Blast Noise Management and Prediction

The aim of this work is to manage adverse occupational and environmental impacts from industrial blast noise sources at the DNV Spadeadam Testing & Research Site. Situated in Cumbria, UK, the site carries out crucial major hazards work including improving safety concerns within industry decarbonization sectors and government agencies and performs a variety of explosives and blast testing. This PhD project is concerned with two issues related to blast noise: occupational blast noise impacts to personnel in the near field, and environmental blast noise impacts on communities at long-range.Part I of this thesis concerns assessments of hearing protection suitability for the protection of site personnel against two differing blast operations carried out at the DNV Spadeadam site. Field measurements of real-world personnel exposures were found to exist beyond the scope of the current national legislative guidance for the selection of hearing protection against impulsive noise, DEF-STD 27:2015. Analysis of waveforms showed that both personnel exposures contain frequency and temporal characteristics not currently represented by the scope of the legislative guidance.Part II of this thesis is dedicated to implementing tools for the management of blast noise impacts at long-range on residential communities, for a variety of industrial blast and explosion testing carried out at the site. Currently, the operational decisions regarding large explosion trials rely upon computationally expensive prediction models. A Live Noise Monitoring System (LNMS) was deployed across a number of sensitive residential receptors, to monitor environmental noise levels from the site's activities, and correlate the noise measurements with measured and forecast meteorological data. The monitoring network identified that smaller but more frequent blast operations most adversely impacted long-range communities. The database of measurements has been used to assess the performance of existing heuristic and computational models for the prediction of noise impacts up to a number of days in the future. Furthermore, a data-driven model in the form of a deep neural network has been trained and validated for the prediction of noise impacts from a unique explosive process using surface meteorological data. Further measurements characterising the source terms of the operation are required to improve the model. It is concluded that blast noise impacts are best managed by a combination of live monitoring networks and a mixture of predictive tools

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Managing occupational noise from blasts

The aim of this work is to examine the current best practice for the assessment of auditory hazards associated with occupational impulsive noise for a UK-based test site. A summary of the literature is presented on the measurement methodologies, hearing conservation, and relevant guidance for the selection of hearing protection within the context of near-field impulsive noise. The current U,K. best practice recommends the adapted HML method from Defence Standard 0027:2015 using a C-peak measurement of exposure to compare with the national regulations. On-site measurements were made at the DNV Spadeadam Testing and Research Site (STaR), which performs full-scale high-intensity blast testing. Analyses of the trials data show that the C-peak personnel exposures resulted in acceptable levels below the 140dBCpk limit within the national regulations when using the prescribed hearing protection, according to the adapted HML method. It is concluded that the adapted HML assessment is unclear on how excessive low-frequency content and multiple pressure peaks are accounted for. The implication of this work is that further research is required to improve current best practice to quantify the uncertainties introduced by the additional characteristics found within real impulsive noise exposures

Caveolin-1 deficiency leads to increased susceptibility to cell death and fibrosis in white adipose tissue: characterization of a lipodystrophic model

Caveolin-1 (CAV1) is an important regulator of adipose tissue homeostasis. In the present study we examined the impact of CAV1 deficiency on the properties of mouse adipose tissue both in vivo and in explant cultures during conditions of metabolic stress. In CAV1(-/-) mice fasting caused loss of adipose tissue mass despite a lack of hormone-sensitive lipase (HSL) phosphorylation. In addition, fasting resulted in increased macrophage infiltration, enhanced deposition of collagen, and a reduction in the level of the lipid droplet protein perilipin A (PLIN1a). Explant cultures of CAV1(-/-) adipose tissue also showed a loss of PLIN1a during culture, enhanced secretion of IL-6, increased release of lactate dehydrogenase, and demonstrated increased susceptibility to cell death upon collagenase treatment. Attenuated PKA-mediated signaling to HSL, loss of PLIN1a and increased secretion of IL-6 were also observed in adipose tissue explants of CAV1(+/+) mice with diet-induced obesity. Together these results suggest that while alterations in adipocyte lipid droplet biology support adipose tissue metabolism in the absence of PKA-mediated pro-lipolytic signaling in CAV1(-/-) mice, the tissue is intrinsically unstable resulting in increased susceptibility to cell death, which we suggest underlies the development of fibrosis and inflammation during periods of metabolic stress

Macrophage infiltration and IL-6 analysis in CAV1^−/− adipose tissue.

<p>The infiltration of macrophage into adipose tissue and the release of IL-6 was analysed in CAV1^+/+ and CAV1^−/− adipose tissue from fed and 24 h-fasted mice. (<b>A</b>) Immunohistochemistry of the macrophage marker protein F4/80 showing macrophage infiltration in CAV1^+/+ and CAV1^−/− adipose tissue from fed and 24 h-fasted mice. (<b>B</b>) Quantitation of F4/80-positive infiltrated macrophage (n = 6−8 mice). (<b>C</b>) The release of IL-6 from epididymal adipose tissue explants of CAV1^+/+ and CAV1^−/− mice was measured over an 8 h period (mean ± sem, n = 3−6, except 8 h where n = 2). (<b>D</b>) The basal release of glycerol from unstimulated explants was determined after 4 h in culture (mean ± sem, n = 5−6). (<b>E</b>) Systemic IL-6 levels in serum from CAV1^−/− and CAV1^+/+ mice following a 24 h fast (mean ± sem, n = 10−11 mice). (<b>F</b>) The release of mIL-6 over 4 h from epididymal adipose tissue explants of CAV1^+/+ and CAV1^−/− mice maintained on a Control or high fat diet (HFD) (mean ± sem, n = 5−6). *p<0.05, **p<0.01, ***p<0.001.</p

Activation of lipolysis in epididymal adipose tissue explants from CAV1^+/+ and CAV1^−/− mice.

<p>Adipose tissue explants were cultured from epididymal adipose tissue of CAV1^−/− and CAV1^+/+ mice and lipolysis activated using the beta-adrenergic agonist isoproterenol (Isop, 10 µM) or by direct elevation of cAMP levels using forskolin (10 µM) and IBMX (500 µM) (Fsk/IBMX). In CAV1^−/− explants neither activation regime resulted in the PKA-mediated phosphorylation of HSL on either Ser563 or Ser660, despite the expression of the PKA catalytic subunit (<b>A</b>), or stimulated the release of (<b>B</b>) glycerol or (<b>C</b>) NEFA (n = 3−5, mean ± sem).</p

Fibrosis and cell death characterises adipose tissue from CAV1^−/− mice.

<p>The release of LDH and the deposition of collagen was analysed in CAV1^+/+ and CAV1^−/− adipose tissue. (<b>A</b>) LDH activity in the culture media of epididymal adipose tissue explants after 4 h <i>in vitro</i> (mean ± sem, n = 5−6). (<b>B</b>) Release of LDH from adipose tissue explants during collagenase digestion (mean ± sem, n = 3). (<b>C</b>) Sirius red staining for collagen in paraffin-embedded sections of CAV1^+/+ and CAV1^−/− adipose tissue from fed and 24 h-fasted mice. (<b>D</b>) Protein levels of pro-collagen in CAV1^+/+ and CAV1^−/− adipose tissue from fed and 12 h fasted mice determined by Western blotting of whole tissue lysates. *p<0.05, **p<0.01.</p

Expression and phosphorylation of PLIN1a during fasting and <i>ex vivo</i> culture.

<p>The protein levels and phosphorylation of PLIN1a in epididymal adipose tissue from fed mice and following a 12 h fast (<b>A, B</b>). The expression of PLIN1a was quantified relative to actin. Phosphorylation of PLIN1a was determined using an antibody to phosphorylated PKA-substrate (RRxS/T). (<b>C, D</b>) The protein level of PLIN1a was compared between tissue (Ti) and explants of the same tissue following <i>ex vivo</i> culture for 4 h (Ex). Adipose tissue was analysed from mice maintained on a Control or high fat (HFD) diet for 12 weeks. The expression of PLIN1a in explants was quantified relative to tissue (mean ± sem, n = 3). *p<0.05, ***p<0.001.</p