Aortic Valve Embryology, Mechanobiology, and Second Messenger Pathways: Implications for Clinical Practice.

During the Renaissance, Leonardo Da Vinci was the first person to successfully detail the anatomy of the aortic root and its adjacent structures. Ever since, novel insights into morphology, function, and their interplay have accumulated, resulting in advanced knowledge on the complex functional characteristics of the aortic valve (AV) and root. This has shifted our vision from the AV as being a static structure towards that of a dynamic interconnected apparatus within the aortic root as a functional unit, exhibiting a complex interplay with adjacent structures via both humoral and mechanical stimuli. This paradigm shift has stimulated surgical treatment strategies of valvular disease that seek to recapitulate healthy AV function, whereby AV disease can no longer be seen as an isolated morphological pathology which needs to be replaced. As prostheses still cannot reproduce the complexity of human nature, treatment of diseased AVs, whether stenotic or insufficient, has tremendously evolved, with a similar shift towards treatments options that are more hemodynamically centered, such as the Ross procedure and valve-conserving surgery. Native AV and root components allow for an efficient Venturi effect over the valve to allow for optimal opening during the cardiac cycle, while also alleviating the left ventricle. Next to that, several receptors are present on native AV leaflets, enabling messenger pathways based on their interaction with blood and other shear-stress-related stimuli. Many of these physiological and hemodynamical processes are under-acknowledged but may hold important clues for innovative treatment strategies, or as potential novel targets for therapeutic agents that halt or reverse the process of valve degeneration. A structured overview of these pathways and their implications for cardiothoracic surgeons and cardiologists is lacking. As such, we provide an overview on embryology, hemodynamics, and messenger pathways of the healthy and diseased AV and its implications for clinical practice, by relating this knowledge to current treatment alternatives and clinical decision making.

Paediatric aortic valve replacement: a meta-analysis and microsimulation study.

AIMS: To support decision-making in children undergoing aortic valve replacement (AVR), by providing a comprehensive overview of published outcomes after paediatric AVR, and microsimulation-based age-specific estimates of outcome with different valve substitutes. METHODS AND RESULTS: A systematic review of published literature reporting clinical outcome after paediatric AVR (mean age <18 years) published between 1/1/1990 and 11/08/2021 was conducted. Publications reporting outcome after paediatric Ross procedure, mechanical AVR (mAVR), homograft AVR (hAVR), and/or bioprosthetic AVR were considered for inclusion. Early risks (<30d), late event rates (>30d) and time-to-event data were pooled and entered into a microsimulation model. Sixty-eight studies, of which one prospective and 67 retrospective cohort studies, were included, encompassing a total of 5259 patients (37 435 patient-years; median follow-up: 5.9 years; range 1-21 years). Pooled mean age for the Ross procedure, mAVR, and hAVR was 9.2 ± 5.6, 13.0 ± 3.4, and 8.4 ± 5.4 years, respectively. Pooled early mortality for the Ross procedure, mAVR, and hAVR was 3.7% (95% CI, 3.0%-4.7%), 7.0% (5.1%-9.6%), and 10.6% (6.6%-17.0%), respectively, and late mortality rate was 0.5%/year (0.4%-0.7%/year), 1.0%/year (0.6%-1.5%/year), and 1.4%/year (0.8%-2.5%/year), respectively. Microsimulation-based mean life-expectancy in the first 20 years was 18.9 years (18.6-19.1 years) after Ross (relative life-expectancy: 94.8%) and 17.0 years (16.5-17.6 years) after mAVR (relative life-expectancy: 86.3%). Microsimulation-based 20-year risk of aortic valve reintervention was 42.0% (95% CI: 39.6%-44.6%) after Ross and 17.8% (95% CI: 17.0%-19.4%) after mAVR. CONCLUSION: Results of paediatric AVR are currently suboptimal with substantial mortality especially in the very young with considerable reintervention hazards for all valve substitutes, but the Ross procedure provides a survival benefit over mAVR. Pros and cons of substitutes should be carefully weighed during paediatric valve selection.

Quantum Non-Gaussianity of Multiphonon States of a Single Atom.

Quantum non-Gaussian mechanical states are already required in a range of applications. The discrete building blocks of such states are the energy eigenstates-Fock states. Despite progress in their preparation, the remaining imperfections can still invisibly cause loss of the aspects critical for their applications. We derive and apply the most challenging hierarchy of quantum non-Gaussian criteria on the characterization of single trapped-ion oscillator mechanical Fock states with up to 10 phonons. We analyze the depth of these quantum non-Gaussian features under intrinsic mechanical heating and predict their requirement for reaching quantum advantage in the sensing of a mechanical force.

Natural History of a Traumatic Olecranon Loss Resulting in a "Reversed Elbow": A Case Report.

Case description: A 58-year-old woman suffered an open displaced olecranon fracture with extensive soft tissue damage when she was involved in a car accident in Africa. Local doctors performed a debridement of the elbow. Later, she presented in our centre for further treatment. There was a possibility of active infection, for which antibiotics were given and a debridement was performed. We then applied dynamic external fixation to minimize infection risk. Physiotherapy started soon after. External fixation was removed after 2 months. On follow-up, the patient reported no pain and no signs of major instability were present. Therefore, we agreed not to perform additional surgery. Annual follow-up radiographs showed progressive remodelling of the joint. Eleven years after the initial trauma, a reversed elbow has formed. It is a fully functional neo-articulation that is shaped by osteophyte formation and erosion of ulna, radius and humerus. The patient is free of pain and shows intact flexion and supination, while extension and pronation are limited. She has regained good elbow function and can perform most of her daily activities. Conclusion: Invasive reconstructive surgery with implantation of foreign material should be avoided or postponed in heavily contaminated fractures to avoid infection. It could be valuable to consider a watchful waiting strategy, which sometimes results in a good functional end result. Nature can be kind, which has been proven in our case. How to cite this article: Hendrikx FR, Heusdens CHW, Van Dyck P, et al. Natural History of a Traumatic Olecranon Loss Resulting in a "Reversed Elbow": A Case Report. Strategies Trauma Limb Reconstr 2020;15(2):126-129.

Valgus instability of the elbow: acute and chronic form.

There has been an increase in thrower-specific elbow injuries in recent years. High valgus stresses during the late cocking and acceleration phases of throwing need to be compensated by the flexor pronator muscles as these can exceed the tensile strength of the medial collateral ligament complex. Prevention of injuries is the priority, with a focus on strengthening, reducing throwing frequency, decreasing force, and promoting a technique. The spectrum of thrower injuries ranges from a simple sprain to complete failure of the valgus stabilizing factors. The medial collateral ligament can stretch, leading to posteromedial impingement and radiocapitellar compression forces. This in turn can result in arthrosis and the formation of osteophytes. Ligament failure may eventually occur, making it impossible for the athlete to continue their throwing activities. The outcome of conservative treatment with strengthening, improvement of technique, and relative rest is often disappointing. Direct repair may no longer be possible in these acute-on-chronic injuries and a reconstruction with a tendon graft may be necessary.

Nonclassical Light from Large Ensembles of Trapped Ions.

The vast majority of physical objects we are dealing with are almost exclusively made of atoms. Because of their discrete level structure, single atoms have proved to be emitters of light, which is incompatible with the classical description of electromagnetic waves. We demonstrate this incompatibility for atomic fluorescence when scaling up the size of the source ensemble, which consists of trapped atomic ions, by several orders of magnitude. The presented measurements of nonclassical statistics on light unconditionally emitted from ensembles containing up to more than a thousand ions promise further scalability to much larger emitter numbers. The methodology can be applied to a broad range of experimental platforms focusing on the bare nonclassical character of single isolated emitters.

Slowing Quantum Decoherence by Squeezing in Phase Space.

Non-Gaussian states, and specifically the paradigmatic cat state, are well known to be very sensitive to losses. When propagating through damping channels, these states quickly lose their nonclassical features and the associated negative oscillations of their Wigner function. However, by squeezing the superposition states, the decoherence process can be qualitatively changed and substantially slowed down. Here, as a first example, we experimentally observe the reduced decoherence of squeezed optical coherent-state superpositions through a lossy channel. To quantify the robustness of states, we introduce a combination of a decaying value and a rate of decay of the Wigner function negativity. This work, which uses squeezing as an ancillary Gaussian resource, opens new possibilities to protect and manipulate quantum superpositions in phase space.

How to obtain and maintain favorable results after heart transplantation: keys to success?

We compared survival in our heart recipients with survival rates reported by the International Society of Heart and Lung Transplantation (ISHLT) Registry. As recipient and donor characteristics are changing over time, we studied four different eras. In order to differentiate between short- and long-term survival, we analyzed both overall survival and survival at one year. Obviously, this exercise is only relevant when baseline donor and recipient characteristics are comparable, as these differences may affect the outcome in opposite directions. To overcome this potential bias as much as possible, we calculated the Index for Mortality Prediction After Cardiac Transplantation (IMPACT)-scores and the Donor Risk Index (DRI). Looking to our results, we found that our DRIs in the different eras are almost equal to those obtained from the United Network for Organ Sharing database in the very same eras. Our IMPACT-scores, on the other hand, seem higher than those reported by ISHLT. Survival after transplantation and conditional on 1-year survival was higher than the outcome reported by the ISHLT Registry. As our operation technique and post-transplant immunosuppressive schedule did not differ from most centers, we speculated on potential factors that might contribute to our positive results. Patient selection and a relatively short waiting time are important contributors to the overall survival benefit. Our centralized follow-up may also have played an important role. Finally, the indefinite compulsory health insurance coverage in our country and easy access to different screening programs might also have influenced our outcome in a positive way. We are well aware that with challenges like donor organ shortage, more and more patients on mechanical circulatory support (MCS) will affect outcomes in the future.

Work and information from thermal states after subtraction of energy quanta.

Quantum oscillators prepared out of thermal equilibrium can be used to produce work and transmit information. By intensive cooling of a single oscillator, its thermal energy deterministically dissipates to a colder environment, and the oscillator substantially reduces its entropy. This out-of-equilibrium state allows us to obtain work and to carry information. Here, we propose and experimentally demonstrate an advanced approach, conditionally preparing more efficient out-of-equilibrium states only by a weak dissipation, an inefficient quantum measurement of the dissipated thermal energy, and subsequent triggering of that states. Although it conditionally subtracts the energy quanta from the oscillator, average energy grows, and second-order correlation function approaches unity as by coherent external driving. On the other hand, the Fano factor remains constant and the entropy of the subtracted state increases, which raise doubts about a possible application of this approach. To resolve it, we predict and experimentally verify that both available work and transmitted information can be conditionally higher in this case than by arbitrary cooling or adequate thermal heating up to the same average energy. It qualifies the conditional procedure as a useful source for experiments in quantum information and thermodynamics.

Faithful conditional quantum state transfer between weakly coupled qubits.

One of the strengths of quantum information theory is that it can treat quantum states without referring to their particular physical representation. In principle, quantum states can be therefore fully swapped between various quantum systems by their mutual interaction and this quantum state transfer is crucial for many quantum communication and information processing tasks. In practice, however, the achievable interaction time and strength are often limited by decoherence. Here we propose and experimentally demonstrate a procedure for faithful quantum state transfer between two weakly interacting qubits. Our scheme enables a probabilistic yet perfect unidirectional transfer of an arbitrary unknown state of a source qubit onto a target qubit prepared initially in a known state. The transfer is achieved by a combination of a suitable measurement of the source qubit and quantum filtering on the target qubit depending on the outcome of measurement on the source qubit. We experimentally verify feasibility and robustness of the transfer using a linear optical setup with qubits encoded into polarization states of single photons.

The Protective and Therapeutic Effect of Exclusive and Combined Treatment with Alpha-ketoglutarate Sodium Salt and Ipriflavone on Bone Loss in Orchidectomized Rats.

OBJECTIVE: This study investigated the effect of alpha-ketoglutarate sodium salt (AKG) and ipriflavone (IP) treatment on the mineralization of the tibia in male rats during the development and after the establishment of osteopenia. DESIGN: One hundred and twenty eight male rats were randomly selected and submitted to either sham-operation (SHO) or orchidectomy (ORX), after which each group were then randomly divided between the two experiments. In Experiment-1, treatment with AKG or/and IP started after a 7-day recovery period, whereas in Experiment-2, the experimental protocol proceeded after a 60-day period of osteopenia establishment. AKG was then administered as an experimental drinking, at a concentration of 1.0 mol/l. As a control, a placebo solution was administered. IP at 50 mg/kg b.w., and physiological saline - PhS (as a control for IP) were applied daily via gavage. MEASUREMENTS: After 60 days of experimental treatment, in both experiments, the rats were sacrificed, their body weight recorded, while blood serum (Osteocalcin, CTX) and isolated tibia (weight, length, pQCT, DXA, 3-point bending test) were stored for further analysis. RESULTS AND CONCLUSIONS: Our results show that during the development of osteopenia, AKG and IP when applied exclusively, counteracts osteopenia development, whereas their usage after the establishment of osteopenia, significantly limits the development of bone disorders. Furthermore, combined treatment of AKG and IP exceeded the effects of their sole usage. In addition, during the development of osteopenia, AKG and IP not only inhibited bone resorption, but markedly stimulated the formation of bone tissue. Finally, after the development of osteopenia, combined treatment with AKG and IP protected the bone tissue against orchidectomy-induced bone loss.

Deterministic nonclassicality from thermal states.

Coupling an oscillator to a single two-level system is one of the most fundamental interactions in quantum physics. We report on a dynamical effect during which a thermal state of an oscillator is unconditionally transformed to a highly nonclassical state with negative Wigner function values by mere absorbtion by a single uncontrolled two-level system. This complements the traditional test of Rabi oscillations and it serves as a simply measurable witness that the process in question is highly nonclassical. The process is experimentally feasible with possible experimental implementation in a number of experimental platforms with intrinsic Jaynes-Cummings interaction and it has the potential of enabling deterministic generation of nonclassical quantum states.

Heralded source of bright multi-mode mesoscopic sub-Poissonian light.

In a direct detection scheme, we observed 7.8 dB of twin-beam squeezing for multi-mode two-color squeezed vacuum generated via parametric downconversion. Applying post-selection, we conditionally prepared a sub-Poissonian state of light containing 6.3·105 photons per pulse on the average with the Fano factor 0.63±0.01. The scheme can be considered as the heralded preparation of pulses with the mean energy varying between tens and hundreds of fJ and the uncertainty considerably below the shot-noise level. Such pulses can be used in metrology (for instance, for radiometer calibration), as well as for probing multi-mode nonlinear optical effects.

Optical Synthesis of Large-Amplitude Squeezed Coherent-State Superpositions with Minimal Resources.

We propose and experimentally realize a novel versatile protocol that allows the quantum state engineering of heralded optical coherent-state superpositions. This scheme relies on a two-mode squeezed state, linear mixing, and a n-photon detection. It is optimally using expensive non-Gaussian resources to build up only the key non-Gaussian part of the targeted state. In the experimental case of a two-photon detection based on high-efficiency superconducting nanowire single-photon detectors, the freely propagating state exhibits a 67% fidelity with a squeezed even coherent-state superposition with a size |α|(2)=3. The demonstrated procedure and the achieved rate will facilitate the use of such superpositions in subsequent protocols, including fundamental tests and optical hybrid quantum information implementations.

Selective Radical-Radical Cross-Couplings: Design of a Formal ß-Mannich Reaction.

A direct ß-coupling of cyclic ketones with imines has been accomplished via the synergistic combination of photoredox catalysis and organocatalysis. Transient ß-enaminyl radicals derived from ketones via enamine and oxidative photoredox catalysis readily combine with persistent α-amino radicals in a highly selective hetero radical-radical coupling. This novel pathway to γ-aminoketones is predicated upon the use of DABCO as both a base and an electron transfer agent. This protocol also formally allows for the direct synthesis of ß-Mannich products via a chemoselective three-component coupling of aryl aldehydes, amines, and ketones.

Decarboxylative Fluorination of Aliphatic Carboxylic Acids via Photoredox Catalysis.

The direct conversion of aliphatic carboxylic acids to the corresponding alkyl fluorides has been achieved via visible light-promoted photoredox catalysis. This operationally simple, redox-neutral fluorination method is amenable to a wide variety of carboxylic acids. Photon-induced oxidation of carboxylates leads to the formation of carboxyl radicals, which upon rapid CO2-extrusion and F(•) transfer from a fluorinating reagent yield the desired fluoroalkanes with high efficiency. Experimental evidence indicates that an oxidative quenching pathway is operable in this broadly applicable fluorination protocol.

Twelve-month consumption of a polyphenol extract from olive (Olea europaea) in a double blind, randomized trial increases serum total osteocalcin levels and improves serum lipid profiles in postmenopausal women with osteopenia.

OBJECTIVES: Osteoporosis is a skeletal disorder characterized by impaired bone turnover and compromised bone strength, thereby predisposing to increased risk of fracture. Preclinical research has shown that compounds produced by the olive tree (Olea europaea), may protect from bone loss, by increasing osteoblast activity at the expense of adipocyte formation. The aim of this exploratory study was to obtain a first insight on the effect of intake of an olive extract on bone turnover in postmenopausal women with decreased bone mass (osteopenia). DESIGN AND SETTING: For that, a double blind, placebo-controlled study was performed in which participants were randomly allocated to either treatment or placebo groups. PARTICIPANTS: 64 osteopenic patients, with a mean bone mineral density (BMD) T-score between -1.5 and -2.5 in the lumbar spine (L2-L4) were included in the study. INTERVENTION AND MEASUREMENTS: PARTICIPANTS received for 12 months daily either 250 mg/day of olive extract and 1000 mg Ca (treatment) or 1000 mg Ca alone (placebo). Primary endpoints consisted of evaluation of bone turnover markers. Secondary endpoints included BMD measurements and blood lipid profiles. RESULTS: After 12 months, the levels of the pro-osteoblastic marker osteocalcin were found to significantly increase in the treatment group as compared to placebo. Simultaneously, BMD decreased in the placebo group, while remaining stable in the treatment group. In addition, improved lipid profiles were observed, with significant decrease in total- and LDL-cholesterol in the treatment group. CONCLUSION: This exploratory study supports preclinical observations and warrants further research by showing that a specific olive polyphenol extract (Bonolive®) affects serum osteocalcin levels and may stabilize lumbar spine BMD. Moreover, the improved blood lipid profiles suggest additional health benefits associated to the intake of the olive polyphenol extract.

Retrograde flush is more protective than heparin in the uncontrolled donation after circulatory death lung donor.

BACKGROUND: Formation of microthrombi after circulatory arrest is a concern for the development of reperfusion injury in lung recipients from donation after circulatory death (DCD) donors. In this isolated lung reperfusion study, we compared the effect of postmortem heparinization with preharvest retrograde pulmonary flush or both. METHODS: Domestic pigs (n = 6/group) were sacrificed by ventricular fibrillation and left at room temperature for 1 h. This was followed by 2.5 h of topical cooling. In control group [C], no heparin and no pulmonary flush were administered. In group [R], lungs were flushed with Perfadex in a retrograde way before explantation. In group [H], heparin (300 IU/kg) was administered 10 min after cardiac arrest followed by closed chest massage for 2 min. In the combined group, animals were heparinized and the lungs were explanted after retrograde flush [HR]. The left lung was assessed for 60 min in an ex vivo reperfusion model. RESULTS: Pulmonary vascular resistance at 50 and 55 min was significantly lower in [R] and [HR] groups compared with [C] and [H] groups (P < 0.01 and P < 0.001) and at 60 min in [R], [H], and [HR] groups compared with [C] group (P < 0.001). Oxygenation, compliance, and plateau airway pressure were more stable in [R] and [HR] groups. Plateau airway pressure was significantly lower in [R] group compared with the [H] group at 60 min (P < 0.05). No significant differences in wet-dry weight ratio were observed between the groups. CONCLUSIONS: This study suggests that preharvest retrograde flush is more protective than postmortem heparinization to prevent reperfusion injury in lungs recovered from donation after circulatory death donors.

Direct ß-functionalization of cyclic ketones with aryl ketones via the merger of photoredox and organocatalysis.

The direct ß-coupling of cyclic ketones with aryl ketones has been achieved via the synergistic combination of photoredox catalysis and organocatalysis. Diaryl oxymethyl or aryl-alkyl oxymethyl radicals, transiently generated via single-electron reduction of ketone precursors, readily merge with ß-enaminyl radical species, generated by photon-induced enamine oxidation, to produce γ-hydroxyketone adducts. Experimental evidence indicates that two discrete reaction pathways can be operable in this process depending upon the nature of the ketyl radical precursor and the photocatalyst.

Partial mechanical circulatory support in an ovine model of post-infarction remodeling.

BACKGROUND: Full unloading of the left ventricle (LV) in chronic heart failure (CHF) induces reversal of LV dilation and geometric distortion. In this study we describe the partial unloading effects in ischemic CHF. METHODS: Six weeks after myocardial infarction, sheep were randomized to partial support ("pump," n = 5), as provided by the CircuLite Synergy micro-pump, or to no therapy ("sham," n = 6) for an additional 6 weeks. At baseline, and at 6 and 12 weeks after infarction, pressure-volume (PV) recordings were made. Systolic and diastolic functions were characterized by the end-systolic volume (ESV) where LV end-systolic pressure reached 90 mm Hg (V90), and the end-diastolic volume (EDV) where LV end-diastolic pressure reached 15 mm Hg (V15), respectively. Magnetic resonance imaging (MRI) was performed 6 and 12 weeks after infarction. During autopsy at 12 weeks, isolated LVs were weighed. Histologically, the degree of fibrosis in the non-infarcted area was assessed using systematic randomized sampling, and myocyte hypertrophy was measured by the mean linear intercept method. RESULTS: At 6 weeks, PV measurements showed a V90 and V15 increase (p = NS between groups). Six weeks later, V90 and V15 increased in the sham group. In the pump group, V90 decreased but V15 did not change significantly. At 6 weeks, MRI indicated no significant difference between groups. Six weeks later, in the sham group, EDV and ESV increased significantly. In the pump group, EDV decreased significantly and ESV trended to decrease. Sphericity index increased in the sham group and decreased in the pump group, although not significantly. Explanted LV masses were significantly higher in the sham group than in the pump group. The pump group had a decrease in fibrosis and less myocyte hypertrophy. CONCLUSION: Partial support 6 weeks after major myocardial infarction halts and reverses ventricular dilation and hypertrophy.