The association of soluble ACE2 change with metabolic health, body composition and proteome dynamics during a weight loss diet intervention: Implications for the COVID-19 pandemic

Background: Angiotensin-converting enzyme 2 (ACE2) serves protective functions in metabolic, cardiovascular, renal and pulmonary diseases and is linked to COVID-19 pathology. We explored the association between soluble AC2 (sACE2) and metabolic health and proteome dynamics during a weight loss diet intervention. Methods: We analyzed 457 healthy individuals (mean age 39.8±6.6) with BMI 28-40 kg/m2 who participated in the Diet Intervention Examining the Factors Interacting with Treatment Success (DIETFITS). Biochemical markers of metabolic health and 236 proteins measured by Olink CVD II, CVD III and Inflammation arrays were available at baseline and 6 months following dietary intervention. We determined clinical and routine biochemical correlates of the diet-induced change in sACE2 (ΔsACE2) using stepwise linear regression. We then combined feature selection models and multivariable-adjusted linear regression to identify protein dynamics associated with ΔsACE2. Results: sACE2 decreased significantly on average at 6-months in the diet intervention. A stronger decline in sACE2 during the diet intervention was independently associated with female sex, lower HOMA-IR and LDL cholesterol at baseline, and a stronger decline in HOMA-IR, triglycerides, HDL-cholesterol and fat mass. In line, participants with decreasing HOMA-IR and triglycerides had significantly higher odds for a decrease in sACE2 during the diet intervention than those who did not (P≤0.0073 for both). Feature selection models linked ΔsACE2 to changes in AMBP, E-selectin, HAOX1, KIM-1, MERTK, PGF, thrombomodulin and TRAIL-R2. ΔsACE2 remained independently associated with these protein changes in multivariable-adjusted linear regression. Conclusion: Decrease in sACE2 during a weight loss diet intervention was associated with improvements in metabolic health, fat mass and markers of angiotensin peptide metabolism, vascular injury, renal function, chronic inflammation and oxidative stress. Our findings may improve the risk stratification, prevention, and management of cardiometabolic and COVID-19- related complications. (Figure Presented).

Changes in objectively-measured adolescent sleep and light exposure during the COVID-19 pandemic

Introduction: U.S. adolescents have high rates of insufficient sleep. School closures and stay-at-home orders were implemented to mitigate disease spread during the Coronavirus 2019 (COVID-19) pandemic. Without the restriction of imposed early school start times, we hypothesized that adolescents would have longer, later, and less variable sleep compared to pre-COVID-19. We further hypothesized these changes would be associated with increased and later light exposure. Methods: High school students age 14-19 years with <7h sleep on school nights completed two weeks of at-home monitoring. The Pre-COVID-19 week took place between October 2018-February 2020 and the COVID-19 week occurred in May 2020 during statewide stay-at-home orders. Participants wore an accelerometer to assess sleep and light exposure while completing a concurrent sleep log. Paired-samples t-tests examined differences in sleep and light between Pre-COVID-19 and COVID-19. Pearson correlations assessed associations between change in sleep and change in light. Results: Participants (N=16) were 16.5 ±1.2-years-old at Pre- COVID-19, 70.6% female, 68.8% White, and 25.1% Hispanic. Youth were participating in online learning due to in-person school closures and only 2 participants (14.3%) had a set start time, while the remainder reported learning per their own schedule. Youth obtained approximately one hour more weekday sleep per night during the COVID-19 week compared to Pre-COVID-19 (p<0.001). Bed and waketimes were significantly delayed on weekdays and weekends during COVID-19 compared to Pre-COVID-19 (p< 0.01). The greatest change was a delay in weekday waketime of 2.9±0.9h (p<0.001). Social jetlag during COVID-19 was reduced by 1/3 compared to Pre- COVID-19 (p=0.02). Average 24h lux levels were 2.5x higher during the COVID-19 week compared to Pre- COVID-19 (p=0.008). Change in average lux and timing of light were not significantly associated with change in sleep duration or timing. Conclusion: An unintended effect of the switch to online learning may have been affording adolescents the opportunity to obtain longer and more regular sleep. Understanding the impact of these changed sleep behaviors on daytime functioning, academic performance, and health outcomes is particularly urgent as schools plan for the remainder of the academic year and eventual return to in-person learning.

Clinician prognostic scoring system reveals COVID-19 patients' prognosis more likely to be limited by acute illness relative to traditional ICU patients

Introduction: There has been substantial lay press interest in whether patients who die of COVID-19 are dying of COVID-19 or other underlying illnesses. We have previously described a clinician scoring system that delineates whether a patient's prognosis is driven by acute illness vs comorbidities. In this study we compared this clinician phenotyping system in patients with COVID-19 to ICU biobank patients enrolled prior to 2020. Methods: Clinician phenotyping was performed on patients enrolled into 2 Stanford ICU biobanks: (1) Patients admitted to Stanford ICU before 2020 with at least one ARDS risk factor (non-COVID-19 cohort) and (2) Patients admitted to the ICU with confirmed COVID-19 infection (COVID-19 cohort). The roles of each of the following categories in determining prognosis at time of enrollment were scored from 1-5 (1 being non-contributory and 5 being highly contributory): goals of care, comorbidities, baseline functional status, acute multi-system organ failure (MSOF), ARDS, acute neurologic injury, and terminal illness. Each patient's primary determinant of mortality was then grouped into one of four categories: (1) MSOF or ARDS (>=4 for ARDS or multi-organ failure), (2) Comorbidities (>=4 for goals of care, comorbidities, acute neurologic injury, or baseline functional status), (3) Mixed (>= 4 for both of the above), or (4) None (<4 for all categories). The odds ratio for prognostic subgroupings was compared between patient cohorts.Results: Clinician phenotyping was performed on 70 non-COVID-19 patients admitted to the ICU with at least one risk factor for ARDS, and 28 patients with COVID-19 admitted to the ICU. Compared to the general ICU population, COVID-19 patients were younger (median age 53 vs 71), more likely to be male (71% vs 54%), and more likely to identify as Hispanic (64% vs 13%). 60-day mortality was higher in the COVID-19 group (29% vs 20%). ARDS or MSOF was the primary determinant of prognosis in 64% of patients with COVID-19 compared to 31% of traditional ICU patients (OR 3.9, 95% CI 1.6-9.9, Figure 1). Only 11% of COVID-19 patients' primary determinant of prognosis was comorbidities or goals of care relative to 31% in the traditional ICU population (OR 0.26, 95% CI 0.07-0.9).Conclusion: In this study, ARDS or MSOF is far more likely to be the main risk factor for death in patients with COVID-19 than in a traditional ICU population. This suggests that most COVID-19 fatalities are attributable to acute infection with SARS-CoV-2 rather than progression of underlying disease.

Physical properties of covid-19 acute respiratory distress syndrome (ARDS) sputum

Introduction: COVID-19 respiratory infections are associated with copious, adherent respiratory secretions that prolong chronic ventilation and contribute to the morbidity and mortality caused by the disease. To target thinning these secretions requires understanding the physical properties that contribute to these tenacious secretions. Methods: We received surrogate consent from 11 patients with COVID-19 ARDS to collect an undiluted tracheal aspirate obtained as part of routine care. All samples were frozen at-80C immediately after collection and heat inactivated at 65C for 30 minutes to render them noninfectious prior to further analyses. These were compared with sputum collected from 4 patients with Cystic Fibrosis and 15 healthy controls. Clinical phenotypes of COVID patients included ARDS severity, treatments related to sputum clearance, and patient outcomes including length of mechanical ventilation and mortality. Sputum was characterized for percent solids, double strand DNA, and hyaluronin content. Results: Sputum samples were collected from 11 patients intubated with COVID-19 ARDS, with aspirates sampled between 2-18 days into their course. 63% of patients had thick secretions described by respiratory therapy, 81% had moderate or severe ARDS, and 90% had prolonged mechanical ventilation > 14 days. We found that the physical characteristics of COVID-19 sputum are similar to CF sputum, with markedly higher percent solid, hyaluronin, and double strand DNA content than that seen in sputum from healthy controls (Figure 1). Conclusion: In this proof of concept study, we show the feasibility of measuring numerous physical characteristics of COVID-19 sputum. As expected, we found that percent solids, DNA content and hyaluronin were similar to the known thick secretions of CF, and markedly increased in comparison to sputum of healthy controls. We were unable to identify differences in outcomes in this small cohort, with collection of additional samples ongoing to improve power. Figure 1. Physical characteristics of COVID sputum are much more similar to CF than normal sputum.

The COVID-19 lockdowns: a window into the Earth System

The COVID-19 pandemic has caused substantial global impact. This Perspective provides insight into the environmental effects of the pandemic, documenting how it offers an opportunity to better understand the Earth System. Restrictions to reduce human interaction have helped to avoid greater suffering and death from the COVID-19 pandemic, but have also created socioeconomic hardship. This disruption is unprecedented in the modern era of global observing networks, pervasive sensing and large-scale tracking of human mobility and behaviour, creating a unique test bed for understanding the Earth System. In this Perspective, we hypothesize the immediate and long-term Earth System responses to COVID-19 along two multidisciplinary cascades: energy, emissions, climate and air quality;and poverty, globalization, food and biodiversity. While short-term impacts are dominated by direct effects arising from reduced human activity, longer-lasting impacts are likely to result from cascading effects of the economic recession on global poverty, green investment and human behaviour. These impacts offer the opportunity for novel insight, particularly with the careful deployment of targeted data collection, coordinated model experiments and solution-oriented randomized controlled trials, during and after the pandemic.