Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

The aim of the current Valvular Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)- clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand understanding of patient risk stratification and case selection.

Predicting failure in mammalian enamel

Dentition is a vital element of human and animal function, yet there is little fundamental knowledge about how tooth enamel endures under stringent oral conditions. This paper describes a novel approach to the issue. Model glass dome specimens fabricated from glass and back­filled with polymer resin are used as representative of the basic enamel/dentine shell structure. Contact loading is used to deform the dome structures to failure, in simulation of occlusal loading with opposing dentition or food bolus. To investigate the role of enamel microstructure, additional contact tests are conducted on two­phase materials that capture the essence of the mineralized­rod/organic­sheath structure of dental enamel. These materials include dental glass­ceramics and biomimicked composites fabricated from glass fibers infiltrated with epoxy. The tests indicate how enamel is likely to deform and fracture along easy sliding and fracture paths within the binding phase between the rods. Analytical relations describing the critical loads for each damage mode are presented in terms of material properties (hardness, modulus, toughness) and tooth geometry variables (enamel thickness, cusp radius). Implications in dentistry and evolutionary biology are discussed.

Shear bond strength of resin cements to human dentin

OBJECTIVES: The objectives of this in vitro study were (1) to assess the bond strength of the universal cement RelyX Unicem to dentin and to compare it with three conventional resin cements, (2) to test the influence of aging on their bonding capacity and (3) to test the influence of the operator on bonding quality by performing the same test in two different centers. METHODS: 160 third molars, divided into 80 for tests at the University of Zurich (Z) and 80 for tests at the University of Berne (B), were assigned to 2 x 8 subgroups of 10 teeth each. The specimens were prepared with the corresponding bonding agents and acrylic rods were luted either with RelyX Unicem (U), RelyX ARC (A), Multilink (M) or Panavia 21 (P). All specimens were stored in water for 24h (W) and half of the specimens were subjected to 1500 cycles of thermocycling (5 degrees C and 55 degrees C) (T). Bond strength was measured by means of a shear test. RESULTS: After water storage RelyX Unicem exhibited lowest bond strength (UWZ: 9.2+/-1.6 MPa, UWB: 9.9+/-1.2 MPa, AWZ: 15.3+/-6.0 MPa, AWB: 12.2+/-4.3 MPa, MWZ: 15.6+/-3.3 MPa, MWB: 12.4 MPa+/-2.4, PWZ: 13.4+/-2.9 MPa, PWB: 14.9+/-2.6 MPa). Thermocycling affected the bonding performance of all four cements. However, bond strength of RelyX Unicem was least influenced by thermocycling (UTZ: 9.4+/-2.9 MPa, UTB: 8.6+/-1.3 MPa, ATZ: 11.4+/-6.3 MPa, ATB: 13.3+/-3.7 MPa, MTZ: 15.4+/-3.1 MPa, MTB: 10.3+/-2.4 MPa, PTZ: 11.1+/-2.8 MPa, PTB: 11.3+/-2.8 MPa). SIGNIFICANCE: Although the bond strength of RelyX Unicem to dentin was lower in comparison to RelyX ARC, Multilink and Panavia 21, its bond strength was less sensitive to variations in handling and aging.

In vitro biomechanical testing of a micro external skeletal fixator

OBJECTIVE To biomechanically test the properties of three different Universal Micro External Fixator (UMEX™) configurations with regard to their use in very small animals (<5kg) and compare the UMEX system to the widely used IMEX External Skeletal Fixation (SK™) system in terms of stiffness, space needed for pin placement and weight. METHODS Three different UMEX configurations (type Ia, type Ib, and type II modified) and one SK configuration type Ia were used to stabilize Delrin plastic rods in a 1 cm fracture gap model. These constructs were tested in axial compression, craniocaudal bending, mediolateral bending, and torsion. Testing was conducted within the elastic range and mean stiffness in each mode was determined from the slope of the linear portion of the load-deformation curve. A Kruskal Wallis one-way analysis of variance on ranks test was utilized to assess differences between constructs (p <0.05). RESULTS The UMEX type II modified configuration was significantly stiffer than the other UMEX configurations and the SK type Ia, except in craniocaudal bending, where the SK type Ia configuration was stiffer than all UMEX constructs. The UMEX type Ia configuration was significantly the weakest of those frames. The UMEX constructs were lighter and smaller than the SK, thus facilitating closer pin placement. CONCLUSIONS Results supported previous reports concerning the superiority of more complex constructs regarding stiffness. The UMEX system appears to be a valid alternative for the treatment of long-bone fractures in very small animals.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

OBJECTIVES The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. BACKGROUND A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS Two in-person meetings (held in September 2011 in Washington, DC, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and noninterventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).

Characteristics of rod regeneration in a novel zebrafish retinal degeneration model using N-methyl-N-nitrosourea (MNU)

Primary loss of photoreceptors caused by diseases such as retinitis pigmentosa is one of the main causes of blindness worldwide. To study such diseases, rodent models of N-methyl-N-nitrosourea (MNU)-induced retinal degeneration are widely used. As zebrafish (Danio rerio) are a popular model system for visual research that offers persistent retinal neurogenesis throughout the lifetime and retinal regeneration after severe damage, we have established a novel MNU-induced model in this species. Histology with staining for apoptosis (TUNEL), proliferation (PCNA), activated Müller glial cells (GFAP), rods (rhodopsin) and cones (zpr-1) were performed. A characteristic sequence of retinal changes was found. First, apoptosis of rod photoreceptors occurred 3 days after MNU treatment and resulted in a loss of rod cells. Consequently, proliferation started in the inner nuclear layer (INL) with a maximum at day 8, whereas in the outer nuclear layer (ONL) a maximum was observed at day 15. The proliferation in the ONL persisted to the end of the follow-up (3 months), interestingly, without ongoing rod cell death. We demonstrate that rod degeneration is a sufficient trigger for the induction of Müller glial cell activation, even if only a minimal number of rod cells undergo cell death. In conclusion, the use of MNU is a simple and feasible model for rod photoreceptor degeneration in the zebrafish that offers new insights into rod regeneration.

In Situ Monitoring of Free-Phase Gas Accumulation and Release in Peatlands Using Ground Penetrating Radar (GPR)

We tested a set of surface common mid-point (CMP) ground penetrating radar (GPR) surveys combined with elevation rods ( to monitor surface deformation) and gas flux measurements to investigate in-situ biogenic gas dynamics and ebullition events in a northern peatland ( raised bog). The main findings are: ( 1) changes in the two-way travel time from the surface to prominent reflectors allow estimation of average gas contents and evolution of free-phase gas (FPG); ( 2) peat surface deformation and gas flux measurements are strongly consistent with GPR estimated changes in FPG content over time; ( 3) rapid decreases in atmospheric pressure are associated with increased gas flux; and ( 4) single ebullition events can induce releases of methane much larger ( up to 192 g/m(2)) than fluxes reported by others. These results indicate that GPR is a useful tool for assessing the spatial distribution, temporal variation, and volume of biogenic gas deposits in peatlands.

Open issues in transcatheter aortic valve implantation. Part 2: procedural issues and outcomes after transcatheter aortic valve implantation.

This article provides an overview on procedure-related issues and uncertainties in outcomes after transcatheter aortic valve implantation (TAVI). The different access sites and how to select them in an individual patient are discussed. Also, the occurrence and potential predictors of aortic regurgitation (AR) after TAVI are addressed. The different methods to quantify AR are reviewed, and it appears that accurate and reproducible quantification is suboptimal. Complications such as prosthesis-patient mismatch and conduction abnormalities (and need for permanent pacemaker) are discussed, as well as cerebrovascular events, which emphasize the development of optimal anti-coagulative strategies. Finally, recent registries have shown the adoption of TAVI in the real world, but longer follow-up studies are needed to evaluate the outcome (but also prosthesis durability). Additionally, future studies are briefly discussed, which will address the use of TAVI in pure AR and lower-risk patients.

Open issues in transcatheter aortic valve implantation. Part 1: patient selection and treatment strategy for transcatheter aortic valve implantation.

An exponential increase in the use of transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis has been witnessed over the recent years. The current article reviews different areas of uncertainty related to patient selection. The use and limitations of risk scores are addressed, followed by an extensive discussion on the value of three-dimensional imaging for prosthesis sizing and the assessment of complex valve anatomy such as degenerated bicuspid valves. The uncertainty about valvular stenosis severity in patients with a mismatch between the transvalvular gradient and the aortic valve area, and how integrated use of echocardiography and computed tomographic imaging may help, is also addressed. Finally, patients referred for TAVI may have concomitant mitral regurgitation and/or coronary artery disease and the management of these patients is discussed.

Transcatheter aortic valve implantation in failed bioprosthetic surgical valves.

IMPORTANCE Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES Survival, stroke, and New York Heart Association functional class. RESULTS Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.

Higher order parametric excitation modes for spaceborne quadrupole mass spectrometers

This paper describes a technique to significantly improve upon the mass peak shape and mass resolution of spaceborne quadrupolemass spectrometers (QMSs) through higher order auxiliary excitation of the quadrupole field. Using a novel multiresonant tank circuit, additional frequency components can be used to drive modulating voltages on the quadrupole rods in a practical manner, suitable for both improved commercial applications and spaceflight instruments. Auxiliary excitation at frequencies near twice that of the fundamental quadrupole RF frequency provides the advantages of previously studied parametric excitation techniques, but with the added benefit of increased sensed excitation amplitude dynamic range and the ability to operate voltage scan lines through the center of upper stability islands. Using a field programmable gate array, the amplitudes and frequencies of all QMS signals are digitally generated and managed, providing a robust and stable voltage control system. These techniques are experimentally verified through an interface with a commercial Pfeiffer QMG422 quadrupole rod system. When operating through the center of a stability island formed from higher order auxiliary excitation, approximately 50% and 400% improvements in 1% mass resolution and peak stability were measured, respectively, when compared with traditional QMS operation. Although tested with a circular rod system, the presented techniques have the potential to improve the performance of both circular and hyperbolic rod geometry QMS sensors.

Enabling the Next Generation of Spaceborne Quadrupole Mass Spectrometers

The quadrupole mass spectrometer (QMS) has over 30 years of spaceflight heritage in making important neutral gas and low energy ion observations. Given their geometrical constraints, these instruments are currently operated at the extreme limit of their capabilities. However, a technique called higher order auxiliary excitation provides a set of novel, robust, electronics-based solutions for improving the performance of these sensors. By driving the quadrupole rods with an additional frequency nearly twice that of the normal RF operating frequency, substantially increased abundance sensitivity, maximum attainable mass resolution, and peak stability can be achieved through operation of voltage scan lines through the center of formed upper stability islands. Such improvements are modeled using numerical simulations of ion trajectories in a quadrupole field with and without applied higher order auxiliary excitation. When compared to a traditional QMS with a mass range up to 500Da, sensors can be designed with the same precision electronics to have expected mass ranges beyond 1500Da with a power increase of less than twice that of its heritage implementations.

Treatment of posttraumatic cubitus varus in children and adolescents. Supracondylar humeral osteotomy using radial external fixation

OBJECTIVE Precise adaptable fixation of a supracondylar humerus osteotomy with a radial/lateral external fixator to correct posttraumatic cubitus varus. INDICATIONS Acquired, posttraumatic cubitus varus as a result of a malhealed and unsatisfactorily treated supracondylar humerus fracture. Idiopathic, congenital cubitus varus (very seldom) if the child (independent of age and after complete healing) is cosmetically impaired; stability of the elbow is reduced due to malalignment (hyperextension); secondary problems and pain (e. g., irritation of the ulnar nerve) are expected or already exist; or there is an explicit wish of the child/parents (relative indication). CONTRAINDICATIONS In principle there are no contraindications provided that the indication criteria are filled. The common argument of age does not represent a contraindication in our opinion, since angular remodeling at the distal end of the humerus is practically nonexistent. SURGICAL TECHNIQUE Basically, the surgical technique of the radial external fixator is used as previously described for stabilization of complex supracondylar humeral fractures. With the patient in supine position, the arm is placed freely on an arm table. Using a 4-5 cm long skin incision along the radial, supracondylar, the extracapsular part of the distal humerus is prepared, whereby great caution regarding the radial nerve is advised. In contrast to the procedure used in radial external fixation for supracondylar humeral fracture treatment, two Schanz screws are always fixed in each fragment at a distance of 1.5-2 cm. The osteotomy must allow the fragment to freely move in all directions. The proximal and distal two Schanz screws are then connected with short 4 mm carbon or stainless steel rods. These two rods are connected with each other over another rod using the tub-to-tub technique. Now the preliminary correction according the clinical situation can be performed and the clamps are tightened. Anatomical axis and function are checked. If these are radiologically and clinically perfect, all clamps are definitively tightened; if the alignment or the function is not perfect, then further adjustments can be made. POSTOPERATIVE MANAGEMENT Due to the excellent stability, further immobilization not necessary. Immediate functional follow-up treatment performed according to pain. RESULTS Adequate healing is usually expected within 6 weeks. At this time the external fixator can be removed in the fracture clinic. Because the whole operation is performed in an extraarticular manner and the mobility of the elbow is not affected, deterioration of function has never been observed. Also regarding the cosmetic/anatomical situation, good results are expected because they were already achieved intraoperatively.