Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.

Background Many patients with hand osteoarthritis (HOA) experience reduced health-related quality of life. This study sought to better understand the disease and treatment experience of individuals with HOA, explore any differences in experiences between erosive and non-erosive HOA sub-types, and evaluate content validity of the Michigan Hand Outcomes Questionnaire (MHQ) in HOA. Methods Thirty subjects from the United States (n = 15 erosive HOA; n = 15 non-erosive HOA) participated in semi-structured interviews: concept elicitation explored symptoms/impacts important to patients; cognitive interviews assessed understanding and relevance of the MHQ. A sub-sample participated in real-time data capture (RTDC) activities via a smartphone/tablet app over 7 days. Verbatim transcripts were coded using Atlas.ti software and thematically analyzed. Concept saturation and MHQ content validity were evaluated. Results Most participants reported experiencing pain, swelling and stiffness, symptoms that most commonly had a direct impact on physical functioning. Substantial impacts on activities of daily living, emotional functioning, sleep and work were also reported. RTDC findings corroborated concept elicitation findings. There were no notable differences between erosive and non-erosive HOA, except nodules were reported more frequently in erosive disease. Most participants used analgesic treatments, but effects were short-lived. Pain was the symptom most frequently reported as most bothersome and important to treat. Concept saturation was achieved. MHQ items and instructions were well understood and relevant to most participants; stiffness and swelling were reported as important symptoms not included in the MHQ. Conclusions This study characterizes key symptoms of HOA which are burdensome for patients and not well controlled by current therapies, highlighting an unmet treatment need. Although the study is limited by a small sample size that may not be representative of the broader erosive and non-erosive HOA population, concept saturation was achieved, and our findings suggest that disease experience is similar for patients with erosive and non-erosive HOA. Evaluation of stiffness and swelling items in conjunction with the MHQ may enhance relevance and improve measurement precision to assess important domains of HQRoL in an HOA population.

BACKGROUND Increasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19. METHODS We conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60. RESULTS Overall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI 0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined ≥70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19. CONCLUSIONS Although not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged ≥70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged ≥70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684).

Background Medical activity performed outside regular work hours may increase risk for patients and professionals. There is few data with respect to urgent colorectal surgery. The aim of this work was to evaluate the impact of daytime versus nighttime surgery on postoperative period of patients with acute colorectal disease. Methods A retrospective study was conducted in a sample of patients with acute colorectal disease who underwent urgent surgery at the General Surgery Unit of Braga Hospital, between January 2005 and March 2013. Patients were stratified by operative time of day into a daytime group (surgery between 8:00 and 20:59) and the nighttime group (21:00-7:59) and compared for clinical and surgical parameters. A questionnaire was distributed to surgeons, covering aspects related to the practice of urgent colorectal surgery and fatigue. Results A total of 330 patients were included, with 214 (64.8 %) in the daytime group and 116 (35.2 %) in the nighttime group. Colorectal cancer was the most frequent pathology. Waiting time (p < 0.001) and total length of hospital stay (p = 0.008) were significantly longer in the daytime group. There were no significant differences with respect to early or late complications. However, 100 % of surgeons reported that they are less proficient during nighttime. Conclusions Among patients with acute colorectal disease subjected to urgent surgery, there was no significant association between nighttime surgery and the presence of postoperative medical and surgical morbidities. Patients who were subjected to daytime surgery had longer length of stay at the hospital.

BackgroundGranulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of coronavirus disease 2019 (COVID-19).MethodsIn this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18–79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure, and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti–GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28.ResultsIn Part 1 (N=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28versus67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI −0.8, 11.4; p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2, 33.1; p=0.009) was observed in the predefined 70–79 years subgroup, but this was not confirmed in Part 2 (N=350 randomised) where the model-adjusted difference was 0.9% (95% CI −9.3, 11.2; p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CCL17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19.ConclusionsThere was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.