Lightweight structural design of a bolted case joint for the space shuttle solid rocket motor

The structural design of a bolted joint with a static face seal which can be used to join Space Shuttle Solid Rocket Motor (SRM) case segments is given. Results from numerous finite element parametric studies indicate that the bolted joint meets the design requirement of preventing joint opening at the O-ring locations during SRM pressurization. A final design recommended for further development has the following parameters: 180 one-in.-diam. studs, stud centerline offset of 0.5 in radially inward from the shell wall center line, flange thickness of 0.75 in, bearing plate thickness of 0.25 in, studs prestressed to 70 percent of ultimate load, and the intermediate alcove. The design has a mass penalty of 1096 lbm, which is 164 lbm greater than the currently proposed capture tang redesign

Influence of landscape-scale forest structure on the presence of pileated woodpeckers (dryocopus pileatus) in Central Ontario forests

The goal of my research was to investigate the influence of landscape-scale forest structure on the presence of pileated woodpeckers (Dryocopus pileatus) in central Ontario forests. Study sites were located in Algonquin Provincial Park. The presence of pileated woodpeckers was recorded along 5 km transect lines. The area around each transect line was used for landscape analysis and represented S km2. Landscape-scale structure analysis was conducted on the composition and configuration of pileated woodpecker habitat. The habitat was classified based on several methods and focused on the variations of the pileated woodpecker habitat supply model (PWPHSM) for central Ontario. To determine which of the classifications best predicted the presence of pileated woodpeckers, logistic regression was run on the variable “percent of land (%LAND)” for each classification. The landscape structure of the best classification was further examined to explain the presence of pileated woodpeckers by entering all landscape-level and class-level FRAGSTATS variables into a logistic regression procedure

Two-versus one photon excitation laser scanning microscopy: Critical importance of excitation wavelength

It is often anticipated that two-photon excitation (TPE) laser scanning microscopy should improve cell survival and tissue penetration relative to conventional one-photon excitation (OPE) confocal scanning laser microscopy (CLSM). However few studies have directly compared live cell imaging using one- vs two-photon laser scanning microscopy. We have used calcein-loaded in situ chondrocytes within cartilage as a model for quantitatively comparing these techniques. TPE reduced photo-bleaching and improved cell viability compared to OPE. Using improved detection sensitivity coupled with increased tissue penetration of the near infra-red TPE laser, it was possible to capture images deeper within the cartilage. However, the advantages of TPE vs OPE were strongly dependent on excitation wavelength. We conclude that optimising TPE conditions is essential if the full benefits of this approach are to be realised

Engineering of TIMP-3 as a LAP-fusion protein for targeting to sites of inflammation

Tissue inhibitor of metalloproteinase (TIMP)‐3 is a natural inhibitor of a range of enzymes that degrade connective tissue and are involved in the pathogenesis of conditions such as arthritis and cancer. We describe here the engineering of TIMP‐3 using a novel drug‐delivery system known as the ‘LAP technology’. This involves creating therapeutic proteins in fusion with the latency‐associated peptide (LAP) from the cytokine TGF‐? to generate proteins that are biologically inactive until cleavage of the LAP to release the therapy. LAP‐TIMP‐3 was successfully expressed in mammalian cells and the presence of the LAP resulted in a 14‐fold increase in the quantity of recombinant TIMP‐3 produced. LAP‐TIMP‐3 was latent until release from the LAP by treatment with matrix metalloproteinase when it could inhibit proteases of the adamalysins and adamalysins with thrombospondin motifs families, but not matrix metalloproteinases, indicating that this version of TIMP‐3 is a more specific inhibitor than the native protein. There was sufficient protease activity in synovial fluid from human joints with osteoarthritis to release TIMP‐3 from the LAP fusion. These results demonstrate the potential for development of TIMP‐3 as a novel therapy for conditions where upregulation of catabolic enzymes are part of the pathology

Over a third of palliative medicine physicians meet burnout criteria: Results from a survey study during the COVID-19 pandemic

Background: Palliative medicine physicians may be at higher risk of burnout due to increased stressors and compromised resilience during the COVID-19 pandemic. Burnout prevalence and factors influencing this among UK and Irish palliative medicine physicians is unknown. Aim: To determine the prevalence of burnout and the degree of resilience among UK and Irish palliative medicine physicians during the COVID-19 pandemic, and associated factors. Design: Online survey using validated assessment scales assessed burnout and resilience: The Maslach Burnout Inventory Human Services Survey for Medical Personnel [MBI-HSS (MP)] and the Connor-Davidson Resilience Scale (CD-RISC). Additional tools assessed depressive symptoms, alcohol use, and quality of life. Setting/participants: Association of Palliative Medicine of UK and Ireland members actively practising in hospital, hospice or community settings. Results: There were 544 respondents from the 815 eligible participants (66.8%), 462 provided complete MBI-HSS (MP) data and were analysed. Of those 181/462 (39.2%) met burnout criteria, based on high emotional exhaustion or depersonalisation subscales of the MBI-HSS (MP). A reduced odds of burnout was observed among physicians who worked ⩽20 h/week (vs 31–40 h/week, adjusted odds ratio (aOR) 0.03, 95% confidence interval (CI) 0.002–0.56) and who had a greater perceived level of clinical support (aOR 0.70, 95% CI 0.62–0.80). Physicians with higher levels of depressive symptoms had higher odds of burnout (aOR 18.32, 95% CI 6.75–49.73). Resilience, mean (SD) CD-RISC score, was lower in physicians who met burnout criteria compared to those who did not (62.6 (11.1) vs 70.0 (11.3); p < 0.001). Conclusions: Over one-third of palliative medicine physicians meet burnout criteria. The provision of enhanced organisational and colleague support is paramount in both the current and future pandemics

Ferritin Levels in the Cerebrospinal Fluid Predict Alzheimer\u27s Disease Outcomes and Are Regulated by APOE

Brain iron elevation is implicated in Alzheimer\u27s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer\u27s risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD

Initial Steps Towards a Clinical FLASH Radiotherapy System: Pediatric Whole Brain Irradiation with 40 MeV Electrons at FLASH Dose Rates

In this work, we investigated the delivery of a clinically acceptable pediatric whole brain radiotherapy plan at FLASH dose rates using two lateral opposing 40-MeV electron beams produced by a practically realizable linear accelerator system. The EGSnrc Monte Carlo software modules, BEAMnrc and DOSXYZnrc, were used to generate whole brain radiotherapy plans for a pediatric patient using two lateral opposing 40-MeV electron beams. Electron beam phase space files were simulated using a model of a diverging beam with a diameter of 10 cm at 50 cm SAD (defined at brain midline). The electron beams were collimated using a 10-cm-thick block composed of 5 cm of aluminum oxide and 5 cm of tungsten. For comparison, a 6-MV photon plan was calculated with the Varian AAA algorithm. Electron beam parameters were based on a novel linear accelerator designed for the PHASER system and powered by a commercial 6-MW klystron. Calculations of the linear accelerator's performance indicated an average beam current of at least 6.25 µA, providing a dose rate of 115 Gy/s at isocenter, high enough for cognition-sparing FLASH effects. The electron plan was less homogenous with a homogeneity index of 0.133 compared to the photon plan's index of 0.087. Overall, the dosimetric characteristics of the 40-MeV electron plan were suitable for treatment. In conclusion, Monte Carlo simulations performed in this work indicate that two lateral opposing 40-MeV electron beams can be used for pediatric whole brain irradiation at FLASH dose rates of >115 Gy/s and serve as motivation for a practical clinical FLASH radiotherapy system, which can be implemented in the near future

Stakeholder perspectives of a pilot multicomponent delirium prevention intervention for adult patients with advanced cancer in palliative care units: A behaviour change theory-based qualitative study

Background: Theory-based and qualitative evaluations in pilot trials of complex clinical interventions help to understand quantitative results, as well as inform the feasibility and design of subsequent effectiveness and implementation trials. Aim: To explore patient, family, clinician and volunteer (‘stakeholder’) perspectives of the feasibility and acceptability of a multicomponent non-pharmacological delirium prevention intervention for adult patients with advanced cancer in four Australian palliative care units that participated in a phase II trial, the ‘PRESERVE pilot study’. Design: A trial-embedded qualitative study via semi-structured interviews and directed content analysis using Michie’s Behaviour Change Wheel and the Theoretical Domains Framework. Setting/participants: Thirty-nine people involved in the trial: nurses (n = 17), physicians (n = 6), patients (n = 6), family caregivers (n = 4), physiotherapists (n = 3), a social worker, a pastoral care worker and a volunteer. Results: Participants’ perspectives aligned with the ‘capability’, ‘opportunity’ and ‘motivation’ domains of the applied frameworks. Of seven themes, three were around the alignment of the delirium prevention intervention with palliative care (intervention was considered routine care; intervention aligned with the compassionate and collaborative culture of palliative care; and differing views of palliative care priorities influenced perspectives of the intervention) and four were about study processes more directly related to adherence to the intervention (shared knowledge increased engagement with the intervention; impact of the intervention checklist on attention, delivery and documentation of the delirium prevention strategies; clinical roles and responsibilities; and addressing environmental barriers to delirium prevention). Conclusion: This theory-informed qualitative study identified multiple influences on the delivery and documentation of a pilot multicomponent non-pharmacological delirium prevention intervention in four palliative care units. Findings inform future definitive studies of delirium prevention in palliative care

Realising local government visions for developing district heating: experiences from a learning country

District heating (DH) has an important role to play in enabling cities to transition to low-carbon heating. Although schemes are commonplace in some countries, in ‘learning countries’ where building-level technologies make up the majority of heating systems there are numerous barriers to introducing DH. Local governments are seen as key actors in helping to create a ‘shared vision’ for DH amongst stakeholders. This study uses interviews with stakeholders from a range of sectors in the UK (an example of a learning country) to examine the visions of local actors for developing DH and the types of national policy that would support local implementation of these visions. The analysis shows that in engaging with DH development local governments seek multiple types of value. Realising this value will most likely happen by taking a long-term, planned approach to development. In contrast, national government policy is geared towards techno-economic criteria and may lead to only a minority of potential sites being developed, without realisation of wider social or environmental benefits aligned to local visions. The work highlights the importance of local strategic planning, enabled by aligned national policy, in realising the full economic, environmental and social benefits of DH

PhotoAffinity bits : a photoaffinity-based fragment screening platform for efficient identification of protein ligands

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutic