/25483264/factors-predicting-the-cause-and-prognosis-of-central-line-associated-bloodstream-infections
#3
Takaaki Nemoto, Hiroyuki Kunishima, Gohji Shimizu, Masanori Hirose, Yukitaka Yamasaki, Hisashi Nishisako, Taeko Takagi, Takahide Matsuda
The increased use of indwelling catheters has led to an increased number of deaths due to central line-associated bloodstream infection (CLABSI). Improving CLABSI outcomes requires the identification of clinical characteristics affecting drug selection and factors associated with poor prognosis. The medical records of inpatients admitted to St. Marianna University School of Medicine between April 1, 2010 and March 31, 2013 were evaluated for the results of catheter tip cultures. The clinical characteristics of these cases and the characteristics of the pathogens involved were investigated to identify prognostic factors...
February 2015: Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy
https://www.readbyqxmd.com/read/24873836/complications-associated-with-parenteral-nutrition-in-the-neonate
#4
REVIEW
Kara L Calkins, Robert S Venick, Sherin U Devaskar
Although parenteral nutrition (PN) is life-sustaining, it is associated with many complications including parenteral nutrition-associated liver disease (PNALD) and central line-associated bloodstream infections (CLASBIs), which carry a high morbidity and mortality and impose a burden on the health care system. Evidence has emerged that the dose and composition of intravenous lipid products may alter the incidence of PNALD. However, other patient and PN-related factors, such as prematurity, birth weight, and gastrointestinal anatomy and function, are important...
June 2014: Clinics in Perinatology
https://www.readbyqxmd.com/read/24243150/carpal-tunnel-syndrome-as-an-expression-of-muscular-dysfunction-in-the-neck
#5
D L Skubick, R Clasby, C C Stuart Donaldson, W M Marshall
Carpal tunnel syndrome (CTS) may be a consequence of increased forearm flexor activity secondary to muscle dysfunction in the neck. Eighteen CTS patients, with an average duration of symptoms of 10 months, were studied. Standardized nerve-conduction studies were administered before and after treatment. Surface-EMG techniques measured sternomastoid and cervical paraspinal muscle activity and flexor and extensor muscle activity during head movement. Both sets of neck muscles were found to be asymmetrical when compared side to side...
March 1993: Journal of Occupational Rehabilitation
https://www.readbyqxmd.com/read/21622689/short-dwell-ethanol-lock-therapy-in-children-is-associated-with-increased-clearance-of-central-line-associated-bloodstream-infections
#6
Eric J McGrath, Ralph Salloum, Xinguang Chen, Yifan Jiang, Kathrina Boldt-MacDonald, Cristie Becker, Roland Chu, Jocelyn Y Ang
BACKGROUND: Central line-associated bloodstream infection (CLABSI) is a known complication of central line use. Salvage of infected central lines with ethanol lock therapy (ELT) with systemic antimicrobials may be an alternative treatment option in children. METHODS: Retrospective review was performed in children with CLASBI who underwent short-dwell ELT (70% ethanol, 4- to 25-hour dwell times ≤3 days) with systemic antimicrobials from January 1, 2007 to July 15, 2009...
October 2011: Clinical Pediatrics
https://www.readbyqxmd.com/read/17854166/heterotricyclic-himbacine-analogs-as-potent-orally-active-thrombin-receptor-protease-activated-receptor-1-antagonists
#7
Mariappan V Chelliah, Samuel Chackalamannil, Yan Xia, Keith Eagen, Martin C Clasby, Xiaobang Gao, William Greenlee, Ho-Sam Ahn, Jacqueline Agans-Fantuzzi, George Boykow, Yunsheng Hsieh, Matthew Bryant, Jairam Palamanda, Tze-Ming Chan, David Hesk, Madhu Chintala
Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4...
October 18, 2007: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/17578395/offloading-social-care-responsibilities-recent-experiences-of-local-voluntary-organisations-in-a-remote-urban-centre-in-british-columbia-canada
#8
Neil Hanlon, Mark Rosenberg, Rachael Clasby
Services offered by voluntary organisations are an integral but often overlooked component of health and social care. Of late, there has been a renewed interest in voluntary welfare provision as a viable alternative to state and market. Recent developments in welfare provision in Canada appear to have brought greater social care roles for the voluntary sector at the same time as new and arguably more restrictive funding and accountability mechanisms are being imposed by different arms of the state. To explore these issues more closely, the present paper examines the impressions and experiences of voluntary and formal sector providers of services for senior citizens and people with disabilities in a remote urban centre (population less than 100 000) in the interior of British Columbia, Canada...
July 2007: Health & Social Care in the Community
https://www.readbyqxmd.com/read/17574850/himbacine-derived-thrombin-receptor-par-1-antagonists-sar-of-the-pyridine-ring
#9
Yan Xia, Samuel Chackalamannil, Martin Clasby, Darío Doller, Keith Eagen, William J Greenlee, Hsingan Tsai, Jacqueline Agans-Fantuzzi, Ho-Sam Ahn, George C Boykow, Yunsheng Hsieh, Charles A Lunn, Madhu Chintala
The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate...
August 15, 2007: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/17490877/himbacine-derived-thrombin-receptor-antagonists-discovery-of-a-new-tricyclic-core
#10
Martin C Clasby, Samuel Chackalamannil, Michael Czarniecki, Darío Doller, Keith Eagen, William J Greenlee, Yan Lin, Jayaram R Tagat, Hsingan Tsai, Yan Xia, Ho-Sam Ahn, Jacqueline Agans-Fantuzzi, George Boykow, Madhu Chintala, Yunsheng Hsieh, Andrew T McPhail
The synthesis and biological activity of a novel series of thrombin receptor antagonists is described. This series of compounds showed excellent in vitro and in vivo potency. The most potent compound 40 had an IC(50) of 7.6 nM and showed robust inhibition of platelet aggregation in a cynomolgus monkey model after oral administration.
July 1, 2007: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/17201416/metabolism-based-identification-of-a-potent-thrombin-receptor-antagonist
#11
Martin C Clasby, Samuel Chackalamannil, Michael Czarniecki, Dario Doller, Keith Eagen, William Greenlee, Grace Kao, Yan Lin, Hsingan Tsai, Yan Xia, Ho-Sam Ahn, Jacqueline Agans-Fantuzzi, George Boykow, Madhu Chintala, Carolyn Foster, April Smith-Torhan, Kevin Alton, Matthew Bryant, Yunsheng Hsieh, Janice Lau, Jairam Palamanda
The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose...
January 11, 2007: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/16809059/the-place-embeddedness-of-social-care-restructuring-work-and-welfare-in-mackenzie-bc
#12
Neil Hanlon, Greg Halseth, Rachael Clasby, Virginia Pow
The concept of social care is valuable in examining how responsibilities for social support are distributed amongst private, public and voluntary interests. We argue that social care is embedded in place, by which we mean the social relations that determine who provides what are closely connected with the physically bounded settings of meaning and interaction in which these activities and relations occur. To illustrate the usefulness of these conceptions, we present a case study of the restructuring of work and welfare arrangements in Mackenzie, British Columbia, a remote and resource-dependent community in the province's northern interior...
June 2007: Health & Place
https://www.readbyqxmd.com/read/16380251/discovery-and-synthesis-of-a-novel-series-of-quinoline-based-thrombin-receptor-par-1-antagonists
#13
Martin C Clasby, Samuel Chackalamannil, Michael Czarniecki, Dario Doller, Keith Eagen, William J Greenlee, Yan Lin, Hsingan Tsai, Yan Xia, Ho-Sam Ahn, Jacqueline Agans-Fantuzzi, George Boykow, Madhu Chintala, Carolyn Foster, Matthew Bryant, Janice Lau
The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study.
March 15, 2006: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/16161991/discovery-of-potent-orally-active-thrombin-receptor-protease-activated-receptor-1-antagonists-as-novel-antithrombotic-agents
#14
Samuel Chackalamannil, Yan Xia, William J Greenlee, Martin Clasby, Darìo Doller, Hsingan Tsai, Theodros Asberom, Michael Czarniecki, Ho-Sam Ahn, George Boykow, Carolyn Foster, Jacqueline Agans-Fantuzzi, Matthew Bryant, Janice Lau, Madhu Chintala
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration...
September 22, 2005: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/12827994/the-use-of-surface-electromyographic-techniques-in-assessing-musculoskeletal-disorders-in-production-operations
#15
R G Clasby, D J Derro, L Snelling, S Donaldson
The use of surface electromyographic (SEMG) techniques in evaluating production line workstations is illustrated through the use of two case studies. Evaluation procedures are introduced. The results illustrate how SEMG can be used to document the strain upon muscles of the neck and shoulders and how workstations may be altered to comply with government regulations.
June 2003: Applied Psychophysiology and Biofeedback
https://www.readbyqxmd.com/read/9653512/potential-contributions-of-neck-muscle-dysfunctions-to-initiation-and-maintenance-of-carpal-tunnel-syndrome
#16
REVIEW
C C Donaldson, D V Nelson, D L Skubick, R G Clasby
A biomechanical perspective of the carpal tunnel (CT) is reviewed that lends itself to an understanding of carpal tunnel syndrome (CTS) from a broader pathophysiological perspective than focusing narrowly or solely on nerve disturbance in the extremity. A wider integration of physiological systems in the etiology and maintenance of CTS is proposed that links muscular dysfunction in the neck and possibly elsewhere to dysfunction at the CT. A significant subset of individuals who develop CTS have a primary contribution from muscular dysfunctions rather distal to the CT itself...
March 1998: Applied Psychophysiology and Biofeedback
https://www.readbyqxmd.com/read/9448617/variable-management-of-soft-tissue-sarcoma-regional-audit-with-implications-for-specialist-care
#17
R Clasby, K Tilling, M A Smith, C D Fletcher
BACKGROUND: The aim of this study was to determine how and by which specialties patients with soft tissue sarcoma are investigated and treated within a single large health region and with what outcomes and implications for resource uptake. METHODS: By retrieving the records of 377 patients with primary soft tissue sarcoma treated in the South-East Thames Region between 1986 and 1992, the presentation, investigation, treatment and outcome were compared with defined criteria for optimal management...
December 1997: British Journal of Surgery
https://www.readbyqxmd.com/read/9337464/management-of-sports-related-anterior-cruciate-ligament-injuries
#18
REVIEW
L Clasby, M A Young
Injuries from recreational and competitive sports activities have increased significantly during the past two decades. The anterior cruciate ligament (ACL) is one of the most commonly injured knee ligament in athletes. As the ACL is the knee's primary intra-articular stabilizer, injuries to this ligament can seriously alter athletes' physical activity levels or end their sports careers. The medical and surgical treatment options for a sports-related ACL injury depend upon the age of the patient, the type and degree of the ACL injury, and the anticipated future activity level of the athlete...
October 1997: AORN Journal
https://www.readbyqxmd.com/read/7778905/implementing-a-parent-present-induction-program
#19
P A Larosa-Nash, J M Murphy, L A Wade, L L Clasby
One of the greatest fears of children undergoing surgery is separation from their parents. Children for whom preoperative sedation is contraindicated often endure the distress of this separation and the beginning of anesthesia surrounded by masked strangers. Those who receive sedation often experience the invasiveness of a medication administered rectally or intramuscularly or the insertion of an IV line. Until recently, the doors to the operating room remained closed to family members. Like other hospitals throughout the country, however, Children's Hospital in Boston has responded to the concerns of parents and staff members by implementing a parent-present anesthesia induction program...
March 1995: AORN Journal
https://www.readbyqxmd.com/read/4499722/how-the-board-of-trustees-supports-the-director-of-the-school-of-nursing
#20
E M Clasby
No abstract text is available yet for this article.
1974: NLN Publications
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