A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19

Humanistic medicine in anaesthesiology: development and assessment of a curriculum in humanism for postgraduate anaesthesiology trainees.

BackgroundAn unintended consequence of medical technologies is loss of personal interactions and humanism between patients and their healthcare providers, leading to depersonalisation of medicine. As humanism is not integrated as part of formal postgraduate anaesthesiology education curricula, our goal was to design, introduce, and evaluate a comprehensive humanism curriculum into anaesthesiology training.MethodsSubject-matter experts developed and delivered the humanism curriculum, which included interactive workshops, simulation sessions, formal feedback, and patient immersion experience. The effectiveness of the programme was evaluated using pre- and post-curriculum assessments in first-year postgraduate trainee doctors (residents).ResultsThe anaesthesiology residents reported high satisfaction scores. Pre-/post-Jefferson Scale of Patient Perceptions of Physician Empathy showed an increase in empathy ratings with a median improvement of 12 points (range; P=0.013). After training, patients rated the residents as more empathetic (31 [4] vs 22 [5]; P<0.001; 95% confidence interval [CI]: 7-12) and professional (47 [3] vs 35 [8]; P<0.001; 95% CI: 9-16). Patient overall satisfaction with their anaesthesia provider improved after training (51 [6] vs 37 [10]; P<0.001; 95% CI: 10-18). Patients rated their anxiety lower in the post-training period compared with pretraining (1.8 [2.3] vs 3.6 [1.6]; P=0.001; 95% CI: 0.8-2.9). Patient-reported pain scores decreased after training (2.3 [2.5] vs 3.8 [2.1]; P=0.010; 95% CI: 0.4-2.8).ConclusionsImplementation of a humanism curriculum during postgraduate anaesthesiology training was well accepted, and can result in increased physician empathy and professionalism. This may improve patient pain, anxiety, and overall satisfaction with perioperative care

Pharmacovigilance in hospice/palliative care: Net effect of amitriptyline or nortriptyline on neuropathic pain: UTS/IMPACCT Rapid programme international consecutive cohort

Background: Real-world effectiveness of interventions in palliative care need to be systematically quantified to inform patient/clinical decisions. Neuropathic pain is prevalent and difficult to palliate. Tricyclic antidepressants have an established role for some neuropathic pain aetiologies, but this is less clear in palliative care. Aim: To describe the real-world use and outcomes from amitriptyline or nortriptyline for neuropathic pain in palliative care. Design: An international, prospective, consecutive cohort post-marketing/phase IV/pharmacovigilance/quality improvement study of palliative care patients with neuropathic pain where the treating clinician had already made the decision to use a tricyclic antidepressant. Data were entered at set times: baseline, and days 7 and 14. Likert scales graded benefits and harms. Setting/participants: Twenty-one sites (inpatient, outpatient, community) participated in six countries between June 2016 and March 2019. Patients had clinician-diagnosed neuropathic pain. Results: One hundred and fifty patients were prescribed amitriptyline (110) or nortriptyline (40) of whom: 85% had cancer; mean age 73.2 years (SD 12.3); mean 0–4 scores for neuropathic pain at baseline were 1.8 (SD 1.0). By day 14, doses of amitriptyline were 57 mg (SD 21) and nortriptyline (48 mg (SD 21). Fifty-two (34.7%) patients had pain improvement by day 14 (amitriptyline (45/110 (43.3%); nortriptyline (7/40 (18.9%)). Thirty-nine (27.7%) had new harms; (amitriptyline 29/104 (27.9%); nortriptyline 10/37 (27.0%); dizziness (n = 23), dry mouth (n = 20), constipation (n = 14), urinary retention (n = 10)). Benefits without harms occurred (amitriptyline (26/104 (25.0%); nortriptyline (4/37 (10.8%)). Conclusions: Benefits favoured amitriptyline while harms were similar for both medications

Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms.

Over half of all children with autism spectrum disorders (ASD) have gastrointestinal (GI) co-morbidities including chronic constipation, diarrhea, and irritable bowel syndrome. The severity of these symptoms has been correlated with the degree of GI microbial dysbiosis. The study objective was to assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities. This pilot study is a randomized, double blind, controlled trial of combination treatment (BCP + B. infantis) vs. BCP alone in a cross-over study in children ages 2-11 with ASD and GI co-morbidities (n = 8). This 12-week study included 5 weeks of probiotic-prebiotic supplementation, followed by a two-week washout period, and 5 weeks of prebiotic only supplementation. The primary outcome of tolerability was assessed using validated questionnaires of GI function and atypical behaviors, along with side effects. Results suggest that the combination treatment is well-tolerated in this cohort. The most common side effect was mild gassiness. Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors. Improvement may be explained by a reduction in IL-13 and TNF-α production in some participants. Although limited conclusions can be drawn from this small pilot study, the results support the need for further research into the efficacy of these treatments