Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.
In this randomized, double-blind study, we compared apixaban (at a dose of 10 ...mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.
The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval CI, 0.60 to 1.18; difference in risk apixaban minus conventional therapy, -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.
A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).
Tidal freshwater wetlands linking terrestrial, riverine, and saline habitats are critical areas for material processing and exchange. Once historically widespread, herbaceous marsh and forested tidal ...freshwater wetlands especially are now highly degraded worldwide. Additionally, quantitative assessments of hydrology and material exchange from these systems are lacking compared to lotic and estuarine (saltmarsh) habitats. Here we investigate macroinvertebrate and energy export from tidal marsh and forested wetlands and consider potential benefits from this ecological process to endangered Pacific salmon in a large tidal freshwater system, the Columbia River (USA). Macroinvertebrate (salmon prey) concentration, water velocity, and discharge were measured at several wetland habitat types (forested swamp, emergent marsh, and restored marsh). We used these data to compute prey flux and transport metrics. Then, applying literature values to calculate prey energy equivalents and juvenile salmon metabolic requirements, we estimated the potential energy subsidy available to juvenile salmon. Numerically, larval stages of aquatic insects were the predominant type of prey exported from the wetlands, with Diptera chironomid fly abundance exceeding other groups. Energetically, however, non-chironomid dipterans and hemipteran prey comprised most of energy transport due to their higher energetic content (energy density × mean weight). We determined the prey energy transported from the sampled tidal channels was sufficient to meet energetic needs of tens to thousands of juvenile salmon per day, depending on prey production and hydrography. The prey taxonomic composition differed among organisms exiting forested swamp, emergent marsh, and restored marsh habitats with corresponding differences in energy transport, but all habitat types supported similar numbers of juvenile salmon. We conclude that macroinvertebrate prey exported from varied tidal freshwater wetlands likely provide significant benefits to juvenile salmon over a larger ecological footprint than the wetland area would suggest.
Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism.
In this randomized, double-blind ...study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months.
A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval CI, 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group.
Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to ...specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.
Purpose
CT ventilation imaging (CTVI) is being used to achieve functional avoidance lung cancer radiation therapy in three clinical trials (NCT02528942, NCT02308709, NCT02843568). To address the need ...for common CTVI validation tools, we have built the Ventilation And Medical Pulmonary Image Registration Evaluation (VAMPIRE) Dataset, and present the results of the first VAMPIRE Challenge to compare relative ventilation distributions between different CTVI algorithms and other established ventilation imaging modalities.
Methods
The VAMPIRE Dataset includes 50 pairs of 4DCT scans and corresponding clinical or experimental ventilation scans, referred to as reference ventilation images (RefVIs). The dataset includes 25 humans imaged with Galligas 4DPET/CT, 21 humans imaged with DTPA‐SPECT, and 4 sheep imaged with Xenon‐CT. For the VAMPIRE Challenge, 16 subjects were allocated to a training group (with RefVI provided) and 34 subjects were allocated to a validation group (with RefVI blinded). Seven research groups downloaded the Challenge dataset and uploaded CTVIs based on deformable image registration (DIR) between the 4DCT inhale/exhale phases. Participants used DIR methods broadly classified into B‐splines, Free‐form, Diffeomorphisms, or Biomechanical modeling, with CT ventilation metrics based on the DIR evaluation of volume change, Hounsfield Unit change, or various hybrid approaches. All CTVIs were evaluated against the corresponding RefVI using the voxel‐wise Spearman coefficient rS, and Dice similarity coefficients evaluated for low function lung (DSClow) and high function lung (DSChigh).
Results
A total of 37 unique combinations of DIR method and CT ventilation metric were either submitted by participants directly or derived from participant‐submitted DIR motion fields using the in‐house software, VESPIR. The rS and DSC results reveal a high degree of inter‐algorithm and intersubject variability among the validation subjects, with algorithm rankings changing by up to ten positions depending on the choice of evaluation metric. The algorithm with the highest overall cross‐modality correlations used a biomechanical model‐based DIR with a hybrid ventilation metric, achieving a median (range) of 0.49 (0.27–0.73) for rS, 0.52 (0.36–0.67) for DSClow, and 0.45 (0.28–0.62) for DSChigh. All other algorithms exhibited at least one negative rS value, and/or one DSC value less than 0.5.
Conclusions
The VAMPIRE Challenge results demonstrate that the cross‐modality correlation between CTVIs and the RefVIs varies not only with the choice of CTVI algorithm but also with the choice of RefVI modality, imaging subject, and the evaluation metric used to compare relative ventilation distributions. This variability may arise from the fact that each of the different CTVI algorithms and RefVI modalities provides a distinct physiologic measurement. Ultimately this variability, coupled with the lack of a “gold standard,” highlights the ongoing importance of further validation studies before CTVI can be widely translated from academic centers to the clinic. It is hoped that the information gleaned from the VAMPIRE Challenge can help inform future validation efforts.
Telavancin: A Novel Lipoglycopeptide Saravolatz, Louis D.; Stein, Gary E.; Johnson, Leonard B.
Clinical infectious diseases,
12/2009, Volume:
49, Issue:
12
Journal Article
Peer reviewed
Open access
Telavancin, a derivative of vancomycin, is a lipoglycopeptide antibiotic that has been shown to be effective for the treatment of complicated skin and skin-structure infections. It has also been ...effective in the treatment of gram-positive pneumonia. This antibiotic has a dual mechanism of action by inhibiting peptidoglycan synthesis and causing membrane depolarization. Telavancin is consistently active against Staphylococcus aureus , including methicillin-resistant S. aureus , vancomycin-intermediate S. aureus , linezolid-resistant S. aureus , and daptomycin-nonsusceptible strains. The drug is usually administrated intravenously at 10 mg/kg every 24 h. Telavancin is excreted by the kidneys, and thus, dosage adjustments are required in cases of renal failure. Clinical trials have demonstrated non-inferiority, compared with vancomycin, in the treatment of complicated skin and skin-structure infections and pneumonia. Telavancin is associated with higher rates of renal events, altered taste, nausea, and vomiting but lesser rates of pruritus and infusion-related events, compared with vancomycin.
Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute ...bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.
Abstract Background Bipolar disorder carries a substantive morbidity and mortality burden, particularly related to cardiovascular disease. Abnormalities in peripheral inflammatory markers, which have ...been commonly reported in case-control studies, potentially link these co-morbidities. However, it is not clear whether inflammatory markers change episodically in response to mood states or are indicative of chronic pro-inflammatory activity, regardless of mood, in bipolar disorder. Methods Investigations focused on comparing concentrations of specific inflammatory cytokines associated with immune activation status (primary outcome=tumor necrosis factor alpha (TNF-α)) in 37 participants with bipolar disorder across 3 mood states (mania N =15, depression N =9, normal mood N =13) and 29 controls without a psychiatric disorder (total N =66). Cytokine levels were also compared to T1ρ, a potential neuroimaging marker for inflammation, in select brain regions in a subsample ( N =39). Results Participants with bipolar disorder and healthy controls did not differ significantly in inflammatory cytokine concentrations. However, compared to cases with normal mood, cases with abnormal mood states (mania and depression) had significantly elevated levels of TNF-α, its soluble receptors (sTNFR1/sTNFR2), other macrophage-derived cytokines (interleukin 1β (IL-1β), IL-6, IL-10, and IL-18) in addition to IL-4, interferon-γ, monocyte chemotactic protein-1, fibroblast growth factor β, and vascular endothelial growth factor. Cytokine levels were not correlated with signals from T1ρ imaging in selected structures (amygdalae, hippocampi, hypothalamus, anterior cingulate gyrus, and middle frontal gyrus). Limitations Participants were not followed prospectively across mood states. Conclusion Activation of inflammatory markers was found in abnormal mood states of bipolar disorder. Longitudinal study of individuals with mood disorders is needed to confirm these findings and to elucidate the time course of any such changes.
Reducing length of stay (LOS) has been a priority for hospitals and health care systems. However, there is concern that this reduction may result in increased hospital readmissions.
To determine ...trends in hospital LOS and 30-day readmission rates for all medical diagnoses combined and 5 specific common diagnoses in the Veterans Health Administration.
Observational study from 1997 to 2010.
All 129 acute care Veterans Affairs hospitals in the United States.
4,124,907 medical admissions with subsamples of 2 chronic diagnoses (heart failure and chronic obstructive pulmonary disease) and 3 acute diagnoses (acute myocardial infarction, community-acquired pneumonia, and gastrointestinal hemorrhage).
Unadjusted LOS and 30-day readmission rates with multivariable regression analyses to adjust for patient demographic characteristics, comorbid conditions, and admitting hospitals.
For all medical diagnoses combined, risk-adjusted mean hospital LOS decreased by 1.46 days from 5.44 to 3.98 days, or 2% annually (P < 0.001). Reductions in LOS were also observed for the 5 specific common diagnoses, with greatest reductions for acute myocardial infarction (2.85 days) and community-acquired pneumonia (2.22 days). Over the 14 years, risk-adjusted 30-day readmission rates for all medical diagnoses combined decreased from 16.5% to 13.8% (P < 0.001). Reductions in readmissions were also observed for the 5 specific common diagnoses, with greatest reductions for acute myocardial infarction (22.6% to 19.8%) and chronic obstructive pulmonary disease (17.9% to 14.6%). All-cause mortality 90 days after admission was reduced by 3% annually. Of note, hospitals with mean risk-adjusted LOS that was lower than expected had a higher readmission rate, suggesting a modest tradeoff between hospital LOS and readmission (6% increase for each day lower than expected).
This study is limited to the Veterans Health Administration system; non-Veterans Affairs admissions were not available. No measure of readmission preventability was used.
Veterans Affairs hospitals demonstrated simultaneous improvements in hospital LOS and readmissions over 14 years, suggesting that as LOS improved, hospital readmission did not increase. This is important because hospital readmission is being used as a quality indicator and may result in payment incentives. Future work should explore these relationships to see whether a tipping point exists for LOS reduction and hospital readmission.
Office of Rural Health and the Health Services Research & Development Service, Veterans Health Administration, U.S. Department of Veterans Affairs.
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