Fragment Merging Using a Graph Database Samples Different Catalogue Space than Similarity Search.

Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge. We use an iteration of the database containing >120 million catalogue compounds to find fragment merges for four crystallographic screening campaigns and contrast the results with a traditional fingerprint-based similarity search. The two approaches identify complementary sets of merges that recapitulate the observed fragment-protein interactions but lie in different regions of chemical space. We further show our methodology is an effective route to achieving on-scale potency by retrospective analyses for two different targets; in analyses of public COVID Moonshot and Mycobacterium tuberculosis EthR inhibitors, potential inhibitors with micromolar IC50 values were identified. This work demonstrates the use of the Fragment Network to increase the yield of fragment merges beyond that of a classical catalogue search.

Durvalumab: a newly approved checkpoint inhibitor for the treatment of urothelial carcinoma.

Until a recent introduction to checkpoint inhibitors, there were limited second-line chemotherapy options for urothelial carcinoma (UC) patients with disease progression after first-line, platinum-based treatment. Outcomes for patients with advanced disease over the past 30 years have highlighted a need for new and better therapy. In response to evolving interest, durvalumab (MEDI4736) was introduced as a potential treatment for advanced stages of UC. Durvalumab is a selective, high-affinity, human IgG1 kappa monoclonal antibody engineered with a triple mutation to reduce toxicity. This checkpoint inhibitor has shown promise in advanced UC and is currently the topic of much discussion in the cancer research community. This review article will explore the details surrounding durvalumab, while also giving a brief overview of additional immunotherapeutic agents utilized for UC.

Critical Care Nurses' Perceived Need for Guidance in Addressing Spirituality in Critically Ill Patients.

BACKGROUND: The term spirituality is highly subjective. No common or universally accepted definition for the term exists. Without a clear definition, each nurse must reconcile his or her own beliefs within a framework mutually suitable for both nurse and patient. OBJECTIVES: To examine individual critical care nurses' definition of spirituality, their comfort in providing spiritual care to patients, and their perceived need for education in providing this care. METHODS: Individual interviews with 30 nurses who worked in a critical care unit at a large Midwestern teaching hospital. RESULTS: Nurses generally feel comfortable providing spiritual care to critically ill patients but need further education about multicultural considerations. Nurses identified opportunities to address spiritual needs throughout a patient's stay but noted that these needs are usually not addressed until the end of life. CONCLUSIONS: A working definition for spirituality in health care was developed: That part of person that gives meaning and purpose to the person's life. Belief in a higher power that may inspire hope, seek resolution, and transcend physical and conscious constraints.

Association between perioperative NSAID use and post-cardiothoracic surgery atrial fibrillation, blood transfusions, and cardiovascular outcomes: a nested cohort study from the AF Suppression Trials (AFIST) I, II and III.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use may reduce the incidence of post-cardiothoracic surgery (CTS) atrial fibrillation (AF). The cerebrovascular and cardiovascular safety of using NSAIDs for post-CTS AF has not been determined. OBJECTIVE: To evaluate whether NSAIDs could reduce the incidence of post-CTS atrial fibrillation without increasing patients' risk of stroke or myocardial infarction (MI). METHODS: Patients (n = 555) undergoing CTS from the Atrial Fibrillation Suppression Trials I, II and III were evaluated in this nested cohort study. Demographic, surgical and medication use characteristics were prospectively collected as part of the AFIST trials. Endpoints included post-CTS atrial fibrillation, stroke, MI and the need for red blood cell transfusion. Multivariable logistic regression was used to control for potential confounders and calculate adjusted odds ratios with 95% confidence intervals. RESULTS: The population was 67.8 +/- 8.6 years old and 77.1% male with 127 (22.9%) patients receiving an NSAID postoperatively. Overall, 14.6% underwent valve surgery, 6.1% had prior AF, 12.6% had heart failure and 84.0% and 44.1% received postoperative beta-blockade and prophylactic amiodarone. NSAID use was associated with reductions in the adjusted odds of post-CTS atrial fibrillation (0.54 (0.32-0.90)) and the need for RBC transfusions (0.63 (0.41-0.97)). No elevation in the odds of developing stroke (1.10 (0.21-5.66)) or MI (1.70 (0.40-7.10)) was observed. LIMITATIONS: Patients were not randomized to receive NSAIDs versus a control. We may not have had adequate power to evaluate stoke or MI in this analysis. CONCLUSIONS: NSAIDs decreased the odds of developing post-CTS atrial fibrillation, further supporting the hypothesis of inflammation as a trigger for post-CTS atrial fibrillation. The need for RBC transfusions was also reduced with NSAID use. We may have been underpowered to evaluate stroke or MI incidence, but the qualitative elevations in these variables suggest more safety data is needed before NSAIDs can be routinely recommended.