A Nodal Immersed Finite Element-Finite Difference Method.

The immersed finite element-finite difference (IFED) method is a computational approach to modeling interactions between a fluid and an immersed structure. The IFED method uses a finite element (FE) method to approximate the stresses, forces, and structural deformations on a structural mesh and a finite difference (FD) method to approximate the momentum and enforce incompressibility of the entire fluid-structure system on a Cartesian grid. The fundamental approach used by this method follows the immersed boundary framework for modeling fluid-structure interaction (FSI), in which a force spreading operator prolongs structural forces to a Cartesian grid, and a velocity interpolation operator restricts a velocity field defined on that grid back onto the structural mesh. With an FE structural mechanics framework, force spreading first requires that the force itself be projected onto the finite element space. Similarly, velocity interpolation requires projecting velocity data onto the FE basis functions. Consequently, evaluating either coupling operator requires solving a matrix equation at every time step. Mass lumping, in which the projection matrices are replaced by diagonal approximations, has the potential to accelerate this method considerably. This paper provides both numerical and computational analyses of the effects of this replacement for evaluating the force projection and for the IFED coupling operators. Constructing the coupling operators also requires determining the locations on the structure mesh where the forces and velocities are sampled. Here we show that sampling the forces and velocities at the nodes of the structural mesh is equivalent to using lumped mass matrices in the IFED coupling operators. A key theoretical result of our analysis is that if both of these approaches are used together, the IFED method permits the use of lumped mass matrices derived from nodal quadrature rules for any standard interpolatory element. This is different from standard FE methods, which require specialized treatments to accommodate mass lumping with higher-order shape functions. Our theoretical results are confirmed by numerical benchmarks, including standard solid mechanics tests and examination of a dynamic model of a bioprosthetic heart valve.

Patient-Specific Immersed Finite Element-Difference Model of Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve replacement (TAVR) first received FDA approval for high-risk surgical patients in 2011 and has been approved for low-risk surgical patients since 2019. It is now the most common type of aortic valve replacement, and its use continues to accelerate. Computer modeling and simulation (CM&S) is a tool to aid in TAVR device design, regulatory approval, and indication in patient-specific care. This study introduces a computational fluid-structure interaction (FSI) model of TAVR with Medtronic's CoreValve Evolut R device using the immersed finite element-difference (IFED) method. We perform dynamic simulations of crimping and deployment of the Evolut R, as well as device behavior across the cardiac cycle in a patient-specific aortic root anatomy reconstructed from computed tomography (CT) image data. These IFED simulations, which incorporate biomechanics models fit to experimental tensile test data, automatically capture the contact within the device and between the self-expanding stent and native anatomy. Further, we apply realistic driving and loading conditions based on clinical measurements of human ventricular and aortic pressures and flow rates to demonstrate that our Evolut R model supports a physiological diastolic pressure load and provides informative clinical performance predictions.

Rapidly developed heterotopic ossification: a rare complication after trauma.

Heterotopic ossification (HO) is a condition where aberrant bone grows in tissues. This case study presents a rare complication of trauma and laparotomies, where the rapid and extensive occurrence of HO has delayed abdominal incision closure resulting in multiple surgeries and prolonged recovery. A 44-year-old man was retrieved after a truck accident resulting in multi-organ injuries. He required damage control trauma laparotomy followed by several relooks and multiple orthopaedic procedures. Despite several attempts, approximation of the laparostomy wound was not possible due to abdominal rigidity. Computed tomography scans done 20 days after injury demonstrated advanced HO over the wound edge. Early development of HO may explain why the abdominal incision was difficult to close and highlights the importance of being aware of HO as an early complication after trauma and midline laparotomy.

On the Lagrangian-Eulerian Coupling in the Immersed Finite Element/Difference Method.

The immersed boundary (IB) method is a non-body conforming approach to fluid-structure interaction (FSI) that uses an Eulerian description of the momentum, viscosity, and incompressibility of a coupled fluid-structure system and a Lagrangian description of the deformations, stresses, and resultant forces of the immersed structure. Integral transforms with Dirac delta function kernels couple the Eulerian and Lagrangian variables, and in practice, discretizations of these integral transforms use regularized delta function kernels. Many different kernel functions have been proposed, but prior numerical work investigating the impact of the choice of kernel function on the accuracy of the methodology has often been limited to simplified test cases or Stokes flow conditions that may not reflect the method's performance in applications, particularly at intermediate-to-high Reynolds numbers, or under different loading conditions. This work systematically studies the effect of the choice of regularized delta function in several fluid-structure interaction benchmark tests using the immersed finite element/difference (IFED) method, which is an extension of the IB method that uses a finite element structural discretization combined with a Cartesian grid finite difference method for the incompressible Navier-Stokes equations. Whereas the conventional IB method spreads forces from the nodes of the structural mesh and interpolates velocities to those nodes, the IFED formulation evaluates the regularized delta function on a collection of interaction points that can be chosen to be denser than the nodes of the Lagrangian mesh. This opens the possibility of using structural discretizations with wide node spacings that would produce gaps in the Eulerian force in nodally coupled schemes (e.g., if the node spacing is comparable to or broader than the support of the regularized delta functions). Earlier work with this methodology suggested that such coarse structural meshes can yield improved accuracy for shear-dominated cases and, further, found that accuracy improves when the structural mesh spacing is increased. However, these results were limited to simple test cases that did not include substantial pressure loading on the structure. This study investigates the effect of varying the relative mesh widths of the Lagrangian and Eulerian discretizations in a broader range of tests. Our results indicate that kernels satisfying a commonly imposed even-odd condition require higher resolution to achieve similar accuracy as kernels that do not satisfy this condition. We also find that narrower kernels are more robust, in the sense that they yield results that are less sensitive to relative changes in the Eulerian and Lagrangian mesh spacings, and that structural meshes that are substantially coarser than the Cartesian grid can yield high accuracy for shear-dominated cases but not for cases with large normal forces. We verify our results in a large-scale FSI model of a bovine pericardial bioprosthetic heart valve in a pulse duplicator.

Incidence of spinal cord ischemia according to the patency of reimplanted segmental arteries during thoracoabdominal aortic replacement.

BACKGROUND: This study aimed to investigate the impact of segmental artery reimplantation and its patency on spinal cord ischemia (SCI) in thoracoabdominal aorta replacement. METHODS: For 193 patients who underwent early postoperative computed tomographic (CT) angiography after thoracoabdominal aorta replacement, the technique of segmental artery reimplantation, their patency, and postoperative SCI were retrospectively investigated. RESULTS: The early patency rate of reimplanted segmental artery was 83.3% (210 of 252), as 13 were taken down intraoperatively and 42 were not visualized in the postoperative CT angiography. The patency rate differed according to the reimplantation technique: 93.6% (131/140) for en bloc patch, 95.6% (43/45) for small individual patch, and 53.7% (36/67) for graft interposition. SCI occurred in 13 (6.3%) patients, 4 of whom (2.0%) remained paraplegic permanently. SCI was significantly more frequent (P=0.044) in the patients in whom segmental artery reimplantation was not successful (take-down or occlusion, 6/37=16.2%) than in those who had all segmental arteries sacrificed intentionally (2/64=3.1%) and those who showed patency of all reimplanted segmental arteries (5/92=5.4%). Especially, there was no permanent paraplegia in the last group. Failure of intended segmental artery reimplantation was a significant risk factor of postoperative SCI in logistic regression analysis (P=0.012; odds ratio 4.65, 95% confidence interval 1.41-15.36). CONCLUSIONS: During thoracoabdominal aorta replacement, attention should be paid to the segmental artery reimplantation technique, which affects the risk of occlusion or intraoperative take-down and thereby may have impact on postoperative SCI.

Intra-articular pressure characteristics of the knee joint: An exploratory study.

Inflammation-predominant osteoarthritis is an important clinical type of osteoarthritis, with synovitis suggested as its distinct pathophysiology. We investigated whether the synovium's mechanical properties in knees differed by osteoarthritis and other clinical parameters through retrospectively analyzing intra-articular pressure-volume characteristics. We analyzed 60 knees that were administered intra-articular corticosteroids while undergoing pressure monitoring. McMurray's test, pain complaints at end-range knee flexion, Kellgren-Lawrence classification from standing anteroposterior radiographs, and suprapatellar effusion from ultrasound constituted clinical parameters. Pressure-volume profiles-phasic changes in pressure by volume infusion, the volume of Phase 1-the potential volume of the synovial space, the pressure at 45 ml infusion-intra-articular pressure at a standardized volume, and the slope of Phase 2-synovial stiffness were compared with clinical parameters. All graphs were biphasic. Knees with suprapatellar effusion or radiologically definite osteoarthritis (Kellgren-Lawrence grade ≥2), had a lower Phase 1 volume. Knees with definite radiographic osteoarthritis also showed higher pressures at 45 ml and Phase 2 slopes (171.11 ± 94.35 mmHg and 5.08 ± 3.07 mmHg/ml, respectively) than those without (101.88 ± 58.12 mmHg and 2.84 ± 1.27 mmHg/ml, respectively). The Phase 2 slope was higher for knees with positive provocative tests than in those with negative provocative tests, although not statistically significant. The synovium stretched earlier in knees with effusion or radiologically definite osteoarthritis. Intra-articular pressure and synovial stiffness were significantly higher in patients with radiologically definite osteoarthritis. The synovium's mechanical characteristics are altered by osteoarthritis of the knee joint. Intra-articular pressure characteristics could be utilized for synovial evaluation clinically.

Bioprosthetic aortic valve diameter and thickness are directly related to leaflet fluttering: Results from a combined experimental and computational modeling study.

OBJECTIVE: Bioprosthetic heart valves (BHVs) are commonly used in surgical and percutaneous valve replacement. The durability of percutaneous valve replacement is unknown, but surgical valves have been shown to require reintervention after 10 to 15 years. Further, smaller-diameter surgical BHVs generally experience higher rates of prosthesis-patient mismatch, which leads to higher rates of failure. Bioprosthetic aortic valves can flutter in systole, and fluttering is associated with fatigue and failure in flexible structures. The determinants of flutter in BHVs have not been well characterized, despite their potential to influence durability. METHODS: We use an experimental pulse duplicator and a computational fluid-structure interaction model of this system to study the role of device geometry on BHV dynamics. The experimental system mimics physiological conditions, and the computational model enables precise control of leaflet biomechanics and flow conditions to isolate the effects of variations in BHV geometry on leaflet dynamics. RESULTS: Both experimental and computational models demonstrate that smaller-diameter BHVs yield markedly higher leaflet fluttering frequencies across a range of conditions. The computational model also predicts that fluttering frequency is directly related to leaflet thickness. A scaling model is introduced that rationalizes these findings. CONCLUSIONS: We systematically characterize the influence of BHV diameter and leaflet thickness on fluttering dynamics. Although this study does not determine how flutter influences device durability, increased flutter in smaller-diameter BHVs may explain how prosthesis-patient mismatch could induce BHV leaflet fatigue and failure. Ultimately, understanding the effects of device geometry on leaflet kinematics may lead to more durable valve replacements.

Comparing clinical outcomes between rotator cuff repairs, SLAP repairs, and combined repairs.

BACKGROUND: Superior labrum lesion from anterior to posterior (SLAP) often presents together with other shoulder pathologies such as rotator cuff tear (RCT), but it is uncertain if repairing both SLAP and RCT has superior clinical outcomes over isolated repairs of SLAP and RCT. MATERIALS AND METHODS: This was a retrospective cohort study with prospectively collected data, reviewing 157 patients who underwent arthroscopic repair of either RCT, SLAP (type II lesion), or both. Before surgery and after 6 weeks, 12 weeks, and 24 weeks, shoulder objective range of motion and strength were measured, patient-reported function and pain was assessed by the modified L'Insalata questionnaire with a Likert scale, and complications after each repair were examined. RESULTS: At 24 weeks after surgery, the combined group (n = 22) and SLAP group (n = 47) had significantly higher forward flexion (165° ± 4° and 167° ± 4° vs. 154° ± 3°, P = .01 and P = .01), external rotation strength (82 ± 6 N, 81 ± 6 N vs. 61 ± 3 N, P = .01 and P = .01), and abduction strength (94 ± 14 N, 78 ± 8 N vs. 53 ± 3 N, P = .001 and P = .02) compared with the rotator cuff tear repair (RCR) group (n = 88). The combined group also had stronger internal rotation than the RCR group (107 ± 12 N vs. 72 ± 4 N, P = .02). Function and pain improved from "severe-moderate" to "moderate-mild" in all groups after surgery. CONCLUSION: Repairing RCT and SLAP tears together results in significant clinical benefits compared to repairing just RCT and analogous results against SLAP-only repair.

Risk factors of posthepatectomy liver failure for perihilar cholangiocarcinoma: Risk score and significance of future liver remnant volume-to-body weight ratio.

BACKGROUND: Surgery for perihilar cholangiocarcinoma (PHCC) is associated with high morbidity. This study aimed to investigate the clinical value of the future liver remnant volume-to-body weight (FLRV/BW) and propose a risk score for predicting the risk of patients with PHCC developing posthepatectomy liver failure (PHLF). METHODS: This study included 348 patients who underwent major hepatectomy with bile duct resection for PHCC during 2008-2015 at a single center in Korea and they were retrospectively analyzed. RESULTS: Clinically relevant PHLF was noted in 40 patients (11.4%). The area under the curve (AUC) for FLRV/BW was not significantly different from that for FLRV/total liver volume (P = .803) or indocyanine green clearance of the future liver remnant (P = .629) in terms of predicting PHLF. On multivariate analysis, predictors of PHLF (P < .05) were male sex, albumin less than 3.5 g/dL, preoperative cholangitis, portal vein resection, FLRV/BW less than 0.5%, and FLRV/BW 0.5% to 0.75%. These variables were included in the risk score that showed good discrimination (AUC, 0.853; 95% CI, 0.802-0.904). It will help rank patients into three risk subgroups with a predicted liver failure incidence of 4.75%, 18.73%, and 51.58%, respectively. CONCLUSIONS: FLRV/BW is a comparable risk prediction factor of PHLF and the proposed risk score can help to predict the risk of planned surgery in PHCC.

Fluid-Structure Interaction Models of Bioprosthetic Heart Valve Dynamics in an Experimental Pulse Duplicator.

Computer modeling and simulation is a powerful tool for assessing the performance of medical devices such as bioprosthetic heart valves (BHVs) that promises to accelerate device design and regulation. This study describes work to develop dynamic computer models of BHVs in the aortic test section of an experimental pulse-duplicator platform that is used in academia, industry, and regulatory agencies to assess BHV performance. These computational models are based on a hyperelastic finite element extension of the immersed boundary method for fluid-structure interaction (FSI). We focus on porcine tissue and bovine pericardial BHVs, which are commonly used in surgical valve replacement. We compare our numerical simulations to experimental data from two similar pulse duplicators, including a commercial ViVitro system and a custom platform related to the ViVitro pulse duplicator. Excellent agreement is demonstrated between the computational and experimental results for bulk flow rates, pressures, valve open areas, and the timing of valve opening and closure in conditions commonly used to assess BHV performance. In addition, reasonable agreement is demonstrated for quantitative measures of leaflet kinematics under these same conditions. This work represents a step towards the experimental validation of this FSI modeling platform for evaluating BHVs.

Mesenchymal Stem Cell-Derived Extracellular Vesicles Decrease Lung Injury in Mice.

Human mesenchymal stem cell (MSC) extracellular vesicles (EV) can reduce the severity of bacterial pneumonia, but little is known about the mechanisms underlying their antimicrobial activity. In the current study, we found that bacterial clearance induced by MSC EV in Escherichia coli pneumonia in C57BL/6 mice was associated with high levels of leukotriene (LT) B4 in the injured alveolus. More importantly, the antimicrobial effect of MSC EV was abrogated by cotreatment with a LTB4 BLT1 antagonist. To determine the role of MSC EV on LT metabolism, we measured the effect of MSC EV on a known ATP-binding cassette transporter, multidrug resistance-associated protein 1 (MRP1), and found that MSC EV suppressed MRP1 mRNA, protein, and pump function in LPS-stimulated Raw264.7 cells in vitro. The synthesis of LTB4 and LTC4 from LTA4 are competitive, and MRP1 is the efflux pump for LTC4 Inhibition of MRP1 will increase LTB4 production. In addition, administration of a nonspecific MRP1 inhibitor (MK-571) reduced LTC4 and subsequently increased LTB4 levels in C57BL/6 mice with acute lung injury, increasing overall antimicrobial activity. We previously found that the biological effects of MSC EV were through the transfer of its content, such as mRNA, microRNA, and proteins, to target cells. In the current study, miR-145 knockdown abolished the effect of MSC EV on the inhibition of MRP1 in vitro and the antimicrobial effect in vivo. In summary, MSC EV suppressed MRP1 activity through transfer of miR-145, thereby resulting in enhanced LTB4 production and antimicrobial activity through LTB4/BLT1 signaling.

Cytotoxicity and biomechanics of suture anchors used in labral repairs.

BACKGROUND: Biodegradable suture anchors are associated with higher redislocation rates. This study examined whether the biocompatibility and/or biomechanical properties of suture anchors contribute to the increase in complications. METHODS: Human glenohumeral capsule cells were cultured with 4 types of suture anchors, Opus LabraFix (titanium alloy; ArthroCare, Austin, TX, USA), PushLock (poly-ether-ether-ketone; Arthrex, Naples, FL, USA), BioKnotless (poly-l-lactic acid; DePuy Mitek, Warsaw, IN, USA), and Suretac II (polyglycolic acid; Smith & Nephew, London, UK), to measure cell viability and pH. Four groups of 6 ovine shoulders were used to repair the labrum, which was completely detached from the glenoid rim anteroinferiorly and reattached with 2 suture anchors and subject to failure load testing. RESULTS: In cell culture, BioKnotless at 48 and 72 hours (85.2% ± 2.1% and 84.5% ± 3.6%) and Suretac II groups (33.9% ± 3.1% and 42.8% ± 6.4%) had fewer viable cells compared with control (P = .048). The pH of Suretac II was lower than control (7.51 to 7.65) at 24 hours (7.31 ± 0.08, P = .049), 48 hours (7.25 ± 0.02, P = .046), and 72 hours (7.29 ± 0.04, P = .04). During mechanical testing, 83% of repairs failed by the capsule tearing. Among the anchors, the BioKnotless repair group had a significantly lower failure load (37 ± 5 N) compared with the PushLock (61 ± 7 N), Opus (60 ± 6 N), and Suretac II (57 ± 7 N) groups (P = .038). CONCLUSION: BioKnotless and Suretac II anchors are cytotoxic. The BioKnotless biodegradable anchor has significantly lower failure load. Absorbable suture anchors may cause higher redislocation of arthroscopic Bankart repair.

Comparison of the laryngeal mask airway supreme and the i-gel in paralysed elderly patients: A randomised controlled trial.

BACKGROUND: The laryngeal mask airway supreme (LMA-S) and i-gel are both popular second-generation supraglottic airway devices that have been widely studied in surgical patients, but their differences in clinical performance in the elderly are not clear. OBJECTIVE: We compared the efficacy and safety of the LMA-S and i-gel in anaesthetised and paralysed elderly patients. DESIGN: A randomised study. SETTING: Single-centre trial, study period January 2014 from to October 2016. PATIENTS: One hundred and six elderly patients who underwent urological or orthopaedic surgery with an expected duration less than 2 h. INTERVENTION: Patients were allocated to either the LMA-S (n = 53) or i-gel (n = 53) group. All insertions were performed in a standardised manner according to the manufacturers' instructions. MAIN OUTCOME MEASURES: Our primary endpoint was the rate of successful insertion at the first attempt. The adequacy of positive pressure ventilation and airway sealing, fibreoptic laryngoscopy grades and stability of airway maintenance during anaesthesia were also assessed. RESULTS: Although the rate of successful insertion at the first attempt was similar between the two groups (94.3 vs. 82.7%, P = 0.072), more patients required device manipulation during insertion with the LMA-S than the i-gel (42.3 vs. 18.9%, P = 0.011). Good fibreoptic laryngoscopy grades were significantly more common with the i-gel than the LMA-S (79.3 vs. 55.8%, P = 0.042), and peak inspiratory pressures were lower in the i-gel group both immediately after insertion and at the end of surgery. Leak pressures were significantly higher in the i-gel group than the LMA-S group, both immediately after insertion and at the end of surgery (25.8 vs. 23.0, P = 0.036; and 28.1 vs. 23.7, P < 0.001, respectively). CONCLUSION: Both the LMA-S and i-gel were used successfully and safely in elderly patients. However, the i-gel demonstrated better airway sealing than the LMA-S at insertion and during maintenance of anaesthesia. TRIAL REGISTRATION: NCT02026791 at clinicaltrial.gov.

Comparison of in vivo and ex vivo viscoelastic behavior of the spinal cord.

Despite efforts to simulate the in vivo environment, post-mortem degradation and lack of blood perfusion complicate the use of ex vivo derived material models in computational studies of spinal cord injury. In order to quantify the mechanical changes that manifest ex vivo, the viscoelastic behavior of in vivo and ex vivo porcine spinal cord samples were compared. Stress-relaxation data from each condition were fit to a non-linear viscoelastic model using a novel characterization technique called the direct fit method. To validate the presented material models, the parameters obtained for each condition were used to predict the respective dynamic cyclic response. Both ex vivo and in vivo samples displayed non-linear viscoelastic behavior with a significant increase in relaxation with applied strain. However, at all three strain magnitudes compared, ex vivo samples experienced a higher stress and greater relaxation than in vivo samples. Significant differences between model parameters also showed distinct relaxation behaviors, especially in non-linear relaxation modulus components associated with the short-term response (0.1-1 s). The results of this study underscore the necessity of utilizing material models developed from in vivo experimental data for studies of spinal cord injury, where the time-dependent properties are critical. The ability of each material model to accurately predict the dynamic cyclic response validates the presented methodology and supports the use of the in vivo model in future high-resolution finite element modeling efforts. STATEMENT OF SIGNIFICANCE: Neural tissues (such as the brain and spinal cord) display time-dependent, or viscoelastic, mechanical behavior making it difficult to model how they respond to various loading conditions, including injury. Methods that aim to characterize the behavior of the spinal cord almost exclusively use ex vivo cadaveric or animal samples, despite evidence that time after death affects the behavior compared to that in a living animal (in vivo response). Therefore, this study directly compared the mechanical response of ex vivo and in vivo samples to quantify these differences for the first time. This will allow researchers to draw more accurate conclusions about spinal cord injuries based on ex vivo data (which are easier to obtain) and emphasizes the importance of future in vivo experimental animal work.

Tyrosine-610 in the Receptor Kinase BAK1 Does Not Play a Major Role in Brassinosteroid Signaling or Innate Immunity.

The plasma membrane-localized BRI1-ASSOCIATED KINASE1 (BAK1) functions as a co-receptor with several receptor kinases including the brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1), which is involved in growth, and the receptors for bacterial flagellin and EF-Tu, FLAGELLIN-SENSING 2 (FLS2) and EF-TU RECEPTOR (EFR), respectively, which are involved in immunity. BAK1 is a dual specificity protein kinase that can autophosphorylate on serine, threonine and tyrosine residues. It was previously reported that phosphorylation of Tyr-610 in the carboxy-terminal domain of BAK1 is required for its function in BR signaling and immunity. However, the functional role of Tyr-610 in vivo has recently come under scrutiny. Therefore, we have generated new BAK1 (Y610F) transgenic plants for functional studies. We first produced transgenic Arabidopsis lines expressing BAK1 (Y610F)-Flag in the homozygous bak1-4 bkk1-1 double null background. In a complementary approach, we expressed untagged BAK1 and BAK1 (Y610F) in the bak1-4 null mutant. Neither BAK1 (Y610F) transgenic line had any obvious growth phenotype when compared to wild-type BAK1 expressed in the same background. In addition, the BAK1 (Y610F)-Flag plants responded similarly to plants expressing BAK1-Flag in terms of brassinolide (BL) inhibition of root elongation, and there were only minor changes in gene expression between the two transgenic lines as monitored by microarray analysis and quantitative real-time PCR. In terms of plant immunity, there were no significant differences between plants expressing BAK1 (Y610F)-Flag and BAK1-Flag in the growth of the non-pathogenic hrpA- mutant of Pseudomonas syringae pv. tomato DC3000. Furthermore, untagged BAK1 (Y610F) transgenic plants were as responsive as plants expressing BAK1 (in the bak1-4 background) and wild-type Col-0 plants toward treatment with the EF-Tu- and flagellin-derived peptide epitopes elf18- and flg22, respectively, as measured by reactive oxygen species production, mitogen-activated protein kinase activation, and seedling growth inhibition. These new results do not support any involvement of Tyr-610 phosphorylation in either BR or immune signaling.

Changes in Pressure, Hemodynamics, and Metabolism within the Spinal Cord during the First 7 Days after Injury Using a Porcine Model.

Traumatic spinal cord injury (SCI) triggers many perturbations within the injured cord, such as decreased perfusion, reduced tissue oxygenation, increased hydrostatic pressure, and disrupted bioenergetics. While much attention is directed to neuroprotective interventions that might alleviate these early pathophysiologic responses to traumatic injury, the temporo-spatial characteristics of these responses within the injured cord are not well documented. In this study, we utilized our Yucatan mini-pig model of traumatic SCI to characterize intraparenchymal hemodynamic and metabolic changes within the spinal cord for 1 week post-injury. Animals were subjected to a contusion/compression SCI at T10. Prior to injury, probes for microdialysis and the measurement of spinal cord blood flow (SCBF), oxygenation (in partial pressure of oxygen; PaPO2), and hydrostatic pressure were inserted into the spinal cord 0.2 and 2.2 cm from the injury site. Measurements occurred under anesthesia for 4 h post-injury, after which the animals were recovered and measurements continued for 7 days. Close to the lesion (0.2 cm), SCBF levels decreased immediately after SCI, followed by an increase in the subsequent days. Similarly, PaPO2 plummeted, where levels remained diminished for up to 7 days post-injury. Lactate/pyruvate (L/P) ratio increased within minutes. Further away from the injury site (2.2 cm), L/P ratio also gradually increased. Hydrostatic pressure remained consistently elevated for days and negatively correlated with changes in SCBF. An imbalance between SCBF and tissue metabolism also was observed, resulting in metabolic stress and insufficient oxygen levels. Taken together, traumatic SCI resulted in an expanding area of ischemia/hypoxia, with ongoing physiological perturbations sustained out to 7 days post-injury. This suggests that our clinical practice of hemodynamically supporting patients out to 7 days post-injury may fail to address persistent ischemia within the injured cord. A detailed understanding of these pathophysiological mechanisms after SCI is essential to promote best practices for acute SCI patients.

Continuous treatment with lenalidomide and low-dose dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma in Asia: subanalysis of the FIRST trial.

The phase 3 FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) trial demonstrated that lenalidomide plus low-dose dexamethasone (Rd) until disease progression (Rd continuous) is an effective treatment option for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Given genetic differences between Asian and Western populations, this subanalysis of the FIRST trial examined the safety and efficacy of Rd (given continuously or for 18 cycles [Rd18]) and MPT (melphalan, prednisone, thalidomide) in 114 Asian patients from Mainland China, South Korea and Taiwan. Efficacy and safety with Rd continuous in Asian patients were consistent with those in the overall study population. The overall response rates were 77·8% for Rd continuous, 57·5% for MPT and 65·8% for Rd18. The risk of progression or death was reduced by 39% with Rd continuous versus MPT and by 35% with Rd continuous versus Rd18. Rd continuous improved the 3-year survival rate compared with MPT (70·2% vs. 56·4%) and Rd18 (58·1%). Common grade 3/4 adverse events in the Rd continuous and MPT arms were neutropenia (25·0% vs. 43·6%), infection (19·4% vs. 28·2%) and anaemia (19·4% vs. 15·4%), respectively. Thromboembolic event rates were low, and no second primary malignancies were observed. Rd continuous is safe and effective in transplant-ineligible Asian patients with NDMM.

ß-Mannanase Derived from Bacillus Subtilis WL-7 Improves the Performance of Commercial Laying Hens Fed Low or High Mannan-Based Diets.

A trial was conducted to investigate the effects of dietary mannan level and ß-mannanase supplementation on egg production performance, nutrient retention and blood metabolites of laying hens. Two hundred and forty Hy-Line Brown layers (52 wk-old) were randomly allotted to 6 treatments on the basis of laying performance. Each treatment had 8 replicates with 5 birds (40 birds per treatment). Laying hens were fed low or high mannan diets containing 0, 0.4 or 0.8 g ß-mannanase/kg diet in a 2×3 factorial arrangement during 56 d feeding period. Laying hens fed diets supplemented with high ß-mannanase level had greater (P<0.05) overall egg production, egg weight, egg mass, retention of gross energy, crude protein and mannan than hens fed the diets without ß-mannanase. Laying hens fed diets without ß-mannanase or supplemented with high ß-mannanase level had greater (P<0.05) retention of dry matter than hens fed diets with low ß-mannanase level. Moreover, laying hens fed high mannan diets had higher (P<0.05) feed intake and feed conversion ratio than that of hens fed low mannan diets. Furthermore, laying hens fed diets supplemented with a high level of ß-mannanase had increased serum glucose (P<0.05) concentrations but these diets had no effect on total cholesterol, total protein or blood urea nitrogen. The results obtained in the present study indicate that a high mannan content in diets had adverse effect on the performance of laying hens and that dietary supplementation with ß-mannanase has the potential to improve laying hen performance and nutrient retention.

Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. METHODS: PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308. FINDINGS: Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50). INTERPRETATION: The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this. FUNDING: Novartis Pharmaceuticals.