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Background Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial. Trial registration:NCT04510194; IND 152439

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Reduced light availability is a leading cause of seagrass declines worldwide. Light deficiency can be chronic or episodic, where pulsed light stress is punctuated by periods of optimal light. Seagrass resilience to light stress is likely modulated by the durations of light stress and the level of light reduction, yet remains poorly understood. We used a laboratory experiment to examine the response and recovery of Zostera marina to 16 weeks of three types of light disturbance: (i) continuous (C; constant shade), (ii) episodic low (EL; cycles of 4 days shade:3 days no shade), and (iii) episodic high (EH; cycles of 12 days shade:2 days no shade), each implemented at three shade levels (40, 60, and 80% shade). Declines in shoot density and biomass began after 8 weeks and were highest in C and EH disturbance in 60 and 80% shade. Declines were minimal in 40% shade across all light disturbances and in EL across all shade levels. Sheath length responded mainly to shade level, initially increasing in 60 and 80% shade before decreasing. Rhizome carbohydrates initially declined in all light disturbances with 80% shade but did so earlier in C and EH disturbance, and then increased once shoot density decreased. When ambient light was restored, physiological measures recovered, but shoot density, biomass, and morphology did not. Our study showed that shade level strongly modulated Z. marina responses to light disturbance. Not only will chronic high light reduction have negative impacts but pulsed light disturbance can as well, especially when light-stress periods are long and light reduction high.