ABSTRACT
Radiation exposure during trauma care has increased in recent years. Radiation risk to providers during the care of injured patients is not well defined. We aimed to gather environmental exposure data from dosimeters placed at fixed points in the trauma bay to act as surrogates for personnel radiation exposure during trauma team activations. Forty-four (44) radiation dosimeters were placed throughout a single trauma bay in a university level 1 trauma center. We analyzed shallow (SDE) and deep dose equivalents (DDE) over 6 months. We measured distance from the radiation source for each dosimeter. Four controls were included. We recorded patient injury and X-ray data for each patient. During the study period, 417 patients were evaluated in the trauma bay under study. Mean ISS was 14.3 (range 0-75). A total of 2,107 plain X-rays were taken, with a mean of 5.1 X-rays per patient (range 0-32). Extremity films were most often performed, followed by chest and shoulder films. No measurable dose was identified with the dosimeter controls. The majority (27, 68 %) of dosimeters registered the lowest doses (<1 mSv DDE). Five dosimeters revealed doses between 1 and 2 mSv DDE. Four dosimeters registered over 2 mSv DDE, with a mean DDE of 3 mSv. Distances of less than 5 ft from the radiation source had the highest DDE dose. Maximum annual occupational DDE dose is conventionally 50 mSv. None of the dosimeters registered DDE doses over 4.31 mSv during the study period, supporting low radiation risk to providers in the trauma bay.
Subject(s)
Occupational Exposure/analysis , Radiation Dosage , Radiology , Trauma Centers , Wounds and Injuries/diagnostic imaging , Female , Humans , Male , Prospective Studies , Radiography , Radiometry , Risk Assessment , Risk Factors , X-RaysABSTRACT
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Janus Kinase 2/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Proline/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , Haplorhini , High-Throughput Screening Assays , Janus Kinase 2/metabolism , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Proline/administration & dosage , Proline/chemistry , Proline/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.
Subject(s)
Antineoplastic Agents/chemical synthesis , Receptors, Lysosphingolipid/antagonists & inhibitors , Administration, Oral , Amides/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line , Cell Proliferation/drug effects , Dogs , Haplorhini , High-Throughput Screening Assays , Mice , Neovascularization, Pathologic , Proline/analogs & derivatives , Proline/chemical synthesis , Proline/pharmacokinetics , Proline/pharmacology , Rats , Serine/analogs & derivatives , Serine/chemical synthesis , Serine/pharmacokinetics , Serine/pharmacology , Stereoisomerism , Xenograft Model Antitumor AssaysABSTRACT
This paper presents a new approach to cost analysis of family planning programmes that focuses on behaviour change of programme clients as the final 'output' rather than units of contraceptive services delivered, as does the familiar couple-years-of-protection index. It is useful to know how much it costs to deliver a unit of contraceptive services, but it would also seem useful to know how much it costs to change a prospective client's behaviour. The proposed approach rests on the familiar 'steps to behaviour change' paradigm and: (1) develops a methodology for applying a client-behaviour-change-centred cost analysis to programme activities; (2) tests the methodology and concepts by applying them retrospectively to a case study of mass media interventions in Egypt; (3) derives cost per unit of behaviour changes for these Egyptian communications campaigns to demonstrate the workability of the approach. This framework offers a new approach to impact evaluation that would seem to be applicable to other components of family planning and reproductive health programmes.
