Surface-sensitive vibrational spectroscopy is a common tool for measuring molecular organization and intermolecular interactions at interfaces. Peak intensity ratios are typically used to extract molecular information from one-dimensional spectra but vibrational coupling between surfactant molecules can manifest as signal depletion in one-dimensional spectra. Through a combination of experiment and theory, we demonstrate the emergence of vibrational exciton delocalization in infrared reflection-absorption spectra of soluble and insoluble surfactants at the air/water interface. Vibrational coupling causes a significant decrease in peak intensities corresponding to C-F vibrational modes of perfluorooctanoic acid molecules. Vibrational excitons also form between arachidic acid surfactants within a compressed monolayer, manifesting as signal reduction of C-H stretching modes. Ionic composition of the aqueous phase impacts surfactant intermolecular distance, thereby modulating vibrational coupling strength between surfactants. Our results serve as a cautionary tale against employing alkyl and fluoroalkyl vibrational peak intensities as proxies for concentration, although such analysis is ubiquitous in interface science.

Surfactant monolayers at sea spray aerosol (SSA) surfaces regulate various atmospheric processes including gas transfer, cloud interactions, and radiative properties. Most experimental studies of SSA employ a simplified surfactant mixture of long-chain fatty acids (LCFAs) as a proxy for the sea surface microlayer or SSA surface. However, medium-chain fatty acids (MCFAs) make up nearly 30% of the FA fraction in nascent SSA. Given that LCFA monolayers are easily disrupted upon the introduction of chemical heterogeneity (such as mixed chain lengths), simple FA proxies are unlikely to represent realistic SSA interfaces. Integrating experimental and computational techniques, we characterize the impact that partially soluble MCFAs have on the properties of atmospherically relevant LCFA mixtures. We explore the extent to which the MCFA lauric acid (LA) is surface stabilized by varying acidity, salinity, and monolayer composition. We also discuss the impacts of pH on LCFA-assisted LA retention, where the presence of LCFAs may shift the surface-adsorption equilibria of laurate─the conjugate base─toward higher surface activities. Molecular dynamic simulations suggest a mechanism for the enhanced surface retention of laurate. We conclude that increased FA heterogeneity at SSA surfaces promotes surface activity of soluble FA species, altering monolayer phase behavior and impacting climate-relevant atmospheric processes.

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

Background

Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.

Objective

To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.

Design

Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.

Setting

114 centers in 10 countries.

Participants

Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.

Measurements

Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.

Results

Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity.

Limitations

Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.

Conclusion

Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.

Primary funding source

U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Background

Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.

Objective

To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.

Design

Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).

Setting

Multinational, multicenter trial.

Participants

Adults hospitalized with COVID-19.

Intervention

Intravenous ensovibep, 600 mg, or placebo.

Measurements

Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.

Results

An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).

Limitation

The trial was prematurely stopped because of futility, limiting power for the primary outcome.

Conclusion

Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.

Primary funding source

National Institutes of Health.