Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization. Methods In this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here. Results At the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was −3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) or the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19–related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group. Conclusions In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501 .)

Background Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications. Methods In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19–related hospitalization or death from any cause by day 29. Results A total of 1035 patients underwent randomization and received an infusion of bamlanivimab–etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab–etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19–related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, −1.20; 95% CI, −1.46 to −0.94; P<0.001). Conclusions Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501 .)

SUMMARYFibroblast heterogeneity has long been recognized in mouse and human lungs, homeostasis, and disease states. However, there is no common consensus on fibroblast subtypes, lineages, biological properties, signaling, and plasticity, which severely hampers our understanding of the mechanisms of fibrosis. To comprehensively classify fibro-blast populations in the lung using an unbiased approach, single-cell RNA sequencing was performed with mesenchymal preparations from either uninjured or bleomycin-treated mouse lungs. Single-cell transcriptome analyses classified and defined six mesenchymal cell types in normal lung and seven in fibrotic lung. Furthermore, delineation of their differentiation trajectory was achieved by a machine learning method. This collection of single-cell transcriptomes and the distinct classification of fibroblast subsets provide a new resource for understanding the fibroblast landscape and the roles of fibroblasts in fibrotic diseases.

The apolipoprotein E (APOE) ε2 allele has been associated with both Parkinson's disease (PD) and lower low density lipoprotein cholesterol (LDL-C). The study is to test the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 110 controls, the PD cases recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and controls recruited from the spouse populations of the same clinic. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were calculated from unconditional logistic regressions, adjusting for age, gender, smoking status, and use of cholesterollowering agents. Lower LDL-C concentrations were associated with a higher prevalence of PD. Compared with participants with the highest LDL-C (≥139 mg/dL), the OR was 2.2 (95% CI 0.9-5.1) for participants with LDL-C of 115-138, 3.5 (95% CI 1.6-8.1) for LDL-C of 93-114, and 2.6 (95% CI 1.1 -5.9) for LDL-C ≤ 92. Interestingly, use of cholesterol lowering drugs or just statins was related to lower PD prevalence. Our data provide preliminary evidence that low LDL-C may be associated with higher occurrence of PD, and/or that statin use may lower PD occurrence; either of which findings warrant further investigations. KeywordsParkinson's disease; LDL cholesterol; apolipoprotein E; statin; case control study Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder affecting 1-2% of the population over the age of 60 years. The lifetime risk for PD is higher in men than in women. 1 Although a few PD cases are due to several known genetic mutations, the disorder is largely idiopathic, and likely involves interactions of the genome and the environment 2 .The role of apolipoprotein (APOE) in Alzheimer's disease (AD), another age-related neurodegenerative disease, has been elucidated in the past decade. It is generally believed that the ε4 allele is a major susceptibility gene, whereas the ε2 allele is protective for AD and possibly other neurological disorders see review 3 . A recent systematic review, however, Previous epidemiological evidence on dietary fats/cholesterol and PD risk has not been consistent. 10;11 Further, these studies are not directly relevant to the potential role of cholesterol in PD etiology, as non-dietary factors may play more important roles in regulating serum lipid levels. For example, the APOE ε4 allele has been associated with higher low density lipid cholesterol (LDL-C), whereas the ε2 allele has been consistently associated with lower plasma LDL-C. 12;13 Interestingly, there has been one published abstract reporting lower plasma cholesterol concentrations in PD patients than in controls. 14 Further, Musanti et al. 15 reported dramatically lower cholesterol biosynthesis in PD patients than in controls, although there has been no subsequent follow up on this association. The above evidence, coupled with the association between ε2 and PD, led us to test hypothesis that lower serum LDL-C may be ass...

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: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.

BackgroundLung injury promotes the expression of matrix metalloproteinase-7 (MMP7, matrilysin), which is required for neutrophil recruitment and re-epithelialization. MMP7 governs the lung inflammatory response through the shedding of syndecan-1. Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.Methodology/Principal FindingEpithelial injury induced syndecan-1 shedding from wild-type epithelium but not from Mmp7−/− mice in vitro and in vivo. Moreover, cell migration and wound closure was enhanced by MMP7 shedding of syndecan-1. Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the α2β1 integrin.Conclusion/SignificanceMMP7 shedding of syndecan-1 facilitates wound closure by causing the α2β1 integrin to assume a less active conformation thereby removing restrictions to migration. MMP7 acts in the lungs to regulate inflammation and repair, and our data now show that both these functions are controlled through the shedding of syndecan-1.

Unlike Alzheimer disease, for which the APOE-epsilon4 allele increases the prevalence and the APOE-epsilon2 allele is protective, the authors' analysis shows the APOE-epsilon2 allele, but not the APOE-epsilon4 allele, to be positively associated with sporadic Parkinson disease.