Modified compression therapy in mixed arterial–venous leg ulcers: An integrative review

Leg ulcers remain an increased burden to healthcare cost and morbidity in modern society. While most leg ulcers are venous in origin, recognition and prompt identification of concomitant arterial occlusive disease is critical to determine underlying aetiology and subsequent management. This integrative review presents the current evidence to establish the role of modified compression therapy (MCT) in treatment of mixed arterial venous leg ulcers (MAVLU). A literature search was conducted using the electronic databases CINAHL, MEDLINE, PUBMED, and Embase. Ten studies met the eligibility criteria and were subsequently analysed. Our review concludes that MCT, with compression pressures between 20 and 30 mmHg, can promote healing in MAVLU with moderate arterial insufficiency (0.5 ≤ ABPI ≤0.8). If ABPI is <0.5, MCT can be considered once restoration of acceptable ABPI is achieved. Intolerance, lack of response or further deterioration of disease within 3 months should prompt further arterial imaging and intervention. MCT is generally well tolerated with no adverse outcomes reported. A holistic yet individualised approach is vital in order to account for all factors influencing this patient-led decision-making process, ultimately ensuring effective treatment, which improves patient's quality of life and reduces socioeconomic burden of the disease

Humidified warmed CO2 treatment therapy strategies can save lives with mitigation and suppression of SARS-CoV-2 infection: an evidence review

The coronavirus disease (COVID-19) outbreak has presented enormous challenges for healthcare, societal, and economic systems worldwide. There is an urgent global need for a universal vaccine to cover all SARS-CoV-2 mutant strains to stop the current COVID-19 pandemic and the threat of an inevitable second wave of coronavirus. Carbon dioxide is safe and superior antimicrobial, which suggests it should be effective against coronaviruses and mutants thereof. Depending on the therapeutic regime, CO2 could also ameliorate other COVID-19 symptoms as it has also been reported to have antioxidant, anti-inflammation, anti-cytokine effects, and to stimulate the human immune system. Moreover, CO2 has beneficial effects on respiratory physiology, cardiovascular health, and human nervous systems. This article reviews the rationale of early treatment by inhaling safe doses of warmed humidified CO2 gas, either alone or as a carrier gas to deliver other inhaled drugs may help save lives by suppressing SARS-CoV-2 infections and excessive inflammatory responses. We suggest testing this somewhat counter-intuitive, but low tech and safe intervention for its suitability as a preventive measure and treatment against COVID-19. Overall, development and evaluation of this therapy now may provide a safe and economical tool for use not only during the current pandemic but also for any future outbreaks of respiratory diseases and related conditions

Slow relaxation of magnetization in a bis-mer-tridentate octahedral Co(II) complex

Reaction of a rigid tridentate ligand o-[(1H-imidazol-2-yl)methylideneamino]phenol (2-H(2)imap) with Co(ClO4) in the presence of NaN3, or Co(NO3)(2) without a base yields [Co-II(2-Himap)(2)] 1 and [Co-III(2-Himap) (2)]NO3 center dot MeOH2, respectively. Both complexes exhibit a mer-octahedral geometry with the cobalt centre being distorted along an octahedral-trigonal prismatic pathway. The packing in 1 and 2 is dominated by H-bonding forming 2D sheets and 1D chains, respectively. Detailed dc and ac magnetic studies indicate that 1 is a field-induced single-ion magnet (SIM) with D = 36.7 cm(-1) and E = 2.0 cm(-1). Extensive ab initio calculations support these conclusions and suggest that relaxation of the magnetization occurs principally through direct quantum tunnelling in the ground state, with the Raman process dominant in an applied field. This contrasts with the recently reported series of mer-[Co(L)(2)] (L = monoanionic NNO donor ligand; Inorg. Chem., 2017, 56, 6056-6066) complexes where D is negative, as these compounds have a more ambiguous geometry, and highlights the importance of supramolecular interactions in subtly altering the coordination sphere thereby impacting the magnetic behaviour

nWASP Inhibition Increases Wound Healing via TrKb/PLCγ Signalling

Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this can be regulated. (2) Methods: Clinical cohorts from patients with chronic wounds were tested for the expression of nWASP and cell models were employed to evaluate the influence of nWASP on cellular functions that are key to the healing process following knockdown and/or the use of nWASP-specific inhibitors. (3) Results: nWASP was significantly elevated at transcript levels in human non-healing chronic wounds versus healing tissues. nWASP inhibitors, wiskostatin and 187-1, along with the knockdown of nWASP, modified both HaCaT and HECV cell behaviour. We then identified two signalling pathways affected by nWASP inhibition: TrkB signalling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells. The healing of wounds in a diabetic murine model was significantly improved with an nWASP inhibitor treatment. (4) Conclusions: This study showed that nWASP activity was related to the non-healing behaviour of chronic wounds and together with the findings in the in vivo models, it strongly suggested nWASP as a therapeutic target in non-healing wounds that are regulated via TrkB and PLCγ1 signalling

Sensitivity of the Wound Edge Gene Signature “WD14” in Responding to Clinical Change: A Longitudinal Cohort Study

Introduction: Genetic prognostication of chronic wounds is one recognised method of early identification of clinical wound healing status in order to target rigorous and advanced treatment regimens to hard-to-heal wounds. The WounD14 (WD14) gene signature is a recently developed scoring tool, derived from genetic interrogation of wound edge biopsies. It has been shown to predict the propensity of chronic venous leg ulcers to heal. However, it is unknown how WD14 responds with time and to changes in clinical wound healing status. The aim of this pilot study was therefore to evaluate if changes in the clinical healing status of wounds were identified by WD14 gene signature changes. Methods: WD14 was developed through a process of gene screening, refining and subsequent validation in three separate patient cohorts. Validation was undertaken in 85 consecutive patients referred to a tertiary wound healing unit with chronic venous leg ulcers, who underwent a wound edge biopsy to interrogate for a ‘healing’ or ‘non-healing’ genotype. A smaller cohort of patients (18%) underwent a second biopsy, which comprises this pilot cohort reported herein. 12 weeks after the biopsy wounds were clinically assessed for healing status and compared to WD14 genotype. Results: Sequential biopsies and WD14 scores were obtained from 16 patients. WD14 gene signature predicted clinical wound healing status among this cohort at either visit (total analysis of 32 wound edge biopsies) with a positive predictive value (PPV) of 85.2% (95% CI 74.1% to 92.0%) and negative predictive value (NPV) of 80.0% (95% CI 34.2% to 96.9%). Six wounds altered their clinical status between the two visits; in this cohort WD14 has a PPV of 66.7% (95% CI 47.3% to 81.7%) and NPV of 100%. Conclusion: Although the WD14 gene signature did change with wound healing status, further and larger studies are required to clarify precisely the role of this gene signature and its ability to prognosticate accurately over time with wounds of differing clinical status

Pulsar Results with the Fermi Large Area Telescope

The launch of the Fermi Gamma-ray Space Telescope has heralded a new era in the study of gamma-ray pulsars. The population of confirmed gamma-ray pulsars has gone from 6-7 to more than 60, and the superb sensitivity of the Large Area Telescope (LAT) on Fermi has allowed the detailed study of their spectra and light curves. Twenty-four of these pulsars were discovered in blind searches of the gamma-ray data, and twenty-one of these are, at present, radio quiet, despite deep radio follow-up observations. In addition, millisecond pulsars have been confirmed as a class of gamma-ray emitters, both individually and collectively in globular clusters. Recently, radio searches in the direction of LAT sources with no likely counterparts have been highly productive, leading to the discovery of a large number of new millisecond pulsars. Taken together, these discoveries promise a great improvement in the understanding of the gamma-ray emission properties and Galactic population of pulsars. We summarize some of the results stemming from these newly-detected pulsars and their timing and multi-wavelength follow-up observations.Comment: 21 pages, 9 figures, to appear in Proceedings of ICREA Workshop on The High-Energy Emission from Pulsars and their Systems, Sant Cugat, Spain, 2010 April 12-16 (Springer

In vitro significance of SOCS-3 and SOCS-4 and potential mechanistic links to wound healing

Wound healing and the management of chronic wounds represent a significant burden on the NHS. Members of the suppressor of cytokine signalling (SOCS) family have been implicated in the regulation of a range of cellular processes. The current study aims to explore the importance of SOCS-3 and SOCS-4 in regulating cellular traits associated with wound healing. SOCS-3 over-expression and SOCS-4 knockdown mutant lines were generated and verified using q-PCR and western blotting in human keratinocytes (HaCaT) and endothelial cells (HECV). Over-expression of SOCS-3 resulted in a significantly reduced proliferative rate in HaCaT keratinocytes and also enhanced the tubule formation capacity of HECV cells. SOCS-4 knockdown significantly reduced HaCaT migration and HECV cell tubule formation. Suppression of SOCS-4 influenced the responsiveness of HaCaT and HECV cells to EGF and TGFβ and resulted in a dysregulation of phospho-protein expression in HaCaT cells. SOCS-3 and SOCS-4 appear to play regulatory roles in a number of keratinocyte and endothelial cellular traits associated with the wound healing process and may also be able to regulate the responsiveness of these cells to EGF and TGFβ. This implies a potential regulatory role in the wound healing process and, thus highlights their potential as novel therapies

Sensitivity of the wound edge gene signature "WD14" in responding to clinical change: a longitudinal cohort study

Introduction: WounD14 (WD14) gene signature is a recently developed tool derived from genetic interrogation of wound edge biopsies of chronic venous leg ulcers to identify heard-to-heal wounds and enable clinicians to target aggressive therapies to promote wound healing. This study aimed to evaluate if changes in wound clinical healing status were detected by the WD14 gene signature over time as this is currently poorly understood. Material and methods: WD14 was developed through gene screening and subsequent validation in 3 patient cohorts involving 85 consecutive patients with chronic venous leg ulcers referred to a tertiary wound healing unit. Patients underwent a wound edge biopsy to interrogate for a “healing” or “non-healing” genotype. A smaller cohort (18%) underwent a second biopsy, which comprised this pilot cohort reported herein. Twelve weeks following biopsy, wounds were clinically assessed for healing status based on reduction in size and compared to WD14 genotype. Results: Sequential biopsies and WD14 scores were derived from 16 patients. WD14 signature predicted wound healing status among this cohort at either visit (32 wound edge biopsies) with a positive predictive value (PPV) of 85.2% (95% CI 74.1%-92.0%) and negative predictive value (NPV) of 80.0% (95% CI 34.2%-96.9%). A total of 6 wounds underwent altered clinical status between the 2 visits. In this cohort, WD14 has a PPV of 66.7% (95% CI 47.3%-81.7%) and NPV of 100%. Conclusion: Although the WD14 gene signature did change with wound healing status, larger studies are required to precisely clarify its role and ability to prognosticate wounds of differing clinical status over time

Three Millisecond Pulsars in FERMI LAT Unassociated Bright Sources

We searched for radio pulsars in 25 of the non-variable, unassociated sources in the Fermi LAT Bright Source List with the Green Bank Telescope at 820 MHz. We report the discovery of three radio and gamma-ray millisecond pulsars (MSPs) from a high Galactic latitude subset of these sources. All of the pulsars are in binary systems, which would have made them virtually impossible to detect in blind gamma-ray pulsation searches. They seem to be relatively normal, nearby (<=2 kpc) millisecond pulsars. These observations, in combination with the Fermi detection of gamma-rays from other known radio MSPs, imply that most, if not all, radio MSPs are efficient gamma-ray producers. The gamma-ray spectra of the pulsars are power-law in nature with exponential cutoffs at a few GeV, as has been found with most other pulsars. The MSPs have all been detected as X-ray point sources. Their soft X-ray luminosities of ~10^{30-31} erg/s are typical of the rare radio MSPs seen in X-rays.Comment: Accepted for publication in ApJ Letter

Revisiting the 'Missing Middle' in English Sub-National Governance

In the light of the new Coalition Government’s proposed ‘rescaling’ of sub-national governance away from the regional level, it is an opportune time to re-consider the strength and weaknesses of the city or sub-regional approach to economic development and to search, once more, for the ‘missing middle’ in English Governance. In this context, the article initially assesses the case for city or sub regions as tiers of economic governance, before examining the lessons to be learnt from the experiences of the existing city regions in the North East of England. It argues that while contemporary plans to develop Local Enterprise Partnerships (LEPs) can be usefully considered within the context of the emerging city regional developments under the previous Labour Governments, a number of important challenges remain, particularly in relation to ensuring accountable structures of governance, a range of appropriate functions, adequate funding, and comprehensive coverage across a variety of sub-regional contexts. While the proposals of the new Government create the necessary ‘space’ to develop sub-regional bodies and offer genuine opportunities for both city and county LEPs, the scale of the sub-regional challenge should not be underestimated, particularly given the context of economic recession and major reductions in the public sector