Clinical failures of endovascular abdominal aortic aneurysm repair: Incidence, causes, and management

AbstractObjective: Despite well-documented good early results and benefits of endoluminal stent graft repair of abdominal aortic aneurysm (J Vasc Surg 2002;35:1137-44.)(AAA), the long-term outcome of this method of treatment remains uncertain. In particular, concern exists that late effectiveness and durability are inferior to that of open repair. To determine the incidence and causes of clinical failures of endovascular AAA repair, a 7-year experience with 362 primary AAA endografts was reviewed. Methods: Clinical failures were defined as deaths within 30 days of the procedure, conversions (early and late) to open AAA repair, AAA rupture after endoluminal treatment, or AAA sac growth of more than 5 mm in maximal diameter despite endograft repair. Endoleak status per se was not considered unless it resulted in an adverse event. If clinical problems arose but could be corrected with catheter-based therapies or limited surgical procedures, thereby maintaining the integrity of successful stent graft treatment of the AAA, such cases were considered as primary assisted success and not classified as clinical failures. Results: The average follow-up period was 1.5 years. Six deaths (1.6%) occurred after the procedure, all in elderly patients or patients at high risk. Five patients (1.4%) needed early conversion (immediate, 2 days) to open repair for access problems or technical difficulties with deployment, resulting in an implantation success rate of 98.6%. Eight patients (2.2%) underwent late conversion for a variety of problems, including AAA expansion (n = 4), endograft thrombosis (n = 1), secondary graft infection (n = 2), and rupture at 3 years (n = 1). Rupture occurred in an additional two patients for a total incidence rate of 0.8%. AAA sac growth of greater than 5 mm was observed in 20 patients (5.6%), four of whom have undergone successful catheter-based treatments to date. Overall, 39 patients (10.7%) needed catheter-based (n = 45) or limited surgical (n = 4) reinterventions for a variety of late problems that were successful in 92%. Conclusion: In our 7-year experience, one or more clinical failures of endovascular AAA repair were observed in 31 patients (8.3%). Reinterventions were necessitated in a total of 10.7% of patients but were usually successful in maintaining AAA exclusion and limiting AAA growth. These results emphasize that endovascular repair provides good results and many benefits for most properly selected patients but is not as durable as standard open repair. (J Vasc Surg 2002;35:1137-44.

Identifying Exoplanets with Deep Learning. III. Automated Triage and Vetting of TESS Candidates

NASA’s Transiting Exoplanet Survey Satellite (TESS) presents us with an unprecedented volume of space-based photometric observations that must be analyzed in an efficient and unbiased manner. With at least ∼1,000,000 new light curves generated every month from full-frame images alone, automated planet candidate identification has become an attractive alternative to human vetting. Here we present a deep learning model capable of performing triage and vetting on TESS candidates. Our model is modified from an existing neural network designed to automatically classify Kepler candidates, and is the first neural network to be trained and tested on real TESS data. In triage mode, our model can distinguish transit-like signals (planet candidates and eclipsing binaries) from stellar variability and instrumental noise with an average precision (the weighted mean of precisions over all classification thresholds) of 97.0% and an accuracy of 97.4%. In vetting mode, the model is trained to identify only planet candidates with the help of newly added scientific domain knowledge, and achieves an average precision of 69.3% and an accuracy of 97.8%. We apply our model on new data from Sector 6, and present 288 new signals that received the highest scores in triage and vetting and were also identified as planet candidates by human vetters. We also provide a homogeneously classified set of TESS candidates suitable for future training

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune

Identifying predictors of translocation success in rare plant species

The fundamental goal of a rare plant translocation is to create self-sustaining populations with the evolutionary resilience to persist in the long term. Yet, most plant translocation syntheses focus on a few factors influencing short-term benchmarks of success (e.g., survival and reproduction). Short-term benchmarks can be misleading when trying to infer future growth and viability because the factors that promote establishment may differ from those required for long-term persistence. We assembled a large (n = 275) and broadly representative data set of well-documented and monitored (7.9 years on average) at-risk plant translocations to identify the most important site attributes, management techniques, and species' traits for six life-cycle benchmarks and population metrics of translocation success. We used the random forest algorithm to quantify the relative importance of 29 predictor variables for each metric of success. Drivers of translocation outcomes varied across time frames and success metrics. Management techniques had the greatest relative influence on the attainment of life-cycle benchmarks and short-term population trends, whereas site attributes and species' traits were more important for population persistence and long-term trends. Specifically, large founder sizes increased the potential for reproduction and recruitment into the next generation, whereas declining habitat quality and the outplanting of species with low seed production led to increased extinction risks and a reduction in potential reproductive output in the long-term, respectively. We also detected novel interactions between some of the most important drivers, such as an increased probability of next-generation recruitment in species with greater seed production rates, but only when coupled with large founder sizes. Because most significant barriers to plant translocation success can be overcome by improving techniques or resolving site-level issues through early intervention and management, we suggest that by combining long-term monitoring with adaptive management, translocation programs can enhance the prospects of achieving long-term success

Functional Electrical Stimulation of Intrinsic Laryngeal Muscles under Varying Loads in Exercising Horses

Bilateral vocal fold paralysis (BVCP) is a life threatening condition and appears to be a good candidate for therapy using functional electrical stimulation (FES). Developing a working FES system has been technically difficult due to the inaccessible location and small size of the sole arytenoid abductor, the posterior cricoarytenoid (PCA) muscle. A naturally-occurring disease in horses shares many functional and etiological features with BVCP. In this study, the feasibility of FES for equine vocal fold paralysis was explored by testing arytenoid abduction evoked by electrical stimulation of the PCA muscle. Rheobase and chronaxie were determined for innervated PCA muscle. We then tested the hypothesis that direct muscle stimulation can maintain airway patency during strenuous exercise in horses with induced transient conduction block of the laryngeal motor nerve. Six adult horses were instrumented with a single bipolar intra-muscular electrode in the left PCA muscle. Rheobase and chronaxie were within the normal range for innervated muscle at 0.55±0.38 v and 0.38±0.19 ms respectively. Intramuscular stimulation of the PCA muscle significantly improved arytenoid abduction at all levels of exercise intensity and there was no significant difference between the level of abduction achieved with stimulation and control values under moderate loads. The equine larynx may provide a useful model for the study of bilateral fold paralysis

The TESS-Keck Survey. XVI. Mass Measurements for 12 Planets in Eight Systems

With JWST's successful deployment and unexpectedly high fuel reserves, measuring the masses of sub-Neptunes transiting bright, nearby stars will soon become the bottleneck for characterizing the atmospheres of small exoplanets via transmission spectroscopy. Using a carefully curated target list and more than two years' worth of APF-Levy and Keck-HIRES Doppler monitoring, the TESS-Keck Survey is working toward alleviating this pressure. Here we present mass measurements for 11 transiting planets in eight systems that are particularly suited to atmospheric follow-up with JWST. We also report the discovery and confirmation of a temperate super-Jovian-mass planet on a moderately eccentric orbit. The sample of eight host stars, which includes one subgiant, spans early-K to late-F spectral types ($T_\mathrm{eff} =$ 5200--6200 K). We homogeneously derive planet parameters using a joint photometry and radial velocity modeling framework, discuss the planets' possible bulk compositions, and comment on their prospects for atmospheric characterization.Comment: Accepted for publication in The Astronomical Journal on 2023-Jun-22. 60 pages, 17 Tables, 28 Figure

Intracellular calcium strongly potentiates agonist-activated TRPC5 channels

TRPC5 is a calcium (Ca2+)-permeable nonselective cation channel expressed in several brain regions, including the hippocampus, cerebellum, and amygdala. Although TRPC5 is activated by receptors coupled to phospholipase C, the precise signaling pathway and modulatory signals remain poorly defined. We find that during continuous agonist activation, heterologously expressed TRPC5 currents are potentiated in a voltage-dependent manner (∼5-fold at positive potentials and ∼25-fold at negative potentials). The reversal potential, doubly rectifying current–voltage relation, and permeability to large cations such as N-methyl-d-glucamine remain unchanged during this potentiation. The TRPC5 current potentiation depends on extracellular Ca2+: replacement by Ba2+ or Mg2+ abolishes it, whereas the addition of 10 mM Ca2+ accelerates it. The site of action for Ca2+ is intracellular, as simultaneous fura-2 imaging and patch clamp recordings indicate that potentiation is triggered at ∼1 µM [Ca2+]. This potentiation is prevented when intracellular Ca2+ is tightly buffered, but it is promoted when recording with internal solutions containing elevated [Ca2+]. In cell-attached and excised inside-out single-channel recordings, increases in internal [Ca2+] led to an ∼10–20-fold increase in channel open probability, whereas single-channel conductance was unchanged. Ca2+-dependent potentiation should result in TRPC5 channel activation preferentially during periods of repetitive firing or coincident neurotransmitter receptor activation

Nonvirally Modified Autologous Primary Hepatocytes Correct Diabetes and Prevent Target Organ Injury in a Large Preclinical Model

BACKGROUND: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes. METHODS AND RESULTS: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs. The vector was comprised of a bifunctional, glucose-responsive promoter linked to human insulin cDNA. Ambient glucose concentrations appropriately altered human insulin mRNA expression and C-peptide secretion within minutes in vitro and in vivo. Treated swine showed correction of hyperglycemia, glucose intolerance, dyslipidemia and other metabolic abnormalities for > or = 47 weeks. Metabolic correction correlated significantly with the number of hepatocytes implanted. Importantly, we observed no hypoglycemia even under fasting conditions. Direct intrahepatic implantation of hepatocytes did not alter biochemical indices of liver function or induce abnormal hepatic lobular architecture. About 70% of implanted hepatocytes functionally engrafted, appeared histologically normal, retained vector DNA and expressed human insulin for > or = 47 weeks. Based on structural tissue analyses and transcriptome data, we showed that early correction of diabetes attenuated and even prevented pathological changes in the eye, kidney, liver and aorta. CONCLUSIONS: We demonstrate that autologous hepatocytes can be efficiently, simply and safely modified by electroporation of a nonviral vector to express, process and secrete insulin durably. This strategy, which achieved significant and sustained therapeutic efficacy in a large preclinical model without adverse effects, warrants consideration for clinical development especially as it could have broader future applications for the treatment of other acquired and inherited diseases for which systemic reconstitution of a specific protein deficiency is critical