We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant ...tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients.
Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 (low dose) or 3 μg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0).
Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively.
In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated.
URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.
The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, ...randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).
Non-timber forest products (NTFPs) are derived from natural populations of plants or fungi, or farmed in forests. Harvesters and producers often benefit from NTFPs by selling them to generate income. ...This article explores research on the producers, production, marketing, and sales of NTFPs in the United States, including the continuum of production from wild-harvesting to forest farming of NTFPs, and their costs and benefits. Specific examples are presented, but the concepts and generalizations are broadly applicable to many NTFPs throughout the U.S. and other parts of the world. Integrating NTFPs into forest management can enhance economic opportunities but also will increase complexity, and will entail balancing multiple and potentially conflicting objectives among a diverse community of stakeholders. We identify information gaps including the need for inventories and yield models of NTFPs, understanding the effect of silvicultural activities on NTFP survival and yield, time series and trends in collection of NTFPs by U.S. households, identification of vulnerable and marginalized communities associated with NTFP harvest, and harvesters’ motivations and drivers.
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•This model accounts for chemistry, temperature, radiolysis, U(VI) minerals, and hydrogen effect.•The hydrogen effect dominates processes determining spent fuel dissolution rate.•The ...hydrogen effect protects uranium oxide spent fuel from oxidative dissolution.
The Fuel Matrix Dissolution Model (FMDM) is an electrochemical reaction/diffusion model for the dissolution of spent uranium oxide fuel. The model was developed to provide radionuclide source terms for use in performance assessment calculations for various types of geologic repositories. It is based on mixed potential theory and consists of a two-phase fuel surface made up of UO2 and a noble metal bearing fission product phase in contact with groundwater. The corrosion potential at the surface of the dissolving fuel is calculated by balancing cathodic and anodic reactions occurring at the solution interfaces with UO2 and NMP surfaces. Dissolved oxygen and hydrogen peroxide generated by radiolysis of the groundwater are the major oxidizing agents that promote fuel dissolution. Several reactions occurring on noble metal alloy surfaces are electrically coupled to the UO2 and can catalyze or inhibit oxidative dissolution of the fuel. The most important of these is the oxidation of hydrogen, which counteracts the effects of oxidants (primarily H2O2 and O2). Inclusion of this reaction greatly decreases the oxidation of U(IV) and slows fuel dissolution significantly. In addition to radiolytic hydrogen, large quantities of hydrogen can be produced by the anoxic corrosion of steel structures within and near the fuel waste package.
The model accurately predicts key experimental trends seen in literature data, the most important being the dramatic depression of the fuel dissolution rate by the presence of dissolved hydrogen at even relatively low concentrations (e.g., less than 1mM). This hydrogen effect counteracts oxidation reactions and can limit fuel degradation to chemical dissolution, which results in radionuclide source term values that are four or five orders of magnitude lower than when oxidative dissolution processes are operative. This paper presents the scientific basis of the model, the approach for modeling used fuel in a disposal system, and preliminary calculations to demonstrate the application and value of the model.
Postpartum depression (PPD) and postpartum psychosis (PPP) are linked to negative consequences for women and families. Virtual applications present a solution to the challenge of recruiting large ...samples for genetic PPD/PPP research. This study aimed to evaluate the feasibility of a protocol for enrolling Canadian women with PPD and PPP to a large international psychiatric genetics study using a mobile application (PPD-ACT), and identify clinically distinct subtypes of PPD in the recruited sample.
From April 2017-June 2019, Canadian women provided phenotypic data through the PPD-ACT app. Requests for a genetic sample were made from those with a current or past PPD episode based on an Edinburgh Postnatal Depression Scale (EPDS) score > 12 with onset in pregnancy or 0-3 months postpartum, and from those self-reporting lifetime PPP. Latent class analysis (LCA) was used to identify clinically distinct PPD subgroups based on participant responses to the EPDS scale.
We identified 797 PPD cases, 404 of whom submitted DNA. There were 109 PPP cases, with 66 submitting DNA. PPD cases (86.7% White, mean 4.7 +/- 7.0 years since their episode) came from across Canadian provinces/territories. LCA identified two PPD classes clinically distinct by symptom severity: 1 moderate-severity (mean EPDS = 18.5+/- 2.5; 8.6% with suicidality), and 2 severe (mean EPDS = 24.5+/- 2.1; 52.8% with suicidality).
A mobile application rapidly collected data from individuals with moderate and severe symptoms of PPD, an advantage for genetics where specificity is optimal, as well as from women with a history of PPP, supporting future work using this approach.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to ...understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 0.21, 0.51, p = 1.42 × 10
) and intergenic rs6916777 (Beta = 14.03 8.47, 19.59, p = 1.25 × 10
), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10
, FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer's disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 0.59, 0.79, Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10
). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.
Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains ...unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein-DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.
Renewable natural resources that have biological constraints on reproduction and are open-access may be subjected to intense harvest activity that limits regeneration, potentially leading to a ...backward-bending long-run supply curve. Empirical evidence of such supply abnormalities has been found for some open-access fish species but not yet for non-timber forest products (NTFPs). We describe the theory of the backward-bending long-run supply and how such a supply relationship could produce multiple market equilibria, affecting regulatory outcomes. An empirical example is provided to test the theory in the case of wild American ginseng (Panax quinquefolius), which has been subjected to habitat loss and harvest pressure since the 18th Century and now has its exports regulated. We find evidence that quantities supplied are negatively related to price in the long run, indicating that harvest pressure is restricting wild ginseng harvestable stocks. Also, we find that a federal regulation banning exports of roots from plants under five years old, in effect since 1999, coincided with a reduction of supply. This result could be due to the slow natural rate of population recovery.
•Harvests of certain non-timber forest products are difficult to monitor and control.•Open-access biological resources can be impacted by intense harvest.•In the extreme, populations can be driven to extinction.•Wild American ginseng may have such a backward-bending long-run supply curve.•Regulations to stem the decline in ginseng populations have not increased harvests.
BACKGROUND AND PURPOSE—A large number of patients with symptoms of acute cerebral ischemia are stroke mimics (SMs). In this study, we sought to develop a scoring system (FABS) for screening and ...stratifying SM from acute cerebral ischemia and to identify patients who may require magnetic resonance imaging to confirm or refute a diagnosis of stroke in the emergency setting.
METHODS—We designed a scoring systemFABS (6 variables with 1 point for each variable present)absence of Facial droop, negative history of Atrial fibrillation, Age <50 years, systolic Blood pressure <150 mm Hg at presentation, history of Seizures, and isolated Sensory symptoms without weakness at presentation. We evaluated consecutive patients with symptoms of acute cerebral ischemia and a negative head computed tomography for any acute finding within 4.5 hours after symptom onset in 2 tertiary care stroke centers for validation of FABS.
RESULTS—A total of 784 patients (41% SMs) were evaluated. Receiver operating characteristic curve (C statistic, 0.95; 95% confidence interval CI, 0.93–0.98) indicated that FABS≥3 could identify patients with SM with 90% sensitivity (95% CI, 86%–93%) and 91% specificity (95% CI, 88%–93%). The negative predictive value and positive predictive value were 93% (95% CI, 90%–95%) and 87% (95% CI, 83%–91%), respectively.
CONCLUSIONS—FABS seems to be reliable in stratifying SM from acute cerebral ischemia cases among patients in whom the head computed tomography was negative for any acute findings. It can help clinicians consider advanced imaging for further diagnosis.
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