Cost and Scalability Analysis of Porcine Islet Isolation for Islet Transplantation: Comparison of Juvenile, Neonatal and Adult Pigs.

The limited availability of human islets has led to the examination of porcine islets as a source of clinically suitable tissue for transplantation in patients with diabetes mellitus. Islets from porcine donors are commonly used in both in vitro and in vivo experiments studying diabetes mellitus. However, there are significant differences in quality and quantity of islet yield depending on donor pig age, as well as substantial differences in the costs of pancreas procurement in adult versus neonatal and juvenile pigs. In this study, we compared the total cost per islet of juvenile pig pancreata with that of neonatal and adult pigs. Although adult porcine pancreata yield, on average, more than five times the amount of islets than do juvenile and neonatal pancreata, we found that the high price of adult pigs led to the cost per islet being more than twice that of juvenile and neonatal islets (US $0.09 vs$0.04 and $0.02, respectively). In addition, neonatal and juvenile islets are advantageous in their scalability and retention of viability after culture. Our findings indicate that isolating neonatal and juvenile porcine islets is more cost-effective and scalable than isolating adult porcine islets

The effects of anti-inflammatory drugs on cartilage breakdown and their mechanism of action chondrocytes

The progressive loss of cartilage matrix is a major characteristic of arthritic disease, ultimately leading to a loss of joint function. A number of therapeutics are used in the treatment of arthritic disease, with non-steroidal anti-inflammatory drugs used to treat the pain and inflammation seen in osteoarthritis and rheumatoid arthritis, whilst disease modifying anti-rheumatic drugs are used to slow disease progression. However it is not fully understood if and how many of these drugs effect the disease processes in arthritis. The objective of this study is to look at a number of therapeutics and investigate their effect on the breakdown of proteoglycan and collagen, and on the expression of a number of key degradation enzymes, whilst trying to identify the possible mechanisms used by the drugs. Using the bovine nasal cartilage explant model IL-1 + OSM were used to stimulate the release of proteoglycan and collagen from the cartilage. Interleukin-1 (IL-1) and oncostatin M (OSM) together promote the degradation of cartilage by up regulating and activating MMPs that are found within the diseased joint. Treatment of the resorbing cartilage with indomethacin, indomethacin heptyl ester, simvastatin, mevastatin, pravastatin and sulfasalazine produced a variation of findings with many resulting in the inhibition of cartilage degradation. The stimulation of human articular chondrocytes with IL-1 + OSM caused a significant up regulation of MMPs by the cells at both a gene and protein level when measured by TaqMan PCR and ELISA respectively. Again treatment of the stimulated chondrocytes with a number of the drugs showed a significant reduction in the expression of key cartilage degrading enzymes. The investigation of signalling mechanisms affected by one specific drug, namely sulfasalazine by immunoblotting and signalling microarray, showed some interesting results not previously documented. Sulfasalazine is well known to inhibit NF-I(13 activation by blocking the degradation of IicB to the proteosome and data in this study supports these finding. However, study of the MAPK pathway showed that sulfasalazine appears to be able to block the signalling cascade which ultimately leads to AP-1 activation in chondrocytes stimulated with IL-1 + OSM. This study has identified possible chondroprotective properties in a number of the drugs which were screened and whilst the exact mechanisms behind these events still require further investigation, the results highlight the potential of these drugs in being used to prevent further cartilage degradation in arthritis and thus further delaying the possible need for joint replacement operations

The effects of anti-inflammatory drugs on cartilage breakdown and their mechanism of action chondrocytes

The progressive loss of cartilage matrix is a major characteristic of arthritic disease, ultimately leading to a loss of joint function. A number of therapeutics are used in the treatment of arthritic disease, with non-steroidal anti-inflammatory drugs used to treat the pain and inflammation seen in osteoarthritis and rheumatoid arthritis, whilst disease modifying anti-rheumatic drugs are used to slow disease progression. However it is not fully understood if and how many of these drugs effect the disease processes in arthritis. The objective of this study is to look at a number of therapeutics and investigate their effect on the breakdown of proteoglycan and collagen, and on the expression of a number of key degradation enzymes, whilst trying to identify the possible mechanisms used by the drugs. Using the bovine nasal cartilage explant model IL-1 + OSM were used to stimulate the release of proteoglycan and collagen from the cartilage. Interleukin-1 (IL-1) and oncostatin M (OSM) together promote the degradation of cartilage by up regulating and activating MMPs that are found within the diseased joint. Treatment of the resorbing cartilage with indomethacin, indomethacin heptyl ester, simvastatin, mevastatin, pravastatin and sulfasalazine produced a variation of findings with many resulting in the inhibition of cartilage degradation. The stimulation of human articular chondrocytes with IL-1 + OSM caused a significant up regulation of MMPs by the cells at both a gene and protein level when measured by TaqMan PCR and ELISA respectively. Again treatment of the stimulated chondrocytes with a number of the drugs showed a significant reduction in the expression of key cartilage degrading enzymes. The investigation of signalling mechanisms affected by one specific drug, namely sulfasalazine by immunoblotting and signalling microarray, showed some interesting results not previously documented. Sulfasalazine is well known to inhibit NF-I(13 activation by blocking the degradation of IicB to the proteosome and data in this study supports these finding. However, study of the MAPK pathway showed that sulfasalazine appears to be able to block the signalling cascade which ultimately leads to AP-1 activation in chondrocytes stimulated with IL-1 + OSM. This study has identified possible chondroprotective properties in a number of the drugs which were screened and whilst the exact mechanisms behind these events still require further investigation, the results highlight the potential of these drugs in being used to prevent further cartilage degradation in arthritis and thus further delaying the possible need for joint replacement operations.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Dual bronchodilators in Bronchiectasis study (DIBS): protocol for a pragmatic, multicentre, placebo-controlled, three-arm, double-blinded, randomised controlled trial studying bronchodilators in preventing exacerbations of bronchiectasis

INTRODUCTION: Bronchiectasis is a long-term lung condition, with dilated bronchi, chronic inflammation, chronic infection and acute exacerbations. Recurrent exacerbations are associated with poorer clinical outcomes such as increased severity of lung disease, further exacerbations, hospitalisations, reduced quality of life and increased risk of death. Despite an increasing prevalence of bronchiectasis, there is a critical lack of high-quality studies into the disease and no treatments specifically approved for its treatment. This trial aims to establish whether inhaled dual bronchodilators (long acting beta agonist (LABA) and long acting muscarinic antagonist (LAMA)) taken as either a stand-alone therapy or in combination with inhaled corticosteroid (ICS) reduce the number of exacerbations of bronchiectasis requiring treatment with antibiotics during a 12 month treatment period. METHODS: This is a multicentre, pragmatic, double-blind, randomised controlled trial, incorporating an internal pilot and embedded economic evaluation. 600 adult patients (≥18 years) with CT confirmed bronchiectasis will be recruited and randomised to either inhaled dual therapy (LABA+LAMA), triple therapy (LABA+LAMA+ICS) or matched placebo, in a 2:2:1 ratio (respectively). The primary outcome is the number of protocol defined exacerbations requiring treatment with antibiotics during the 12 month treatment period. ETHICS AND DISSEMINATION: Favourable ethical opinion was received from the North East-Newcastle and North Tyneside 2 Research Ethics Committee (reference: 21/NE/0020). Results will be disseminated in peer-reviewed publications, at national and international conferences, in the NIHR Health Technology Assessments journal and to participants and the public (using lay language). TRIAL REGISTRATION NUMBER: ISRCTN15988757

Dual bronchodilators in Bronchiectasis study (DIBS): protocol for a pragmatic, multicentre, placebo-controlled, three-arm, double-blinded, randomised controlled trial studying bronchodilators in preventing exacerbations of bronchiectasis

Introduction: Bronchiectasis is a long-term lung condition, with dilated bronchi, chronic inflammation, chronic infection and acute exacerbations. Recurrent exacerbations are associated with poorer clinical outcomes such as increased severity of lung disease, further exacerbations, hospitalisations, reduced quality of life and increased risk of death. Despite an increasing prevalence of bronchiectasis, there is a critical lack of high-quality studies into the disease and no treatments specifically approved for its treatment. This trial aims to establish whether inhaled dual bronchodilators (long acting beta agonist (LABA) and long acting muscarinic antagonist (LAMA)) taken as either a stand-alone therapy or in combination with inhaled corticosteroid (ICS) reduce the number of exacerbations of bronchiectasis requiring treatment with antibiotics during a 12 month treatment period. Methods: This is a multicentre, pragmatic, double-blind, randomised controlled trial, incorporating an internal pilot and embedded economic evaluation. 600 adult patients (≥18 years) with CT confirmed bronchiectasis will be recruited and randomised to either inhaled dual therapy (LABA+LAMA), triple therapy (LABA+LAMA+ICS) or matched placebo, in a 2:2:1 ratio (respectively). The primary outcome is the number of protocol defined exacerbations requiring treatment with antibiotics during the 12 month treatment period. Ethics and dissemination: Favourable ethical opinion was received from the North East—Newcastle and North Tyneside 2 Research Ethics Committee (reference: 21/NE/0020). Results will be disseminated in peer-reviewed publications, at national and international conferences, in the NIHR Health Technology Assessments journal and to participants and the public (using lay language). Trial registration number: ISRCTN15988757

The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth

We present new measurements of cosmic microwave background (CMB) lensing over $9400$ sq. deg. of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at $2.3\%$ precision ($43\sigma$ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. The baseline spectrum is well fit by a lensing amplitude of $A_{\mathrm{lens}}=1.013\pm0.023$ relative to the Planck 2018 CMB power spectra best-fit $\Lambda$CDM model and $A_{\mathrm{lens}}=1.005\pm0.023$ relative to the $\text{ACT DR4} + \text{WMAP}$ best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination $S^{\mathrm{CMBL}}_8 \equiv \sigma_8 \left({\Omega_m}/{0.3}\right)^{0.25}$ of $S^{\mathrm{CMBL}}_8= 0.818\pm0.022$ from ACT DR6 CMB lensing alone and $S^{\mathrm{CMBL}}_8= 0.813\pm0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with $\Lambda$CDM model constraints from Planck or $\text{ACT DR4} + \text{WMAP}$ CMB power spectrum measurements. Our lensing measurements from redshifts $z\sim0.5$--$5$ are thus fully consistent with $\Lambda$CDM structure growth predictions based on CMB anisotropies probing primarily $z\sim1100$. We find no evidence for a suppression of the amplitude of cosmic structure at low redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see companion papers Madhavacheril et al and MacCrann et a

The Atacama Cosmology Telescope: High-resolution component-separated maps across one-third of the sky

Observations of the millimeter sky contain valuable information on a number of signals, including the blackbody cosmic microwave background (CMB), Galactic emissions, and the Compton-$y$ distortion due to the thermal Sunyaev-Zel'dovich (tSZ) effect. Extracting new insight into cosmological and astrophysical questions often requires combining multi-wavelength observations to spectrally isolate one component. In this work, we present a new arcminute-resolution Compton-$y$ map, which traces out the line-of-sight-integrated electron pressure, as well as maps of the CMB in intensity and E-mode polarization, across a third of the sky (around 13,000 sq.~deg.). We produce these through a joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release 4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We present detailed verification of an internal linear combination pipeline implemented in a needlet frame that allows us to efficiently suppress Galactic contamination and account for spatial variations in the ACT instrument noise. These maps provide a significant advance, in noise levels and resolution, over the existing \textit{Planck} component-separated maps and will enable a host of science goals including studies of cluster and galaxy astrophysics, inferences of the cosmic velocity field, primordial non-Gaussianity searches, and gravitational lensing reconstruction of the CMB.Comment: The Compton-y map and associated products will be made publicly available upon publication of the paper. The CMB T and E mode maps will be made available when the DR6 maps are made publi

The Atacama Cosmology Telescope: DR6 Gravitational Lensing Map and Cosmological Parameters

We present cosmological constraints from a gravitational lensing mass map covering 9400 sq. deg. reconstructed from CMB measurements made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with BAO measurements (from SDSS and 6dF), we obtain the amplitude of matter fluctuations $\sigma_8 = 0.819 \pm 0.015$ at 1.8% precision, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.840\pm0.028$ and the Hubble constant $H_0= (68.3 \pm 1.1)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$ at 1.6% precision. A joint constraint with CMB lensing measured by the Planck satellite yields even more precise values: $\sigma_8 = 0.812 \pm 0.013$, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.831\pm0.023$ and $H_0= (68.1 \pm 1.0)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$. These measurements agree well with $\Lambda$CDM-model extrapolations from the CMB anisotropies measured by Planck. To compare these constraints to those from the KiDS, DES, and HSC galaxy surveys, we revisit those data sets with a uniform set of assumptions, and find $S_8$ from all three surveys are lower than that from ACT+Planck lensing by varying levels ranging from 1.7-2.1$\sigma$. These results motivate further measurements and comparison, not just between the CMB anisotropies and galaxy lensing, but also between CMB lensing probing $z\sim 0.5-5$ on mostly-linear scales and galaxy lensing at $z\sim 0.5$ on smaller scales. We combine our CMB lensing measurements with CMB anisotropies to constrain extensions of $\Lambda$CDM, limiting the sum of the neutrino masses to $\sum m_{\nu} < 0.12$ eV (95% c.l.), for example. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the $\Lambda$CDM model, while paving a promising path for neutrino physics with gravitational lensing from upcoming ground-based CMB surveys.Comment: 30 pages, 16 figures, prepared for submission to ApJ. Cosmological likelihood data is here: https://lambda.gsfc.nasa.gov/product/act/actadv_prod_table.html ; likelihood software is here: https://github.com/ACTCollaboration/act_dr6_lenslike . Also see companion papers Qu et al and MacCrann et al. Mass maps will be released when papers are publishe

Paramedic Acute Stroke Treatment Assessment (PASTA): study protocol for a randomised controlled trial

BACKGROUND: Despite evidence from clinical trials that intravenous (IV) thrombolysis is a cost-effective treatment for selected acute ischaemic stroke patients, there remain large variations in the rate of IV thrombolysis delivery between stroke services. This study is evaluating whether an enhanced care pathway delivered by paramedics (the Paramedic Acute Stroke Treatment Assessment (PASTA)) could increase the number of patients who receive IV thrombolysis treatment. METHODS: Study design: Cluster randomised trial with economic analysis and parallel process evaluation. SETTING: National Health Service ambulance services, emergency departments and hyper-acute stroke units within three geographical regions of England and Wales. Randomisation: Ambulance stations within each region are the units of randomisation. According to station allocation, paramedics based at a station deliver the PASTA pathway (intervention) or continue with standard stroke care (control). Study intervention: The PASTA pathway includes structured pre-hospital information collection, prompted pre-notification, structured handover of information in hospital and assistance with simple tasks during the initial hospital assessment. Study-trained intervention group paramedics deliver this pathway to adults within 4 h of suspected stroke onset. Study control: Standard stroke care according to national and local guidelines for the pre-hospital and hospital assessment of suspected stroke. PARTICIPANTS: Participants enrolled in the study are adults with confirmed stroke who were assessed by a study paramedic within 4 h of symptom onset. PRIMARY OUTCOME: Proportion of participants receiving IV thrombolysis. SAMPLE SIZE: 1297 participants provide 90% power to detect a 10% difference in the proportion of patients receiving IV thrombolysis. DISCUSSION: The results from this trial will determine whether an enhanced care pathway delivered by paramedics can increase thrombolysis delivery rates. TRIAL REGISTRATION: ISRCTN registry, ISRCTN12418919 . Registered on 5 November 2015

The Atacama Cosmology Telescope: A measurement of the DR6 CMB lensing power spectrum and its implications for structure growth

We present new measurements of cosmic microwave background (CMB) lensing over 9400 deg2 of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB data set, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at 2.3% precision (43σ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure that our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. Our CMB lensing power spectrum measurement provides constraints on the amplitude of cosmic structure that do not depend on Planck or galaxy survey data, thus giving independent information about large-scale structure growth and potential tensions in structure measurements. The baseline spectrum is well fit by a lensing amplitude of A lens = 1.013 ± 0.023 relative to the Planck 2018 CMB power spectra best-fit ΛCDM model and A lens = 1.005 ± 0.023 relative to the ACT DR4 + WMAP best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination S8CMBL≡σ8Ωm/0.30.25 of S8CMBL=0.818±0.022 from ACT DR6 CMB lensing alone and S8CMBL=0.813±0.018 when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with ΛCDM model constraints from Planck or ACT DR4 + WMAP CMB power spectrum measurements. Our lensing measurements from redshifts z ∼ 0.5–5 are thus fully consistent with ΛCDM structure growth predictions based on CMB anisotropies probing primarily z ∼ 1100. We find no evidence for a suppression of the amplitude of cosmic structure at low redshifts