Notes

Metal-free combination of quinoline-2,4-dicarboxylate types employing aryl amines and also acetylenedicarboxylates through a pseudo three-component reaction.
Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert 'cold' tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a 'hot' tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.Hyperuricemia and gout have been linked to an increased risk for cardiovascular (CV) disease, stroke, hypertension, heart failure, and chronic kidney disease, possibly through a proinflammatory milieu. However, not all the drugs used in gout treatment improve CV outcomes; colchicine has shown improved CV outcomes in patients with recent myocardial infarction and stable coronary artery disease independent of lipid-lowering effects. There is resurging interest in colchicine following publication of the COLCOT, LoDoCo, LoDoCo2, LoDoCo-MI trials, and COLCORONA trial which will shed light on its utility in COVID-19. Our aim is to review the CV use of colchicine beyond pericardial diseases, as well as CV outcomes of the available gout therapies, including allopurinol and febuxostat. The CARES trial and its surrounding controversies, which lead to the US FDA 'black box' warning on febuxostat, in addition to the recent FAST trial which contradicts this and finds febuxostat to be non-inferior, are discussed in this paper.Atrial fibrillation is the most common arrhythmia. It increases the risk of thromboembolism by up to fivefold. Guidelines provide evidence-based recommendations to effectively mitigate thromboembolic events using oral anticoagulants while minimizing the risk of bleeding. This review focuses on non-adherence to contemporary guidelines and the factors associated with guideline non-adherence. The extent of guideline non-adherence differs according to geographic region, healthcare setting, and risk stratification tools used. Guideline adherence has gradually improved over recent years, but a significant proportion of patients are still not receiving guideline-recommended therapy. Physician-related and patient-related factors (such as patient refusals, bleeding risk, older age, and recurrent falls) also contribute to guideline non-adherence, especially to undertreatment. Quality improvement initiatives that focus on undertreatment, especially in the primary healthcare setting, may help to improve guideline adherence.Contrast-associated acute kidney injury has multiple definitions, but is generally described as worsening renal function after administration of iodinated contrast media. It is associated with high in-hospital mortality and poor long-term survival. Furthermore, patients undergoing coronary angiography commonly have comorbidities such as hypertension or congestive heart failure, which are often treated with renin-angiotensin-aldosterone system-blocking agents such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Trials assessing the effects of these renin-angiotensin-aldosterone system-blocking agents on the subsequent development of contrast-associated acute kidney injury have shown conflicting data, suggesting both beneficial and harmful effects. Therefore, there are no clear guidelines on whether clinicians should discontinue renin-angiotensin-aldosterone system-blocking agents peri-procedurally. In this article, we review the data from trials assessing the effects of peri-procedural renin-angiotensin system-blocking agent use in patients undergoing coronary and peripheral angiography and intervention. Future studies will likely focus on the extent of damage or potential benefit of these agents on renal function, cardiac function, as well as morbidity and mortality. Currently, there is insufficient evidence to recommend discontinuation of angiotensin-converting enzyme inhibitors prior to coronary angiography.
Rivaroxaban reduces the risk of thromboembolism in atrial fibrillation (AF) patients, who often also receive antiarrhythmic drugs (AADs) to maintain sinus rhythm. Current guidelines contraindicate concomitant use of rivaroxaban with the popular AAD dronedarone, despite little data demonstrating interactions with AADs. This study investigates the outcomes of concomitant rivaroxaban and AAD drug use in a real-world cohort.

This retrospective study included 1777 non-permanent AF patients taking rivaroxaban for ≥ 1 month between 2011 and 2016 from a multicenter cohort in Taiwan, and compared concomitant AAD use against clinical outcome endpoints for safety, effectiveness, and major adverse cardiac events (MACE). Multivariate Cox proportional hazard analyses were used to evaluate the association between concomitant AAD use and outcomes.

Patients were divided into rivaroxaban alone (n=1205) and with concomitant amiodarone (n=177), dronedarone (n=231), or propafenone (n=164) groups. The proportion of patients with dronedarone.
Concomitant use of rivaroxaban with AADs appears to be well tolerated, warranting further investigation into the apparent benefits of a reduced dose of rivaroxaban combined with dronedarone.
University students are at aheightened risk of developing mental health disorders. Online interventions are becoming increasingly popular in this target group, both to prevent the development of mental health disorders and to treat existing ones. The PLUS (Personality and Living of University Students) programme is aweb-based targeted prevention intervention which has been tested across two European countries. Completion of this programme has been relatively poor. Understanding university students' opinions, experiences and perceptions of the PLUS programme can lead to future improvements in intervention design, engagement and dissemination.

Semistructured interviews were conducted with university students from the UK (n = 10) and Austria (n = 14) who had previously had access to PLUS. Students were asked about their perception and experiences of the programme, and how it could be improved. Results were analysed using thematic analysis.

Experience of online prevention programmes in general were limited d to increase engagement. By considering this feedback, uptake and intervention completion can be improved for future preventative interventions.This article shares our experiences and surprises as we developed, implemented and evaluated a 12-week faculty development program for registrars as clinical supervisors over three cohorts. The program has consistently been rated highly by participants. Yet, following a comprehensive curriculum review, we were surprised that our goal of encouraging identity development in clinical supervisors seemed to be unmet. Whilst our evaluation suggests that the program made important contributions to the registrars' knowledge, application and readiness as clinical supervisors, challenges linked to developing a supervisor identity and managing the dual identity of supervisor and clinician remain. In this article we describe our program and argue for the importance of designing faculty development programs to support professional identity formation. We present the findings from our program evaluation and discuss the surprising outcomes and ongoing challenges of developing a cohesive clinical educator identity. Informed by recent evidence and workplace learning theory we critically appraise our program, explain the mechanisms for the unintended outcomes and offer suggestions for improving curricular and pedagogic practices of embedded faculty development programs. A key recommendation is to not only consider identity formation of clinical supervisors from an individualist perspective but also from a social perspective.
COVID-19 infection has been associated with a high rate of thrombotic events, such as deep vein thrombosis (DVT) and acute pulmonary embolism (APE).

The purpose of our retrospective study was to evaluate the prevalence of asymptomatic DVT in lower limbs in critically ill COVID-19 patients (n = 23) with severe respiratory failure and high levels of D-dimer by bedside Doppler ultrasound (DU).

DVT was diagnosed in 14 cases (60.87%), 5 in proximal venous territory and 9 in infrapopliteal veins. Computed Tomography Pulmonary Angiography (CTPA) was performed in six patients and all of them showed acute pulmonary embolism (APE) at segmental or subsegmental branches of pulmonary arteries. These patients (APE or DVT confirmed) were treated with therapeutic doses of anticoagulant therapy.

In critically COVID-19 ill ICU patients with severe respiratory failure and elevated D-dimer, the incidence of asymptomatic DVT is high. We propose that DU allows detection of DVT in asymptomatic patients, adding a factor that may balance the decision to fully anticoagulate these patients.
In critically COVID-19 ill ICU patients with severe respiratory failure and elevated D-dimer, the incidence of asymptomatic DVT is high. We propose that DU allows detection of DVT in asymptomatic patients, adding a factor that may balance the decision to fully anticoagulate these patients.Natural killer (NK) cells, a type of cytotoxic lymphocytes, can infiltrate into ischemic brain and exacerbate neuronal cell death. Astragaloside IV (ASIV) is the major bioactive ingredient of Astragalus membranaceus, a Chinese herbal medicine, and possesses potent immunomodulatory and neuroprotective properties. This study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK cells. ASIV reduced brain infarction and alleviated functional deficits in MCAO rats, and these beneficial effects persisted for at least 7 days. Abundant NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia, and this infiltration was suppressed by ASIV. Strikingly, ASIV reversed NK cell deficiency in the spleen and blood after brain ischemia. ASIV inhibited astrocyte-derived CCL2 upregulation and reduced CCR2+ NK cell levels in the ischemic brain. Meanwhile, ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γ production. ASIV restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain, suggesting inhibition of histone deacetylase (HDAC).
Here's my website: