Even though in situ breast cancer (BCIS) accounts for a large proportion of the breast cancers diagnosed, few studies have investigated potential risk factors for BCIS. Their results suggest that some established risk factors for invasive breast cancer have a similar impact on BCIS risk, but large population-based studies on lifestyle factors and BCIS risk are lacking. Thus, we investigated the association between lifestyle and BCIS risk within the European Prospective Investigation into Cancer and Nutrition cohort.Lifestyle was operationalized by a score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. The recommendations utilized in these analyses were the ones pertinent to healthy body weight, physical activity, consumption of plant-based foods, energy-dense foods, red and processed meat, and sugary drinks and alcohol, as well as the recommendation on breastfeeding. Cox proportional hazards regression was used to assess the association between lifestyle score and BCIS risk. The results were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI).After an overall median follow-up time of 14.9 years, 1277 BCIS cases were diagnosed. Greater adherence to the WCRF/AICR cancer prevention recommendations was not associated with BCIS risk . An inverse association between the lifestyle score and BCIS risk was observed in study centers, where participants were recruited mainly via mammographic screening and attended additional screening throughout follow-up , but not in the remaining ones .While we did not observe an overall association between lifestyle and BCIS risk, our results indicate that lifestyle is associated with BCIS risk among women recruited via screening programs and with regular screening participation. This suggests that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by a lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our analyses is consistent with the inverse associations between lifestyle scores and breast cancer risk reported from previous studies. In situ breast cancer (BCIS) is an intraepithelial lesion with malignant potential. Generally, it is considered a non-obligatory precursor or a potential risk factor for invasive breast cancer. Women with BCIS rarely report symptoms, and the majority of in situ tumors are detected through organized or opportunistic mammographic screening attendance .Even though BCIS accounts for up to 20% of the breast cancer cases diagnosed , censoreConsidering the abovementioned studies suggesting an inverse association of a more health-conscious lifestyle with a decreased risk of BCIS, and the lack of large epidemiological studies, we investigated the association between lifestyle, operationalized by a score reflecting the adherence to cancer prevention recommendations, and BCIS risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.EPIC is a multicenter prospective cohort study designed to investigate the associations between diet, lifestyle, genetic and environmental factors, and the incidence of cancers and other chronic diseases. Over 520,000 participants, aged 25–70 years, were recruited between 1992 and 2000 in 10 European countries . The French cohort included members of a health insurance plan for school and university employees. Participants at the Spanish and Italian centers (except Florence) included blood donors, members of several health insurance programs, employees of several enterprises, civil servants, and people from the general population. In Utrecht and Florence, women mainly participating in mammographic screening programs were recruited for the study. In Oxford, most of the cohort consisted of “health-conscious” persons from England, Wales, Scotland, and Northern Ireland, many of whom were vegetarians. Participants were recruited from the general population in the other centers. The cohorts of France, Norway, Utrecht, and Naples included only women. All study participants provided written informed consent. Ethical approval for this study was obtained from the International Agency for Research on Cancer review board and local participating centers.Detailed information on the study design, methods, and rationale of the EPIC cohort has been previously reported , 14. Upon = 20,477), women who were lost to follow-up (n = 2557), pregnant women at study enrollment (n = 556), and women with missing data on diet, weight or height, physical activity, or breastfeeding were excluded from the analyses . The latter exclusions due to missing covariates comprised all participants from Umeå, Sweden, and Norway, where physical activity was not collected in sufficient detail as well as participants from Bilthoven, the Netherlands, where information on breastfeeding was not collected. Additionally, in order to exclude implausible dietary intakes, participants within the lowest and highest 1% of the cohort distribution of the ratio of total energy intake to estimated energy requirements were excluded (n = 5033). Therefore, 260,151 women were finally included in the analytical sample.For the present study, women with prevalent cancers (except non-melanoma skin cancer) at study enrollment (A score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations was constructed, as in previous studies , 17, 18.Detailed information on the construction of the WCRF/AICR lifestyle score for the EPIC cohort has previously been reported . In shorThe main difference between our WCRF/AICR lifestyle score and the scores used previously in EPIC and other studies , 17, 18 Of note, we decided to assign 1 point for adherence to the WCRF/AICR recommendation on alcohol consumption to individuals, who had reported moderate alcohol consumption (≤ 10 g of ethanol intake per day), in addition to non-consumers , 17. ThiWomen who developed first primary incident and histologically confirmed BCIS between recruitment and the latest date of complete information were considered as cases. BCIS cases were identified through population cancer registries in Denmark, Italy, the Netherlands, Spain, Sweden, and the UK. In France, Germany, and Greece, a combination of methods was used including health insurance records, cancer pathology registries, and active follow-up of study participants and their next of kin. The latest dates of complete information for BCIS incidence varied among centers, ranging between 2008 and 2013. Cancer cases were coded according to the 10th Revision of the International Statistical Classification of Diseases, Injuries, and Causes of Death and the Second Revision of the International Classification of Diseases for Oncology.In situ tumors were further classified based on their morphology as ductal carcinoma in situ  or lobular carcinoma in situ .Categorical variables were presented by percentages and continuous variables by arithmetic means and standard deviations (SD) for descriptive purposes. Missing covariate values were sporadic  and occurred in all participating study centers. We used multiple imputation with a fully conditional specification as provided by PROC MI in SAS , and misCox proportional hazards regression was used to assess the association between the WCRF/AICR lifestyle score as well as its individual components and the risk of BCIS development. Entry time was defined as the date of a participant’s recruitment in the study and exit time as the date of diagnosis of BCIS. Participants who were not diagnosed with BCIS were censored on the date of diagnosis of other cancers, except non-melanoma skin cancer, or on the date of loss to follow-up, end of follow-up, or death, whichever came first. All analyses were stratified by age at recruitment  and center.Two sets of covariates were evaluated for statistical adjustment. In model 1, we adjusted for the highest level of attained education , smoking status , and total dietary energy consumption . Model 2 was additionally adjusted for a priori determined confounders including the presence of chronic diseases at recruitment , age at menarche , age at first full-term pregnancy , menopausal status , ever use of oral contraceptive pills , and ever use of menopausal hormone therapy . The WCRF/AICR lifestyle score was assessed both as a continuous and as a categorical variable. BCIS was evaluated as a composite outcome  and by morphological subtypes (DCIS vs. LCIS). The results are presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI).n = 1794). Analyses were conducted using SAS version 9.4 . All statistical tests were two-sided, and p values < 0.05 were considered statistically significant.Given that BCIS is mainly diagnosed by mammographic screening, we conducted subgroup analyses evaluating the association in centers where most women were recruited via screening programs and in which screening participation during follow-up was high  cases were diagnosed in the EPIC cohort. Proportions of BCIS to overall breast cancer cases varied between 4.3 and 15.8% across the study centers  in the full EPIC cohort. A significant inverse BCIS risk association for WCRF/AICR lifestyle score was observed in the screening-recruited cohorts , but not in the other centers . While prespecified subgroup analyses of smoking status and menopausal status showed similar associations as the overall analyses, the inverse association between lifestyle score and BCIS risk was more pronounced among women with lower education level in the screening-recruited cohorts  breast cancer risk. The majority of these studies have reported inverse associations between the WCRF/AICR lifestyle score and invasive [both in postmenopausal and in mixed  populations] , 24, 25 The lack of a statistically significant association between the individual components of the WCRF/AICR lifestyle score and BCIS risk that we observed in the present study is overall consistent with the findings from studies on invasive breast cancer risk using similar scores , 25–27, Our findings from the subgroup analyses in the screening-recruited EPIC cohorts could suggest that a combined healthy lifestyle  is important for the carcinogenetic process in the breast. However, the lack of association for individual components of the WCRF/AICR lifestyle score in our analyses could also be due to the relatively small proportion of the study population in the screening-recruited EPIC cohorts . Future large-scale studies with more detailed information on mammographic screening attendance during follow-up and BCIS status at recruitment are needed in order to investigate the individual lifestyle factors in relation to BCIS risk in more detail.Given the agreement between our subgroup finding of an inverse association between lifestyle score and BCIS risk and those reported in other studies for invasive or total breast cancer  , 18, 25,The strengths of this study included the prospective design and the substantial number of histologically confirmed incident BCIS cases, but it also had some limitations. Information on lifestyle habits was only available from baseline and thus may not reflect the long-term lifestyle habits of the study participants. Furthermore, information on mammographic screening attendance was not available for large parts of our study population. The fact that proportions of BCIS to total breast cancer cases ranged between 4.3 and 15.8% across the centers of the EPIC cohort suggests that screening participation but potentially also BCIS registration were different across study sites. In this context, it should be noted that we could not disentangle the underlying reasons with our data. Temporal and regional differences in BCIS reporting are not expected to be differential among EPIC participants with different lifestyle behaviors or characteristics , differential detection bias, i.e., a differential individual likelihood to participate in screening related to individual health consciousness and socio-economic status cannot be ruled out. Nevertheless, we were able to perform analyses restricted to women mainly recruited via organized mammographic screening programs at the EPIC centers in Florence and Utrecht and reported the results from these analyses separately. While our main objective was to evaluate the adherence to lifestyle recommendations in relation to BCIS risk, we acknowledge that more etiology-oriented analyses on BCIS risk from EPIC and other cohorts are needed, also taking into account morphological tumor subtypes based on larger case numbers. Finally, as in any observational study, we cannot exclude the possibility of residual confounding.In summary, women with a higher lifestyle score including healthy body weight, regular physical activity, consumption of a high-quality diet, breastfeeding, and drinking a moderate amount of alcohol, if any, did not have a statistically significant lower risk of BCIS compared to participants who did not adhere to these habits in the EPIC cohort. However, there was a statistically significant inverse association among participants recruited via screening programs and with high screening participation during follow-up, suggesting that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by the lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our subgroup analyses restricted to screening-recruited EPIC cohorts is consistent with the inverse associations between lifestyle scores and mammographic density as well as breast cancer risk reported in previous studies. These findings may indicate that BCIS and invasive breast cancer have a similar risk factor profile. Additional studies, with more detailed information on screening participation, are required in order to validate our findings.Additional file 1: This file contains Table S1. The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and the operationalization of the WCRF/AICR lifestyle score in the European Prospective Investigation into Cancer and Nutrition cohort; Table S2. The proportion of primary in situ breast cancer cases over the total primary breast cancer cases diagnosed in the European Prospective Investigation into Cancer and Nutrition cohort; Table S3. The association between the World Cancer Research Fund/American Institute for Cancer Research lifestyle score and the risk for the most common morphological subtypes of BCIS  in the European Prospective Investigation into Cancer and Nutrition cohort; Table S4. The associations between the individual components of the World Cancer Research Fund/American Institute for Cancer Research lifestyle score and in situ breast cancer risk by menopausal status and menopausal hormone use assessed in the total study population.


Human embryonic stem (ES) cell lines have opened great potential and expectation for cell therapy and regenerative medicine. Monkey and human ES cell lines, which are very similar to each other, have been established from monkey blastocysts and surplus human blastocysts from fertility clinics.Nonhuman primate ES cell lines provide important research tools for basic and applicative research. Firstly, they provide wider aspects of investigation of the regulative mechanisms of stem cells and cell differentiation among primate species. Secondly, their usage does not need clearance or permission from the regulative rules in many countries that are associated with the ethical aspects of human ES cells, although human and nonhuman embryos and fetuses are very similar to each other. Lastly and most importantly, they are indispensable for animal models of cell therapy to test effectiveness, safety, and immunological reaction of the allogenic transplantation in a setting similar to the treatment of human diseases.So far, ES cell lines have been established from rhesus monkey (Macaca mulatta), common marmoset , and cynomolgus monkey (Macaca fascicularis), using blastocysts produced naturally or by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). These cell lines seem to have very similar characteristics. They express alkaline phosphatase activity and stage-specific embryonic antigen (SSEA)-4 and, in most cases, SSEA-3. Their pluripotency was confirmed by the formation of embryoid bodies and differentiation into various cell types in culture and also by the formation of teratomas that contained many types of differentiated tissues including derivatives of three germ layers after transplantation into the severe combined immunodeficiency (SCID) mice.The noneffectiveness of the leukemia inhibitory factor (LIF) signal makes culture of primate and human ES cell lines prone to undergo spontaneous differentiation and thus it is difficult to maintain these stem cell colonies. Also, these ES cells are more susceptible to various stresses, causing difficulty with subculturing using enzymatic treatment and cloning from single cells. However, with various improvements in culture methods, it is now possible to maintain stable colonies of monkey ES cells using a serum-free medium and subculturing with trypsin treatment. Under such conditions, cynomolgus monkey ES cell lines can be maintained in an undifferentiated state with a normal karyotype and pluripotency even after prolonged periods of culture over 1 year. Such progress should facilitate many aspects of stem cell research using both nonhuman primate and human ES cell lines.


Formal training in team leadership is not taught in biomedical research graduate training programs or medical schools.We piloted a Leadership Training Workshop for graduate biomedical and medical students enrolled in our Interprofessional Research Design Course.t-test, p=0.04).The Kane–Baltes self-efficacy survey demonstrated improved leadership skills (median scores pretraining and post-training were 71 and 76.6; paired Most students demonstrated significant improvement in self-awareness pertaining to their own innate leadership styles. The successful biomedical researcher will need to lead research teams effectively in order to understand relevant gaps in knowledge and solve complex problems required to advance the broad field of medicine. Multidisciplinary and interprofessional team science is increasingly recognized as a key driver for the most impactful and efficient way to translate scientific knowledge to improve public health . While iFormal training in team leadership and project management is not routinely taught in biomedical research graduate training programs or medical schools . By defaWe report our experience piloting a leadership training program at the University of Texas Medical Branch (UTMB) during the Summer Term of 2017 with graduate students enrolled in the Human Pathophysiology and Translational Medicine Graduate Program’s core course, Translational Research Design and Interprofessional Skills Development , and first-year medical students in the Translational Research Track. The structured curricula we developed and implemented focused more on processes rather than outcomes, given the time limitation of the course and our instructional objectives. We devoted 12 hours of a 7-week course toward leadership training. Following best practices from team science educators , we adapSince 2012, the Interprofessional Research Design Course partnered predoctoral Ph.D. students with medical students who also participated in summer research rotations. The overall course goals are to promote: (1) development of interprofessional collaborative skills, (2) skills of research project development and study design, (3) oral and written presentation skills, and beginning in 2017, (4) understanding leadership styles that foster collaboration in translational research projects. The course uses a combination of guided inquiry, team-based learning, workshop and seminar formats. These varied active learning styles lead students through the processes related to the conduct and performance relevant to team science: formation and refinement of a study hypothesis or research question, selection of (an) appropriate experimental design(s), and development of data evaluation plan(s).The final product of the course is a multidisciplinary, collaborative research project proposal on a translational topic in the NIH R21 format. Each group of students (1 Ph.D. and 2–3 M.D. students per group) collectively was required to create a translational research proposal. Each student negotiated their individual contributions toward the final product in a team contract, and documented (assessed) the meaningful contributions of each member, including their own, in the final product at the end of the course. Their research proposal was graded based on scientific soundness, and evidence of interdisciplinary, interprofessional collaborative interactions (includes consultation with a biostatistician).The Institutional Review Board at UTMB reviewed and approved this project. We designed a 12-hour leadership training and used pre–post mixed methods design to assess the effects of the intervention.A total of 17 students  were enrolled in the Interprofessional Research Design Course  during the Summer Term (May–June) of 2017 at the UTMB Graduate School of Basic Sciences and the School of Medicine.Students took a pretest before attending class and then attended a 12-hour session on leadership training over 1.5 days (intervention). At the beginning of the training, every participant took the Myers–Briggs personality inventory , obtaineStudents were also required to have team contract agreements, which delineated each member’s proposed contributions and timeline to completion of tasks before engaging in the group exercises. At the end of the class, the students were told to document the meaningful contributions of each team member, relative to their own contributions.Research based on self-efficacy theory shows that efficacious persons are motivated, resilient, and goal oriented , and thiThe pre-post-leadership workshop test asked open-ended questions, probed whether the students recognized their own leadership style, and whether they are aware of communication methods that minimize conflict and maximize team productivity. Although the Myers-Briggs, the Blake–Mouton, and the Thomas–Kilmann instruments were used as learning tools to help students gain awareness of their own innate leadership styles, we also used these 3 tests as measures (preworkshop and postworkshop) of whether the students were self-aware of their authentic leadership style.Lastly, the students were required to submit a final writing assignment reflecting on a meaningful event in the team process that will carry influence with them beyond the Interprofessional Research Design course. From the essays, we identified 4 major themes.t-test . Since this is a practical intervention, we are interested in detecting large effect sizes for a difference between preassessment and postassessment values. Our power analysis indicates that we have sufficient (at least 80%) power to detect significant differences for Questions 4 and 5 which have large effect sizes  the development of interprofessional respect and learning from their peers , (2) learning to trust their teammates , (3) good communication and use of a team contract , and (4) personal growth and development . Overall, participants understand that a leader in team science is one who creates an environment for intellectual exchange of information, encourages risk-taking and problem solving, and develops strategies for overcoming challenges associated with merging scholars from diverse backgrounds. Further, these qualities are attainable after establishing trust, respect, and a mutual set of ground-rules by which all team members follow.Over the past years, students who have participated in the Interprofessional Design course have provided overall positive feedback being engaged in a team science project. However, before 2017, self-reflection essays by some prior students revealed that not all team members carried their weight. Working in a team effectively requires a different skill set compared with working alone on an assignment, leading to predictable discord among team members. In 2017, we implemented a leadership workshop so that all students can be introduced to skills that will allow them to work within the context of a scientific team [Postworkshop analysis revealed that students’ demonstrated improvement in leadership self-efficacy, developed an awareness of their own individual authentic leadership styles as well as understanding that of their colleagues’ styles, and further recognized that their styles differed under nonstressed versus stressed situations. The results of this study extend previous studies that involved developing leadership capacities in healthcare organizations , and alsGiven that the current course design significantly influenced student beliefs concerning teamwork skills required to be successful and beliefs concerning taking charge of a project, additional research should explore other training designs that might influence other components of leadership self-efficacy . Perhaps the key to improving self-efficacy scores that seem less temporally related to the training design might involve implementation of a longitudinal leadership-coaching model.


In 2015, we reported on a new national “worm index” for human development using data released by the World Health Organization (WHO) for the total number of school-aged children requiring mass drug administration (MDA) to treat their intestinal helminth infections and schistosomiasis, together with the population requiring MDA for lymphatic filariasis (LF) [Our finding that high national worm indices link to low human development generates a number of hypotheses regarding how human helminth infections adversely affect child development, overall health, and even economic development. Including all intestinal helminth infections, schistosomiasis, and LF also helps to evaluate global effects. For example, many Asian nations might have high worm indices due to widespread intestinal helminth infections and LF, whereas in many African countries, schistosomiasis also contributes greatly to calculating national worm indices , 2. EmplHere, we extend our earlier findings by calculating worm indices for all 191 countries for which there are available data. We also calculate the worm index in 2 different ways, using both the methods described earlier that rely on WHO data (now with the most recently reported data in 2016) . It shouUsing either approach, we confirm a strong inverse association between worm indices and HDIs. In addition, we observed especially strong associations between worm indices and low educational attainment, years of schooling, and school completion. Our findings suggest that helminth control and elimination might comprise an essential element of global efforts to improve childhood education.The most recent HDI and mean years of schooling are from the UNDP data 2015 . HDI meaFrom the WB, we examined 3 educational parameters, which also compared female and male students . First, Figs In addition, we looked at the association between worm indices and HDI separated by 6 regions of the world defined by the WB . With WHO data, Latin America and Caribbean region shows the greatest decrease of SD unit in HDI (−0.707) change associated with one SD increase in worm index, followed by Europe and Central Asia (−0.674), sub-Saharan Africa (−0.525), and East Asia and Pacific (−0.59). In contrast, South Asia and Middle East and North Africa regions were not statistically significant. For the GBD data, all regions are statistically significant results. South Asia shows the greatest decrease of SD unit in HDI (−0.742), followed by Europe and Central Asia (−0.716), Latin America and Caribbean (−0.639), East Asia and Pacific (−0.634), Middle East and North Africa (−0.627), and sub-Saharan Africa (−0.447).In summary, utilizing 2 different worm indices data available, our findings showed negative associations between helminthic neglected tropical diseases (NTDs) and both human development and educational indicators for children globally. The negative links to HDI for all 191 nations globally extend previous information provided for the 25 largest nations and OIC countries, respectively [The negative association of worm infections with child intelligence and educational attainment was noted almost 100 years ago among school children infected with hookworm in rural Alabama . It’s ofMore recently, Kremer and Miguel have conducted randomized control trials (RCTs) to show that deworming has strong effects on improving school participation and reducing absenteeism in Kenya . The lowCountering these findings, a systematic review and meta-analysis based on RCTs has called into question the benefits of deworming on child nutrition and school performance , leadingOverall, the results here indicate a strong negative association between high endemic worm burdens from intestinal helminth infections, schistosomiasis, and LF and negative educational attainment. In terms of interpretation, one has to be careful, however, of not reading too much into the bivariate associations without further multivariate analysis and appropriate statistical modeling, which can help us better understand the extent to which there is reverse causality (high-HDI countries tend to have lower worms) or the extent to which there are other “omitted variables”—countries that have low HDI and high-worm indices, for example, may also tend to be those with bad governance, which makes deworming ineffective in them.Nevertheless, our findings indicate an urgent need to better explore mechanisms behind worm-associated educational deficits and for studies on mechanisms to confirm whether the worms exert these effects directly, possibly through malnutrition, or whether worms are “biomarkers” indicative of severe poverty or other negative aspects of human development. The general finding of potential greater negative educational effects on female children is also of interest for future research. Further studies are underway to better identify the links between high-worm indices and poor education and to identify potential mechanisms. Finally, in terms of data collection and reporting, despite the similar results between WHO and GBD data, sometimes discrepant results suggest that there is pressing need for more extensive and coherent high-quality data.Our findings reported here also have potential implications for public policy. Confirmation of our identified links between human helminth infection and development highlight key roles for the WB and international ministries of finance to prioritize global deworming as a potentially important tool for human capital accumulation and global economic development. Linking human helminth infection to education, especially the education of girls and women, could shape new public policies around global deworming as essential to the United Nations Girls Education Initiative (UNGEI), which was launched in the same year as the UN Millennium Development Goals. Similarly, the emphasis on deworming in girls and women as endorsed by the WHO’s 2017 Bellagio Declaration for NTDs would align well with our findings.In summary, our results here generate some key and provocative hypotheses that take global deworming beyond the health sector by linking such activities to international development and education. Potentially, our findings also highlight research into new anthelminthic drugs, diagnostics, and vaccines as novel technologies for advancing educational attainment and economic development.S1 Table(DOCX)Click here for additional data file.


The bioinformatics and data science training program at USTTB commenced in 2017 focusing on student, faculty, and curriculum tiers of enhancement. The program’s sustainable measures included institutional support for core elements, university tuition and fees, resource sharing and coordination with local research projects and companion training programs, increased student and faculty publication rates, and increased research proposal submissions. Challenges reliance of high-speed bandwidth availability on short-term funding, lack of a discounted software portal for basic software applications, protracted application processes for United States visas, lack of industry job positions, and low publication rates in the areas of bioinformatics and data science. Long-term, incremental processes are necessary for engaging historically underserved countries in bioinformatics and data science research. The multi-tiered enhancement approach laid out here provides a platform for generating bioinformatics and data science technicians, teachers, researchers, and program managers. Increased literature on bioinformatics and data science training approaches and progress is needed to provide a framework for establishing benchmarks on the topics.Bioinformatics and data science research have boundless potential across Africa due to its high levels of genetic diversity and disproportionate burden of infectious diseases, including malaria, tuberculosis, HIV and AIDS, Ebola virus disease, and Lassa fever. This work lays out an incremental approach for reaching underserved countries in bioinformatics and data science research through a progression of capacity building, training, and research efforts. Two global health informatics training programs sponsored by the Fogarty International Center (FIC) were carried out at the University of Sciences, Techniques and Technologies of Bamako, Mali (USTTB) between 1999 and 2011. Together with capacity building efforts through the West Africa International Centers of Excellence in Malaria Research (ICEMR), this progress laid the groundwork for a bioinformatics and data science training program launched at USTTB as part of the Human Heredity and Health in Africa (H3Africa) initiative. Prior to the global health informatics training, its trainees published first or second authorship and third or higher authorship manuscripts at rates of 0.40 and 0.10 per year, respectively. Following the training, these rates increased to 0.70 and 1.23 per year, respectively, which was a statistically significant increase ( African countries have long been disproportionately burdened by the “big three” infectious diseases  and neglected emerging infectious diseases such as EVD and Lassa fever. African populations maintain the world’s highest levels of genetic diversity which decline proportionately with increasing distance from Africa . BioinfoAfrican researchers and participant populations have historically been underrepresented in GWAS. Through 2014, only 11 of the thousands of the GWAS have included African participants . While ATo fully benefit from advances in bioinformatics and data science research, it is imperative to train the next generation of African scientists on their use . Tastan Multi-country organizations such as the H3Africa and H3Africa BioNet (H3ABioNet) consortiums have yielded extensive training and research opportunities within Africa . The H3AThe focus of the current work are bioinformatics and data science training in sub-Saharan Mali. Research in Mali has emphasized malaria as it is the country’s primary cause of morbidity and mortality, representing 42% of consultations in its health centers . MalariaAs with many countries in sub-Saharan Africa, Mali has significant limitations in developing, implementing, sustaining, and expanding innovative mechanisms for research efforts and clinical trials that are central to its health improvement . Recent Here we describe an incremental approach for engaging the next generation of African scientists in research through a progressive sequence of informatics, bioinformatics, and data science training programs at the USTTB. We describe the approaches, developments, and challenges incurred culminating with the West African Center of Excellence for Global Health Bioinformatics Research Training program in an effort assist researchers for reaching underserved populations in similar environments.Situated in urban Bamako, Mali, USTTB is comprised of schools of medicine, pharmacy, and basic sciences; an institute of applied science; and research laboratories focusing on malaria, tuberculosis, and retrovirology . The sitFormal research and training infrastructure at USTTB dates back to 1989 with the launch the MRTC. The facility maintained hardwired internet access, laboratories, classrooms, conference rooms, and a library . The MRTThe West African Center of Excellence for Global Health Bioinformatics Research Training program was launched in 2017 (Africa). The program leveraged infrastructure and personnel from: two earlier informatics training programs, a malaria research project, the USTTB bioinformatics M.Sc. program, and the African Center of Excellence in Bioinformatics (ACE) teaching computer laboratories . DescripFrom 1999 to 2003, the ITMI program provided short and long term training in informatics for Malian researchers at the MRTC and governmental health agencies across West Africa. The ITMI program was complemented with research on determinants of drug resistance, immune evasion and virulence in malaria, development of field research sites to study drug resistance, human response to malaria, pathogenesis of severe malaria, and malaria vaccine trials. The informatics focus for the ITMI occurred in the sense of research question formulation and data collection, capture, linkage processes, management, and analysis. The program included five trainees with the overall goal of completing master’s degrees in public health and preparing manuscripts and submitting them for publication in peer-reviewed journals.Building on the ITMI program, the ITGH program was a carried between 2004 and 2011 and provided training toward completion of M.Sc. degrees in public health. Several trainees also participated in an online master’s diploma program known as epidemiology and public health . With training delivered entirely in French, ESPEL was a consortium serving Francophone countries in the Mediterranean and North Africa through the University of Bordeaux with courses in statistics and epidemiology. Course instruction in the ESPEL program was provided by USTTB medical faculty and online tutoring tools.Plasmodium falciparum  infection and incidence in uncomplicated malaria  African countries . The ACEThe AFRO VECTGEN program was initiated in 2003 through a partnership with the WHO Special Programme for Research and Training in Tropical Diseases (TDR) and the MRTC Department of Medical Entomology and Vector Ecology . The proUSTTB maintains a M.Sc. in Bioinformatics program established in 2015 in collaboration with the H3ABionNet Consortium. The program is one of only 13 such programs in 7 African countries . The proA key component of the curriculum for engaging underserved populations in research included a formal course on English speaking and writing in scientific research  degree. The impact of the ITMI on publication productivity is shown in p < 0.001). Publications following the ITMI program were focused in the areas of malaria interventions, vaccine development, and epidemiology (Publication rates per year in first authorship and third and higher authorship increased by 690% (0.10 per year to 0.79 per year) and 253% (0.40 per year to 1.41 per year), respectively, following the ITMI training program. Each of these increases was statistically significant  and the University of Strasbourg . The WABT integrated three intertwined training components, namely faculty training and development, curriculum enhancement, and student training enhancement for students enrolled in the USTTB master’s degree program in bioinformatics. The feedback loop illustrating the approach for launching new trainees into academic and research positions is shown in The program provided a direct pipeline of trainees into the USTTB bioinformatics program and local research projects. An advisory board provided independent oversight and insight for the program. The three tiers of enhancement covered in the training program follow.Faculty trainees were recruited from USTTB faculty with responsibilities in developing and overseeing the USTTB bioinformatics and data science curriculum. This component was carried out through participation in scientific workshops; delivery of oral and poster presentations at scientific conferences; mentorship on proposal development and manuscript preparation; and development and implementation of an annual bioinformatics symposium at the USTTB site. Research proposal topics focused on mobile health in malaria surveillance and efficacy evaluation for seasonal malaria chemotherapy in malaria prevention through the application of bioinformatics and data science approaches and technologies.Training activities included mentored program and curriculum development for the USTTB M.Sc. in bioinformatics program. The program’s course competencies were compared and evaluated according to The project provided partial scholarships for current and incoming students in the USTTB M.Sc. in bioinformatics program as well as partial scholarships for related doctoral programs. Trainees were recruited among students enrolled in the USTTB M.Sc. in bioinformatics program or doctoral students working in research programs with bioinformatics focuses. Training activities included “study abroad” training at outside institutions through the following mentored activities: formal coursework; literature review preparation; data capture, management, and analysis; and manuscript preparation. Manuscript data were provided through the West Africa ICEMR research projects. Trainees were responsible for attending and presenting research findings at professional research conferences, including the American Society of Tropical Medicine and Hygiene (ASTMH) and H3Africa consortium meetings. Funds were allocated for pilot research projects per year in the amount of $10,000 USD, which were intended to foster mentorship, incorporation of research into the classroom, and research evaluation. An online portal was developed for proposal submissions, and proposals were reviewed and scored by the training program’s key investigators and advisory board .Workshop training was provided annually at USTTB aimed toward two aspects: (1) enabling junior trainees to effectively manage and interpret genetic data, including major bioinformatics database sources and integration with biological data; and (2) performing computational tasks and carrying out analytical approaches to process, analyze, and interpret biological data. The program’s workshop themes are listed in The official language in Mali is French, but Bombari is the most widely spoken . The worFinancial program management training was provided for USTTB financial administrators through in-person discussion sessions with trained sponsored projects personnel. Training was also provided on biographical sketch development, COI and disclosure, and research ethics.The challenges incurred during the bioinformatics and data science training program included language barriers, complexity in obtaining United States. Exchange Visitor visas (J-1), high-speed internet availability, and the lack of discounted software portals. While the training was primarily delivered in English, many of the trainees were not fully fluent in English. Also, this effort required the availability of high-speed bandwidth for utilizing software extensions and accessing biomedical databases. While high-speed bandwidth was available for training at USTTB, its funding was dependent on ongoing short-term funding. The lack of a discounted software portal for commercial software presented challenges for acquiring and upgrading several common software applications such as Microsoft Access . This effort focused on freeware applications including R, REDCap, ArcGIS Online , and QGIS . While the training program included cohorts of trainees with similar academic focuses, the participants with bioinformatics expertise ranged from beginning to advanced skill sets. The program strategy here incorporated basic biological concepts prior to covering more advanced topics in bioinformatics and data science. The lack of industry opportunities for trainees primarily limited post-training employment prospects to academia, research, and governmental health agencies.Mali bioinformatics yielded N = 63 publications between 2006 (the year of the first observed bioinformatics publication) and November 2018. None of these hits focused exclusively on bioinformatics or data science training  visa program mandate English proficiency . InclusiTrainee outcomes were considered primarily in terms of publications, grant proposal submissions and awards, research conference presentations, and employment outcomes. In the absence of strong industry or pharmaceutical presence, it is likely that trainees will ultimately gain employment in research, academic, or government settings. Emphasizing proposal preparation within the training programs therefore has great utility in this regard. The training efforts in this work benefitted from several complementary malaria research projects that provided training and data sources for manuscript development and publication. Our programs also benefitted from the biannual H3Africa research conferences, which provided an international venue for our trainees to present their work in oral or written discourses. Professional responsibilities in Africa are perhaps less dependent on scientific publishing for measuring scientific productivity than in other parts of the world, and thus additional incentives for publishing may be useful to conform to the extramural funding process where publication is highly prioritized. One such incentive occurs at the University of Cape Town where governmental supplements are provided for completed publications . While oIdeally trainees should develop diverse research portfolios including topics focused on practical needs with utility in all facets of research, such as DCMS development and oversight. These practical skills provide opportunities over the entire course of research endeavors as opposed to sole skill sets in advanced analytical techniques that are suited for latter stages research. The challenges associated with bioinformatics and data science training parallel those for related data intensive research processes such as DCMS. Core bioinformatics and data science research infrastructure shares common elements with data intensive epidemiological and clinical research such as the setup of data systems, data management, and data warehousing. Because of the overlap in bioinformatics and DCMS responsibilities, we provided training on the development and use of REDCap databases and tablet-based data collection. Other practical training in our programs included biographic sketch and curriculum vitae and resume development and program management.While the training programs covered in this work focused on Mali, we believe that they made a positive impact more broadly across the region of sub-Saharan Africa. These programs regularly hosted trainees from Mali’s neighboring countries, including Nigeria and Ghana. The West Africa ICEMR also fostered collaborations among multiple sub-Saharan countries, including Mali, Senegal, and The Gambia.Regional training approaches may increase research participation for countries lacking necessary capacity for hosting training efforts independently. The utility of regional-based approaches is recognized to yield sharing of study protocols and standardization of case definitions and reporting practices . IntegraLong-term sustainability of training and capacity development in Africa will likely require additional support within the host countries in the area of research and development. Among 13 African countries , only 3 countries  achieved a modest goal for spending at least 1% of GDP on research and development. GDP expenditures on research and development among the remainder of surveyed countries ranged between 0.20 and 0.48% . By contIncreased pharmaceutical involvement within Africa is greatly needed for developing bioinformatics and data science expertise and clinical research participation within the continent. To our knowledge, this is the first manuscript on bioinformatics and data science training in Mali. Additional literature on bioinformatics and data science training in Africa is needed for establishing training priorities, monitoring progress, and developing goal-based strategies for its improvement. Such literature also allows investigators developing new training programs to build on prior efforts and adapt training approaches. It is therefore essential for journal publishers to recognize the importance of publishing work on training programs as they often serve as the backbone for their associated research.Bioinformatics and data science training programs in developing countries necessitate incremental and collaborative strategies for their feasible and sustainable development. The progress described here covered decades of collaborative efforts centered on training and research on computationally intensive topics. These efforts laid the groundwork and platforms conducive for hosting a bioinformatics and data science training program in Mali. Training programs are perhaps best facilitated through Africa’s university systems as they are perhaps best positioned to maintain core resources during lapses in short-term funding. While bioinformatics and data science training programs are rapidly growing across Africa, much of the continent currently lacks substantial commercial investment and is reliant on short-term funding for training and research efforts. It is therefore critical to incentivize, commercial and governmental investment within African countries to complement short-term funding efforts. It is also of central importance to publish literature on scientific training programs to monitor and evaluate progress, develop standards, and share training approaches and experiences.JGS conceived and drafted the manuscript which was reviewed and approved by all authors. JGS, FM, MW, CT, JL, OT, SKS, DK, and SD participated in study design. JGS, FM, JL, SKS, OT, MW, DK, JJL, MD, MS, DD, MT, YK, AAD, ST, BD, MC, OK, YL, and SD assisted in carrying out the training program. JSS and ML assisted in manuscript editing and consultation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


OBJECTIVES/SPECIFIC AIMS: Dissemination of research findings through the published literature is a complex but critical part of the scholarly communication process. Additionally, this time point on the translational spectrum is a key objective of the National Clinical Association for Advancing Translational Sciences (NCATS). Tracking the dissemination of research outputs can be difficult to identify and evaluate. The purpose of this case study was 2-fold: (1) identify tools and resources available freely to the public and through university subscriptions used to assess research output; and (2) compare the effectiveness of these tools oat tracking output at different levels of granularity. METHODS/STUDY POPULATION: The authors, Spectrum staff (D.A.) and School of Medicine librarian (M.B.), attended webinars hosted by other Academic Medical Center libraries conducting work on impact tracking and learned from vendor product managers about available tools and resources during on-site campus visits. Publications from Stanford’s Clinical and Translational Science Award (CTSA) were used to track the diffusion of research outputs  via library subscription services  and freely available tools . RESULTS/ANTICIPATED RESULTS: The authors found certain tools were more inclusive in retrieving grant funded research outputs. For example, in the case of UL1 grant , on a grant-level output, there were discrepancies in the number of publications retrieved: (1) PubMed found 644 outputs; (2) Web of Science found 497 outputs; and (3) Scopus found 190 outputs. After de-duplication, the search across Web of Science (WoS), Scopus, and PubMed yielded 899 publications. In total, 389 outputs were unique to PubMed; 165 were unique to WoS; and 90 were unique to Scopus. Future analysis will be conducted to identify the source of unique outputs from each database . Additional analysis based on other units of research outputs  are expected to yield similar discrepancies. DISCUSSION/SIGNIFICANCE OF IMPACT: Citation analysis is a valuable method of assessing research output and, to a larger extent, research impact in a given field. It can help investigators illustrate qualifications for undertaking new projects, highlight collaborations across schools and departments, justify a grant renewal, and/or highlight accomplishments for promotion. However, systematic and comprehensive evaluations are needed in tandem with citation analysis/bibliometric analysis to assess the translation and uptake of research outputs and activities that result in research impact. Furthermore, both investigators and staff need adequate time and training to process research outputs/activities and to effectively organize them in easily understood visualizations.


Since the 2014–2016 West Africa Ebola epidemic, the concept of measuring health security capacity has become increasingly important within the broader context of health systems-strengthening, enhancing responses to public health emergencies, and reducing global catastrophic biological risks. Efforts to regularly and sustainably track the evolution of health security capabilities and capacities over time – while also accounting for political, social, and environmental risks – could help countries progress toward eliminating sources of health insecurity. We sought to aggregate evidence-based principles that capture a country’s baseline public health and healthcare capabilities, its health security system performance before and during infectious disease crises, and its broader social, political, security, and ecological risk environments.We conducted a scoping review of English-language scholarly and gray literature to identify evidence- and practice-based indicators and proxies for measuring health security at the country level over time. We then used a qualitative coding framework to identify recurrent themes in the literature and synthesize foundational principles for measuring global health security. Documents reviewed included English-language literature published after 2001 until the end of the research period—September 2017—to ensure relevance to the current global health security landscape; literature examining acute infectious disease threats with potential for transnational spread; and literature addressing global health security efforts at the country level.We synthesized four foundational principles for measuring global health security: measurement requires assessment of existing capacities, as well as efforts to build core public health, healthcare, and biosecurity capabilities; assessments of national programs and efforts to mitigate a critical subset of priority threats could inform efforts to generate useful metrics for global health security; there are measurable enabling factors facilitating health security-strengthening efforts; and finally, measurement requires consideration of social, political, and ecological risk environments.The themes identified in this review could inform efforts to systematically assess the impacts and effectiveness of activities undertaken to strengthen global health security.The online version of this article (10.1186/s12889-019-7216-0) contains supplementary material, which is available to authorized users. Since tThe WHO’s Joint External Evaluation (JEE) tool partially addresses this need by articulating country-level capacities required to mitigate infectious disease threats; the JEE also establishes a scoring system for quantifying progress made toward meeting benchmarks specified in the International Health Regulations (IHR). However, the JEE process is voluntary and relies on an in-country assessment and in-kind contributions of personnel who conduct the evaluation. While this process remains vital, additional universal approaches to measuring baseline, country-level health security are needed. Efforts to regularly and sustainably track and reproducibly compare the evolution of health security capabilities and capacities over time – while also accounting for political, social, security, and environmental risks – could help countries progress toward eliminating sources of health insecurity.To inform ongoing efforts to strengthen health systems and establish new mechanisms for monitoring health security -- and as a preliminary step in an ongoing project to develop a Global Health Security Index -- we performed a scoping literature review to articulate foundational principles for measuring global health security. Our objective was to identify evidence-based principles that not only capture health security capabilities before and during infectious disease crises, but also a country’s baseline public health and healthcare capacities and its broader social, environmental, and political risk environments. Themes that emerged from the literature informed our selection of indicators and sub-indicators that could help conceptualize and quantify health security capacities at the country level. In this paper, we summarize the themes we identified in the literature and also offer suggestions for improving future efforts to measure country-level health security.We conducted a scoping review of the biomedical and social science scholarly literature, as well as the gray literature. We searched PubMed, Web of Science, and OAIster using the search terms and search limits outlined in Fig. Documents eligible for review included only English-language literature published after 2001—to ensure relevance to the current global health security landscape—until the end of the research period (September 2017). Sources were selected if they examined acute infectious disease threats with potential for transnational spread and addressed health security-strengthening efforts at the country level. Documents were excluded if they addressed health security at subnational levels ; biological threats without national or international consequences; or plant, animal, or marine infectious disease threats without known implications for human health.After exclusion of duplicate titles , all titles were reviewed by one researcher for relevancy using the above inclusion and exclusion criteria. For those included articles, the abstracts were then reviewed to determine relevancy. All articles deemed relevant were then read in its entirety by a researcher to identify recurrent themes and proxies for measuring global health security. Using NVivo software and a qualitative coding framework developed from a priori themes derived from the JEE and previous global health security research, we coded the documents iteratively, adding new codes to the framework as we identified additional global health security themes and indicators. From the coding process, we synthesized foundational principles for measuring global health security.The qualitative coding framework containing all of the themes we identified, and a full list of documents reviewed are provided in Additional file Our search initially yielded 1092 articles from PubMed, 440 articles from OAIster, and 356 articles from Web of Science . We eliminated 396 duplicate documents, and, using the aforementioned criteria, eliminated another 1255 documents that were deemed irrelevant upon review of their titles and abstracts, producing a final set of 237 documents which were subsequently coded using NVivo 11 Pro qualitative software  pathogens has diminished the effectiveness of many first-line drugs. Thus, national standards, policies, and programs promoting antimicrobial stewardship  could help mitigate AMR threats, thereby strengthening health security , 34. AddMass gatherings present additional health security challenges by amplifying the risk of disease transmission both in host countries and countries of returning attendees. As such, the frequency of mass gatherings, as well as the size, location, duration, and season of gathering, could serve as another indicator for measuring countries’ health security vulnerabilities; for example, outbreaks of bacterial meningitis linked to annual Hajj pilgrimages resulted in global spread in 1987 and 2000 , 35. ImpIn addition to efforts addressing mass gatherings, the literature cited national programs targeting risks associated with biotechnology and the life sciences as similarly important components of global health security –40. The Historical experiences with infectious disease outbreaks can act as an impetus for biosecurity programs, policies, and funding needed to prevent future crises. For example, the September 2001 terrorist and anthrax attacks in the United States catalyzed increased spending and support for biodefense programs . HoweverAdditionally, early disease detection and prevention depends on collaboration and communication between health authorities at local, national, regional, and international levels. International norms and strategies play important roles in promoting international collaboration and communication; the IHR, for example, include a directive for signatories to help build health security capacities in resource-poor countries , 45. OthIn addition to norms, laws, policies, and regulations also shape health security approaches and outcomes (and vice-versa), and their presence or absence could further modulate a country’s ability to mitigate infectious disease threats. Anema notes, for instance, that many IHR signatories have met the specified core capacity requirements for establishing national legislation and policy; among these states, those which “centralized and harmonized their public health policies and practices” demonstrated greater capacities for overall IHR compliance . AdditioIn addition to highlighting linkages between law, policy, and global health security, the literature broadly affirmed the value of participation in global multilateral institutions  and compliance with international agreements aimed at strengthening global health security  , 46, 47.With respect to local and regional collaboration around global health security, the literature highlighted the importance of engaging civil society and private-sector stakeholders, law enforcement, the intelligence community, academia, and political leaders , 48, 49.Political leadership and commitment are instrumental in ensuring that health security remains a top priority. The U.S. federal government, for example, has launched global health programs, such as the President’s Emergency Plan for AIDS Relief, the President’s Malaria Initiative, the Global Disease Detection Program of the U.S. Centers for Disease Control and Prevention, and the Emerging Pandemic Threats Program through the United States Agency for International Development. Political support also helps ensure adequate funding for biosecurity programs, such as the U.S. Department of Defense Cooperative Threat Reduction Program Biological Threat Reduction Program and the U.S. Department of State Biosecurity Engagement Program. As such, the federal budget typically includes funds for “both biodefense and non-biodefense goals and applications,” which address a range of public health, healthcare, national security, and international security issues in addition to biosecurity, and improve preparedness and response , 51. GloFinally, legislative frameworks for biosecurity and biosafety may also be useful measures of country-level health security. The U.S. Federal Select Agent Program, for example, defines a set of microorganisms and toxins deemed to carry high risks of deliberate misuse and establishes strict security requirements for facilities working with designated high-priority agents; in 2017, the U.S. also implemented policies addressing oversight of pathogens with pandemic potential and enacted a brief moratorium on federally funded gain-of-function studies involving such pathogens , 58. SimIn addition, any legislative frameworks underpinning research should respect the rights of the individual, including ethical considerations when conducting human subject research, and also when implementing public health policies (i.e. quarantine and monitoring policies). Integration of such ethical considerations into legal frameworks will likely become increasingly important in the context of risks associated with biotechnology and the life sciences , 61.The interplay between built and natural environments, climate, and human and animal activity is a critical determinant of global health security –64, 46. Globalization was widely cited as a driving force behind transnational disease spread. Increasing travel, tourism, and trade were described as important promoters of economic growth, but ones that concomitantly elevate the risk of disease transmission among highly mobile populations connected through increasingly accessible modes of global transit . EffortsThe literature also identified urbanization, changes in land use, and evolving agricultural practices as important components of the health security risk environment, given their roles in modulating disease spread between humans and animals, and creating conditions that could enable emergence of novel zoonoses , 65, 66.Our review highlighted country-level considerations that could inform efforts to monitor global health security, including the presence of existing prevention, detection, and response capacities and capabilities; the presence of national programs, policies, and laws to mitigate various kinds of threats; coordination and communication between health authorities at all levels of government, as well as with other sectors (including public and private); political leadership that supports health security issues; as well as engagement in global multilateral institutions and an understanding of the risk environment.There was considerable overlap between the themes identified in the literature and priorities outlined in the Global Health Security Agenda (GHSA), IHR, and JEE tool. Generally, the literature affirmed that many of the goals and indicators specified in both are valuable benchmarks for assessing baseline, country-level health security capacities. The prevent-detect-respond paradigm articulated in the GHSA serves as a useful organizing principle for conceptualizing global health security, and the JEE tool puts forth a valuable methodology for measuring both health security capacities and country progress toward IHR targets. The JEE also rightly prioritizes inter-sectoral discussion between agencies of national governments and is intended as a tool to begin the development of a national action plan for health security containing specific milestones to be filled and financed over a specific set of timeframes. Given that the JEE consists of subjectively assigned scores based largely on qualitative observation, the comparisons between countries and over years of the JEE process over time remains in question. Therefore, in addition to the JEE, efforts to measure global health security over time might benefit from focusing on outcome-based metrics that capture a country’s demonstrated prevention, detection, and response capabilities during an infectious disease outbreak. With respect to syndromic surveillance, for example, the JEE considers the size and coverage of a given surveillance system, its electronic reporting capacities, and its methods of data validation; by contrast, Glassman suggests that a country measuring the effectiveness of its syndromic surveillance systems should consider metrics such as rates of disease underreporting or numbers of misidentified cases . Other sWe found little overlap between the global health security literature – which focuses primarily on acute infectious disease threats – and scholarly work on health system resilience, which encompasses a broader universe of core public health and healthcare assets and functions, such as health workforces, financing, universal health coverage, public risk communication, and integration between the sectors involved in mitigating infectious disease threats. Though our review yielded few tangible metrics for measuring healthcare sector performance, it did underscore the critical roles that healthcare capabilities play in strengthening country-level health security. As demonstrated during the 2014 Ebola outbreak, a healthcare sector’s ability to scale up operations in response to an accelerating threat, diagnose and isolate sick patients, and prevent the spread of infection in clinical settings – all while minimizing disruptions to routine healthcare delivery – are crucial determinants of an outbreak’s broader community impacts. However, current frameworks for assessing global health security – including the JEE – feature few indicators addressing core healthcare capacities and capabilities and their integration into emergency response activities. Given that a country’s infectious disease response capabilities depend on the broader functionality of its health systems, these core public health and healthcare capacities should figure more prominently in efforts to conceptualize and measure global health security. For example, researchers have already sought to identify global and public health core competencies for nursing education; a similar explication of core public health and healthcare functions essential to strengthening health security could enhance efforts to improve infectious disease threat mitigation .Notably, our review also highlighted the importance of the risk environment. Historically, the risk environment framework has been used in the context of drug-related harm reduction activities, HIV prevention, and assessments of global nuclear security , 70. HowIn addition to the conceptual challenges associated with measuring global health security, several practical barriers continue posing technical challenges. Even with a strong theoretical foundation, measurement efforts might still be hindered by limited data availability. Many of the metrics employed in the JEE and other tools – both qualitative and quantitative – are not regularly or systematically collected in a standardized manner. Though alternative metrics could support more conceptually sound methods of measurement, poor data availability would still preclude their adoption and meaningful use. International organizations that routinely collect needed metrics should accelerate efforts to identify high-priority data needs, collect said data, and make them readily accessible to the public; the private sector might play an important role in making greater data availability a reality. Finally, although measuring global health security is a critical step in progressing toward greater IHR compliance, measurement alone cannot improve country-level health security capacities. As such, measurement efforts should be linked to incentives (i.e. funding and programmatic support) that promote capacity-building across all sectors involved in infectious disease mitigation.Our investigation had a few limitations; namely, that the themes identified are a function of available published scholarship. The majority of the articles reviewed were produced by researchers representing predominantly high-income countries. As such, the literature skewed heavily toward themes  that may not be top health security priorities for policymakers in lower-income countries with differing health security threat landscapes  as compared to industrialized nations. Additionally, though we attempted to systematically review the gray literature, our search engines did not produce many of the foundational documents published by the WHO, ministries of health, and non-governmental groups in the health security space. Future efforts to measure global health security might benefit from additional, complementary modes of data collection, such as consultations with subject matter experts. This might also be useful in further refining those capacities and capabilities that are necessary in countries with poor healthcare and public health infrastructure. Finally, we acknowledge that there is ongoing debate over the definition of global health security itself, and that our inclusion and exclusion criteria – while reflective of the definition used by the WHO – might not have allowed us to identify literature proposing alternative definitions.In light of ongoing international initiatives aiming to enhance global capacities and capabilities for infectious disease preparedness and response, the evidence-based themes identified in this review could inform efforts to systematically assess the impacts and effectiveness of activities undertaken to strengthen global health security.Additional file 1: Coding Framework Coding Framework. The formal coding framework used to identify metrics in the literature for measuring global health security. The definition of each code is provided, along with the number of sources in which the code was used, and the number of times the code was used across all sources. (DOCX 29 kb)Additional file 2: GHS Literature Review. Comprehensive List of Literature Reviewed  The full list of gray & scholarly publications identified in our review. (DOCX 35 kb)


Colorectal cancer is a major health concern as a very common cancer and a leading cause of cancer-related mortality worldwide. The liver is a very common site of metastatic spread for colorectal cancers, and, while nearly half of the patients develop metastases during the course of their disease, synchronous liver metastases are detected in 15% to 25% of cases. There is no standardized treatment in this setting and no consensus exists on optimal sequencing of multimodality management for rectal cancer with synchronous liver metastases. Herein, we review the use of pelvic radiation therapy (RT) as part of potentially curative or palliative management of rectal cancer with synchronous liver metastases. There is accumulating evidence on the utility of pelvic RT for facilitating subsequent surgery, improving local tumor control, and achieving palliation of symptoms in patients with stage IV rectal cancer. Introduction of superior imaging capabilities and contemporary RT approaches such as Intensity Modulated Radiation Therapy (IMRT) and Image Guided Radiation Therapy (IGRT) offer improved precision and toxicity profile of radiation delivery in the modern era. Even in the setting of stage IV rectal cancer with synchronous liver metastases, there may be potential for extended survival and cure by aggressive management of primary tumor and metastases in selected patients. Despite lack of consensus on sequencing of treatment modalities, pelvic RT may serve as a critical component of multidisciplinary management. Resectability of primary rectal tumor and liver metastases, patient preferences, comorbidities, symptomatology, and logistical issues should be thoroughly considered in decision making for optimal management of patients. Colorectal cancer is a major health concern as a very common cancer and a leading cause of cancer-related mortality worldwide –4. CanceThe role of radiation therapy (RT) in the management of nonmetastatic locally advanced rectal cancers is well established; however, its utility in the setting of synchronous liver metastases needs elucidation. Herein, we address the utility of pelvic RT as part of potentially curative or palliative management of rectal cancer with synchronous liver metastases in light of the literature.The utility of RT has been well established in nonmetastatic locally advanced rectal cancer, and preoperative sequencing of pelvic irradiation rather than postoperative administration has been shown to reduce the risk of local recurrence and cancer related mortality –50. In tGiven the increased life expectancy of patients with metastatic stage IV rectal cancer treated in the modern era using more effective local and systemic therapies, addressing of the primary disease becomes more critical to improve patient comfort and quality of life with contemporary RT techniques allowing improved toxicity profile. Indeed, 7% of the study population consisted of patients with stage IV rectal cancer in the landmark Dutch trial assessing preoperative RT followed by TME, and reported rates of 2-year local recurrence were 10.1% and 23.8% for patients treated with or without preoperative RT, respectively . Other sSeveral studies investigating the omission of RT in the setting of nonmetastatic or metastatic disease consistently reported inferior outcomes, substantiating the utility of RT in multimodality management of rectal cancer –91. MoreSelected series incorporating pelvic RT in multimodality management of stage IV rectal cancer with liver metastases (with or without other distant metastases) as a palliative therapeutic strategy are summarized in Pelvic RT achieves effective palliation of symptoms due to primary tumor in stage IV rectal cancer. Two reviews focusing on studies conducted in different time periods (1949-1999 and 2011-2016) confirmed the palliative efficacy of RT for management of primary rectal tumor related symptoms .In the systematic review by Cameron et al. based on 27 studies, pooled overall symptomatic response rate was 75%, while response rates were 78%, 81%, 71%, and 72% for symptoms of pain, bleeding and discharge, mass effect, and other pelvic symptoms, respectively .Buwenge et al. reviewed more recently published series and reported response rates of 79%, 87%, and 78% for symptoms of pain, bleeding, and obstruction, respectively . In addiSynchronous liver metastases have been variably defined in the literature. Most common definition includes metastases detected at or before diagnosis of primary rectal cancer; however, metastases detected within 3 to 6 months of diagnosis have also been included in the “synchronous” group in several studies –101. ComDespite heterogeneity in patient and treatment characteristics in these studies, several conclusions may be drawn.Although with a very limited sample size, the study by Shin et al. using SCRT in multimodality management reported a high rate (84%) of R0 resection with no LR during the follow-up period .In the study by Fossum et al. including 93 patients, LR was not observed in patients receiving neoadjuvant RT, and omission of neoadjuvant RT was associated with development of subsequent LR .Overall, outcomes of 8 retrospective and 4 prospective studies reveal that pelvic RT may serve as a critical component of multidisciplinary management . ContempEven in the setting of stage IV rectal cancer with synchronous liver metastases, there may be potential for extended survival and cure by aggressive management of primary tumor and metastases in selected patients. Despite lack of consensus on sequencing of treatment modalities, pelvic RT may serve as a critical component of multidisciplinary management. Resectability of primary rectal tumor and liver metastases, patient preferences, comorbidities, symptomatology, and logistical issues should be thoroughly considered in decision making for optimal management of patients. Similar response rates in earlier and more recent palliative RT series suggest that the palliative efficacy of RT may not be neglected in the modern era and persists despite the availability of newer effective systemic treatments.Given the increased life expectancy of patients with rectal cancer and synchronous liver metastases, addressing of the primary tumor with pelvic RT may have utility as part of potentially curative management. SCRT may be preferred in this setting to avoid delaying of systemic treatment, and improving distant as well as local control may be attempted by use of intensified chemoradiotherapy regimens. Modern RT techniques offer excellent precision and accuracy with an improved toxicity profile.Backdating of liver surgery to be performed in the interval between RT and rectal surgery may be a viable therapeutic approach to shorten the overall treatment time and liver first strategies may be thoroughly investigated to avoid progression of liver metastases during the disease course. Intensification of systemic treatment with or without biological agents, immunotherapy, optimal dose and fractionation for RT, optimal sequencing, and combination of treatment modalities warrant further extensive research.


Little is known about the utilization of cardiac diagnostic testing in Brazil and how such testing is related with local rates of acute coronary syndrome (ACS)-related mortality.Using data from DATASUS, the public national healthcare database, absolute counts of diagnostic tests performed were calculated for each of the 5570 municipalities and mapped. Spatial error regression and geographic weighted regression models were used to describe the geographic variation in the association between ACS mortality, income, and access to diagnostic testing.From 2008 to 2014, a total of 4,653,884 cardiac diagnostic procedures were performed in Brazil, at a total cost of $271 million USD. The overall ACS mortality rate during this time period was 133.8 deaths per 100,000 inhabitants aged 20 to 79. The most commonly utilized test was the stress ECG , followed by catheterization , scintigraphy  and stress echocardiography . The majority of these procedures were conducted in large urban centers in more economically developed regions of the country. Increased access to testing and increased income were not uniformly associated with decreased ACS mortality, and tremendous geographic heterogeneity was observed in the relationship between these variables.The majority of testing for ACS in Brazil is conducted at referral centers in developed urban settings. Stress ECG is the dominant testing modality in use. Increased access to diagnostic testing was not consistently associated with decreased ACS mortality across the country. Acute coronary syndrome (ACS) and other forms of cardiovascular disease remain one of the leading causes of death and morbidity worldwide, currently accounting for one of every three deaths . One of Globally, the incidence of ACS is rising with better treatment of infectious diseases and development-related lifestyle changes that predispose to heart disease, such as obesity, hypertension, and diabetes . Brazil Brazil’s unified national healthcare system has developed several national health information systems containing comprehensive nationwide health-related data, which allows for the unique opportunity to perform large ecological studies about health systems challenges and outcomes. These national databases contain detailed registries of procedures, diagnoses, costs, deaths, and patient demographics for the entire country . The avaThis observational, cross-sectional, and ecological study utilized secondary data from 5570 Brazilian municipalities with spatial analysis techniques to investigate geographic association of ACS testing and mortality from 2008 to 2014. This time period was chosen due to changes in data collection systems that led to improved data quality beginning in 2008 ; 2014 isBrazil is the largest country in South America, occupying an area of 8,516,000 square kilometers with a total population of 190,732,694 persons, according to the 2010 Brazilian Census . Brazil’Socioeconomic data, specifically the gross domestic product per capita, at the municipality level were extracted from Brazilian Institute of Geography and Statistic (IBGE)  and the Testing rates per population of cardiac catheterization, stress electrocardiography (ECG), scintigraphy, and stress echocardiography were compiled by municipality from the Ambulatory Information System database (SIA)  Table 1Table 1. Additional data about public hospitals performing cardiac diagnostic procedures  were obtained. Geolocation and infrastructure data were obtained from Cadastro Nacional de Estabelecimentos de Saúde / National Register of Health Facilities . Fig 2 pAll socioeconomic and health indicators were normalized to the Brazilian population. Conversion from Brazilian reals (BRL) to US dollars (USD) was performed using 2017 values. ACS-related mortality rates, diagnostic procedure rates, and cost data were summarized using descriptive statistics. The population between 20 and 79 years of age was selected to adjust the mortality and procedure rates by 100,000 persons, as per American College of Cardiology and American Heart Association guidelines . All anakj is the distance between k and j, D k is the demand at location k that falls within the catchment, and S j is the capacity of supply of cardiac diagnostic testing performed at location j [To evaluate geographical availability of ACS diagnostic procedures, the two-step floating catchment area (2SFCA) method was used . The 2SFcation j .0 from location i and sum up the supply-to-demand ratios Rj at those locations to obtain the full accessibility AiF at demand location i. The final equation of accessibility index is [In the second step, the capability indices of all hospitals within 120 km from each municipality’s centroid were combined. For each demand location i, we search all supply locations j that are within the threshold distance dindex is :AiF=∑j∈accessibility index of cardiac diagnostic procedures for each municipality. A higher accessibility index indicates more access to cardiac diagnostic testing for a given municipality. The 2SFCA method was performed for each of the four procedures considered  using the average rate of procedures between 2008 and 2014. Choropleth maps were generated using software ArcGIS 10.5 to visualize the accessibility index to the ACS diagnostic procedures.This produced an Geospatial based regression models were used to model the effect of income and accessibility indices of each diagnostic modality on ACS mortality. These models use multivariate regression to evaluate associations between predictors  and ACS mortality rate taking into account any spatial dependency. Spatial dependency is observed when one variable behavior  in one given geographical space  is dependent on the behavior of that variable in the neighboring geographic spaces. In other words, spatial dependency occurs when the likelihood of a municipality having a high ACS mortality rate coincides with high ACS mortality rates of its neighboring municipalities. The Jarque-Bera method was used to test the multivariate normality of the residuals of the models, while the Breush-Pagan and Koenker-Basset tests were used to evaluate heteroscedasticity. Finally, Moran’s I and the Lagrange multiplier test were used to evaluate the spatial dependency of the models.Initially, we analyzed the data with an Ordinary Least Squares model (OLS) without taking into account the spatial dependency. Given that the data showed high spatial autocorrelation of the residuals, two geospatial regression techniques were used. The first technique was the spatial error regression model which produces a regression model where the spatially correlated errors are controlled for and included in the model as an indicator. This analysis performs a global analysis of the entirety of the Brazilian geographical area, adjusting for the geospatial dependency.However, since the spatial error model still showed high heteroscedasticity, measured by the Koenker-Basset test, we used the second geospatial regression technique. The Geographically Weighted Regression (GWR) model, which controls for non-stationarity by conducting multiple separate post hoc regressions for sub-areas within the global geographical area (Brazil). The fixed distance bandwidth considered for the GWR analysis was 363 kilometers. Each separate regression model is calculated aggregating the municipalities that are clustered together based on their outcome behavior . This method yields an estimation for the association of ACS mortality rate and the predictors for each municipality. The performance of the GWR model was evaluated based on the adjusted R2 indicators, Akaike’s information criterion parameters (AICc) and Moran’s I of the residuals. Sensitivity analyses were conducted by comparing the model to a standard Ordinary Least Squares (OLS) model. The spatial self-correlation and OLS model were processed using GeoDa software 1·10·0·8 , and the GWR model by GWR 4·0.22. Choropleth maps were created using QGIS 2·14 software.From 2008 to 2014, there were 714,670 ACS-related deaths in Brazil with an overall mortality rate of 133.8 deaths per 100,000 inhabitants between 20 and 79 years of age. Most of the deaths occurred in the South, Northeast and Southeast regions . The NorDuring this time period, a total of 4,653,884 cardiac diagnostic procedures were performed in Brazil, at a total cost of $271 million USD . These pThe spatial distribution of the four ACS diagnostic modalities and ACS-related mortality rates observed from 2008 until 2014 are presented in The accessibility indices for cardiac diagnostic procedures were higher in the more economically developed regions of the South and Southeast regions . Stress The association between ACS-related mortality, income, and accessibility of cardiac diagnostic modalities tested through the unadjusted OLS model showed high spatial dependency, with low adjusted R-squared and higher AIC. The unadjusted OLS model found that higher ACS-related mortality was associated with lower income, lower access to scintigraphy, higher access to catheterization and high access to stress ECG testing . HoweverIn the post hoc type analysis of the GWR model, higher ACS-related mortality rates were associated with higher income and increased access to stress echocardiography and stress ECG, as well as decreased access to catheterization and scintigraphy. However, the standard deviations of the estimated coefficients are large indicating an heterogeneous distribution of the locally estimated association. This is the first nation-wide analysis of the geospatial distribution of the utilization of various cardiac diagnostic modalities and its association with local ACS-related mortality. It is performed in Brazil, the fifth most populated nation in the world , with a As expected with Brazil’s public health system’s centralization of testing facilities, accessibility to cardiac testing was largely limited to urban areas and was extremely variable across the country. Large segments of rural and underdeveloped areas of the country did not have access to either stress echocardiography, scintigraphy or cardiac catheterization, while there was abundant access to testing in urban centers such as Sao Paulo, Rio de Janeiro and other regions around large cities. The uneven distribution of test utilization observed in Brazil is not unique and has also been described in high income countries such as the United States . AlthougIn our analysis, the relationship between ACS mortality and access to cardiac diagnostic testing was complex and not geographically uniform. Although stress testing is widely used in high income countries, recent evidence suggests that increased utilization of such testing is not associated with lower cardiovascular mortality in such settings –32. To oAlthough ACS mortality rates also tended to be higher in more urban areas in Brazil, access to testing and local ACS mortality rates were often not well matched. For example, large segments of the South, Southeast, Center West and Northeast regions of the country were characterized by relatively high rates of ACS-related mortality but very limited access to cardiac diagnostic testing. These underserved areas warrant particular attention from public health officials when planning to expand cardiac diagnostic testing. Expansion of the existing network of hospitals with advanced cardiac capabilities must be considered to ensure that all Brazilians can have prompt access to potentially life-saving procedures (particularly catheterization) in the event of cardiac emergencies. Alternatively, we must also consider that potentially prolonged wait times for diagnostic testing in the public system, inappropriate use of stress testing, differences in test sensitivity and specificity, and variable adherence to diagnostic algorithms could also potentially explain the observed absence of association between access to testing and ACS mortality. As such, if expansion were to occur, additional research is needed to determine the benefits of stress testing on cardiovascular mortality, or whether targeted strategies and locally-developed appropriate use guidelines might result in a reduction in morbidity and mortality in these countries. In the meantime, public health officials should also consider devoting limited resources to strategies with proven mortality benefits in both high and low income countries, such as control of risk factors like hypertension, diabetes, and tobacco use –37.Similarly, we secondarily noted no overall nationwide association between income and ACS mortality. This observation stands in contrast to data from other global comparison studies that have found that cardiovascular mortality tended to be lower in higher income settings –40. The Due to the retrospective, observational nature of this study, the findings presented here are accompanied by some limitations. First, our findings demonstrate associations and causality cannot be determined. Thus, any locally observed association between access to testing and increased or decreased ACS mortality does not imply that the presence of such testing caused the observed local ACS mortality rate. Although DATASUS is meant to be a comprehensive and accurate database, the quality of this dataset is dependent on uniform and reliable data collection. Even if reporting of utilization of diagnostic testing were perfectly accurate, reporting of ACS-related mortality is contingent upon accurate diagnosis. It is possible, therefore, that areas with poor access to cardiac testing may be subject to lower reported rates of ACS-related mortality simply due to under-detection. Furthermore, because of the de-identified nature of the data used here, analysis of the association of an individual’s socioeconomic status with testing utilization and ACS mortality was not possible, because the sociodemographic profiles of individual patients were not available. Thus, the average income of the individual’s municipality was used as a proxy measure for socioeconomic status, but more granular data would have allowed for a more robust analysis of the interactions of personal wealth, utilization, and mortality. The use of an approach based on the 2SFCA has some limitations, particularly lack of accounting for distance decay within a catchment; and failure to allow for variable catchment sizes or variable application of distance-decay . HoweverIn Brazil, great variation exists in the distribution of ACS-related mortality and the utilization of cardiac diagnostic testing. As Brazil faces rising rates of risk factors for coronary artery disease that accompany rapid development, optimizing use of resources for cardiovascular care will become only more important. Access to testing was limited largely to specific developed areas, but increased access to such testing was overall not associated with geographically consistent reduction in ACS mortality. Given the lack of mortality benefit observed in this study, consistent with the results of analyses in high income countries, any expansion of advanced cardiac diagnostic testing in Brazil should be accompanied by rigorous post-expansion analysis to measure impact on local morbidity and mortality. Future research should focus on developing evidence-based strategies for the use of advanced cardiac testing in low and middle income countries.S1 Fig(TIF)Click here for additional data file.