Apixaban or Warfarin in Patients with an On-X Mechanical Aortic Valve.

BACKGROUND: Vitamin K antagonists are the only oral anticoagulants approved to prevent valve thrombosis and valve-related thromboembolism in patients with mechanical heart valves. Whether patients with an On-X mechanical aortic valve can be safely anticoagulated with apixaban is unknown. METHODS: Patients with an On-X aortic valve implanted at least 3 months before enrollment were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalized ratio 2.0 to 3.0). The primary efficacy end point was the composite of valve thrombosis or valve-related thromboembolism with coprimary analyses comparing apixaban with warfarin for noninferiority and comparing the apixaban event rate with an objective performance criterion (OPC). RESULTS: The trial was stopped after 863 participants were enrolled owing to an excess of thromboembolic events in the apixaban group. Most (94%) participants took aspirin. A total of 26 primary end-point events occurred, 20 (in 16 participants) in the apixaban group (4.2%/patient-year; 95% confidence interval [CI], 2.3 to 6.0) and 6 (in 6 participants) in the warfarin group (1.3%/patient-year; 95% CI, 0.3 to 2.3). The difference in primary end-point rates between the apixaban and warfarin groups was 2.9 (95% CI, 0.8 to 5.0); noninferiority and OPC success criteria were not met. Major bleeding rates were 3.6%/patient-year with apixaban and 4.5%/patient-year with warfarin. CONCLUSIONS: Apixaban did not demonstrate noninferiority to warfarin and is less effective than warfarin for the prevention of valve thrombosis or thromboembolism in patients with an On-X mechanical aortic valve. (Funded by Artivion; ClinicalTrials.gov number, NCT04142658.)

Comparable prediction of breast cancer risk from a glimpse or a first impression of a mammogram.

Expert radiologists can discern normal from abnormal mammograms with above-chance accuracy after brief (e.g. 500 ms) exposure. They can even predict cancer risk viewing currently normal images (priors) from women who will later develop cancer. This involves a rapid, global, non-selective process called "gist extraction". It is not yet known whether prolonged exposure can strengthen the gist signal, or if it is available solely in the early exposure. This is of particular interest for the priors that do not contain any localizable signal of abnormality. The current study compared performance with brief (500 ms) or unlimited exposure for four types of mammograms (normal, abnormal, contralateral, priors). Groups of expert radiologists and untrained observers were tested. As expected, radiologists outperformed naïve participants. Replicating prior work, they exceeded chance performance though the gist signal was weak. However, we found no consistent performance differences in radiologists or naïves between timing conditions. Exposure time neither increased nor decreased ability to identify the gist of abnormality or predict cancer risk. If gist signals are to have a place in cancer risk assessments, more efforts should be made to strengthen the signal.

Ten-year fracture risk predicted by proximal femur Hounsfield units.

Colon cancer screening occurs at younger ages than osteoporosis screening. Bone density measurements using virtual colonoscopy performed for colon cancer screening can provide an early warning sign of patients at potential risk for osteoporosis-related fractures. Earlier identification may improve treatment and potentially fracture prevention. INTRODUCTION: Opportunistic osteoporosis screening with computed tomography colonography (CTC) offers an opportunity to capitalize on earlier colorectal cancer screening to identify patients at risk of future fractures. The purpose of this study is to evaluate 10-year fracture and specifically hip fracture risk based on Hounsfield units (HU) obtained from CTC. METHODS: We identified all CTC scans between 2004 and 2007 of patients 40 years and older with 10 years minimum follow-up. Hounsfield units were measured within the proximal femur and fractures identified via worldwide military records. Patients were stratified into two cohorts based on the presence or lack of a fracture in the wrist, spine, hip, or proximal humerus. Hounsfield unit measurements were compared between groups using Student's t test and the HU threshold was calculated that best approximated an 80% sensitivity to optimally screen patients for fracture risk. The odds ratio, negative predictive value, 10-year incidence of fracture, and survival curves were calculated. RESULTS: We identified 3711 patients with 183 fractures over 10 years. The HU threshold that corresponded with an 80% sensitivity to identify fractures was 112 HU. The negative predictive value (NPV) for overall fractures and hip fractures was over 97%. The 10-year fracture incidence was higher in patients below 112 HU compared to those above for both overall fractures (6.3% vs 1.7%) and hip fractures (2.7% vs 0.07%). The 112 HU threshold corresponds with an odds ratio for overall fracture and hip fractures of 2.5 (95% confidence interval (CI), 1.7-3.6) and 24.5 (95% CI, 3.3-175.5), respectively. CONCLUSION: In the 10 years following CTC, patients who experienced a fracture had lower hip HU. Decreasing HU on CTC may be an early warning sign of fracture potential.

Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin.

BACKGROUND: Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). METHODS: Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. RESULTS: 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0-79.7) months, respectively for Trial A and B. CONCLUSIONS: Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

Tuberculosis in the Circumpolar Region, 2006-2012.

SETTING: The northern circumpolar jurisdictions Canada (Northwest Territories, Nunavik, Nunavut, Yukon), Finland, Greenland, Norway, Russian Federation (Arkhangelsk), Sweden and the United States (Alaska). OBJECTIVE: To describe and compare demographic, clinical and laboratory characteristics, including drug resistance and treatment completion, of tuberculosis (TB) cases in the northern circumpolar populations. DESIGN: Descriptive analysis of all active TB cases reported from 2006 to 2012 for incidence rate (IR), age and sex distribution, sputum smear and diagnostic site characteristics, drug resistance and treatment completion rates. RESULTS: The annual IR of TB disease ranged from a low of 4.3 per 100 000 population in Northern Sweden to a high of 199.5/100 000 in Nunavik, QC, Canada. For all jurisdictions, IR was higher for males than for females. Yukon had the highest proportion of new cases compared with retreatment cases (96.6%). Alaska reported the highest percentage of laboratory-confirmed cases (87.4%). Smear-positive pulmonary cases ranged from 25.8% to 65.2%. Multidrug-resistant cases ranged from 0% (Northern Canada) to 46.3% (Arkhangelsk). Treatment outcome data, available up to 2011, demonstrated >80% treatment completion for four of the 10 jurisdictions. CONCLUSION: TB remains a serious public health issue in the circumpolar regions. Surveillance data contribute toward a better understanding and improved control of TB in the north.

Dating phototrophic microbial lineages with reticulate gene histories.

Phototrophic bacteria are among the most biogeochemically significant organisms on Earth and are physiologically related through the use of reaction centers to collect photons for energy metabolism. However, the major phototrophic lineages are not closely related to one another in bacterial phylogeny, and the origins of their respective photosynthetic machinery remain obscured by time and low sequence similarity. To better understand the co-evolution of Cyanobacteria and other ancient anoxygenic phototrophic lineages with respect to geologic time, we designed and implemented a variety of molecular clocks that use horizontal gene transfer (HGT) as additional, relative constraints. These HGT constraints improve the precision of phototroph divergence date estimates and indicate that stem green non-sulfur bacteria are likely the oldest phototrophic lineage. Concurrently, crown Cyanobacteria age estimates ranged from 2.2 Ga to 2.7 Ga, with stem Cyanobacteria diverging ~2.8 Ga. These estimates provide a several hundred Ma window for oxygenic photosynthesis to evolve prior to the Great Oxidation Event (GOE) ~2.3 Ga. In all models, crown green sulfur bacteria diversify after the loss of the banded iron formations from the sedimentary record (~1.8 Ga) and may indicate the expansion of the lineage into a new ecological niche following the GOE. Our date estimates also provide a timeline to investigate the temporal feasibility of different photosystem HGT events between phototrophic lineages. Using this approach, we infer that stem Cyanobacteria are unlikely to be the recipient of an HGT of photosystem I proteins from green sulfur bacteria but could still have been either the HGT donor or the recipient of photosystem II proteins with green non-sulfur bacteria, prior to the GOE. Together, these results indicate that HGT-constrained molecular clocks are useful tools for the evaluation of various geological and evolutionary hypotheses, using the evolutionary histories of both genes and organismal lineages.

The mechanism producing initial transients on the clarinet.

In self-sustained instruments, starting transients are important timbral characteristics that help identify the instrument and the playing style. Often, the oscillation starts as a growing exponential. This study investigates the starting amplitude of this exponential for the clarinet. After a rapid tongue release, the reed quickly returns to its equilibrium position. The sudden change in aperture produces an abrupt change in both the airflow into the mouthpiece and the mouthpiece pressure. This perturbation travels along the bore and reflects at the open end. Returning to the mouthpiece with slight attenuation, the perturbation can be amplified by the reed acting as an active element-effectively a negative resistance. When the reed release time exceeds the time for sound to travel twice the bore length, the airflow and pressure wave into the bore via the aperture are superposed over their own returning reflection. Measurements of reed motion and mouthpiece pressures during reed release yield values that are used in a model to calculate waveforms showing similarities to those observed experimentally. The initial amplitude decreases with increasing reed release time, though not always monotonically. It can become very small in special cases due to synchronisation between the initial pulse and its reflection.

Minimally Invasive Mitral Valve Surgery I: Patient Selection, Evaluation, and Planning.

Widespread adoption of minimally invasive mitral valve repair and replacement may be fostered by practice consensus and standardization. This expert opinion, first of a 3-part series, outlines current best practices in patient evaluation and selection for minimally invasive mitral valve procedures, and discusses preoperative planning for cannulation and myocardial protection.

Minimally Invasive Mitral Valve Surgery II: Surgical Technique and Postoperative Management.

Techniques for minimally invasive mitral valve repair and replacement continue to evolve. This expert opinion, the second of a 3-part series, outlines current best practices for nonrobotic, minimally invasive mitral valve procedures, and for postoperative care after minimally invasive mitral valve surgery.

Minimally Invasive Mitral Valve Surgery III: Training and Robotic-Assisted Approaches.

Minimally invasive mitral valve operations are increasingly common in the United States, but robotic-assisted approaches have not been widely adopted for a variety of reasons. This expert opinion reviews the state of the art and defines best practices, training, and techniques for developing a successful robotics program.

Mifepristone-inducible transgene expression in neural progenitor cells in vitro and in vivo.

Numerous gene and cell therapy strategies are being developed for the treatment of neurodegenerative disorders. Many of these strategies use constitutive expression of therapeutic transgenic proteins, and although functional in animal models of disease, this method is less likely to provide adequate flexibility for delivering therapy to humans. Ligand-inducible gene expression systems may be more appropriate for these conditions, especially within the central nervous system (CNS). Mifepristone's ability to cross the blood-brain barrier makes it an especially attractive ligand for this purpose. We describe the production of a mifepristone-inducible vector system for regulated expression of transgenes within the CNS. Our inducible system used a lentivirus-based vector platform for the ex vivo production of mifepristone-inducible murine neural progenitor cells that express our transgenes of interest. These cells were processed through a series of selection steps to ensure that the cells exhibited appropriate transgene expression in a dose-dependent and temporally controlled manner with minimal background activity. Inducible cells were then transplanted into the brains of rodents, where they exhibited appropriate mifepristone-inducible expression. These studies detail a strategy for regulated expression in the CNS for use in the development of safe and efficient gene therapy for neurological disorders.

Enantioselective Synthesis of Tetrahydroquinolines, Tetrahydroquinoxalines, and Tetrahydroisoquinolines via Pd-Catalyzed Alkene Carboamination Reactions.

A catalyst composed of Pd2(dba)3 and (S)-Siphos-PE provides excellent results in Pd-catalyzed alkene carboamination reactions between aniline derivatives bearing pendant alkenes and aryl or alkenyl halides. These transformations generate tetrahydroquinolines and tetrahydroquinoxalines that contain quaternary carbon stereocenters with high levels of asymmetric induction. In addition this catalyst also effects the asymmetric synthesis of tetrahydroisoquinolines via related transformations of 2-allylbenzylamines. In contrast to most other approaches to the asymmetric synthesis of these compounds, which frequently involve functional group interconversion or a single C-C or C-N bond-forming event, the carboamination reactions generate both a C-N bond, a C-C bond, and a stereocenter.

Minithoracotomy for mitral valve repair improves inpatient and postdischarge economic savings.

OBJECTIVE: Small series of thoracotomy for mitral valve repair have demonstrated clinical benefit. This multi-institutional administrative database analysis compares outcomes of thoracotomy and sternotomy approaches for mitral repair. METHODS: The Premier database was queried from 2007 to 2011 for mitral repair hospitalizations. Premier contains billing, cost, and coding data from more than 600 US hospitals, totaling 25 million discharges. Thoracotomy and sternotomy approaches were identified through expert rules; robotics were excluded. Propensity matching on baseline characteristics was performed. Regression analysis of surgical approach on outcomes and costs was modeled. RESULTS: Expert rule analysis positively identified thoracotomy in 847 and sternotomy in 566. Propensity matching created 2 groups of 367. Mortalities were similar (thoracotomy 1.1% vs sternotomy 1.9%). Sepsis and other infections were significantly lower with thoracotomy (1.1% vs 4.4%). After adjustment for hospital differences, thoracotomy carried a 17.2% lower hospitalization cost (-$8289) with a 2-day stay reduction. Readmission rates were significantly lower with thoracotomy (26.2% vs 35.7% at 30 days and 31.6% vs 44.1% at 90 days). Thoracotomy was more common in southern and northeastern hospitals (63% vs 37% and 64% vs 36%, respectively), teaching hospitals (64% vs 36%) and larger hospitals (>600 beds, 78% vs 22%). CONCLUSIONS: Relative to sternotomy, thoracotomy for mitral repairs provides similar mortality, less morbidity, fewer infections, shorter stay, and significant cost savings during primary admission. The markedly lower readmission rates for thoracotomy will translate into additional institutional cost savings when a penalty on hospitals begins under the Affordable Care Act's Hospital Readmissions Reduction Program.

Optimizing the outcome of vascular intervention for Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TA) predisposes to the development of arterial stenoses and aneurysms, and is associated with considerable morbidity and mortality amongst young patients. The aims of this study were to analyse indications and outcomes of surgical intervention, and to assess the potential benefits of immunosuppression and the use of perioperative imaging. METHODS: This was a retrospective review of patients with TA referred between 2001 and 2012. RESULTS: A series of 97 patients with TA, seen at a single tertiary centre, is reported. Immunosuppression was required in 87 patients (90 per cent). Thirty-seven (38 per cent) underwent 64 procedures: 27 patients underwent 33 open surgical procedures and 20 patients had 31 endovascular procedures. After a median follow-up of 6 years, the overall success rate was 79 per cent for open surgery (mean graft patency 9.4 years) and 52 per cent for endovascular procedures (P = 0.035). Procedural failure was significantly reduced in patients receiving preoperative immunosuppression, and particularly endovascular procedures (P = 0.001). In addition to clinical examination and measurement of acute-phase reactants, combination non-invasive imaging including Doppler ultrasonography, [18F]fluorodeoxyglucose combined positron emission and computed tomography (CT), magnetic resonance angiography and CT angiography was used to identify arterial lesions, establish the diagnosis and monitor treatment outcomes. CONCLUSION: Outcomes of vascular intervention in TA may be improved by detailed preoperative assessment including measurement of disease activity, and by ensuring optimal immunomodulatory therapy before and after the procedure.

Takayasu arteritis: criteria for surgical intervention should not be ignored.

Takayasu aortoarteritis is a rare, chronic granulomatous panarteritis with significant morbidity amongst young patients. Current challenges include a lack of awareness about the condition, delays in diagnosis due to its varied presentation, and suboptimal methods for assessing disease activity. The development of noninvasive imaging including magnetic resonance angiography and positron emission tomography is aiding earlier diagnosis. Early initiation of immunosuppressive treatment is crucial to control active inflammation and minimize arterial injury. Recent studies investigating biological agents such as tumour necrosis factor- α antagonists are encouraging. Surgical revascularization should only be undertaken following careful consideration, as restenosis is common. The indications for considering intervention include uncontrolled hypertension due to renal artery stenosis, severe symptomatic coronary artery or cerebrovascular disease, severe aortic regurgitation, stenotic or occlusive lesions resulting in critical limb ischemia, and aneurysms at risk of rupture. In these cases, the risk benefit ratio for intervention is good. Open surgery, at present, has better outcomes compared to endovascular techniques. However, technological advances in endovascular treatment are continually improving. Controlling disease activity prior to and following revascularization is key to preventing complications. A multidisciplinary approach to the diagnosis and management of Takayasu arteritis is essential to achieve satisfactory patient outcomes.

Flexible optitrode for localized light delivery and electrical recording.

We present optitrode, a miniaturized flexible probe for integrated, localized light delivery and electrical recording. This device features an annular light guide with transparent polymer and fused silica layers surrounding a twisted-wire tetrode. We have developed a novel fabrication process, V-groove guided capillary assembly, to achieve high-precision, coaxial alignment of the various layers of the device. Optitrode with a length-to-diameter ratio ∼500 (5 cm long, 100 µm diameter) has been fabricated, and both the electrical and optical functions have been characterized. The prototype can deliver 11% (110 mW) of the total laser power under abrupt bending angle ∼25°.

Longitudinal changes in liver fibrosis in children with sickle cell disease undergoing chronic transfusion therapy.

BACKGROUND AND STUDY AIMS: The progression of liver injury from transfusional iron overload in sickle cell disease (SCD) is poorly understood. We sought to identify predictors liver fibrosis development over time. PATIENTS AND METHODS: We performed a retrospective cohort study of chronically transfused SCD patients who had > or = 2 serial liver biopsies. Core biopsies were scored for fibrosis in a blinded fashion. Primary analyses evaluated longitudinal changes in liver fibrosis and changes in surrogate markers. Secondary analyses determined the relationship between liver iron concentration (LIC) and serum biomarkers. RESULTS: 26 people had > or = 2 serial biopsies for evaluation (n = 70 biopsies total). Fibrosis was Ishak grade 0 or 1 in all biopsies. Evaluation of the first 2 biopsies showed fibrosis regression (n = 6), development (n = 2), persistence (n = 1), and absence (n = 17). There was no consistent association of fibrosis with LIC over time, or between changes in fibrosis status and surrogate markers. For predicting fibrosis on a cross-sectional basis, ALT and ferritin performed moderately (AUCs 0.80 and 0.63, respectively) but LIC performed poorly (AUC 0.30). The highest positive likelihood ratios for fibrosis were for ferritin cutoff of 5000 ng/mL (LR + 5.7) and ALT cutoff of 65 U/L (LR + 5.2). CONCLUSIONS: Liver fibrosis progression is minimal in chronically transfused SCD. LIC does not correlate well with fibrosis development. We propose routine liver biopsies are not necessary components in the standard monitoring of chronically transfused SCD patients.

Contemporary management of splanchnic and renal artery aneurysms: results of endovascular compared with open surgery from two European vascular centers.

INTRODUCTION: Splanchnic and renal artery aneurysms (SRAAs) are uncommon but potentially life-threatening in case of rupture. Whether these aneurysms are best treated by open repair or endovascular intervention is unknown. The aim of this retrospective study is to report the results of open and endovascular repairs in two European institutions over a fifteen-year period. We have reviewed the available literature published over the 10 last years. METHODS: All patients with SRAAs diagnosed from 1995 to 2010 in St Marys Hospital (London, UK) and Henri Mondor Hospital (Créteil, France) were reviewed. Preoperative clinical and anatomical data, operative management and outcomes were recorded from the charts and analyzed. RESULTS: 40 patients with 51 SRAAs were identified. There were 21 males and 19 females with a mean age of 57 ± 14.9 years. The aneurysms locations were: 14 (27%) renal, 11 (22%) splenic, 7 (14%) celiac trunk, 7 (14%) superior mesenteric artery, 4 (8%) hepatic, 4 (8%) pancreaticoduodenal arcades, 3 (6%) left gastric and 1 (2%) gastroduodenal. 4 patients presented with a ruptured SRAA. 17 SRAAs in 16 patients were treated by open repair, 15 in 15 patients were treated endoluminally and 17 (mean diameter: 18 mm, range: 8-75 mm) were managed conservatively. One patient with metastatic pulmonary cancer with two mycotic aneurysms of the superior mesenteric artery (75 mm) and celiac trunk (15 mm) was palliated. After endovascular treatment, the immediate technical success rate was 100%. There was no significant difference between open repair and endovascular patients in terms of 30-day post-operative mortality rate and peri-operative complications. No in-hospital death occurred in patients treated electively. Postoperatively, four patients (1 ruptured and 3 elective) suffered non-lethal mild to severe complication in the open repair group, as compared with one in the endovascular group (p = .34). The mean length of stay was significantly higher after open repair as compared with endovascular repair (17 days, range: 8-56 days vs. 4 days, range: 2-6; p < .001). The mean follow-up time was 17.8 months (range: 0-143 months) after open repair, 15.8 months (range: 0-121 months) after endovascular treatment, and 24.8 (range: 3-64 months) for patient being managed conservatively. No late death related to the VAA occurred. In each group, 2 successful reoperations were deemed necessary. In the endovascular group, two patients presented a reperfusion of the aneurysmal sac at 6 and 24 months respectively. CONCLUSION: No significant difference in term of 30-day mortality and post-operative complication rates could be identified between open repair and endovascular treatment in the present series. Endovascular treatment is a safe alternative to open repair but patients are exposed to the risk of aneurysmal reperfusion. This mandates careful long-term imaging follow up in patients treated endoluminally.

Evaluation of endoscopic vein extraction on structural and functional viability of saphenous vein endothelium.

OBJECTIVES: Endothelial injury during harvest influences graft patency post CABG. We have previously shown that endoscopic harvest causes structural and functional damage to the saphenous vein (SV) endothelium. However, causes of such injury may depend on the extraction technique. In order to assess this supposition, we evaluated the effect of VirtuoSaph endoscopic SV harvesting technique (VsEVH) on structural and functional viability of SV endothelium using multiphoton imaging, biochemical and immunofluorescence assays. METHODS: Nineteen patients scheduled for CABG were prospectively identified. Each underwent VsEVH for one portion and "No-touch" open SV harvesting (OSVH) for another portion of the SV. A two cm segment from each portion was immersed in GALA conduit preservation solution and transported overnight to our lab for processing. The segments were labeled with fluorescent markers to quantify cell viability, calcium mobilization and generation of nitric oxide. Morphology, expression, localization and stability of endothelial caveolin, eNOS, von Willebrand factor and cadherin were evaluated using immunofluorescence, Western blot and multiphoton microscopy (MPM). RESULTS: Morphological, biochemical and immunofluorescence parameters of viability, structure and function were well preserved in VsEVH group as in OSVH group. However, tonic eNOS activity, agonist-dependent calcium mobilization and nitric oxide production were partially attenuated in the VsEVH group. CONCLUSIONS: This study indicates that VirtuoSaph endoscopic SV harvesting technique preserves the structural and functional viability of SV endothelium, but may differentially attenuate the vasomotor function of the saphenous vein graft.