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Objective: To scope the relationships between rugby union, and health and well-being., Design: Scoping review., Data Sources: Published and unpublished reports of any age, identified by searching electronic databases, platforms and reference lists., Methods: A three-step search strategy identified relevant published primary, secondary studies and grey literature, which were screened using a priori inclusion criteria. Data were extracted using a standardised tool, to form (1) a numerical analysis and (2) a thematic summary., Results and Discussion: 6658 records were identified, and 198 studies met the inclusion criteria. All forms of rugby union can provide health-enhancing physical activity (PA). 'Non-contact' and wheelchair rugby in particular provide a wide range of physical and mental health and well-being benefits. The evidence is either mixed or unclear in relation to 'contact' rugby union and its effects on a range of physical health domains. Injury and concussion incidence rates are high for contact rugby union relative to other sports., Conclusions: A wide range of stakeholders as well as existing and potential participants can use this information to make a more informed decision about participating in and promoting rugby union as a health-enhancing activity. Industry and policy-makers can use this review to inform policies and strategies that look to increase participation rates and use rugby union as a vehicle to contribute positively to population health. Further research understanding rugby union's contribution to PA as well as to muscle-strengthening and balance is indicated, as well as research examining more health and well-being outcomes across more diverse cohorts., Competing Interests: Competing interests: SAG receives remuneration for clinical work in professional rugby union, and is employed by the Rugby Football Union as a Sports Medicine Training Fellow. AM receives remuneration from Scottish Rugby Union for clinical work. SK is employed by the Rugby Football Union as medical services director. KAS is employed by the Rugby Football Union as medical research lead., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Environmental enteropathy is an example of a poorly-understood intestinal disorder affecting millions of children worldwide, characterized by malabsorption and stunting. Although there is increasing interest in non-invasive means of assessing intestinal structure and function, the potential value of intestinal biopsy for histology, immunostaining, RNA sequencing and epigenetic work means that endoscopic biopsy remains extremely valuable. We here report our experience in the BEECH (Biomarkers of Environmental Enteropathy in CHildren) study of stunting in Zambia, in the belief that it may help address the knowledge gap regarding the safety of endoscopic biopsy in vulnerable young children., Methods: We report our experience of safety in 119 children undergoing endoscopic biopsy in the BEECH study in Lusaka Children's Hospital, Lusaka, and discuss ethical considerations in this light., Results: Upper gastrointestinal endoscopy was performed on children with stunting (length-for-age z score -2 or less) not responsive to nutritional interventions. Conscious sedation was provided by anaesthetists. Of 119 children, 5 (4%) developed transient desaturation, but no serious adverse events were experienced; no clinical, demographic or anaesthetic characteristics were identified as predictive of desaturation. Two children derived clinically useful information from the endoscopy, one life-saving. Of 105 lactase tests, 59 (54%) showed hypolactasia., Discussion: Children with stunting underwent endoscopy safely, and some derived clinical benefit. Safety and the possibility of clinical benefit are usually felt to be preconditions for the ethical justification for endoscopy for research in children, and we believe that these conditions were met in this study., (© The Author(s) [2020]. Published by Oxford University Press.)

Hematoxylin and Eosin (H&E) stained Whole Slide Images (WSIs) are utilized for biopsy visualization-based diagnostic and prognostic assessment of diseases. Variation in the H&E staining process across different lab sites can lead to significant variations in biopsy image appearance. These variations introduce an undesirable bias when the slides are examined by pathologists or used for training deep learning models. Traditionally proposed stain normalization and color augmentation strategies can handle the human level bias. But deep learning models can easily disentangle the linear transformation used in these approaches, resulting in undesirable bias and lack of generalization. To handle these limitations, we propose a Self-Attentive Adversarial Stain Normalization (SAASN) approach for the normalization of multiple stain appearances to a common domain. This unsupervised generative adversarial approach includes self-attention mechanism for synthesizing images with finer detail while preserving the structural consistency of the biopsy features during translation. SAASN demonstrates consistent and superior performance compared to other popular stain normalization techniques on H&E stained duodenal biopsy image data.

Background: Environmental enteropathy (EE) is associated with stunting, impairment of responses to oral vaccines, and other adverse health consequences in young children throughout the developing world. EE is characterized by chronic low-grade intestinal inflammation and disrupted epithelial barrier integrity, partly resulting from dysregulation of tight junction proteins, observed in other enteropathies such as celiac disease. During EE, this dysregulation of tight junction expression amplifies translocation of pathogenic bacteria across the intestinal mucosa., Aims: The aim was to determine whether enteropathogen-mediated epithelial barrier failure can be ameliorated using contra-pathogenicity therapies., Methods: Intestinal epithelial barrier damage was assessed in Caco-2 cells incubated with three important enteropathogens identified in EE patients: Enteropathogenic Escherichia coli (EPEC), Citrobacter rodentium (C. rodentium), and Cryptosporidium parvum (C. parvum). Potential therapeutic molecules were tested to detect effects on transepithelial resistance (TER), bacterial translocation (BT), claudin-4 expression, and regulation of the inflammatory cytokine response., Results: All three enteropathogens compared to uninfected cells, reduced TER (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0007), reduced claudin-4 expression, and permitted BT (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0003) through the monolayer. Zinc, colostrum, epidermal growth factor, trefoil factor 3, resistin-like molecule-β, hydrocortisone, and the myosin light chain kinase inhibitor ML7 (Hexahydro-1-[(5-iodo-1-naphthalenyl)sulfonyl]-1H-1,4-diazepine hydrochloride); ML7) improved TER (up to 70%) and decreased BT (as much as 96%). Only zinc demonstrated modest antimicrobial activity., Conclusion: The enteropathogens impaired intestinal-epithelial barrier integrity with dysregulation of claudin-4 and increased bacterial translocation. Enteropathogen-mediated damage was reduced using contra-pathogenicity agents which mitigated the effects of pathogens without direct antimicrobial activity.

Purpose: The eastern corridor of Africa is affected by a high burden of esophageal cancer (EC), with > 90% of patients presenting with advanced disease. Self-expanding metal stents (SEMS) have been previously reported as safe and effective for palliation of malignant dysphagia in resource-limited settings; however, access is limited throughout Eastern Africa., Methods: In response to demand for palliative interventions for patients with dysphagia because of EC, the African Esophageal Cancer Consortium (AfrECC) partnered with the Clinton Health Access Initiative to improve access to SEMS in Eastern Africa. We undertook a stepwise implementation approach to (1) identify barriers to SEMS access, (2) conduct a market analysis, (3) select an industry partner, (4) establish regulatory and procurement processes, (5) develop endoscopic training resources, (6) create a medical device registry, and (7) establish principles of accountability., Results: Following an evaluation of market demand and potential SEMS manufacturers, Boston Scientific Corporation announced its commitment to launch an access program to provide esophageal SEMS to patients in Tanzania, Kenya, Malawi, and Zambia at a subsidized price. Parallel regulatory and procurement processes were established in each participating country. Endoscopy training courses were designed and conducted, using the Training-of-Trainers model. A device registry was created to centralize data for quality control and to monitor channels of SEMS distribution. Principles of accountability were developed to guide the sustainability of this endeavor., Conclusion: The AfrECC Stent Access Initiative is an example of a multisector partnership formed to provide an innovative solution to align regional needs with a supply chain for a high-priority medical device.

We compared cardiometabolic demand and post-exercise enjoyment between continuous walking (CW) and time- and intensity-matched interval walking (IW) in insufficiently active adults. Sixteen individuals (13 females and three males, age 25.3 ± 11.1 years) completed one CW and one IW session lasting 30 min in a randomised-counterbalanced design. For CW, participants walked at a mean intensity of 65-70% predicted maximum heart rate (HR max ). For IW, participants alternated between 3 min at 80% HR max and 2 min at 50% HR max . Expired gas was measured throughout each protocol. Participants rated post-exercise enjoyment following each protocol. Mean HR and V˙O 2 showed small positive differences in IW vs. CW (2, 95%CL 0, 4 beat.min -1 ; d = 0.23, 95%CL 0.06, 0.41 and 1.4, 95%CL 1.2 ml.kg -1 .min -1 , d = 0.36, 95%CL 0.05, 0.65, respectively). There was a medium positive difference in overall kcal expenditure in IW vs. CW (25, 95%CL 7 kcal, d = 0.58, 95%CL 0.33, 0.82). Post-exercise enjoyment was moderately greater following IW vs. CW (9.1, 95%CL 1.4, 16.8 AU, d = 0.62, 95%CL 0.06, 0.90), with 75% of participants reporting IW as more enjoyable. Interval walking elicits meaningfully greater energy expenditure and is more enjoyable than CW in insufficiently active, healthy adults.

Competing Interests: Competing interests: SAG receives remuneration for clinical work in professional rugby union, and is employed by the Rugby Football Union as a Sports Medicine Training Fellow. AM receives remuneration from Scottish Rugby Union for clinical work. SK is employed by the rugby football union as medical services director. KAS is employed by the rugby football union as medical research lead.

We performed prospective screening of stool for multidrug-resistant organisms from 608 US international travelers and identified an acquisition rate of 38% following travel. Carriage rates remained significantly elevated for at least 6 months post-travel. Travel-related diarrhea was a risk factor for acquisition, as well as for long-term carriage upon return., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Physical Activity Referral Schemes (PARS), including exercise referral schemes, are a popular approach to health improvement, but understanding of effectiveness is limited by considerable heterogeneity in reporting and evaluation. We aimed to gain consensus for a PARS taxonomy as a comprehensive method for reporting and recording of such schemes., Methods: We invited 62 experts from PARS policy, research and practice to complete a modified Delphi study. In round one, participants rated the need for a PARS taxonomy, the suitability of three proposed classification levels and commented on proposed elements. In round two, participants rated proposed taxonomy elements on an 11-point Likert scale. Elements scoring a median of ≥7, indicating high agreement, were included in the final taxonomy., Results: Of those invited, 47 (75.8%) participated in round one, with high retention in round two (n = 43; 91.5%). 42 were UK-based, meaning the resultant taxonomy has been scrutinised for fit to the UK context only. The study gained consensus for a three-level taxonomy: Level 1: PARS classification (primary classification, provider, setting, conditions accepted [have or at risk of], activity type and funding). Level 2: scheme characteristics (staff structure, staff qualifications, behaviour change theories, behaviour change techniques, referral source, referrers, referral process, scheme duration, session frequency, session length, session times, session type, exit routes, action in case of non-attendance, baseline assessment, exit assessment, feedback to referrer and exclusion criteria) and Level 3: participant measures (demographics, monitoring and evaluation, and measures of change)., Conclusion: Using a modified Delphi method, this study developed UK-based consensus on a PARS classification taxonomy. We encourage PARS practitioners and public health colleagues, especially those working with similar service models internationally, to test, refine and use this taxonomy to inform policy and practice.

Objectives: Physical activity guidelines are evidence-based statements on recommended physical activity levels for good health. Guidelines, in isolation, are unlikely to increase population levels of physical activity; appropriate and effective communication is fundamental to maximising their impact. The aim of this paper is to provide a planning framework for physical activity guideline communication, including an overview of key audiences, aims and approaches., Methods: All authors considered and agreed on the three broad issues to address by consensus. We identified key sources of evidence through scoping of the literature and our knowledge of the research area., Results: Whether guidelines are global or national, communication of the physical activity guidelines should be informed by: (1) a situational analysis that considers the context in which the communication will take place and (2) a stakeholder analysis to determine the key target audiences for the communication and their values, needs and preferences. Audiences include policy-makers within and outside the health sector, other key stakeholders, the general public, specific population subgroups, health professionals and non-health professionals with a role in physical activity promotion. The aims and approach to communication will differ depending on the target audience., Conclusion: Communication to raise awareness and knowledge of the physical activity guidelines must be supported by policies, environments and opportunities for physical activity. Besides the intrinsic value of the physical activity guidelines, it is essential that substantial effort is put in to diligently planning, funding and implementing their communication from the outset., Competing Interests: Competing interests: KM and PK received financial reimbursement for some background work which informed parts of the manuscript. All other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Electrically assisted bicycles (e-bikes) have become increasingly popular in the past decade. This review aimed to scope the literature to identify what is known about the frequency and duration of e-bike use, their impact on travel behaviour, the purposes for which e-bikes are used and factors associated with e-bike use. In addition, the review aimed to identify gaps in the literature and highlight future research priorities., Methods: A scoping review of published and unpublished literature in any language. Relevant articles were identified through searching six databases, two grey literature platforms and reference lists. Searches were conducted until August 2019. Data were extracted using a standardised extraction form and descriptive and narrative results are provided., Results: Seventy-six studies met the inclusion criteria. The volume of research has increased since 2017 and primarily examines personal e-bike use, as opposed to e-bike share/rental schemes or organizational e-bike initiatives. The use of e-bikes increased the frequency and duration of cycling compared to conventional cycling and may help overcome barriers associated with conventional cycling. The uptake in e-cycling largely substitutes for conventional cycling or private car journeys, though the degree of substitution depends on the primary transport mode prior to e-bike acquisition. E-bikes are primarily used for utilitarian reasons, though older adults also engage in recreational e-cycling. Research priorities include quantitatively examining e-bike use, their impact on overall transport behaviour and identifying determinants of e-cycling to inform intervention and policy., Conclusions: This review suggests that the personal use of e-bikes is associated with a reduction in motorized vehicle use, which has potential positive impacts on the environment and health. The impacts of e-bike share schemes and workplace initiatives are less well understood. Evidence describing the purposes for which e-bikes are used, and the factors associated with usage, are useful to inform e-cycling promotion policy., Competing Interests: The authors declare that they have no competing interests., (© 2020 Elsevier Ltd. All rights reserved.)

Background: The standard of care for total knee arthroplasty (TKA) is a medial parapatellar approach (MPA). We aimed to study a novel lateral subvastus lateralis approach (SLA), which offers the benefit of keeping the extensor mechanism and medial soft tissues intact. To ensure the approach could be used safely in vivo, a biomechanical study was performed to assess whether the joint kinematics would be preserved after performing a TKA., Methods: A biomechanical study was conducted using 14 fresh-frozen cadaveric knees, with seven specimens each for the MPA and SLA. After a single radius, cemented cruciate retaining TKA was performed, specimens were tested on a VIVO joint motion simulator to measure and compare anterior/posterior, internal/external, and varus/valgus kinematics and laxity., Results: There was no significant difference in joint kinematics or laxity between the SLA and MPA groups., Conclusion: Both the SLA and MPA offer similar knee kinematics and laxity based on a cadaveric model. Although the surgical approach was different, inherently releasing different ligaments, both approaches resulted in a stable knee. This suggests that either approach will enable the surgeon to provide a stable knee, and that the implant itself may contribute a significant portion of the knee's kinematics., Competing Interests: Declaration of Competing Interest R.W. reports non-financial support from Stryker during the conduct of the study. B.L. reports grants, personal fees and other from Smith and Nephew; grants, personal fees and other from DePuy; grants, personal fees and other from Stryker; personal fees from IntelliJoint, outside the submitted work. All other authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Physical activity (PA) and exercise are among the most important determinants of health. However, PA is a complex and heterogeneous behavior and the biological mechanisms through which it impacts individuals and populations in different ways are not well understood. Genetics and environment likely play pivotal roles but further work is needed to understand their relative contributions and how they may be mediated. Metabolomics offers a promising approach to explore these relationships. In this review, we provide a comprehensive appraisal of the PA-metabolomics literature to date. This overwhelmingly supports the hypothesis of a metabolomic response to PA, which can differ between groups and individuals. It also suggests a biological gradient in this response based on PA intensity, with some evidence for global longer-term changes in the metabolome of highly active individuals. However, many questions remain and we conclude by highlighting future critical research avenues to help elucidate the role of PA in the maintenance of health and the development of disease., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background/objectives: Cycling has well-established positive relationships with health. Evidence suggests that large-scale infrastructure and built-environment initiatives to promote cycling are likely to be necessary but not sufficient to maximise cycling participation. Smaller-scale initiatives that can be implemented by organisations (eg, employers) and groups (eg, community groups) are therefore also important, but the full range of feasible activities to promote cycling is not known. We aimed to scope the literature and map organisational, social and individual level activities to increase cycling., Methods: Design: Scoping review following an established five-stage process.Eligibility criteria: Studies or publicly available reports describing cycling promotion initiatives deemed feasible for organisations or groups to implement.Sources of evidence and selection: (i) online databases (Ovid (Medline), Ovid (Embase), SportDISCUS (Ebscohost), ProQuest, Web of Science), (ii) existing systematic reviews, (iii) expert stakeholder consultation., Results: We extracted data from 129 studies and reports, from 20 different countries, identifying 145 cycling promotion initiatives. From these initiatives we identified 484 actions within 93 action types within 33 action categories under the nine intervention functions described by Michie et al . Environmental restructuring (micro-level), enablement, education and persuasion were the functions with the most action types, while coercion, modelling and restriction had the fewest action types., Conclusion: This is the first comprehensive map to summarise the broad range of action types feasible for implementation within organisation/group-based cycling promotion initiatives. The map will be a critical tool for communities, employers, practitioners and researchers in designing interventions to increase cycling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Environmental enteropathy (EE) is suspected to be a cause of growth faltering in children with sustained exposure to enteric pathogens, typically in resource-limited settings. A major hindrance to EE research is the lack of sensitive, non-invasive biomarkers. Current biomarkers measure intestinal permeability and inflammation, but not the functional capacity of the gut. Australian researchers have demonstrated proof of concept for an EE breath test based on using naturally 13 C-enriched sucrose, derived from maize, to assay intestinal sucrase activity, a digestive enzyme that is impaired in villus blunting. Here, we describe a coordinated research project to optimise, validate and evaluate the usability of a breath test protocol based on highly enriched 13 C-sucrose to quantify physiological dysfunction in EE in relevant target populations., Methods and Analysis: We use the 13 C-sucrose breath test ( 13 C-SBT) to evaluate intestinal sucrase activity in two phases. First, an optimisation and validation phase will (1) confirm that a 13 C-SBT using highly enriched sucrose tracers reports similar information to the naturally enriched 13 C-SBT; (2) examine the dose-response relationship of the test to an intestinal sucrase inhibitor; (3) validate the 13 C-SBT in paediatric coeliac disease (4) validate the highly enriched 13 C-SBT against EE defined by biopsy in adults and (5) validate the 13 C-SBT against EE defined by the urinary lactulose:rhamnose ratio (LR) among children in Peru. Second, a cross-sectional study will be conducted in six resource-limited countries (Bangladesh, India, Jamaica, Kenya, Peru and Zambia) to test the usability of the optimised 13 C-SBT to assess EE among 600 children aged 12-15 months old., Ethics and Dissemination: Ethical approval will be obtained from each participating study site. By working as a consortium, the test, if shown to be informative of EE, will demonstrate strong evidence for utility across diverse, low-income and middle-income country paediatric populations., Trial Registration Number: NCT04109352; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Persistent oxidative stress predisposes to various non-communicable diseases (NCDs), whose occurrence is increasing in sub-Saharan Africa. The aim of this study was to evaluate the link between markers of oxidative stress and some risk factors for NCDs in a Zambian cohort., Methods: We assessed oxidative stress by measuring 8-isoprostane (lipid oxidative stress) and 8-hydroxydeoxyguanosine (DNA oxidative stress). In addition, we measured mycotoxins (aflatoxin M1 and ochratoxin A), salt intake estimated from 24-hour sodium excretion calculated using the Tanaka and Kawaski formulae, and 1-hydroxypyrene (a metabolite of polycyclic aromatic hydrocarbons). Data on lifestyle risk factors were collected using questionnaires., Results: Included were 244 participants; 128 (52%) were female and the median age was 48 years (IQR 39-58). The median level of 8-isoprostane was 0.13 ng/mg creatinine (IQR 0.08-0.23) while that of 8-hydroxydeoxyguanosine (8-OHdG) was 4 ng/mg creatinine (IQR 2-10). The median 24-hour sodium excretion was 21 g (IQR 16-25 g), with none being less than the 5 g recommended by WHO. Unadjusted urinary levels of 8-isoprostane were moderately correlated with 1-hydroxypyrene (Spearman r = 0.30, p<0.001) and estimated 24-hour urine sodium (Spearman r = 0.38, p<0.001). Urinary levels of 8-OHdG were not correlated with 1-hydroxypyrene, estimated 24-hour urine sodium, aflatoxin M1 or ochratoxin A (all p-values >0.05). Using logistic regression, adjusted and unadjusted 8-isoprostanes levels were associated with 1-hydroxypyrene (p = 0.02 and p = 0.001 respectively) and estimated 24-hour urine sodium method (p = 0.003 and p<0.001 respectively). However, only unadjusted 8-OHdG was associated with 1-hydroxypyrene (p = 0.03) and age (p = 0.007)., Conclusions: Estimated 24-hour urinary sodium is high among Zambians and it is associated with lipid but not DNA oxidative stress. High exposure to polycyclic aromatic hydrocarbons is also associated with oxidative stress., Competing Interests: The authors have declared that no competing interests exist.

Poor mental health contributes significantly to global morbidity. The evidence regarding physical benefits of running are well-established. However, the mental health impacts of running remain unclear. An overview of the relationship between running and mental health has not been published in the last 30 years. The purpose of this study was to review the literature on the relationship between running and mental health. Our scoping review used combinations of running terms (e.g., Run* and Jog*) and mental health terms (general and condition specific). Databases used were Ovid(Medline), Ovid(Embase), ProQuest and SportDiscus. Quantitative study types reporting on the relationships between running and mental health were included. Database searches identified 16,401 studies; 273 full-texts were analysed with 116 studies included. Overall, studies suggest that running bouts of variable lengths and intensities, and running interventions can improve mood and mental health and that the type of running can lead to differential effects. However, lack of controls and diversity in participant demographics are limitations that need to be addressed. Cross-sectional evidence shows not only a range of associations with mental health but also some associations with adverse mental health (such as exercise addiction). This review identified extensive literature on the relationship between running and mental health.

Enteric fever, caused by Salmonella enterica serovar Typhi ( S Typhi) and S. enterica serovar Paratyphi ( S Paratyphi), is a common travel-related illness. Limited data are available on the antimicrobial resistance (AMR) patterns of these serovars among travelers. Records of travelers with a culture-confirmed diagnosis seen during or after travel from January 2007 to December 2018 were obtained from GeoSentinel. Traveler demographics and antimicrobial susceptibility data were analyzed. Isolates were classified as nonsusceptible if intermediate or resistant or as susceptible in accordance with the participating site's national guidelines. A total of 889 travelers ( S Typhi infections, n  = 474; S Paratyphi infections, n  = 414; coinfection, n  = 1) were included; 114 (13%) were children of <18 years old. Most individuals (41%) traveled to visit friends and relatives (VFRs) and acquired the infection in South Asia (71%). Child travelers with S Typhi infection were most frequently VFRs (77%). The median trip duration was 31 days (interquartile range, 18 to 61 days), and 448 of 691 travelers (65%) had no pretravel consultation. Of 143 S Typhi and 75 S Paratyphi isolates for which there were susceptibility data, nonsusceptibility to antibiotics varied (fluoroquinolones, 65% and 56%, respectively; co-trimoxazole, 13% and 0%; macrolides, 8% and 16%). Two S Typhi isolates (1.5%) from India were nonsusceptible to third-generation cephalosporins. S Typhi fluoroquinolone nonsusceptibility was highest when infection was acquired in South Asia (70 of 90 isolates; 78%) and sub-Saharan Africa (6 of 10 isolates; 60%). Enteric fever is an important travel-associated illness complicated by AMR. Our data contribute to a better understanding of region-specific AMR, helping to inform empirical treatment options. Prevention measures need to focus on high-risk travelers including VFRs and children., (Copyright © 2020 American Society for Microbiology.)

One integral step in the transition from a nucleic acid encoded-genome to functional proteins is the aminoacylation of tRNA molecules. To perform this activity, aminoacyl-tRNA synthetases (aaRSs) activate free amino acids in the cell forming an aminoacyl-adenylate before transferring the amino acid on to its cognate tRNA. These newly formed aminoacyl-tRNA (aa-tRNA) can then be used by the ribosome during mRNA decoding. In Escherichia coli , there are twenty aaRSs encoded in the genome, each of which corresponds to one of the twenty proteinogenic amino acids used in translation. Given the shared chemicophysical properties of many amino acids, aaRSs have evolved mechanisms to prevent erroneous aa-tRNA formation with non-cognate amino acid substrates. Of particular interest is the post-transfer proofreading activity of alanyl-tRNA synthetase (AlaRS) which prevents the accumulation of Ser-tRNA Ala and Gly-tRNA Ala in the cell. We have previously shown that defects in AlaRS proofreading of Ser-tRNA Ala lead to global dysregulation of the E. coli proteome, subsequently causing defects in growth, motility, and antibiotic sensitivity. Here we report second-site AlaRS suppressor mutations that alleviate the aforementioned phenotypes, revealing previously uncharacterized residues within the AlaRS proofreading domain that function in quality control.

The World Health Organization's Health Economic Assessment Tool (HEAT) for walking and cycling is a user-friendly web-based tool to assess the health impacts of active travel. HEAT, developed over 10 years ago, has been used by researchers, planners and policymakers alike in appraisals of walking and cycling policies at both national and more local scales. HEAT has undergone regular upgrades adopting the latest scientific evidence. This article presents the most recent upgrades of the tool. The health impacts of walking and/or cycling in a specified population are quantified in terms of premature deaths avoided (or caused). In addition to the calculation of benefits derived from physical activity, HEAT was recently expanded to include assessments of the burden associated with air pollution exposure and crash risks while walking or cycling. Further, the impacts on carbon emissions from mode shifts to active travel modes can now be assessed. The monetization of impacts using Value of Statistical Life and Social Costs of Carbon now uses country-specific values. As active travel inherently results in often substantial health benefits as well as not always negligible risks, assessments of active travel behavior or policies are incomplete without considering health implications. The recent developments of HEAT make it easier than ever to obtain ballpark estimates of health impacts and carbon emissions related to walking and cycling., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Introduction: The dissemination of research, and evaluation of its impact is an increasing priority for the scientific community and funders. We take the topic of golf and health and aim to outline processes that may contribute to improved research uptake, use and impact proposing a research impact (RI) tool. We then evaluate our published research using the Research Contributions Framework (RCF)., Methods: Building on existing research and frameworks we i) assessed the need for, ii) carried out and iii) published research, before iv) creating digital resources, v) sharing these resources widely and vi) evaluating our research.To evaluate uptake, use and impact of our three principal golf and health research outputs, we performed a contributions analysis, using the RCF first proposed by Morton., Results/discussion: We developed a specific six-step Research Impact tool. Having implemented this, research uptake and use included over 300 press articles, a dedicated website and social media channels. Golf's global industry leadership dispersed information across >150 countries, embedded golf and health into curricula for industry professionals and used leading tournaments to promote health. National policy makers hosted dedicated meetings regarding golf and health and began to implement policy change., Conclusion: To date, strong uptake and use can be demonstrated for these studies, while a final contribution to impact requires further time to determine.Frameworks we used aiming to maximise impact (Research Impact tool) and evaluate its contribution to uptake, use and impact (Research Contribution Framework) could potentially add value to public health/sports medicine researchers., Competing Interests: Competing interests: AM/RH are supported by an unrestricted grant from the World Golf Foundation. RH and AM receive fees from the European Tour Golf for clinical work. AM receives remuneration from Scottish Government., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Strongyloides stercoralis is a soil-transmitted helminth, but it has a unique life cycle that can be completed in the human host, in a process known as autoinfection. Worldwide, the burden of disease is substantial (300 to 400 million infections). Strongyloidiasis is mainly prevalent in the tropics and subtropics, but there is as yet no global public health strategy for controlling the parasite.

Aims: Ki67 proliferative index (PI) is essential for grading gastroenteric and pancreatic neuroendocrine tumours (GEP NETs). Analytical and preanalytical variables can affect Ki67 PI. In contrast to counting methodology, until now little attention has focused on the question of clone equivalence and the effect of hot-spot size on Ki67 PI in GEP NETs. Using manual counting and image analysis, this study compared the Ki67 PI achieved using MM1, K2 and 30-9 to MIB1, a clone which has been validated for, and is referenced in, guidelines relating to assessment of Ki67 PI in GEP NETs., Methods and Results: Forty-two pancreatic NETs were each immunohistochemically stained for the anti-Ki67 clones MIB1, MM1, K2 and 30-9. Ki67 PI was calculated manually and by image analysis, the latter using three different hot-spot sizes. In manual comparisons using single hot-spot high-power fields, non-MIB1 clones overestimated Ki67 PI compared to MIB1, resulting in grading discordances. Image analysis shows good agreement with manual Ki67 PI but a tendency to overestimate absolute Ki67 PI. Increasing the size of tumour hot-spot from 500 to 2000 cells resulted in a decrease in Ki67 PI., Conclusion: Different anti-Ki67 clones do not produce equivalent PIs in GEP NETs, and clone selection may therefore affect patient care. Increasing the hot-spot size decreases the Ki67 PI. Greater standardisation in terms of antibody clone selection and hot-spot size is required for grading GEP NETs. Image analysis is an effective tool for assisting Ki67 assessment and allows easier standardisation of the size of the tumour hot-spot., (© 2020 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Gastro-intestinal function plays a vital role in conditions ranging from inflammatory bowel disease and HIV through to sepsis and malnutrition. However, the techniques that are currently used to assess gut function are either highly invasive or unreliable. Here we present an alternative, non-invasive sensing modality for assessment of gut function based on fluorescence spectroscopy. In this approach, patients receive an oral dose of a fluorescent contrast agent and a fibre-optic probe is used to make fluorescence measurements through the skin. This provides a readout of the degree to which fluorescent dyes have permeated from the gut into the blood stream. We present preliminary results from our first measurements in human volunteers demonstrating the potential of the technique for non-invasive monitoring of multiple aspects of gastro-intestinal health.

Organisms encounter stress throughout their lives, and therefore require the ability to respond rapidly to environmental changes. Although transcriptional responses are crucial for controlling changes in gene expression, regulation at the translational level often allows for a faster response at the protein levels which permits immediate adaptation. The fidelity and robustness of protein synthesis are actively regulated under stress. For example, mistranslation can be beneficial to cells upon environmental changes and also alters cellular stress responses. Additionally, stress modulates both global and selective translational regulation through mechanisms including the change of aminoacyl-tRNA activity, tRNA pool reprogramming and ribosome heterogeneity. In this review, we draw on studies from both the prokaryotic and eukaryotic systems to discuss current findings of cellular adaptation at the level of translation, specifically translational fidelity and activity changes in response to a wide array of environmental stressors including oxidative stress, nutrient depletion, temperature variation, antibiotics and host colonization., (Copyright © 2020 Elsevier Inc. All rights reserved.)

RNA sequencing (RNASeq) has been widely used to associate alterations in Chinese hamster ovary (CHO) cell gene expression with bioprocess phenotypes; however, alternative messenger RNA (mRNA) splicing, has thus far, received little attention. In this study, we utilized RNASeq for transcriptomic analysis of a monoclonal antibody (mAb) producing CHO K1 cell line subjected to a temperature shift. More than 2,465 instances of differential splicing were observed 24 hr after the reduction of cell culture temperature. A total of 1,197 of these alternative splicing events were identified in genes where no changes in abundance were detected by standard differential expression analysis. Ten examples of alternative splicing were selected for independent validation using quantitative polymerase chain reaction in the mAb-producing CHO K1 cell line used for RNASeq and a further two CHO K1 cell lines. This analysis provided evidence that exon skipping and mutually exclusive splicing events occur in genes linked to the cellular response to changes in temperature and mitochondrial function. While further work is required to determine the impact of these changes in mRNA sequence on cellular phenotype, this study demonstrates that alternative splicing analysis can be utilized to gain a deeper understanding of post-transcriptional regulation in CHO cells during biopharmaceutical production., (© 2020 Wiley Periodicals LLC.)

Aims: The introduction of TNM 8 into UK pathology practice in January 2018 considers tumour deposits in colorectal cancer staging for the first time. The impact of this new classification on pathology reporting practices has yet to be evaluated., Methods and Results: A clinical audit was conducted, comparing consecutive colorectal cancer resection specimens reported under TNM 5 classification guidelines in 2017 (n = 177) and TNM 8 guidelines in 2018 (n = 234). Tumour features (venous invasion, perineural invasion, lymph node metastatic disease, tumour deposits) and changes in reporting practices were evaluated among four specialist gastrointestinal pathologists working within a large pathology department. Adoption of TNM 8 practice led to an approximate doubling in the use of ancillary stains (41.0% of TNM 8 versus 22.0% of TNM 5 cases, P < 0.001) to help evaluate tumours. A narrowing of the range between pathologists was observed in reporting cases as having one or more form of regional, extramural, discontinuous tumour (TNM 5 range = 50.0-79.0%, TNM 8 range = 57.8-65.7%), with no change in the overall proportion of cases reported as such (62.7% versus 62.4%, P = 0.95). However, significant interobserver variation in reporting rates for individual parameters remained., Conclusion: TNM 8 colorectal cancer staging offers potentially greater reproducibility in pathology reporting of regional, extramural, discontinuous disease with similar proportions of patients reported as having one or more of these forms of tumour spread compared with TNM 5. Further guidance in defining individual features is required to reduce interobserver variation in pathology assessments and to help elucidate the clinical significance of each parameter., (© 2020 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Cirrhosis commonly complicates portal hypertension worldwide but in Zambia hepatosplenic schistosomiasis (HSS) dominates as the cause of portal hypertension. We need easier and non-invasive ways to assess HSS. Transient elastography (TE), a measure of liver stiffness can diagnose liver cirrhosis. TE remains unexplored in HSS patients, who generally have normal liver parenchyma. We aimed to explore liver stiffness in HSS. This nested case control study was conducted at the University Teaching Hospital, Lusaka, Zambia between January 2015 and January 2016. We enrolled 48 adults with HSS and 22 healthy controls. We assessed liver stiffness using TE while plasma hyaluronan was used to assess liver fibrosis. Plasma tumor necrosis factor receptor 1 (TNFR1) and soluble cluster of differentiation 14 (sCD14) were used to assess inflammation. The median (interquartile range) liver stiffness was higher in patients, 9.5 kPa (7.8, 12.8) than in controls, 4.7 kPa (4.0, 5.4), P < 0.0001. We noted linear correlations of hyaluronan and TNFR1 with the liver stiffness, P = 0.0307 and P = 0.0003 respectively. HSS patients seem to have higher liver stiffness than healthy controls. TE may be useful in identifying fibrosis in HSS. The positive correlations of inflammatory markers with TE suggest that HSS has both periportal and parenchymal pathophysiology., (© 2020 Published by Elsevier Ltd.)

BACKGROUND Cytomegalovirus (CMV) is a member of Herpesviridae family with its name derived from the fact that it causes enlargement of the infected cell resulting in the characteristic inclusion bodies seen on microscopy. CMV virus has an incubation period of about 4 to 6 weeks. Symptoms of CMV infection vary and depend on factors including the age and immune status of the patient. It usually presents as asymptomatic infection in immunocompetent individuals whereas severe disease is usually seen in immunocompromised patients. Here we present a case of an immunocompetent patient who presented with acute CMV hepatitis. CASE REPORT A 35-year-old male with no significant prior medical history who presented to the Emergency Department with a 2-week history of low-grade fever. Acute CMV infection was diagnosed by positive CMV antibody and polymerase chain reaction (PCR) testing. The patient was treated with valganciclovir that resulted in rapid improvement in clinical status as well as normalization of the liver enzymes. CONCLUSIONS This article presents a rare case of immunocompetent young male with acute CMV hepatitis who responded favorably to antiviral therapy.

Background: Microbial biorefinery approaches are beginning to define renewable and sustainable routes to clean-burning and non-fossil fuel-derived gaseous alkanes (known as 'bio-LPG'). The most promising strategies have used a terminal fatty acid photodecarboxylase, enabling light-driven propane production from externally fed waste butyric acid. Use of Halomonas (a robust extremophile microbial chassis) with these pathways has enabled bio-LPG production under non-sterile conditions and using waste biomass as the carbon source. Here, we describe new engineering approaches to produce next-generation pathways that use amino acids as fuel precursors for bio-LPG production (propane, butane and isobutane blends)., Results: Multiple pathways from the amino acids valine, leucine and isoleucine were designed in E. coli for the production of propane, isobutane and butane, respectively. A branched-chain keto acid decarboxylase-dependent pathway utilising fatty acid photodecarboxylase was the most effective route, generating higher alkane gas titres over alternative routes requiring coenzyme A and/or aldehyde deformylating oxygenase. Isobutane was the major gas produced in standard (mixed amino acid) medium, however valine supplementation led to primarily propane production. Transitioning pathways into Halomonas strain TQ10 enabled fermentative production of mixed alkane gases under non-sterile conditions on simple carbon sources. Chromosomal integration of inducible (~ 180 mg/g cells/day) and constitutive (~ 30 mg/g cells/day) pathways into Halomonas generated production strains shown to be stable for up to 7 days., Conclusions: This study highlights new microbial pathways for the production of clean-burning bio-LPG fuels from amino acids. The use of stable Halomonas production strains could lead to gas production in the field under non-sterile conditions following process optimisation., Competing Interests: Competing interestsA patent application (PCT/EP2019/060013) entitled ‘Hydrocarbon production’ is pending in relation to the production of hydrocarbon gases in engineered microbial strains. M.S. and N.S.S. are founding directors of C3 Biotech Ltd., (© The Author(s) 2020.)

Background: Disease and mortality burdens of unhealthy lifestyle behaviours are often reported. In contrast, the positive narrative around the burdens that an existing behaviour have averted is rarely acknowledged. We aimed to estimate the prevented fraction for the population (PFP) for premature mortality averted by physical activity on a global scale., Methods: In this descriptive study, we obtained previously published data on physical activity prevalence (2001-16) and relative risks of all-cause mortality for 168 countries. We combined the data in Monte-Carlo simulations to estimate country-specific, mean PFP values, corresponding to percentage of mortality averted, and their 95% CIs. High prevented fractions indicated an increased proportion of deaths averted due to physical activity. Using mortality data for all people in a country aged 40-74 years, we estimated the number of premature deaths averted for all adults and by gender. We present the median and range of the prevented fractions globally, by WHO region, and by World Bank income classification., Findings: The global median PFP was 15·0% (range 6·6-20·5), conservatively equating to 3·9 million (95% CI 2·5-5·6) premature deaths averted annually. The African region had the highest median prevented fraction (16·6% [range 12·1-20·5]) and the Americas had the lowest (13·1% [10·8-16·6]). Low-income countries tended to have higher prevented fractions (group median 17·9% [12·3-20·5]) than high-income countries (14·1% [6·6-17·8]). Globally, the median prevented fraction was higher for men (16·0% [7·8-20·7] than women (14·1% [5·0-20·4])., Interpretation: Existing physical activity prevalence has contributed to averting premature mortality across all countries. PFP has utility as an advocacy tool to promote healthy lifestyle behaviours. By making the case of what has been achieved, the prevented fraction can show the value of current investment and services, which might be conducive to political support., Funding: UK Medical Research Council, British Heart Foundation, Cancer Research UK, Economic and Social Research Council, National Institute for Health Research, Wellcome Trust, Heart Foundation Australia., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To explore the feasibility of delivering and evaluating a web-based walking intervention for people with long term musculoskeletal conditions (LTMCs), to determine its acceptability and the feasibility of conducting a definitive trial., Design: Prospective randomised feasibility study, with blind outcome assessment at baseline, 3 and 6 months., Setting: Hospital based physiotherapy service., Participants: Forty one adults referred for assessment and advice for any mild/moderate LTMCs. doing <120minutes of moderate intensity activity per week., Interventions: Participants randomised to: 1. Usual care: one usual physiotherapy advice and assessment session, including setting a physical activity goal and one follow up session (8 weeks). 2. "Walk30×5": session one, usual care plus intervention of walking programme. Participants were shown the website and podcasts and practiced how to use them. One follow up session (8 weeks)., Outcome Measures: Primary: timed six minute walk test (T6MWT). Secondary: step count, self-reported pain, fatigue, mood, self-efficacy, happiness, objective blood pressure, peak expiratory flow rate, and self-report and accelerometer measured physical activity., Results: Recruitment target achieved. No adverse events occurred. Adherence was high and the intervention acceptable. Loss to follow up n=3 (7%) at 3 months, n=8 (20%) at 6 months. T6MWT and step count proved suitable outcomes, unlike accelerometry. Estimated sample size for a definitive trial is 216., Conclusions: "Walk30×5" is ready for evaluation in a future, appropriately powered (n=216), phase III trial. If effective, the intervention will provide a cheap, highly accessible intervention to enable people with mild/moderate LTMCs to achieve UK physical activity guidelines., Clinical Trial Registration Number: ISRCTN78581097., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Image classification is central to the big data revolution in medicine. Improved information processing methods for diagnosis and classification of digital medical images have shown to be successful via deep learning approaches. As this field is explored, there are limitations to the performance of traditional supervised classifiers. This paper outlines an approach that is different from the current medical image classification tasks that view the issue as multi-class classification. We performed a hierarchical classification using our Hierarchical Medical Image classification (HMIC) approach. HMIC uses stacks of deep learning models to give particular comprehension at each level of the clinical picture hierarchy. For testing our performance, we use biopsy of the small bowel images that contain three categories in the parent level (Celiac Disease, Environmental Enteropathy, and histologically normal controls). For the child level, Celiac Disease Severity is classified into 4 classes (I, IIIa, IIIb, and IIIC)., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; nor in the decision to publish the results.

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI., Methods: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022., Findings: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84)., Interpretation: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients., Funding: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Inflammatory bowel disease (IBD) is increasingly recognized as a global disease in the twenty-first century; however, little is known about its epidemiology in Africa. We conducted a literature review in order to assess what is currently known on this subject, the results of which are reported here. Based on available observational studies, it appears that the incidence of IBD in Africa is rising, although comprehensive epidemiological data are lacking. This is likely due to multiple factors, including shifting trends in diet and exposure to environmental pathogens. Many challenges relating to IBD exist for healthcare systems in Africa, including the need for improved access to diagnostic facilities such as endoscopy and histopathology, and the potential economic burden of treatment. Intestinal TB also represents a significant confounding factor in the diagnosis of IBD in Africa., (© The Author(s) 2020. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

The human immunodeficiency virus (HIV) pandemic heavily affects sub-Saharan Africa. It is associated with persistently active Epstein-Barr virus (EBV) infection. To determine if this translates into increased frequency of EBV-associated gastric cancer (EBVaGC), we evaluated molecular profiles of gastric cancer (GC) in Zambia. Patients with GC or premalignant gastric lesions were enrolled in Lusaka, Zambia. We used patients without any of these lesions as a control group. Chromogenic in situ hybridization (CISH) on tumor tissue was used to identify EBVaGC. To identify the microsatellite unstable subtype, immunofluorescence staining for MutL homolog 1 (MLH1) was used. Exposure to EBV and HIV was assessed serologically. We enrolled 369 patients (median age 52 years [IQR 41-65]; 198 (54%) female). Of these, 72 (20%) had GC and 35 (9%) had gastric premalignant lesions (PL). CISH identified EBVaGC in 5/44 (11%) of those with adequate tissue, while MLH1 loss was identified in 29/45 (64%). Both GC and PL were associated with the highest titers of antibodies to Early antigen-diffuse (OR 2.5, 95% CI 1.0-6.1, P = .048 and OR 3.9, 95% CI 1.1-12.9, P = .03, respectively) at high concentrations. Human immunodeficiency virus infection was associated with a range of antibodies to EBV, but not with any cancer subtype. Despite the association of HIV with persistent EBV, the proportion of EBVaGC in Zambia is similar to populations with a low prevalence of HIV infection. The proportion of microsatellite unstable tumors may be higher than other populations., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Understanding how to create and deliver effective physical activity (PA) messages for and to various population subgroups may play a role in increasing population PA levels. This scoping review aimed to provide an overview of what is known about PA messaging and highlight key research gaps., Methods: We followed a 5-stage protocol proposed by Arksey & O'Malley and the Preferred Reporting Items For Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews checklist. Stage 1: research questions were identified. Stage 2: we identified relevant studies by searching electronic databases, contacting existing networks and hand searching reference lists. Stage 3: studies were screened in Covidence™ software. Stage 4: study data were extracted and charted. Stage 5: findings from included studies were collated, summarised and reported in two ways: (1) a descriptive numerical analysis providing insight into extent, nature and distribution of the included studies, and (2) a narrative summary summarizing the evidence reviewed organised by messaging concepts and by population subgroup., Results: A total of 9525 references were imported into Covidence™ for screening. Of these, 123 studies were included in final analysis. We found that PA messaging evidence is complex and multidimensional in nature, with numerous concepts to consider when creating or evaluating messages. The extent to which these different PA messaging concepts have been researched is variable. Where research has accumulated and evidence is consistent, it supports the following: (1) PA messages should be framed positively and highlight short-term outcomes specifically relating to social and mental health, (2) message content should be tailored or targeted to intended recipient(s), and (3) when developing messages, formative research, psychological theory and/or social marketing principles should be used., Conclusion: While it is unlikely to address global inactivity on its own, PA messaging may play a valuable role improving population PA levels. However, it is a complex and multidimensional concept and greater understanding is still needed. We present a synthesis of the existing evidence, highlighting key areas where evidence has accumulated and where gaps lie, as well as recommendations for PA messaging to different population subgroups.

Objectives: Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide hormone released from enteroendocrine L-cells following nutrient ingestion. It has been shown to exert trophic effects on the gut. We set out to measure GLP-2 concentrations in blood in children with diarrhoea and malnutrition., Methods: GLP-2 levels were measured in blood samples collected from 5 different groups of children (n = 324) at different time points: those with acute diarrhoea, during illness and 3 weeks after recovery; persistent diarrhoea and severe acute malnutrition; controls contemporaneous for diarrhoea; stunted children from the community; and controls contemporaneous for the stunted children. Stool biomarkers and pathogen analysis were carried out on the children with stunting., Results: GLP-2 concentrations were higher during acute diarrhoea (median 3.1 ng/mL, interquartile range 2.1, 4.4) than on recovery (median 1.8, interquartile range 1.4, 3.1; P = 0.001), but were not elevated in children with persistent diarrhoea and severe acute malnutrition. In stunted children, there was a progressive decline in GLP-2 levels from 3.2 ng/mL (1.9, 4.9) to 1.0 (0.0, 2.0; P < 0.001) as the children became more stunted. Measures of seasonality (rainfall, temperature,Food Price Index, and Shiga toxin-producing Escherichia coli) were found to be significantly associated with GLP-2 concentrations in multivariable analysis. We also found a correlation between stool inflammatory biomarkers and GLP-2., Conclusions: In diarrhoea, GLP-2 levels increased in acute but not persistent diarrhoea. Malnutrition was associated with reduced concentrations. GLP-2 displayed seasonal variation consistent with variations in nutrient availability.

Schistosomiasis is an acute and chronic parasitic disease caused by blood flukes of the genus Schistosoma. More than 220 million people worldwide were estimated to have active schistosomiasis in 2017, 90% of whom live on the African continent, but only 102 million were reported to have received treatment. Africa is also disproportionately burdened by HIV, with an estimated 26 million people living with HIV in 2017. Given these overlapping epidemics, we conducted a systematic review to ascertain the contribution of schistosomes to HIV acquisition risk, the contribution of HIV to schistosome acquisition, the impact of HIV on schistosomiasis-related morbidity, the impact of schistosomes on HIV disease progression and immune response, the impact of HIV on the efficacy of praziquantel treatment, and the impact of HIV on egg shedding. We reviewed studies of people living in sub-Saharan Africa coinfected with HIV and Schistosoma spp. between January 1996 and July 2018. We found that 1) infection with Schistosoma haematobium increases the risk of HIV acquisition, 2) there is currently a lack of data on whether HIV infection increases the risk of Schistosoma acquisition, 3a) HIV coinfection was not an accelerating factor for adverse Schistosoma outcomes, 3b) schistosomiasis may be an important contributor to immune activation in HIV coinfected people, 4) praziquantel use in coinfected people may improve immune reconstitution on antiretroviral therapy for HIV, and 5) there is evidence that HIV infection reduces egg excretion in individuals infected with Schistosoma mansoni .

Hepatosplenic schistosomiasis (HSS) complicates portal hypertension, leading to life-threatening variceal bleeding. Variceal bleeding is associated with increased portal vein diameter (PVD). Beta-blockers prevent variceal bleeding. It is unclear whether beta-blockers such as propranolol can reduce PVD in HSS. We aimed to explore the effect of propranolol on PVD in HSS. A longitudinal study was conducted at the University Teaching Hospital, Zambia, as an extension of a clinical trial of rifaximin undertaken to test the hypothesis that rifaximin could reduce bacterial translocation in HSS. We randomized 85 adults to either rifaximin and standard care, or propranolol-based standard care only for 42 days. We then followed up all the patients on propranolol up to day 180. We used ultrasound to measure PVD at baseline and day 180. The primary outcome was reduction in PVD. Beta-blockade and splenic size reduction were secondary outcomes. Portal vein diameter reduced after 180 days of propranolol therapy from median 12 mm (interquartile range (IQR): 11-14) to median 10 mm (IQR: 9-13) ( P < 0.001). The pulse rate reduced from baseline median 70 beats/minute (IQR: 66-80) to 65 beats/minute (IQR: 60-70) by day 180 ( P = 0.006). Hemoglobin levels improved from baseline median 8 g/dL (IQR: 6-11) to 12 g/dL (10-14) ( P < 0.001). Splenic size remained unchanged. Propranolol led to the reduction in PVD over 180 days. This suggests that ultrasound could be useful in monitoring response and compliance to beta-blockers, especially in resource-constraint areas where portal hypertension measurement facilities are unavailable.

The capacity of physical activity (PA) measures to detect changes in PA within interventions is crucial. This is the first study to examine the responsiveness of activ PAL3™ and the International Physical Activity Questionnaire (IPAQ; Short Form) in detecting PA change during a 12-week group-based, men-only weight management program-Football Fans in Training (FFIT). Participants wore an activ PAL3™ and completed the IPAQ pre- and post-program ( n = 30). Relationships between change scores were assessed by Spearman's correlations. Mean or median changes in PA were measured using paired samples t -tests and Wilcoxon signed-rank tests. Responsiveness to change was assessed utilizing Standardized Response Mean (SRM). Both device-based and self-report measures demonstrated significant changes pre-post intervention, although these changes were not significantly correlated. The SRM values for changes in activ PAL3™ metrics were: 0.54 (MET-mins/day); 0.53 (step counts/day); and 0.44 (MVPA/day), indicating a small to medium responsiveness to change. SRM values for changes in IPAQ scores were: 0.59 (for total PA mins/day); 0.54 (for total MET-mins/day); 0.59 (for walking MET-mins/day); 0.38 (for vigorous MET-mins/day); and 0.38 (for moderate MET-mins/day), revealing a small to medium responsiveness to change. These findings reveal that two commonly used device-based and self-report measures demonstrated responsiveness to changes in PA. While inclusion of both device-based and self-report measures is desirable within interventions it is not always feasible. The results from this study support that self-reported measures can detect PA change within behavioral interventions, although may have a tendency to overestimate changes compared with device-based measures on absolute values, but not standardized response values.

Purpose: We investigated the association between gastric cancer and environmental and dietary exposures. In addition, we explored probable mechanistic pathways for the influence of biomass smoke on gastric carcinogenesis., Patients and Methods: The study was conducted in Lusaka, Zambia. Questionnaires were used to collect data on risk factors, whereas enzyme-linked immunosorbent assays and high-performance liquid chromatography were used to measure biologic exposures. Study data were analyzed using contingency tables and logistic regression., Results: We enrolled 72 patients with gastric adenocarcinoma and 244 controls. Gastric cancer was positively associated with rural residence (odds ratio [OR], 2.9; 95% CI, 1.5 to 5.3), poverty (OR, 4.2; 95% CI, 1.9 to 9.1), and daily consumption of processed meat (OR, 6.4; 95% CI, 1.3 to 32) and negatively associated with consumption of green vegetables (OR, 0.2; 95% CI, 0.1 to 0.5). Gastric cancer was also associated with biomass smoke exposure (OR, 3.5; 95% CI, 1.9 to 6.2; P < .0001), an association that was stronger for intestinal-type cancers (OR, 3.6; 95% CI, 1.5 to 9.1; P = .003). Exposure to biomass smoke in controls was associated with higher urinary levels of 8-isoprostane ( P < .0001), 8-hydroxydeoxyguanosine ( P = .029), and 1-hydroxypyrene ( P = .041). Gastric cancer was not associated with biochemical measures of current exposure to aflatoxins or ochratoxins., Conclusion: In Zambia, exposure to biomass smoke, daily consumption of processed meat, and poverty are risk factors for gastric cancer, whereas daily consumption of green vegetables is protective against gastric cancer. Exposure to biomass smoke was associated with evidence of oxidative stress and DNA damage, suggesting mechanistic plausibility for the observed association, and the association was restricted to intestinal-type gastric cancer.

The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including base pairs and base mis-pairs, that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase (aaRS) interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. We also identified Leishmania major threonyl-tRNA synthetase (ThrRS) inhibitors from the same library. We discuss why chemotherapies targeting multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To evaluate the odds of vitamin B12 and folate deficiencies among Zambian clinic attendees with distal symmetric polyneuropathy (DSP) and age, sex, and HIV matched controls., Methods: Cases were adults from clinics in urban/peri-urban Zambia. Controls were enrolled among persons not seeking personal medical care, such as a caregiver or person collecting antiretrovirals without a medical complaint. Participants underwent structured interviews, physician examination, and assessments of complete blood count, renal and liver profiles, serum vitamin B12 and folate, erythrocyte folate, plasma total homocysteine and methylmalonic acid. HIV testing and CD4 counts were performed when appropriate., Results: Among 107 consenting matched case-control pairs, 65% were female, 52% HIV positive, with mean age of 47.6 (SD 13.5) years. Among HIV positive participants, mean CD4 count was 484 (SD 221) and 482 (SD 236) for cases and controls, respectively (p = .93). DSP symptoms and severity did not differ by HIV status (p's > 0.05). Height, history of tuberculosis treatment, alcohol use, education, asset index, dietary diversity, and nutritional supplement use did not differ between cases and controls (p's > 0.05). DSP cases had at least 3:1 odds of having low serum folate (p = .0001), severely low erythrocyte folate (p = .014), and elevated total homocysteine (p = .001) levels compared to controls. Markers of vitamin B12 deficiency were not associated with case status (p's > 0.05)., Conclusion: Markers of folate deficiency are highly associated with DSP among Zambian clinic attendees. Future studies should consider a broader range of comorbid nutritional deficiencies, and strategies for interventions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Clostridium difficile infection (CDI) has emerged as an important nosocomial and antibiotic-associated diarrhoeal problem leading to increasing morbidity and mortality, especially in resource-privileged regions. CDI varies in incidence, pathogenicity and risk factors across geographical locations, yet little information is available on CDI in sub-Saharan Africa. This study aimed to determine the prevalence of Clostridium difficile and related toxin expression in stool specimens from patients with diarrhoeal disease at the University Teaching Hospital, Lusaka, Zambia., Methods: Between June and September 2017, patients presenting with acute or persistent diarrhoea provided stool samples that were cultured anaerobically on cycloserine cefoxitin fructose agar. Isolates were identified by Gram staining, C. difficile latex agglutination and confirmed by PCR targeting of the tpi housekeeping gene. Toxins A or B were detected by ELISA., Results: Of 135 participants enrolled, 13 (10%) were C. difficile positive, of which four (31%) were toxigenic by ELISA. Among HIV-positive and HIV-negative participants, the frequency of culturable C. difficile (19% vs 12%; p=0.17) and of toxigenic isolates (15% vs 0%, p=0.19) did not differ., Conclusions: We can now revise previous research and confirm that CDI contributes to diarrhoea among hospitalised adult patients irrespective of HIV status., (© The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is evidence that children with malnutrition have an increased frequency of small intestinal bacterial overgrowth (SIBO) due to impaired gastric acidity, impaired intestinal motility, and dysbiosis. Children with malnutrition respond to antibiotic therapy but it is not clear if this effect is mediated by treatment of SIBO. We set out to determine the frequency of SIBO in children of varying nutritional status in a poor community in Lusaka, Zambia. Hydrogen breath testing, following a dose of 1g/kg oral glucose, was used to determine the presence of SIBO amongst the study participants. Forty nine children, 45 of whom had varying degrees of malnutrition, completed a full series of observations at 15, 30 and 60 minutes. Four children (8%) had a rise of 10ppm from baseline, consistent with SIBO. No correlation with nutritional status was observed. In this small study of Zambian children, SIBO was infrequent and unrelated to nutritional status., Competing Interests: The authors declare no competing interests., (© Namwiinga Ndulo et al.)

Objectives: Isolation and culture of distinct primary endometrial cells are key to reliable in-vitro models to investigate the uterine immune response and optimse new disease interventions. Details on the isolation method and purity of distinct cell populations is lacking in currently available protocols leading to inconsistent results across laboratories., Methods: Bovine endometrial tissue from non-pregnant bovine uteri were collected immediately post-mortem and separated using differential size filtering. Isolations (n = 15) yielded an average of 3.1 × 10 5  ± 0.7 × 10 5 epithelial cells and 1.88 × 10 6  ± 5.44 × 10 5 stromal fibroblasts per uterine horn. Following expansion in culture, the purity of cell populations was confirmed using morphology and positive staining for cytokeratin and vimentin which identifies epithelial and stromal fibroblast populations, respectively. Using PCR, cDNA from both cell populations was negative for CD45, a marker of immune cells., Results: On challenge with a bacterial PAMP (LPS), epithelial and stromal fibroblasts showed a marked increase in the expression of the inflammatory mediators IL8, IL6, S100A8 and S100A9, with both cell populations displaying distinct expression profiles. Here we provide a detailed methodology on the culture of primary bovine endometrial epithelial and stromal cells and demonstrate these cells provide a physiologically relevant model for studies of endometrial inflammation and its regulation.