Identifying clusters of coexisting conditions and outcomes among adults admitted to hospital with community-acquired pneumonia: a multicentre cohort study.

BACKGROUND: Little is known about patterns of coexisting conditions and their influence on clinical care or outcomes in adults admitted to hospital for community-acquired pneumonia (CAP). We sought to evaluate how coexisting conditions cluster in this population to advance understanding of how multimorbidity affects CAP. METHODS: We studied 11 085 adults admitted to hospital with CAP at 7 hospitals in Ontario, Canada. Using cluster analysis, we identified patient subgroups based on clustering of comorbidities in the Charlson Comorbidity Index. We derived and replicated cluster analyses in independent cohorts (derivation sample 2010-2015, replication sample 2015-2017), then combined these into a total cohort for final cluster analyses. We described differences in medications, imaging and outcomes. RESULTS: Patients clustered into 7 subgroups. The low comorbidity subgroup (n = 3052, 27.5%) had no comorbidities. The DM-HF-Pulm subgroup had prevalent diabetes, heart failure and chronic lung disease (n = 1710, 15.4%). One disease category defined each remaining subgroup, as follows: pulmonary (n = 1621, 14.6%), diabetes (n = 1281, 11.6%), heart failure (n = 1370, 12.4%), dementia (n = 1038, 9.4%) and cancer (n = 1013, 9.1%). Corticosteroid use ranged from 11.5% to 64.9% in the dementia and pulmonary subgroups, respectively. Piperacillin-tazobactam use ranged from 9.1% to 28.0% in the pulmonary and cancer subgroups, respectively. The use of thoracic computed tomography ranged from 5.7% to 36.3% in the dementia and cancer subgroups, respectively. Adjusting for patient factors, the risk of in-hospital death was greater in the cancer (adjusted odds ratio [OR] 3.12, 95% confidence interval [CI] 2.44-3.99), dementia (adjusted OR 1.57, 95% CI 1.05-2.35), heart failure (adjusted OR 1.66, 95% CI 1.35-2.03) and DM-HF-Pulm subgroups (adjusted OR 1.35, 95% CI 1.12-1.61), and lower in the diabetes subgroup (adjusted OR 0.67, 95% CI 0.50-0.89), compared with the low comorbidity group. INTERPRETATION: Patients admitted to hospital with CAP cluster into clinically recognizable subgroups based on coexisting conditions. Clinical care and outcomes vary among these subgroups with little evidence to guide decision-making, highlighting opportunities for research to personalize care.

Choosing Words Wisely: Residents' Use of Rhetorical Appeals in Conversations About Unnecessary Tests.

PURPOSE: To characterize how residents employ rhetorical appeals (i.e., the strategic use of communication to achieve specifiable goals) when discussing unnecessary diagnostic tests with patients. METHOD: In 2015, senior hematology residents from 10 Canadian universities participating in a national formative objective structured clinical examination (OSCE) completed a resource stewardship communication station. In this communication scenario, a standardized patient (SP) portrayed a patient requesting unnecessary thrombophilia testing following early pregnancy loss. The authors performed a thematic analysis of audio transcripts using a qualitative description approach to identify residents' rhetorical appeals to logic (rational appeals), credibility, and emotion. RESULTS: For persuasive communication, residents (n = 27) relied primarily on rational appeals that fit into 3 categories (with themes) focused on medical evidence (poor utility, professional guidelines and recommendations), avoidance of harm (insurance implications, unnecessary or potentially harmful interventions, patient anxiety), and reassurance to patient (normalizing, clinical pretest probability, criteria for reconsidering testing). Appeals to credibility and emotion were rarely used. CONCLUSIONS: In an OSCE setting, residents relied predominantly on rational appeals when engaging SPs in conversations about unnecessary tests. These observations yield insights into how recent emphasis within residency education on appropriate test utilization may manifest when residents put recommendations into practice in conversations with patients. This study's framework of rational appeals may be helpful in designing communication curricula about unnecessary testing. Future studies should explore rhetoric about unnecessary testing in the clinical environment, strategies to teach and coach residents leading these conversations, and patients' preferences and responses to different appeals.

Value of routine echocardiography in the management of stroke.

BACKGROUND: Transthoracic echocardiography is routinely performed in patients with stroke or transient ischemic attack (TIA) to help plan secondary stroke management, but recent data evaluating its usefulness in this context are lacking. We sought to evaluate the value of echocardiography for identifying clinically actionable findings for secondary stroke prevention. METHODS: We conducted a multicentre cohort study of patients admitted to hospital with stroke or TIA between 2010 and 2015 at 2 academic hospitals in Toronto, Ontario, Canada. Clinically actionable echocardiographic findings for secondary stroke prevention included cardiac thrombus, patent foramen ovale, atrial myxoma or valvular vegetation. We identified patient characteristics associated with clinically actionable findings using logistic regression. RESULTS: Of the 1862 patients with stroke or TIA we identified, 1272 (68%) had at least 1 echocardiogram. Nearly all echocardiograms were transthoracic; 1097 (86%) were normal, 1 (0.08%) had an atrial myxoma, 2 (0.2%) had a valvular vegetation, 11 (0.9%) had a cardiac thrombus and 66 (5.2%) had a PFO. Patent foramen ovale was less likely among patients older than 60 years (adjusted odds ratio [OR] 0.34, 95% confidence interval [CI] 0.20-0.57), with prior stroke or TIA (adjusted OR 0.31, 95% CI 0.09-0.76) or with dyslipidemia (adjusted OR 0.39, 95% CI 0.15-0.84). Among the 130 patients with cryptogenic stroke who had an echocardiogram (n = 110), a PFO was detected in 19 (17%) on transthoracic echocardiogram. INTERPRETATION: Most patients with stroke or TIA had a normal echocardiogram, with few having clinically actionable findings for secondary stroke prevention. Clinically actionable findings, specifically PFO, were more common in patients with cryptogenic stroke.

Communicating wisely: teaching residents to communicate effectively with patients and caregivers about unnecessary tests.

BACKGROUND: With rising healthcare costs and a focus on quality, there is a growing need to promote resource stewardship in medical education. Physicians need to be able to communicate effectively with patients/caregivers seeking tests and treatments that are unnecessary. This study aimed to evaluate the impact of an interactive workshop on residents' knowledge of resource stewardship and communication skills when counseling patients/caregivers about requests for unnecessary testing. METHODS: Participants were 83 Internal Medicine and Pediatrics residents at the University of Toronto in 2014-15. The evaluation compared resource stewardship knowledge and communication skills of 57 (69%) residents that attended the resource stewardship workshop to 26 residents (31%) who did not. Knowledge and communication skills assessment consisted of a written test and a structured assessment using standardized patient raters, respectively. A linear regression was applied to determine predictors of overall communication skills performance. RESULTS: Workshop attendance resulted in better performance on the knowledge test (4.3 ± 1.9 vs. 3.1 ± 1.7 out of 8, p = 0.01), but not better performance on the communication skills assessment (4.1 ± 0.8 vs. 4.0 ± 0.9 out of 5, p = 0.56). Higher training level (p = 0.01) and knowledge test scores (p = 0.046) were independent predictors of better overall communication skills, after adjusting for gender, training level, workshop attendance, knowledge and self-reported prior feedback on communication skills. CONCLUSIONS: An interactive workshop can improve knowledge of resource stewardship, but improving communication skills with patients/caregivers about unnecessary testing may require additional training or reinforcement in the clinical learning environment. These teaching and assessment approaches can support the integration of education on resource stewardship into medical education.

Design and methods of the Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen SignificantlY) study: An investigator-blinded randomized controlled trial of education and feedback intervention to reduce inappropriate echocardiograms.

BACKGROUND: Appropriate use criteria (AUC) for transthoracic echocardiography (TTE) were developed to address concerns regarding inappropriate use of TTE. A previous pilot study suggests that an educational and feedback intervention can reduce inappropriate TTEs ordered by physicians in training. It is unknown if this type of intervention will be effective when targeted at attending level physicians in a variety of clinical settings. AIMS: The aim of this international, multicenter study is to evaluate the hypothesis that an AUC-based educational and feedback intervention will reduce the proportion of inappropriate echocardiograms ordered by attending physicians in the ambulatory environment. METHODS: In an ongoing multicentered, investigator-blinded, randomized controlled trial across Canada and the United States, cardiologists and primary care physicians practicing in the ambulatory setting will be enrolled. The intervention arm will receive (1) a lecture outlining the AUC and most recent available evidence highlighting appropriate use of TTE, (2) access to the American Society of Echocardiography mobile phone app, and (3) individualized feedback reports e-mailed monthly summarizing TTE ordering behavior including information on inappropriate TTEs and brief explanations of the inappropriate designation. The control group will receive no education on TTE appropriate use and order TTEs as usual practice. CONCLUSIONS: The Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly in an education RCT) study is the first multicenter randomized trial of an AUC-based educational intervention. The study will examine whether an education and feedback intervention will reduce the rate of outpatient inappropriate TTEs ordered by attending level cardiologists and primary care physicians (www.clinicaltrials.gov identifier NCT02038101).

Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia.

The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy.

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents.

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.

Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies.

A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non-tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.