Multimodel ensembles improve predictions of crop-environment-management interactions.

A recent innovation in assessment of climate change impact on agricultural production has been to use crop multimodel ensembles (MMEs). These studies usually find large variability between individual models but that the ensemble mean (e-mean) and median (e-median) often seem to predict quite well. However, few studies have specifically been concerned with the predictive quality of those ensemble predictors. We ask what is the predictive quality of e-mean and e-median, and how does that depend on the ensemble characteristics. Our empirical results are based on five MME studies applied to wheat, using different data sets but the same 25 crop models. We show that the ensemble predictors have quite high skill and are better than most and sometimes all individual models for most groups of environments and most response variables. Mean squared error of e-mean decreases monotonically with the size of the ensemble if models are added at random, but has a minimum at usually 2-6 models if best-fit models are added first. Our theoretical results describe the ensemble using four parameters: average bias, model effect variance, environment effect variance, and interaction variance. We show analytically that mean squared error of prediction (MSEP) of e-mean will always be smaller than MSEP averaged over models and will be less than MSEP of the best model if squared bias is less than the interaction variance. If models are added to the ensemble at random, MSEP of e-mean will decrease as the inverse of ensemble size, with a minimum equal to squared bias plus interaction variance. This minimum value is not necessarily small, and so it is important to evaluate the predictive quality of e-mean for each target population of environments. These results provide new information on the advantages of ensemble predictors, but also show their limitations.

A potato model intercomparison across varying climates and productivity levels.

A potato crop multimodel assessment was conducted to quantify variation among models and evaluate responses to climate change. Nine modeling groups simulated agronomic and climatic responses at low-input (Chinoli, Bolivia and Gisozi, Burundi)- and high-input (Jyndevad, Denmark and Washington, United States) management sites. Two calibration stages were explored, partial (P1), where experimental dry matter data were not provided, and full (P2). The median model ensemble response outperformed any single model in terms of replicating observed yield across all locations. Uncertainty in simulated yield decreased from 38% to 20% between P1 and P2. Model uncertainty increased with interannual variability, and predictions for all agronomic variables were significantly different from one model to another (P < 0.001). Uncertainty averaged 15% higher for low- vs. high-input sites, with larger differences observed for evapotranspiration (ET), nitrogen uptake, and water use efficiency as compared to dry matter. A minimum of five partial, or three full, calibrated models was required for an ensemble approach to keep variability below that of common field variation. Model variation was not influenced by change in carbon dioxide (C), but increased as much as 41% and 23% for yield and ET, respectively, as temperature (T) or rainfall (W) moved away from historical levels. Increases in T accounted for the highest amount of uncertainty, suggesting that methods and parameters for T sensitivity represent a considerable unknown among models. Using median model ensemble values, yield increased on average 6% per 100-ppm C, declined 4.6% per °C, and declined 2% for every 10% decrease in rainfall (for nonirrigated sites). Differences in predictions due to model representation of light utilization were significant (P < 0.01). These are the first reported results quantifying uncertainty for tuber/root crops and suggest modeling assessments of climate change impact on potato may be improved using an ensemble approach.

Can sub-Saharan Africa feed itself?

Although global food demand is expected to increase 60% by 2050 compared with 2005/2007, the rise will be much greater in sub-Saharan Africa (SSA). Indeed, SSA is the region at greatest food security risk because by 2050 its population will increase 2.5-fold and demand for cereals approximately triple, whereas current levels of cereal consumption already depend on substantial imports. At issue is whether SSA can meet this vast increase in cereal demand without greater reliance on cereal imports or major expansion of agricultural area and associated biodiversity loss and greenhouse gas emissions. Recent studies indicate that the global increase in food demand by 2050 can be met through closing the gap between current farm yield and yield potential on existing cropland. Here, however, we estimate it will not be feasible to meet future SSA cereal demand on existing production area by yield gap closure alone. Our agronomically robust yield gap analysis for 10 countries in SSA using location-specific data and a spatial upscaling approach reveals that, in addition to yield gap closure, other more complex and uncertain components of intensification are also needed, i.e., increasing cropping intensity (the number of crops grown per 12 mo on the same field) and sustainable expansion of irrigated production area. If intensification is not successful and massive cropland land expansion is to be avoided, SSA will depend much more on imports of cereals than it does today.

The implication of irrigation in climate change impact assessment: a European-wide study.

This study evaluates the impacts of projected climate change on irrigation requirements and yields of six crops (winter wheat, winter barley, rapeseed, grain maize, potato, and sugar beet) in Europe. Furthermore, the uncertainty deriving from consideration of irrigation, CO2 effects on crop growth and transpiration, and different climate change scenarios in climate change impact assessments is quantified. Net irrigation requirement (NIR) and yields of the six crops were simulated for a baseline (1982-2006) and three SRES scenarios (B1, B2 and A1B, 2040-2064) under rainfed and irrigated conditions, using a process-based crop model, SIMPLACE . We found that projected climate change decreased NIR of the three winter crops in northern Europe (up to 81 mm), but increased NIR of all the six crops in the Mediterranean regions (up to 182 mm yr(-1) ). Climate change increased yields of the three winter crops and sugar beet in middle and northern regions (up to 36%), but decreased their yields in Mediterranean countries (up to 81%). Consideration of CO2 effects can alter the direction of change in NIR for irrigated crops in the south and of yields for C3 crops in central and northern Europe. Constraining the model to rainfed conditions for spring crops led to a negative bias in simulating climate change impacts on yields (up to 44%), which was proportional to the irrigation ratio of the simulation unit. Impacts on NIR and yields were generally consistent across the three SRES scenarios for the majority of regions in Europe. We conclude that due to the magnitude of irrigation and CO2 effects, they should both be considered in the simulation of climate change impacts on crop production and water availability, particularly for crops and regions with a high proportion of irrigated crop area.

Multimodel ensembles of wheat growth: many models are better than one.

Crop models of crop growth are increasingly used to quantify the impact of global changes due to climate or crop management. Therefore, accuracy of simulation results is a major concern. Studies with ensembles of crop models can give valuable information about model accuracy and uncertainty, but such studies are difficult to organize and have only recently begun. We report on the largest ensemble study to date, of 27 wheat models tested in four contrasting locations for their accuracy in simulating multiple crop growth and yield variables. The relative error averaged over models was 24-38% for the different end-of-season variables including grain yield (GY) and grain protein concentration (GPC). There was little relation between error of a model for GY or GPC and error for in-season variables. Thus, most models did not arrive at accurate simulations of GY and GPC by accurately simulating preceding growth dynamics. Ensemble simulations, taking either the mean (e-mean) or median (e-median) of simulated values, gave better estimates than any individual model when all variables were considered. Compared to individual models, e-median ranked first in simulating measured GY and third in GPC. The error of e-mean and e-median declined with an increasing number of ensemble members, with little decrease beyond 10 models. We conclude that multimodel ensembles can be used to create new estimators with improved accuracy and consistency in simulating growth dynamics. We argue that these results are applicable to other crop species, and hypothesize that they apply more generally to ecological system models.

Aging impairs long-term hematopoietic regeneration after autologous stem cell transplantation.

Most of our knowledge of the effects of aging on the hematopoietic system comes from studies in animal models. In this study, to explore potential effects of aging on human hematopoietic stem and progenitor cells (HSPCs), we evaluated CD34(+) cells derived from young (<35 years) and old (>60 years) adult bone marrow with respect to phenotype and in vitro function. We observed an increased frequency of phenotypically defined stem and progenitor cells with age, but no distinct differences with respect to in vitro functional capacity. Given that regeneration of peripheral blood counts can serve as a functional readout of HSPCs, we compared various peripheral blood parameters between younger patients (≤50 years; n = 64) and older patients (≥60 years; n = 55) after autologous stem cell transplantation. Patient age did not affect the number of apheresis cycles or the amount of CD34(+) cells harvested. Parameters for short-term regeneration did not differ significantly between the younger and older patients; however, complete recovery of all 3 blood lineages at 1 year after transplantation was strongly affected by advanced age, occurring in only 29% of the older patients, compared with 56% of the younger patients (P = .009). Collectively, these data suggest that aging has only limited effects on CD34(+) HSPCs under steady-state conditions, but can be important under consitions of chemotoxic and replicative stress.

Loss of quiescence and impaired function of CD34(+)/CD38(low) cells one year following autologous stem cell transplantation.

Patients who have undergone autologous stem cell transplantation are subsequently more susceptible to chemotherapy-induced bone marrow toxicity. In the present study, bone marrow primitive progenitor cells were examined one year after autologous stem cell transplantation and compared with normal bone marrow and mobilized peripheral blood stem cells. Post-transplantation bone marrow contained a significantly lower percentage of quiescent cells in the CD34(+)/CD38(low) fraction compared to normal bone marrow. In addition, we observed a strong decrease in stem cell/primitive progenitor frequency in post-transplantation CD34(+) cells as defined by long-term culture assays. Measurement of the levels of reactive oxygen species by flow cytometry revealed comparable levels in post-transplantation and normal bone marrow CD34(+)/CD38(low) cells, while significantly higher levels of reactive oxygen species were observed in CD34(+)/CD38(high) cells following autologous stem cell transplantation compared to normal bone marrow. Moreover, post-transplantation CD34(+) bone marrow cells demonstrated an increased sensitivity to buthionine sulfoximine, a trigger for endogenous production of reactive oxygen species. Gene expression analysis on CD34(+) cells revealed a set of 195 genes, including HMOX1, EGR1, FOS and SIRPA that are persistently down-regulated in mobilized peripheral blood cells and post-transplantation bone marrow compared to normal bone marrow. In conclusion, our data indicate that the diminished regenerative capacity of bone marrow following autologous stem cell transplantation is possibly related to a loss of quiescence and a reduced tolerability to oxidative stress.

In vivo hemostatic efficacy of polyurethane foam compared to collagen and gelatin.

OBJECTIVES: Topical hemostatic agents are used in all surgical disciplines. Most of these hemostats are based on animal-derived products like collagen and gelatin. They carry the potential risk of pathogen transmission. A newly developed biodegradable, fully synthetic hemostatic agent based on polyurethane foam (PU) with 55 % polyethylene glycol (PEG) would prevent these potential risks. MATERIALS AND METHODS: The hemostatic efficacy of this new agent was compared to gelatin and collagen in humans who underwent extraction of an upper and lower molar (split-mouth model). After extraction of a molar in the maxilla and mandible, a PU foam and collagen or gelatin were inserted in the extraction socket for 2 min. Hereafter, the agents were removed and stored in ethylenediaminetetraacetic acid to stop coagulation. Then, the concentration of coagulation parameters thrombin-antithrombin III (TAT) complexes, fibrinogen, and thromboxane B2 (TxB2) in blood extracts from the agents was measured. The concentrations were also determined in baseline blood samples which were collected from the extraction socket. RESULTS: The concentrations of TAT and TxB2 were significantly increased, and fibrinogen concentration was significantly reduced compared to baseline wound blood concentrations indicating enhanced hemostasis. No significant differences were seen in the concentrations of these coagulation parameters in the three different hemostatic agents. CONCLUSIONS: These results show that PU combined with 55 % PEG is a promising alternative for the animal-derived hemostatic agents. CLINICAL RELEVANCE: The synthetic hemostatic agent could replace the animal-derived products like collagen and gelatin and therewith prevent the potential risk of pathogen transmission.

F-18 FLT PET: a noninvasive diagnostic tool for visualization of the bone marrow compartment in patients with aplastic anemia: a pilot study.

RATIONALE: A discordant relationship between bone marrow cellularity and peripheral blood findings is regularly noticed in patients with aplastic anemia (AA). Therefore, the feasibility of 3-F-18 fluoro-3-deoxy-L-thymidine (F-18 FLT PET was tested as a noninvasive tool to visualize the total distribution of the hematopoietic bone marrow compartment in AA at presentation or after treatment. METHODS: In vivo scanning was performed with F-18 FLT PET in AA patients (n = 17), including patients upfront (n = 11) and following treatment (n = 6), in addition to peripheral blood cell counts and a bone marrow biopsy. RESULTS: A striking abnormal F-18 FLT scan was observed in all patients upfront treatment, in particular a reduced uptake of the pelvis was shown, the area that is biopsied for the bone marrow biopsy. Following treatment, the number of solitary lesions with increased proliferative activity outside the pelvis was noticed in patients with partial response, whereas patients with a complete remission showed a homogenous uptake throughout the skeleton. CONCLUSION: This pilot study demonstrates that F-18 FLT scan provides a highly distinctive overview of the bone marrow compartment in AA that might be helpful for making a proper diagnosis and monitoring treatment response of AA patients.

An assessment of clinical interchangeability of TEG and RoTEM thromboelastographic variables in cardiac surgical patients.

BACKGROUND: Bedside thromboelastography is increasingly used, but an assessment of the clinical interchangeability of the 2 major systems, TEG (Hemoscope) and RoTEM (Pentapharm), has not been performed. METHODS: We measured blood samples from 46 cardiac surgical patients after induction of anesthesia with kaolin TEG(R) (kaoTEG), native TEG(R) (natTEG), intrinsic RoTEM (inTEM), and extrinsic RoTEM (exTEM). Each measurement consisted of reaction time (R), coagulation time (K), maximum amplitude (MA), and angle (alpha). Bland-Altman plots and mixed-model analysis were used. To assess repeatability, we made 7 replicated measurements in rapid succession in 2 volunteers. RESULTS: One hundred sixty-six measurements were available for analysis. The R time of the kaoTEG (345 + or - 102 seconds, mean + or - sd) was longer than that of the inTEM (179 + or - 74 seconds, P < 0.001) and the exTEM (55 + or - 28 seconds, P < 0.001). The K time of the kaoTEG (78 + or - 18s) was not different from that of the inTEM (75 + or - 52 seconds, P = 0.60) but was longer than the K time of the exTEM (61 + or - 24 seconds, P < 0.003). The MA of the kaoTEG (71 + or - 6.5 mm) was larger than the MA of the inTEM (67 + or - 5.2 mm, P < 0.02) and almost similar to that of the exTEM (69 + or - 6.3 mm). The alpha of the kaoTEG (72 degrees + or - 4.1 degrees ) was not significantly different from that of both the inTEM (76 degrees + or - 7 degrees ) and the exTEM (79 degrees + or - 4.5 degrees ). The variability for MA and alpha was <10%. The repeatability of the R and K times was poor in both devices, whereas the repeatability of the MA and alpha was sufficient for clinical purposes. CONCLUSIONS: The TEG and RoTEM measurements demonstrated a close correlation for the MA, but the alpha did not for the R and K variables. The kaoTEG had the best agreement with the exTEM measurement. Therefore TEG and RoTEM measurements are not completely interchangeable, and the clinical interpretation of thromboelastograhic data should be used with caution.

Thrombocytopenia affects plasmatic coagulation as measured by thrombelastography.

Thrombelastography (TEG) is used as a point-of-care test of hemostasis. Different components of the test tracing are considered to reflect various parts of the hemostatic system and to distinguish low platelet count, platelet dysfunction or both from lack of plasmatic coagulation factors. To analyze the influence of one single element of the coagulation system, namely the platelet count, we used TEG serially in patients with well documented transient thrombocytopenia. A total of 189 TEG analyses were performed from 16 patients with a hematological malignancy in remission, receiving consolidation courses of chemotherapy. TEG outcomes using unmanipulated and citrated blood samples at a median of 11 times (range 1-17) in the same patients during the decrease of platelet count in response to chemotherapy were compared with outcomes in 120 healthy adults from various age categories. We found a correlation (r = 0.7, P < 0.001) between TEG clot strength (maximum amplitude) and platelet count. Moreover, platelet count was correlated respectively with the initial rate of clot formation (reaction time and clotting time), the rate of clot growth (alpha angle), and also with maximum thrombus generation, time to maximum thrombus generation and total thrombus generation. We conclude that platelet count not only affects the strength of clot formation, as was expected, but also all other phases of plasmatic coagulation. Citration of the blood sample, aiming at easy storage of the material, masked some of the important biological parameters of coagulation.

In normal controls, both age and gender affect coagulability as measured by thrombelastography.

BACKGROUND: Our objective was to analyze the effects of age, gender, and the use of oral contraceptives (OCs) on coagulation using thrombelastography (TEG), a single test to analyze both plasma coagulation factors and cellular elements in whole blood. METHODS: TEG variables were measured in native whole blood and in recalcified citrated blood from 120 healthy adults (60 men and 60 women) with various ages and in an additional 29 healthy women using OCs. RESULTS: We observed hypercoagulability in women compared with men and in women using OCs compared with age-matched nonusers. Moreover, we found hypercoagulability with aging. Using the method of Bland and Altman (Lancet 1986;1:307-10), we demonstrated no correlation between TEG measurements in native and recalcified citrated blood. CONCLUSIONS: Aging, female gender, use of OCs, and low-normal hematocrit levels have significant procoagulant effects. TEG measurements in native and recalcified citrated blood are not interchangeable, as indicated by differences between the 2 measurements ranging from 20% in maximal amplitude to 246% in clotting time. Furthermore, the limits of agreement strongly exceeded clinical acceptability to conclude interchangeability.

Efficacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with ring sideroblasts and thrombocytosis.

Patients with refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) are difficult to treat because the cytoreductive treatment might be beneficial for the thrombocytosis component but harmful for the RARS component. As lenalidomide has shown to be efficacious in both myelodysplastic syndromes and myeloproliferative neoplasms, we have treated 2 RARS-T patients, who were transfusion dependent, with lenalidomide. We report the results of lenalidomide treatment in these patients and show that lenalidomide has clinical activity in this rare disorder. Both patients became transfusion independent, and 1 of the patients attained indeed a complete molecular remission.

Effects of red blood cells on hemostasis.

BACKGROUND: Currently there is no sensitive laboratory test to establish the influence of red blood cells (RBCs) on hemostasis. As thromboelastography (TEG) measures hemostasis in whole blood, taking into account the interactions of all cellular elements, we used this instrument to investigate the role that RBCs play in hemostasis. STUDY DESIGN AND METHODS: In 29 patients with chemotherapy-induced anemia we studied the effect of progressive anemia on the coagulation profile. In 24 patients with chronic anemia we studied the effect of transfusion of RBCs on coagulation. Finally, in 18 patients we evaluated whether storage time of RBCs has additional effects on hemostasis. RESULTS: We observed a significant negative correlation between hemoglobin and TEG variables related to both clot strength and elasticity (p < 0.05). Moreover, anemia was associated with a delay in the initiation of the coagulation cascade. Correction of anemia by RBC transfusion resulted in significant shortening of this initiation phase with now the opposite effect on clot strength and elasticity. The negative effects on clot quality were significantly worse when fresh RBCs were transfused compared to longer-stored RBCs. Furthermore, in contrast to the longer-stored RBCs, fresh RBCs did not enhance initial fibrin formation. CONCLUSIONS: In this study we found that anemia was associated with a delay in the initiation of the coagulation cascade with a finally formed clot with superior strength and viscoelastic properties. Transfusion of RBCs was associated with impaired clot quality, with even worse effects on the initial fibrin build-up and clot quality by fresh RBCs.

Platelet production rate predicts the response to prednisone therapy in patients with idiopathic thrombocytopenic purpura.

The predictive value of clinical and platelet kinetic parameters for treatment outcome in idiopathic thrombocytopenic purpura (ITP) was investigated in 75 patients with platelets355x10(9)/day) in 33%, 48%, and 19% of patients, respectively. All patients started with prednisone at diagnosis (1 mg/kg/day). Initial complete and partial response (CR/PR) rate was 84% and a durable CR/PR (>or=6 months without treatment) was attained in 44% of the patients. Durable CR/PR was noticed in 64% of the patients with decreased PPR during a median follow-up time without treatment of 81 (range 18-92) months, compared to 34% of the patients with normal or increased PPR during a median follow-up time without treatment of 141 (range 10-284) months (p=0.03). Splenectomy was performed in 32% of patients with decreased PPR and in 62% of patients with normal or increased PPR (p=0.03). In conclusion, ITP patients with suppressed PPR have a significant higher durable CR/PR rate to prednisone therapy and are less frequently exposed to splenectomy than those with a normal or increased PPR.

Increased glycocalicin index and normal thrombopoietin levels in patients with idiopathic thrombocytopenic purpura with a decreased rate of platelet production.

Platelet kinetic studies in idiopathic thrombocytopenic purpura (ITP) have shown that in a subgroup of patients a shortened mean platelet life (MPL) is associated with a decreased platelet production rate (PPR). Other methods of studying certain aspects of thrombocytopoiesis are the plasma concentrations of thrombopoietin and glycocalicin.