Mechanistic and Clinical Studies of Platelet Rich Plasma: A Simple Clinical Method for Enhancing Bone and Soft Tissue Healing

Platelet rich plasma (PRP) is a methodology of using a patient\u27s own platelets to enhance bone and soft tissue healing following oral surgical procedures. Whole blood is drawn from the patient by conventional phlebotomy techniques and then centrifuged with the formation of a distinct middle layer that contains platelets and white blood cells (WBCs). This layer of platelets and WBCs is then placed into the surgical site to enable faster and more predictable healing. This technique has also found use in general medical surgeries and is gaining in popularity. Platelets contain growth factors and other cytokines that are beneficial for healing following surgical trauma. This project uses both in vitro and in vivo studies to provide the mechanistic basis for the continued and possible expanded clinical use of PRP. A simple and inexpensive technique for acquiring PRP is examined and provides evidence that during the platelet harvesting steps the platelets are properly concentrated, not altered, and that growth factors (GFs) critical to bone formation are present. A retrospective clinical trial provides data that illustrate a significant decrease (p \u3c .0001) in the frequent complication of dry socket (alveolar osteitis, AO) formation following mandibular tooth extractions. The study reveals that not using PRP is a risk factor for AO formation. The project also utilizes a molecular study utilizing human mesenchymal stem cells (hMSCs) to provide a mechanistic basis for bone formation following PRP use. Enhanced proliferation and inducement of differentiation of hMSCs were found to the possible explanations for the clinical successes reported with PRP use. A prospective clinical study provides radiographic evidence for increased radiographic opacity (indicating bone formation) during the initial two weeks following placement of PRP at the time of mandibular third molar removal. This translational research offers scientific support for the use of PRP in osseous surgeries. The use of this simple and inexpensive PRP technique could help patients recover faster, with fewer complications and greater bone formation predictability following surgeries involving bone manipulation

A High Space Density of Luminous Lyα Emitters at z ~ 6.5

We present the results of a systematic search for Lyα emitters (LAEs) at 6 ≾ z ≾ 7.6 using the HST WFC3 Infrared Spectroscopic Parallel (WISP) Survey. Our total volume over this redshift range is ~ 8 x 10^5 Mpc^3, comparable to many of the narrowband surveys despite their larger area coverage. We find two LAEs at z = 6.38 and 6.44 with line luminosities of L_(Lyα) ~ 4.7 x 10^(43) erg s^(−1), putting them among the brightest LAEs discovered at these redshifts. Taking advantage of the broad spectral coverage of WISP, we are able to rule out almost all lower-redshift contaminants. The WISP LAEs have a high number density of 7.7 x 10(-6) Mpc^(−3). We argue that the LAEs reside in megaparsec-scale ionized bubbles that allow the Lyα photons to redshift out of resonance before encountering the neutral intergalactic medium. We discuss possible ionizing sources and conclude that the observed LAEs alone are not sufficient to ionize the bubbles

The mass-metallicity relation at z~1-2 and its dependence on star formation rate

We present a new measurement of the gas-phase mass-metallicity relation (MZR), and its dependence on star formation rates (SFRs) at 1.3 < z < 2.3. Our sample comprises 1056 galaxies with a mean redshift of z = 1.9, identified from the Hubble Space Telescope Wide Field Camera 3 (WFC3) grism spectroscopy in the Cosmic Assembly Near-Infrared Deep Extragalactic Survey (CANDELS) and the WFC3 Infrared Spectroscopic Parallel Survey (WISP). This sample is four times larger than previous metallicity surveys at z ~ 2, and reaches an order of magnitude lower in stellar mass (10^8 M_sun). Using stacked spectra, we find that the MZR evolves by 0.3 dex relative to z ~ 0.1. Additionally, we identify a subset of 49 galaxies with high signal-to-noise (SNR) spectra and redshifts between 1.3 < z < 1.5, where H-alpha emission is observed along with [OIII] and [OII]. With accurate measurements of SFR in these objects, we confirm the existence of a mass-metallicity-SFR (M-Z-SFR) relation at high redshifts. These galaxies show systematic differences from the local M-Z-SFR relation, which vary depending on the adopted measurement of the local relation. However, it remains difficult to ascertain whether these differences could be due to redshift evolution, as the local M-Z-SFR relation is poorly constrained at the masses and SFRs of our sample. Lastly, we reproduced our sample selection in the IllustrisTNG hydrodynamical simulation, demonstrating that our line flux limit lowers the normalization of the simulated MZR by 0.2 dex. We show that the M-Z-SFR relation in IllustrisTNG has an SFR dependence that is too steep by a factor of around three.Comment: Accepted for publication in ApJ; 41 pages, 20 figure

Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy

We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (∼10 fold). It was also reported by others to have anti-tumor activity in vivo and selective toxicity against cancer cells under glucose starvation in vitro, but with unknown mechanism. Here, we provide evidence that pyrvinium suppresses the transcriptional activation of GRP78 and GRP94 induced by glucose deprivation or 2-deoxyglucose (2DG, a glycolysis inhibitor), but not by tunicamycin or A23187. Other UPR pathways induced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgene partially protected cells from pyrvinium induced cell death under glucose starvation, suggesting that suppression of the UPR is involved in pyrvinium mediated cytotoxicity under glucose starvation. Xenograft experiments showed rather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR

A spatially resolved analysis of star-formation burstiness by comparing UV and Hα\alpha in galaxies at z∼\sim1 with UVCANDELS

The UltraViolet imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) program provides HST/UVIS F275W imaging for four CANDELS fields. We combine this UV imaging with existing HST/near-IR grism spectroscopy from 3D-HST+AGHAST to directly compare the resolved rest-frame UV and H$\alpha$ emission for a sample of 979 galaxies at $0.7<z<1.5$ spanning a range in stellar mass of $10^{8-11.5}~M_\odot$. Since both rest-UV and H$\alpha$ are sensitive to on-going star-formation but over different timescales, their resolved comparison allows us to infer the burstiness in star-formation as a function of galaxy structural parameters. We generate homogenized maps of rest-UV and H$\alpha$ emission for all galaxies in our sample and stack them to compute the average UV-to-H$\alpha$ luminosity ratio as a function of galactocentric radius. We find that galaxies below stellar mass of $\sim10^{9.5}~M_\odot$, at all radii, have a UV-to-H$\alpha$ ratio higher than the equilibrium value expected from constant star-formation, indicating a significant contribution from bursty star-formation. Even for galaxies with stellar mass $\gtrsim10^{9.5} M_\odot$, the UV-to-H$\alpha$ ratio is elevated towards in their outskirts ($R/R_{eff}>1.5$), suggesting that bursty star-formation is likely prevalent in the outskirts of even the most massive galaxies but is likely over-shadowed by their brighter cores. Furthermore, we present the UV-to-H$\alpha$ ratio as a function of galaxy surface brightness, a proxy for stellar mass surface density, and find that regions below $\sim10^8~M_\odot~kpc^{-2}$ are consistent with bursty star-formation, regardless of their galaxy stellar mass, potentially suggesting that local star-formation is independent of global galaxy properties at the smallest scales.Comment: 19 pages, 8 figures; submitted to Ap

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Paper 1: The JWST PEARLS View of the El Gordo Galaxy Cluster and of the Structure It Magnifies

The massive galaxy cluster El Gordo (z=0.87) imprints multitudes of gravitationally lensed arcs onto James Webb Space Telescope (JWST) Near-Infrared Camera (NIRCam) images. Eight bands of NIRCam imaging were obtained in the ``Prime Extragalactic Areas for Reionization and Lensing Science'' (``PEARLS'') program. PSF-matched photometry across Hubble Space Telescope (HST) and NIRCam filters supplies new photometric redshifts. A new light-traces-mass lens model based on 56 image multiplicities identifies the two mass peaks and yields a mass estimate within 500 kpc of ~(7.0 +/- 0.30) x 10^14 Msun. A search for substructure in the 140 cluster members with spectroscopic redshifts confirms the two main mass components. The southeastern mass peak that contains the BCG is more tightly bound than the northwestern one. The virial mass within 1.7 Mpc is (5.1 +/- 0.60) x 10^14 Msun, lower than the lensing mass. A significant transverse velocity component could mean the virial mass is underestimated. We contribute one new member to the previously known z=4.32 galaxy group. Intrinsic (delensed) positions of the five secure group members span a physical extent of ~60 kpc. Thirteen additional candidates selected by spectroscopic/photometric constraints are small and faint with a mean intrinsic luminosity ~2.2 mag fainter than L*. NIRCam imaging admits a fairly wide range of brightnesses and morphologies for the group members, suggesting a more diverse galaxy population in this galaxy overdensity.Comment: 24 pages, accepted by Ap

A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine

Investigating the mechanism of cocaine's effect on fetal brain development, Chun-Ting Lee and colleagues find that down-regulation of cyclin A by a cocaine metabolite inhibits neural proliferation

The European Renal Association - European Dialysis and Transplant Association Registry Annual Report 2014 : a summary

Background: This article summarizes the European Renal Association - European Dialysis and Transplant Association Registry's 2014 annual report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2014 within 35 countries. Methods: In 2016, the ERA-EDTA Registry received data on patients who in 2014 where undergoing RRT for ESRD, from 51 national or regional renal registries. Thirty-two registries provided individual patient level data and 19 provided aggregated patient level data. The incidence, prevalence and survival probabilities of these patients were determined. Results: In 2014, 70 953 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 133 per million population (pmp). The incidence ranged by 10-fold; from 23 pmp in the Ukraine to 237 pmp in Portugal. Of the patients commencing RRT, almost two-thirds were men, over half were aged >= 65 years and a quarter had diabetes mellitus as their primary renal diagnosis. By day 91 of commencing RRT, 81% of patients were receiving haemodialysis. On 31 December 2014, 490 743 individuals were receiving RRT for ESRD, equating to an unadjusted prevalence of 924 pmp. This ranged throughout Europe by more than 10-fold, from 157 pmp in the Ukraine to 1794 pmp in Portugal. In 2014, 19 406 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 36 pmp. Again this varied considerably throughout Europe. For patients commencing RRT during 2005-09, the 5-year-adjusted patient survival probabilities on all RRT modalities was 63.3% (95% confidence interval 63.0-63.6). The expected remaining lifetime of a 20-to 24-year-old patient with ESRD receiving dialysis or living with a kidney transplant was 21.9 and 44.0 years, respectively. This was substantially lower than the 61.8 years of expected remaining lifetime of a 20-year-old patient without ESRD.Peer reviewe

The Lyman Continuum Escape Fraction of Star-forming Galaxies at 2.4≲z≲3.72.4\lesssim z\lesssim3.7 from UVCANDELS

The UltraViolet Imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) survey is a Hubble Space Telescope (HST) Cycle-26 Treasury Program, allocated in total 164 orbits of primary Wide-Field Camera 3 Ultraviolet and Visible light F275W imaging with coordinated parallel Advanced Camera for Surveys F435W imaging, on four of the five premier extragalactic survey fields: GOODS-N, GOODS-S, EGS, and COSMOS. We introduce this survey by presenting a thorough search for galaxies at $z\gtrsim2.4$ that leak significant Lyman continuum (LyC) radiation, as well as a stringent constraint on the LyC escape fraction ($f_{\rm esc}$) from stacking the UV images of a population of star-forming galaxies with secure redshifts. Our extensive search for LyC emission and stacking analysis benefit from the catalogs of high-quality spectroscopic redshifts compiled from archival ground-based data and HST slitless spectroscopy, carefully vetted by dedicated visual inspection efforts. We report a sample of five galaxies as individual LyC leaker candidates, showing $f_{\rm esc}^{\rm rel}\gtrsim60\%$ estimated using detailed Monte Carlo analysis of intergalactic medium attenuation. We develop a robust stacking method to apply to five samples of in total 85 non-detection galaxies in the redshift range of $z\in[2.4,3.7]$. Most stacks give tight 2-$\sigma$ upper limits below $f_{\rm esc}^{\rm rel}<6\%$. A stack for a subset of 32 emission-line galaxies shows tentative LyC leakage detected at 2.9-$\sigma$, indicating $f_{\rm esc}^{\rm rel}=5.7\%$ at $z\sim2.65$, supporting the key role of such galaxies in contributing to the cosmic reionization and maintaining the UV ionization background. These new F275W and F435W imaging mosaics from UVCANDELS have been made publicly available on the Barbara A. Mikulski Archive for Space Telescopes.Comment: 33 pages, 21 figures, and 5 tables. Resubmitted after addressing the referee repor