Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial.

OBJECTIVE: We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19. DESIGN: Randomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory). RESULTS: Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms. CONCLUSIONS: Famotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

Foliar respiration is related to photosynthetic, growth and carbohydrate response to experimental drought and elevated temperature.

Short-term plant respiration (R) increases exponentially with rising temperature, but drought could reduce respiration by reducing growth and metabolism. Acclimation may alter these responses. We examined if species with different drought responses would differ in foliar R response to +4.8°C temperature and -45% precipitation in a field experiment with mature piñon and juniper trees, and if any differences between species were related to differences in photosynthesis rates, shoot growth and nonstructural carbohydrates (NSCs). Short-term foliar R had a Q10 of 1.6 for piñon and 2.6 for juniper. Piñon foliar R did not respond to the +4.8°C temperatures, but R increased 1.4× for juniper. Across treatments, piñon foliage had higher growth, lower NSC content, 29% lower photosynthesis rates, and 44% lower R than juniper. Removing 45% precipitation had little impact on R for either species. Species differences in the response of R under elevated temperature were related to substrate availability and stomatal response to leaf water potential. Despite not acclimating to the higher temperature and having higher R than piñon, greater substrate availability in juniper suggests it could supply respiratory demand for much longer than piñon. Species responses will be critical in ecosystem response to a warmer climate.

Plant respiration: Controlled by photosynthesis or biomass?

Two simplifying hypotheses have been proposed for whole-plant respiration. One links respiration to photosynthesis; the other to biomass. Using a first-principles carbon balance model with a prescribed live woody biomass turnover, applied at a forest research site where multidecadal measurements are available for comparison, we show that if turnover is fast the accumulation of respiring biomass is low and respiration depends primarily on photosynthesis; while if turnover is slow the accumulation of respiring biomass is high and respiration depends primarily on biomass. But the first scenario is inconsistent with evidence for substantial carry-over of fixed carbon between years, while the second implies far too great an increase in respiration during stand development-leading to depleted carbohydrate reserves and an unrealistically high mortality risk. These two mutually incompatible hypotheses are thus both incorrect. Respiration is not linearly related either to photosynthesis or to biomass, but it is more strongly controlled by recent photosynthates (and reserve availability) than by total biomass.

Tropical rainforest carbon sink declines during El Niño as a result of reduced photosynthesis and increased respiration rates.

Changes in tropical forest carbon sink strength during El Niño Southern Oscillation (ENSO) events can indicate future behavior under climate change. Previous studies revealed ˜6 Mg C ha-1  yr-1 lower net ecosystem production (NEP) during ENSO year 1998 compared with non-ENSO year 2000 in a Costa Rican tropical rainforest. We explored environmental drivers of this change and examined the contributions of ecosystem respiration (RE) and gross primary production (GPP) to this weakened carbon sink. For 1998-2000, we estimated RE using chamber-based respiration measurements, and we estimated GPP in two ways: using (1) the canopy process model MAESTRA, and (2) combined eddy covariance and chamber respiration data. MAESTRA-estimated GPP did not statistically differ from GPP estimated using approach 2, but was ˜ 28% greater than published GPP estimates for the same site and years using eddy covariance data only. A 7% increase in RE (primarily increased soil respiration) and a 10% reduction in GPP contributed equally to the difference in NEP between ENSO year 1998 and non-ENSO year 2000. A warming and drying climate for tropical forests may yield a weakened carbon sink from both decreased GPP and increased RE. Understanding physiological acclimation will be critical for the large carbon stores in these ecosystems.

Global variability in leaf respiration in relation to climate, plant functional types and leaf traits.

Leaf dark respiration (Rdark ) is an important yet poorly quantified component of the global carbon cycle. Given this, we analyzed a new global database of Rdark and associated leaf traits. Data for 899 species were compiled from 100 sites (from the Arctic to the tropics). Several woody and nonwoody plant functional types (PFTs) were represented. Mixed-effects models were used to disentangle sources of variation in Rdark . Area-based Rdark at the prevailing average daily growth temperature (T) of each site increased only twofold from the Arctic to the tropics, despite a 20°C increase in growing T (8-28°C). By contrast, Rdark at a standard T (25°C, Rdark (25) ) was threefold higher in the Arctic than in the tropics, and twofold higher at arid than at mesic sites. Species and PFTs at cold sites exhibited higher Rdark (25) at a given photosynthetic capacity (Vcmax (25) ) or leaf nitrogen concentration ([N]) than species at warmer sites. Rdark (25) values at any given Vcmax (25) or [N] were higher in herbs than in woody plants. The results highlight variation in Rdark among species and across global gradients in T and aridity. In addition to their ecological significance, the results provide a framework for improving representation of Rdark in terrestrial biosphere models (TBMs) and associated land-surface components of Earth system models (ESMs).

Forest ecosystem respiration estimated from eddy covariance and chamber measurements under high turbulence and substantial tree mortality from bark beetles.

Eddy covariance nighttime fluxes are uncertain due to potential measurement biases. Many studies report eddy covariance nighttime flux lower than flux from extrapolated chamber measurements, despite corrections for low turbulence. We compared eddy covariance and chamber estimates of ecosystem respiration at the GLEES Ameriflux site over seven growing seasons under high turbulence [summer night mean friction velocity (u*) = 0.7 m s(-1)], during which bark beetles killed or infested 85% of the aboveground respiring biomass. Chamber-based estimates of ecosystem respiration during the growth season, developed from foliage, wood, and soil CO2 efflux measurements, declined 35% after 85% of the forest basal area had been killed or impaired by bark beetles (from 7.1 ± 0.22 µmol m(-2) s(-1) in 2005 to 4.6 ± 0.16 µmol m(-2) s(-1) in 2011). Soil efflux remained at ~3.3 µmol m(-2) s(-1) throughout the mortality, while the loss of live wood and foliage and their respiration drove the decline of the chamber estimate. Eddy covariance estimates of fluxes at night remained constant over the same period, ~3.0 µmol m(-2) s(-1) for both 2005 (intact forest) and 2011 (85% basal area killed or impaired). Eddy covariance fluxes were lower than chamber estimates of ecosystem respiration (60% lower in 2005, and 32% in 2011), but the mean night estimates from the two techniques were correlated within a year (r(2) from 0.18 to 0.60). The difference between the two techniques was not the result of inadequate turbulence, because the results were robust to a u* filter of >0.7 m s(-1). The decline in the average seasonal difference between the two techniques was strongly correlated with overstory leaf area (r(2) = 0.92). The discrepancy between methods of respiration estimation should be resolved to have confidence in ecosystem carbon flux estimates.

Continued warming could transform Greater Yellowstone fire regimes by mid-21st century.

Climate change is likely to alter wildfire regimes, but the magnitude and timing of potential climate-driven changes in regional fire regimes are not well understood. We considered how the occurrence, size, and spatial location of large fires might respond to climate projections in the Greater Yellowstone ecosystem (GYE) (Wyoming), a large wildland ecosystem dominated by conifer forests and characterized by infrequent, high-severity fire. We developed a suite of statistical models that related monthly climate data (1972-1999) to the occurrence and size of fires >200 ha in the northern Rocky Mountains; these models were cross-validated and then used with downscaled (~12 km × 12 km) climate projections from three global climate models to predict fire occurrence and area burned in the GYE through 2099. All models predicted substantial increases in fire by midcentury, with fire rotation (the time to burn an area equal to the landscape area) reduced to <30 y from the historical 100-300 y for most of the GYE. Years without large fires were common historically but are expected to become rare as annual area burned and the frequency of regionally synchronous fires increase. Our findings suggest a shift to novel fire-climate-vegetation relationships in Greater Yellowstone by midcentury because fire frequency and extent would be inconsistent with persistence of the current suite of conifer species. The predicted new fire regime would transform the flora, fauna, and ecosystem processes in this landscape and may indicate similar changes for other subalpine forests.

Evaluating theories of drought-induced vegetation mortality using a multimodel-experiment framework.

SUMMARY: Model-data comparisons of plant physiological processes provide an understanding of mechanisms underlying vegetation responses to climate. We simulated the physiology of a piñon pine-juniper woodland (Pinus edulis-Juniperus monosperma) that experienced mortality during a 5 yr precipitation-reduction experiment, allowing a framework with which to examine our knowledge of drought-induced tree mortality. We used six models designed for scales ranging from individual plants to a global level, all containing state-of-the-art representations of the internal hydraulic and carbohydrate dynamics of woody plants. Despite the large range of model structures, tuning, and parameterization employed, all simulations predicted hydraulic failure and carbon starvation processes co-occurring in dying trees of both species, with the time spent with severe hydraulic failure and carbon starvation, rather than absolute thresholds per se, being a better predictor of impending mortality. Model and empirical data suggest that limited carbon and water exchanges at stomatal, phloem, and below-ground interfaces were associated with mortality of both species. The model-data comparison suggests that the introduction of a mechanistic process into physiology-based models provides equal or improved predictive power over traditional process-model or empirical thresholds. Both biophysical and empirical modeling approaches are useful in understanding processes, particularly when the models fail, because they reveal mechanisms that are likely to underlie mortality. We suggest that for some ecosystems, integration of mechanistic pathogen models into current vegetation models, and evaluation against observations, could result in a breakthrough capability to simulate vegetation dynamics.

No carbon storage in growth-limited trees in a semi-arid woodland.

Plant survival depends on a balance between carbon supply and demand. When carbon supply becomes limited, plants buffer demand by using stored carbohydrates (sugar and starch). During drought, NSCs (non-structural carbohydrates) may accumulate if growth stops before photosynthesis. This expectation is pervasive, yet few studies have combined simultaneous measurements of drought, photosynthesis, growth, and carbon storage to test this. Using a field experiment with mature trees in a semi-arid woodland, we show that growth and photosynthesis slow in parallel as [Formula: see text] declines, preventing carbon storage in two species of conifer (J. monosperma and P. edulis). During experimental drought, growth and photosynthesis were frequently co-limited. Our results point to an alternative perspective on how plants use carbon that views growth and photosynthesis as independent processes both regulated by water availability.

A synthesis of current knowledge on forests and carbon storage in the United States.

Using forests to mitigate climate change has gained much interest in science and policy discussions. We examine the evidence for carbon benefits, environmental and monetary costs, risks and trade-offs for a variety of activities in three general strategies: (1) land use change to increase forest area (afforestation) and avoid deforestation; (2) carbon management in existing forests; and (3) the use of wood as biomass energy, in place of other building materials, or in wood products for carbon storage. We found that many strategies can increase forest sector carbon mitigation above the current 162-256 Tg C/yr, and that many strategies have co-benefits such as biodiversity, water, and economic opportunities. Each strategy also has trade-offs, risks, and uncertainties including possible leakage, permanence, disturbances, and climate change effects. Because approximately 60% of the carbon lost through deforestation and harvesting from 1700 to 1935 has not yet been recovered and because some strategies store carbon in forest products or use biomass energy, the biological potential for forest sector carbon mitigation is large. Several studies suggest that using these strategies could offset as much as 10-20% of current U.S. fossil fuel emissions. To obtain such large offsets in the United States would require a combination of afforesting up to one-third of cropland or pastureland, using the equivalent of about one-half of the gross annual forest growth for biomass energy, or implementing more intensive management to increase forest growth on one-third of forestland. Such large offsets would require substantial trade-offs, such as lower agricultural production and non-carbon ecosystem services from forests. The effectiveness of activities could be diluted by negative leakage effects and increasing disturbance regimes. Because forest carbon loss contributes to increasing climate risk and because climate change may impede regeneration following disturbance, avoiding deforestation and promoting regeneration after disturbance should receive high priority as policy considerations. Policies to encourage programs or projects that influence forest carbon sequestration and offset fossil fuel emissions should also consider major items such as leakage, the cyclical nature of forest growth and regrowth, and the extensive demand for and movement of forest products globally, and other greenhouse gas effects, such as methane and nitrous oxide emissions, and recognize other environmental benefits of forests, such as biodiversity, nutrient management, and watershed protection. Activities that contribute to helping forests adapt to the effects of climate change, and which also complement forest carbon storage strategies, would be prudent.

Physical structure and biological composition of canopies in tropical secondary and old-growth forests.

The area of tropical secondary forests is increasing rapidly, but data on the physical and biological structure of the canopies of these forests are limited. To obtain such data and to measure the ontogeny of canopy structure during tropical rainforest succession, we studied patch-scale (5 m2) canopy structure in three areas of 18-36 year-old secondary forest in Costa Rica, and compared the results to data from old-growth forest at the same site. All stands were sampled with a stratified random design with complete harvest from ground level to the top of the canopy from a modular portable tower. All canopies were organized into distinct high- and low-leaf-density layers (strata), and multiple strata developed quickly with increasing patch height. The relation of total Leaf Area Index (LAI, leaf area per area of ground) to patch canopy height, the existence of distinct high and low leaf- density layers (strata and free air spaces), the depth and LAI of the canopy strata and free air spaces, and the relation of the number of strata to patch canopy height were remarkably constant across the entire successional gradient. Trees were the most important contributor to LAI at all stages, while contribution of palm LAI increased through succession. We hypothesize that canopy physical structure at the patch scale is driven by light competition and discuss how this hypothesis could be tested. That canopy physical structure was relatively independent of the identity of the species present suggests that canopy physical structure may be conserved even as canopy floristics shift due to changing climate.

Height is more important than light in determining leaf morphology in a tropical forest.

Both within and between species, leaf physiological parameters are strongly related to leaf dry mass per area (LMA, g/m2), which has been found to increase from forest floor to canopy top in every forest where it has been measured. Although vertical LMA gradients in forests have historically been attributed to a direct phenotypic response to light, an increasing number of recent studies have provided evidence that water limitation in the upper canopy can constrain foliar morphological adaptations to higher light levels. We measured height, light, and LMA of all species encountered along 45 vertical canopy transects across a Costa Rican tropical rain forest. LMA was correlated with light levels in the lower canopy until approximately 18 m sample height and 22% diffuse transmittance. Height showed a remarkably linear relationship with LMA throughout the entire vertical canopy profile for all species pooled and for each functional group individually (except epiphytes), possibly through the influence of gravity on leaf water potential and turgor pressure. Models of forest function may be greatly simplified by estimating LMA-correlated leaf physiological parameters solely from foliage height profiles, which in turn can be assessed with satellite- and aircraft-based remote sensing.

Wood CO(2) efflux and foliar respiration for Eucalyptus in Hawaii and Brazil.

We measured CO(2) efflux from wood for Eucalyptus in Hawaii for 7 years and compared these measurements with those on three- and four-and-a-half-year-old Eucalyptus in Brazil. In Hawaii, CO(2) efflux from wood per unit biomass declined approximately 10x from age two to age five, twice as much as the decline in tree growth. The CO(2) efflux from wood in Brazil was 8-10x lower than that for comparable Hawaii trees with similar growth rates. Growth and maintenance respiration coefficients calculated from Hawaii wood CO(2) efflux declined with tree age and size (the growth coefficient declined from 0.4 mol C efflux mol C(-1) wood growth at age one to 0.1 mol C efflux mol C(-1) wood growth at age six; the maintenance coefficient from 0.006 to 0.001 micromol C (mol C biomass)(-1) s(-1) at 20 degrees C over the same time period). These results suggest interference with CO(2) efflux through bark that decouples CO(2) efflux from respiration. We also compared the biomass fractions and wood CO(2) efflux for the aboveground woody parts for 3- and 7-year-old trees in Hawaii to estimate how focusing measurements near the ground might bias the stand-level estimates of wood CO(2) efflux. Three-year-old Eucalyptus in Hawaii had a higher proportion of branches < 0.5 cm in diameter and a lower proportion of stem biomass than did 7-year-old trees. Biomass-specific CO(2) efflux measured at 1.4 m extrapolated to the tree could bias tree level estimates by approximately 50%, assuming no refixation from bark photosynthesis. However, the bias did not differ for the two tree sizes. Foliar respiration was identical per unit nitrogen for comparable treatments in Brazil and Hawaii (4.2 micromol C mol N(-1) s(-1) at 20 degrees C).

First direct landscape-scale measurement of tropical rain forest Leaf Area Index, a key driver of global primary productivity.

Leaf Area Index (leaf area per unit ground area, LAI) is a key driver of forest productivity but has never previously been measured directly at the landscape scale in tropical rain forest (TRF). We used a modular tower and stratified random sampling to harvest all foliage from forest floor to canopy top in 55 vertical transects (4.6 m(2)) across 500 ha of old growth in Costa Rica. Landscape LAI was 6.00 +/- 0.32 SEM. Trees, palms and lianas accounted for 89% of the total, and trees and lianas were 95% of the upper canopy. All vertical transects were organized into quantitatively defined strata, partially resolving the long-standing controversy over canopy stratification in TRF. Total LAI was strongly correlated with forest height up to 21 m, while the number of canopy strata increased with forest height across the full height range. These data are a benchmark for understanding the structure and functional composition of TRF canopies at landscape scales, and also provide insights for improving ecosystem models and remote sensing validation.

Foliar and ecosystem respiration in an old-growth tropical rain forest.

Foliar respiration is a major component of ecosystem respiration, yet extrapolations are often uncertain in tropical forests because of indirect estimates of leaf area index (LAI). A portable tower was used to directly measure LAI and night-time foliar respiration from 52 vertical transects throughout an old-growth tropical rain forest in Costa Rica. In this study, we (1) explored the effects of structural, functional and environmental variables on foliar respiration; (2) extrapolated foliar respiration to the ecosystem; and (3) estimated ecosystem respiration. Foliar respiration temperature response was constant within plant functional group, and foliar morphology drove much of the within-canopy variability in respiration and foliar nutrients. Foliar respiration per unit ground area was 3.5 +/- 0.2 micromol CO2 m(-2) s(-1), and ecosystem respiration was 9.4 +/- 0.5 micromol CO2 m(-2) s(-1)[soil = 41%; foliage = 37%; woody = 14%; coarse woody debris (CWD) = 7%]. When modelled with El Niño Southern Oscillation (ENSO) year temperatures, foliar respiration was 9% greater than when modelled with temperatures from a normal year, which is in the range of carbon sink versus source behaviour for this forest. Our ecosystem respiration estimate from component fluxes was 33% greater than night-time net ecosystem exchange for the same forest, suggesting that studies reporting a large carbon sink for tropical rain forests based solely on eddy flux measurements may be in error.

Carbohydrate regulation of photosynthesis and respiration from branch girdling in four species of wet tropical rain forest trees.

How trees sense source-sink carbon balance remains unclear. One potential mechanism is a feedback from non-structural carbohydrates regulating photosynthesis and removing excess as waste respiration when the balance of photosynthesis against growth and metabolic activity changes. We tested this carbohydrate regulation of photosynthesis and respiration using branch girdling in four tree species in a wet tropical rainforest in Costa Rica. Because girdling severs phloem to stop carbohydrate export while leaving xylem intact to allow photosynthesis, we expected carbohydrates to accumulate in leaves to simulate a carbon imbalance. We varied girdling intensity by removing phloem in increments of one-quarter of the circumference (zero, one--quarter, half, three-quarters, full) and surrounded a target branch with fully girdled ones to create a gradient in leaf carbohydrate content. Light saturated photosynthesis rate was measured in situ, and foliar respiration rate and leaf carbohydrate content were measured after destructive harvest at the end of the treatment. Girdling intensity created no consistent or strong responses in leaf carbohydrates. Glucose and fructose slightly increased in all species by 3.4% per one-quarter girdle, total carbon content and leaf mass per area increased only in one species by 5.4 and 5.5% per one-quarter girdle, and starch did not change. Only full girdling lowered photosynthesis in three of four species by 59-69%, but the decrease in photosynthesis was unrelated to the increase in glucose and fructose content. Girdling did not affect respiration. The results suggest that leaf carbohydrate content remains relatively constant under carbon imbalance, and any changes are unlikely to regulate photosynthesis or respiration. Because girdling also stops the export of hormones and reactive oxygen species, girdling may induce physiological changes unrelated to carbohydrate accumulation and may not be an effective method to study carbohydrate feedback in leaves. In three species, removal of three-quarters of phloem area did not cause leaf carbohydrates to accumulate nor did it change photosynthesis or respiration, suggesting that phloem transport is flexible and transport rate per unit phloem can rapidly increase under an increase in carbohydrate supply relative to phloem area. Leaf carbohydrate content thus may be decoupled from whole plant carbon balance by phloem transport in some species, and carbohydrate regulation of photosynthesis and respiration may not be as common in trees as previous girdling studies suggest. Further studies in carbohydrate regulation should avoid using girdling as girdling can decrease photosynthesis through unintended means without the tested mechanisms of accumulating leaf carbohydrates.