Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase

Objectives (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. Methods Biomimetic Pictet–Spengler or Bischler–Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. Results In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. Conclusions As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis

Talented suppliers? Strategic change and innovation in the UK aerospace industry

The 1990s marked the start of extensive re-structuring in the aerospace industry throughout the world. While the ensuing consolidation among prime contractors has been widely researched, the changes affecting the aerospace supply chain have received less attention. This study focuses on the re-structuring taking place within the supply chain of the UK aerospace industry. The findings point to extensive re-structuring. Unlike most earlier studies the lean supply model was found to be a powerful influence, with suppliers moving away from subcontractor status and instead taking on the mantle of ‘talented’ suppliers. While some of the implications of lean supply, in terms of the dynamics of innovation, were not apparent, there were modest signs of increased process innovation on the part of some suppliers

Characteristics of Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Comparison With Influenza in Children Admitted to U.K. PICUs

Objectives: Severe acute respiratory syndrome coronavirus-2 affects adults disproportionately more than children. A small proportion of children with severe acute respiratory syndrome coronavirus-2 required admission to a PICU. We describe the nationwide U.K. PICU experience of severe acute respiratory syndrome coronavirus-2 infection during the first wave of the pandemic and compare this with the critical care course of the 2019 influenza cohort. Design: Prospective nationwide cohort study of characteristics of severe acute respiratory syndrome coronavirus-2–positive children. Data collection utilized routine Pediatric Intensive Care Audit Network and severe acute respiratory syndrome coronavirus-2–specific data. Setting: All U.K. PICUs. Patients: Children less than 18 years old, admitted to U.K. PICUs between March 14, 2020, and June 13, 2020, and a positive severe acute respiratory syndrome coronavirus-2 polymerase chain reaction. Children admitted to U.K. PICUs in 2019 with influenza provided comparison. Interventions: None. Measurements and Main Results: We identified 76 PICU admissions among 73 children with a positive severe acute respiratory syndrome coronavirus-2 polymerase chain reaction test. Prevalence of PICU admissions per million was 5.2 for children versus 260 for adults. Ten children (14%) were identified on routine screening. Seventeen children (23%) had pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2. Seventeen (23%) had coinfections. Invasive ventilation was required in seven of 17 children (41%) with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 versus 38 of 56 other severe acute respiratory syndrome coronavirus-2 positive children (68%), with 77% requiring vasoactive support versus 43%, respectively. Seven children (10%) died. In comparison with influenza children, severe acute respiratory syndrome coronavirus-2 children were older (median [interquartile range]: 10 [1–13] vs 3 yr [1–8 yr]), more often Black or Asian (52% v 18%), higher weight z score (0.29 [–0.80 to 1.62] vs –0.41 [–1.37 to 0.63]), and higher deprivation index (3.3 [–1 to 6.3] vs 1.2 [–1.8 to 4.4]). Comorbidities, frequency of organ supports, and length of stay were similar. Conclusions: This nationwide study confirms that PICU admissions with severe acute respiratory syndrome coronavirus-2 infections were infrequent. We have reported similarities and differences in sociodemographic characteristics, organ support interventions, and outcomes of children affected by severe acute respiratory syndrome coronavirus-2 compared with influenza

Foot pain and foot health in an educated population of adults: results from the Glasgow Caledonian University Alumni Foot Health Survey

Abstract Background Foot pain is common amongst the general population and impacts negatively on physical function and quality of life. Associations between personal health characteristics, lifestyle/behaviour factors and foot pain have been studied; however, the role of wider determinants of health on foot pain have received relatively little attention. Objectives of this study are i) to describe foot pain and foot health characteristics in an educated population of adults; ii) to explore associations between moderate-to-severe foot pain and a variety of factors including gender, age, medical conditions/co-morbidity/multi-morbidity, key indicators of general health, foot pathologies, and social determinants of health; and iii) to evaluate associations between moderate-to-severe foot pain and foot function, foot health and health-related quality-of-life. Methods Between February and March 2018, Glasgow Caledonian University Alumni with a working email address were invited to participate in the cross-sectional electronic survey (anonymously) by email via the Glasgow Caledonian University Alumni Office. The survey was constructed using the REDCap secure web online survey application and sought information on presence/absence of moderate-to-severe foot pain, patient characteristics (age, body mass index, socioeconomic status, occupation class, comorbidities, and foot pathologies). Prevalence data were expressed as absolute frequencies and percentages. Multivariate logistic and linear regressions were undertaken to identify associations 1) between independent variables and moderate-to-severe foot pain, and 2) between moderate-to-severe foot pain and foot function, foot health and health-related quality of life. Results Of 50,228 invitations distributed, there were 7707 unique views and 593 valid completions (median age [inter-quartile range] 42 [31–52], 67.3% female) of the survey (7.7% response rate). The sample was comprised predominantly of white Scottish/British (89.4%) working age adults (95%), the majority of whom were overweight or obese (57.9%), and in either full-time or part-time employment (82.5%) as professionals (72.5%). Over two-thirds (68.5%) of the sample were classified in the highest 6 deciles (most affluent) of social deprivation. Moderate-to-severe foot pain affected 236/593 respondents (39.8%). High body mass index, presence of bunions, back pain, rheumatoid arthritis, hip pain and lower occupation class were included in the final multivariate model and all were significantly and independently associated with moderate-to-severe foot pain (p < 0.05), except for rheumatoid arthritis (p = 0.057). Moderate-to-severe foot pain was significantly and independently associated lower foot function, foot health and health-related quality of life scores following adjustment for age, gender and body mass index (p < 0.05). Conclusions Moderate-to-severe foot pain was highly prevalent in a university-educated population and was independently associated with female gender, high body mass index, bunions, back pain, hip pain and lower occupational class. Presence of moderate-to-severe foot pain was associated with worse scores for foot function, foot health and health-related quality-of-life. Education attainment does not appear to be protective against moderate-to-severe foot pain

Endurance Exercise as a Countermeasure for Aging

OBJECTIVE— We determined whether reduced insulin sensitivity, mitochondrial dysfunction, and other age-related dysfunctions are inevitable consequences of aging or secondary to physical inactivity

A toolbox for the longitudinal assessment of healthspan in ageing mice

The number of people aged over 65 is expected to double in the next 30 years. For many, living longer will mean spending more years with the burdens of chronic diseases such as Alzheimer’s, cardiovascular disease, and diabetes. Although researchers have made rapid progress in developing geroprotective interventions that target mechanisms of ageing and delay or prevent the onset of multiple concurrent age-related diseases, a lack of standardized techniques to assess healthspan in preclinical murine studies has resulted in reduced reproducibility and slowed progress. To overcome this, major centres in Europe and the USA skilled in healthspan analysis came together to agree upon a toolbox of techniques which can be used to consistently assess the healthspan of mice. Here, we describe the agreed toolbox which contains protocols for echocardiography, novel object recognition, grip strength, rotarod, glucose and insulin tolerance tests, body composition, and energy expenditure. They can be performed longitudinally in the same mouse over a period of 4-6 weeks to test how candidate geroprotectors affect cardiac, cognitive, neuromuscular and metabolic health

Barriers and enablers to the implementation of a complex quality improvement intervention for acute kidney injury: A qualitative evaluation of stakeholder perceptions of the Tackling AKI study

Background Acute kidney injury in hospital patients is common and associated with reduced survival and higher healthcare costs. The Tackling Acute Kidney Injury (TAKI) quality improvement project aimed to reduce mortality rates in patients with acute kidney injury by implementing a multicomponent intervention comprising of an electronic alert, care bundle and education in five UK hospitals across a variety of wards. A parallel developmental evaluation using a case study approach was conducted to provide the implementation teams with insights into factors that might impact intervention implementation and fidelity. The qualitative element of the evaluation will be reported. Methods 29 semi-structured interviews with implementation teams across the five hospitals were carried out to identify perceived barriers and enablers to implementation. Interviews were taped and transcribed verbatim and Framework analysis was conducted. Results Interviews generated four ‘barriers and enablers’ to implementation themes: i) practical/contextual factors, ii) skills and make-up of the TAKI implementation team, iii) design, development and implementation approach, iv) staff knowledge, attitudes, behaviours and support. Enablers included availability of specialist teams (e.g. educational teams), multi-disciplinary implementation teams with strong leadership, team-based package completion and proactive staff. Barriers were frequently the converse of facilitators. Conclusions Despite diversity of sites, a range of common local factors–contextual, intervention-based and individual–were identified as potential barriers and enablers to fidelity, including intervention structure/design and process of/approach to implementation. Future efforts should focus on early identification and management of barriers and tailored optimisation of known enablers such as leadership and multidisciplinary teams to encourage buy-in. Improved measures of real-time intervention and implementation fidelity would further assist local teams to target their support during such quality improvement initiatives

Strategic positioning:an integrated decision process for manufacturers

Purpose – This paper describes research that has sought to create a formal and rational process that guides manufacturers through the strategic positioning decision. Design/methodology/approach – The methodology is based on a series of case studies to develop and test the decision process. Findings – A decision process that leads the practitioner through an analytical process to decide which manufacturing activities they should carryout themselves. Practical implications – Strategic positioning is concerned with choosing those production related activities that an organisations should carry out internally, and those that should be external and under the ownership and control of suppliers, partners, distributors and customers. Originality/value – This concept extends traditional decision paradigms, such as those associated with “make versus buy” and “outsourcing”, by looking at the interactions between manufacturing operations and the wider supply chain networks associated with the organisation

ScreenTrack: Using a Visual History of a Computer Screen to Retrieve Documents and Web Pages

Computers are used for various purposes, so frequent context switching is inevitable. In this setting, retrieving the documents, files, and web pages that have been used for a task can be a challenge. While modern applications provide a history of recent documents for users to resume work, this is not sufficient to retrieve all the digital resources relevant to a given primary document. The histories currently available do not take into account the complex dependencies among resources across applications. To address this problem, we tested the idea of using a visual history of a computer screen to retrieve digital resources within a few days of their use through the development of ScreenTrack. ScreenTrack is software that captures screenshots of a computer at regular intervals. It then generates a time-lapse video from the captured screenshots and lets users retrieve a recently opened document or web page from a screenshot after recognizing the resource by its appearance. A controlled user study found that participants were able to retrieve requested information more quickly with ScreenTrack than under the baseline condition with existing tools. A follow-up study showed that the participants used ScreenTrack to retrieve previously used resources and to recover the context for task resumption.Comment: CHI 2020, 10 pages, 7 figure