R-spondins are secreted ligands that bind cell surface receptors and activate Wnt/β-catenin signaling. Human mutations and gene inactivation studies in mice have revealed a role for these four proteins (RSPO1-4) in diverse developmental processes ranging from sex determination to limb development. Among the genes coding for R-spondins, only inactivation of Rspo3 shows early embryonic lethality (E10.5 in mice). Therefore, a conditional allele of this gene is necessary to understand the function of R-spondins throughout murine development. To address this need, we have produced an allele in which loxP sites flank exons 2-4 of Rspo3, allowing tissue-specific deletion of these exons in the presence of Cre recombinase. We used these mice to investigate the role of Rspo3 during limb development and found that limbs ultimately developed normally in the absence of Rspo3 function. However, severe hindlimb truncations resulted when Rspo3 and Rspo2 mutations were combined, demonstrating redundant function of these genes.

Invasive aspergillosis (IA) is an opportunistic infection that is often life threatening in the immunocompromised host. Early diagnosis is critical, especially given the efficacy and availability of several new anti-fungal therapies. Current (2008) diagnostic criteria have limited ability to detect early infection and are aimed at establishing disease. Although histopathology and culture techniques have traditionally been used to make a proven diagnosis of IA, their dependence on tissue samples and slow turnaround times hamper early confirmation of IA. Serologic detection of circulating galactomannan and 1,3-β-D-glucan fungal biomarkers show promise for improving the diagnosis of IA, and their use is included in the EORTC/MSG diagnostic criteria for IA. Numerous studies have evaluated the diagnostic performance of these two biomarkers and shown that they have suboptimal sensitivity when used alone for early diagnosis of proven IA. Currently available molecular assays also suffer from a lack of standardization. Evaluation of the use of different combinations of test methods to enhance diagnostic accuracy is also being done but prompt, accurate diagnosis of IA remains a clinical and diagnostic challenge. The clinical validity and limitations of biomarkers and current molecular methods for the early diagnosis of IA are summarized in this review with respect to the different patient populations at risk for this serious infection.

BackgroundCurriculum development and implementation for internal medicine point-of-care ultrasound (IM POCUS) continues to be a challenge for many residency training programs. Education indicators may provide a useful framework to support curriculum development and implementation efforts across programs in order to achieve a consistent high-quality educational experience.ObjectiveThis study seeks to establish consensus-based recommendations for education indicators for IM POCUS training programs in Canada.DesignThis consensus study uses a modified nominal group technique for voting in the initial round, followed by two additional rounds of online voting, with consensus defined as agreement by at least 80% of the participants.ParticipantsParticipants were 22 leaders with POCUS and/or education expertise from 13 Canadian internal medicine residency programs across 7 provinces.Main MeasuresEducation indicators considered were those that related to aspects of the POCUS educational system, could be presented by a single statistical measure, were readily understood, could be reliably measured to provide a benchmark for measuring change, and represented a policy issue. We excluded a priori indicators with low feasibility, are impractical, or assess learner reactions. Candidate indicators were drafted by two academic internists with post-graduate training in POCUS and medical education. These indicators were reviewed by two internists with training in quality improvement prior to presentation to the expert participants.Key ResultsOf the 52 candidate education indicators considered, 6 reached consensus in the first round, 12 in the second, and 4 in the third round. Only 5 indicators reached consensus to be excluded; the remaining indicators did not reach consensus.ConclusionsThe Canadian Internal Medicine Ultrasound (CIMUS) group recommends 22 education indicators be used to guide and monitor internal medicine POCUS curriculum development efforts in Canada.Electronic supplementary materialThe online version of this article (10.1007/s11606-019-05124-1) contains supplementary material, which is available to authorized users.

BackgroundRepetitive inpatient laboratory testing contributes to waste in healthcare. We evaluated an intervention bundle combining education and multilevel social comparison feedback to safely reduce repetitive use of inpatient routine laboratory tests.MethodsThis non-randomised controlled pre-intervention post-intervention study was conducted in four adult hospitals from October 2016 to March 2018. In the medical teaching unit (MTU) of the intervention site, learners received education and aggregate social comparison feedback and attending internists received individual comparison feedback on routine laboratory test utilisation. MTUs of the remaining three sites served as control units. Number and cost of routine laboratory tests ordered per patient-day before and after the intervention was compared with the control units, adjusting for patient factors. Safety endpoints included number of critically abnormal laboratory test results, number of stat laboratory test orders, patient length of stay, transfer rate to the ICU, and 30-day readmission and mortality.ResultsA total of 14 000 patients were included. Pre-intervention and post-intervention groups were similar in age, sex, Charlson Comorbidity Index and length of stay. From the pre-intervention period to the post-intervention period, significantly fewer routine laboratory tests were ordered at the intervention MTU (incidence rate ratio=0.89; 95% CI 0.79 to 1.00; p=0.048) with associated costs savings of $C68 877 (p=0.020) as compared with the control sites. The variability in the ordering pattern of internists at the intervention site also decreased post-intervention. No worsening was noted in the safety endpoints between the pre-intervention and post-intervention period at the intervention unit compared with the controls.ConclusionsCombination of education and multilevel social comparison feedback significantly and safely led to cost savings through reduced use of routine laboratory tests in hospitalised patients.

Pneumocystis pneumonia is caused by Pneumocystis jirovecii, an opportunistic fungal pathogen. Presently, many clinical microbiology laboratories rely on direct microscopic detection of P jirovecii. The validation, and clinical and laboratory development of a qualitative P jirovecii real-time polymerase chain reaction assay for the rapid detection of Pneumocystis pneumonia is discussed by the authors. In addition, this new technique is compared with the existing gold-standard immunofluorescence assay.