The analysis of exosomal micro-RNAs in peripheral blood mononuclear cell-derived macrophages after infection with bacillus Calmette–Guérin by RNA sequencing

AbstractObjective/BackgroundTuberculosis (TB) is a major global threat to human health, especially in low-income countries. The diagnosis of TB is challenging because of the limitations of specificity and sensitivity with the current diagnostics. Novel, selective biomarkers for TB would be of great practical value. Exosomes are bioactive vesicles with 30–100nm in diameter, which are secreted from almost all cell types and are found in virtually every human body fluid. Exosomes transport micro-RNAs (miRNAs), which are post-transcriptional regulators of gene expression, around the body and allow miRNAs to modulate biological pathways in target cells. Our aim was to investigate the potential of exosomal miRNAs as biomarkers by examining their release from human monocyte-derived macrophages (MDMs) after infection with Mycobacterium using miRNA sequencing.MethodsHuman monocytes were obtained from blood and driven to an MDM phenotype using standard protocols. MDMs were infected with Mycobacterium bovis Bacillus Calmette–Guérin (BCG) or left uninfected as control. Exosomes were collected 72 h postinfection from the cell culture medium and subjected to RNA isolation. Small RNA libraries were constructed and RNA sequencing performed. The raw reads were filtered to eliminate adaptor and primer sequences, and the sequences in FASTQ format were run against the mature human miRNA sequences available in miRBase using BLAST software using a Linux operating system. Micro-RNAs were identified using E=0.01 or 1.ResultsInfection of MDMs with BCG lead to the release of a number of exosomal miRNAs. These mainly consisted with Let-7 family members, miR-155, miR-146a, miR-145, and miR-21 all of which were predicted to target important immune-related genes and pathways.ConclusionThis study provides evidence for the release of specific miRNAs from BCG-infected MDMs. These results need to be confirmed and the presence of this panel of miRNAs tested in the blood of patients to determine their selectivity and specificity as a diagnostic in patients with TB

Immunologic finding of disseminated granuloma reaction in patients with Mycobacterium tuberculosis and sarcoidosis

AbstractIntroductionNecrotizing sarcoid granulomatosis (NSG) is a rare syndrome with unknown etiology. The disease is frequently confused with sarcoidosis and other granulomatous diseases. Diagnosis is made based on typical histologic criteria. No specific laboratory finding can confirm NSG diagnosis. The gender ratio of women to men has been reported as being as high as 4:1 and has a good prognosis.Methods and resultsIn this report, the clinical and genetic features were surveyed of a 36-year-old male with extra-pulmonary NSG with unique manifestations, such as inguinal mass with positive smear and negative culture for the infection of Mycobacterium tuberculosis (MTB), which was not responsive to the first-line TB treatment and was characterized as a multidrug-resistant (MDR) tuberculosis (TB). Later on, he was admitted for the MDR cure, and he did not react to the gold standard of MDR treatment. Finally, he presented with a huge lymphoid granuloma with massive ascites that was diagnosed as an NSG by IHC. He cured well with prednisolone and all symptoms of the disease were gone. At the hospitalization time, all laboratory experiments were well planned, such as a workup for the detection of defects of loop IL-12/IFN-γ, HLA-DR typing, and immunologic workup by flow-cytometry analysis.ConclusionThis is the first case report from patients with unique features of NSG combined with MTB

Layperson perception of reflux-related symptoms

OBJECTIVE: To assess for differences of intended meaning in the description of reflux-related symptoms among otolaryngology patients and clinicians. STUDY DESIGN: Cross-sectional survey-based study. SETTING: Five tertiary, academic otolaryngology practices. METHODS: Between June 2020 and July 2022, a questionnaire consisting of 20 common descriptors of reflux-related symptoms within four domains (throat-, chest-, stomach-, and sensory-related symptoms) was completed by patients. Attending otolaryngologists at five academic medical centers then completed the same survey. The primary outcome was to assess differences in patient and clinician perceptions of reflux-related symptoms. Differences based on geographic location was a secondary outcome. RESULTS: A total of 324 patients and 27 otolaryngologists participated. Patients selected a median of six terms compared with 10.5 for otolaryngologists ( CONCLUSION: There are differences between otolaryngologists and their patients in the interpretation of the symptoms of reflux. Patients tended to have a narrower interpretation of reflux with symptoms primarily limited to classic stomach-related symptoms, while clinicians tended to have a broader definition of reflux that included extra-esophageal manifestations of disease. This has important counseling implications for the clinician, as patients presenting with reflux symptoms may not comprehend the relationship of those symptoms to reflux disease

Knowledge user survey and Delphi process to inform development of a new risk of bias tool to assess systematic reviews with network meta-analysis (RoB NMA tool)

Background: Network meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We aimed to develop a risk of bias (RoB) tool to assess NMAs (RoB NMA tool). An international steering committee recommended that the RoB NMA tool to be used in combination with the Risk of Bias in Systematic reviews (ROBIS) tool (i.e. because it was designed to assess biases only) or other similar quality appraisal tools (eg, A MeaSurement Tool to Assess systematic Reviews 2 [AMSTAR 2]) to assess quality of systematic reviews. The RoB NMA tool will assess NMA biases and limitations regarding how the analysis was planned, data were analysed and results were presented, including the way in which the evidence was assembled and interpreted. Objectives: Conduct (a) a Delphi process to determine expert opinion on an item's inclusion and (b) a knowledge user survey to widen its impact. Design: Cross-sectional survey and Delphi process. Methods: Delphi panellists were asked to rate whether items should be included. All agreed-upon item were included in a second round of the survey (defined as 70% agreement). We surveyed knowledge users' views and preferences about the importance, utility and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and we followed a knowledge translation plan to disseminate the survey through social media and professional networks. Results: 22 items were entered into a Delphi survey of which 28 respondents completed round 1, and 22 completed round 2. Seven items did not reach consensus in round 2. A total of 298 knowledge users participated in the survey (14% respondent rate). 75% indicated that their organisation produced NMAs, and 78% showed high interest in the tool, especially if they had received adequate training (84%). Most knowledge users and Delphi panellists preferred a tool to assess both bias in individual NMA results and authors' conclusions. Response bias in our sample is a major limitation as knowledge users working in high-income countries were more represented. One of the limitations of the Delphi process is that it depends on the purposive selection of experts and their availability, thus limiting the variability in perspectives and scientific disciplines. Conclusions: This Delphi process and knowledge user survey informs the development of the RoB NMA tool

Oral health and elite sport performance

While the research base is limited, studies have consistently reported poor oral health in elite athletes since the first report from the 1968 Olympic Games. The finding is consistent both across selected samples attending dental clinics at major competitions and more representative sampling of teams and has led to calls from the International Olympic Committee for more accurate data on oral health. Poor oral health is an important issue directly as it can cause pain, negative effects on appearance and psychosocial effects on confidence and quality of life and may have long-term consequences for treatment burden. Self-reported evidence also suggests an impact on training and performance of athletes. There are many potential challenges to the oral health of athletes including nutritional, oral dehydration, exercise-induced immune suppression, lack of awareness, negative health behaviours and lack of prioritisation. However, in theory, oral diseases are preventable by simple interventions with good evidence of efficacy. The consensus statement aims to raise awareness of the issues of oral health in elite sport and recommends strategies for prevention and health promotion in addition to future research strategies

A Prospective Multicenter Study Evaluating Learning Curves and Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography Among Advanced Endoscopy Trainees: The Rapid Assessment of Trainee Endoscopy Skills (RATES) Study

Background and aims Based on the Next Accreditation System, trainee assessment should occur on a continuous basis with individualized feedback. We aimed to validate endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) learning curves among advanced endoscopy trainees (AETs) using a large national sample of training programs and to develop a centralized database that allows assessment of performance in relation to peers. Methods ASGE recognized training programs were invited to participate and AETs were graded on ERCP and EUS exams using a validated competency assessment tool that assesses technical and cognitive competence in a continuous fashion. Grading for each skill was done using a 4-point scoring system and a comprehensive data collection and reporting system was built to create learning curves using cumulative sum analysis. Individual results and benchmarking to peers were shared with AETs and trainers quarterly. Results Of the 62 programs invited, 20 programs and 22 AETs participated in this study. At the end of training, median number of EUS and ERCP performed/AET was 300 (range 155-650) and 350 (125-500). Overall, 3786 exams were graded (EUS:1137; ERCP–biliary 2280, pancreatic 369). Learning curves for individual endpoints, and overall technical/cognitive aspects in EUS and ERCP demonstrated substantial variability and were successfully shared with all programs. The majority of trainees achieved overall technical (EUS: 82%; ERCP: 60%) and cognitive (EUS: 76%; ERCP: 100%) competence at conclusion of training. Conclusions These results demonstrate the feasibility of establishing a centralized database to report individualized learning curves and confirm the substantial variability in time to achieve competence among AETs in EUS and ERCP

The Future of the Correlated Electron Problem

The understanding of material systems with strong electron-electron interactions is the central problem in modern condensed matter physics. Despite this, the essential physics of many of these materials is still not understood and we have no overall perspective on their properties. Moreover, we have very little ability to make predictions in this class of systems. In this manuscript we share our personal views of what the major open problems are in correlated electron systems and we discuss some possible routes to make progress in this rich and fascinating field. This manuscript is the result of the vigorous discussions and deliberations that took place at Johns Hopkins University during a three-day workshop January 27, 28, and 29, 2020 that brought together six senior scientists and 46 more junior scientists. Our hope, is that the topics we have presented will provide inspiration for others working in this field and motivation for the idea that significant progress can be made on very hard problems if we focus our collective energies.Comment: 55 pages, 19 figure

Sport, Muslim Identities and Cultures in the UK, an Emerging Policy Issue: Case Studies of Leicester and Birmingham

This is an Accepted Manuscript of an article published by Taylor & Francis Group in European Sport Management Quarterly on 04/09/2010, available online: http://dx.doi.org/10.1080/16184742.2010.502743An understanding of diversity and its implications for policy is critical to those charged with delivering sporting services in culturally plural societies. This paper reports a research project which aimed to examine how, on the one hand, Muslims in two specific local contexts in the UK (Leicester in the East Midlands; Birmingham in the West Midlands) make sense of the relationship between their religious (Islamic) identities and sporting interests and, on the other, how local policy makers perceived and responded to the sporting needs of these Muslim communities. According to the 2001 census, Leicester and Birmingham represent, respectively, one of the most ethnically diverse areas in Britain and the domicile for one-third of the Muslim population in Britain. Interviews were undertaken with representatives of Muslim organizations, governmental and quasi-governmental sporting organizations, in both cities. Critical Discourse Analysis of interviewees’ responses reveal pluralistic views on a range of issues such as: the ‘‘(un)suitability’’ of the environment/space provided for, or accessed by, Muslims to practise sport; funding; gender equity; equity and social inclusion agenda versus cultural and religious diversities; and a resistance (on the part of policy makers) to target provision at faith groups

Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis.

Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations