A Simple Admission Order-set Improves Adherence to Canadian Guidelines for Hospitalized Patients With Severe Ulcerative Colitis.

Background: Individuals hospitalized with severe ulcerative colitis represent a complex group of patients. Variation exists in the quality of care of admitted patients with inflammatory bowel disease. We hypothesized that implementation of a standardized admission order set could result in improved adherence to current best practice guidelines (Toronto Consensus Statements) for the management of this patient population. Methods: A retrospective cohort study of patients admitted with severe ulcerative colitis to a Montreal tertiary center was conducted. Two cohorts were defined based on pre- and post-implementation of a standardized order set. Adherence to 11 quality indicators was assessed before and after implementation of the intervention. These included: Clostridioides difficile and stool cultures testing, ordering an abdominal X-ray and CRP, organizing a flexible sigmoidoscopy, documenting latent tuberculosis, initiating thromboprophylaxis, use of intravenous steroids, prescribing infliximab if refractory to steroids, limiting narcotics, and surgical consultation if refractory to medical therapy. Results: Adherence to 6 of the 11 quality indicators was improved in the post-intervention cohort. Significant increases were noted in adherence to C difficile testing (75.5% versus 91.9%, P < 0.05), CRP testing (71.4% versus 94.6%, P < 0.01), testing for latent tuberculosis (38.1% versus 84.6%, P < 0.01), thromboprophylaxis (28.6% versus 94.6%, P < 0.01), adequate corticosteroids prescription (72.9% versus 94.6%, P < 0.01), and limitation of narcotics prescribed (68.8% versus 38.9%, P < 0.01). Conclusions: Implementation of a standardized order set, focused on pre-defined quality indicators for hospitalized patients with severe UC, was associated with meaningful improvements to most quality indicators defined by the Toronto Consensus Statements.

Efficacy of Intravenous Ustekinumab Reinduction in Patients With Crohn's Disease With a Loss of Response.

Background/Aims: In patients receiving ustekinumab (UST) for treatment of Crohn's disease, there is no proven strategy to enhance or re-capture response. We assessed the utility of UST intravenous (IV) reinduction (~6 mg/kg) to achieve clinical, biochemical and endoscopic response or remission, in patients with partial or loss of response to UST maintenance therapy. Methods: A multicentre, retrospective cohort study was performed. Adults who received an IV reinduction dose of UST for either partial response or secondary loss of response to UST were assessed. The primary outcome was clinical remission off corticosteroids (Harvey Bradshaw Index <5), with biochemical response (defined as ≥ 50% decrease of CRP or FCP and/or endoscopic response (defined as a decrease in Simple Endoscopic Score-CD ≥ 50%). Secondary outcomes included clinical, biomarker and endoscopic response/remission, as well as safety. Results: Sixty-five patients (median age 38 years, 54.7% women) underwent IV UST reinduction between January 2017 and April 2019. Most patients (88.3%) were already on escalated maintenance dosing of UST 90 mg subcutaneous every 4 weeks. Clinical outcomes were assessed at a median of 14 weeks (IQR: 12-19) post-reinduction. The primary outcome of clinical remission off corticosteroids with biochemical and/or endoscopic response was achieved in 31.0% (n = 18). Pre-reinduction UST concentrations were ≥1 µg/mL in 88.6% (mean 3.2 ± 2.0 µg/mL). No serious adverse events were reported. Conclusions: UST IV reinduction can be effective in patients with Crohn's disease with partial or loss of response to UST maintenance therapy. Further studies evaluating this strategy are warranted.

Renal Cell Carcinoma With Cardiac Metastases.

The median survival of metastatic renal cell carcinoma (mRCC) is 5 months with a 1-year survival rate of 29%. Cardiac metastasis from RCC is a rare finding and there is scarce data available on treatment options. Recently, the combination of nivolumab and ipilimumab has been approved as a first-line treatment for advanced RCC in patients with a poor prognosis. Here we present a case of a 45-year-old male who presented to the emergency room with cough, dyspnea, and fever. Chest X-ray showed hilar lymphadenopathy and diffuse reticulonodular opacities, whereas a thoracic computed tomography (CT) scan revealed carcinomatosis lymphangitis, pleural carcinosis and multiple heterogenous zones on the cardiac wall. A transthoracic echocardiogram and a cardiac magnetic resonance imaging (MRI) revealed cardiac metastases. Subsequent imaging showed abundant distal metastases whereas a renal biopsy confirmed clear cell RCC making it a high-grade stage IV metastatic RCC. The patient was treated with the combination of nivolumab and ipilimumab. The unique feature about this case is that we have found a rare case of cardiac metastases that persists after a 3-month follow-up. Previously, there was only one case report of a patient with RCC and cardiac metastases who showed persistent response to nivolumab after 12 months. The key points from this case report are that a high index of suspicion is required for diagnosing cardiac metastases given that the signs and symptoms of metastatic cardiac involvement can be non-specific. Spread has been described as directly through the renal vein and vena cava or indirectly via the lymphatic system, which confers a worse prognosis. Furthermore, cardiac metastases can be mistaken for thrombi, endocarditis, or primary tumors, therefore echocardiograms can be limiting. Supplemental imaging with cardiac MRI or positron emission tomography/CT (PET/CT) is often needed for further characterization.

Dynamic regulation of TREK1 gating by Polycystin 2 via a Filamin A-mediated cytoskeletal Mechanism.

Mechanosensing is essential for several physiological functions including touch and pain sensations, osmoregulation, and controlling the myogenic tone of resistance arteries. Understanding how mechanosensitive ion channels (MSCs) are gated can provide important information regarding these processes. We have previously demonstrated that during pathological conditions such as polycystic kidney disease, polycystin 2 (TRPP2) inhibits the activity of potassium-selective MSCs through a filamin A-mediated cytoskeletal effect, and renders tubular epithelial cells susceptible to apoptosis. However, the nature of this cytoskeletal inhibition remains poorly understood. In this study we use a combination of electrophysiology, structured illumination microscopy, and fluorescence recovery after photobleaching (FRAP) to examine the dynamic nature of the TRPP2-mediated cytoskeletal inhibition of the potassium-selective MSC TREK1. Our data indicate that this inhibition of MSC activity occurs through an accelerated cytoskeletal inhibition, and ultimately decreases the open probability of the TREK1 channel. These results shed light on a novel mode of regulation of MSCs gating, which may be at play in several physiological functions.

Differential Regulation of 6- and 7-Transmembrane Helix Variants of µ-Opioid Receptor in Response to Morphine Stimulation.

The pharmacological effect of opioids originates, at the cellular level, by their interaction with the µ-opioid receptor (mOR) resulting in the regulation of voltage-gated Ca2+ channels and inwardly rectifying K+ channels that ultimately modulate the synaptic transmission. Recently, an alternative six trans-membrane helix isoform of mOR, (6TM-mOR) has been identified, but its function and signaling are still largely unknown. Here, we present the structural and functional mechanisms of 6TM-mOR signaling activity upon binding to morphine. Our data suggest that despite the similarity of binding modes of the alternative 6TM-mOR and the dominant seven trans-membrane helix variant (7TM-mOR), the interaction with morphine generates different dynamic responses in the two receptors, thus, promoting the activation of different mOR-specific signaling pathways. We characterize a series of 6TM-mOR-specific cellular responses, and observed that they are significantly different from those for 7TM-mOR. Morphine stimulation of 6TM-mOR does not promote a cellular cAMP response, while it increases the intracellular Ca2+ concentration and reduces the cellular K+ conductance. Our findings indicate that 6TM-mOR has a unique contribution to the cellular opioid responses. Therefore, it should be considered as a relevant target for the development of novel pharmacological tools and medical protocols involving the use of opioids.