Exhausted CD4⁺ T Cells during Malaria Exhibit Reduced mTORc1 Activity Correlated with Loss of T-bet Expression

CD4⁺ T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4⁺ T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (Ag-exp) CD4⁺ T cell exhaustion during Plasmodium yoelii nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4+ T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted Ag-expCD4⁺ T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4⁺ T cells. Consistent with this, Ag-expTh1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) Ag-expT cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-γ production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4⁺ T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4⁺ T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in Ag-expCD4⁺ T cells but that reduction in mTOR activity may not directly underpin Ag-expTh1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4⁺ T cells during malaria infection and other chronic conditions

Is chronic pelvic pain a comfortable diagnosis for primary care practitioners: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Chronic pelvic pain (CPP) has a prevalence similar to asthma and chronic back pain, but little is known about how general practitioners (GPs) and practice nurses manage women with this problem. A clearer understanding of current management is necessary to develop appropriate strategies, in keeping with current health care policy, for the supported self-management of patients with long term conditions. The aim of this study was to explore GPs' and practice nurses' understanding and perspectives on the management of chronic pelvic pain.</p> <p>Methods</p> <p>Data were collected using semi-structured interviews with a purposive sample of 21 GPs and 20 practice nurses, in three primary care trusts in the North West of England. Data were analysed using the principles of Framework analysis.</p> <p>Results</p> <p>Analysis suggests that women who present with CPP pose a challenge to GPs and practice nurses. CPP is not necessarily recognized as a diagnostic label and making the diagnosis was achieved only by exclusion. This contrasts with the relative acceptability of labels such as irritable bowel syndrome (IBS). GPs expressed elements of therapeutic nihilism about the condition. Despite practice nurses taking on increasing responsibilities for the management of patients with long term conditions, respondents did not feel that CPP was an area that they were comfortable in managing.</p> <p>Conclusions</p> <p>The study demonstrates an educational/training need for both GPs and practice nurses. GPs described a number of skills and clinical competencies which could be harnessed to develop a more targeted management strategy. There is potential to develop facilitated self- management for use in this patient group, given that this approach has been successful in patients with similar conditions such as IBS.</p

Activity pacing: moving beyond taking breaks and slowing down

This brief communication responds to the paper by Jeong and Cho (Qual Life Res 26(4):903–911, 2017) that has described activity pacing in limited terms of adjusting activities through going at a slower rate and taking breaks. Activity pacing was reported as not involving goal setting, in comparison to other strategies for long-term conditions such as Acceptance and Commitment Therapy. This brief communication aims to challenge this limited perception of activity pacing in light of numerous studies that recognise pacing to be a more complex strategy. Pacing is considered to be a multifaceted coping strategy, including broad themes of not only adjusting activities, but also planning activities, having consistent activity levels, acceptance of current abilities and gradually increasing activities, and one that includes goal setting as a key facet. It is essential that pacing is both defined and measured as a multifaceted strategy in order to assess the outcomes of pacing, and for meaningful comparisons with other strategies regarding efficacy for the management of long-term conditions

Comfort and utility of school-based weight screening: the student perspective

<p>Abstract</p> <p>Background</p> <p>Weight screening in schools has been proposed as one strategy to address childhood obesity. Students' response to such screening is unexplored, however. In this study we evaluated the perceived comfort, utility and impact of school-based weight screening from the perspective of middle school-aged students.</p> <p>Methods</p> <p>A cross-sectional study of 852 ethnically diverse 5^th–8^thgrade students. Associations were investigated between measured height and weight screening data and responses to a self-administered questionnaire completed immediately following weight screening in physical education class. BMI categories were based on the revised 2000 CDC growth chart and definitions: 5^th–85^thBMI percentile = healthy weight, 85^th–95^thBMI percentile = at risk for overweight, and >95^thpercentile BMI = overweight.</p> <p>Results</p> <p>Overall, students' comfort level with weight screening varied depending on the student's own weight status. More overweight students (38.1%) reported being uncomfortable than healthy weight students (8.1%) (p < 0.001). In particular, overweight female students (54.8%) compared to healthy weight female students (21.6%) reported being uncomfortable (p < 0.01). About half (54.9%) of all students reported knowing their weight prior to screening, and 58.9% reported that it was useful to learn their height and weight. Compared to healthy weight students, overweight students were significantly more likely to report the intention to perform weight modification related activities such as visiting a doctor (Odds ratio (OR) = 2.0, 95% CI = 1.3, 3.1), eating more fruits and vegetables (OR = 2.7, 95% CI = 1.7, 4.1), and increasing physical activity (OR = 4.3, 95% CI = 2.7, 7.0).</p> <p>Conclusion</p> <p>Overall, the majority of the middle school students did not report discomfort with school-based weight screening, did report that receiving height and weight information was useful, and generally report appropriate weight control intentions. These proportions varied across weight status categories, however, with students who were at risk for overweight or overweight reporting higher levels of discomfort. For schools that conduct weight screening, it is essential that they also provide comfortable and private settings as well as education or counseling regarding healthy weight control practices.</p

Epidemiology of Exertional Rhabdomyolysis Susceptibility in Standardbred Horses Reveals Associated Risk Factors and Underlying Enhanced Performance

BACKGROUND: Exertional rhabdomyolysis syndrome is recognised in many athletic horse breeds and in recent years specific forms of the syndrome have been identified. However, although Standardbred horses are used worldwide for racing, there is a paucity of information about the epidemiological and performance-related aspects of the syndrome in this breed. The objectives of this study therefore were to determine the incidence, risk factors and performance effects of exertional rhabdomyolysis syndrome in Standardbred trotters and to compare the epidemiology and genetics of the syndrome with that in other breeds. METHODOLOGY/PRINCIPAL FINDINGS: A questionnaire-based case-control study (with analysis of online race records) was conducted following identification of horses that were determined susceptible to exertional rhabdomyolysis (based on serum biochemistry) from a total of 683 horses in 22 yards. Thirty six exertional rhabdomyolysis-susceptible horses were subsequently genotyped for the skeletal muscle glycogen synthase (GYS1) mutation responsible for type 1 polysaccharide storage myopathy. A total of 44 susceptible horses was reported, resulting in an annual incidence of 6.4 (95% CI 4.6-8.2%) per 100 horses. Female horses were at significantly greater risk than males (odds ratio 7.1; 95% CI 2.1-23.4; p = 0.001) and nervous horses were at a greater risk than horses with calm or average temperaments (odds ratio 7.9; 95% CI 2.3-27.0; p = 0.001). Rhabdomyolysis-susceptible cases performed better from standstill starts (p = 0.04) than controls and had a higher percentage of wins (p = 0.006). All exertional rhabdomyolysis-susceptible horses tested were negative for the R309H GYS1 mutation. CONCLUSIONS/SIGNIFICANCE: Exertional rhabdomyolysis syndrome in Standardbred horses has a similar incidence and risk factors to the syndrome in Thoroughbred horses. If the disorder has a genetic basis in Standardbreds, improved performance in susceptible animals may be responsible for maintenance of the disorder in the population

Computer literacy and attitudes towards e-learning among first year medical students

BACKGROUND: At the Medical University of Vienna, most information for students is available only online. In 2005, an e-learning project was initiated and there are plans to introduce a learning management system. In this study, we estimate the level of students' computer skills, the number of students having difficulty with e-learning, and the number of students opposed to e-learning. METHODS: The study was conducted in an introductory course on computer-based and web-based training (CBT/WBT). Students were asked to fill out a questionnaire online that covered a wide range of relevant attitudes and experiences. RESULTS: While the great majority of students possess sufficient computer skills and acknowledge the advantages of interactive and multimedia-enhanced learning material, a small percentage lacks basic computer skills and/or is very skeptical about e-learning. There is also a consistently significant albeit weak gender difference in available computer infrastructure and Internet access. As for student attitudes toward e-learning, we found that age, computer use, and previous exposure to computers are more important than gender. A sizable number of students, 12% of the total, make little or no use of existing e-learning offerings. CONCLUSION: Many students would benefit from a basic introduction to computers and to the relevant computer-based resources of the university. Given to the wide range of computer skills among students, a single computer course for all students would not be useful nor would it be accepted. Special measures should be taken to prevent students who lack computer skills from being disadvantaged or from developing computer-hostile attitudes

Methods for calculating Protection Equality for conservation planning

Protected Areas (PAs) are a central part of biodiversity conservation strategies around the world. Today, PAs cover c15% of the Earth’s land mass and c3% of the global oceans. These numbers are expected to grow rapidly to meet the Convention on Biological Diversity’s Aichi Biodiversity target 11, which aims to see 17% and 10% of terrestrial and marine biomes protected, respectively, by 2020. This target also requires countries to ensure that PAs protect an “ecologically representative” sample of their biodiversity. At present, there is no clear definition of what desirable ecological representation looks like, or guidelines of how to standardize its assessment as the PA estate grows. We propose a systematic approach to measure ecological representation in PA networks using the Protection Equality (PE) metric, which measures how equally ecological features, such as habitats, within a country’s borders are protected. Extending research in Barr et al. (2011), we present an R package and two Protection Equality (PE) measures; proportional to area PE, and fixed area PE, which measure the representativeness of a country’s PA network. We illustrate the PE metrics with two case studies: coral reef protection across countries and ecoregions in the Coral Triangle, and representation of ecoregions of six of the largest countries in the world. Our results provide repeatable transparency to the issue of representation in PA networks and provide a starting point for further discussion, evaluation and testing of representation metrics. They also highlight clear shortcomings in current PA networks, particularly where they are biased towards certain assemblage types or habitats. Our proposed metrics should be used to report on measuring progress towards the representation component of Aichi Target 11. The PE metrics can be used to measure the representation of any kind of ecological feature including: species, ecoregions, processes or habitats

Cellular preservation of musculoskeletal specializations in the Cretaceous bird Confuciusornis

The hindlimb of theropod dinosaurs changed appreciably in the lineage leading to extant birds, becoming more ‘crouched’ in association with changes to body shape and gait dynamics. This postural evolution included anatomical changes of the foot and ankle, altering the moment arms and control of the muscles that manipulated the tarsometatarsus and digits, but the timing of these changes is unknown. Here, we report cellular-level preservation of tendon- and cartilage-like tissues from the lower hindlimb of Early Cretaceous Confuciusornis. The digital flexor tendons passed through cartilages, cartilaginous cristae and ridges on the plantar side of the distal tibiotarsus and proximal tarsometatarsus, as in extant birds. In particular, fibrocartilaginous and cartilaginous structures on the plantar surface of the ankle joint of Confuciusornis may indicate a more crouched hindlimb posture. Recognition of these specialized soft tissues in Confuciusornis is enabled by our combination of imaging and chemical analyses applied to an exceptionally preserved fossil

The antibacterial properties of Malaysian tualang honey against wound and enteric microorganisms in comparison to manuka honey

<p>Abstract</p> <p>Background</p> <p>Antibiotic resistance of bacteria is on the rise, thus the discovery of alternative therapeutic agents is urgently needed. Honey possesses therapeutic potential, including wound healing properties and antimicrobial activity. Although the antimicrobial activity of honey has been effectively established against an extensive spectrum of microorganisms, it differs depending on the type of honey. To date, no extensive studies of the antibacterial properties of tualang (<it>Koompassia excelsa</it>) honey on wound and enteric microorganisms have been conducted. The objectives of this study were to conduct such studies and to compare the antibacterial activity of tualang honey with that of manuka honey.</p> <p>Methods</p> <p>Using a broth dilution method, the antibacterial activity of tualang honey against 13 wound and enteric microorganisms was determined; manuka honey was used as the control. Different concentrations of honey [6.25-25% (w/v)] were tested against each type of microorganism. Briefly, two-fold dilutions of honey solutions were tested to determine the minimum inhibitory concentration (MIC) against each type of microorganism, followed by more assays within a narrower dilution range to obtain more precise MIC values. MICs were determined by both visual inspection and spectrophotometric assay at 620 nm. Minimum bactericidal concentration (MBC) also was determined by culturing on blood agar plates.</p> <p>Results</p> <p>By visual inspection, the MICs of tualang honey ranged from 8.75% to 25% compared to manuka honey (8.75-20%). Spectrophotometric readings of at least 95% inhibition yielded MIC values ranging between 10% and 25% for both types of honey. The lowest MBC for tualang honey was 20%, whereas that for manuka honey was 11.25% for the microorganisms tested. The lowest MIC value (8.75%) for both types of honey was against <it>Stenotrophomonas maltophilia</it>. Tualang honey had a lower MIC (11.25%) against <it>Acinetobacter baumannii </it>compared to manuka honey (12.5%).</p> <p>Conclusion</p> <p>Tualang honey exhibited variable activities against different microorganisms, but they were within the same range as those for manuka honey. This result suggests that tualang honey could potentially be used as an alternative therapeutic agent against certain microorganisms, particularly <it>A. baumannii </it>and <it>S. maltophilia</it>.</p