A first-in-human, randomized, controlled, subject- and reviewer-blinded multicenter study of Actamax™ Adhesion Barrier

Purpose: Post-surgical adhesions remain a significant concern following abdominopelvic surgery. This study was to assess safety, manageability and explore preliminary efficacy of applying a degradable hydrogel adhesion barrier to areas of surgical trauma following gynecologic laparoscopic abdominopelvic surgery. Methods: This first-in-human, prospective, randomized, multicenter, subject- and reviewer-blinded clinical study was conducted in 78 premenopausal women (18–46 years) wishing to maintain fertility and undergoing gynecologic laparoscopic abdominopelvic surgery with planned clinically indicated second-look laparoscopy (SLL) at 4–12 weeks. The first two patients of each surgeon received hydrogel, up to 30 mL sprayed over all sites of surgical trauma, and were assessed for safety and application only (n = 12). Subsequent subjects (n = 66) were randomized 1:1 to receive either hydrogel (Treatment, n = 35) or not (Control, n = 31); 63 completed the SLL. Results: No adverse event was assessed as serious, or possibly device related. None was severe or fatal. Adverse events were reported for 17 treated subjects (17/47, 36.2%) and 13 Controls (13/31, 41.9%). For 95.7% of treated subjects, surgeons found the device “easy” or “very easy” to use; in 54.5%, some residual material was evident at SLL. For 63 randomized subjects who completed the SLL, adjusted between-group difference in the change from baseline adhesion score demonstrated a 41.4% reduction for Treatment compared with Controls (p = 0.017), with a 49.5% reduction (p = 0.008) among myomectomy subjects (n = 34). Conclusion: Spray application of a degradable hydrogel adhesion barrier during gynecologic laparoscopic abdominopelvic surgery was performed easily and safely, without evidence of clinically significant adverse outcomes. Data suggest the hydrogel was effective in reducing postoperative adhesion development, particularly following myomectomy

Evaluation of Average and Maximum Heart Rate of Wrist-worn Wearable Technology Devices During Trail Running

It has been estimated that there are 20 million people who participate in trail running, and these numbers are expected to increase by 15% each year. Our laboratory group has conducted studies on the validity of wearable technology watches and heart rate (HR) during trail running. The previous generation devices were mostly inaccurate, and a limitation was that reliability was not measured. PURPOSE: To determine both validity and reliability in newer models of wearable devices during trail running. METHODS: Seventeen participants (F = 7) ran on the Thunderbird Gardens Lightning Switch trail in Cedar City, UT. Demographic characteristics: Age = 25 (9) years (mean [standard deviation]), ht = 168 (9) cm, mass = 72 (14) kg. Two Garmin Instincts and two Polar Vantage M2s were evaluated, along with the Polar H10 chest strap as the criterion measure. Participants ran out on the trail for 10-minutes, and then returned to the trailhead. Maximum HR and average HR were measured during the run. Data were analyzed for validity (Mean Absolute Percent Error [MAPE] and Lin’s Concordance [CCC]) and reliability (Coefficient of Variation [CV] and Intraclass Correlation Coefficient [ICC]). Predetermined thresholds were: MAPE0.70, CV0.70. RESULTS: The Garmin Instinct met the threshold for both reliability tests for average and maximum HR (see table). The Garmin Instinct and Polar Vantage met the threshold for both validity tests for maximum HR. CONCLUSION: In order for a device to be considered valid, it must meet the predetermined thresholds for both validity and reliability. These results indicate that only the Garmin Instinct is valid and reliable, but only for measuring maximum HR. This is challenging for those who wish to track their HR while trail running, because neither of the studied devices were valid and reliable for maximum and average HR

Average Heart Rate and Energy Expenditure Validity of Garmin Vivoactive 3 and Fenix 6 Wrist Watches During Light Circuit Resistance Training

Our laboratory recently found wrist-worn wearable technology devices to be valid for measuring average heart rate (HR), but not valid for estimated energy expenditure (EE) compared to criterion devices, during steady state aerobic training (walking, running, biking). However, the validity of wrist-worn devices for HR and EE measures during resistance training is largely unknown. PURPOSE: The purpose of this study was to determine if two wrist-worn devices, Garmin Vivoactive 3 and Garmin Fenix 6 Pro, record valid measures of average HR and EE while performing circuit resistance training. METHODS: Twenty participants (n=10 female, n=10 male; age: 23.2 ± 7.7 years) completed this study. The Garmin Vivoactive 3 and Garmin Fenix 6 Pro were tested along with the Polar H10 chest strap and Cosmed K5 portable metabolic unit as the criterions for average HR and EE, respectively. Participants completed 4 circuits of 4 exercises (front squat, reverse lunge, push-ups, and shoulder press) using dumbbells at a light intensity with 1 set of 10 repetitions per exercise and 30 seconds rest between exercises and 1-1.5 min. rest between circuits. Mean absolute percent error (MAPE, ≤10%) and Lin’s Concordance (ρ≥0.7) were used to validate the device’s average HR (in bpm) and estimated EE (in kcals) compared to criterion reference devices. Dependent T-tests determined differences (p≤0.05). RESULTS: Average HR for Garmin Vivoactive 3 and Fenix 6 Pro were significantly different (p\u3c0.01) than the Polar H10 (115.0±23.9 and 124.5±15.4 vs 128.9±19.0 bpm, respectively), and were not considered valid (MAPE: 44.8% and 25.1%; Lin’s Concordance: 0.50 and 0.63, respectively). Estimated EE for Garmin Vivoactive 3 and Fenix 6 Pro were significantly different (p\u3c0.0001) than the Cosmed K5 (31.7±12.3 and 39.7±13.1 vs 20.3±5.5 kcals, respectively), and were not considered valid (MAPE: 309.7% and 322.1%; Lin’s Concordance: 0.04 and 0.15, respectively). CONCLUSION: Anyone involved in any resistance training aspect should be aware of the limitations of these wrist-worn devices in measuring average HR or EE

The DEEP Groth Strip Survey IX: Evolution of the Fundamental Plane of Field Galaxies

Fundamental Plane studies provide an excellent means of understanding the evolutionary history of early-type galaxies. Using the Low Resolution Imaging Spectrograph on the Keck telescope, we obtained internal stellar kinematic information for 36 field galaxies in the Groth Strip--21 early-type and 15 disk galaxies. Their redshifts range from 0.3--1.0, with a median redshift 0.8. The slope of the relation shows no difference compared with the local slope. However, there is significant evolution in the zero-point offset; an offset due to evolution in magnitude requires a 2.4 magnitude luminosity brightening at z=1. We see little differences of the offset with bulge fraction, which is a good surrogate for galaxy type. Correcting for the luminosity evolution reduces the orthogonal scatter in the Fundamental Plane to 8%, consistent with the local scatter. This scatter is measured for our sample, and does not include results from other studies which may have different selection effects. The difference in the degree of evolution between our field sample and published cluster galaxies suggests a more recent formation epoch--around z=1.5 for field galaxies compared to z>2.0 for cluster galaxies. The magnitude difference implies that the field early-type galaxies are about 2 Gyr younger than the cluster ellipticals using standard single-burst models. However, the same models imply a significant change in the rest-frame U-B color from then to present, which is not seen in our sample. Continuous low-level star formation, however, would serve to explain the constant colors over this large magnitude change. A consistent model has 7% of the stellar mass created after the initial burst, using an exponentially decaying star formation rate with an e-folding time of 5 Gyr.Comment: 25 pages, accepted for publication in the Astrophysical Journal, high resolution version at http://hoku.as.utexas.edu/~gebhardt/FPpaper.p

Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy

Micrometeoroid Events in LISA Pathfinder

The zodiacal dust complex, a population of dust and small particles that pervades the Solar System, provides important insight into the formation and dynamics of planets, comets, asteroids, and other bodies. Here we present a new set of data obtained using a novel technique: direct measurements of momentum transfer to a spacecraft from individual particle impacts. This technique is made possible by the extreme precision of the instruments flown on the LISA Pathfinder spacecraft, a technology demonstrator for a future space-based gravitational wave observatory that operated near the first Sun-Earth Lagrange point from early 2016 through Summer of 2017. Using a simple model of the impacts and knowledge of the control system, we show that it is possible to detect impacts and measure properties such as the transferred momentum (related to the particle's mass and velocity), direction of travel, and location of impact on the spacecraft. In this paper, we present the results of a systematic search for impacts during 4348 hours of Pathfinder data. We report a total of 54 candidates with momenta ranging from 0.2$\,\mu\textrm{Ns}$ to 230$\,\mu\textrm{Ns}$. We furthermore make a comparison of these candidates with models of micrometeoroid populations in the inner solar system including those resulting from Jupiter-family comets, Oort-cloud comets, Hailey-type comets, and Asteroids. We find that our measured population is consistent with a population dominated by Jupiter-family comets with some evidence for a smaller contribution from Hailey-type comets. This is in agreement with consensus models of the zodiacal dust complex in the momentum range sampled by LISA Pathfinder.Comment: 22 pages, 14 figures, accepted in Ap

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs

Effective knowledge translation approaches and practices in Indigenous health research: A systematic review protocol

Background: Effective knowledge translation (KT) is critical to implementing program and policy changes that require shared understandings of knowledge systems, assumptions, and practices. Within mainstream research institutions and funding agencies, systemic and insidious inequities, privileges, and power relationships inhibit Indigenous peoples' control, input, and benefits over research. This systematic review will examine literature on KT initiatives in Indigenous health research to help identify wise and promising Indigenous KT practices and language in Canada and abroad. Methods: Indexed databases including Aboriginal Health Abstract Database, Bibliography of Native North Americans, CINAHL, Circumpolar Health Bibliographic Database, Dissertation Abstracts, First Nations Periodical Index, Medline, National Indigenous Studies Portal, ProQuest Conference Papers Index, PsycInfo, Social Services Abstracts, Social Work Abstracts, and Web of Science will be searched. A comprehensive list of non-indexed and grey literature sources will also be searched. For inclusion, documents must be published in English; linked to Indigenous health and wellbeing; focused on Indigenous people; document KT goals, activities, and rationale; an

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.