373 research outputs found
Experimental Spinal Fusion With Recombinant Human Bone Morphogenetic Protein-2 Without Decortication of Osseous Elements
Study Design. L4-L5 intertransverse process fusions were produced with 58 Ī¼g, 230 Ī¼g, or 920 Ī¼g of recombinant human bone morphogenetic protein-2 in 20 dogs. Eleven had traditional decortication of posterior elements before insertion of the implant. Nine were left undecorticated. All animals were evaluated 3 months after surgery.
Objectives. To determine whether decortication is a prerequisite for successful fusion in the presence of osteoinductive proteins such as bone morphogenetic protein-2.
Summary of Background Data. Recombinant osteoinductive proteins can induce de novo bone in ectopic soft-tissue sites in the absence of bone marrow elements. Traditional methods for achieving spinal fusion rely on exposure of bone marrow through decortication to facilitate osteogenesis. It is hypothesized that the presence of an implanted osteoinductive protein obviates the need for exposure and release of host inductive factors.
Methods. Recombinant human bone morphogenetic protein-2-induced intertransverse process fusions were performed with and without decortication. Fusion sites were evaluated by computed tomography imaging, high-resolution radiography, manual testing, mechanical testing, and histologic analysis.
Results. One hundred percent of decorticated spines and 89% of undecorticated spines were clinically fused by 3 months. Ninety-one percent of decorticated spines and 78% of undecorticated specimens exhibited bilateral transverse process osseous bridging. The only spines that failed to achieve solid bilateral arthrodesis were in the lowest dose group. With the higher two doses, there was histologic evidence of osseous continuity between the fusion mass and undecorticated transverse processes.
Conclusions. There were no statistical differences in clinical and radiographic fusion rates between decorticated and undecorticated sites. With higher doses of recombinant human bone morphogenetic protein-2, there was little histologic distinction between fusions in decorticated versus undecorticated spines
Histologic Evaluation of the Efficacy of rhBMP-2 Compared With Autograft Bone in Sheep Spinal Anterior Interbody Fusion
Study Design. The sheep anterior lumbar spinal fusion model was used to study the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2)ācollagen composite in comparison with autograft to enhance spinal interbody fusion. Comparisons were drawn from temporal radiographic and end-point biomechanical and histologic data.
Objective. To analyze histologically the ability of rhBMP-2 to achieve complete arthrodesis between vertebral bodies.
Summary of Background Data. Studies using rhBMP for enhancement of anterior interbody fusion have used numerous endpoints. However, systematic histologic evaluation of the fusion has not been conducted.
Methods. Twelve sheep underwent single-level anterior lumbar interbody fusion performed with a cylindrical fenestrated titanium interbody fusion device (INTER FIX, Medtronic Sofamor Danek, Inc., Memphis, TN). The device was filled either with rhBMP-2ācollagen (n = 6) or autogenous iliac crest bone graft (n = 6). Radiologic evaluation was carried out at 2-month intervals, and all sheep were killed 6 months after surgery. Nondestructive biomechanical testing for stiffness to flexion, extension, and lateral bending moments, un-decalcified histology, and qualitative and quantitative histologic evaluation were performed.
Results. Radiographs revealed a bony bridge anterior to the cage in five of six rhBMP-2-treated animals, whereas it was present only in one of five in the autogenous bone graft group. Segments treated with rhBMP-2 were 20% stiffer in flexion than autograft-treated segments at 6 months. Six of six in the rhBMP-2 group and two of six in the autograft group showed complete fusion. There was a significantly higher rate of bony continuity observed at the fenestrations of the rhBMP-2 group. Three times more number of cage fenestrations in the rhBMP-2 group demonstrated āall-boneā when compared with the autograft group (P \u3c 0.001). Further, the scar tissue in and around the autograft-treated cages was 16-fold more (P \u3c 0.01) than that seen for rhBMP-2-treated cages.
Conclusions. The study demonstrates that rhBMP-2 can lead to earlier radiologic fusion and a more consistent increased stiffness of the segments when compared with autograft in sheep anterior lumbar interbody fusion. Furthermore, a three times higher histologic fusion rate is attainable with significantly reduced fibrous tissue around the implant when rhBMP-2 is used
Effective Doses of Recombinant Human Bone Morphogenetic Protein-2 in Experimental Spinal Fusion
Study Design Nineteen dogs underwent L4-L5 intertransverse process fusions with either 58 Ī¼g, 115 Ī¼g, 230 Ī¼g, 460 Ī¼g, or 920 Ī¼g of recombinant human bone morphogenetic protein-2 carried by a polylactic acid polymer. A previous study (12 dogs) compared 2300 Ī¼g of recombinant human bone morphogenetic protein-2, autogenous iliac bone, and carrier alone in this model. All fusions subsequently were compared.
Objectives To characterize the dose-response relationship of recombinant human bone morphogenetic protein-2 in a spinal fusion model.
Summary of Background Data Recombinant osteoinductive morphogens, such as recombinant human bone morphogenetic protein-2, are effective in vertebrate diaphyseal defect and spinal fusion models. It is hypothesized that the quality of spinal fusion produced with recombinant human bone morphogenetic protein-2, above a threshold dose, does not change with increasing amounts of inductive protein.
Methods After decortication of the posterior elements, the designated implants were placed along the intertransverse process space bilaterally. The fusion sites were evaluated after 3 months by computed tomography imaging, high-resolution radiography, manual testing, mechanical testing, and histologic analysis.
Results As in the study using 2300 Ī¼g of recombinant human bone morphogenetic protein-2, implantation of 58ā920 Ī¼g of recombinant human bone morphogenetic protein-2 successfully resulted in intertransverse process fusion in the dog by 3 months. This had not occurred in animals containing autograft or carrier alone. The cross-sectional area of the fusion mass and mechanical stiffness of the L4-L5 intersegment were not dose-dependent. Histologic findings varied but were not related to rhBMP-2 dose. Inflammatory reaction to the composite implant was proportional inversely to the volume of the fusion mass.
Conclusions No mechanical, radiographic, or histologic differences in the quality of intertransverse process fusion resulted from a 40-fold variation in dose of recombinant human bone morphogenetic protein-2
A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia
BACKGROUND Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/ kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. METHODS We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. RESULTS Among the 901 patients included in the primary analysis, the overall least-squares mean (Ā±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0Ā±2.1% (P<0.001). The mean reduction was 55.7Ā±4.2% among patients who underwent background therapy with diet alone, 61.6Ā±2.6% among those who received 10 mg of atorvastatin, 56.8Ā±5.3% among those who received 80 mg of atorvastatin, and 48.5Ā±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. CONCLUSIONS At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks
Friedewald-Estimated Versus Directly Measured Low-Density Lipoprotein Cholesterol and Treatment Implications
ObjectivesThe aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values.BackgroundLDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients.MethodsWe examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ā„400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl.ResultsPatients were 59 Ā± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ā„70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl).ConclusionsThe Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ā„150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ā„70 mg/dl, and therefore additional evaluation is warranted in high-risk patients
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An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.
Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs
Computer aided characterization of early cancer in Barrett's esophagus on i-scan magnification imaging - Multicenter international study
BACKGROUND AND AIMS: We aimed to develop a computer aided characterization system that can support the diagnosis of dysplasia in Barrett's esophagus (BE) on magnification endoscopy. METHODS: Videos were collected in high-definition magnification white light and virtual chromoendoscopy with i-scan (Pentax Hoya, Japan) imaging in patients with dysplastic/ non-dysplastic BE (NDBE) from 4 centres. We trained a neural network with a Resnet101 architecture to classify frames as dysplastic or non-dysplastic. The network was tested on three different scenarios: high-quality still images, all available video frames and a selected sequence within each video. RESULTS: 57 different patients each with videos of magnification areas of BE (34 dysplasia, 23 NDBE) were included. Performance was evaluated using a leave-one-patient-out cross-validation methodology. 60,174 (39,347 dysplasia, 20,827 NDBE) magnification video frames were used to train the network. The testing set included 49,726 iscan-3/optical enhancement magnification frames. On 350 high-quality still images the network achieved a sensitivity of 94%, specificity of 86% and Area under the ROC (AUROC) of 96%. On all 49,726 available video frames the network achieved a sensitivity of 92%, specificity of 82% and AUROC of 95%. On a selected sequence of frames per case (total of 11,471 frames) we used an exponentially weighted moving average of classifications on consecutive frames to characterize dysplasia. The network achieved a sensitivity of 92%, specificity of 84% and AUROC of 96% The mean assessment speed per frame was 0.0135 seconds (SD, + 0.006) CONCLUSION: Our network can characterize BE dysplasia with high accuracy and speed on high-quality magnification images and sequence of video frames moving it towards real time automated diagnosis
A new artificial intelligence system successfully detects and localises early neoplasia in Barrett's esophagus by using convolutional neural networks
BACKGROUND AND AIMS:
Seattle protocol biopsies for Barrett's Esophagus (BE) surveillance are labour intensive with low compliance. Dysplasia detection rates vary, leading to missed lesions. This can potentially be offset with computer aided detection. We have developed convolutional neural networks (CNNs) to identify areas of dysplasia and where to target biopsy.
METHODS:
119 Videos were collected in high-definition white light and optical chromoendoscopy with i-scan (Pentax Hoya, Japan) imaging in patients with dysplastic and non-dysplastic BE (NDBE). We trained an indirectly supervised CNN to classify images as dysplastic/non-dysplastic using whole video annotations to minimise selection bias and maximise accuracy. The CNN was trained using 148,936 video frames (31 dysplastic patients, 31 NDBE, two normal esophagus), validated on 25,161 images from 11 patient videos and tested on 264 iscan-1 images from 28 dysplastic and 16 NDBE patients which included expert delineations. To localise targeted biopsies/delineations, a second directly supervised CNN was generated based on expert delineations of 94 dysplastic images from 30 patients. This was tested on 86 i-scan one images from 28 dysplastic patients.
FINDINGS:
The indirectly supervised CNN achieved a per image sensitivity in the test set of 91%, specificity 79%, area under receiver operator curve of 93% to detect dysplasia. Per-lesion sensitivity was 100%. Mean assessment speed was 48 frames per second (fps). 97% of targeted biopsy predictions matched expert and histological assessment at 56 fps. The artificial intelligence system performed better than six endoscopists.
INTERPRETATION:
Our CNNs classify and localise dysplastic Barrett's Esophagus potentially supporting endoscopists during surveillance
Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis
Background: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs).
Methods: We estimated the incidence of infections with 16 antibiotic resistanceābacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011ā12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature.
Findings: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671ā689 (95% uncertainty interval [UI] 583ā148ā763ā966) infections with antibiotic-resistant bacteria, of which 63Ā·5% (426ā277 of 671ā689) were associated with health care. These infections accounted for an estimated 33ā110 (28ā480ā38ā430) attributable deaths and 874ā541 (768ā837ā989ā068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece.
Interpretation: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases
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