Knowing the Biosphere: Documentation, Specimens, Archives, and Names Reveal Environmental Change and Emerging Pathogens

One Health programs and trajectories are now the apparent standard for exploring the occurrence and distribution of emerging pathogens and disease. By definition, One Health has been characterized as a broadly inclusive, collaborative, and transdisciplinary approach with connectivity across local to global scales, which integrates the medical and veterinary community to recognize health outcomes emerging at the environmental nexus for people, animals, plants, and their shared landscapes. One Health has been an incomplete model, conceptually and operationally, focused on reactive and response-based foundations, to limit the impact of emerging pathogens and emerging infectious diseases and, as such, lacks a powerful proactive capacity. A proactive, predictive One Health is necessary, emanating in part from geographically/taxonomically broad and temporally deep biological collections of pathogen-host assemblages. The DAMA protocol (Document, Assess, Monitor, Act), the operational extension of the Stockholm paradigm (SP), accomplishes this task by encompassing holistic and strategic biological sampling of reservoir host assemblages and pathogens at environmental interfaces and more extensively through resurveys, with development of informatics resources digitally linked to physical specimens held in publicly accessible museum biorepositories. Archives of specimens are the foundations for accumulating interrelated archives of information (the baselines against which change can be identified and tracked), with collections serving as fundamental resources for biodiversity informatics under the conceptual evolutionary and ecological umbrella of the SP. A cultural and conceptual transformation is essential among the diverse practitioners in the One Health community, one that recognizes the necessity of placing pathogens in an evolutionary, ecological, and environmental context by integrating specimens and associated informatics into an infrastructure and networks for actionable information. As a community, it is essential to abandon response-based business as usual while looking forward toward proactive transboundary approaches that maximize our conceptual and taxonomic view of diversity across interconnected planetary scales that influence the complexity of pathogen-host interfaces. Evolution, where the past always influences the present and the future, defines our trajectory, as the need for sustained archives that describe the biosphere becomes more acute with each passing day

Reflecting back, looking forward: the challenges for location-based learning

This final section of the report has been reproduced from “D3.1 The STELLAR Rendez-Vous I report and white papers”, published in 2009 by the STELLAR Network of Excellence. It is included here for completeness; we, as co-authors, felt that it was important to look back at the main contributions to theworkshop and also where the challenges lie for the future. This chapter addresses two critical questions: - What has been learned from this workshop, especially in respect to the STELLAR Grand Challenges (“Connecting learners”, “Orchestration” and “Contextualisation”)? - What are the new research questions and issues for location-based learning, with respect to the Grand Challenges (“Connecting learners”, “Orchestration”and “Contextualisation”)

Cerenkov Luminescence Imaging and Flexible Autoradiography for specimen margin assessment during breast-conserving cancer surgery

Background Among women with breast cancer who undergo breast-conserving surgery (BCS), 20-25% require further surgery due to close or involved margins. Improved techniques are needed to assess resection margins.PurposeThe study aims were to assess the feasibility of the combined techniques of Cerenkov Luminescence Imaging - Flexible AutoRadiography (CLI-FAR) to assess excision specimen margins in women undergoing BCS and to determine the diagnostic performance of intraoperative CLI-FAR imaging with postoperative histopathology as the reference standard..Materials and Methods Women undergoing BCS were recruited prospectively at a single centre over thirteen months. Patients were injected with 250MBq +/- 10MBq of 18F-fluorodeoxyglucose (18F-FDG), 145 minutes before surgery and the excised specimens were imaged intraoperatively. The surgically excised tumour was initially imaged using conventional x-ray, and margins suspected to be involved by tumor were then imaged using CLI-FAR. CLI-FAR imaging was performed using the LightPath system® (Lightpoint®), an in vitro diagnostic device designed to identify and locate positron-emitting radionuclides. Any suspicious margin underwent an immediate re-excision in the form of cavity shavings. Sensitivity, specificity, positive and negative predictive value whilst considering histopathological assessment as the golden standard were used to assess the performance of CLI-FAR.ResultsIn all, 54 specimens were imaged in 52 patients with a total of 104 margins reviewed using CLI-FAR. The results showed a specificity of 97.8% (89/91, 95% CI: 95.0%, 100.6%), sensitivity of 76.9% (10/13, 95% CI: 68.3%, 85.0%), PPV of 83.3% (10/12, 95% CI: 76.2%, 90.5%) and NPV of 96.7% (89/92, 95% CI: 93.3%, 100.2%). In all, 8 patients had 10 positive margins on CLI-FAR imaging and were treated accordingly. CLI-FAR imaging reduced the re-excision rate by (17.3/25) 69%. ConclusionCLI-FAR imaging is a promising technique for intraoperative margin assessment in women undergoing BCS for invasive breast cancer. <br/

Leveraging natural history biorepositories as a global, decentralized, pathogen surveillance network

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic reveals a major gap in global biosecurity infrastructure: a lack of publicly available biological samples representative across space, time, and taxonomic diversity. The shortfall, in this case for vertebrates, prevents accurate and rapid identification and monitoring of emerging pathogens and their reservoir host(s) and precludes extended investigation of ecological, evolutionary, and environmental associations that lead to human infection or spillover. Natural history museum biorepositories form the backbone of a critically needed, decentralized, global network for zoonotic pathogen surveillance, yet this infrastructure remains marginally developed, underutilized, underfunded, and disconnected from public health initiatives. Proactive detection and mitigation for emerging infectious diseases (EIDs) requires expanded biodiversity infrastructure and training (particularly in biodiverse and lower income countries) and new communication pipelines that connect biorepositories and biomedical communities. To this end, we highlight a novel adaptation of Project ECHO’s virtual community of practice model: Museums and Emerging Pathogens in the Americas (MEPA). MEPA is a virtual network aimed at fostering communication, coordination, and collaborative problem-solving among pathogen researchers, public health officials, and biorepositories in the Americas. MEPA now acts as a model of effective international, interdisciplinary collaboration that can and should be replicated in other biodiversity hotspots. We encourage deposition of wildlife specimens and associated data with public biorepositories, regardless of original collection purpose, and urge biorepositories to embrace new specimen sources, types, and uses to maximize strategic growth and utility for EID research. Taxonomically, geographically, and temporally deep biorepository archives serve as the foundation of a proactive and increasingly predictive approach to zoonotic spillover, risk assessment, and threat mitigation

Mitotic Arrest in Teratoma Susceptible Fetal Male Germ Cells

Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma susceptible and non-susceptible mouse strains. This study examines the entry of fetal germ cells into the male pathway and mitotic arrest in 129T2/SvJ mice. We find that although the entry of fetal germ cells into mitotic arrest is similar between 129T2/SvJ, C57Bl/6 and CD1 mice, there were significant differences in the size and germ cell content of the testis cords in these strains. In 129T2/SvJ mice germ cell mitotic arrest involves upregulation of p27KIP1, p15INK4B, activation of RB, the expression of male germ cell differentiation markers NANOS2, DNMT3L and MILI and repression of the pluripotency network. The germ-line markers DPPA2 and DPPA4 show reciprocal repression and upregulation, respectively, while FGFR3 is substantially enriched in the nucleus of differentiating male germ cells. Further understanding of fetal male germ cell differentiation promises to provide insight into disorders of the testis and germ cell lineage, such as testis tumour formation and infertility

Pregabalin in fibromyalgia - responder analysis from individual patient data

<p>Abstract</p> <p>Background</p> <p>Population mean changes are difficult to use in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration. A consensus group has defined what constitutes minimal, moderate, and substantial benefit based on pain intensity and Patient Global Impression of Change scores.</p> <p>Methods</p> <p>We obtained individual patient data from four randomised double blind trials of pregabalin in fibromyalgia lasting eight to 14 weeks. We calculated response for all efficacy outcomes using any improvement (≥ 0%), minimal improvement (≥ 15%), moderate improvement (≥ 30%), substantial improvement (≥ 50%), and extensive improvement (≥ 70%), with numbers needed to treat (NNT) for pregabalin 300 mg, 450 mg, and 600 mg daily compared with placebo.</p> <p>Results</p> <p>Information from 2,757 patients was available. Pain intensity and sleep interference showed reductions with increasing level of response, a significant difference between pregabalin and placebo, and a trend towards lower (better) NNTs at higher doses. Maximum response rates occurred at 4-6 weeks for higher levels of response, and were constant thereafter. NNTs (with 95% confidence intervals) for ≥ 50% improvement in pain intensity compared with placebo after 12 weeks were 22 (11 to 870) for pregabalin 300 mg, 16 (9.3 to 59) for pregabalin 450 mg, and 13 (8.1 to 31) for pregabalin 600 mg daily. NNTs for ≥ 50% improvement in sleep interference compared with placebo after 12 weeks were 13 (8.2 to 30) for pregabalin 300 mg, 8.4 (6.0 to 14) for pregabalin 450 mg, and 8.4 (6.1 to 14) for pregabalin 600 mg. Other outcomes had fewer respondents at higher response levels, but generally did not discriminate between pregabalin and placebo, or show any dose response. Shorter duration and use of 'any improvement' over-estimated treatment effect compared with longer duration and higher levels of response.</p> <p>Conclusions</p> <p>Responder analysis is useful in fibromyalgia, particularly for pain and sleep outcomes. Some fibromyalgia patients treated with pregabalin experience a moderate or substantial pain response that is consistent over time. Short trials using 'any improvement' as an outcome overestimate treatment effects.</p

Identifying the domains of context important to implementation science: a study protocol

Background There is growing recognition that “context” can and does modify the effects of implementation interventions aimed at increasing healthcare professionals’ use of research evidence in clinical practice. However, conceptual clarity about what exactly comprises “context” is lacking. The purpose of this research program is to develop, refine, and validate a framework that identifies the key domains of context (and their features) that can facilitate or hinder (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. Methods/design A multi-phased investigation of context using mixed methods will be conducted. The first phase is a concept analysis of context using the Walker and Avant method to distinguish between the defining and irrelevant attributes of context. This phase will result in a preliminary framework for context that identifies its important domains and their features according to the published literature. The second phase is a secondary analysis of qualitative data from 13 studies of interviews with 312 healthcare professionals on the perceived barriers and enablers to their application of research evidence in clinical practice. These data will be analyzed inductively using constant comparative analysis. For the third phase, we will conduct semi-structured interviews with key health system stakeholders and change agents to elicit their knowledge and beliefs about the contextual features that influence the effectiveness of implementation interventions and healthcare professionals’ use of evidence in clinical practice. Results from all three phases will be synthesized using a triangulation protocol to refine the context framework drawn from the concept analysis. The framework will then be assessed for content validity using an iterative Delphi approach with international experts (researchers and health system stakeholders/change agents). Discussion This research program will result in a framework that identifies the domains of context and their features that can facilitate or hinder: (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. The framework will increase the conceptual clarity of the term “context” for advancing implementation science, improving healthcare professionals’ use of evidence in clinical practice, and providing greater understanding of what interventions are likely to be effective in which contexts

The research on endothelial function in women and men at risk for cardiovascular disease (REWARD) study: methodology

Background Endothelial function has been shown to be a highly sensitive marker for the overall cardiovascular risk of an individual. Furthermore, there is evidence of important sex differences in endothelial function that may underlie the differential presentation of cardiovascular disease (CVD) in women relative to men. As such, measuring endothelial function may have sex-specific prognostic value for the prediction of CVD events, thus improving risk stratification for the overall prediction of CVD in both men and women. The primary objective of this study is to assess the clinical utility of the forearm hyperaemic reactivity (FHR) test (a proxy measure of endothelial function) for the prediction of CVD events in men vs. women using a novel, noninvasive nuclear medicine -based approach. It is hypothesised that: 1) endothelial dysfunction will be a significant predictor of 5-year CVD events independent of baseline stress test results, clinical, demographic, and psychological variables in both men and women; and 2) endothelial dysfunction will be a better predictor of 5-year CVD events in women compared to men. Methods/Design A total of 1972 patients (812 men and 1160 women) undergoing a dipyridamole stress testing were recruited. Medical history, CVD risk factors, health behaviours, psychological status, and gender identity were assessed via structured interview or self-report questionnaires at baseline. In addition, FHR was assessed, as well as levels of sex hormones via blood draw. Patients will be followed for 5 years to assess major CVD events (cardiac mortality, non-fatal MI, revascularization procedures, and cerebrovascular events). Discussion This is the first study to determine the extent and nature of any sex differences in the ability of endothelial function to predict CVD events. We believe the results of this study will provide data that will better inform the choice of diagnostic tests in men and women and bring the quality of risk stratification in women on par with that of men