High Throughput Screening of a GlaxoSmithKline Protein Kinase Inhibitor Set Identifies an Inhibitor of Human Cytomegalovirus Replication that Prevents CREB and Histone H3 Post-Translational Modification.

To identify new compounds with anti-human cytomegalovirus (HCMV) activity and new anti-HCMV targets, we developed a high throughput strategy to screen a GlaxoSmithKline (GSK) Published Kinase Inhibitor Set (PKIS). This collection contains a range of extensively characterized compounds grouped into chemical families (chemotypes). From our screen we identified compounds within chemotypes that impede HCMV replication and identified kinase proteins associated with inhibition of HCMV replication that are potential novel anti-HCMV targets. We focused our study on a top "hit" in our screen, SB-734117, which we found inhibits productive replication of several HCMV strains. Kinase selectivity data indicated that SB-734117 exhibits polypharmacology and is an inhibitor of several proteins from the AGC and CMCG kinase groups. Using western blotting we found that SB-734711 inhibited accumulation of HCMV immediate-early proteins, phosphorylation of cellular proteins involved in immediate-early protein production (CREB and histone H3) and histone H3 lysine 36 trimethylation (H3K36me3). Therefore, we identify SB-734117 as a novel anti-HCMV compound and find that inhibition of AGC and CMCG kinase proteins during productive HCMV replication is associated with inhibition of viral protein production and prevents post-translational modification of cellular factors associated with viral protein production

Measuring maternal mortality : an overview of opportunities and options for developing countries

Background:There is currently an unprecedented expressed need and demand for estimates of maternal mortality in developing countries. This has been stimulated in part by the creation of a Millennium Development Goal that will be judged partly on the basis of reductions in maternal mortality by 2015. Methods: Since the launch of the Safe Motherhood Initiative in 1987, new opportunities for data capture have arisen and new methods have been developed, tested and used. This paper provides a pragmatic overview of these methods and the optimal measurement strategies for different developing country contexts. Results: There are significant recent advances in the measurement of maternal mortality, yet also room for further improvement, particularly in assessing the magnitude and direction of biases and their implications for different data uses. Some of the innovations in measurement provide efficient mechanisms for gathering the requisite primary data at a reasonably low cost. No method, however, has zero costs. Investment is needed in measurement strategies for maternal mortality suited to the needs and resources of a country, and which also strengthen the technical capacity to generate and use credible estimates. Conclusion: Ownership of information is necessary for it to be acted upon: what you count is what you do. Difficulties with measurement must not be allowed to discourage efforts to reduce maternal mortality. Countries must be encouraged and enabled to count maternal deaths and act.WJG is funded partially by the University of Aberdeen. OMRC is partially funded by the London School of Hygiene and Tropical Medicine. CS and SA are partially funded by Johns Hopkins University. CAZ is funded by the Health Metrics Network at the World Health Organization. WJG, OMRC, CS and SA are also partially supported through an international research program, Immpact, funded by the Bill & Melinda Gates Foundation, the Department for International Development, the European Commission and USAID

Surgical physiology of inguinal hernia repair - a study of 200 cases

BACKGROUND: Current inguinal hernia operations are generally based on anatomical considerations. Failures of such operations are due to lack of consideration of physiological aspects. Many patients with inguinal hernia are cured as a result of current techniques of operation, though factors that are said to prevent hernia formation are not restored. Therefore, the surgical physiology of inguinal canal needs to be reconsidered. METHODS: A retrospective study is describer of 200 patients operated on for inguinal hernia under local anaesthesia by the author's technique of inguinal hernia repair. RESULTS: The posterior wall of the inguinal canal was weak and without dynamic movement in all patients. Strong aponeurotic extensions were absent in the posterior wall. The muscle arch movement was lost or diminished in all patients. The movement of the muscle arch improved after it was sutured to the upper border of a strip of the external oblique aponeurosis (EOA). The newly formed posterior wall was kept physiologically dynamic by the additional muscle strength provided by external oblique muscle to the weakened muscles of the muscle arch. CONCLUSIONS: A physiologically dynamic and strong posterior inguinal wall, and the shielding and compression action of the muscles and aponeuroses around the inguinal canal are important factors that prevent hernia formation or hernia recurrence after repair. In addition, the squeezing and plugging action of the cremasteric muscle and binding effect of the strong cremasteric fascia, also play an important role in the prevention of hernia

Returning persons with SARS-CoV-2 to the field of play in professional golf: a risk assessment and risk reduction approach

Objectives This pilot study aimed to see whether a risk assessment and risk reduction approach was a practical and feasible approach, as compared with standard isolation for fully vaccinated, asymptomatic persons positive for SARS-CoV-2. Methods This prospective cohort study included all players and caddies participating in two large professional golf events from 7 to 20 February 2022 in South Africa. Fully vaccinated persons testing positive who were asymptomatic were subject to risk assessment and risk reduction measures to protect the integrity of the event. Asymptomatic individuals who could socially distance in outdoor areas were allowed to participate. Close contacts were subject to daily rapid antigen tests and asked to prioritise outdoor space. Results The protocols put in place for the events were practical, feasible, and well accepted by event participants and staff during the study period. There was a total of 378 player-week episodes and 378 caddie-week episodes during the study period. Three persons tested positive while registered at events during the study period (0.4% of person episodes). The positive tests were returned from two players and one caddie, all of which were asymptomatic at the time of testing. There was one high-risk contact who consistently returned negative antigen tests. There was no evidence of transmission. Conclusions The approach was practical and feasible. A risk assessment and risk reduction approach allowed fully vaccinated asymptomatic persons with SARS-CoV-2 to participate in golf, an outdoor sport where social distancing is possible, compared with standard isolation

Effect of preoperative thoracic duct drainage on canine kidney transplantation

Chronic drainage of the thoracic duct to the esophagus was developed in dogs, and its efficacy in immunomodulation was tested using kidney transplantation. Compared to 9.7 days in the control, the mean animal survival was prolonged to 9.9 days, 17.8 days, and 18.5 days when TDD was applied preoperatively for 3 weeks, 6 weeks, and 9 weeks, respectively. Prolongation was significant after 6 weeks. Patency of the fistula was 93.5, 80.4, and 76.1% at respective weeks. Number of peripheral T-lymphocytes determined by a new monoclonal antibody diminished after 3 weeks. All animals were in normal health, requiring no special care for fluid, electrolyte, or protein replacement

Estimating the prevalence of breast cancer using a disease model: data problems and trends

BACKGROUND: Health policy and planning depend on quantitative data of disease epidemiology. However, empirical data are often incomplete or are of questionable validity. Disease models describing the relationship between incidence, prevalence and mortality are used to detect data problems or supplement missing data. Because time trends in the data affect their outcome, we compared the extent to which trends and known data problems affected model outcome for breast cancer. METHODS: We calculated breast cancer prevalence from Dutch incidence and mortality data (the Netherlands Cancer Registry and Statistics Netherlands) and compared this to regionally available prevalence data (Eindhoven Cancer Registry, IKZ). Subsequently, we recalculated the model adjusting for 1) limitations of the prevalence data, 2) a trend in incidence, 3) secondary primaries, and 4) excess mortality due to non-breast cancer deaths. RESULTS: There was a large discrepancy between calculated and IKZ prevalence, which could be explained for 60% by the limitations of the prevalence data plus the trend in incidence. Secondary primaries and excess mortality had relatively small effects only (explaining 17% and 6%, respectively), leaving a smaller part of the difference unexplained. CONCLUSION: IPM models can be useful both for checking data inconsistencies and for supplementing incomplete data, but their results should be interpreted with caution. Unknown data problems and trends may affect the outcome and in the absence of additional data, expert opinion is the only available judge

An Action-Based Approach to Presence: Foundations and Methods

This chapter presents an action-based approach to presence. It starts by briefly describing the theoretical and empirical foundations of this approach, formalized into three key notions of place/space, action and mediation. In the light of these notions, some common assumptions about presence are then questioned: assuming a neat distinction between virtual and real environments, taking for granted the contours of the mediated environment and considering presence as a purely personal state. Some possible research topics opened up by adopting action as a unit of analysis are illustrated. Finally, a case study on driving as a form of mediated presence is discussed, to provocatively illustrate the flexibility of this approach as a unified framework for presence in digital and physical environment

Estimating summary measures of health: a structured workbook approach

BACKGROUND: Summary measures of health that combine mortality and morbidity into a single indicator are being estimated in the Canadian context for approximately 200 diseases and conditions. To manage the large amount of data and calculations for this many diseases, we have developed a structured workbook system with easy to use tools. We expect this system will be attractive to researchers from other countries or regions of Canada who are interested in estimating the health-adjusted life years (HALYs) lost to premature mortality and year-equivalents lost to reduced functioning, as well as population attributable fractions (PAFs) associated with risk factors. This paper describes the workbook system using cancers as an example, and includes the entire system as a free, downloadable package. METHODS: The workbook system was developed in Excel and runs on a personal computer. It is a database system that stores data on population structure, mortality, incidence, distributions of cases entering a multitude of health states, durations of time spent in health states, preference scores that weight for severity, life table estimates of life expectancies, and risk factor prevalence and relative risks. The tools are Excel files with embedded macro programs. The main tool generates workbooks that estimate HALY, one per disease, by copying data from the database into a pre-defined template. Other tools summarize the HALY results across diseases for easy analysis. RESULTS: The downloadable zip file contains the database files initialized with Canadian data for cancers, the tools, templates and workbooks that estimate PAF and a user guide. The workbooks that estimate HALY are generated from the system at a rate of approximately one minute per disease. The resulting workbooks are self-contained and can be used directly to explore the details of a particular disease. Results can be discounted at different rates through simple parameter modification. CONCLUSION: The structured workbook approach offers researchers an efficient, easy to use, and easy to understand set of tools for estimating HALY and PAF summary measures for their country or region of interest

Age-Related Attenuation of Dominant Hand Superiority

The decline of motor performance of the human hand-arm system with age is well-documented. While dominant hand performance is superior to that of the non-dominant hand in young individuals, little is known of possible age-related changes in hand dominance. We investigated age-related alterations of hand dominance in 20 to 90 year old subjects. All subjects were unambiguously right-handed according to the Edinburgh Handedness Inventory. In Experiment 1, motor performance for aiming, postural tremor, precision of arm-hand movement, speed of arm-hand movement, and wrist-finger speed tasks were tested. In Experiment 2, accelerometer-sensors were used to obtain objective records of hand use in everyday activities