Differential contributions of peripheral and central mechanisms to pain in a rodent model of osteoarthritis

The mechanisms underlying the transition from acute nociceptive pain to centrally maintained chronic pain are not clear. We have studied the contributions of the peripheral and central nervous systems during the development of osteoarthritis (OA) pain. Male Sprague-Dawley rats received unilateral intra-articular injections of monosodium iodoacetate (MIA 1mg) or saline, and weight bearing (WB) asymmetry and distal allodynia measured. Subgroups of rats received intra-articular injections of, QX-314 (membrane impermeable local anaesthetic)+capsaicin, QX-314, capsaicin or vehicle on days 7, 14 or 28 post-MIA and WB and PWT remeasured. On days 7&14 post-MIA, but not day 28, QX-314+capsaicin signfcantly attenuated changes in WB induced by MIA, illustrating a crucial role for TRPV1 expressing nociceptors in early OA pain. The role of top-down control of spinal excitability was investigated. The mu-opioid receptor agonist DAMGO was microinjected into the rostroventral medulla, to activate endogenous pain modulatory systems, in MIA and control rats and refex excitability measured using electromyography. DAMGO (3ng) had a signifcantly larger inhibitory effect in MIA treated rats than in controls. These data show distinct temporal contribtuions of TRPV1 expressing nociceptors and opioidergic pain control systems at later timepoints

Microbial community structure mediates response of soil C decomposition to litter addition and warming

Microbial activity has been highlighted as one of the main unknowns controlling the fate and turnover of soil organic matter (SOM) in response to climate change. How microbial community structure and function may (or may not) interact with increasing temperature to impact the fate and turnover of SOM, in particular when combined with changes in litter chemistry, is not well understood. The primary aim of this study was to determine if litter chemistry impacted the decomposition of soil and litter-derived carbon (C), and its interaction with temperature, and whether this response was controlled by microbial community structure and function. Fresh or pre-incubated eucalyptus leaf litter (13C enriched) was added to a woodland soil and incubated at 12, 22, or 32 �C. We tracked the movement of litter and soilderived C into CO2, water-extractable organic carbon (WEOC), and microbial phospholipids (PLFA). The litter additions produced significant changes in every parameter measured, while temperature, interacting with litter chemistry, predominately affected soil C respiration (priming and temperature sensitivity), microbial community structure, and the metabolic quotient (a proxy for microbial carbon use efficiency [CUE]). The direction of priming varied with the litter additions (negative with fresh litter, positive with pre-incubated litter) and was related to differences in the composition of microbial communities degrading soil-C, particularly gram-positive and gram-negative bacteria, resulting from litter addition. Soil-C decomposition in both litter treatments was more temperature sensitive (higher Q10) than in the soil-only control, and soil-C priming became increasingly positive with temperature. However, microbes utilizing soil-C in the litter treatments had higher CUE, suggesting the longer-term stability of soil-C may be increased at higher temperature with litter addition. Our results show that in the same soil, the growth of distinct microbial communities can alter the turnover and fate of SOM and, in the context of global change, its response to temperature

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Degree of woody encroachment into grasslands controls soil carbohydrate and amino compound changes during long term laboratory incubation

Up to 50% of organic C and 80% of organic N within soil can exist as amino acids, amino sugars and carbohydrates. To determine how potential microbial accessibility and turnover of these compounds is impacted by encroachment of woody plants into grasslands, we investigated changes in evolved CO2 during thermal analysis and in carbohydrate and amino compound chemistry after long term laboratory incubation of sandy loam grassland woodland soils from southern Texas, USA. Thermal analysis showed that incubation increased the amount of soil organic matter (SOM) released at higher temperatures and that evolved CO2 profiles correlated with increases in amino C. During incubation, total carbohydrate C decreased slightly faster than bulk soil C, with preferential loss of plant-derived carbohydrates and/or production of microbial carbohydrates most strongly expressed in grassland and younger woodland soils. Total N content did not change during incubation, so the reduction in extractable amino N in older woodland soils suggested that N became more resistant to extraction during incubation. These data, along with previous measurements of respired CO2, indicate that changes in carbohydrate C and amino C did not predict mineralized CO2 yields and that amino compounds and microbial carbohydrate C were not selectively lost during incubation. The differing response in SOM loss (or enrichment) during incubation of the older woodland soils revealed a system with altered SOM dynamics due to woody encroachment, confirming that the short term ‘lability’ or ‘recalcitrance’ of SOM components is dependent on a number of interacting variables

Alteration of soil carbon and nitrogen pools and enzyme activities as affected by increased soil coarseness

Soil coarseness decreases ecosystem productivity, ecosystem carbon (C) and nitrogen (N) stocks, and soil nutrient contents in sandy grasslands subjected to desertification. To gain insight into changes in soil C and N pools, microbial biomass, and enzyme activities in response to soil coarseness, a field experiment was conducted by mixing native soil with river sand in different mass proportions: 0, 10, 30, 50, and 70% sand addition. Four years after establishing plots and 2 years after transplanting, soil organic C and total N concentrations decreased with increased soil coarseness down to 32.2 and 53.7% of concentrations in control plots, respectively. Soil microbial biomass C (MBC) and N (MBN) declined with soil coarseness down to 44.1 and 51.9 %, respectively, while microbial biomass phosphorus (MBP) increased by as much as 73.9 %. Soil coarseness significantly decreased the enzyme activities of beta-glucosidase, N-acetylglucosaminidase, and acid phosphomonoesterase by 20.2-57.5 %, 24.5-53.0 %, and 22.2-88.7 %, used for C, N and P cycling, respectively. However, observed values of soil organic C, dissolved organic C, total dissolved N, available P, MBC, MBN, and MBP were often significantly higher than would be predicted from dilution effects caused by the sand addition. Soil coarseness enhanced microbial C and N limitation relative to P, as indicated by the ratios of beta-glucosidase and N-acetyl-glucosaminidase to acid phosphomonoesterase (and MBC: MBP and MBN: MBP ratios). Enhanced microbial recycling of P might alleviate plant P limitation in nutrient-poor grassland ecosystems that are affected by soil coarseness. Soil coarseness is a critical parameter affecting soil C and N storage and increases in soil coarseness can enhance microbial C and N limitation relative to P, potentially posing a threat to plant productivity in sandy grasslands suffering from desertification

Response to ‘Stochastic and deterministic interpretation of pool models’

We concur with Azizi-Rad et al. (2021) that it is vital to critically evaluate and compare different soil carbon models, and we welcome the opportunity to further describe the unique contribution of the PROMISE model (Waring et al., 2020) to this literature. The PROMISE framework does share many features with established biogeochemical models, as our original manuscript highlighted in Table 1, and our work builds upon model innovations developed by many different groups, including that of Azizi-Rad and colleagues. Yet, the PROMISE framework is distinctive due to where it places mechanistic emphasis, and how these mechanisms are formalized in the mathematical model structure.This response is published as Waring, B.G., Sulman, B.N., Reed, S., Smith, A.P., Averill, C., Creamer, C.A., Cusack, D.F., Hall, S.J., Jastrow, J.D., Jilling, A., Kemner, K.M., Kleber, M., Allen Liu, X.‐J., Pett‐Ridge, J. and Schulz, M. (2021), Response to ‘Stochastic and deterministic interpretation of pool models’. Glob Change Biol. doi:10.1111/gcb.15580.</p

From pools to flow: The PROMISE framework for new insights on soil carbon cycling in a changing world

Soils represent the largest terrestrial reservoir of organic carbon, and the balance between soil organic carbon (SOC) formation and loss will drive powerful carbon‐climate feedbacks over the coming century. To date, efforts to predict SOC dynamics have rested on pool‐based models, which assume classes of SOC with internally homogenous physicochemical properties. However, emerging evidence suggests that soil carbon turnover is not dominantly controlled by the chemistry of carbon inputs, but rather by restrictions on microbial access to organic matter in the spatially heterogeneous soil environment. The dynamic processes that control the physicochemical protection of carbon translate poorly to pool‐based SOC models; as a result, we are challenged to mechanistically predict how environmental change will impact movement of carbon between soils and the atmosphere. Here, we propose a novel conceptual framework to explore controls on belowground carbon cycling: Probabilistic Representation of Organic Matter Interactions within the Soil Environment (PROMISE). In contrast to traditional model frameworks, PROMISE does not attempt to define carbon pools united by common thermodynamic or functional attributes. Rather, the PROMISE concept considers how SOC cycling rates are governed by the stochastic processes that influence the proximity between microbial decomposers and organic matter, with emphasis on their physical location in the soil matrix. We illustrate the applications of this framework with a new biogeochemical simulation model that traces the fate of individual carbon atoms as they interact with their environment, undergoing biochemical transformations and moving through the soil pore space. We also discuss how the PROMISE framework reshapes dialogue around issues related to SOC management in a changing world. We intend the PROMISE framework to spur the development of new hypotheses, analytical tools, and model structures across disciplines that will illuminate mechanistic controls on the flow of carbon between plant, soil, and atmospheric pools.This article is published as Waring, Bonnie G., Benjamin N. Sulman, Sasha Reed, A. Peyton Smith, Colin Averill, Courtney A. Creamer, Daniela F. Cusack et al. "From pools to flow: The PROMISE framework for new insights on soil carbon cycling in a changing world." Global Change Biology (2020). doi: 10.1111/gcb.15365.</p

From pools to flow: The PROMISE framework for new insights on soil carbon cycling in a changing world

Soils represent the largest terrestrial reservoir of organic carbon, and the balance between soil organic carbon (SOC) formation and loss will drive powerful carbon‐climate feedbacks over the coming century. To date, efforts to predict SOC dynamics have rested on pool‐based models, which assume classes of SOC with internally homogenous physicochemical properties. However, emerging evidence suggests that soil carbon turnover is not dominantly controlled by the chemistry of carbon inputs, but rather by restrictions on microbial access to organic matter in the spatially heterogeneous soil environment. The dynamic processes that control the physicochemical protection of carbon translate poorly to pool‐based SOC models; as a result, we are challenged to mechanistically predict how environmental change will impact movement of carbon between soils and the atmosphere. Here, we propose a novel conceptual framework to explore controls on belowground carbon cycling: Probabilistic Representation of Organic Matter Interactions within the Soil Environment (PROMISE). In contrast to traditional model frameworks, PROMISE does not attempt to define carbon pools united by common thermodynamic or functional attributes. Rather, the PROMISE concept considers how SOC cycling rates are governed by the stochastic processes that influence the proximity between microbial decomposers and organic matter, with emphasis on their physical location in the soil matrix. We illustrate the applications of this framework with a new biogeochemical simulation model that traces the fate of individual carbon atoms as they interact with their environment, undergoing biochemical transformations and moving through the soil pore space. We also discuss how the PROMISE framework reshapes dialogue around issues related to SOC management in a changing world. We intend the PROMISE framework to spur the development of new hypotheses, analytical tools, and model structures across disciplines that will illuminate mechanistic controls on the flow of carbon between plant, soil, and atmospheric pools.This article is published as Waring, Bonnie G., Benjamin N. Sulman, Sasha Reed, A. Peyton Smith, Colin Averill, Courtney A. Creamer, Daniela F. Cusack et al. "From pools to flow: The PROMISE framework for new insights on soil carbon cycling in a changing world." Global Change Biology (2020). doi: 10.1111/gcb.15365.</p