Provider Perspectives on the Use of Evidence-based Risk Stratification Tools in the Evaluation of Pulmonary Embolism: A Qualitative Study.

OBJECTIVES: Providers often pursue imaging in patients at low risk of pulmonary embolism (PE), resulting in imaging yields <10% and false-positive imaging rates of 10% to 25%. Attempts to curb overtesting have had only modest success and no interventions have used implementation science frameworks. The objective of this study was to identify barriers and facilitators to the adoption of evidence-based diagnostic testing for PE. METHODS: We conducted semistructured interviews with a purposeful sample of providers. An interview guide was developed using the implementation science frameworks, consolidated framework for implementation research, and theoretical domains framework. Interviews were recorded, transcribed, and analyzed in an iterative process. Emergent themes were identified, discussed, and organized. RESULTS: We interviewed 23 providers from four hospital systems, and participants were diverse with regard to years in practice and practice setting. Barriers were predominately at the provider level and included lack of knowledge of the tools, particularly misunderstanding of the validated scoring systems in Wells, as well as risk avoidance and need for certainty. Barriers to prior implementation strategies included the perception of a clinical decision support (CDS) tool for PE as adding steps with little value; most participants reported that they overrode CDS interventions because they had already made the decision. All providers identified institution-level strategies as facilitators to use, including endorsed guidelines, audit feedback with peer comparison about imaging yield, and peer pressure. CONCLUSIONS: This exploration of the use of risk stratification tools in the evaluation of PE found that barriers to use primarily exist at the provider level, whereas facilitators to the use of these tools are largely perceived at the level of the institution. Future efforts to promote the evidence-based diagnosis of PE should be informed by these determinants.

Avoidance of APOBEC3B-induced mutation by error-free lesion bypass.

APOBEC cytidine deaminases mutate cancer genomes by converting cytidines into uridines within ssDNA during replication. Although uracil DNA glycosylases limit APOBEC-induced mutation, it is unknown if subsequent base excision repair (BER) steps function on replication-associated ssDNA. Hence, we measured APOBEC3B-induced CAN1 mutation frequencies in yeast deficient in BER endonucleases or DNA damage tolerance proteins. Strains lacking Apn1, Apn2, Ntg1, Ntg2 or Rev3 displayed wild-type frequencies of APOBEC3B-induced canavanine resistance (CanR). However, strains without error-free lesion bypass proteins Ubc13, Mms2 and Mph1 displayed respective 4.9-, 2.8- and 7.8-fold higher frequency of APOBEC3B-induced CanR. These results indicate that mutations resulting from APOBEC activity are avoided by deoxyuridine conversion to abasic sites ahead of nascent lagging strand DNA synthesis and subsequent bypass by error-free template switching. We found this mechanism also functions during telomere re-synthesis, but with a diminished requirement for Ubc13. Interestingly, reduction of G to C substitutions in Ubc13-deficient strains uncovered a previously unknown role of Ubc13 in controlling the activity of the translesion synthesis polymerase, Rev1. Our results highlight a novel mechanism for error-free bypass of deoxyuridines generated within ssDNA and suggest that the APOBEC mutation signature observed in cancer genomes may under-represent the genomic damage these enzymes induce.

Incidentally discovered osseous metaplasia within high-grade urothelial carcinoma of the bladder.

A 66-year-old male presented with gross hematuria and acute renal failure secondary to bilateral ureteral obstruction. Further work-up revealed muscle invasive urothelial carcinoma. Pathologic examination following radical cystoprostatectomy revealed high grade urothelial carcinoma with focal tumor-associated stromal osseous metaplasia. Reactive bone formation within urothelial carcinoma is a very rare clinical entity. Although typically benign, the presence of mature bone elements warrants thorough examination for sarcomatoid components.

Thermoregulation during mild exercise at different circadian times.

Eight healthy subjects exercised at 90watts on a cycle ergometer on four occasions, at times close to the minimum, maximum rate of rise, maximum, and maximum rate of fall of their resting core temperature. The duration of exercise was determined by the time taken for the core (rectal) temperature to reach an equilibrium value. Forearm skin blood flow and temperature were measured regularly during the exercise, as were heart rate and ratings of perceived exertion. Sweat loss was calculated by weighing the subjects nude before and after the exercise. The rise of heart rate was not significantly different at the four times of exercise, though the rating of perceived exertion was greatest at 05:00 h. Resting core temperatures showed a significant circadian rhythm at rest (the timing of which confirmed that exercise was being performed at the required times), but the amplitude of this rhythm was decreased significantly by the exercise. The initial rate of rise of core temperature, and the total rise from the resting to the equilibrium value, were both inversely proportional to resting temperature. The time-course of the rise was accurately described by a negative-exponential model, but this model gave no evidence that the kinetics of the equilibration process depended upon the time of day. The thermoregulatory responses to the rise in core temperature--the amount of total sweat loss and rises in forearm skin blood flow and temperature--differed according to the time of exercise. In general, the responses were significantly greater at 17:00h compared with 05:00h, and at 23:00 h compared with 11:00 h. The results accord with predictions made on the basis of previous work by us in which core temperature rhythms have been separated into components due to the endogenous body clock and due to the direct effects of spontaneous activity. The results are discussed in terms of the ecological implications of the differing capabilities of humans to deal with heat loads produced by spontaneous activity or mild exercise at different phases of the circadian rhythm of resting core temperature.