Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EVISF ) reveals sex-dependent changes in microglial EV proteome in response to Aß pathology.

Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF ) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labelling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g., APPswe, PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with Aß deposition. Genotype, age, and Aß deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse- EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV-ISF) reveals sex-dependent changes in microglial EV proteome in response to Aß pathology.

Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. Circulating EVs are protected from degradation, making them attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labeling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g. APPswe,PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with A deposition. Genotype, age, and Aß deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse- EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.

Exploration of current pharmacy practice in cardio-oncology: Experiences & perspectives.

INTRODUCTION: Cardiovascular complications can occur in oncology patients secondary to certain cancer therapies. Pharmacists are involved in the care of oncology patients who are at risk of or experiencing cardiotoxicity related to their cancer therapy. Our study aimed to understand how pharmacists in Canada care to these patients and to explore their experiences, perceptions, and challenges. METHODS: Canadian pharmacists currently involved in the care of patients receiving cancer treatments and at risk of or experiencing cardiotoxicity were invited to participate in a 30-min telephone interview using an interview guide. A combination of inductive and deductive reasoning was applied using two coders who independently reviewed the transcribed interviews and identified key concepts and themes. RESULTS: Eight pharmacists were interviewed. Perceived benefits included sharing specialized knowledge and conducting safety assessments. Perceived challenges were the lack of role recognition and resources and fractured continuity of care. Proposed future directions were to play a more substantial role in direct medication management, creation of specific guidance and tools to support the clinical decision-making process, and to understand how pharmacists at other sites were providing care through the creation of a community of practice. CONCLUSIONS: As patient-focused medication specialists, pharmacists help guide clinical decision-making, assess cardiac risk factors, and offer individualized education to meet the holistic needs of oncology patients at risk of or experiencing cardiotoxicities. The creation of a cardio-oncology community of practice may allow pharmacists with a common interest to connect, share learnings, and collaborate on how to continue to advance the delivery of care.

Clinical relevance of lung transplantation for COVID-19 ARDS: a nationwide study.

BACKGROUND: Although the number of lung transplantations (LTx) performed worldwide for COVID-19 induced acute respiratory distress syndrome (ARDS) is still low, there is general agreement that this treatment can save a subgroup of most severly ill patients with irreversible lung damage. However, the true proportion of patients eligible for LTx, the overall outcome and the impact of LTx to the pandemic are unknown. METHODS: A retrospective analysis was performed using a nationwide registry of hospitalised patients with confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-Cov-2) infection admitted between January 1, 2020 and May 30, 2021 in Austria. Patients referred to one of the two Austrian LTx centers were analyzed and grouped into patients accepted and rejected for LTx. Detailed outcome analysis was performed for all patients who received a LTx for post-COVID-19 ARDS and compared to patients who underwent LTx for other indications. RESULTS: Between January 1, 2020 and May 30, 2021, 39.485 patients were hospitalised for COVID-19 in Austria. 2323 required mechanical ventilation, 183 received extra-corporeal membrane oxygenation (ECMO) support. 106 patients with severe COVID-19 ARDS were referred for LTx. Of these, 19 (18%) underwent LTx. 30-day mortality after LTx was 0% for COVID-19 ARDS transplant recipients. With a median follow-up of 134 (47-450) days, 14/19 patients are alive. CONCLUSIONS: Early referral of ECMO patients to a LTx center is pivotal in order to select patients eligible for LTx. Transplantation offers excellent midterm outcomes and should be incorporated in the treatment algorithm of post-COVID-19 ARDS.

Infraglottic versus supraglottic jet-ventilation for endobronchial ultrasound-guided transbronchial needle aspiration: A randomised controlled trial.

BACKGROUND: For endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) under general anaesthesia, both rigid bronchoscopy and laryngeal masks (LMAs) with superimposed high-frequency jet ventilation can be used. Despite the fact that in Europe rigid bronchoscopy for EBUS-TBNA is still widely used, an increasing number of centres use jet ventilation via the LMA for this procedure. To our knowledge no clinical trials have ever been made to compare these two methods. This trial aimed to evaluate whether patients recover from the procedure more quickly when a LMA is used for ventilation compared with rigid bronchoscopy where muscle relaxants and deep anaesthesia are required. OBJECTIVES: We wanted to test the hypothesis that there is no difference in the postoperative recovery of patients in the postanaesthesia care unit (PACU) after EBUS-TBNA with jet ventilation via a rigid bronchoscope and a LMA. Secondary outcomes were the difference of duration of anaesthesia, the diagnostic outcome of the procedure and drug quantities for both groups. DESIGN: Prospective randomised single blinded two centre controlled trial. SETTING: Two centres in Austria participated. Patients were enrolled from December 2016 until January 2018. PATIENTS: Ninety patients for elective EBUS-TBNA were enrolled and assigned to one of two intervention groups. Two patients were excluded before and eleven patients were excluded after EBUS-TBNA. Seventy-seven were analysed. INTERVENTIONS: Patients assigned to group 1 were ventilated with a LMA; those assigned to group 2 were ventilated via a rigid bronchoscope. Vital signs, drug dosage, duration of anaesthesia, recovery, PACU stay and Aldrete score at the PACU were recorded. MAIN OUTCOME MEASURES: The primary endpoint was an integral over time of a modified Aldrete score. Secondary endpoints were the durations of the interventions, the recovery from anaesthesia and PACU stay, initial and mean Aldrete values at PACU, the effect site concentration of Propofol according to the Schnider pharmacokinetic model, the peak ultiva rates and the diagnostic outcome. RESULTS: We were not able to show any significant difference regarding the postoperative recovery criteria based on the Aldrete score, the durations measured and the diagnostic outcomes. Vital signs remained stable and in an equal range in both groups. There were no differences in the mean effect site propofol concentration and the peak ultiva rates. CONCLUSION: EBUS-TBNA under general anaesthesia using a LMA with SHJV is equal to rigid bronchoscopy with superimposed high-frequency jet ventilation for the variables analysed. TRIAL REGISTRATION: ISRCTN (ISRCTN58911367).

Capecitabine-induced myopericarditis - A case report and review of literature.

OBJECTIVE: To describe a possible case of capecitabine-induced myopericarditis in a patient at the Cardio-Oncology Clinic in Calgary, AB. DESIGN: A literature search and adverse drug reaction assessment with the Naranjo tool was conducted. RESULTS: A 39-year-old male with recurrent locally advanced rectal adenocarcinoma presented two days after adjuvant treatment with capecitabine and oxaliplatin complaining of intermittent, severe interscapular pain. Based on symptoms, laboratory investigations, and imaging, the patient was diagnosed with acute myopericarditis. Management included aspirin, colchicine, and discontinuing adjuvant chemotherapy. A literature review revealed one case report of capecitabine-induced myopericarditis; however, more data were found regarding the cardiotoxicity of fluorouracil, for which capecitabine is a pro-drug. No case reports were found for oxaliplatin. CONCLUSION: Due to the timeline of capecitabine administration, symptom onset, and improvement upon medication discontinuation, capecitabine is the probable cause of the myopericarditis. Although rare, it is important to consider the possibility of myopericarditis in patients receiving a fluoropyrimidine who present with cardiovascular symptoms.

The use of sacubitril/valsartan in anthracycline-induced cardiomyopathy: A mini case series.

BACKGROUND: Sacubitril/valsartan has been shown to significantly reduce cardiovascular mortality and hospitalizations due to heart failure in adult patients with reduced ejection fraction when compared to enalapril. To the best of our knowledge, the combination of sacubitril (neprilysin inhibitor) and valsartan (angiotensin receptor blocker) has not been evaluated in patients with chemotherapy-induced cardiomyopathy, as these patients were excluded from the recent pivotal trial, PARADIGM-HF. However, current guidelines for the evaluation and management of cardiovascular complications of cancer therapy, published by the Canadian Cardiovascular Society, direct clinicians to the Canadian Cardiovascular Society Heart Failure Guidelines for the management of cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction (e.g. >10% reduction from baseline or left ventricular ejection fraction <53%), which could include the use of sacubitril/valsartan. METHODS: Retrospective descriptive comparative case study of two patients treated with sacubitril/valsartan. RESULTS: We present data from two patients who experienced anthracycline-induced cardiomyopathy and were successfully managed with sacubitril/valsartan after suboptimal responses to traditional evidence-based heart failure therapies. Both patients demonstrated some recovery of function and normalization of N-terminal pro B-type natriuretic peptide levels. Sacubitril/valsartan was well tolerated with minimal side effects. To date, neither patient has required hospitalization or additional clinic interventions for heart failure. CONCLUSIONS: While further large scale studies are required to determine a comprehensive safety and efficacy profile, we report two cases of anthracycline-induced cardiomyopathy survivors managed with sacubitril/valsartan with minimal side effects and no hospitalizations.