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The quality and quantity of the influence that atmospheric CO2 has on cropgrowth is still a matter of debate. This study's aim is to estimate if CO2 will have an effect on biomass yields at all, to quantify and spatially locate the effects and to explore if an elevated photosynthesis rate or water-use-efficiency is predominantly responsible. This study uses a numerical carbon based crop model (BioSTAR) to estimate biomass yields within theadministrative boundaries of Niedersachsen in Northern Germany. 10 crops are included (winter grains: wheat, barley,rye, triticale - early, medium, late maize variety - sunflower, sorghum, spring wheat), modeled annuallyfor the entire 21st century on 91,014 separate sites. Modeling was conducted twice, once with an annually adaptedCO2 concentration according to the SRES-A1B scenario and once with a fixed concentration of 390 ppm to separate the influence of CO2 from that of the other input variables.Rising CO2 concentrations will play a central role in keeping future yields of all crops above or aroundtoday's level. Differences in yields between modeling with fixed or adapted CO2 can be as high as60 % towards the century's end. Generally yields will increase when CO2 rises and decline whenit is kept constant. As C4-crops are equivalently affected it is presumed that anelevated efficiency in water use is the main responsible factor for all plants.

Background: Acute coronary syndrome patients receiving dual antiplatelet therapy who need emergent or urgent cardiac surgery are at high risk of major bleeding, which can impair postoperative outcomes. CytoSorb ® , a blood purification technology based on adsorbent polymer, has been demonstrated to remove ticagrelor from blood during on-pump cardiac surgery., Objective: The aim of this study was to evaluate the cost utility of intraoperative removal of ticagrelor using CytoSorb versus usual care among patients requiring emergent or urgent cardiac surgery in the UK., Methods: A de novo decision analytic model, based on current treatment pathways, was developed to estimate the short- and long-term costs and outcomes. Results from randomised clinical trials and national standard sources such as National Health Service (NHS) reference costs were used to inform the model. Costs were estimated from the NHS and Personal Social Services perspective. Deterministic and probabilistic sensitivity analyses (PSAs) explored the uncertainty surrounding the input parameters., Results: In emergent cardiac surgery, intraoperative removal of ticagrelor using CytoSorb was less costly (£12,933 vs. £16,874) and more effective (0.06201vs. 0.06091 quality-adjusted life-years) than cardiac surgery without physiologic clearance of ticagrelor over a 30-day time horizon. For urgent cardiac surgery, the use of CytoSorb was less costly than any of the three comparators-delaying surgery for natural washout without adjunctive therapy, adjunctive therapy with short-acting antiplatelet agents, or adjunctive therapy with low-molecular-weight heparin. Results from the PSAs showed that CytoSorb has a high probability of being cost saving (99% in emergent cardiac surgery and 53-77% in urgent cardiac surgery, depending on the comparators). Cost savings derive from fewer transfusions of blood products and re-thoracotomies, and shorter stay in the hospital/intensive care unit., Conclusions: The implementation of CytoSorb as an intraoperative intervention for patients receiving ticagrelor undergoing emergent or urgent cardiac surgery is a cost-saving strategy, yielding improvement in perioperative and postoperative outcomes and decreased health resource use.

Background Variants of the desmosomal protein desmoplakin are associated with arrhythmogenic cardiomyopathy, an important cause of ventricular arrhythmias in children and young adults. Disease penetrance of desmoplakin variants is incomplete and variant carriers may display noncardiac, dermatologic phenotypes. We describe a novel cardiac phenotype associated with a truncating desmoplakin variant, likely causing mechanical instability of myocardial desmosomes. Methods and Results In 2 young brothers with recurrent myocarditis triggered by physical exercise, screening of 218 cardiomyopathy-related genes identified the heterozygous truncating variant p.Arg1458Ter in desmoplakin. Screening for infections yielded no evidence of viral or nonviral infections. Myosin and troponin I autoantibodies were detected at high titers. Immunohistology failed to detect any residual DSP protein in endomyocardial biopsies, and none of the histologic criteria of arrhythmogenic cardiomyopathy were fulfilled. Cardiac magnetic resonance imaging revealed no features associated with right ventricular arrhythmogenic cardiomyopathy, but multifocal subepicardial late gadolinium enhancement was present in the left ventricles of both brothers. Screening of adult cardiomyopathy cohorts for truncating variants identified the rare genetic variants p.Gln307Ter, p.Tyr1391Ter, and p.Tyr1512Ter, suggesting that over subsequent decades critical genetic/exogenous modifiers drive pathogenesis from desmoplakin truncations toward different end points. Conclusions The described novel phenotype of familial recurrent myocarditis associated with a desmoplakin truncation in adolescents likely represents a serendipitously revealed subtype of arrhythmogenic cardiomyopathy. It may be caused by a distinctive adverse effect of the variant desmoplakin upon the mechanical stability of myocardial desmosomes. Variant screening is advisable to allow early detection of patients with similar phenotypes.

Background: Endomyocardial biopsies (EMB) are the gold standard for the diagnosis of myocarditis in children and adults. The existing WHO/ISFC criteria for lymphocytic cell infiltrates by are based on the myocardium of adults. The aim of this study was to present a paediatric control cohort for the evaluation of inflammation in EMB of children., Methods: In this study endomyocardial tissue from 62 children under 4 years of age was investigated, being collected during a planned open heart surgery with routine resection from ventricular site. Patients had no history of infection or myocardial inflammation. The heart tissue was formalin fixed and embedded in paraffin. Four μm thick tissue sections were stained with haematoxylin and eosin, Masson's trichrome, and Giemsa. Immunohistochemical stainings included quantitative evaluation of CD3 + T cells, CD20 +  B cells, CD68 +  macrophages and MHCII expression., Results: The myocardium was obtained in 96.8% (n = 60) of the cases from the right and in 3.2% (n = 2) from the left ventricle. The median age (interquartile range) at biopsy was 0.5 years (0.3-0.9), 66.1% male. Within this cohort, a median of 2.5/mm 2 (1.0-4.0) CD3 + T cells, 0.5/mm 2 (0.0-0.6) CD20 +  B cells and 4.0/mm 2 (2.5-6.0) CD68 +  macrophages were detected. The MHC II grade was 0 in 71.0% (n = 44) and 1 in 29.0% (n = 18)., Conclusion: This is the first paediatric control cohort being relevant for the correct interpretation of inflammatory heart diseases in EMB. The lymphocytic cell numbers in children needing congenital heart surgery without myocardial inflammation are below the existing values in adults., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation-not only in adult-but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP., (© 2019 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Myocarditis represents an important cause for acute heart failure. MYKKE, a prospective multicenter registry of pediatric patients with myocarditis, aims to gain knowledge on courses, diagnostics, and therapy of pediatric myocarditis. The role of mechanical circulatory support (MCS) in children with severe heart failure and myocarditis is unclear. The aim of this study was to determine characteristics and outcome of patients with severe heart failure requiring MCS and/or heart transplantation. The MYKKE cohort between September 2013 and 2016 was analyzed. A total of 195 patients were prospectively enrolled by 17 German hospitals. Twenty-eight patients (14%) received MCS (median 1.5 years), more frequently in the youngest age group (0-2 years) than in the older groups (P < 0.001; 2-12 and 13-18 years). In the MCS group, 50% received a VAD, 36% ECMO, and 14% both, with a survival rate of 79%. The weaning rate was 43% (12/28). Nine (32%) patients were transplanted, one had ongoing support, and six (21%) died. Histology was positive for myocarditis in 63% of the MCS group. Patients within the whole cohort with age <2 years and/or ejection fraction <30% had a significantly worse survival with high risk for MCS, transplantation, and death (P < 0.001). Myocarditis represents a life-threatening disease with an overall mortality of 4.6% in this cohort. The fulminant form more often affected the youngest, leading to significantly higher rate of MCS, transplantation, and mortality. MCS represents an important and life-saving therapeutic option in children with myocarditis with a weaning rate of 43%., (© 2019 Wiley Periodicals, Inc.)

Purpose: While novel tools for segmentation of the mitral valve are often based on automatic image processing, they mostly require manual interaction by a proficient user. Those segmentations are essential for numerical support of mitral valve treatment using computational fluid dynamics, where the reconstructed geometry is incorporated into a simulation domain. To quantify the uncertainty and reliability of hemodynamic simulations, it is crucial to examine the influence of user-dependent variability in valve segmentation., Methods: Previously, the inter-user variability of landmarks in mitral valve segmentation was investigated. Here, the inter-user variability of geometric parameters of the mitral valve, projected orifice area (OA) and projected annulus area (AA), is investigated for 10 mitral valve geometries, each segmented by three users. Furthermore, the propagation of those variations into numerically calculated hemodynamics, i.e., the blood flow velocity, was investigated., Results: Among the three geometric valve parameters, AA was least user-dependent. Almost all deviations to the mean were below 10%. Larger variations were observed for OA. Variations observed for the numerically calculated hemodynamics were in the same order of magnitude as those of geometric parameters. No correlation between variation of geometric parameters and variation of calculated hemodynamic parameters was found., Conclusion: Errors introduced due to the user-dependency were of the same size as the variations of calculated hemodynamics. The variation was thereby of the same scale as deviations in clinical measurements of blood flow velocity using Doppler echocardiography. Since no correlation between geometric and hemodynamic uncertainty was found, further investigation of the complex relationship between anatomy, leaflet shape and flow is necessary.

Background Cardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life-threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease-modulating factors in children and adolescents is relatively unknown. In this prospective study, in-depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first-degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors. Methods and Results Sixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001), and left ventricular dysfunction (P<0.001) and dilatation (P=0.005). The worst prognosis was observed in dilated and restrictive cardiomyopathies. Genetic variants of interest were detected in patients (79%) and FMs (67%). In all 15 families with at least 1 FM with cardiomyopathy, we found a variant of interest in the index patient. Increased number of variants of interest per patient was associated with adverse events (P=0.021). Late gadolinium enhancement was related to positive genotypes in patients (P=0.041). Conclusions Lower body surface area, increased NT-proBNP, left ventricular dysfunction or dilatation, late gadolinium enhancement, and increased number of variants of interest were associated with adverse outcome and should be considered for risk assessment in pediatric primary cardiomyopathies. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03572569.

Purpose: Various options are available for the treatment of mitral valve insufficiency, including reconstructive approaches such as annulus correction through ring implants. The correct choice of general therapy and implant is relevant for an optimal outcome. Additional to guidelines, decision support systems (DSS) can provide decision aid by means of virtual intervention planning and predictive simulations. Our approach on virtual downsizing is one of the virtual intervention tools that are part of the DSS workflow. It allows for emulating a ring implantation based on patient-specific lumen geometry and vendor-specific implants., Methods: Our approach is fully automatic and relies on a lumen mask and an annulus contour as inputs. Both are acquired from previous DSS workflow steps. A virtual surface- and contour-based model of a vendor-specific ring design (26-40 mm) is generated. For each case, the ring geometry is positioned with respect to the original, patient-specific annulus and additional anatomical landmarks. The lumen mesh is parameterized to allow for a vertex-based deformation with respect to the user-defined annulus. Derived from post-interventional observations, specific deformation schemes are applied to atrium and ventricle and the lumen mesh is altered with respect to the ring location., Results: For quantitative evaluation, the surface distance between the deformed lumen mesh and segmented post-operative echo lumen close to the annulus was computed for 11 datasets. The results indicate a good agreement. An arbitrary subset of six datasets was used for a qualitative evaluation of the complete lumen. Two domain experts compared the deformed lumen mesh with post-interventional echo images. All deformations were deemed plausible., Conclusion: Our approach on virtual downsizing allows for an automatic creation of plausible lumen deformations. As it takes only a few seconds to generate results, it can be added to a virtual intervention toolset without unnecessarily increasing the pipeline complexity.

Purpose: Severe mitral valve regurgitation can either be treated by a replacement or a repair of the valve. The latter is recommended due to lower perioperative mortality and better long-term survival. On the other hand, recurrence rates after mitral valve repair are high compared to those after replacements and the repair intervention can cause induced mitral valve stenosis. So far, there are no methods to predict the hemodynamic outcome of a chosen treatment or to compare different treatment options in advance. To overcome this, diastolic mitral valve hemodynamics are simulated using computational fluid dynamics after different virtual treatments of the valve., Methods: The left ventricular geometry of one patient was reconstructed using trans-esophageal echocardiography and computed tomography data. Pre-op hemodynamics are simulated using a referenced wall model to avoid expansive modeling of wall motion. Subsequently, the flow structures are compared to in vivo measurements. After manipulating the patient-specific geometry in order to mimic a restrictive mitral annuloplasty as well as a MitraClip intervention, hemodynamics results are calculated., Results: Good agreements exist between calculated pre-op hemodynamics and in vivo measurements. The virtual annuloplasty did not result in any remarkable change of hemodynamics. Neither the pressure drop nor the velocity field showed strong differences. In contrast, the virtual MitraClip intervention led to a complete change in blood flow structures as well as an elevated pressure drop across the valve., Conclusion: The presented approach allows fast simulation of the diastolic hemodynamic situation before and after treatment of a mitral valve insufficiency. However, this approach is limited to the early diastolic phase of the cardiac cycle and needs to be validated using a larger sample size.

Purpose: The importance of mitral valve therapies is rising due to an aging population. Visualization and quantification of the valve anatomy from image acquisitions is an essential component of surgical and interventional planning. The segmentation of the mitral valve from computed tomography (CT) acquisitions is challenging due to high variation in appearance and visibility across subjects. We present a novel semi-automatic approach to segment the open-state valve in 3D CT volumes that combines user-defined landmarks to an initial valve model which is automatically adapted to the image information, even if the image data provide only partial visibility of the valve., Methods: Context information and automatic view initialization are derived from segmentation of the left heart lumina, which incorporates topological, shape and regional information. The valve model is initialized with user-defined landmarks in views generated from the context segmentation and then adapted to the image data in an active surface approach guided by landmarks derived from sheetness analysis. The resulting model is refined by user landmarks., Results: For evaluation, three clinicians segmented the open valve in 10 CT volumes of patients with mitral valve insufficiency. Despite notable differences in landmark definition, the resulting valve meshes were overall similar in appearance, with a mean surface distance of [Formula: see text] mm. Each volume could be segmented in 5-22 min., Conclusions: Our approach enables an expert user to easily segment the open mitral valve in CT data, even when image noise or low contrast limits the visibility of the valve.

The aim of this registry is to provide data on age-related clinical features of suspected myocarditis and to create a study platform allowing for deriving diagnostic criteria and, at a later stage, testing therapeutic interventions in patients with myocarditis., Study Design and Results: After an initial 6-month pilot phase, MYKKE was opened in June 2014 as a prospective multicenter registry for patients from pediatric heart centers, university hospitals, and community hospitals with pediatric cardiology wards in Germany. Inclusion criteria consisted of age<18 years and hospitalization for suspected myocarditis as leading diagnosis at the discretion of the treating physician. By December 31, 2015, fifteen centers across Germany were actively participating and had enrolled 149 patients. Baseline data reveal 2 age peaks (<2 years, >12 years), show higher proportions of males, and document a high prevalence of severe disease courses in pediatric patients with suspected myocarditis. Severe clinical courses and early adverse events were more prevalent in younger patients and were related to severely impaired leftventricular ejection fraction at initial presentation., Summary: MYKKE represents a multicenter registry and research platform for children and adolescents with suspected myocarditis that achieve steady recruitment and generate a wide range of real-world data on clinical course, diagnostic workup, and treatment of this group of patients. The baseline data reveal the presence of 2 age peaks and provide important insights into the severity of disease in children with suspected myocarditis. In the future, MYKKE might facilitate interventional substudies by providing an established collaborating network using common diagnostic approaches., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: In September 2014, the PARADIGM-HF trial showed the heart failure drug combination sacubitril/valsartan to be superior to enalapril for patients with a reduced ejection fraction., Objectives: To determine the incremental cost-effectiveness of sacubitril/valsartan compared with enalapril in the Netherlands using the clinical data from the PARADIGM-HF trial., Methods: To compare sacubitril/valsartan and enalapril in a cost-effectiveness study, a Markov model was developed using the effectiveness data from the PARADIGM-HF trial. A health care payer's perspective was applied in the economic evaluation. The developed model was used to evaluate the cost-effectiveness for sacubitril/valsartan at different per diem prices., Results: The base-case analysis showed that sacubitril/valsartan can be cost-effective at maximum daily costs of €5.50 and €14.14 considering willingness-to-pay thresholds of €20,000 and €50,000 per quality-adjusted life-year (QALY), respectively. Sensitivity analysis demonstrated the robustness of the model, identifying only the price of sacubitril/valsartan and the mortality within the sacubitril/valsartan group as significant drivers of the cost-effectiveness ratio. Sacubitril/valsartan was cost-effective at a willingness-to-pay threshold of €20,000 per QALY (€50,000 per QALY) in more than 80% of the replications with certainty at the price point of €3 (€10)., Conclusions: Sacubitril/valsartan can be considered a cost-effective treatment at a daily price of €5.25. Unless priced lower than enalapril (<€0.045 per day), sacubitril/valsartan is very unlikely to be cost-saving/dominant., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anticancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibition and uncover potential resistance mechanisms, identification of these currently unknown genes is necessary. The aim of this study was therefore to identify gene mutations that determine Wee1 inhibitor sensitivity. We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G1/S regulatory genes, including SKP2, CUL1, and CDK2. Stable depletion of SKP2, CUL1, or CDK2 or chemical Cdk2 inhibition rescued the γ-H2AX induction and abrogation of G2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1, or CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patients. Conversely, loss of the identified S-phase genes could serve as a mechanism of acquired resistance, which goes along with development of severe genomic instability.

Background: Left ventricular rotation is physiologically affected by acute changes in preload. We investigated the acute effect of preload changes in chronically underloaded and overloaded left ventricles in children with shunt lesions., Methods: A total of 15 patients with atrial septal defects (Group A: 7.4 ± 4.7 years, 11 females) and 14 patients with patent arterial ducts (Group B: 2.7 ± 3.1 years, 10 females) were investigated using 2D speckle-tracking echocardiography before and after interventional catheterisation. The rotational parameters of the patient group were compared with those of 29 matched healthy children (Group C)., Results: Maximal torsion (A: 2.45 ± 0.9°/cm versus C: 1.8 ± 0.8°/cm, p < 0.05), apical peak systolic rotation (A: 12.6 ± 5.7° versus C: 8.7 ± 3.5°, p < 0.05), and the peak diastolic torsion rate (A: -147 ± 48°/second versus C: -110 ± 31°/second, p < 0.05) were elevated in Group A and dropped immediately to normal values after intervention (maximal torsion 1.5 ± 1.1°/cm, p < 0.05, apical peak systolic rotation 7.2 ± 4.1°, p < 0.05, and peak diastolic torsion rate -106 ± 35°/second, p < 0.05). Patients in Group B had decreased maximal torsion (B: 1.8 ± 1.1°/cm versus C: 3.8 ± 1.4°/cm, p < 0.05) and apical peak systolic rotation (B: 8.3 ± 6.1° versus C: 13.9 ± 4.3°, p < 0.05). Defect closure was followed by an increase in maximal torsion (B: 2.7 ± 1.4°/cm, p < 0.05) and the peak diastolic torsion rate (B: -133 ± 66°/second versus -176 ± 84°/second, p < 0.05)., Conclusions: Patients with chronically underloaded left ventricles compensate with an enhanced apical peak systolic rotation, maximal torsion, and quicker diastolic untwisting to facilitate diastolic filling. In patients with left ventricular dilatation by volume overload, the peak systolic apical rotation and the maximal torsion are decreased. After normalisation of the preload, they immediately return to normal and diastolic untwisting rebounds. These mechanisms are important for understanding the remodelling processes.

The onset of wheals and/or angioedema following the exposure to cold may be associated with a number of different diseases. Most frequently this occurs in cold contact urticaria, a type of physical urticaria, which is characterized by a positive cold stimulation test. The clinical symptoms are based on cold-dependent mast cell activation with subsequent release of proinflammatory mediators. In cases of negative or atypical reaction to cold stimulation testing rare acquired atypical or familiar cold urticaria forms may be suspected. Strict avoidance of cold should be recommended as far as possible. As the underlying causes of cold contact urticaria are widely unknown, the symptomatic use of non-sedating antihistamines is the treatment of first choice. The very rare familiar cold auto-inflammatory syndrome (FCAS) is based on CIAS1/NLRP3 mutations and may be treated effectively by neutralization of pathogenic interleukin 1beta.

Background: Increased dosing of nonsedating antihistamines is recommended by the current European Academy of Allergology and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum guidelines on patients with acquired cold urticaria (ACU) who do not respond satisfactorily to the standard dose. Prospective data supporting this recommendation are scant., Objective: We sought to assess the effects of 5 and 20 mg of desloratadine and placebo on cold-induced urticarial reactions in patients with ACU., Methods: In this prospective, randomized, double-blind, 3-way crossover trial, patients with ACU (n = 30) received placebo, 5 mg of desloratadine, and 20 mg of desloratadine every day each for 7 days separated by 14-day washout periods. At the end of each treatment, patients underwent cold provocation with the TempTest 2.0/2.1 system, and urticarial reactions were assessed by using digital 3-dimensional time-lapse photography and thermography; the critical temperature threshold (CTT) and critical stimulation time threshold (CSTT) were measured. Adverse events (AEs) reported during the study were assessed., Results: Compared with placebo, 7 days of desloratadine at 5 and 20 mg/d significantly reduced the volume of cold-induced wheals and areas of hyperthermic skin and improved CTT and CSTT results. Desloratadine at 20 mg/d significantly reduced cold-induced wheal volume and CTT and CSTT values versus desloratadine at 5 mg/d. Desloratadine was well tolerated, with no increased rate of somnolence or other AEs with 20 mg of desloratadine., Conclusions: Desloratadine at standard and high doses significantly improved objective signs of ACU provoked by cold exposure. Desloratadine at 4 times the standard dose significantly reduced ACU lesion severity versus 5 mg of desloratadine without an increase in AEs. This study supports current guidelines that increased desloratadine dosing might benefit patients with urticaria who do not respond to standard doses.