Derivation of the Falls Decision Rule to exclude intracranial bleeding without head CT in older adults who have fallen.

BACKGROUND: Ground-level falls are common among older adults and are the most frequent cause of traumatic intracranial bleeding. The aim of this study was to derive a clinical decision rule that safely excludes clinically important intracranial bleeding in older adults who present to the emergency department after a fall, without the need for a computed tomography (CT) scan of the head. METHODS: This prospective cohort study in 11 emergency departments in Canada and the United States enrolled patients aged 65 years or older who presented after falling from standing on level ground, off a chair or toilet seat, or out of bed. We collected data on 17 potential predictor variables. The primary outcome was the diagnosis of clinically important intracranial bleeding within 42 days of the index emergency department visit. An independent adjudication committee, blinded to baseline data, determined the primary outcome. We derived a clinical decision rule using logistic regression. RESULTS: The cohort included 4308 participants, with a median age of 83 years; 2770 (64%) were female, 1119 (26%) took anticoagulant medication and 1567 (36%) took antiplatelet medication. Of the participants, 139 (3.2%) received a diagnosis of clinically important intracranial bleeding. We developed a decision rule indicating that no head CT is required if there is no history of head injury on falling; no amnesia of the fall; no new abnormality on neurologic examination; and the Clinical Frailty Scale score is less than 5. Rule sensitivity was 98.6% (95% confidence interval [CI] 94.9%-99.6%), specificity was 20.3% (95% CI 19.1%-21.5%) and negative predictive value was 99.8% (95% CI 99.2%-99.9%). INTERPRETATION: We derived a Falls Decision Rule, which requires external validation, followed by clinical impact assessment. Trial registration: ClinicalTrials. gov, no. NCT03745755.

POCUS literature primer: key papers on POCUS in cardiac arrest and shock.

OBJECTIVE: The objective of this study is to identify the top five most influential papers published on the use of point-of-care ultrasound (POCUS) in cardiac arrest and the top five most influential papers on the use of POCUS in shock in adult patients. METHODS: An expert panel of 14 members was recruited from the Canadian Association of Emergency Physicians (CAEP) Emergency Ultrasound Committee and the Canadian Ultrasound Fellowship Collaborative. The members of the panel are ultrasound fellowship trained or equivalent, are engaged in POCUS research, and are leaders in POCUS locally and nationally in Canada. A modified Delphi process was used, consisting of three rounds of sequential surveys and discussion to achieve consensus on the top five most influential papers for the use of POCUS in cardiac arrest and shock. RESULTS: The panel identified 39 relevant papers on POCUS in cardiac arrest and 42 relevant papers on POCUS in shock. All panel members participated in all three rounds of the modified Delphi process, and we ultimately identified the top five most influential papers on POCUS in cardiac arrest and also on POCUS in shock. Studies include descriptions and analysis of safe POCUS protocols that add value from a diagnostic and prognostic perspective in both populations during resuscitation. CONCLUSION: We have developed a reading list of the top five influential papers on the use of POCUS in cardiac arrest and shock to better inform residents, fellows, clinicians, and researchers on integrating and studying POCUS in a more evidence-based manner.

RéSUMé: OBJECTIF: L'objectif de cette étude est d'identifier les cinq articles les plus influents publiés sur l'utilisation de l'échographie au point de soin (POCUS) dans l'arrêt cardiaque et les cinq articles les plus influents sur l'utilisation de POCUS dans le choc chez les patients adultes. MéTHODES: Un comité d'experts composé de 14 membres a été recruté par le Comité d'échographie d'urgence de l'Association canadienne des médecins d'urgence (ACMU) et le Canadian Ultrasound Fellowship Collaborative. Les membres du comité sont formés en échographie ou l'équivalent, participent à la recherche sur le POCUS et sont des chefs de file du POCUS à l'échelle locale et nationale au Canada. Un processus Delphi modifié a été utilisé, consistant en trois séries de sondages séquentiels et de discussions pour parvenir à un consensus sur les cinq articles les plus influents pour l'utilisation de POCUS dans les arrêts cardiaques et les chocs. RéSULTATS: Le panel a identifié 39 articles pertinents sur le POCUS en arrêt cardiaque et 42 articles pertinents sur le POCUS en état de choc. Tous les membres du panel ont participé aux trois cycles du processus Delphi modifié, et nous avons finalement identifié les cinq articles les plus influents sur le POCUS en arrêt cardiaque et aussi sur le POCUS en état de choc. Les études comprennent des descriptions et des analyses de protocoles POCUS sûrs qui ajoutent de la valeur d'un point de vue diagnostique et pronostique dans les deux populations pendant la réanimation. CONCLUSION: Nous avons dressé une liste de lecture des cinq principaux articles influents sur l'utilisation du POCUS en cas d'arrêt cardiaque et de choc afin de mieux informer les résidents, les boursiers, les cliniciens et les chercheurs sur l'intégration et l'étude du POCUS d'une manière plus factuelle.

Point-of-Care Ultrasound (POCUS) Literature Primer: Key Papers on Renal and Biliary POCUS.

Objective The objective of this study is to identify the top five influential papers published on renal point-of-care ultrasound (POCUS) and the top five influential papers on biliary POCUS in adult patients. Methods A 14-member expert panel was recruited from the Canadian Association of Emergency Physicians (CAEP) Emergency Ultrasound Committee and the Canadian Ultrasound Fellowship Collaborative. All panel members have had ultrasound fellowship training or equivalent, are actively engaged in POCUS scholarship, and are involved with POCUS at their local site and nationally in Canada. We used a modified Delphi process consisting of three rounds of sequential surveys and discussion to achieve consensus on the top five influential papers for renal POCUS and biliary POCUS. Results The panel identified 27 relevant papers on renal POCUS and 30 relevant papers on biliary POCUS. All panel members participated in all three rounds of the modified Delphi process, and after completing this process, we identified the five most influential papers on renal POCUS and the five most influential papers on biliary POCUS. Conclusion We have developed a list, based on expert opinion, of the top five influential papers on renal and biliary POCUS to better inform all trainees and clinicians on how to use these applications in a more evidence-based manner. This list will also be of interest to clinicians and researchers who strive to further advance the field of POCUS.

Radiosensitization of glioma cells by modulation of Met signalling with the hepatocyte growth factor neutralizing antibody, AMG102.

The hepatocyte growth factor (HGF)/Met signalling pathway is up-regulated in many cancers, with downstream mediators playing a role in DNA double strand break repair. Previous studies have shown increased radiosensitization of tumours through modulation of Met signalling by genetic methods. We investigated the effects of the anti-HGF monoclonal antibody, AMG102, on the response to ionizing radiation in a model of glioblastoma multiforme in vitro and in vivo. Radiosensitivity was evaluated in vitro in the U-87 MG human glioma cell line. Met activation was measured by Western blot, and the effect on survival following radiation was evaluated by clonogenic assay. Mechanism of cell death was evaluated by apoptosis and mitotic catastrophe assays. DNA damage was quantitated by γH2AX foci and neutral comet assay. Growth kinetics of subcutaneous tumours was used to assess the effects of AMG102 on in vivo tumour radiosensitivity. AMG102 inhibited Met activation after irradiation. An enhancement of radiation cell killing was shown with no toxicity using drug alone. Retention of γH2AX foci at 6 and 24 hrs following the drug/radiation combination indicated an inhibition of DNA repair following radiation, and comet assay confirmed DNA damage persisting over the same duration. At 48 and 72 hrs following radiation, a significant increase of cells undergoing mitotic catastrophe was seen in the drug/radiation treated cells. Growth of subcutaneous tumours was slowed in combination treated mice, with an effect that was greater than additive for each modality individually. Modulation of Met signalling with AMG102 may prove a novel radiation sensitizing strategy. Our data indicate that DNA repair processes downstream of Met are impaired leading to increased cell death through mitotic catastrophe.

Imaging intratumoral convection: pressure-dependent enhancement in chemotherapeutic delivery to solid tumors.

PURPOSE: Low-molecular weight (LMW) chemotherapeutics are believed to reach tumors through diffusion across capillary beds as well as membrane transporters. Unexpectedly, the delivery of these agents seems to be augmented by reductions in tumor interstitial fluid pressure, an effect typically associated with high-molecular weight molecules that reach tumors principally through convection. We investigated the hypothesis that improved intratumoral convection can alter tumor metabolism and enhance the delivery of a LMW chemotherapeutic agent to solid tumors. EXPERIMENTAL DESIGN: For this purpose, we applied 31P/19F magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging (MRSI) to examine the influence of type I collagenase on tumor bioenergetics and the delivery of 5-fluorouracil (5FU) to HT29 human colorectal tumors grown s.c. in mice. RESULTS: Collagenase effected a 34% reduction in tumor interstitial fluid pressure with an attendant disintegration of intratumoral collagen. Neither mice-administered collagenase nor controls receiving PBS showed changes in (31)phosphorus MRS-measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pi(e)) was observed in tumors of collagenase-treated animals. (31)Phosphorus MRSI showed that this increase underscored a more homogeneous distribution of Pi(e) in tumors of experimental mice. (19)Fluorine MRS showed that these changes were associated with a 50% increase in 5FU uptake in tumors of experimental versus control animals; however, this increase resulted in an increase in 5FU catabolites rather than fluoronucleotide intermediates that are required for subsequent cytotoxicity. CONCLUSIONS: These data indicate that the modulation of convective flow within tumors can improve the delivery of (LMW) chemotherapeutics and show the potential role for noninvasive imaging of this process in vivo.

Targeted elimination of prostate cancer by genetically directed human T lymphocytes.

The genetic transfer of antigen receptors is a powerful approach to rapidly generate tumor-specific T lymphocytes. Unlike the physiologic T-cell receptor, chimeric antigen receptors (CARs) encompass immunoglobulin variable regions or receptor ligands as their antigen recognition moiety, thus permitting T cells to recognize tumor antigens in the absence of human leukocyte antigen expression. CARs encompassing the CD3zeta chain as their activating domain induce T-cell proliferation in vitro, but limited survival. The requirements for genetically targeted T cells to function in vivo are less well understood. We have, therefore, established animal models to assess the therapeutic efficacy of human peripheral blood T lymphocytes targeted to prostate-specific membrane antigen (PSMA), an antigen expressed in prostate cancer cells and the neovasculature of various solid tumors. In vivo specificity and antitumor activity were assessed in mice bearing established prostate adenocarcinomas, using serum prostate-secreted antigen, magnetic resonance, computed tomography, and bioluminescence imaging to investigate the response to therapy. In three tumor models, orthotopic, s.c., and pulmonary, we show that PSMA-targeted T cells effectively eliminate prostate cancer. Tumor eradication was directly proportional to the in vivo effector-to-tumor cell ratio. Serial imaging further reveals that the T cells must survive for at least 1 week to induce durable remissions. The eradication of xenogeneic tumors in a murine environment shows that the adoptively transferred T cells do not absolutely require in vivo costimulation to function. These results thus provide a strong rationale for undertaking phase I clinical studies to assess PSMA-targeted T cells in patients with metastatic prostate cancer.

Does Mode of Transport Confer a Mortality Benefit in Trauma Patients? Characteristics and Outcomes at an Ontario Lead Trauma Hospital.

OBJECTIVES: Evidence-based guidelines regarding the optimal mode of transport for trauma patients from scene to trauma centre are lacking. The purpose of this study was to investigate the relationship between trauma patient outcomes and mode of transport at a single Ontario Level I Trauma Centre, and specifically to investigate if the mode of transport confers a mortality benefit. METHODS: A historical, observational cohort study was undertaken to compare rotor-wing and ground transported patients. Captured data included demographics, injury severity, temporal and mortality variables. TRISS-L analysis was performed to examine mortality outcomes. RESULTS: 387 rotor-wing transport and 2,759 ground transport patients were analyzed over an 18-year period. Rotor-wing patients were younger, had a higher Injury Severity Score, and had longer prehospital transport times. Mechanism of injury was similarly distributed between groups. After controlling for heterogeneity with TRISS-L analysis, the mortality of rotor-wing patients was found to be lower than predicted mortality, whereas the converse was found with ground patients. CONCLUSION: Rotor-wing and ground transported trauma patients represent heterogeneous populations. Accounting for these differences, rotor-wing patients were found to outperform their predicted mortality, whereas ground patients underperformed predictions.

A systematic review of curricular interventions teaching transitional care to physicians-in-training and physicians.

PURPOSE: To systematically review and describe published interventions about teaching continuity-of-care best practices, embodied by transitional care, to physician-trainees and physicians. METHOD: The authors performed a systematic review of interventions indexed in PubMed, ISI Web of Science, Educational Resources Information Center, professional society Web sites, education databases, and hand-selected references. English-language articles published between 1973 and 2010 that demonstrated purposeful, directed education of physician-trainees and physicians on topics consistent with the contemporary definition of transitional care were included. Abstracted data included intended audience, duration/intensity, objectives, resources used, learner assessment, and curricular evaluation method. RESULTS: A dramatic increase in the number of published interventions teaching transitional care was noted in the last 10 years. Learners included preclinical medical students through attending physicians and also included allied health professionals. Brief, self-limited interactions in large groups were the most frequent mode of interaction. A wide array of objectives and resources used were represented. Most interventions provided a method for assessing knowledge acquisition by the learner; however, few interventions provided a mechanism for eliciting feedback from learners. CONCLUSIONS: Proficiency in providing transitional care is an essential skill for medical practitioners. Historically, there have been few curricular interventions teaching this topic; however, recently a dramatic increase in the number of interventions has occurred. A diverse range of learners, modes of delivery, and intended objectives are represented. In establishing a pooled description of published interventions, this review provides a comprehensive and novel resource for educators charged with designing curricula for all medical professionals.

Imaging transgene activity in vivo.

The successful translation of gene therapy for clinical application will require the assessment of transgene activity as a measure of the biological function of a therapeutic transgene. Although current imaging permits the noninvasive detection of transgene expression, the critical need for quantitative imaging of the action of the expressed transgene has not been met. In vivo magnetic resonance spectroscopic imaging (MRSI) was applied to quantitatively delineate both the concentration and activity of a cytosine deaminase-uracil phosphoribosyltransferase (CD-UPRT) fusion enzyme expressed from a transgene. MRSI enabled the generation of anatomically accurate maps of the intratumoral heterogeneity in fusion enzyme activity. We observed an excellent association between the CD-UPRT concentration and activity and the percentage of CD-UPRT(+) cells. Moreover, the regional levels of UPRT activity, as measured by imaging, correlated well with the biological affect of the enzyme. This study presents a translational imaging paradigm for precise, in vivo measurements of transgene activity with potential applications in both preclinical and clinical settings.

High-resolution imaging of bone precursor cells within the intact bone marrow cavity of living mice.

Bone precursor cells (BPCs) play a critical role in bone maintenance and regeneration. Currently, no tool exists to study BPCs or other bone marrow cell types directly within their complex microenvironment. Here, we describe in vivo magnetic resonance imaging (MRI) of anatomical structures inside the medullary cavity of the mouse femur. We demonstrate that BPCs passively labeled with iron oxide-containing particles can be monitored by MRI within the intact bone marrow at an in-plane resolution of 43x25 microm. Anatomical detail provided by MRI is complemented by functional optical imaging of reporter gene expression. Single-cell dual iron oxide-reporter gene labeling has potential for combined cell tracking and cell biology studies. In summary, we describe a versatile platform suitable for studying the biology of many bone marrow cell types in living bone.