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Over the last century, many peatlands in northern Europe have been drained for forestry. Forest management with different harvesting regimes has a significant impact on soil water status and consequently on greenhouse gas emissions from peat soils. In this paper, we have used the process-based JSBACH-HIMMELI model to simulate the effects of alternative harvesting regimes, namely non-harvested (NH), selection harvesting (SH; 70 % of stem volume harvested) and clear-cutting (CC; 100 % of stem volume harvested), on soil CH 4 and CO 2 fluxes in peatland forests. We modified the model to account for the specific characteristics of peatland forests, where the water level (WL) is generally low and is regulated by the amount of aboveground vegetation through evapotranspiration. Multi-year measurements before and after the forest harvesting in a nutrient-rich peatland forest in southern Finland were used to constrain the model. The results showed that the modified model was able to reproduce the seasonal dynamics of water level, soil CH 4 and soil CO 2 fluxes under alternative harvesting regimes with reasonable accuracy. The averaged Pearson's r (Pearson correlation coefficient) and RMSE (Root Mean Square Error) between the model and the measurement were 0.75 and 7.3 cm for WL, 0.75 and 0.23 nmol m -2  s -1 for soil CH 4 flux, 0.73 and 0. 88 μmol m -2  s -1 for soil CO 2 flux. The modified model successfully reproduced soil CH 4 uptake at both NH and SH sites and soil CH 4 emission at the CC site, as observed in the measurements. Our study showed that increasing harvesting intensity (NH → SH → CC) in the model increased soil CH 4 emission and decreased soil CO 2 emission on an annual basis, but the magnitude of the decreased soil CO 2 emission was much larger than that of the increased soil CH 4 emission when comparing their global warming potentials. Therefore, in the short term as in our study (first three years after the harvest), the climate impacts of the soil GHG was reduced more in CC than in SH, which yet can be fundamentally different when considering in the long term., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Traditional photosynthesis-driven growth models have considerable uncertainties in predicting tree growth under changing climates, partially because sink activities are directly affected by the environment but not adequately addressed in growth modelling. Therefore, we developed a semi-mechanistic model coupling stomatal optimality, temperature control of enzymatic activities and phenology of cambial growth. Parameterized using Bayesian inference and measured data on Picea abies and Pinus sylvestris in peatland and mineral soils in Finland, the coupled model simulates transpiration and assimilation rates and stem radial dimension (SRD) simultaneously at 30 min resolution. The results suggest that both the sink and phenological formulations with environmental effects are indispensable for capturing SRD dynamics across hourly to seasonal scales. Simulated using the model, growth was more sensitive than assimilation to temperature and soil water, suggesting carbon gain is not driving growth at the current temporal scale. Also, leaf-specific production was occasionally positively correlated with growth duration but not with growth onset timing or annual cambial area increment. Thus, as it is hardly explained by carbon gain, phenology itself should be included in sink-driven growth models of the trees in the boreal zone and possibly other environments where sink activities and photosynthesis are both restrained by harsh conditions., (© 2024 The Author(s). Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Children with Cerebral Palsy (CP) exhibit less-selective, simplified muscle activation during gait due to injury of the developing brain. Abnormal motor unit recruitment, altered excitation-inhibition balance, and muscle morphological changes all affect the CP electromyogram. High-density surface electromyography (HDsEMG) has potential to reveal novel manifestations of CP neuromuscular pathology and functional deficits by assessing spatiotemporal details of myoelectric activity. We used HDsEMG to investigate spatial-EMG distribution and temporal-EMG complexity of gastrocnemius medialis (GM) muscle during treadmill walking in 11 adolescents with CP and 11 typically developed (TD) adolescents. Our results reveal more-uniform spatial-EMG amplitude distribution across the GM in adolescents with CP, compared to distal emphasis in TD adolescents. More-uniform spatial-EMG was associated with stronger ankle co-contraction and spasticity. CP adolescents exhibited a non-significant trend towards elevated EMG-temporal complexity. Homogenous spatial distribution and disordered temporal evolution of myoelectric activity in CP suggests less-structured and desynchronized recruitment of GM motor units, in combination with muscle morphological changes. Using HDsEMG, we uncovered novel evidence of atypical spatiotemporal activation during gait in CP, opening paths towards deeper understanding of motor control deficits and better characterization of changes in muscular activation from interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels., (© 2024. The Author(s).)

Process-based forest models combine biological, physical, and chemical process understanding to simulate forest dynamics as an emergent property of the system. As such, they are valuable tools to investigate the effects of climate change on forest ecosystems. Specifically, they allow testing of hypotheses regarding long-term ecosystem dynamics and provide means to assess the impacts of climate scenarios on future forest development. As a consequence, numerous local-scale simulation studies have been conducted over the past decades to assess the impacts of climate change on forests. These studies apply the best available models tailored to local conditions, parameterized and evaluated by local experts. However, this treasure trove of knowledge on climate change responses remains underexplored to date, as a consistent and harmonized dataset of local model simulations is missing. Here, our objectives were (i) to compile existing local simulations on forest development under climate change in Europe in a common database, (ii) to harmonize them to a common suite of output variables, and (iii) to provide a standardized vector of auxiliary environmental variables for each simulated location to aid subsequent investigations. Our dataset of European stand- and landscape-level forest simulations contains over 1.1 million simulation runs representing 135 million simulation years for more than 13,000 unique locations spread across Europe. The data were harmonized to consistently describe forest development in terms of stand structure (dominant height), composition (dominant species, admixed species), and functioning (leaf area index). Auxiliary variables provided include consistent daily climate information (temperature, precipitation, radiation, vapor pressure deficit) as well as information on local site conditions (soil depth, soil physical properties, soil water holding capacity, plant-available nitrogen). The present dataset facilitates analyses across models and locations, with the aim to better harness the valuable information contained in local simulations for large-scale policy support, and for fostering a deeper understanding of the effects of climate change on forest ecosystems in Europe., (© 2024 The Authors.)

Continuous cover forestry (CCF) has gained interest as an alternative to even-aged management particularly on drained peatland forests. However, relatively little is known about the physiological response of suppressed trees when larger trees are removed as a part of CCF practices. Consequently, studies concentrating on process-level modeling of the response of trees to selection harvesting are also rare. Here, we compared, modeled and measured harvest response of previously suppressed Norway spruce (Picea abies) trees to a selection harvest. We quantified the harvest response by collecting Norway spruce tree-ring samples in a drained peatland forest site and measuring the change in stable carbon and oxygen isotopic ratios of wood formed during 2010-20, including five post-harvest years. The measured isotopic ratios were compared with ecosystem-level process model predictions for ${\kern0em }^{13}$C discrimination and ${\kern0em }^{18}$O leaf water enrichment. We found that the model predicted similar but lower harvest response than the measurements. Furthermore, accounting for mesophyll conductance was important for capturing the variation in ${\kern0em }^{13}$C discrimination. In addition, we performed sensitivity analysis on the model, which suggests that the modeled ${\kern0em }^{13}$C discrimination is sensitive to parameters related to CO2 transport through stomata to the mesophyll., (© The Author(s) 2023. Published by Oxford University Press.)

Managed boreal peatlands are widespread and economically important, but they are a large source of greenhouse gases (GHGs). Peatland GHG emissions are related to soil water-table level (WT), which controls the vertical distribution of aerobic and anaerobic processes and, consequently, sinks and sources of GHGs in soils. On forested peatlands, selection harvesting reduces stand evapotranspiration and it has been suggested that the resulting WT rise decreases soil net emissions, while the tree growth is maintained. We monitored soil concentrations of CO 2 , CH 4 , N 2 O and O 2 by depth down to 80 cm, and CO 2 and CH 4 fluxes from soil in two nutrient-rich Norway spruce dominated peatlands in Southern Finland to examine the responses of soil GHG dynamics to WT rise. Selection harvesting raised WT by 14 cm on both sites, on average, mean WTs of the monitoring period being 73 cm for unharvested control and 59 cm for selection harvest. All soil gas concentrations were associated with proximity to WT. Both CH 4 and CO 2 showed remarkable vertical concentration gradients, with high values in the deepest layer, likely due to slow gas transfer in wet peat. CH 4 was efficiently consumed in peat layers near and above WT where it reached sub-atmospheric concentrations, indicating sustained oxidation of CH 4 from both atmospheric and deeper soil origins also after harvesting. Based on soil gas concentration data, surface peat (top 25/30 cm layer) contributed most to the soil-atmosphere CO 2 fluxes and harvesting slightly increased the CO 2 source in deeper soil (below 45/50 cm), which could explain the small CO 2 flux differences between treatments. N 2 O production occurred above WT, and it was unaffected by harvesting. Overall, the WT rise obtained with selection harvesting was not sufficient to reduce soil GHG emissions, but additional hydrological regulation would have been needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The notions of change , such as birth, death, growth, evolution and longevity, extend across reality, including biological, cultural and societal phenomena. Patterns of change describe how success and composition of every entity, from species to societies, vary across time. Languages develop into new languages, music and fashion continuously evolve, economies rise and decline, ecological and societal crises come and go. A common way to perceive and analyse change processes is through patterns of rise and decline, the ubiquitous, often distinctively unimodal trajectories describing life histories of various entities. These patterns come in different shapes and are measured according to varying definitions. Depending on how they are measured, patterns of rise and decline can reveal, emphasize, mask or obscure important dynamics in natural and cultural phenomena. Importantly, the variations of how dynamics are measured can be vast, making it impossible to directly compare patterns of rise and decline across fields of science. Standardized analysis of these patterns has the potential to uncover important but overlooked commonalities across natural phenomena and potentially help us catch the onset of dramatic shifts in entities' state, from catastrophic crashes in success to gradual emergence of new entities. We provide a framework for standardized recognizing, characterizing and comparing patterns of change by combining understanding of dynamics across fields of science. Our toolkit aims at enhancing understanding of the most general tendencies of change, through two complementary perspectives: dynamics of emergence and dynamics of success. We gather comparable cases and data from different research fields and summarize open research questions that can help us understand the universal principles, perception-biases and field-specific tendencies in patterns of rise and decline of entities in nature., Competing Interests: We declare we have no competing interests., (© 2023 The Authors.)

Uncertainties are essential, yet often neglected, information for evaluating the reliability in forest carbon balance projections used in national and regional policy planning. We analysed uncertainties in the forest net biome exchange (NBE) and carbon stocks under multiple management and climate scenarios with a process-based ecosystem model. Sampled forest initial state values, model parameters, harvest levels and global climate models (GCMs) served as inputs in Monte Carlo simulations, which covered forests of the 18 regions of mainland Finland over the period 2015-2050. Under individual scenarios, the results revealed time- and region-dependent variability in the magnitude of uncertainty and mean values of the NBE projections. The main sources of uncertainty varied with time, by region and by the amount of harvested wood. Combinations of uncertainties in the representative concentration pathways scenarios, GCMs, forest initial values and model parameters were the main sources of uncertainty at the beginning, while the harvest scenarios dominated by the end of the simulation period, combined with GCMs and climate scenarios especially in the north. Our regionally explicit uncertainty analysis was found a useful approach to reveal the variability in the regional potentials to reach a policy related, future target level of NBE, which is important information when planning realistic and regionally fair national policy actions., (© 2023. The Author(s).)

Forest management methods and harvest intensities influence wood production, carbon sequestration and biodiversity. We devised different management scenarios by means of stakeholder analysis and incorporated them in the forest growth simulator PREBAS. To analyse impacts of harvest intensity, we used constraints on total harvest: business as usual, low harvest, intensive harvest and no harvest. We carried out simulations on a wall-to-wall grid in Finland until 2050. Our objectives were to (1) test how the management scenarios differed in their projections, (2) analyse the potential wood production, carbon sequestration and biodiversity under the different harvest levels, and (3) compare different options of allocating the scenarios and protected areas. Harvest level was key to carbon stocks and fluxes regardless of management actions and moderate changes in proportion of strictly protected forest. In contrast, biodiversity was more dependent on other management variables than harvesting levels, and relatively independent of carbon stocks and fluxes., (© 2023. The Author(s).)

We present regionally aggregated emissions of greenhouse gases (GHG) from five land cover categories in Finland: artificial surfaces, arable land, forest, waterbodies, and wetlands. Carbon (C) sequestration to managed forests and unmanaged wetlands was also assessed. Models FRES and ALas were applied for emissions (CO 2 , CH 4 , N 2 O) from artificial surfaces and agriculture, and PREBAS for forest growth and C balance. Empirical emission coefficients were used to estimate emissions from drained forested peatland (CH 4 , N 2 O), cropland (CO 2 ), waterbodies (CH 4 , CO 2 ), peat production sites and undrained mires (CH 4 , CO 2 , N 2 O). We calculated gross emissions of 147.2 ± 6.8 TgCO 2 eq yr -1 for 18 administrative units covering mainland Finland, using data representative of the period 2017-2025. Emissions from energy production, industrial processes, road traffic and other sources in artificial surfaces amounted to 45.7 ± 2.0 TgCO 2 eq yr -1 . The loss of C in forest harvesting was the largest emission source in the LULUCF sector, in total 59.8 ± 3.3 TgCO 2 eq yr -1 . Emissions from domestic livestock production, field cultivation and organic soils added up to 12.2 ± 3.5 TgCO 2 eq yr -1 from arable land. Rivers and lakes (13.4 ± 1.9 TgCO 2 eq yr -1 ) as well as undrained mires and peat production sites (14.7 ± 1.8 TgCO 2 eq yr -1 ) increased the total GHG fluxes. The C sequestration from the atmosphere was 93.2 ± 13.7 TgCO 2 eq yr -1 . with the main sink in forest on mineral soil (79.9 ± 12.2 TgCO 2 eq yr -1 ). All sinks compensated 63% of total emissions and thus the net emissions were 53.9 ± 15.3 TgCO 2 eq yr -1 , or a net GHG flux per capita of 9.8 MgCO 2 eq yr -1 ., (© 2023. The Author(s).)

Land-based mitigation measures are needed to achieve climate targets. One option is the mitigation of currently high greenhouse gas (GHG) emissions of nutrient-rich drained peatland forest soils. Continuous cover forestry (CCF) has been proposed as a measure to manage this GHG emission source; however, its emission reduction potential and impact on timber production at regional and national scales have not been quantified. To quantify the potential emission reduction, we simulated four management scenarios for Finnish forests: (i) The replacement of clear-cutting by selection harvesting on nutrient-rich drained peatlands (CCF) and (ii) the current forest management regime (BAU), and both at two harvest levels, namely (i) the mean annual harvesting (2016-2018) and (ii) the maximum sustainable yield. The simulations were conducted at the stand scale with a forest simulator (MELA) coupled with a hydrological model (SpaFHy), soil C model (Yasso07) and empirical GHG exchange models. Simulations showed that the management scenario that avoided clear-cutting on nutrient-rich drained peatlands (i.e. CCF) produced approximately 1 Tg CO 2 eq. higher carbon sinks annually compared with BAU at equal harvest level for Finland. This emission reduction can be attributed to the maintenance of a higher biomass sink and to the mitigation of soil emissions from nutrient-rich drained peatland sites., (© 2023. Springer Nature Limited.)

With climate change, natural disturbances such as storm or fire are reshuffled, inducing pervasive shifts in forest dynamics. To predict how it will impact forest structure and composition, it is crucial to understand how tree species differ in their sensitivity to disturbances. In this study, we investigated how functional traits and species mean climate affect their sensitivity to disturbances while controlling for tree size and stand structure. With data on 130,594 trees located on 7617 plots that were disturbed by storm, fire, snow, biotic or other disturbances from the French, Spanish, and Finnish National Forest Inventory, we modeled annual mortality probability for 40 European tree species as a function of tree size, dominance status, disturbance type, and intensity. We tested the correlation of our estimated species probability of disturbance mortality with their traits and their mean climate niches. We found that different trait combinations controlled species sensitivity to disturbances. Storm-sensitive species had a high height-dbh ratio, low wood density and high maximum growth, while fire-sensitive species had low bark thickness and high P50. Species from warmer and drier climates, where fires are more frequent, were more resistant to fire. The ranking in disturbance sensitivity between species was overall consistent across disturbance types. Productive conifer species were the most disturbance sensitive, while Mediterranean oaks were the least disturbance sensitive. Our study identified key relations between species functional traits and disturbance sensitivity, that allows more reliable predictions of how changing climate and disturbance regimes will impact future forest structure and species composition at large spatial scales., (© 2023 John Wiley & Sons Ltd.)

Forest models are instrumental for understanding and projecting the impact of climate change on forests. A considerable number of forest models have been developed in the last decades. However, few systematic and comprehensive model comparisons have been performed in Europe that combine an evaluation of modelled carbon and water fluxes and forest structure. We evaluate 13 widely used, state-of-the-art, stand-scale forest models against field measurements of forest structure and eddy-covariance data of carbon and water fluxes over multiple decades across an environmental gradient at nine typical European forest stands. We test the models' performance in three dimensions: accuracy of local predictions (agreement of modelled and observed annual data), realism of environmental responses (agreement of modelled and observed responses of daily gross primary productivity to temperature, radiation and vapour pressure deficit) and general applicability (proportion of European tree species covered). We find that multiple models are available that excel according to our three dimensions of model performance. For the accuracy of local predictions, variables related to forest structure have lower random and systematic errors than annual carbon and water flux variables. Moreover, the multi-model ensemble mean provided overall more realistic daily productivity responses to environmental drivers across all sites than any single individual model. The general applicability of the models is high, as almost all models are currently able to cover Europe's common tree species. We show that forest models complement each other in their response to environmental drivers and that there are several cases in which individual models outperform the model ensemble. Our framework provides a first step to capturing essential differences between forest models that go beyond the most commonly used accuracy of predictions. Overall, this study provides a point of reference for future model work aimed at predicting climate impacts and supporting climate mitigation and adaptation measures in forests., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Objectives: To determine whether surgical technique has an effect on prognosis in coronary artery bypass grafting (CABG)., Design: Retrospective observational., Setting: Single center., Participants: All the off-pump (OPCABG) and on-pump (ONCABG) patients at Turku University Central Hospital in 2018., Interventions: None., Measurements and Main Results: After propensity score matching, perioperative, 1-year and 3-year mortality did not differ between the groups. The ONCABG patients received more allogenic red blood cells (1.3 vs. 0.6 units, p = 0.020), autologous red blood cells (564 vs. 285 ml, p < 0.001) and crystalloids (3388 vs. 2808 ml, p < 0.001), and had higher postoperative values of troponin T (581 vs. 222, p = 0.001) and lactate (1.69 vs. 1.23, p < 0.001) than the OPCABG patients., Conclusions: The both techniques seem equally safe. However, there may be some benefits to avoiding using a heart-lung machine, such as lower infused fluid volumes. Myocardial damage may also be milder and postoperative hemodynamics more balanced in OPCABG patients, based on lower levels of troponin T and lactate., Competing Interests: None., (© 2022 The Authors.)

Waterlogging causes hypoxic or anoxic conditions in soils, which lead to decreases in root and stomatal hydraulic conductance. Although these effects have been observed in a variety of plant species, they have not been quantified continuously over a range of water table depths (WTD) or soil water contents (SWC). To provide a quantitative theoretical framework for tackling this issue, we hypothesized similar mathematical descriptions of waterlogging and drought effects on whole-tree hydraulics and constructed a hierarchical model by connecting optimal stomata and soil-to-leaf hydraulic conductance models. In the model, the soil-to-root conductance is non-monotonic with WTD to reflect both the limitations by water under low SWC and by hypoxic effects associated with inhibited oxygen diffusion under high SWC. The model was parameterized using priors from literature and data collected over four growing seasons from Scots pine (Pinus sylvestris L.) trees grown in a drained peatland in Finland. Two reference models (RMs) were compared with the new model, RM1 with no belowground hydraulics and RM2 with no waterlogging effects. The new model was more accurate than the RMs in predicting transpiration rate (fitted slope of measured against modeled transpiration rate = 0.991 vs 0.979 (RM1) and 0.984 (RM2), R2 = 0.801 vs 0.665 (RM1) and 0.776 (RM2)). Particularly, RM2's overestimation of transpiration rate under shallow water table conditions (fitted slope = 0.908, R2 = 0.697) was considerably reduced by the new model (fitted slope = 0.956, R2 = 0.711). The limits and potential improvements of the model are discussed., (© The Author(s) 2022. Published by Oxford University Press.)

Since 2013, rotational thromboelastometry has been available in our hospital to assess coagulopathy. The aim of the study was to retrospectively evaluate the effect of thromboelastometry testing in cardiac surgery patients. Altogether 177 patients from 2012 and 177 patients from 2014 were included. In 2014, the thromboelastometry testing was performed on 56 patients. The mean blood drainage volume decreased and the number of patients receiving platelets decreased between 2012 and 2014. In addition, the use of fresh frozen plasma units decreased, and the use of prothrombin complex concentrate increased in 2014. When studied separately, the patients with a thromboelastometry testing received platelets, fresh frozen plasma, fibrinogen and prothrombin complex concentrate more often, but smaller amounts of red blood cells. In conclusion, after implementing the thromboelastometry testing to the practice, the blood products were given more cautiously overall. The use of thromboelastometry testing was associated with increased possibility to receive coagulation product transfusions. However, it appears that thromboelastometry testing was mostly used to assist in management of major bleeding.

Climate change mitigation is a global response that requires actions at the local level. Quantifying local sources and sinks of greenhouse gases (GHG) facilitate evaluating mitigation options. We present an approach to collate spatially explicit estimated fluxes of GHGs (carbon dioxide, methane and nitrous oxide) for main land use sectors in the landscape, to aggregate, and to calculate the net emissions of an entire region. Our procedure was developed and tested in a large river basin in Finland, providing information from intensively studied eLTER research sites. To evaluate the full GHG balance, fluxes from natural ecosystems (lakes, rivers, and undrained mires) were included together with fluxes from anthropogenic activities, agriculture and forestry. We quantified the fluxes based on calculations with an anthropogenic emissions model (FRES) and a forest growth and carbon balance model (PREBAS), as well as on emission coefficients from the literature regarding emissions from lakes, rivers, undrained mires, peat extraction sites and cropland. Spatial data sources included CORINE land use data, soil map, lake and river shorelines, national forest inventory data, and statistical data on anthropogenic activities. Emission uncertainties were evaluated with Monte Carlo simulations. Artificial surfaces were the most emission intensive land-cover class. Lakes and rivers were about as emission intensive as arable land. Forests were the dominant land cover in the region (66%), and the C sink of the forests decreased the total emissions of the region by 72%. The region's net emissions amounted to 4.37 ± 1.43 Tg CO 2 -eq yr -1 , corresponding to a net emission intensity 0.16 Gg CO 2 -eq km -2 yr -1 , and estimated per capita net emissions of 5.6 Mg CO 2 -eq yr -1 . Our landscape approach opens opportunities to examine the sensitivities of important GHG fluxes to changes in land use and climate, management actions, and mitigation of anthropogenic emissions., Competing Interests: Declaration of competing interest We have no known competing financial interests or personal relationships that have influenced the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The changing forest disturbance regimes emphasize the need for improved damage risk information. Here, our aim was to (1) improve the current understanding of snow damage risks by assessing the importance of abiotic factors, particularly the modelled snow load on trees, versus forest properties in predicting the probability of snow damage, (2) produce a snow damage probability map for Finland. We also compared the results for winters with typical snow load conditions and a winter with exceptionally heavy snow loads. To do this, we used damage observations from the Finnish national forest inventory (NFI) to create a statistical snow damage occurrence model, spatial data layers from different sources to use the model to predict the damage probability for the whole country in 16 x 16 m resolution. Snow damage reports from forest owners were used for testing the final map. Our results showed that best results were obtained when both abiotic and forest variables were included in the model. However, in the case of the high snow load winter, the model with only abiotic predictors performed nearly as well as the full model and the ability of the models to identify the snow damaged stands was higher than in other years. The results showed patterns of forest adaptation to high snow loads, as spruce stands in the north were less susceptible to damage than in southern areas and long-term snow load reduced the damage probability. The model and the derived wall-to-wall map were able to discriminate damage from no-damage cases on a good level (AUC > 0.7). The damage probability mapping approach identifies the drivers of snow disturbances across forest landscapes and can be used to spatially estimate the current and future disturbance probabilities in forests, informing practical forestry and decision-making and supporting the adaptation to the changing disturbance regimes., Competing Interests: The authors have declared that no competing interests exist.

Background: Spinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown., Methods: We randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery., Results: Of the 100 patients analyzed, patients receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml-1 (74.7 mg) or 0.25 mg ml-1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups., Conclusions: Oxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects., Competing Interests: The authors have declared that no competing interests exist.

The capability of viscoelastic measurement parameters to screen anticoagulation activity of edoxaban in relation to its plasma concentrations was evaluated in 15 healthy male volunteers. Blood samples were drawn before the oral administration of edoxaban 60 mg and 2, 4, 6, 8, and 24 hours after administration. At each time, standard coagulation tests were performed, blood viscoelastic properties were measured with a thromboelastometry device ROTEM delta analyzer (Instrumentation Laboratory, Werfen, Barcelona, Spain), and edoxaban plasma concentrations were measured. Our primary interest was the possible correlation between edoxaban plasma concentrations and values for ROTEM ExTEM, and FibTEM. We also studied the correlation of edoxaban plasma concentrations with the results of standard coagulation tests. We saw the effect of a single dose of edoxaban most clearly in clotting time (CT) of ROTEM ExTEM and FibTEM. Changes in these parameters correlated significantly with edoxaban plasma concentrations up to 6 hours from the ingestion of the drug. Activated partial thromboplastin time, prothrombin time, and anti-factor Xa were also affected. Peak changes were observed 2 and 4 hours after administration of edoxaban. The changes were mostly reversed after 8 hours. In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site., (© 2020, The American College of Clinical Pharmacology.)

Applications of ecosystem flux models on large geographical scales are often limited by model complexity and data availability. Here we calibrated and evaluated a semi-empirical ecosystem flux model, PREdict Light-use efficiency, Evapotranspiration and Soil water (PRELES), for various forest types and climate conditions, based on eddy covariance data from 55 sites. A Bayesian approach was adopted for model calibration and uncertainty quantification. We applied the site-specific calibrations and multisite calibrations to nine plant functional types (PFTs) to obtain the site-specific and PFT-specific parameter vectors for PRELES. A systematically designed cross-validation was implemented to evaluate calibration strategies and the risks in extrapolation. The combination of plant physiological traits and climate patterns generated significant variation in vegetation responses and model parameters across but not within PFTs, implying that applying the model without PFT-specific parameters is risky. But within PFT, the multisite calibrations performed as accurately as the site-specific calibrations in predicting gross primary production (GPP) and evapotranspiration (ET). Moreover, the variations among sites within one PFT could be effectively simulated by simply adjusting the parameter of potential light-use efficiency (LUE), implying significant convergence of simulated vegetation processes within PFT. The hierarchical modelling of PRELES provides a compromise between satellite-driven LUE and physiologically oriented approaches for extrapolating the geographical variation of ecosystem productivity. Although measurement errors of eddy covariance and remotely sensed data propagated a substantial proportion of uncertainty or potential biases, the results illustrated that PRELES could reliably capture daily variations of GPP and ET for contrasting forest types on large geographical scales if PFT-specific parameterizations were applied., (© 2020 John Wiley & Sons Ltd.)

The role of plant phenology as a regulator for gross ecosystem productivity (GEP) in peatlands is empirically not well constrained. This is because proxies to track vegetation development with daily coverage at the ecosystem scale have only recently become available and the lack of such data has hampered the disentangling of biotic and abiotic effects. This study aimed at unraveling the mechanisms that regulate the seasonal variation in GEP across a network of eight European peatlands. Therefore, we described phenology with canopy greenness derived from digital repeat photography and disentangled the effects of radiation, temperature and phenology on GEP with commonality analysis and structural equation modeling. The resulting relational network could not only delineate direct effects but also accounted for possible effect combinations such as interdependencies (mediation) and interactions (moderation). We found that peatland GEP was controlled by the same mechanisms across all sites: phenology constituted a key predictor for the seasonal variation in GEP and further acted as a distinct mediator for temperature and radiation effects on GEP. In particular, the effect of air temperature on GEP was fully mediated through phenology, implying that direct temperature effects representing the thermoregulation of photosynthesis were negligible. The tight coupling between temperature, phenology and GEP applied especially to high latitude and high altitude peatlands and during phenological transition phases. Our study highlights the importance of phenological effects when evaluating the future response of peatland GEP to climate change. Climate change will affect peatland GEP especially through changing temperature patterns during plant phenologically sensitive phases in high latitude and high altitude regions., (© 2019 John Wiley & Sons Ltd.)

Background: Post-operative pain after an above-knee amputation is often severe, and in the elderly patients the adverse effects of post-operative opioids are evident. We hypothesized that continuous perineural local anesthetic infusion (CPI) combined to a wound infusion will reduce acute pain and opioid consumption compared to placebo after above knee amputation., Methods: Ninety-three patients going through an above knee amputation were recruited for this randomized, controlled trial. Two catheters were placed, one to the sciatic nerve sheath and one under the fasciae during the amputation. After two 10 mL boluses of ropivacaine 0.75% a post-operative infusion of ropivacaine 0.2% or placebo (NaCl 0.9%) at 2 mL/h was administered for 72 hours to both catheters. The primary outcome was average stump pain during the first 5 days., Results: The mean intensity of stump pain during the first five post-operative days was 1.4 (0.8) in the CPI group and 1.9 (0.9) in the placebo group on VRS, mean (SD), P = .006. The opioid consumption on first five post-operative days did not differ between the groups., Conclusion: A combination of continuous perineural and wound local anesthetic infusion seems to diminish the intensity of stump pain after above knee amputation., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Globally 40-70 Pg of carbon (C) are stored in coarse woody debris on the forest floor. Climate change may reduce the function of this stock as a C sink in the future due to increasing temperature. However, current knowledge on the drivers of wood decomposition is inadequate for detailed predictions. To define the factors that control wood respiration rate of Norway spruce and to produce a model that adequately describes the decomposition process of this species as a function of time, we used an unprecedentedly diverse analytical approach, which included measurements of respiration, fungal community sequencing, N 2 fixation rate, nifH copy number, 14 C-dating as well as N%, δ 13 C and C% values of wood. Our results suggest that climate change will accelerate C flux from deadwood in boreal conditions, due to the observed strong temperature dependency of deadwood respiration. At the research site, the annual C flux from deadwood would increase by 27% from the current 117 g C/kg wood with the projected climate warming (RCP4.5). The second most important control on respiration rate was the stage of wood decomposition; at early stages of decomposition low nitrogen content and low wood moisture limited fungal activity while reduced wood resource quality decreased the respiration rate at the final stages of decomposition. Wood decomposition process was best described by a Sigmoidal model, where after 116 years of wood decomposition mass loss of 95% was reached. Our results on deadwood decomposition are important for C budget calculations in ecosystem and climate change models. We observed for the first time that the temperature dependency of N 2 fixation, which has a major role at providing N for wood-inhabiting fungi, was not constant but varied between wood density classes due to source supply and wood quality. This has significant consequences on projecting N 2 fixation rates for deadwood in changing climate., (© 2019 The Authors. Global Change Biology Published by John Wiley & Sons Ltd.)

Forests regulate climate, as carbon, water and nutrient fluxes are modified by physiological processes of vegetation and soil. Forests also provide renewable raw material, food, and recreational possibilities. Rapid climate warming projected for the boreal zone may change the provision of these ecosystem services. We demonstrate model based estimates of present and future ecosystem services related to carbon cycling of boreal forests. The services were derived from biophysical variables calculated by two dynamic models. Future changes in the biophysical variables were driven by climate change scenarios obtained as results of a sample of global climate models downscaled for Finland, assuming three future pathways of radiative forcing. We introduce continuous monitoring on phenology to be used in model parametrization through a webcam network with automated image processing features. In our analysis, climate change impacts on key boreal forest ecosystem services are both beneficial and detrimental. Our results indicate an increase in annual forest growth of about 60% and an increase in annual carbon sink of roughly 40% from the reference period (1981-2010) to the end of the century. The vegetation active period was projected to start about 3 weeks earlier and end ten days later by the end of the century compared to currently. We found a risk for increasing drought, and a decrease in the number of soil frost days. Our results show a considerable uncertainty in future provision of boreal forest ecosystem services.

Most glycosyltransferases, including B4GalT1 (EC 2.4.1.38), are known to assemble into enzyme homomers and functionally relevant heteromers in vivo. However, it remains unclear why and how these enzymes interact at the molecular/atomic level. Here, we solved the crystal structure of the wild-type human B4GalT1 homodimer. We also show that B4GalT1 exists in a dynamic equilibrium between monomer and dimer, since a purified monomer reappears as a mixture of both and as we obtained crystal forms of the monomer and dimer assemblies in the same crystallization conditions. These two crystal forms revealed the unliganded B4GalT1 in both the open and the closed conformation of the Trp loop and the lid regions, responsible for donor and acceptor substrate binding, respectively. The present structures also show the lid region in full in an open conformation, as well as a new conformation for the GlcNAc acceptor loop (residues 272-288). The physiological relevance of the homodimer in the crystal was validated by targeted mutagenesis studies coupled with FRET assays. These showed that changing key catalytic amino acids impaired homomer formation in vivo. The wild-type human B4GalT1 structure also explains why the variant proteins used for crystallization in earlier studies failed to reveal the homodimers described in this study., Competing Interests: The authors have declared that no competing interests exist.

Trees scale leaf (A L ) and xylem (A X ) areas to couple leaf transpiration and carbon gain with xylem water transport. Some species are known to acclimate in A L  : A X balance in response to climate conditions, but whether trees of different species acclimate in A L  : A X in similar ways over their entire (continental) distributions is unknown. We analyzed the species and climate effects on the scaling of A L vs A X in branches of conifers (Pinus sylvestris, Picea abies) and broadleaved (Betula pendula, Populus tremula) sampled across a continental wide transect in Europe. Along the branch axis, A L and A X change in equal proportion (isometric scaling: b ˜ 1) as for trees. Branches of similar length converged in the scaling of A L vs A X with an exponent of b = 0.58 across European climates irrespective of species. Branches of slow-growing trees from Northern and Southern regions preferentially allocated into new leaf rather than xylem area, with older xylem rings contributing to maintaining total xylem conductivity. In conclusion, trees in contrasting climates adjust their functional balance between water transport and leaf transpiration by maintaining biomass allocation to leaves, and adjusting their growth rate and xylem production to maintain xylem conductance., (© 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.)

Spray-dried protein formulations commonly require stabilising excipients to prevent protein degradation during processing and storage, and trehalose has been commonly used. The purpose of this work was to evaluate melibiose in spray-dried protein formulations in comparison to trehalose. The protein-activity-preserving efficacy, process behaviour and storage stability were studied. Spray drying of β-galactosidase was carried out using different process temperature, drying air flow and feed liquid atomisation settings. Both melibiose and trehalose reduced protein activity loss during drying. A decrease in activities was observed when the process temperature exceeded a threshold temperature. During storage (30 days at 18% RH and 20 or 40 °C), the formulations dried below this threshold temperature showed no further activity loss, and the stabilising efficacy of the two disaccharides was equal. With higher process temperatures, the remaining protein activities after storage trended higher with melibiose formulations. All formulations remained amorphous. The powder yields of melibiose formulations were similar to trehalose. There was a difference in residual moisture contents, with melibiose formulations giving drier products. In conclusion, protein formulations with melibiose could be spray dried into amorphous powders that were physically stable, contained lower moisture contents and protected protein activity at least as well as trehalose formulations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Many studies have reported that hydraulic properties vary considerably between tree species, but little is known about their intraspecific variation and, therefore, their capacity to adapt to a warmer and drier climate. Here, we quantify phenotypic divergence and clinal variation for embolism resistance, hydraulic conductivity and branch growth, in four tree species, two angiosperms (Betula pendula, Populus tremula) and two conifers (Picea abies, Pinus sylvestris), across their latitudinal distribution in Europe. Growth and hydraulic efficiency varied widely within species and between populations. The variability of embolism resistance was in general weaker than that of growth and hydraulic efficiency, and very low for all species but Populus tremula. In addition, no and weak support for a safety vs. efficiency trade-off was observed for the angiosperm and conifer species, respectively. The limited variability of embolism resistance observed here for all species except Populus tremula, suggests that forest populations will unlikely be able to adapt hydraulically to drier conditions through the evolution of embolism resistance.

MK-467 is a peripherally acting α 2 -adrenoceptor antagonist due to its low lipid solubility and poor penetration of the blood-brain barrier (BBB). The aim of this study was to assess whether MK-467 could be a substrate of an active efflux transport mechanism. Using Madin-Darby Canine Kidney cells (MDCKII) and MDCKII cells transfected with the human multidrug resistance gene 1, drug transport was assessed in apical-basolateral and basolateral-apical directions. MK-467 was studied at 2 concentrations: 200 and 1000 ng/mL. Samples for analysis were taken at 15, 30, 45, 60, and 90 min after drug application. Drug concentrations were measured using liquid chromatography and mass spectrometry. MK-467 showed no apparent permeability in the apical-basolateral direction, transport in the basolateral-apical direction occurred in both cell lines. Efflux ratios were not calculated. However, MK-467 appeared to undergo active cellular transport. The identity of the transporter requires further investigation.

Forest disturbances are sensitive to climate. However, our understanding of disturbance dynamics in response to climatic changes remains incomplete, particularly regarding large-scale patterns, interaction effects and dampening feedbacks. Here we provide a global synthesis of climate change effects on important abiotic (fire, drought, wind, snow and ice) and biotic (insects and pathogens) disturbance agents. Warmer and drier conditions particularly facilitate fire, drought and insect disturbances, while warmer and wetter conditions increase disturbances from wind and pathogens. Widespread interactions between agents are likely to amplify disturbances, while indirect climate effects such as vegetation changes can dampen long-term disturbance sensitivities to climate. Future changes in disturbance are likely to be most pronounced in coniferous forests and the boreal biome. We conclude that both ecosystems and society should be prepared for an increasingly disturbed future of forests., Competing Interests: Competing financial interests The authors declare no competing financial interests.

Tree mortality is a key factor influencing forest functions and dynamics, but our understanding of the mechanisms leading to mortality and the associated changes in tree growth rates are still limited. We compiled a new pan-continental tree-ring width database from sites where both dead and living trees were sampled (2970 dead and 4224 living trees from 190 sites, including 36 species), and compared early and recent growth rates between trees that died and those that survived a given mortality event. We observed a decrease in radial growth before death in ca. 84% of the mortality events. The extent and duration of these reductions were highly variable (1-100 years in 96% of events) due to the complex interactions among study species and the source(s) of mortality. Strong and long-lasting declines were found for gymnosperms, shade- and drought-tolerant species, and trees that died from competition. Angiosperms and trees that died due to biotic attacks (especially bark-beetles) typically showed relatively small and short-term growth reductions. Our analysis did not highlight any universal trade-off between early growth and tree longevity within a species, although this result may also reflect high variability in sampling design among sites. The intersite and interspecific variability in growth patterns before mortality provides valuable information on the nature of the mortality process, which is consistent with our understanding of the physiological mechanisms leading to mortality. Abrupt changes in growth immediately before death can be associated with generalized hydraulic failure and/or bark-beetle attack, while long-term decrease in growth may be associated with a gradual decline in hydraulic performance coupled with depletion in carbon reserves. Our results imply that growth-based mortality algorithms may be a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark-beetle outbreaks., (© 2016 John Wiley & Sons Ltd.)

Tree mortality is a key process shaping forest dynamics. Thus, there is a growing need for indicators of the likelihood of tree death. During the last decades, an increasing number of tree-ring based studies have aimed to derive growth-mortality functions, mostly using logistic models. The results of these studies, however, are difficult to compare and synthesize due to the diversity of approaches used for the sampling strategy (number and characteristics of alive and death observations), the type of explanatory growth variables included (level, trend, etc.), and the length of the time window (number of years preceding the alive/death observation) that maximized the discrimination ability of each growth variable. We assess the implications of key methodological decisions when developing tree-ring based growth-mortality relationships using logistic mixed-effects regression models. As examples, we use published tree-ring datasets from Abies alba (13 different sites), Nothofagus dombeyi (one site), and Quercus petraea (one site). Our approach is based on a constant sampling size and aims at (1) assessing the dependency of growth-mortality relationships on the statistical sampling scheme used, (2) determining the type of explanatory growth variables that should be considered, and (3) identifying the best length of the time window used to calculate them. The performance of tree-ring-based mortality models was reasonably high for all three species (area under the receiving operator characteristics curve, AUC > 0.7). Growth level variables were the most important predictors of mortality probability for two species (A. alba, N. dombeyi), while growth-trend variables need to be considered for Q. petraea. In addition, the length of the time window used to calculate each growth variable was highly uncertain and depended on the sampling scheme, as some growth-mortality relationships varied with tree age. The present study accounts for the main sampling-related biases to determine reliable species-specific growth-mortality relationships. Our results highlight the importance of using a sampling strategy that is consistent with the research question. Moving towards a common methodology for developing reliable growth-mortality relationships is an important step towards improving our understanding of tree mortality across species and its representation in dynamic vegetation models., (© 2016 by the Ecological Society of America.)

The possibility of producing amorphous isomalt and melibiose by spray drying was studied. The impact of process parameters on yield and solid-state stability was compared to sucrose and trehalose. All powders remained amorphous during 2-3 weeks. Processing was challenging due to powder stickiness. Low-temperature and low-humidity drying processes generally performed best. Most isomalt and sucrose powder was retrieved when using 60°C inlet temperature, 800L/h atomizing rate, 1.4ml/min feed rate, 15% concentration and 100% aspirator rate, giving 42-43°C outlet temperature. Isomalt was the most problematic, because it had the lowest Tg and became sticky very easily, therefore process parameters needed to be precisely balanced. There was more freedom in designing processes for melibiose but best yields were obtained with low-temperature (50°C inlet temperature, 800L/h atomizing rate, 4.9ml/min feed rate, 10% concentration and 100% aspirator, 39°C outlet temperature). Trehalose was different in that higher temperatures resulted in better yields. Yet, trehalose generally contained the highest moisture contents. The possibility to produce amorphous isomalt and melibiose at low-temperature process conditions makes them promising considering spray drying applications for heat-sensitive proteins. Melibiose is a better candidate than isomalt because of easier processability and superior solid-state stability., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Phloem osmolality and its components are involved in basic cell metabolism, cell growth, and in various physiological processes including the ability of living cells to withstand drought and frost. Osmolality and sugar composition responses to environmental stresses have been extensively studied for leaves, but less for the secondary phloem of plant stems and branches. Leaf osmotic concentration and the share of pinitol and raffinose among soluble sugars increase with increasing drought or cold stress, and osmotic concentration is adjusted with osmoregulation. We hypothesize that similar responses occur in the secondary phloem of branches. We collected living bark samples from branches of adult Pinus sylvestris, Picea abies, Betula pendula and Populus tremula trees across Europe, from boreal Northern Finland to Mediterranean Portugal. In all studied species, the observed variation in phloem osmolality was mainly driven by variation in phloem water content, while tissue solute content was rather constant across regions. Osmoregulation, in which osmolality is controlled by variable tissue solute content, was stronger for Betula and Populus in comparison to the evergreen conifers. Osmolality was lowest in mid-latitude region, and from there increased by 37% toward northern Europe and 38% toward southern Europe due to low phloem water content in these regions. The ratio of raffinose to all soluble sugars was negligible at mid-latitudes and increased toward north and south, reflecting its role in cold and drought tolerance. For pinitol, another sugar known for contributing to stress tolerance, no such latitudinal pattern was observed. The proportion of sucrose was remarkably low and that of hexoses (i.e., glucose and fructose) high at mid-latitudes. The ratio of starch to all non-structural carbohydrates increased toward the northern latitudes in agreement with the build-up of osmotically inactive C reservoir that can be converted into soluble sugars during winter acclimation in these cold regions. Present results for the secondary phloem of trees suggest that adjustment with tissue water content plays an important role in osmolality dynamics. Furthermore, trees acclimated to dry and cold climate showed high phloem osmolality and raffinose proportion.

Purpose: To evaluate adverse drug reactions (ADRs) experienced by chronic myeloid leukemia (CML) patients during per oral tyrosine kinase inhibitor (TKI) treatment and correlation of ADR symptoms with medication adherence and perceived quality of life (QoL)., Patients and Methods: Eighty-six adult, chronic-phase CML patients who had been on TKI treatment (79% on imatinib, 10.5% dasatinib, and 10.5% nilotinib) for at least 6 months participated in the study (mean age: 57.8 years, 52% males). The mean time from diagnosis was 5.1 years. All patients were interviewed, and patient-reported ADRs were obtained using a structured list. Adherence was assessed using Morisky's 8-item Medication Adherence Scale (MMAS). The symptoms' interference with patient's daily QoL was measured by asking patients about the influence of symptom(s) on their mood, general condition, enjoyment of life, walking, relationships, and work., Results: Ninety-seven percent of the patients were suffering from at least one ADR. The mean number of different symptoms was seven (range: 0-15, median 6). The most commonly perceived ADRs were muscle soreness or cramp (69/86, 80%); swelling of hands, legs, feet, or around the eyes (59/86, 69%); and fatigue (43/86, 50%). No correlation was found between adherence and ADRs, because symptoms were equally common in each MMAS adherence class. Half of the patients felt that the ADRs had a negative influence on their daily QoL. A quarter of the patients reported that ADRs affected either their mood, general condition, or enjoyment of life. The incidence of almost all ADRs was much higher among patients reporting negative influence of ADRs on their daily life compared to total study population (P=0.016)., Conclusion: TKI-related ADRs were common among CML patients irrespective of patient's adherence level. Patients who reported that ADRs had a negative influence on their daily QoL perceived more ADRs than those who did not experience a negative influence.

Cytokines are messenger proteins that regulate the proliferation and differentiation of cells and control immune responses. Interferons, interleukins, and growth factors have applications in cancer, autoimmune, and viral disease treatment. The cytokines are susceptible to chemical and physical instability. This article reviews the structure and stability issues of clinically used cytokines, as well as formulation strategies for improved stability. Some general aspects for identifying most probable stability concerns, selecting excipients, and developing stable cytokine formulations are presented. The vast group of cytokines offers possibilities for new biopharmaceuticals. The formulation approaches of the current cytokine products could facilitate development of new biopharmaceuticals., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Hundreds of wood-inhabiting fungal species are now threatened, principally due to a lack of dead wood in intensively managed forests, but the consequences of reduced fungal diversity on ecosystem functioning are not known. Several experiments have shown that primary productivity is negatively affected by a loss of species, but the effects of microbial diversity on decomposition are less studied. We studied the relationship between fungal diversity and the in vitro decomposition rate of slightly, moderately and heavily decayed Picea abies wood with indigenous fungal communities that were diluted to examine the influence of diversity. Respiration rate, wood-degrading hydrolytic enzymes and fungal community structure were assessed during a 16-week incubation. The number of observed OTUs in DGGE was used as a measure of fungal diversity. Respiration rate increased between early- and late-decay stages. Reduced fungal diversity was associated with lower respiration rates during intermediate stages of decay, but no effects were detected at later stages. The activity of hydrolytic enzymes varied among decay stages and fungal dilutions. Our results suggest that functioning of highly diverse communities of the late-decay stage were more resistant to the loss of diversity than less diverse communities of early decomposers. This indicates the accumulation of functional redundancy during the succession of the fungal community in decomposing substrates.

Acetaldehyde is a known mutagenic substance and has been classified as a group-one carcinogen by the WHO. It is possible to bind acetaldehyde locally in the gastrointestinal (GI) tract with the semi-essential amino acid l-cysteine, which reacts covalently with acetaldehyde and forms compound 2-methyl-thiozolidine-4-carboxylic acid (MTCA). The Caco-2 cell line was used to determine the permeation of l-cysteine and MTCA, as well as the possible cell toxicity of both substances. Neither of the substances permeated through the Caco-2 cells at the concentrations used in this study, and only the highest concentration of MTCA affected the viability of the cells in the MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide) test. These results showed that when l-cysteine is administered in formulations releasing it locally in the lower parts of GI tract, it is not absorbed but can react with acetaldehyde, and that neither l-cysteine nor MTCA is harmful to the cells when present locally in the upper parts of GI tract. This study also shows that MTCA is sensitive at a lower pH of 5.5. Since stable MTCA is desired in different parts of the GI tract, this observation raises concern over the influence of lower pH on l-cysteine-containing product ability to bind and eliminate carcinogenic acetaldehyde.

Background: Ketoprofen is a non-steroidal anti-inflammatory drug which has been widely used for domestic animals. Orally administered racemic ketoprofen has been reported to be absorbed well in pigs, and bioavailability was almost complete. The objectives of this study were to analyze R- and S-ketoprofen concentrations in plasma after oral (PO) and intra muscular (IM) routes of administration, and to assess the relative bioavailability of racemic ketoprofen for both enantiomers between those routes of administration in growing pigs., Methods: Eleven pigs received racemic ketoprofen at dose rates of 4 mg/kg PO and 3 mg/kg IM in a randomized, crossover design with a 6-day washout period. Enantiomers were separated on a chiral column and their concentrations were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated and relative bioavailability (Frel) was determined for S and R -ketoprofen., Results: S-ketoprofen was the predominant enantiomer in pig plasma after administration of the racemic mixture via both routes. The mean (± SD) maximum S-ketoprofen concentration in plasma (7.42 mg/L ± 2.35 in PO and 7.32 mg/L ± 0.75 in IM) was more than twice as high as that of R-ketoprofen (2.55 mg/L ± 0.99 in PO and 3.23 mg/L ± 0.70 in IM), and the terminal half-life was three times longer for S-ketoprofen (3.40 h ± 0.91 in PO and 2.89 h ± 0.85 in IM) than R-ketoprofen (1.1 h ± 0.90 in PO and 0.75 h ± 0.48 in IM). The mean (± SD) relative bioavailability (PO compared to IM) was 83 ± 20% and 63 ± 23% for S-ketoprofen and R-ketoprofen, respectively., Conclusions: Although some minor differences were detected in the ketoprofen enantiomer concentrations in plasma after PO and IM administration, they are probably not relevant in clinical use. Thus, the pharmacological effects of racemic ketoprofen should be comparable after intramuscular and oral routes of administration in growing pigs.

Decaying wood plays an important role in forest biodiversity, nutrient cycling and carbon balance. Community structure of wood-inhabiting fungi changes with mass loss of wood, but the relationship between substrate quality and decomposers is poorly understood. This limits the extent to which these ecosystem services can be effectively managed. We studied the fungal community and physico-chemical quality (stage of decay, dimensions, density, moisture, C : N ratio, lignin and water or ethanol extractives) of 543 Norway spruce logs in five unmanaged boreal forest sites of southern Finland. Fungi were identified using denaturing gradient gel electrophoresis and sequencing of DNA extracted directly from wood samples. Macroscopic fruiting bodies were also recorded. Results showed a fungal community succession with decreasing wood density and C : N ratio, and increasing moisture and lignin content. Fungal diversity peaked in the most decayed substrates. Ascomycetes typically colonized recently fallen wood. Brown-rot fungi preferred the intermediate decay stages. White-rot fungi represented approximately one-fifth of sequenced species in all decay phases excluding the final phase, where ectomycorrhizal (ECM) fungi became dominant. Lignin content of logs with white-rot fungi was low, and ECM fungi were associated with substrates containing abundant nitrogen. Macroscopic fruiting bodies were observed for only a small number of species detected with molecular techniques., (© 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

The maximum light use efficiency (LUE = gross primary production (GPP)/absorbed photosynthetic photon flux density (aPPFD)) of plant canopies has been reported to vary spatially and some of this variation has previously been attributed to plant species differences. The canopy nitrogen concentration [N] can potentially explain some of this spatial variation. However, the current paradigm of the N-effect on photosynthesis is largely based on the relationship between photosynthetic capacity (A(max)) and [N], i.e., the effects of [N] on photosynthesis rates appear under high PPFD. A maximum LUE-[N] relationship, if it existed, would influence photosynthesis in the whole range of PPFD. We estimated maximum LUE for 14 eddy-covariance forest sites, examined its [N] dependency and investigated how the [N]-maximum LUE dependency could be incorporated into a GPP model. In the model, maximum LUE corresponds to LUE under optimal environmental conditions before light saturation takes place (the slope of GPP vs. PPFD under low PPFD). Maximum LUE was higher in deciduous/mixed than in coniferous sites, and correlated significantly with canopy mean [N]. Correlations between maximum LUE and canopy [N] existed regardless of daily PPFD, although we expected the correlation to disappear under low PPFD when LUE was also highest. Despite these correlations, including [N] in the model of GPP only marginally decreased the root mean squared error. Our results suggest that maximum LUE correlates linearly with canopy [N], but that a larger body of data is required before we can include this relationship into a GPP model. Gross primary production will therefore positively correlate with [N] already at low PPFD, and not only at high PPFD as is suggested by the prevailing paradigm of leaf-level A(max)-[N] relationships. This finding has consequences for modelling GPP driven by temporal changes or spatial variation in canopy [N].

This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.

Background: The computational models for predicting oral drug absorption in humans using in vitro and in vivo data have been published. However, only a limited number of studies are available on the prediction of local drug efficacy in the mouth using computational models., Aim: The goal of this study was to develop a simulation model for prediction of drug amount and effect on carcinogenic acetaldehyde in the mouth., Methods: The model was based partly on our previous studies in which we showed in vivo that l-cysteine-containing tablets can eliminate carcinogenic salivary acetaldehyde in the mouth during smoking. To develop as informative a model as possible, we also investigated whether a lower saliva pH (4.7) can affect the freely soluble l-cysteine dissolution rate and cysteine stability profile in the mouth, compared to the normal saliva pH of 7.4., Results: Stability of the active drug is not pH dependent and thus users with normal, healthy saliva pH and those with lower pH can benefit from cysteine-containing products. The simulated saliva profiles of l-cysteine and acetaldehyde corresponded to the in vivo results., Conclusions: The model developed can be used as an alternative tool to obtain faster and cheaper answers on how freely soluble drugs affect local conditions in the mouth. Because tobacco smoke contains more than 60 carcinogenic compounds, the model developed can offer a new view in eliminating or reducing not only one toxic compound from smoke but also many others compounds using only one formulation containing various active compounds.

Peroxiredoxins (Prxs) 1-6 were assessed in 138 renal cell carcinomas (RCC) using immunohistochemistry and selected samples by Western blotting analysis. Oxidative/nitrosative damage was evaluated using nitrotyrosine immunoreactivity. The expressions of Prxs were correlated with tumor grade and survival and nitrotyrosine reactivity. Non-malignant kidney tubular cells showed positivity with variable intensity for all six Prxs. In RCCs, most cases were positive for Prxs 1 and 2, while only 15-20% of tumors showed expression for Prxs 3 and 4. Prx 2 was associated with tumors of a lower grade (p=0.009) and with a lower frequency of distant metastases (p=0.046). Patients with tumors expressing Prx2 had better prognosis (p=0.027). Instead, nitrotyrosine was significantly associated with high grade tumors (p=0.001). Compared with the non-malignant kidney tubular cells, low Prx expression in the tumor cells can make them more susceptible to oxidative damage. Prx 2 was more abundantly expressed in low grade tumors, suggesting that this protein could play a role in preventing the development of oxidative damage, which in turn can lead to the activation of pathways leading to aggressive tumors.

The aim of the study was to estimate the significance of oxidative/nitrosative damage and expression of antioxidant enzymes in renal cell carcinomas (RCC). For this we investigated immunohistochemically six antioxidant enzymes (AOEs) including MnSOD, ECSOD, thioredoxin, thioredoxin reductase, and gammaglutamyl cysteine synthetase heavy and light chain in 138 RCCs. As an indicator of oxidative/nitrosative damage, sections were stained with an antibody to nitrotyrosine. The extent of apoptosis was evaluated by TUNEL method and proliferation by immunohistochemistry to Ki67. Variable expression of all AOEs could be seen in RCC with expression of MnSOD being strongest. Nitrotyrosine was significantly associated with high grade tumors. MnSOD was associated with tumors of a lower stage. Cases showing ECSOD reactivity had higher and cases expressing thioredoxin lower apoptotic index than other tumors. No association with patient prognosis was observed. According to the results renal cell carcinomas show oxidative/nitrosative damage which, according to nitrotyrosine staining, was higher in high grade tumors. Of AOEs, MnSOD was more abundantly expressed in low stage tumors suggesting that its antioxidant function could play a main role to prevent development of oxidative damage leading to more aggressive tumors.

Peroxiredoxins (Prxs) are a group of thiol containing proteins that participate both in signal transduction and in the breakdown of hydrogen peroxide (H(2)O(2)) during oxidative stress. Six distinct Prxs have been characterized in human cells (Prxs I-VI). Prxs I-IV form dimers held together by disulfide bonds, Prx V forms intramolecular bond, but the mechanism of Prx VI, so-called 1-Cys Prx, is still unclear. Here we describe the regulation of all six Prxs in cultured human lung A549 and BEAS-2B cells. The cells were exposed to variable concentrations of H(2)O(2), menadione, tumor necrosis factor-alpha or transforming growth factor-beta. To evoke glutathione depletion, the cells were furthermore treated with buthionine sulfoximine. Only high concentrations (300 microM) of H(2)O(2) caused a minor increase (<28%, 4 h) in the expression of Prxs I, IV, and VI. Severe oxidant stress (250-500 microM H(2)O(2)) caused a significant increase in the proportion of the monomeric forms of Prxs I-IV; this was reversible at lower H(2)O(2) concentrations (< or =250 microM). This recovery of Prx overoxidation differed among the various Prxs; Prx I was recovered within 24 h, but recovery required 48 h for Prx III. Overall, Prxs are not significantly modulated by mild oxidant stress or cytokines, but there is variable, though reversible, overoxidation in these proteins during severe oxidant exposure.