Single-Operator Left atrial appendage Occlusion utilizing Conscious sedation TEE, Lack of Outpatient pre-imaging, and Same-day Expedited discharge (SOLO-CLOSE): A comparison with conventional approach.

BACKGROUND: Left atrial appendage occlusion (LAAO) with WATCHMAN currently requires preprocedural imaging, general anesthesia, and inpatient overnight admission. We sought to facilitate simplification of LAAO. AIMS: We describe and compare SOLO-CLOSE (single-operator LAA occlusion utilizing conscious sedation TEE, lack of outpatient pre-imaging, and same-day expedited discharge) with the conventional approach (CA). METHODS: A single-center retrospective analysis of 163 patients undergoing LAAO between January 2017 and April 2022 was conducted. The SOLO-CLOSE protocol was enacted on December 1, 2020. Before this date, we utilized the CA. The primary efficacy endpoint was defined as successful LAAO with ≤5 mm peri-device leak at time of closure. The primary safety endpoint was the composite incidence of all-cause deaths, any cerebrovascular accident (CVA), device embolization, pericardial effusion, or major postprocedure bleeding within 7 days of the index procedure. Procedure times, 7-day readmission rates, and cost analytics were collected as well. RESULTS: Baseline characteristics were similar in both cohorts. Congestive heart failure (37.5% vs. 11.1%) and malignancy (28.8% vs. 12.5%) were higher in SOLO-CLOSE. Median CHA2D2SVASc score was 5 in both cohorts. The primary efficacy endpoint was met 100% in both cohorts. Primary safety endpoint was similar between cohorts (p = 0.078). Mean procedure time was 30 min shorter in SOLO-CLOSE (p < 0.01). Seven-day readmissions for SOLO-CLOSE was zero. After SOLO-CLOSE implementation, there was a 188% increase in positive contribution margin per case. CONCLUSIONS: The SOLO-CLOSE methodology offers similar efficacy and safety when compared to the CA, while improving clinical efficiency, reducing procedural times, and increasing economic benefit.

Death-associated protein kinase 3 regulates the myogenic reactivity of cerebral arteries.

NEW FINDINGS: What is the central question of this study? DAPK3 contributes to the Ca2+ -sensitization of vascular smooth muscle contraction: does this protein kinase participate in the myogenic response of cerebral arteries? What is the main finding and its importance? Small molecule inhibitors of DAPK3 effectively block the myogenic responses of cerebral arteries. HS38-dependent changes to vessel constriction occur independent of LC20 phosphorylation, and therefore DAPK3 appears to operate via the actin cytoskeleton. A role for DAPK3 in the myogenic response was not previously reported, and the results support a potential new therapeutic target in the cerebrovascular system. ABSTRACT: The vascular smooth muscle (VSM) of resistance blood vessels is a target of intrinsic autoregulatory responses to increased intraluminal pressure, the myogenic response. In the brain, the myogenic reactivity of cerebral arteries is critical to homeostatic blood flow regulation. Here we provide the first evidence to link the death-associated protein kinase 3 (DAPK3) to the myogenic response of rat and human cerebral arteries. DAPK3 is a Ser/Thr kinase involved in Ca2+ -sensitization mechanisms of smooth muscle contraction. Ex vivo administration of a specific DAPK3 inhibitor (i.e., HS38) could attenuate vessel constrictions invoked by serotonin as well as intraluminal pressure elevation. The HS38-dependent dilatation was not associated with any change in myosin light chain (LC20) phosphorylation. The results suggest that DAPK3 does not regulate Ca2+ sensitization pathways during the myogenic response of cerebral vessels but rather operates to control the actin cytoskeleton. A slow return of myogenic tone was observed during the sustained ex vivo exposure of cerebral arteries to HS38. Recovery of tone was associated with greater LC20 phosphorylation that suggests intrinsic signalling compensation in response to attenuation of DAPK3 activity. Additional experiments with VSM cells revealed HS38- and siDAPK-dependent effects on the actin cytoskeleton and focal adhesion kinase phosphorylation status. The translational importance of DAPK3 to the human cerebral vasculature was noted, with robust expression of the protein kinase and significant HS38-dependent attenuation of myogenic reactivity found for human pial vessels.

Smoothelin-like 1 knockout mice display sex-dependent alterations in blood flow and cardiac function.

Smoothelin-like 1 (SMTNL1) modulates the contractile performance of smooth muscle and thus has a key role in vascular homeostasis. Elevated vascular tone, recognized as a contributor to the development of progressive cardiac dysfunction, was previously found with SMTNL1 deletion. In this study, we assessed cardiac morphology and function of male and female, wild-type (Smtnl1+/+) and global SMTNL1 knockout (Smtnl1-/-) mice at 10 weeks of age. Gross dissection revealed distinct cardiac morphology only in males; Smtnl1-/- hearts were significantly smaller than Smtnl1+/+, but the left ventricle (LV) proportion of heart mass was greater. Male Smtnl1-/- mice also displayed increased ejection fraction and fractional shortening, as well as elevated aortic and pulmonary flow velocities. The impact of cardiac stress with pressure overload by transverse aortic constriction (TAC) was examined in male mice. With TAC banding, systolic function was preserved, but the LV filling pressure was selectively elevated due to relaxation impairment. Smtnl1-/- mice displayed higher early/passive filling velocity of LV/early mitral annulus velocity ratio (E/E' ratio) and myocardial performance index along with a prolonged isovolumetric relaxation time. Taken together, the findings support a novel, sex-dimorphic role for SMTNL1 in modulating cardiac structure and function of mice.

Intraoperative bile spillage as a risk factor for surgical site infection: a propensity score-matched NSQIP analysis.

BACKGROUND: Laparoscopic cholecystectomy is one of the most commonly performed operations in the USA. Surgical site infection complicates 1-2% of these operations and can be associated with significant morbidity. Bile spillage (bile spillage) occurs in many of these operations. The associated risk of surgical site infection (SSI) is an ongoing area of research. METHODS: NSQIP registries between 2005 and 2018 were queried using Current Procedural Terminology codes 47,562 and 47,563 to identify patients undergoing elective laparoscopic cholecystectomy. Patients were considered to have bile spillage if the wound classification was annotated 3 or 4. Acute cholecystitis was excluded by ICD code. Patients were propensity scored for bile spillage and matched for preoperative risk factors. The rates of surgical site infections, morbidity, and mortality and length of stay were analyzed. RESULTS: 47,919 (31,946 with no spillage and 15,973 with spillage) patients were matched and included in the analysis. After matching, no significant difference was found in superficial or deep SSI regardless of bile spillage. An absolute increase in organ-space SSI of 0.32% was detected. The group with bile spillage had small increases in both minor (1.41% vs. 2.12%) and major (0.67% vs. 1.01%) complications. There was no difference in mortality. CONCLUSIONS: This database analysis demonstrates no clinically relevant difference in surgical site infection rates after intraoperative bile spillage.

Quasiparticle Poisoning of Majorana Qubits.

Qubits based on Majorana zero modes are a promising path towards topological quantum computing. Such qubits, though, are susceptible to quasiparticle poisoning which does not have to be small by topological argument. We study the main sources of the quasiparticle poisoning relevant for realistic devices-nonequilibrium above-gap quasiparticles and equilibrium localized subgap states. Depending on the parameters of the system and the architecture of the qubit either of these sources can dominate the qubit decoherence. However, we find in contrast to naive estimates that in moderately disordered, floating Majorana islands the quasiparticle poisoning can have timescales exceeding seconds.

Inversion-Protected Higher-Order Topological Superconductivity in Monolayer WTe_{2}.

Monolayer WTe_{2}, a centrosymmetric transition metal dichacogenide, has recently been established as a quantum spin Hall insulator and found superconducting upon gating. Here we study the pairing symmetry and topological nature of superconducting WTe_{2} with a microscopic model at mean-field level. Surprisingly, we find that the spin-triplet phases in our phase diagram all host Majorana modes localized on two opposite corners. Even when the conventional pairing is favored, we find that an intermediate in-plane magnetic field exceeding the Pauli limit stabilizes an unconventional equal-spin pairing aligning with the field, which also hosts Majorana corner modes. Motivated by our findings, we obtain a recipe for two-dimensional superconductors featuring "higher-order topology" from the boundary perspective. Generally, a superconducting inversion-symmetric quantum spin Hall material whose normal-state Fermi surface is away from high-symmetry points, such as gated monolayer WTe_{2}, hosts Majorana corner modes if the superconductivity is parity-odd. We further point out that this higher-order phase is an inversion-protected topological crystalline superconductor and study the bulk-boundary correspondence. Finally, we discuss possible experiments for probing the Majorana corner modes. Our findings suggest superconducting monolayer WTe_{2} is a playground for higher-order topological superconductivity and possibly the first material realization for inversion-protected Majorana corner modes without utilizing proximity effect.

Higher-Order Topology and Nodal Topological Superconductivity in Fe(Se,Te) Heterostructures.

We show, theoretically, that a heterostructure of monolayer FeTe_{1-x}Se_{x}-a superconducting quantum spin Hall material-with a monolayer of FeTe-a bicollinear antiferromagnet-realizes a higher order topological superconductor phase characterized by emergent Majorana zero modes pinned to the sample corners. We provide a minimal effective model for this system, analyze the origin of higher order topology, and fully characterize the topological phase diagram. Despite the conventional s-wave pairing, we find a rather surprising emergence of a novel topological nodal superconductor in the phase diagram. Featured by edge-dependent Majorana flat bands, the topological nodal phase is protected by an antiferromagnetic chiral symmetry. We also discuss the experimental feasibility, the estimation of realistic model parameters, and the robustness of the Majorana corner modes against magnetic and potential disorder. Our work provides a new experimentally feasible high-temperature platform for both higher order topology and non-Abelian Majorana physics.

Proposal for Measuring the Parity Anomaly in a Topological Superconductor Ring.

A topological superconductor ring is uniquely characterized by a switch in the ground state fermion number parity upon insertion of one superconducting flux quantum-a direct consequence of the topological "parity anomaly." Despite the many other tantalizing signatures and applications of topological superconductors, this fundamental, defining property remains to be observed experimentally. Here we propose definitive detection of the fermion parity switch from the charging energy, temperature, and tunnel barrier dependence of the flux periodicity of two-terminal conductance of a floating superconductor ring. We extend the Ambegaokar-Eckern-Schön formalism for superconductors with a Coulomb charging energy to establish new explicit relationships between thermodynamic and transport properties of such a ring and the topological invariant of the superconductor. Crucially, we show that the topological contribution to the conductance oscillations can be isolated from Aharonov-Bohm oscillations of nontopological origin by their different dependence on the charging energy or barrier transparency.

Helical Hinge Majorana Modes in Iron-Based Superconductors.

Motivated by recent experiments on FeTe_{1-x}Se_{x}, we construct an explicit minimal model of an iron-based superconductor with band inversion at the Z point and nontopological bulk s_{±} pairing. While there has been considerable interest in Majorana zero modes localized at vortices in such systems, we find that our model-without any vortices-intrinsically supports 1D helical Majorana modes localized at the hinges between (001) and (100) or (010) surfaces, suggesting that this is a viable platform for observing "higher-order" topological superconductivity. We provide a general theory for these hinge modes and discuss their stability and experimental manifestation. Our work indicates the possible experimental observability of hinge Majorana modes in iron-based topological superconductors.

Cyclooxygenase inhibitors for treating preterm labour: What is the molecular evidence? 1.

Preterm birth (<37 weeks of gestation) significantly increases the risk of neonatal mortality and morbidity. As many as half of all preterm births occur following spontaneous preterm labour. Since in such cases there are no known reasons for the initiation of labour, treatment of preterm labour (tocolysis) has sought to stop labour contractions and delay delivery. Despite some success, the use of cyclooxygenase (COX) inhibitors is associated with maternal/fetal side effects, and possibly increased risk of preterm birth. Clinical use of these drugs predates the collection of molecular and biochemical evidence in vitro, examining the expression and activity of COX enzymes in pregnant uterine tissues with and without labour. Such evidence is important to the rationale that COX enzymes are, or are not, appropriate targets for the tocolysis. The current study systematically searched existing scientific evidence to address the hypothesis that COX expression/activity is increased with the onset of human labour, in an effort to determine whether there is a rationale for the use of COX inhibitors as tocolytics. Our review identified 44 studies, but determined that there is insufficient evidence to support or refute a role of COX-1/-2 in the onset of preterm labour that supports COX-targeted tocolysis.

Cellular and Ionic Mechanisms of Arterial Vasomotion.

Rhythmical contractility of blood vessels was first observed in bat wing veins by Jones (Philos Trans R Soc Lond 1852:142, 131-136), and subsequently described in arteries and arterioles of multiple vascular beds in several species. Despite an abundance of descriptive literature regarding the presence of vasomotion, to date we do not have an accurate picture of the cellular and ionic basis of these oscillations in tone, or the physiological relevance of the changes in pulsatile blood flow arising from vasomotion. This chapter reviews our current understanding of the cellular and ionic mechanisms underlying vasomotion in resistance arteries and arterioles. Focus is directed to the ion channels, changes in cytosolic Ca2+ concentration, and involvement of intercellular gap junctions in the development and synchronization of rhythmic changes in membrane potential and cytosolic Ca2+ concentration within the vessel wall that contribute to vasomotion. The physiological consequences of vasomotion are discussed with a focus on the cerebral vasculature, as recent advances show that rhythmic oscillations in cerebral arteriolar diameter appear to be entrained by cortical neural activity to increase the local supply of blood flow to active regions of the brain.

Airway epithelial compression promotes airway smooth muscle proliferation and contraction.

During acute bronchoconstriction, the airway epithelium becomes mechanically compressed, as airway smooth muscle contracts and the airway narrows. This mechanical compression activates airway epithelium to promote asthmatic airway remodeling. However, whether compressed airway epithelium can feed back on the cause of bronchoconstriction has remained an open question. Here we examine the potential for epithelial compression to augment proliferation and contraction of airway smooth muscle, and thus potentiate further bronchoconstriction and epithelial compression. Well-differentiated primary human bronchial epithelial (HBE) cells maintained in air-liquid interface culture were mechanically compressed to mimic the effect of bronchoconstriction. Primary human airway smooth muscle (HASM) cells were incubated with conditioned media collected from mechanically compressed HBE cells to examine the effect of epithelial-derived mediators on HASM cell proliferation using an EdU assay and HASM cell contraction using traction microscopy. An endothelin receptor antagonist, PD-145065, was employed to probe the role of HBE cell-derived endothelin-1 on the proliferation and contraction of HASM cells. Conditioned media from compressed HBE cells increased HASM cell proliferation, independent of the endothelin-1 signaling pathway. However, conditioned media from compressed HBE cells significantly increased HASM cell basal contraction and histamine-induced contraction, both of which depended on the endothelin-1 signaling pathway. Our data demonstrate that mechanical compression of bronchial epithelial cells contributes to proliferation and basal contraction of airway smooth muscle cells and that augmented contraction depends on epithelial cell-derived endothelin-1. By means of both airway smooth muscle remodeling and contractility, our findings suggest a causal role of epithelial compression on asthma pathogenesis.

Transient stretch induces cytoskeletal fluidization through the severing action of cofilin.

With every deep inspiration (DI) or sigh, the airway wall stretches, as do the airway smooth muscle cells in the airway wall. In response, the airway smooth muscle cell undergoes rapid stretch-induced cytoskeletal fluidization. As a molecular mechanism underlying the cytoskeletal fluidization response, we demonstrate a key role for the actin-severing protein cofilin. Using primary human airway smooth muscle cells, we simulated a DI by imposing a transient stretch of physiological magnitude and duration. We used traction microscopy to measure the resulting changes in contractile forces. After a transient stretch, cofilin-knockdown cells exhibited a 29 ± 5% decrease in contractile force compared with prestretch conditions. By contrast, control cells exhibited a 67 ± 6% decrease ( P < 0.05, knockdown vs. control). Consistent with these contractile force changes with transient stretch, actin filaments in cofilin-knockdown cells remained largely intact, whereas actin filaments in control cells were rapidly disrupted. Furthermore, in cofilin-knockdown cells, contractile force at baseline was higher and rate of remodeling poststretch was slower than in control cells. Additionally, the severing action of cofilin was restricted to the release phase of the transient stretch. We conclude that the actin-severing activity of cofilin is an important factor in stretch-induced cytoskeletal fluidization and may account for an appreciable part of the bronchodilatory effects of a DI.

Terahertz VRT Spectroscopy of the Water Hexamer-h12 Cage: Dramatic Libration-Induced Enhancement of Hydrogen Bond Tunneling Dynamics.

We report the assignment and analysis of 176 transitions belonging to a librational band of the (H2O)6 cage isomer near 525 cm-1(15 THz). From a fit of the transitions to an asymmetric top model, we observe both dramatic changes in the rotational constants relative to the ground state, indicating significant nonrigidity, and striking enhancement in the tunneling motions that break and reform the hydrogen bonds in the cluster. This is the fifth water cluster system to display such an enhancement in the 15 THz librational region, the details of which may help to elucidate the hydrogen bond dynamics occurring in bulk liquid water.

The pro-inflammatory cytokine TNF-α inhibits lymphatic pumping via activation of the NF-κB-iNOS signaling pathway.

OBJECTIVE: Mesenteric lymphatic vessel pumping, important to propel lymph and immune cells from the intestinal interstitium to the mesenteric lymph nodes, is compromised during intestinal inflammation. The objective of this study was to test the hypothesis that the pro-inflammatory cytokine TNF-α, is a significant contributor to the inflammation-induced lymphatic contractile dysfunction, and to determine its mode of action. METHODS: Contractile parameters were obtained from isolated rat mesenteric lymphatic vessels mounted on a pressure myograph after 24-hours incubation with or without TNF-α. Various inhibitors were administered, and quantitative real-time PCR, Western blotting, and immunofluorescence confocal imaging were applied to characterize the mechanisms involved in TNF-α actions. RESULTS: Vessel contraction frequency was significantly decreased after TNF-α treatment and could be restored by selective inhibition of NF-кB, iNOS, guanylate cyclase, and ATP-sensitive K+ channels. We further demonstrated that NF-кB inhibition also suppressed the significant increase in iNOS mRNA observed in TNF-α-treated lymphatic vessels and that TNF-α treatment favored the nuclear translocation of the p65 NF-κB subunit. CONCLUSIONS: These findings suggest that TNF-α decreases mesenteric lymphatic contractility by activating the NF-κB-iNOS signaling pathway. This mechanism could contribute to the alteration of lymphatic pumping reported in intestinal inflammation.

Hydrogen bond network rearrangement dynamics in water clusters: Effects of intermolecular vibrational excitation on tunneling rates.

Theoretical studies of hydrogen bond network rearrangement (HBNR) dynamics in liquid water have indicated that librational motions initiate the hydrogen bond breaking/formation processes. We present the results of using a simple time evolution method to extract and compare the tunneling lifetimes for motions that break and reform the hydrogen bond for the water dimer, trimer, and pentamer from the experimentally measured tunneling splittings in the ground and excited intermolecular vibrational states. We find that the specific nature of the intermolecular vibrational excitation does not significantly influence the tunneling lifetime of the dimer, but that only excitations to a librational vibration affect the water trimer and pentamer lifetimes. The specific enhancement of bifurcation tunneling in larger clusters relative to the dimer also indicates that hydrogen bond cooperativity is a vital element of these dynamics.

Hydrogen bond breaking dynamics in the water pentamer: Terahertz VRT spectroscopy of a 20 µm libration.

Hydrogen bonds in solid and liquid water are formed and broken via librational vibrations, hence characterizing the details of these motions is vital to understanding these important dynamics. Here we report the measurement and assignment of 875 transitions comprising 6 subbands originating from out-of-plane librational transitions of the water pentamer-d10 near 512 cm-1. The precisely measured (ca. 1 ppm) transitions reveal bifurcation splittings of ∼1884 MHz, a ∼4000× enhancement over ground state splittings and 100× greater than predicted by theory. The pentamer is thus the third water cluster to display greatly enhanced bifurcation tunneling upon single quantum excitation of librational vibrations. From the intensity pattern of the observed transitions, the mechanism of bifurcation is established by comparison with theoretical predictions.

First Recorded Observations of Pollination and Oviposition Behavior in Tegeticula antithetica (Lepidoptera: Prodoxidae) Suggest a Functional Basis for Coevolution With Joshua Tree (Yucca) Hosts.

Yucca moths (Tegeticula spp.) are the exclusive pollinators of Joshua trees (Yucca brevifolia s. l.). The moths actively pollinate the Joshua tree flowers and lay their eggs in the style. Recent studies have revealed that the plants commonly known as Joshua trees include two distinct, sister-species of plant: Yucca brevifolia Engelm. and Yucca jaegeriana McKelvey, each pollinated by two sister-species of yucca moth Tegeticula synthetica Riley and Tegeticula antithetica Pellmyr, respectively. A number of studies have argued that the moths have coevolved with their hosts, producing a pattern of phenotype matching between moth ovipositor length and floral style length. However, the only known descriptions of yucca moth pollination and oviposition behavior on Joshua trees are observations of T. synthetica made in 1893. The behavior of T. antithetica has never been observed before. We produced the first video recordings of the behavior of T. antithetica, and measured the points of oviposition and egg placement within the floral style. We found a number of differences between the behaviors of T. antithetica and T. synthetica, which appear to be a consequence of differences in floral morphology between Y. jaegeriana and Y. brevifolia. We also found that variation in floral style length strongly influences the placement of eggs within the flower, which may explain patterns of phenotype matching described previously. However, unlike in other yucca moths, we find that the mode of oviposition is unlikely to wound the floral ovules, and thus that oviposition by T. antithetica is unlikely to prompt floral abscission.

Allergen-specific immunotherapy prescription patterns in veterinary practice: a US population-based cohort study.

BACKGROUND: Poor adherence to continuing allergen-specific immunotherapy treatment (ASIT) may be an issue in veterinary medicine. No studies describe how allergen tests are used in general veterinary practice, including the percentage of patients that receive ASIT after allergen testing. HYPOTHESIS/OBJECTIVES: Assess veterinary ASIT patterns in United States general practices. ANIMALS: Dogs (n = 2,557) and 121 cats allergen-tested at 177 hospitals (173 general practice and four specialty practices) in 44 states. METHODS: Invoiced service descriptions of allergen tests and ASIT orders were retrieved from an aggregated database of veterinary practices. RESULTS: In general practice, 42% (992 of 2,360) of patients did not begin ASIT after allergen testing. ASIT was not refilled for 29% (398 of 1,368) of patients after the initial order. ASIT was initiated and refilled more often in dogs (56.6%, 71.4%, respectively) than cats (38%, 67.4%). Specialty practice patients had the highest ASIT initiation (94.4%) and refill (92.7%) percentages in comparison to general practices (P < 0.001). Size, age, geographical region and type of practice were associated with whether dogs were started on ASIT. Geographical region was also associated with refilling a prescription for ASIT, which was considered to be evidence of adherence to continuing treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Almost one third of clients failed to continue ASIT beyond the initial order, which is a much shorter duration of therapy than the 12 months recommended for determining ASIT efficacy. A large number of general practice patients did not begin ASIT after allergen testing, likely due to differences in how clinicians in general and dermatology practices use allergen tests.

WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta.

This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T→G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C→A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.