Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) after total hip or ...total knee arthroplasty, but comparisons with direct oral anticoagulants are lacking for prophylaxis beyond hospital discharge.
We performed a multicenter, double-blind, randomized, controlled trial involving patients who were undergoing total hip or knee arthroplasty. All the patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and then were randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism (the primary effectiveness outcome) and bleeding complications, including major or clinically relevant nonmajor bleeding (the primary safety outcome).
A total of 3424 patients (1804 undergoing total hip arthroplasty and 1620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1707 patients (0.64%) in the aspirin group and in 12 of 1717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval CI, -0.55 to 0.66; P<0.001 for noninferiority and P=0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, -0.65 to 0.29; P=0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, -1.07 to 0.47; P=0.43).
Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT01720108 .).
Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute ...bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment. Safety monitoring included the collection of adverse events (AEs), performance of laboratory tests, determination of vital signs, and performance of electrocardiograms. Omadacycline exposures were similar in patients with hepatic impairment and healthy subjects following i.v. or oral administration, with the geometric mean ratios for the area under the concentration-time curve and the maximum drug concentration ranging from 0.79 to 1.42. Omadacycline was safe and well tolerated. Overall, 13/30 (43.3%) participants experienced an AE; those occurring in more than 1 participant included headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%), with no differences based on the degree of hepatic impairment or the route of administration. Asymptomatic increases in heart rate were observed; none was considered an AE. These findings suggest that no omadacycline dose adjustment is warranted in patients with hepatic impairment.
Abstract Background Context Classification criteria are recommended for diseases that lack specific biomarkers to improve homogeneity in clinical research studies. Because imaging evidence of lumbar ...disc herniations (LDHs) may not be associated with symptoms, clinical classification criteria based on patient symptoms and physical examination findings are required. Purpose This study aimed to produce clinical classification criteria to identify patients with radicular pain caused by LDH. Study Design The study design was a two-stage process. Phase 1 included a Delphi process and Phase 2 included a cohort study. Patient Sample The patient sample included outpatients recruited from spine clinics in five countries. Outcome Measures The outcome measures were items from history and physical examination. Materials and Methods In Phase 1, 17 spine experts participated in a Delphi process to select symptoms and signs suggesting radicular pain caused by LDH. In Phase 2, 19 different clinical experts identified patients they confidently classified as presenting with (1) radicular pain caused by LDH, (2) neurogenic claudication (NC) caused by lumbar spinal stenosis, or (3) non-specific low back pain (NSLBP) with referred leg pain. Patients completed survey items and specialists documented examination signs. A score to predict radicular pain caused by LDH was developed based on the coefficients of the multivariate model. An unrestricted grant of less than US$15,000 was received from MSD: It was used to support the conception of the Delphi, data management, and statistical analysis. No fees were allocated to participating spine specialists. Results Phase 1 generated a final list of 74 potential symptoms and signs. In Phase 2, 209 patients with pain caused by LDH (89), NC (63), or NSLBP (57) were included. Items predicting radicular pain caused by LDH (p<.05) were monoradicular leg pain distribution, patient-reported unilateral leg pain, positive straight leg raise test <60° (or femoral stretch test), unilateral motor weakness, and asymmetric ankle reflex. The score had an AUC of 0.91. An easy-to-use weighted set of criteria with similar psychometric characteristics is proposed (specificity 90.4%, sensitivity 70.6%). Conclusions Classification criteria for identifying patients with radicular pain caused by LDH are proposed. Their use could improve the homogeneity of patients enrolled in clinical research studies.
Omadacycline is a first-in-class aminomethylcycline antibiotic with microbiological activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacteria that is being ...developed for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The bioavailability of a phase 3 tablet formulation relative to that obtained via intravenous (i.v.) administration (and of other oral formulations relative to that of the phase 3 tablet) was investigated in an open-label, randomized, four-period, crossover study with healthy subjects age 18 to 50 years. Subjects received omadacycline at 100 mg i.v., 300 mg orally as two different tablet formulations with different dissolution profiles, and 300 mg as an oral solution. Plasma omadacycline concentrations were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Twenty of 24 subjects completed all treatment periods. The two tablet formulations produced equivalent total exposures. The phase 3 tablet produced an exposure equivalent to that of the 100-mg i.v. dose, with a geometric mean ratio (90% confidence intervals CI) for area under the concentration-time curve from 0 h to infinity AUC
) of 1.00 (0.93, 1.07). The absolute bioavailability of the tablets was approximately 34.5%. Intersubject variability was consistent among the oral formulations (∼20 to 25%). Single oral and i.v. doses of omadacycline were well tolerated; three subjects experienced mild adverse events (dizziness, nausea, and vomiting) that resolved without intervention. A 300-mg dose of the tablet formulation of omadacycline intended for use in phase 3 studies produced a total exposure equivalent to that of a 100-mg i.v. dose.
Because imaging findings of lumbar spinal stenosis (LSS) may not be associated with symptoms, clinical classification criteria based on patient symptoms and physical examination findings are needed.
...The objective of this study was to develop clinical classification criteria that identify patients with neurogenic claudication (NC) caused by LSS.
This study is a two-stage process that includes Phase 1, the Delphi process, and Phase 2, the cross-sectional study.
Outpatients were recruited from spine clinics in five countries.
The outcome measure includes items from the patients' history and physical examination.
In Phase 1, a list of potential predictors of NC caused by LSS was based on the available literature and was evaluated through a Delphi process involving 17 spine specialists (surgeons and non-surgeons) from eight countries. In Phase 2, 19 different clinical spine specialists from five countries identified patients they classified as having (1) NC caused by LSS, (2) radicular pain caused by lumbar disc herniation (LDH), or (3) non-specific low back pain (NSLBP) with radiating leg pain. The patients completed survey items and the specialists documented the examination signs. Coefficients from general estimating equation models were used to select predictors, to generate a clinical classification score, and to obtain a receiver operating characteristic curve. Conduction of the Delphi process, data management, and statistical analysis were partially supported by an unrestricted grant of less than 15,000 US dollars from Merck Sharp & Dohme. No fees were allocated to participating spine specialists.
Phase 1 generated a final list of 46 items related to LSS. In Phase 2, 209 patients with leg pain caused by LSS (n=63), LDH (n=89), or NSLBP (n=57) were included. Criteria that independently predicted NC (p<.05) were age over 60 years, positive 30-second extension test, negative straight leg test, pain in both legs, leg pain relieved by sitting, and leg pain decreased by leaning forward or flexing the spine. A classification score using a weighted set of these criteria was developed. The proposed N-CLASS score ranged from 0 to 19 and had an area under the curve of 0.92, and the cutoff (>10/19) to obtain a specificity of >90.0% resulted in a sensitivity of 82.0%.
Clinical criteria independently associated with neurogenic claudication due to LSS were identified. The use of these symptom and physical variables as a classification score for clinical research could improve homogeneity among enrolled patients.
Extrapolation can be used to address challenges in pediatric drug development. This review describes how these challenges could be addressed by further evolution of quantitative frameworks (i.e., ...model‐based/informed drug discovery and development) and regulatory science in support of pediatric drug development. Included are examples of diseases/indications where extrapolation has been used in different ways as a basis for identifying gaps in the framework and opportunities for continued advancement of pediatric drug development.
Reactivation of BK polyomavirus (BKPyV) can cause significant kidney and bladder disease in immunocompromised patients. There are currently no effective, BKPyV-specific therapies. MAU868 is a novel, ...human immunoglobulin (Ig) G1 monoclonal antibody that binds the major capsid protein, VP1, of BKPyV with picomolar affinity, neutralizes infection by the 4 major BKPyV genotypes (EC50 ranging from 0.009-0.093 μg/mL; EC90 ranging from 0.102-4.160 μg/mL), and has comparable activity against variants with highly prevalent VP1 polymorphisms. No resistance-associated variants were identified in long-term selection studies, indicating a high in vitro barrier-to-resistance. The high-resolution crystal structure of MAU868 in complex with VP1 pentamer identified 3 key contact residues in VP1 (Y169, R170, and K172). A first-in-human study was conducted to assess the safety, tolerability, and pharmacokinetics of MAU868 following intravenous and subcutaneous administration to healthy adults in a randomized, placebo-controlled, double-blinded, single ascending dose design. MAU868 was safe and well-tolerated. All adverse events were grade 1 and resolved. The pharmacokinetics of MAU868 was typical of a human IgG, with dose-proportional systemic exposure and an elimination half-life ranging between 23 and 30 days. These results demonstrate the potential of MAU868 as a first-in-class therapeutic agent for the treatment or prevention of BKPyV disease.
We evaluate the return on investment (ROI) from public land conservation in the state of Minnesota, USA. We use a spatially-explicit modeling tool, the Integrated Valuation of Ecosystem Services and ...Tradeoffs (InVEST), to estimate how changes in land use and land cover (LULC), including public land acquisitions for conservation, influence the joint provision and value of multiple ecosystem services. We calculate the ROI of a public conservation acquisition as the ratio of the present value of ecosystem services generated by the conservation to the cost of the conservation. For the land scenarios analyzed, carbon sequestration services generated the greatest benefits followed by water quality improvements and recreation opportunities. We found ROI values ranged from 0.21 to 5.28 depending on assumptions about future land use change, service values, and discount rate. Our study suggests conservation is a good investment as long as investments are targeted to areas with low land costs and high service values.
Cholesterol biosynthesis is a multi-step process involving several subcellular compartments, including peroxisomes. Cells adjust their sterol content by both transcriptional and post-transcriptional ...feedback regulation, for which sterol regulatory element-binding proteins (SREBPs) are essential; such homeostasis is dysregulated in peroxisome-deficient
knockout mice. Here, we compared the regulation of cholesterol biosynthesis in Chinese hamster ovary (CHO-K1) cells and in three isogenic peroxisome-deficient CHO cell lines harboring
gene mutations. Peroxisome deficiency activated expression of cholesterogenic genes, however, cholesterol levels were unchanged. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein levels were increased in mutant cells, whereas HMGCR activity was significantly decreased, resulting in reduced cholesterol synthesis. U18666A, an inhibitor of lysosomal cholesterol export, induced cholesterol biosynthetic enzymes; yet, cholesterol synthesis was still reduced. Interestingly, peroxisome deficiency promoted ER-to-Golgi SREBP cleavage-activating protein (SCAP) trafficking even when cells were cholesterol-loaded. Restoration of functional peroxisomes normalized regulation of cholesterol synthesis and SCAP trafficking. These results highlight the importance of functional peroxisomes for maintaining cholesterol homeostasis and efficient cholesterol synthesis.
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