Royal University Hospital

D-dimer testing can reduce imaging utilization in the workup of pulmonary embolism, but the optimal cutoff remains unclear. The conventional D-dimer cutoff is < 500µg/L Fibrinogen Equivalent Units, while the age-adjusted cutoff in patients over 50 is age × 10. Newer probability-adjusted strategies-the YEARS criteria and PEGeD algorithm-allow a higher threshold (D-dimer < 1000µg/L) for select low-risk patients. We aimed to retrospectively compare the diagnostic accuracy of four evidence-based pathways to exclude pulmonary embolism without imaging among our emergency department patients who were imaged. A historical patient cohort was generated including all adults who received computed tomography pulmonary angiography or ventilation-perfusion scans after D-dimer testing in three emergency departments in a large urban Canadian center. Electronic medical records were reviewed to retrospectively compare the test performance of four D-dimer pathways: (i) conventional, (ii) age-adjusted, (iii) YEARS, and (iv) PEGeD. Of 1092 patients, 129 had pulmonary embolism. Conventional and age-adjusted cutoffs were both 100% sensitive (95% CI, 97.1-100.0), with specificities of 3.5% (2.5-4.9) and 6.4% (5.1-8.2). YEARS was 93.8% sensitive (88.2-96.8) and 30.4% specific (27.6-33.4), with PPV of 15.3% (13.0-18.0) and NPV of 97.3% (94.8-98.6). PEGeD was the least sensitive (92.2%, 86.3-95.7), but most specific (39.1%, 36.1-42.3), with PPV of 16.9% (14.3-19.8) and NPV of 97.4% (95.3-98.6). PEGeD would have resulted in the most patients managed without imaging (35.4%), followed by YEARS (27.6%), age-adjusted (5.7%), and the conventional cutoff (3.1%). While implementation of a probability-adjusted D-dimer pathway, such as YEARS or PEGeD, would have substantially reduced imaging utilization, these strategies may miss some cases of pulmonary embolism detectable by both age-adjusted and conventional cutoffs. We add to the heterogeneity of safety data, suggesting that adjustment of D-dimer to clinical probability represents a trade-off between sensitivity and imaging utilization.

CANWARD is a Canadian Antimicrobial Resistance Alliance (CARA)/Health Canada partnered national surveillance study established in 2007 to annually assess antimicrobial susceptibilities for bacterial pathogens isolated from patients receiving care in Canadian hospitals. This paper focuses on Gram-positive pathogens. In total, 25 897 Gram-positive pathogens were received and 22 132 underwent CLSI broth microdilution testing providing susceptibility data. 47.9%, 30.2%, 5.7% and 16.2% of isolates tested were from blood, respiratory, urine and wound specimens, respectively; 29.9%, 24.8%, 19.0%, 18.1% and 8.2% of isolates were from patients in medical wards, emergency rooms, intensive care units, hospital clinics and surgical wards. Patient demographics associated with the isolates were: 58.9% male/41.1% female; 13.5% patients aged ≤17 years, 48.5% 18-64 years and 38.0% ≥ 65 years. Of the 25 897 pathogens received, the most common were: Staphylococcus aureus [20.9% (MSSA 16.5%/MRSA 4.4%)], Streptococcus pneumoniae (5.2%) and Enterococcus spp. (Enterococcus faecalis and Enterococcus faecium) (5.0%). MRSA rates (MRSA as a % of all S. aureus tested) decreased significantly during 2007-15 from 26.0% to 19.3% (P < 0.0001); subsequently they increased significantly through study years 2016-23 (16.9%-24.1%; P = 0.002). VRE rates (VRE as a % of all E. faecium tested) ranged from 3.8% to 18.4%, with marked fluctuation year-to-year. Susceptibility rates for MRSA were highest with: 100% ceftobiprole, 99.9% linezolid, vancomycin and daptomycin, 99.8% dalbavancin and 99.4% tedizolid, while susceptibility rates for VRE were 98.4% daptomycin and 86.0% with linezolid. The CANWARD surveillance study has provided 17 years of reference antimicrobial susceptibility testing data on Gram-positive pathogens.

Patients presenting to the emergency department (ED) with hip fractures are typically treated with opioids, which are associated with adverse events such as delirium and respiratory depression. The fascia iliaca compartment block (hereafter fascia iliaca block) is a regional analgesia technique which avoids these negative outcomes. We sought to increase the rate of use of this technique to 50% of all patients with hip fractures who presented to our EDs within an 18-month period. We held three Plan-Do-Study-Act cycles designed in accordance with surveys sent to our physician group. The first cycle consisted of the dissemination of educational materials and standardization of equipment carts. Next, we held educational sessions for staff and trainee physicians. The third cycle consisted of additional education, Audit and Feedback methodology and incentives. Our outcome measure was the rate of fascia iliaca blocks performed. We tracked the number of unique physicians performing the fascia iliaca block as well as physician-reported comfort with the procedure for our process measures. Our balancing measure was the rate of adverse events. We went from a baseline rate of 2.0% to 22.6% of patients receiving fascia iliaca blocks. The number of physicians doing this increased from 6 pre-project to 35. Only one adverse event occurred (arterial puncture), which did not cause any significant patient harm. Our statistical process control chart revealed special cause variation in the form of a shift. Although we did not meet our goal, we were able to significantly improve the rate of fascia iliaca blocks performed at our center. This was largely achieved through educational interventions. Our approach can be adapted by other centers looking to pursue a similar project.

Study ObjectivesThere is a higher risk of cardiovascular disease (CVD) in patients with obstructive sleep apnea (OSA) and innate immunity is a potential pathophysiologic pathway. The objective of this study was to determine whether nocturnal hypoxemia is associated with circulating markers of innate immunity in OSA.MethodsThis was a cross-sectional study of an observational cohort from the multicentre, clinic-based, Canadian Sleep and Circadian Network. Oxygen desaturation index 4% (ODI4%) was used to diagnose and determine the severity of OSA. The percentage of time spent below SpO2 <90% (T90) and minimum SpO2 we considered as other measures of nocturnal hypoxemia. Multiple linear regressions were used to assess associations between total white blood cell (WBC) and subsets and ODI and hypoxemia indices.ResultsA total of 1296 patients were included in the analysis. There was a positive association between ODI4% and lymphocyte count, adjusting for confounders. For every 1-SD increase in ODI4%, lymphocyte counts increased by 0.08 × 109 L (95% CI 0.01 to 0.15) SD. Patients with severe OSA (ODI4% ≥ 30 events/hour) had significantly higher total WBC and lymphocyte count than non-OSA cohort, in the adjusted model, p-value <.02, for both. There was a positive association between T90 and total WBC, neutrophil, lymphocyte, and monocyte count, adjusting for confounders. Minimum SpO2 was independently associated with total WBC, neutrophil, and monocyte counts.ConclusionsIn this pan-Canadian clinic-based cohort of individuals with suspected OSA, nocturnal hypoxemia indices were associated with an increase in total WBC and subset counts.

Fournier's gangrene (FG) is a life-threatening multi-aetiological and polymicrobial infective necrosis of the external genitalia, perineum, and peri-anal regions. Early recognition and aggressive multidisciplinary medical and surgical management are essential to reduce long-term morbidity and mortality. Acute appendicitis is a rare cause of FG. Here, we report the management of a 90-year-old man presenting atypically with a perforated appendicitis resulting in FG.

Validation of biomarker assays is mandatory not only for their applications in clinical trials but also for their subsequent transfer to clinical laboratories in routine clinical care. There are two critical components relevant to their transfer to clinical practice: regulatory oversight and methodology transfer. Both aspects are simplified where companion diagnostic (CDx) assays relevant to a given indication are being implemented in clinical laboratories. However, when laboratory developed tests (LDTs) are being used either because CDx is not available or because LDT is preferred, both aspects need special consideration from regulatory agencies as well as clinical laboratories. The key component that links these two aspects is evidence of validation of the new LDTs. For predictive and prognostic biomarkers in oncology, clinical validation is feasible only in clinical trials. This approach is not available or feasible to clinical laboratories that develop LDTs. While clinical laboratories routinely perform technical/analytical validation, depending on the type of biomarker, this may not be sufficient to provide evidence of the LDT’s clinical relevance. Laboratories must perform and document their assessment for the need for indirect clinical validation. When indirect clinical validation is required, it must be performed according to existing guidelines for this purpose. This paper provides expert consensus guidance and recommendations on how to assess for the need for indirect clinical validation and how to perform indirect clinical validation where required. This paper also provides a conceptual framework to regulatory agencies for determining requirements for validation of predictive and prognostic biomarkers in oncology.

Loss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity Map) analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent “weak points” or “Achilles heels”, whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These “weak points” include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the “weak points” pathways. Our findings described here imply that inhibitors of the “weak points” pathways should be considered as primary candidates in a search for synergistic drug combinations.

ObjectiveWe examined the impact of consenting to the Rick Hansen Spinal Cord Injury Registry on outcomes: acute length of stay, in-hospital mortality, medical complications (pressure injuries and pneumonia), and the final discharge destination following a spinal cord injury using the national Rick Hansen Spinal Cord Injury Registry dataset.DesignA retrospective cohort study was conducted using Rick Hansen Spinal Cord Injury Registry participant data from 2014 to 2019. Participants approached for enrollment were grouped into 1) PC: provided full consent including community follow-up interviews, 2) DWC: declined community follow-up interviews but accepted minimal data collection that may include initial/final interviews and/or those who later withdrew consent, and 3) DC: declined consent to any participation. As no data was collected for the DC group, descriptive, bivariate, and multivariable regression analysis was limited to the PC and DWC groups.ResultsOf 2811 participants, 2101 (74.7%) were PC, 553 (19.7%) were DWC, and 157 (5.6%) were DC. DWC participants had significantly longer acute length of stay, more acute pneumonias/pressure injuries, and were less likely to be discharged home than PC participants. All these associations—except pneumonia—remained significant in the multivariable analyses.ConclusionsNot participating fully in Rick Hansen Spinal Cord Injury Registry was associated with more complications and longer hospital stays.