Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNFα-antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feedforward pathological signaling loop generated by TNFα and IFN-γ synergy in the inflamed lung, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5 mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥50 compared to baseline and sustained for 48 h. Secondary endpoints included 28-day mortality, dynamic cytokine profiles, secondary infections, duration of supplemental oxygen support, and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 years, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953 ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days; 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Three deaths were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant Day 3 declines in IFN-, TNFα, IL-27, CRP, and ferritin occurred. IP-10 and CXCL-9 declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, P-value 0.0006). INTERPRETATION: Infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19.

Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNF-α antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feed-forward pathological signaling loop generated by TNFα and IFN-γ in inflamed lung tissue, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define, sustain and amplify the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay, Eve Technologies), secondary infections, duration of supplemental oxygen support and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65yrs age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and further to 146 pg/ml at Day 14/discharge. Significant declines in IFN- γ , TNFα, IL-27, CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unmodified. IL-6 levels declined sharply among patients with baseline levels >10 pg/ml. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006). INTERPRETATION: Consistent with a pathophysiological role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are required to formally assess mortality outcomes. Funding: National Center for Advancing Translational Sciences.

Are biologists getting the mathematical training they need in college?

Several major organizations have recommended revisions to mathematics requirements for biology majors. To determine whether these changes would benefit future biologists, we investigated mathematics use in research biology. We surveyed prominent journals in high and low math-use areas for articles referencing the use of quantitative methods. In addition, we conducted a large-scale survey of research biologists within these fields about their use of, and training in, mathematics and statistics. We then performed follow-up interviews with a purposeful sample of respondents. Our results indicate that biologists need a base in descriptive and inferential statistics and mathematical modeling, including some concepts from calculus, focused on conceptual understanding rather than computational accuracy, followed by differentiated programs of study in mathematics and statistics, depending on intended discipline within biology. Comparison of our findings with the recommended requirements from major stakeholder groups indicates some alignment but also some discrepancies. © 2018 International Union of Biochemistry and Molecular Biology, 46(6):612-618, 2018.

Microfluidic device enabled quantitative time-lapse microscopic-photography for phenotyping vegetative and reproductive phases in Fusarium virguliforme, which is pathogenic to soybean.

Time-lapse microscopic-photography allows in-depth phenotyping of microorganisms. Here we report development of such a system using a microfluidic device, generated from polydimethylsiloxane and glass slide, placed on a motorized stage of a microscope for conducting time-lapse microphotography of multiple observations in 20 channels simultaneously. We have demonstrated the utility of the device in studying growth, germination and sporulation in Fusarium virguliforme that causes sudden death syndrome in soybean. To measure the growth differences, we developed a polyamine oxidase fvpo1 mutant in this fungus that fails to grow in minimal medium containing polyamines as the sole nitrogen source. Using this system, we demonstrated that the conidiospores of the pathogen take an average of five hours to germinate. During sporulation, it takes an average of 10.5 h for a conidiospore to mature and get detached from its conidiophore for the first time. Conidiospores are developed in a single conidiophore one after another. The microfluidic device enabled quantitative time-lapse microphotography reported here should be suitable for screening compounds, peptides, micro-organisms to identify fungitoxic or antimicrobial agents for controlling serious plant pathogens. The device could also be applied in identifying suitable target genes for host-induced gene silencing in pathogens for generating novel disease resistance in crop plants.

Frost for the trees: Did climate increase erosion in unglaciated landscapes during the late Pleistocene?

Understanding climatic influences on the rates and mechanisms of landscape erosion is an unresolved problem in Earth science that is important for quantifying soil formation rates, sediment and solute fluxes to oceans, and atmospheric CO2 regulation by silicate weathering. Glaciated landscapes record the erosional legacy of glacial intervals through moraine deposits and U-shaped valleys, whereas more widespread unglaciated hillslopes and rivers lack obvious climate signatures, hampering mechanistic theory for how climate sets fluxes and form. Today, periglacial processes in high-elevation settings promote vigorous bedrock-to-regolith conversion and regolith transport, but the extent to which frost processes shaped vast swaths of low- to moderate-elevation terrain during past climate regimes is not well established. By combining a mechanistic frost weathering model with a regional Last Glacial Maximum (LGM) climate reconstruction derived from a paleo-Earth System Model, paleovegetation data, and a paleoerosion archive, we propose that frost-driven sediment production was pervasive during the LGM in our unglaciated Pacific Northwest study site, coincident with a 2.5 times increase in erosion relative to modern rates. Our findings provide a novel framework to quantify how climate modulates sediment production over glacial-interglacial cycles in mid-latitude unglaciated terrain.

Focus on the aging worker.

This article discusses select characteristics of the aging work force, health-related issues that can impact work productivity, and strategies and resources that can foster a more productive work environment. The older work force is vital to the future of the U.S. economy. Employers should recognize the value of older workers. Occupational health nurses can assist older workers in maintaining and optimizing their health.

Rectal irrigation for relief of functional bowel disorders.

This article examines the use of rectal irrigation for the symptomatic relief of functional bowel disorders in certain groups of patients. The authors undertook a study of 80 patients and conclude that it is a valuable treatment for some patients.