Longitudinal-Torsional Frequency Coupling Design of Novel Ultrasonic Horns for Giant Magnetostrictive Transducers.

The use of advanced brittle composites in engineering systems has necessitated robotic rotary ultrasonic machining to attain high precision with minimal machining defects such as delamination, burrs, and cracks. Longitudinal-torsional coupled (LTC) vibrations are created by introducing helical slots to a horn's profile to enhance the quality of ultrasonic machining. In this investigative research, modified ultrasonic horns were designed for a giant magnetostrictive transducer by generating helical slots in catenoidal and cubic polynomial profiles to attain a high amplitude ratio (TA/LA) and low stress concentrations. Novel ultrasonic horns with a giant magnetostrictive transducer were modelled to compute impedances and harmonic excitation responses. A structural dynamic analysis was conducted to investigate the effect of the location, width, depth and angle of helical slots on the Eigenfrequencies, torsional vibration amplitude, longitudinal vibration amplitude, stresses and amplitude ratio in novel LTC ultrasonic horns for different materials using the finite element method (FEM) based on the block Lanczos and full-solution methods. The newly designed horns achieved a higher amplitude ratio and lower stresses in comparison to the Bezier and industrial stepped LTC horns with the same length, end diameters and operating conditions. The novel cubic polynomial LTC ultrasonic horn was found superior to its catenoidal counterpart as a result of an 8.45% higher amplitude ratio. However, the catenoidal LTC ultrasonic horn exhibited 1.87% lower stress levels. The position of the helical slots was found to have the most significant influence on the vibration characteristics of LTC ultrasonic horns followed by the width, depth and angle. This high amplitude ratio will contribute to the improved vibration characteristics that will help realize good surface morphology when machining advanced materials.

Mixed [Formula: see text]-synthesis tracking control and disturbance rejection in a robotic digit of an impaired human hand for anthropomorphic coordination.

In a partially impaired anthropomorphic hand, maintaining the movement coordination of the robotic digits with the central nervous system (CNS) and natural digits is crucial for robust performance. A challenge in the control perspective of movement coordination of a human hand is finding methods robust to the disturbances in a well-posed control problem of a biomechanical model. We use visco-elastic dynamics in the human palm frame of reference to explore the biomechanics of movement coordination to solve this control problem. Our biomechanical model incorporates the time delay due to actuation force, parametric uncertainty, exogenous disturbances, and sensory noise to constitute a 21-degree of freedom model. A mixed [Formula: see text]-synthesis controller, considering the real parametric uncertainty, represents the CNS in the control paradigm. We consider the robotic finger's flexion movement when perturbed from the initial equilibrium. The controller provides feedback force at the joints to regulate the robotic finger movement. The index finger follows a reference trajectory of the joint angular position profile and stabilizes at a flexion angle of 1 rad/s at a time of 1 s. The main control objective is to keep the angular displacement of the finger joint constant when a disturbance force acts. We simulate the modeling scheme in MATLAB/ Simulink. The results demonstrate that our controller scheme is robust against the worst-case disturbance and achieves the desired performance value. Developing a biologically inspired neurophysiological controller with robust performance has many applications, including assistive rehabilitation devices, hand movement disorder diagnosis, and robotic manipulators.

Dual Antiplatelet Therapy Does Not Increase Bleeding Risk in Percutaneous Gastrostomy Tube Placement: Network Meta-Analysis.

BACKGROUND/OBJECTIVE: Gastrostomy tube (G tube) is a commonly performed procedure for nutritional support. Current guidelines recommend discontinuation of dual antiplatelet therapy (DAPT) prior to G tube placement to reduce bleeding risk. AIMS: We aim to compare bleeding risk in single, dual and no antiplatelet therapy during G tube placement. METHODS: We searched PubMed, Embase, Cochrane, and Web of Sciences to include comparative studies evaluating single antiplatelet (aspirin, clopidogrel), dual antiplatelet (DAPT, aspirin and clopidogrel), and no antiplatelet therapy. Direct as well as network meta-analyses comparing these arms were performed. Risk Differences (RD) with confidence intervals were calculated. RESULTS: 12 studies with 8471 patients were included. On direct meta-analysis, there was no significant difference noted between DAPT compared to Aspirin (RD 0.001 95% CI - 0.012 to 0.014, p = 0.87), Clopidogrel (RD 0.001 95% CI - 0.009 to 0.010, p = 0.92) or no antiplatelet group (RD 0.007 95% CI - 0.011 to 0.026, p = 0.44). Results were consistent on network meta-analysis and no difference was noted in bleeding rates when comparing DAPT with Aspirin (RD 0.001, 95% CI - 0.007 to 0.01, p = 0.76), Clopidogrel (RD 0.001, 95% CI - 0.01 to 0.011, p = 0.90) and no antiplatelet group (RD 0.002, 95% CI - 0.007 to 0.012, p = 0.62). CONCLUSION: There is no significant difference in bleeding risk between DAPT, single antiplatelet or no antiplatelet therapy on a population level. On an individual level, risk of ischemic events should be weighed against the risk of bleeding based on patient circumstances and risk profile. Our findings offer to provide additional data to make an informed decision between patients and physicians to make clinical decisions by assessing individual risks and benefits for optimal care of complex patients.

Nonlinear postural control paradigm for larger perturbations in the presence of neural delays.

Maintaining balance is an essential skill regulated by the central nervous system (CNS) that helps humans to function effectively. Developing a physiologically motivated computational model of a neural controller with good performance is a central component for a large range of potential applications, such as the development of therapeutic and assistive devices, diagnosis of balance disorders, and designing robotic control systems. In this paper, we characterize the biomechanics of postural control system by considering the musculoskeletal dynamics in the sagittal plane, proprioceptive feedback, and a neural controller. The model includes several physiological structures, such as the feedforward and feedback mechanism, sensory noise, and proprioceptive feedback delays. A high-gain observer (HGO)-based feedback linearization controller represents the CNS analog in the modeling paradigm. The HGO gives an estimation of delayed states and the feedback linearization control law generates the feedback torques at joints to execute postural recovery movements. The whole scheme is simulated in MATLAB/Simulink. The simulation results show that our proposed scheme is robust against larger perturbations, sensory noises, feedback delays and retains a strong disturbance rejection and trajectory tracking capability. Overall, these results demonstrate that the nonlinear system dynamics, the feedforward and feedback mechanism, and physiological latencies play a key role in shaping the motor control process.

Status of oxidant, antioxidantand serum enzymes in thalassaemic children receiving multiple blood transfusions.

OBJECTIVE: To determine the levels of oxidant, antioxidant and serum enzymes in thalassaemic children receiving multiple blood transfusions. METHODS: The case-control study was done from February to August 2012, and comprised thalassaemic children receiving multiple blood transfusions at Allied Hospital, Ali Zeb Foundation, and the Thalassaemia Centre in Hilal-e-Ahmar Hospital, Faisalabad, Pakistan. Healthy subjects were also screened for any related disease condition that could prejudice the results. Blood samples were analysed for the values of total oxidant status, total antioxidant capacity, serum malondialdehyde, catalase, paraoxonase, arylesterase, glutathione peroxidase and ceruloplasmin. RESULTS: There were 180 children in the study; 90(50%) cases and 90(50%) controls. Of the cases, 48(53.3%) were under-weight while the weight of 42(46.7%) was in the normal range. The values of total oxidant status and total antioxidant capacity were significantly (p<0.01) higher in thalassaemic children compared to normal values. Serum malondialdehyde and catalase levels were also considerably elevated (p<0.05), suggesting the increased activity of these enzymes. However, the concentrations of serum paraoxonase, arylesterase, glutathione peroxidase were significantly (p<0.01) lower in cases than the controls, displaying diminished activities during multiple blood transfusions in these patients. CONCLUSIONS: Multiple blood transfusions disconcert the levels of oxidants, antioxidants and serum enzymes of thalassaemic children. Oxidative damage is seen because of the increased iron overload in these patients. Hence, regular evaluation of oxidant and antioxidant status should be monitored in thalassaemic patients during initial few years of life.

Decoupled optimal control of 3D biped for human voluntary motion.

The sit-to-stand (STS) model from a biomechanical point of view is an enormously important subject, with motor controls simulating human intended behavior. Physiological motion-based biomechanical research is important for designing whole-body prosthetics and understanding physical disabilities. The control strategies for biomechanical models can effectively synergize with the central nervous system (CNS) to facilitate the desired movements of individuals with neurological disabilities. In this study, we present our novel 3D biped model by decoupling it into healthy and neurologically deficient joints. The developed 8-segment model (i.e., 2× feet, 2× shanks, 2× thighs, 1× pelvic, and 1× Head Arm Torso (HAT) segment) with 10 joints is decoupled into 6 healthy joints and 4 deficient joints. This decoupling mimics stroke patients or subjects with neuromuscular deficiency. This novel decoupling establishes through asymmetrical torques in frontal and sagittal plane joints on a bipedal design with one foot fixed and the other a sliding tilt joint. In this design, two decoupled controllers collaborate to stabilize the nonlinear model for biped STS transfer. Utilizing the xml files from SOLIDWORKS, the model is linearized in SIMSCAPE / SIMULINK. We further imply the Linear Quadratic Regulator (LQR) optimal controller design in MATLAB / SIMULINK for torques in both the sagittal and frontal planes, respectively, for six healthy and four deficient joints. We also comprehend the forward thrust velocity controls to pragmatically model the STS of stroke patients. This decoupling enhanced the overall stability of the system and simulated more relevant angular and velocity profiles for neurologically deficient substances.

Investigation of hybrid ultrasonic machining process of Nomex honeycomb composite using a toothed disc cutter.

Nomex honeycomb composite (NHC) has been increasingly used in the automotive, aerospace and defence applications due to its excellent thermal and mechanical properties. Its complex cellular hexagonal thin-walled configuration along with heterogeneous, soft and brittle nature pose substantial processing defects such as burr formation, tearing of walls, surface roughness, dimensional inaccuracy and low machining quality during conventional machining (CM). These surface defects have a substantial influence on the operating life and functional performance of its sandwiched structural members. Hybrid ultrasonic vibration assisted machining (HUSVAM) technology has been introduced to overcome such limitations. For an in depth research on HUSVAM of NHC using ultrasonic toothed disc cutter (UTDC), three dimensional finite element model was developed and experimental validation was carried out. The numerical simulation and experimental results were found to be in good agreement with one another. The influence of various machining parameters including the ultrasonic tool vibration amplitude (UTVA), feed rate (FR), depth of cut (DoC) and spindle angular speed (SAS) on NHC cutting forces, chip formation and surface quality was investigated using both HUSVAM and CM techniques. Furthermore, stresses, deformation and forces near tool-workpiece interaction along with the surface topography and morphologies were also analysed and compared for various operating conditions. A reduction in the cutting forces was found with the increase of SAS and UTVA (up to 65.47 % and 65.74 %, respectively). Although, the cutting forces were observed to increase by increasing the DoC and FR (up to 159.45 % and 126.33 %, respectively). DoC has a greater impact on the cutting forces among all machining parameters according to 4 levels, 4 factors (L16) orthogonal experiments based on Taguchi method. The results show that the chip formation and machining quality of NHC core can be improved with HUSVAM technique using UTDC. HUSVAM also reduced the cutting forces (up to 73 %) compared to CM. The ultrasonic toothed disc cutter generated large number of burr with very short length, no tearing defects and no uncut fibers as observed from scanning electron microscopy of NHC hexagonal cell structure, walls and triple points. A burr formation of less than 10 % was realized during HUSVAM of NHC cores for Fx≤3N, while it was found up to 20 % if Fx>3N, compared to at least 40 % during CM. The finite element model developed can be used to investigate the influence of HUSVAM on modern difficult to machine materials for enhanced surface quality.

Double flap patch closure of VSD with elevated pulmonary vascular resistance: an experience at AFIC/NIHD.

OBJECTIVE: To determine the 30 days outcome measured in terms of morbidity and mortality in cases of ventricular septal defect (VSD) with increased pulmonary vascular resistance (PVR) managed with double flap patch closure. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Armed Forces Institute of Cardiology (AFIC/NIHD), Rawalpindi, from December 2005 to December 2008. METHODOLOGY: Forty patients with VSD having PVR 9.58 + 4.33 wood units underwent double flap patch closure. The patch was fenestrated as one half of the expected aortic annulus diameter. A separate flap patch 5 mm larger than fenestration was attached to superior upper one third margins of fenestration. The patch was placed with flap to open towards the left ventricular apex. Modified ultra filtration (MUF) was employed in every case and sildenafil was given postoperatively. RESULTS: The age of patients ranged from 1 to 28 years with a mean of 6.66 + 5.70 years. There were 22 males and 18 females. All patients were weaned off from inotropic and ventilatory support as earlier as possible postoperatively with intensive care unit (ICU) stay of 77.15 + 54.56 hours. Postoperative pulmonary artery pressures were reduced to 42.63 + 10.86 mmHg as compared to pre-operative pulmonary artery pressures of 88.3 + 15.2 mmHg. Postoperatively 11 patients with suprasystemic pulmonary artery pressures and desaturation went into pulmonary hypertensive crisis in which immediate 2D echo evidenced the functioning flap valve with right to left shunt. There was only one death (early) out of 40 patients with an overall mortality of 2.5% along with limited morbidity. CONCLUSION: Double flap patch is an inexpensive, easy to construct technique with low morbidity and mortality in cases of VSD with raised PVR.

High-gain observer-based nonlinear control scheme for biomechanical sit to stand movement in the presence of sensory feedback delays.

Sit-to-stand movement (STS) is a mundane activity, controlled by the central-nervous-system (CNS) via a complex neurophysiological mechanism that involves coordination of limbs for successful execution. Detailed analysis and accurate simulations of STS task have significant importance in clinical intervention, rehabilitation process, and better design for assistive devices. The CNS controls STS motion by taking inputs from proprioceptors. These input signals suffer delay in transmission to CNS making movement control and coordination more complex which may lead to larger body exertion or instability. This paper deals with the problem of STS movement execution in the presence of proprioceptive feedback delays in joint position and velocity. We present a high-gain observer (HGO) based feedback linearization control technique to mimic the CNS in controlling the STS transfer. The HGO estimates immeasurable delayed states to generate input signals for feedback. The feedback linearization output control law generates the passive torques at joints to execute the STS movement. The H2 dynamic controller calculates the optimal linear gains by using physiological variables. The whole scheme is simulated in MATLAB/Simulink. The simulations illustrate physiologically improved results. The ankle, knee, and hip joint position profiles show a high correlation of 0.91, 0.97, 0.80 with the experimentally generated reference profiles. The faster observer dynamics and global boundness of controller result in compensation of delays. The low error and high correlation of simulation results demonstrate (1) the reliability and effectiveness of the proposed scheme for customization of human models and (2) highlight the fact that for detailed analysis and accurate simulations of STS movement the modeling scheme must consider nonlinearities of the system.

Current Status of Pyrethroids Resistance in Aedes aegypti (Culicidae: Diptera) in Lahore District, Pakistan: A Novel Mechanistic Insight.

Aedes aegypti (Linnaeus, 1762) is a major vector responsible for dengue transmission. Insecticides are being used as the most effective tool to control vector populations in Lahore, Pakistan. Control of Ae. aegypti is threatened by the development of resistance against insecticides. The current status of insecticide resistance was evaluated against pyrethroids (deltamethrin, cypermethrin, and lambda-cyhalothrin) in different populations of Lahore (Model Town, Mishri Shah, Sadar Cantt, Walton, and Valencia). The susceptibility of the larval and adult populations was tested following the standard WHO guidelines. Moderate to high levels of resistance were found against pyrethroids in the larval (RR50: 3.6-27.2 and RR90: 5-90) and adult populations (percentage mortality < 98%). Biochemical assays revealed a statistically significant increase in the enzyme level in all field populations compared to the laboratory strain. The value of esterase was one-fold higher, monooxygenase was 3.9- to 4.7-fold higher, and glutathione S-transferases was 1.9- to 2.6-fold higher in field populations compared to the laboratory strain. These results depict the presence of resistance against deltamethrin, cypermethrin, and lambda-cyhalothrin in field populations of Lahore mediated by metabolic enzymes i.e. esterases, monooxygenases, and glutathione S-transferase.

In-vitro and In-vivo management of Meloidogyne incognita (Kofoid and White) Chitwood and Rhizoctonia bataticola (Taub.) Butler in cotton using organic's.

Root-knot nematodes Meloidogyne incognita (Kofoid and White) Chitwood and Rhizoctonia bataticola (Taub.) Butler, fungus, are very dangerous root damaging pathogens. Present study was planned to establish a chemical control of these root deteriorating pathogens under lab conditions as well as in field. Maximum death rate of nematode juveniles and minimum numbers of nematode eggs hatched were recorded in plates treated with Cadusafos (Rugby® 100G) @12 g/100 ml and Cartap® (4% G) @9g/100 ml. Chemical treatment of Rhizoctonia bataticola with Trifloxystrobin + Tebuconazole (Nativo®) @0.2 g/100 ml and Mancozeb + Matalaxyl (Axiom) @0.25 g/100 ml significantly controlled the mycelial growth in plates. The best treatments tested in laboratory were applied in field as protective and curative treatments. Results proved that chemical control of root-knot nematode and root rot fungi by tested chemicals at recommended time and dose is a significant management technique under field conditions.

Skeletonization of Left Internal Mammary Artery in Coronary Artery Bypass Grafting.

OBJECTIVE: To compare mean per-operative flow capacity between skeletonized and pedicled left internal mammary artery (LIMA) in patients undergoing coronary artery bypass grafting (CABG) surgery. STUDY DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: Department of Cardiac Surgery, Armed Forces Institute of Cardiology and National Institute of Heart Diseases (AFIC-NIHD), Rawalpindi, Pakistan from February to August, 2013. METHODOLOGY: Patients undergoing CABG for coronary artery disease, under 80 years, excluded by the exclusion criteria; and fulfilling the inclusion criteria were randomly assigned to two groups of 70 each. One group underwent skeletonized and the other underwent pedicled technique of LIMAharvesting. Free flow was checked just before anastamosis of each LIMAto the LAD, manually in blood flow in ml per minute during cardiopulmonary bypass by allowing it to bleed into a 100 ml container over 20 seconds. Aspecialized proforma was used to record the age, gender, weight, disease, type of IMA used, and free flow of the IMA. Data was analyzed using SPSS 18. RESULTS: The mean age of the patients was 57.16 years in 40 patients, ranging from 36 to 75 years. Disease pattern analysis showed 5%, 10.7% and 84.3% single, double and triple vessel coronary artery disease, respectively. There was significantly higher free flow in the skeletonized group than the pedicled group (p=0.04). CONCLUSION: Skeletonized IMAhad superior flow to pedicled IMAin addition to its traditional proven advantages, which justifies its further use as a conduit for myocardial revascularization.

The Female Sexual Function Index (FSFI): Translation, Validation, and Cross-Cultural Adaptation of an Urdu Version "FSFI-U".

INTRODUCTION: Female sexual dysfunction (FSD) is a common problem, and many self-report questionnaires are available for its evaluation. Pakistani women with sexual problems feel shy to consult with their physician. A validated self-report questionnaire, in the local language with modest expressions is required for these women. AIM: The aim of this study was to translate, cross-culturally adapt, and perform a psychometric validation of an Urdu translation of the Female Sexual Function Index (FSFI). METHODS: The FSFI was translated in Urdu, and its precision was ascertained through reverse translation. It was pretested on 22 bilingual women and refined again to reach at a reliable Urdu version of the questionnaire FSFI-U. One hundred sixteen bilingual women, in a stable sexual relationship over the previous 6 months were finally asked to fill out the FSFI and FSFI-U. Their sexual function was then clinically evaluated and responses were compared with the clinical assessment as well as with each other. MAIN OUTCOME MEASURES: The responses were analyzed through descriptive statistics for reliability, face validity, agreement between the responses to the original English version and to the FSFI-U, and also for test-retest consistency. The data were analyzed statistically using Cronbach's alpha analysis, Intraclass correlation coefficients, Pearson correlation, and Student's t-test. RESULTS: FSFI was found to be easily understandable and capable of adequately evaluating and measuring various aspects of female sexual function. A high degree of internal consistency was demonstrated on Cronbach's alpha analysis. Cronbach's α coefficient for various domains was sufficiently high ranging from 0.84 to 0.97. The clinical assessment of the presence and severity of FSD also matched with the self-report questionnaire. Similarly, various domains of FSFI had high degree of correlation in the Urdu version of FSFI (P < 0.001). CONCLUSION: The Urdu translation version of FSFI is valid and reliable for use in the literate population of Pakistan. Rehman KU, Asif Mahmood M, Sheikh SS, Sultan T, Khan MA. The Female Sexual Function Index (FSFI): Translation, Validation, and Cross-Cultural Adaptation of an Urdu Version "FSFI-U". Sex Med 2015;3:244-250.

Left ventricular surgical remodelling: is it a matter of shape or volume?.

OBJECTIVE: Left ventricular surgical remodelling (LVSR) can be targeted to volume reduction (VR), (independently of the final shape) or to conical shape (CS). The aim of this study was to evaluate the long-term clinical and echocardiographic results of these two surgical strategies. METHODS: From January 1988 to December 2012, 401 patients underwent LVSR: 107 in Group VR (1988-2001) and 294 in Group CS (1998-2012). The latter group of patients had lower ejection fraction (EF) and higher mitral and tricuspid regurgitation grade, with higher incidence of pulmonary hypertension. A propensity score model was built to adjust long-term results for preoperative and operative profiles. RESULTS: Thirty-day mortality was 6.0%. Median follow-up interval time was 100 (3-300) months. Overall 20-year and event-free survival were 36.1 ± 7.8 and 19.4 ± 7.2, respectively. No differences were found regarding 10-year survival (Group VR: 55.1 ± 4.8 vs Group CS: 64.2 ± 4.2, P = 0.16) and event-free survival (Group VR: 41.1 ± 4.8 vs Group CS: 50.5 ± 4.8, P = 0.12). However, Group CS provided better 10-year freedom from cardiac deaths (74.5 ± 3.7 vs 60.4 ± 4.8, P = 0.03) and from cardiac events (55.6 ± 5.0 vs 45.0 ± 4.9, P = 0.04). After propensity score adjustment, all the main outcomes were significantly better in Group CS. Multivariate Cox analysis confirmed this result; furthermore, to avoid any bias related to improved experience, 30-day mortality being higher in Group VR, we excluded the first month from Cox analysis: left ventricle VR (independently of the final shape) was still confirmed as the wrong approach. At the follow-up, Group CS showed significant improvement in EF (+18 vs +8%), end-systolic volume index (-35 vs -20%) and sphericity index (-6 vs +9%). CONCLUSIONS: LVSR should aim to provide a more physiological shape (conical) rather than simple VR.

Topical application of tranexamic acid reduces postoperative bleeding in open-heart surgery: myth or fact?

OBJECTIVE: To determine the efficacy of topical application of Tranexamic acid in controlling postoperative bleeding in open-heart surgery. STUDY DESIGN: Double blind randomized control trial. PLACE AND DURATION OF STUDY: Departments of Cardiac Surgery and Intensive Care of Armed Forces Institute of Cardiology and National Institute of Heart Diseases (AFIC-NIHD), Rawalpindi, Pakistan, from May to October 2011. METHODOLOGY: A total of 100 consecutive adult patients fulfilling the inclusion criteria undergoing elective on-pump cardiac surgeries were randomly divided in groups 'A' and 'B'. A study solution that contained 2.5 g of Tranexamic acid in 250 ml normal saline in group-A and equal amount of normal saline (placebo) in group-B was poured in the pericardial cavity over the mediastinal tissues before sternal closure. Postoperative bleeding was measured in both groups for 24 hours in the cardiac surgical ICU. Efficacy of Topical Tranexamic Acid / Placebo was measured in terms of mean postoperative bleeding in ml. Kindly again include these lines which seem to have been omitted in the final proof. RESULTS: There was significant difference in the mean postoperative bleeding within 24 hours among the two groups 340.1 ± 112.4 ml in Tranexamic acid group vs. 665 ± 187.28 ml in placebo group (p < 0.001). CONCLUSION: Patients who did not have topical Tranexamic acid before chest closure had a significantly higher postoperative bleeding. Topical Tranexamic acid application is an effective and economical way for controlling non-surgical bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass.

Chordal cutting in ischemic mitral regurgitation: a propensity-matched study.

OBJECTIVE: The optimal surgical treatment of ischemic mitral regurgitation (MR) has not been well defined. Second-order chordal cutting (CC), in selected patients, can improve surgical outcomes. METHODS: From 2007 to 2011, 31 patients underwent CC for ischemic MR. The indication was the presence of increased tethering of the anterior leaflet, with a bending angle (BA) <145°. Patients with same echocardiographic characteristics were identified and propensity matched for age, ejection fraction (EF), MR grade, diameters, and BA. Only patients with preoperative and follow-up echocardiograms were included and divided into 2 groups of 26 patients each, CC and no-CC. RESULTS: Preoperatively, in the CC and no-CC groups, the age was 61 ± 9 and 62 ± 10 years, EF was 31% ± 5% and 29% ± 8%, MR grade (0-4) was 3.6 ± 0.6 and 3.3 ± 0.8, and diastolic and systolic dimension was 56 ± 7 and 43 ± 8 mm and 57 ± 11 and 44 ± 11 mm, respectively. The New York Heart Association class and BA was 2.7 ± 0.6 and 2.6 ± 0.7 and 137° ± 4° and 137° ± 6°, respectively. All patients underwent overreductive annuloplasty. In the CC group, second-order chords were cut using aortotomy. After a mean of 33 ± 15 months, the MR grade was 0.6 ± 0.6 and 1.1 ± 0.8 (P = .014) and the EF was 40% ± 5% and 35% ± 7% (P = .005) in the CC and no-CC groups, respectively. The corresponding diastolic and systolic diameters were 52 ± 5 and 38 ± 8 mm and 53 ± 11 and 41 ± 12 mm (P = NS). The modifications were significant only in the CC group (P = .022 and P = .029 for the diastolic and systolic dimensions, respectively). The corresponding New York Heart Association class decreased to 1.1 ± 0.3 and 1.5 ± 0.6 (P = .004). The BA increased to 182° ± 4° in the CC (P < .001) and remained unchanged (137° ± 6°) in the no-CC group. CONCLUSIONS: In selected patients with a BA <145° and coaptation depth ≤10 mm, CC is related to less MR return or persistence, improved EF, and lower New York Heart Association class.

Repair or prosthesis insertion in ischemic mitral regurgitation: Two faces of the same medal.

OBJECTIVE: The proper treatment of chronic ischemic mitral regurgitation (CIMR) is still under evaluation. The different role of mitral valve repair (MVr) or mitral valve prosthesis insertion (MVPI) is still not defined. METHODS: From May 2009 to December 2011 167 patients with ejection fraction (EF) ≤ 40% had MV surgery for CIMR, MVr in 135 (80.8%) and MVPI in 32 (19.2%). Indication to MVPI was a MV coaptation depth > 10 mm. EF was lower (26 ± 7 vs 32 ± 6, p = 0.0000) in MVPI, whereas MR grade (3.6 ± 0.8 vs 2.7 ± 0.9, p = 0.0000), left ventricle dimensions (end diastolic, LVEDD, 62 ± 7 vs 57 ± 6 mm, p = 0.0001; end systolic, LVESD, 49 ± 8 vs 44 ± 8 mm, p = 0.0018), systolic pulmonary artery pressure (51 ± 22 vs 41 ± 16 mm Hg, p = 0.0037) and NYHA Class (3.6 ± 0.5 vs 2.8 ± 0.6, p = 0.0000) were higher. RESULTS: In-hospital mortality was similar (3.1 vs 3.7%) as well as 3-year survival (86 ± 6 vs 88 ± 4) and survival in NYHA Class I/II (80 ± 5 vs 83 ± 4). One hundred thirty nine patients had an echocardiographic evaluation after a minimum of 4 months (13 ± 8). EF rose significantly in both groups (from 26 ± 7% to 30 ± 4%, p = 0.0122, and from 32 ± 6% to 35 ± 8%, p = 0.0018). LVESD reduced significantly in both groups (from 49 ± 8 to 43 ± 9 mm, p = 0.0109, and from 44 ± 8 to 41 ± 7 mm, p = 0.0033). MR grade was significantly lower in patients who had MVPI (0.1 ± 0.2 vs 0.3 ± 0.3, p = 0.0011). CONCLUSIONS: With appropriate indications, MVPI is a safe procedure which provides similar results to MVr with lower MR return, even if addressed to patients with worse preoperative parameters.

Phase 1 trial of a Candidate Recombinant Virus-Like Particle Vaccine for Covid-19 Disease Produced in Plants

Longer AbstractO_ST_ABSBackgroundC_ST_ABSThe stabilized prefusion form of the SARS-CoV-2 spike protein is produced by transient expression in Nicotiana benthamiana. The trimeric spike glycoproteins are displayed at the surface of self-assembling Virus-Like-Particles that mimic the shape and the size of the virus. The candidate vaccine (CoVLP) administered alone or with AS03 or CpG1018 adjuvants was evaluated in a Phase 1 trial in healthy adults. (ClinicalTrials.gov number NCT04450004) MethodsThe study was a randomized, partially-blinded, prime-boost 21 days apart, dose-escalation Phase 1 study intended to assess the safety, tolerability, and immunogenicity of CoVLP at three dose levels (3.75 {micro}g, 7.5 {micro}g, and 15 {micro}g) unadjuvanted or adjuvanted with either CpG 1018 or AS03 in 180 SARS-CoV-2 seronegative healthy adults 18 to 55 years of age. Enrollment was staggered for dose-escalation. At each dose level, the vaccine was initially administered to a small number of subjects. Vaccination of the remaining subjects at the same dose level and the next higher vaccine dose level was administered with approval of an Independent Data Monitoring Committee (IDMC). The same procedure was followed for the second vaccine administration. Monitoring of safety signals was performed throughout the study with pre-determined pausing/stopping rules if there was clear evidence of harmful effects such as severe adverse events (AEs) related to the treatment. The primary endpoints were the safety and tolerability of the vaccine after each dose and the immunogenicity as assessed by neutralizing antibody responses assessed using a vesicular stomatitis virus (VSV) pseudovirion assay and interferon-gamma (IFN-{gamma}) and interleukin-4 (IL-4) ELISpot assays at Days 0, 21 and 42. Secondary endpoints were anti-spike antibody responses by ELISA and neutralizing antibodies measured by live virus plaque reduction neutralization test (PRNT) assay at Days 0, 21 and 42 and immunogenicity with additional safety and immunogenicity endpoints planned for 6-months following the last vaccination. The anti-spike and neutralizing antibody responses were compared with 23 convalescent serum samples from symptomatic Covid-19 patients. We performed a primary analysis at day 42. ResultsA total of 180 subjects (102 females: 78 males: average 34.3 years) were recruited to the study and interim safety and immunogenicity data up to day 42 after the first dose are reported here. There was no obvious CoVLP dose effect in safety outcomes for any of the formulations tested and all formulations were generally well-tolerated. Most solicited local and systemic AEs were mild-moderate and transient. Reactogenicity was increased in all adjuvanted formulations and was generally highest in the CoVLP+AS03 groups. Local and systemic adverse events were reported with similar frequency after the first and second doses in subjects who received either CoVLP alone or CoVLP+CpG1018 but increased in both frequency and severity after the second dose in the CoVLP+AS03 groups. CoVLP alone only elicited a weak total anti-spike IgG response at the highest dose level and little-to-no neutralization antibody response, even after the second dose. Cellular responses in the CoVLP alone groups (IFN{gamma} and IL-4) were detectable after the second dose but were still only marginally above background levels. The addition of either adjuvant substantially increased both antibody and cellular responses at most CoVLP dose levels and changes were most pronounced after the second dose. However, a substantial neutralizing antibody response after the first dose was only seen in all CoVLP+AS03 groups. After the second dose, both total anti-spike IgG and neutralizing antibody titers in the CoVLP+AS03 groups were higher than those in the CoVLP+CpG1018 groups. The antibody titers achieved were either similar to (CoVLP+CpG1018) or at least 10-times higher (CoVLP+AS03) than those seen in convalescent plasma. Administration of CoVLP with either adjuvant also significantly increased the cellular responses. After 2 doses, both IFN-{gamma} and IL-4 responses were significantly increased in the CoVLP+CpG1018 groups. In the CoVLP+AS03 groups, significant increases in the cellular responses were observed after the first dose while IFN-{gamma} and IL-4 increased further in both magnitude and number of subjects responding after the second dose. Again, the cellular responses in the CoVLP+AS03 groups were higher than those seen in the CoVLP+CpG1018 groups. ConclusionThese data demonstrate that CoVLP administered with either CpG1018 or AS03 has a safety profile similar to other candidate vaccines for SARS-CoV-2. When administered with either AS03 or CpG1018, several of the CoVLP dose levels elicited strong humoral and T cell responses after the second dose. When administered with AS03, even the 3.75 g CoVLP dose elicited neutralizing antibody titers that were [~]10-times higher than those observed in individuals recovering from Covid-19 as well as consistent and balanced IFN-{gamma} and IL-4 responses. Although many CoVLP formulations were immunogenic, in the absence of established correlates of protection and given the advantages of dose-sparing in the context of the on-going pandemic, these findings suggest that CoVLP (3.75 g)+AS03 has a good benefit/risk ratio and support the transition of this formulation to studies in expanded populations and to efficacy evaluations Shorter AbstractO_ST_ABSBackgroundC_ST_ABSVirus-like particles (VLP) displaying recombinant SARS-CoV-2 spike protein trimers were produced by transient expression in Nicotiana benthamiana. This candidate vaccine (CoVLP) was evaluated in healthy adults 18-55 years of age alone or with AS03 or CpG1018 (NCT04450004). MethodsThis randomized, partially-blinded, two-dose, dose-escalation study assessed CoVLP (3.75, 7.5 or 15 {micro}g/dose) administered intramuscularly alone or with CpG1018 or AS03 in SARS-CoV-2 seronegative adults (18-55 years). Primary endpoints of safety and immunogenicity are reported to day 42. Neutralizing antibodies (NtAb) were assessed using a VSV pseudovirus assay and cellular responses by ELISpot (IFN{gamma}, IL-4). Results180 subjects (avg.34.3yrs) were recruited. All formulations were well-tolerated but adjuvants increased reactogenicity. Adverse events were highest in the CoVLP+AS03 groups and increased in frequency/severity after dose two. CoVLP alone elicited weak humoral responses but modest cellular responses were detectable after dose two. Both adjuvants increased immunogenicity significantly, particularly after dose two. A significant NtAb response after dose one was only seen in CoVLP+AS03 groups. The vaccine dose had little impact on levels of NtAb responses achieved in the CoVLP+AS03 groups. Both adjuvants also increased IFN{gamma} and IL-4 responses but these cellular responses also tended to be highest in the AS03-adjuvanted groups. ConclusionCoVLP {+/-} adjuvants was well-tolerated. Several adjuvanted formulations elicited strong humoral and T cell responses after dose 2. Even at the lowest CoVLP+AS03 dose, NtAb titers were [~]10-times higher than in convalescent serum with a balanced IFN{gamma} and IL-4 response. These findings support the transition of CoVLP (3.75g+AS03) to further clinical evaluation. Research In ContextO_ST_ABSEvidence before this studyC_ST_ABSThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recognized as the causative agent of COVID-19 in early 2020. Since that time, >150 candidate vaccines are reported to be under development of which 47 have entered clinical trials (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines accessed Nov 4, 2020). No vaccine to prevent COVID-19 has been licensed yet for either emergency or general use in North America or Europe. We searched PubMed for research articles published between July 2019 and November 4, 2020, using the terms "SARS-CoV-2", "vaccine", "clinical trial" OR "human", AND "phase". The same terms were used to search ClinTrials.gov. No language restrictions were applied. We identified 10 peer-reviewed studies, describing phase 1 or 1/2 trials using a range of novel (eg: RNA, DNA, non-replicating virus vectored) and more traditional vaccine approaches (eg: inactivated virus or recombinant protein {+/-} adjuvants). None of these candidate vaccines was produced in plants. These reports demonstrate that several different vaccination strategies (typically delivered in two doses 14-28 days apart) are capable of eliciting neutralizing antibody responses. In several cases, vaccine-induced cellular responses against SARS-COV-2 antigens - predominantly the spike (S) protein - can also be demonstrated. Although local and systemic adverse events following vaccination have varied between reports, the trials published to date suggest that each of these candidate vaccines is well-tolerated in the context of an evolving pandemic. Added value of this studyWe report the results of the first clinical study of CoVLP, a virus-like particle (VLP) vaccine that is produced by transient transfection of Nicotiana benthamiana plants. These VLPs spontaneously assemble at the plant cell membrane and display SARS-COV-2 trimers of stabilized pre-fusion S protein on their surface. The vaccine was administered as two intramuscular doses 21 days apart at three dose levels (S protein content 3.75, 7,5 or 15g) alone or adjuvanted with either CpG1018 or AS03. All formulations were well-tolerated although both adjuvants increased reactogenicity. Humoral (anti-S IgG and neutralizing antibodies) as well as cellular responses (IFNg and IL4 ELISpots) were detectable in almost all subjects who received adjuvanted formulations 21 days after the second dose at all COVLP dose levels. Both antibody and cellular responses were highest in subjects who received AS03-adjuvanted formulations. Even at the lowest dose level (3.75g), the neutralizing antibody titers 21 days after the second dose in subjects who received the AS03-afdjuvanted vaccine were 10-50-fold higher than those seen in subjects recovering from COVID-19 infection. Implications of all the available evidenceEffective vaccines against SARS-CoV-2 are urgently needed to reduce the burden of disease and contribute to ending the global pandemic. Although no immune correlates for SARS-CoV-2 have been defined, it is likely that both arms of the immune system contribute to protection. After two doses of CoVLP (3.75g+AS03), strong humoral and cellular responses were induced supporting the further clinical development of this vaccine.

Interim Report of a Phase 2 Randomized Trial of a Plant-Produced Virus-Like Particle Vaccine for Covid-19 in Healthy Adults Aged 18-64 and Older Adults Aged 65 and Older

The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and the needs of specific populations. We report herein a pre-specified interim analysis of the phase 2 portion of an ongoing Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein adjuvanted with AS03 (NCT04636697). A total of 753 subjects were recruited between 25 November 2020 and 24 March 2021 into three groups: Healthy Adults (18-64 years: N=306), Older Adults ([≥] 65 years: N=282) and Adults with Comorbidities ([≥]18 years: N=165) and randomized 5:1 to receive two intramuscular doses of either vaccine CoVLP (3.75 g/dose + AS03) or placebo 21 days apart. This report presents safety, tolerability and immunogenicity data collected up to 21 days after the second dose. The immune outcomes presented include neutralizing antibody (NAb) titres and cellular (IFN-{gamma} and IL-4 ELISpot) responses. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults. CoVLP+AS03 induced seroconversion in >35% of subjects in each group after the first dose and in [~]98% of subjects 21 days after the second dose. In all treatment groups, NAb levels were [~]10-fold higher than those in a panel of convalescent sera. A significant minority ([~]20%) of subjects had evidence of a pre-existing IFN-{gamma} response to the S protein and almost all subjects in all groups (>88%) had detectable cellular responses (IFN-{gamma}, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after dose two. These data demonstrated that CoVLP+AS03 will likely be well-tolerated and highly immunogenic in adults [≥]18 years of age with and without comorbidities.

Efficacy and Safety of a Plant-Based Virus-Like Particle Vaccine for COVID-19 Adjuvanted with AS03

BackgroundSeveral COVID-19 vaccines are currently being deployed but supply constraints, concerns over durability of immune responses, solidifying vaccine hesitancy/resistance and vaccine efficacy in the face of emerging variants mean that new vaccines continue to be needed to fight the ongoing pandemic. The vaccine described here is an enveloped, coronavirus-like particle produced in plants (CoVLP) that displays the prefusion-stabilized spike (S) glycoprotein of SARS-CoV-2 (ancestral Wuhan strain) and is adjuvanted with AS03 (CoVLP+AS03). MethodsThis Phase 3 randomized, observer-blind, placebo-controlled trial was conducted at 85 centers in Argentina, Brazil, Canada, Mexico, the UK, and the USA. Adults [≥]18 years of age including those at high risk for COVID-19 complications were randomly assigned 1:1 to receive two intramuscular injections of CoVLP (3.75 g) adjuvanted with AS03 or placebo, 21 days apart. The primary efficacy endpoint was prevention of symptomatic ([≥] 1 symptom), PCR-confirmed SARS-CoV-2 infection with onset at least 7 days after the second injection and was triggered by the identification of [≥]160 virologically-confirmed cases. Tolerability and safety of CoVLP+AS03 were also determined. ResultsA total of 24,141 volunteers were randomly assigned 1:1 to receive vaccine or placebo (N= 12,074 and 12,067, respectively: median age 29, range 18 to 86 years). Overall, 83% received both doses. 14.8% were SARS-CoV-2 seropositive at baseline. Symptomatic SARS-CoV-2 infection was confirmed in 165 study participants in the intention to treat (ITT) set and 157 in the per-protocol population (PP) set. Of the 157 in the PP set, 118 COVID-19 cases were in the placebo group and 39 COVID-19 cases were in the CoVLP+AS03 group for an overall vaccine efficacy (VE) of 71.0% (95% confidence interval (CI) 58.6, 80.0). Moderate-to-severe COVID-19 occurred in 8 and 32 participants in the CoVLP+AS03 and placebo groups, respectively: VE 78.1% (95% CI: 53.9, 90.5) in the PP set overall and 84.5% (95% CI: 62.0, 94.7) in those seronegative at recruitment. To date, 100% of the sequenced strains (122/165 cases: 73.39%) were variants, dominated by Delta (45.9%) and Gamma (43.4%) strains. Vaccine efficacy by variant was 75.3% (95% CI 52.8, 87.9) against Delta and 88.6% (95% CI 74.6, 95.6) against Gamma. Cross-protection was also observed against Alpha, Lambda and Mu variants; although fewer cases were identified, all were in the placebo group. At diagnosis, viral loads in the CoVLP+AS03 breakthrough cases were >100-fold lower than in the placebo cases. Reactogenicity data for solicited adverse events (AEs) was analysed for a subset (N=4,136 in vaccine arm and N=3,683 for placebo) of participants. Reactogenicity was mostly mild to moderate, and transient, and occurred more frequently in the CoVLP+AS03 group. The safety analysis set used for unsolicited AE assessment comprised 24,076 participants who received at least one study injection: 12,036 received CoVLP+AS03 and 12,040 received placebo. All serious adverse events were assessed as unrelated, except two events reported in the same subject in the placebo group. No significant imbalance or safety concern was noted in medically attended AEs (MAAEs), adverse event of special interest (AESIs), AEs leading to withdrawal, deaths, or adverse events potentially associated with currently authorized vaccines. ConclusionsThe CoVLP+AS03 vaccine candidate conferred an efficacy of 71.0% in preventing symptomatic SARS-CoV-2 infection caused by a spectrum of variants. Vaccine efficacy of 78.1% was observed against moderate and severe disease, while variant-specific efficacy ranged from 75.3% to 100%. Markedly lower viral loads in the CoVLP+AS03 group at the time of diagnosis suggests a significant virologic impact of vaccination even in the breakthrough cases. CoVLP+AS03 vaccine candidate was well tolerated, and no safety concerns were identified during the study. If approved by regulators, this more traditional protein+adjuvant vaccine produced using the novel plant-based platform may be able to make an important contribution to the global struggle against the increasingly complex family of SARS-CoV-2 viruses (Funded by Medicago with grants from the governments of Quebec and Canada; NCT04636697).