An implantable magnetic drive mechanism for non-invasive arteriovenous conduit blood flow control.

OBJECTIVE: Hemodialysis patients usually receive an arteriovenous fistula (AVF) in the arm as vascular access conduit to allow dialysis 2-3 times a week. This AVF introduces the high flow necessary for dialysis, but over time the ever-present supraphysiological flow is the leading cause of complications. This study aims to develop an implantable device able to non-invasively remove the high flow outside dialysis sessions. METHODS: The developed prototype features a magnetic ring allowing external coupling and torque transmission to non-invasively control an AVF valve. Mock-up devices were implanted into arm and sheep cadavers to test sizes and locations. The transmission torque, output force, and valve closure are measured for different representative skin thicknesses. RESULTS: The prototype was placed successfully into arm and sheep cadavers. In the prototype, a maximum output force of 78.9±4.2 N, 46.7±1.9 N, 25.6±0.7 N, 13.5±0.6 N and 6.3±0.4 N could be achieved non-invasively through skin thicknesses of 1-5 mm respectively. The fistula was fully collapsible in every measurement through skin thickness up to the required 4 mm. CONCLUSION: The prototype satisfies the design requirements. It is fully implantable and allows closure and control of an AVF through non-invasive torque transmission. In vivo studies are pivotal in assessing functionality and understanding systemic effects. SIGNIFICANCE: A method is introduced to transfer large amounts of energy to a medical implant for actuation of a mechanical valve trough a closed surface. This system allows non-invasive control of an AVF to reduce complications related to the permanent high flow in conventional AVFs.

Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

A chromatography-free asymmetric synthesis of GDC-6036 (1) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol (4) and a global deprotection generates the penultimate heterobiaryl intermediate 2. A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 (1).

Question-based development of high-risk medical devices: A proposal for a structured design and review process.

INTRODUCTION: The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. METHODS: A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilizing the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. The framework can be used in the medical device design phase to define specific questions to be answered during the ensuing clinical development, based upon five general questions, specified by the question-based framework. RESULTS: The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organizations will be guided to the optimal route, also to abandon projects destined for failure early on to minimize development risks. CONCLUSION: The framework could facilitate communication with funding agencies, regulators and clinicians, while highlighting remaining 'known unknowns' that require answering in the post-market phase after sufficient benefit is established relative to the risks.

Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (1), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C-C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, W057-2, which afforded the desired Negishi coupling product (Ra)-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 (1) in 40% overall yield from starting materials pyridine 5 and quinazoline 6.

Phosphoramidates as Steering Elements for Highly Selective Access to Complementary Imidazo[1,2-a]pyrimidine Isomers.

We report that selective N-phosphorylation of aminoimidazoles results in a key steering element that controls isomeric selectivity in the condensation of ß-ethoxy acrylamides and aminoimidazoles to furnish imidazo[1,2-a]pyrimidines. We identified conditions that provide highly selective (99:1) phosphorylation at the endo- or exocyclic nitrogen. Either the 2-amino or 4-amino isomer of the (benzo)imidazo[1,2-a]pyrimidine products could be isolated in 64-95% yield. Mass spectrometric analysis and computational studies give insight into the mechanism of this exceptionally selective transformation.

Pd-Catalyzed C-N Coupling Reactions Facilitated by Organic Bases: Mechanistic Investigation Leads to Enhanced Reactivity in the Arylation of Weakly Binding Amines.

The ability to use soluble organic amine bases in Pd-catalyzed C-N cross-coupling reactions has provided a long-awaited solution to the many issues associated with employing traditional, heterogeneous reaction conditions. However, little is known about the precise function of these bases in the catalytic cycle and about the effect of variations in base structure on catalyst reactivity. We used 19F NMR to analyze the kinetic behavior of C-N coupling reactions facilitated by different organic bases. In the case of aniline coupling reactions employing DBU, the resting state was a DBU-bound oxidative addition complex, LPd(DBU)(Ar)X, and the reaction was found to be inhibited by base. In general, however, depending on the binding properties of the chosen organic base, increased concentration of the base can have a positive or negative influence on the reaction rate. Furthermore, the electronic nature of the aryl triflate employed in the reaction directly affects the reaction rate. The fastest reaction rates were observed with electronically neutral aryl triflates, while the slowest were observed with highly electron-rich and -deficient substrates. We propose a model in which the turnover-limiting step of the catalytic cycle depends on the relative nucleophilicity of the base compared to that of the amine. This hypothesis guided the discovery of new reaction conditions for the coupling of weakly binding amines, including secondary aryl amines, which were unreactive nucleophiles in our original protocol.

Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling.

Due to the low intrinsic acidity of amines, palladium-catalyzed C-N cross-coupling has been plagued continuously by the necessity to employ strong, inorganic, or insoluble bases. To surmount the many practical obstacles associated with these reagents, we utilized a commercially available dialkyl triarylmonophosphine-supported palladium catalyst that facilitates a broad range of C-N coupling reactions in the presence of weak, soluble bases. The mild and general reaction conditions show extraordinary tolerance for even highly base-sensitive functional groups. Additionally, insightful heteronuclear NMR studies using 15N-labeled amine complexes provide evidence for the key acidifying effect of the cationic palladium center.

Oxidatively Initiated NHC-Catalyzed Enantioselective Synthesis of 3,4-Disubstituted Cyclopentanones from Enals.

An unprecedented N-heterocyclic carbene (NHC)-catalyzed annulation of enals to form 3,4-disubstituted cyclopentanones has been discovered. Aryl enals undergo dimerization in the presence of a single-electron oxidant to form C2 symmetric cyclopentanones. A cross-reaction has also been developed, allowing for the synthesis of differentially substituted cyclopentanones. Mechanistically, the reaction is thought to proceed through radical intermediates, further establishing the synthetic utility of this class of reactivity.

Cross-sectional neck response of a total human body FE model during simulated frontal and side automobile impacts.

Human body finite element (FE) models are beginning to play a more prevalent role in the advancement of automotive safety. A methodology has been developed to evaluate neck response at multiple levels in a human body FE model during simulated automotive impacts. Three different impact scenarios were simulated: a frontal impact of a belted driver with airbag deployment, a frontal impact of a belted passenger without airbag deployment and an unbelted side impact sled test. Cross sections were created at each vertebral level of the cervical spine to calculate the force and moment contributions of different anatomical components of the neck. Adjacent level axial force ratios varied between 0.74 and 1.11 and adjacent level bending moment ratios between 0.55 and 1.15. The present technique is ideal for comparing neck forces and moments to existing injury threshold values, calculating injury criteria and for better understanding the biomechanical mechanisms of neck injury and load sharing during sub-injurious and injurious loading.

Rapid Construction of (-)-Paroxetine and (-)-Femoxetine via N-Heterocyclic Carbene Catalyzed Homoenolate Addition to Nitroalkenes.

A concise enantioselective synthesis of (-)-paroxetine (Paxil) and (-)-femoxetine has been achieved. Key to these syntheses is a N-heterocyclic carbene catalyzed homoenolate addition to a nitroalkene followed by in situ reduction of the nitro-group to rapidly access δ-lactams.

Enantioselective N-heterocyclic carbene-catalyzed ß-hydroxylation of enals using nitroarenes: an atom transfer reaction that proceeds via single electron transfer.

A novel oxidative N-heterocyclic carbene-catalyzed reaction pathway has been discovered. Alkyl and aryl enals undergo ß-hydroxylation via oxygen atom transfer from electron-deficient nitrobenzenes, followed by trapping of the resultant acyl azolium by the solvent. The proposed mechanism involves a single electron transfer event to initiate the reaction followed by radical recombination. This represents a profound mechanistic departure from the established two-electron disconnects in NHC catalysis.

Head and neck response of a finite element anthropomorphic test device and human body model during a simulated rotary-wing aircraft impact.

A finite element (FE) simulation environment has been developed to investigate aviator head and neck response during a simulated rotary-wing aircraft impact using both an FE anthropomorphic test device (ATD) and an FE human body model. The head and neck response of the ATD simulation was successfully validated against an experimental sled test. The majority of the head and neck transducer time histories received a CORrelation and analysis (CORA) rating of 0.7 or higher, indicating good overall correlation. The human body model simulation produced a more biofidelic head and neck response than the ATD experimental test and simulation, including change in neck curvature. While only the upper and lower neck loading can be measured in the ATD, the shear force, axial force, and bending moment were reported for each level of the cervical spine in the human body model using a novel technique involving cross sections. This loading distribution provides further insight into the biomechanical response of the neck during a rotary-wing aircraft impact.

Effects of cervical arthrodesis and arthroplasty on neck response during a simulated frontal automobile collision.

BACKGROUND CONTEXT: Whereas arthrodesis is the most common surgical intervention for the treatment of symptomatic cervical degenerative disc disease, arthroplasty has become increasingly more popular over the past decade. Although literature exists comparing the effects of anterior cervical discectomy and fusion and cervical total disc replacement (CTDR) on neck kinematics and loading, the vast majority of these studies apply only quasi-static, noninjurious loading conditions to a segment of the cervical spine. PURPOSE: The objective of this study was to investigate the effects of arthrodesis and arthroplasty on biomechanical neck response during a simulated frontal automobile collision with air bag deployment. STUDY DESIGN: This study used a full-body, 50th percentile seated male finite element (FE) model to evaluate neck response during a dynamic impact event. The cervical spine was modified to simulate either an arthrodesis or arthroplasty procedure at C5-C6. METHODS: Five simulations of a belted driver, subjected to a 13.3 m/s ΔV frontal impact with air bag deployment, were run in LS-DYNA with the Global Human Body Models Consortium full-body FE model. The first simulation used the original model, with no modifications to the neck, whereas the remaining four were modified to represent either interbody arthrodesis or arthroplasty of C5-C6. Cross-sectional forces and moments at the C5 and C6 cervical levels of the neck, along with interbody and facet forces between C5 and C6, were reported. RESULTS: Adjacent-level, cross-sectional neck loading was maintained in all simulations without exceeding any established injury thresholds. Interbody compression was greatest for the CTDRs, and interbody tension occurred only in the fused and nonmodified spines. Some interbody separation occurred between the superior and inferior components of the CTDRs during flexion-induced tension of the cervical spine, increasing the facet loads. CONCLUSIONS: This study evaluated the effects of C5-C6 cervical arthrodesis and arthroplasty on neck response during a simulated frontal automobile impact. Although cervical arthrodesis and arthroplasty at C5-C6 did not appear to significantly alter the adjacent-level, cross-sectional neck responses during a simulated frontal automobile impact, key differences were noted in the interbody and facet loading.

Asymmetric N-heterocyclic carbene catalyzed addition of enals to nitroalkenes: controlling stereochemistry via the homoenolate reactivity pathway to access δ-lactams.

An asymmetric intermolecular reaction between enals and nitroalkenes to yield δ-nitroesters has been developed, catalyzed by a novel chiral N-heterocyclic carbene. Key to this work was the development of a catalyst that favors the δ-nitroester pathway over the established Stetter pathway. The reaction proceeds in high stereoselectivity and affords the previously unreported syn diastereomer. We also report an operationally facile two-step, one-pot procedure for the synthesis of δ-lactams.

Development of numerical models for injury biomechanics research: a review of 50 years of publications in the Stapp Car Crash Conference.

Numerical analyses frequently accompany experimental investigations that study injury biomechanics and improvements in automotive safety. Limited by computational speed, earlier mathematical models tended to simplify the system under study so that a set of differential equations could be written and solved. Advances in computing technology and analysis software have enabled the development of many sophisticated models that have the potential to provide a more comprehensive understanding of human impact response, injury mechanisms, and tolerance. In this article, 50 years of publications on numerical modeling published in the Stapp Car Crash Conference Proceedings and Journal were reviewed. These models were based on: (a) author-developed equations and software, (b) public and commercially available programs to solve rigid body dynamic models (such as MVMA2D, CAL3D or ATB, and MADYMO), and (c) finite element models. A clear trend that can be observed is the increasing use of the finite element method for model development. A review of these modeling papers clearly indicates the progression of the state-of-the-art in computational methods and technologies in injury biomechanics.

Motion Analysis of the Mandible during Low-Speed, Rear-End Impacts using High-Speed X-rays.

There has been much debate over "whiplash"-induced temporomandibular joint (TMJ) dysfunction following low-speed, rear-end automobile collisions. While several authors have reported TMJ injury based on case studies post collision, there has been little biomechanical evidence showing that rear-end impact was the primary cause of such injury. The purpose of this study was to measure the relative translation between the upper and lower incisors in cadavers subjected to low-speed, rearend impacts. High-speed x-ray images used for this analysis were reported previously for the analysis of cadaveric cervical spine kinematics during low-speed, rear-end impacts. The cadavers were positioned at various seatback angles and body postures, producing an overall picture of various seating scenarios. Of the 38 tests conducted using 10 cadavers, there were seven tests from three cadavers in which the positions of the upper and lower incisors could be tracked with precision using imageprocessing software. The relative protrusion, retrusion, and mouth opening were computed from these seven sets of data, providing a better understanding of TMJ motion. Based on this limited data, the average maximum protrusion, retrusion and mouth opening were 1.6+/-1.8, 1.1+/-0.7, and 1.2+/-1.2 mm, respectively. These values appear to fall within normal physiological limits experienced during daily activities such as mastication. It is concluded that low-speed, rear-end automobile collisions do not appear to create the motion required to initiate injury to the TMJ.