Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target–inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.

Pancreatic cancer is an aggressive disease with poor prognosis, due, in part, to the lack of disease-specific biomarkers that could afford early and accurate diagnosis. With a recombinant antibody microarray platform, targeting mainly immunoregulatory proteins, we screened sera from 148 patients with pancreatic cancer, chronic pancreatitis, autoimmune pancreatitis (AIP), and healthy controls (N). Serum biomarker signatures were derived from training cohorts and the predictive power was evaluated using independent test cohorts. The results identified serum portraits distinguishing pancreatic cancer from N [receiver operating characteristics area under the curve (AUC) of 0.95], chronic pancreatitis (0.86), and AIP (0.99). Importantly, a 25-serum biomarker signature discriminating pancreatic cancer from the combined group of N, chronic pancreatitis, and AIP was determined. This signature exhibited a high diagnostic potential (AUC of 0.88). In summary, we present the first prevalidated, multiplexed serum biomarker signature for diagnosis of pancreatic cancer that may improve diagnosis and prevention in premalignant diseases and in screening of high-risk individuals. Cancer Res; 72(10);

There is no consensus on the effects of a prolonged second stage of labor on neonatal outcomes. In this large Swedish population-based cohort study, our objective was to investigate prolonged second stage and risk of low Apgar score at 5 min. All nulliparous women (n = 32,796) delivering a live born singleton infant in cephalic presentation at ≥37 completed weeks after spontaneous onset of labor between 2008 and 2012 in the counties of Stockholm and Gotland were included. Data were obtained from computerized records. Exposure was time from fully retracted cervix until delivery. Logistic regression analyses were used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Adjustments were made for maternal age, height, BMI, smoking, sex, gestational age, sex-specific birth weight for gestational age and head circumference. Epidural analgesia was included in a second model. The primary outcome measure was Apgar score at 5 min <7 and <4. We found that the overall rates of 5 min Apgar score <7 and <4 were 7.0 and 1.3 per 1000 births, respectively. Compared to women with <1 h from retracted cervix to birth, adjusted ORs of Apgar score <7 at 5 min generally increased with length of second stage of labor: 1 to <2 h: OR 1.78 (95% CI 1.19-2.66); 2 to <3 h: OR 1.66 (1.05-2.62); 3 to <4 h: OR 2.08 (1.29-3.35); and ≥4 h: OR 2.71 (1.67-4.40). We conclude that prolonged second stage of labor is associated with an increased risk of low 5 min Apgar score.

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BackgroundWe sought to investigate the impact of the duration of second stage of labor on risk of severe perineal lacerations (third and fourth degree).MethodsThis population based cohort study was conducted in the Stockholm/Gotland region, Sweden, 2008–2014. Study population included 52 211 primiparous women undergoing vaginal delivery with cephalic presentation at term. Unconditional logistic regression analysis was used to calculate crude and adjusted odds ratios (OR), using 95% confidence intervals (CI). Main exposure was duration of second stage of labor, and main outcome was risks of severe perineal lacerations (third and fourth degree).ResultsRisk of severe perineal lacerations increased with duration of second stage of labor. Compared with a second stage of labor of 1 h or less, women with a second stage of more than 2 h had an increased risk (aOR 1.42; 95% CI 1.28–1.58). Compared with non-instrumental vaginal deliveries, the risk was elevated among instrumental vaginal deliveries (aOR 2.24; 95% CI 2.07–2.42). The risk of perineal laceration increased with duration of second stage of labor until less than 3 h in both instrumental and non-instrumental vaginal deliveries, but after 3 h, the ORs did not further increase. After adjustments for potential confounders, macrosomia (birth weight > 4 500 g) and occiput posterior fetal position were risk factors of severe perineal lacerations.ConclusionsThe risk of severe perineal laceration increases with duration until the third hour of second stage of labor. Instrumental delivery is the most significant risk factor for severe lacerations, followed by duration of second stage of labor, fetal size and occiput posterior fetal position.