In a dramatic reversal of longstanding trends, cancer now kills more Africans than malaria. Despite Africa’s growing cancer burden, individuals of African descent, notably those residing in Africa, remain drastically under-represented in cancer clinical trials. Two recent summits—the 1st All Africa Clinical Trial Summit and the Operational Strategy for Clinical Trials in Nigeria Summit—convened experts from governments, the private sector, universities, and professional societies to define the barriers to Africa’s participation in multicenter clinical studies and the strategies to eliminate those impedances.The discussions held during the two clinical trial summits were condensed into a set of 10 recommendations covering five broad categories . In this article, four programs are presented as examples of how the summits’ recommendations can be put into practice to improve Africa’s ability to attract clinical trials, in particular, cancer clinical trials.These example programs all leveraged a multilateral, Africa-driven approach to building Africa’s clinical trial capacity, increasing visibility of Africa’s current clinical trial capabilities and priorities, improving regulatory infrastructure and enforcement on the continent, and optimizing patient and clinician engagement strategies.The four programs are anticipated to catalyze the involvement of more African health care sites in cancer clinical trials, enroll a greater number of African patients with cancer in those trials, and, ultimately, reverse Africa’s growing cancer incidence and mortality rates. Each program acts as a blueprint for organizations—whether government, academic, or industry—seeking to address the summits’ recommendations and increase Africa’s contributions to and active participation in clinical research. In 2018, the US Food and Drug Administration estimated that only 4% of patients enrolled in clinical trials that led to the approval of new cancer drugs were of African descent.2 Similarly, of the 68,673 cancer studies listed in Clinical Trials.gov, < 2% (917) were conducted on the African continent.3 Of these 917 studies, the majority were performed in South Africa and Egypt.4Clinical trials are integral to the development of safe and effective medical treatments and technologies and are necessary to improving clinical care outcomes and identifying solutions to disease management challenges. These studies are also an essential cancer treatment modality, with the National Comprehensive Cancer Network noting that the best option to manage patients with cancer is through clinical trials.Key ObjectiveAre cancer clinical trials in Africa possible, and, if so, what can be done to encourage the engagement of African clinical sites in cancer studies?Knowledge GeneratedCancer clinical trials are, to a limited extent, underway in Africa, but the involvement of a greater number of sites and countries is needed to adequately assess new cancer innovations across all African ethnicities. Programs are underway to map and build clinical trial capabilities in Africa, with the goal of increasing the number of clinical trials performed on the continent.RelevanceWith Africa’s cancer mortality rate predicted to double by 2040, more clinical trials on important cancer innovations can—and must—be conducted in Africa.5 These three cancers are linked to infectious agents and are more prevalent in HIV-positive individuals.7 Beyond HIV/AIDS-associated malignancies, women of African descent are diagnosed with higher rates of triple-negative breast cancer than other ethnicities.8 Men of African descent are disproportionately affected by prostate cancer and have poorer outcomes.9 The risk of dying as a result of cancer before the age of 75 years in Africa is nearly double that of the risk to individuals living in a high development index country.11Despite these statistics, individuals of African descent, in particular those living on the African continent, are disproportionately affected by cancer. The age-standardized incidence rates of Kaposi’s sarcoma are ten times higher, cervical cancer rates are four times higher, and liver cancer rates are 24% higher in Africa than in the United States.12 Although cancer risk, incidence, and survival are known to differ across ethnicities, more troubling are recent predictions that demonstrate an inverse correlation between the drug resistance and susceptibility of lung cancers from patients of European and African descent.13 Clinical trials with subjects of diverse racial and ethnic backgrounds are thus imperative to ensuring that new cancer treatments are equally safe and efficacious across all patients with cancer.These statistics are the result of many complex and interrelated factors, including inadequate health care systems in Africa and African ethnicities’ unique, intrinsic tumor genetics and biologies.In recognition of Africa’s limited involvement in clinical trials, two summits—the 1st All Africa Clinical Trial Summit and the Operational Strategy for Clinical Trials in Nigeria Summit—were held to define Africa’s clinical trial capabilities and gaps and conceptualize strategies to encourage the performance of clinical trials on the continent. Both meetings were attended by key opinion leaders and experts from government health, science, technology, and regulatory agencies; the private sector; universities; and professional societies from seven countries . These e15 We have reviewed these proceedings reports, organized the expert recommendations on the basis of their underlying themes, and distilled the themes and recommendations into five broad categories: funding, regulation, capacity building, Africa-centric approach, and patient engagement  to evaluate African cancer hospitals’ clinical trial “readiness” and promote the hospitals’ capabilities to private industry and international academic investigators.In partnership with African ministries of health and cancer hospitals, private industry, and global oncology experts, BIO Ventures for Global Health (BVGH) launched the African Consortium for Cancer Clinical Trials (AC3T Checklist) to evaluate African hospitals’ management capabilities for clinical trials and patients with cancer , length, questions, and language. The checklist has since been reformatted (PDF), and questions whose responses would be of limited use to external investigators were removed. The checklist is also being translated into French and Portuguese to expand its accessibility to Africa’s francophone and Lusophone countries. Additional refinement to the tool will be made as BVGH receives additional checklists from sites across Africa.To date, 15 of the 24 hospitals have returned their checklists Appendix . On reviWith the pilot complete, BVGH has begun distributing the updated checklist to a wider array of hospitals and clinical research sites, including institutions within the European and Developing Countries Clinical Trials Partnership (EDCTP) networks of excellence. BVGH is also broadening its outreach to institutions without cancer capacities in an effort to increase the number of sites assessed. Although not currently suitable for clinical trials assessing novel cancer treatments, these sites could host studies to assess new cancer diagnostics and vaccines as well as behavioral and epidemiologic studies.3T Checklist also highlights hospitals’ clinical infrastructure, processes, and human resources deficits. Using the results of the AC3T Checklists, BVGH has begun organizing training projects customized to address responding hospitals’ core competency gaps. Each training project leverages BVGH’s alliance and program management experience and the oncology expertise of its partners. For example, BVGH’s assessments revealed that a hospital in Côte d’Ivoire required additional training, laboratory workflow management, and capital investment to improve its diagnosis of patients with cancer. Working with the American Society for Clinical Pathology, BVGH organized a workshop, fellowship, and equipment placement at the Côte d’Ivoire hospital. Each of these activities was specifically undertaken to help the hospital eliminate a competency gap and achieve the standards of diagnosis necessary for the conduct of cancer clinical studies.In addition to promoting hospitals’ clinical trial proficiencies, the AC18 As a global consortium, CaPTC has > 150 members from 15 countries, including a significant presence in Africa. Members include prostate cancer clinicians, scientists, and advocates with complementary expertise and resources who are working collaboratively to eliminate the disproportionate burden of prostate cancer globally. The primary goal of CaPTC is to explore the genetic and environmental etiology of prostate cancer and to develop ethnically sensitive, targeted approaches that will eliminate prostate cancer disparities globally in men of African descent.The Prostate Cancer Transatlantic Consortium (CaPTC) is a National Institutes of Health/National Cancer Institute Epidemiology and Genomics Research Program–supported consortium founded in 2005 to address the complexity of cancer health disparities and the need for a unique approach to better understand and address complex chronic diseases.To achieve the primary goal of CaPTC, the consortium has set a 2020 goal of enhancing the engagement of individuals of African descent in cancer clinical trials. The challenges of conducting cancer clinical trials in Africa are multifaceted and formidable, with the most significant challenge being the lack of cancer clinical trial expertise on the continent. CaPTC has developed and implemented a series of clinical trial workforce development programs to build a cohort of African cancer leaders who can make a significant impact on clinical trials research, education, and training in Africa. The training programs are varied to meet the needs of Africa’s oncology workforce. In late 2018, CaPTC implemented a webinar series targeting African investigators and clinicians. The series covered a range of topics, including the practical steps to implementing clinical trials, the role of clinical research organizations, patient advocacy, tips for successful clinical trials in Africa, and operational considerations and technology innovations for clinical trials.In partnership with the University of Cape Town, CaPTC organized the African Oncology Clinical Trials (AfrOCT) Leadership Training and Development Program. The AfrOCT program aims to implement a didactic training program on the design and funding of clinical trials and to provide experiential training on the execution and management of clinical trials. The learning objectives of the program are to: (1) instill an understanding of clinical trial management processes, inclusive of critical documentation required for efficiency; (2) provide on-site experiential training and link participants with an assigned mentor; (3) provide information on potential business models for clinical trial units; (4) discuss methods for overcoming perceived barriers and challenges expressed by trainees; and (5) develop short- and long-term performance indicators with delegates for program evaluation and future training needs.19 CaPTC is currently developing and testing the usability of its Oncology Clinical Trials AppConnect (OnCTAC), which will help African patients and health care professionals search for cancer clinical trials and connect with clinical trial staff via a smartphone application.Beyond organizing training opportunities for African clinical research professionals, CaPTC has also focused on improving clinicians’ and patients’ access to clinical trials in Africa by developing a virtual cancer clinical trial map. With funding from the Carnegie Corporation, CaPTC investigators created a database of African cancer clinical trials infrastructure, resources, and research sites. As a part of this project, a study was performed to identify ongoing cancer clinical trials in Africa. The quantitative, web-based, retrospective review of clinical trial registries documented a total of 109 open cancer clinical trials in Africa , with mo20 CaPTC developed the African Community Cancer Research Engagement and Support (CCaRES) Network to facilitate linkages between researchers and clinical trial participants and improve adherence to GCP standards. The African CCaRES Network is composed of a participant data warehouse and a scientist information database linked by CCaRES informatics and provides a community-centric system that will educate and direct participants to appropriate, institutional review board (IRB)–approved biomedical research. Five services will be provided through the African CCaRES Network: clinical trial education, enrollment, navigation, matching, and monitoring/follow-up services. The African CCaRES Network will use best practices for patient recruitment, enrollment, and retention in Africa and collect data on and continuously address individual-level barriers that influence clinical trial participation in Africa.Achieving international good clinical practice (GCP) standards is a necessary checkpoint for a site seeking to conduct clinical trials, and yet in Africa there is incomplete compliance with GCP standards, such as those for subject recruitment and enrollment.Established in 2006 and hosted by the University of Nigeria, Nsukka, Enugu campus, the Association for Good Clinical Practice in Nigeria (AGCPN) seeks to encourage the performance of clinical trials in Nigeria by supporting the training of clinical research professionals, advocating for the improvement of Nigeria’s clinical trial infrastructure, increasing global visibility of Nigeria’s clinical trial capabilities, and creating a coordinated and collaborative network of clinical research professionals.AGCPN conducts annual in-person and in-house trainings in GCP, health research ethics, and biostatistics. These trainings are complemented by online educational opportunities offered through a partnership with the University of Miami’s Collaborative Institutional Training Initiative. With funding from EDCTP, AGCPN has also provided certified health research ethics training for 36 IRB members from 18 institutions across Nigeria. AGCPN’s trainings focus on introducing local content germane to African culture, especially as the trainings relate to study subject engagement.As Nigeria’s premier organization responsible for shaping and driving the development of the country’s clinical trial system, AGCPN has built relationships with relevant government agencies and parastatals and provides those entities with guidance and assistance. In particular, AGCPN has supported Nigeria’s National Agency for Food and Drug Administration and Control (NAFDAC) by assisting the agency with the revision of its clinical trial regulations (2010), performing a gap analysis of NAFDAC’s clinical trial unit (2012), and supporting NAFDAC’s launch of the Nigerian Clinical Trial Technical Working Group (2015). AGCPN has also been leading advocacy efforts in Nigeria for the introduction of improved research facilities, multidisciplinary professional infrastructures, standards for GCP designed to protect clinical trial participants, and provision of rigorous and robust clinical trial regulations.Emulating China and India’s strategy of increasing their global visibility through clinical trial summits, AGCPN also launched its first Clinical Trial Summit in 2012. The event convened clinical research professionals from across Nigeria for education and networking opportunities, as well as to highlight the clinical trials ongoing and concluded in Africa’s most populous country.Noting that the African clinical trial sector needs to apply a coordinated, collaborative, continent-wide strategy that mirrors the African Union vision for a developed and economically integrated Africa, AGCPN launched the AGCPN–Clinical Trial Africa (CTA) Vision 2020 Initiative. With signatories from Cameroon, Benin, Ghana, and Nigeria, this initiative was established in 2016 to provide a platform for sustained advocacy, networking, and engagement of relevant stakeholders to nurture African development of African solutions to Africa’s health challenges for both communicable and noncommunicable diseases. The Initiative catalyzes dialogue between sponsor organizations, companies, African governments, and other relevant influencers and led to the formation of the African Clinical Trial Consortium (ACTC) in 2017.21 Beyond the rigorous assessment of natural medicines, other anticipated benefits of ACTC include the expansion of Africa’s cost-effective clinical capabilities that meet global standards, acceleration of clinical trial timelines in Africa, incorporation of a translational research mentality into Africa’s research institutions, and additional definition and institutionalization of the continent’s regulatory systems.Similar to the AGCPN-CTA Vision 2020 Initiative, the mission of ACTC is to promote, nurture, and sustain a continent-wide advancement of health research through the efficient use of local knowledge garnered from the public and private sectors. ACTC focuses on addressing the low number of clinical trials occurring in Africa and developing innovative models for the certification and strategic oversight of clinical trial sites on the continent. ACTC has prioritized the creation of dedicated clinical trial units in Africa and the growth of Africa’s natural medicinal product development. The latter effort was fostered by engaging with Nigeria’s Natural Medicine Development Agency within the Federal Ministry of Science and Technology, natural medicine developers and practitioners, and research clinicians to explore investigator-initiated studies on Nigerian natural products.AGCPN’s efforts in the African clinical trial ecosystem have spanned over two decades and have focused on building the infrastructure for global engagement of Nigeria in single-center and multicenter clinical trials. Through its resultant initiatives, AGCPN-CTA Vision 2020 Initiative and ACTC, AGCPN’s impact has extended beyond Nigeria’s borders. In time, it is expected that additional countries beyond the initial four signatories will join AGCPN’s initiatives, thereby expanding their trainings continent-wide.22 If African cancer hospitals are to attract international cancer clinical trials, regulatory frameworks must be in place at the institutional and the national level. African countries without such oversight should take advantage of multinational entities, such as the Pan African Clinical Trial Registry and EDCTP, as well as leverage the experiences and learnings of their nearest neighbors to guide their installation of clinical trial oversight authorities. Ghana’s introduction of regulations and oversight authorities into its national health and research systems is a strategy that other African countries can emulate as they begin to adopt their own clinical research regulatory systems.Proper regulation and oversight are essential to ensuring clinical trials are conducted with the highest standards of care and achieve clinically relevant and actionable data. All African countries, with the exception of the Sahrawi Arab Democratic Republic, have functioning medicine review agencies. However, their authorities to regulate clinical trials within their countries are varied. Only 17 of 55 African countries have regulatory agencies with control over clinical trials .22 If Af23 The majority of clinical trials performed in Ghana to date have focused on communicable disease interventions, such as the 1968 study, which assessed chloroquine resistance in malaria parasites circulating in Axim, Ghana.24 Oncology-related clinical trials were first recorded in the 1970s and focused on childhood Burkitt lymphoma, including a study on high-dose cyclophosphamide to treat resistant and relapsing Burkitt lymphoma.25Clinical studies have been reported in Ghana since the 1960s, with the earliest interventional study reported in 1968.26 Subsequent to this, the Noguchi Memorial Institute for Medical Research (a semiautonomous branch of the University of Ghana) and Navrongo Health Research Center established their IRBs.28 Additional research institutions and universities eventually began to establish their own IRBs. In 2012, the Ghanaian Legislature further reviewed the Food and Drugs Act and incorporated it into a new law , which broadened the FDB’s clinical trial regulatory activities and transformed the FDB into the Food and Drug Authority (FDA).30 The FDA currently regulates all clinical trial activities in the country and must issue a clinical trial authorization certificate before a clinical study can commence. To receive the certificate from the FDA, the principal investigator, who must be a Ghanaian, must register the study with Pan African Clinical Trial Registry and receive IRB approval from the facility or site at which the study will be conducted.These clinical studies were implemented despite the absence of rigorous nationwide or institutional clinical trial regulations and ethics guidelines. In 1992, the Ghanaian Ministry of Health established the Food and Drug Board (FDB) through the Food and Drugs Act  to regulate clinical trials in Ghana.In concert with the country’s clinical trial policy changes, Ghana began implementing training programs on GCP. Before this, there were minimal opportunities to receive GCP training in the country; most research institutions opted to send their clinical trial staff abroad for the training. Now, as a component of its mandate, the FDA conducts GCP trainings, including “train the trainer” programs. The FDA also now requires that all clinical research teams have GCP certificates before a clinical trial authorization certificate will be issued.3T is mapping clinical trial capabilities across Africa and promoting those capabilities to external investigators. AC3T, AGCPN, and CaPTC are building clinical trial capacity in Africa, while also creating continent-wide clinical trial networks. Through ACTC, AGCPN is building an environment in Nigeria that encourages rigorous clinical assessments on traditional medicines. CaPTC’s OnCTAC is helping connect African patients with cancer and health care providers with open clinical trials. Last, Ghana’s process of establishing a clinical trial regulatory system provides a roadmap for other African countries seeking to improve the regulation of clinical trials within their borders.The four programs described above collectively address many of the challenges identified by the participants of the 1st All Africa Clinical Trial Summit and the Operational Strategy for Clinical Trials in Nigeria Summit . In part3T Checklist with the administrators of AGCPN and CaPTC to ensure their sites are profiled and promoted online. Profiled sites not in compliance with GCP standards will be connected with CaPTC and encouraged to use its CCaRES program. AGCPN, BVGH, and CaPTC will jointly explore the cultivation of online training programs covering topics identified as frequently lacking via the AC3T Checklist. Last, to ensure these activities improve the number of rigorous cancer clinical trials performed across Africa, the involvement of the African Organization for Research and Training in Cancer in these programs will be explored.Although this article describes several programs that are improving Africa’s clinical trial environment, it is important to note that this is not an exhaustive review of such programs. Indeed, many other programs, such as the EDCTP, are improving clinical trial systems and infrastructure within Africa. Furthermore, none of the programs described above currently cover all African countries. As such, a concerted effort must be made to connect relevant initiatives, including those described in this article, to share best practices, minimize duplication, and ensure even coverage across Africa. To this end, BVGH has shared its ACIt is also important to note that, although the two summits highlight factors that are likely to affect Africa’s future participation in clinical trials, they do not comprehensively capture all facets of the continent’s clinical trial landscape. Geographically, both summits were limited in representation and scope. The Operational Strategy for Clinical Trials in Nigeria Summit focused on Nigeria’s clinical trial challenges and opportunities. The 1st All Africa Clinical Trial Summit involved participants from a limited number of African countries. Both summits plan to expand their involvement of additional African countries in the future. In addition, neither summit systematically reviewed and debated all possible factors that affect Africa’s clinical trial participation, yet neither summit was organized with this goal in mind. In the absence of a comprehensive assessment of Africa’s clinical trial challenges and limitations, the recommendations of these two summits’ participants will help to highlight areas of need and opportunities to make a significant impact on the ability of the African continent to attract and conduct clinical trials, including those focused on new cancer interventions.32 These falling mortality patterns are due, in large part, to the development of new innovative cancer treatments. Unfortunately, with experts predicting Africa’s cancer mortality rate to double by 2040, Africans are not reaping the benefits of these innovations to the same degree as other populations.33 Ensuring proportionate enrollment of individuals of African descent in clinical trials will undoubtedly contribute to the reversal of Africa’s disturbing cancer trends.Cancer mortality rates in high-income countries, such as the United States and Canada, have declined significantly over the past three decades.Novel strategies, incentives, and programs are essential to increasing the number of clinical trials conducted in individuals of African descent—in particular, those living in Africa. The two summits and four programs described in this article have highlighted several of the challenges Africa faces in increasing its clinical trial participation and, more importantly, concrete Africa-driven solutions to those challenges. These solutions include building capacity across all levels of the cancer care system. Governments must play an active role by establishing regulatory guidelines and appointing the appropriate entity to enforce those guidelines. Connectivity is key; the augmentation of Africa’s clinical trial output will require the coordinated engagement of all relevant stakeholders, including African government agencies and cancer clinicians, pharmaceutical companies, international cancer experts, and patients with cancer. Improved visibility of Africa’s cancer burden and available clinical trial infrastructure will catalyze the pharmaceutical industry’s interest and demystify entry into the African clinical trial field. Last, and most importantly, collaboration, evaluation, and the sharing of lessons learned will drive clinical trial growth across the continent and, eventually, result in improved outcomes for patients with cancer in Africa and beyond.


Nigeria's digital soil map (DSM) and database is the most comprehensive and detailed source of quantitative information on the country's soil distribution. Digital cartography and geographic information system (GIS) operations were methods used in producing the DSM and database. We obtained analogue soil data in 8 hard copy maps  from the Federal Department of Agricultural Land Resources (FDALR), which archived the result of Nigeria's reconnaissance soil survey. The survey started in 1985 and by 1990; it has completed the compilation of hard copy maps that outline Nigeria's major soil distribution. Our experimental design begins with electronic scanning of these paper maps. We set the scanning system to 500 dpi, creating high-resolution raster images, which were imported into ESRI ArcGIS software, for orthorectification by geo-referencing to WGS 1984 geographic coordinate system. We applied a spatial processing tool on the orthorectified images and created a geometrically-seamless mosaicked raster image for the soil data of the whole Nigeria. Using GIS on-screen digitization – with optimal snapping tolerance – we created vector polygons  of soil components (mapping units). Finally, we coded the metadata (attributes) of Nigeria's soil distribution into Microsoft EXCEL spreadsheet, which we linked to the soil spatial data. The combined spatial and attribute soil data forms the soil database for Nigeria and provides, on-demand, vital soil information, such as thematic maps of soil characteristics. The department of Geoinformatics and surveying University of Nigeria, Enugu Campus (UNEC) is the major repository of Nigeria's DSM and database. Specifications TableValue of the Data•Nigeria's DSM data and database represent a geo-spatial infrastructure, providing a quick, dynamic, quantitative, easily accessible and adaptable soil information platform for agricultural and land-related purposes in Nigeria. The DSM data solve the cartographic and qualitative limitations inherent in the 1990 soil data compilation, which makes it difficult to blend easily for updating and more scientific operations •Nigeria's DSM data and database are of primary value to those working on improving food security through soil suitability assessment, mechanised farming and selective cropping for sustainable land resources management •Considering its quantitative nature, Nigeria's DSM data and database allow users to both explore and interact with its derivatives •Evidence from •Nigeria's DSM data offers flexibility for data sharing, data hosting on the internet, and integration into regional and global digital soil mapping programmes. As well as being able to provide thematic datasets based on soil properties in Nigeria, the digital soil database enhances the knowledge and value of Nigeria's soil for a myriad human and land-related needs. This will help to resolve complex environmental issues consistent within local and regional geological and geomorphological characteristics such as erosion, landslide and drought 1Nigeria's DSM data and soil database of Nigeria is a predictive or computer-assisted digital depiction of Nigeria's soil types, properties and spatial distribution. In this novel DSM data and soil database, secondary data in the form of compiled hard copies, derived from the 1985 reconnaissance soil survey are transformed into vectors and symbols encoded and held as data structures within the map layout. The DSM data and its database hold information relating to the Nigerian soil in geographically referenced numerical format. Thus, it delineates quantitatively and interactively the 58 soil components (soil mapping units), based on three ecological zones, twenty-four broad geomorphic units and parent materials in Nigeria. These soil mapping units are numbered from ‘1a’ to ‘24b’ and provides much quantitative information for environmental modelling and analyses using the Nigeria's DSM data and database , soil classification (USDA and FAO), pH scales  and ecological zones . In this article, we present 2We obtained analogue soil data in 8 hard copy maps  from the Federal Department of Agricultural Land Resources (FDALR). These maps, along with the secondary information that describes the soil characteristics are the key primary input to the Nigerian DSM and soil database. These inputs were derived from the Nigeria's reconnaissance soil survey which was completed in 1990. Our experimental design begins with electronic scanning of these paper maps. We set the scanning system to 500 dpi, creating high-resolution raster images, which were imported into ESRI (Erath System Resource Institute) ArcGIS software, for orthorectification by geo-referencing to WGS 1984 geographic coordinate system. We applied ArcGIS spatial processing tool on the orthorectified images and created a geometrically-seamless mosaicked raster soil image for the whole Nigeria. Using the on-screen digitization – with optimal snapping tolerance – we created vector polygons  of soil components (mapping units). Finally, we coded the metadata (attributes) of Nigeria's soil distribution into Microsoft EXCEL spreadsheet, which we linked to the soil spatial data. The table of soil characteristics description was then linked to the vector features to form the digital Nigeria soil database. Although ESRI ArcGIS is a proprietary software, its versatility, easy to use modes and abundance of toolsets made it a preferred software in the experimental design and development of Nigeria's DSM. Not applicableThe authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article.


Both allergic diseases and neurodevelopmental disorders are non-communicable diseases (NCDs) that not only impact on the quality of life and but also result in substantial economic burden. Immune dysregulation and inflammation are typical hallmarks in both allergic and neurodevelopmental disorders, suggesting converging pathophysiology. Epidemiological studies provided convincing evidence for the link between allergy and neurodevelopmental diseases such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Possible factors influencing the development of these disorders include maternal depression and anxiety, gestational diabetes mellitus, maternal allergic status, diet, exposure to environmental pollutants, microbiome dysbiosis, and sleep disturbances that occur early in life. Moreover, apart from inflammation, epigenetics, gene expression, and mitochondrial dysfunction have emerged as possible underlying mechanisms in the pathogenesis of these conditions. The exploration and understanding of these shared factors and possible mechanisms may enable us to elucidate the link in the comorbidity. Both allergic diseases and neurodevelopmental disorders are non-communicable diseases (NCDs) that pose a serious economic burden and impact quality of life –4. AllerImmune dysregulation and inflammation have been well-documented as typical hallmarks in both allergic and neurodevelopmental conditions. Activation of basophils, mast cells, and eosinophils in allergic diseases release pro-inflammatory factors and cytokines . ElevateDiagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) criteria, a child is diagnosed with ADHD if he presents six or more symptoms of inattention, hyperactivity and impulsivity, or both for a period of at least 6 months that has affected daily activities and functioning appropriate for age , Wei et al. studied 8,580 mother–infant pairs to investigate the link between maternal depressive symptoms during pregnancy and subsequent AD development in the infant at 12 months . They foAnalogous associations have been reported in studies involving ADHD subjects. Van der Bergh and Marcoen found prenatal maternal anxiety to be significantly associated with ADHD traits at 8 and 9 years old . ElevateGestational diabetes mellitus (GDM) has been reported to be a risk factor for both allergic diseases and ASD. A positive association was found between GDM and development of asthma and wheezing in the offspring , 52. TheThe influence of maternal allergy on the development of allergic diseases in the offspring is well-documented. An analysis in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort comprising 553 mother–child pairs showed that offspring born to mothers with allergic history had elevated risks of developing asthma . AnotherEnvironmental factors such as diet may play a role in influencing the development of both allergy and neurodevelopmental disorders. In a review by Skypala et al. the authors presented compelling evidence on how a western diet is composed of refined grains, high fat, and sugar was significantly correlated with wheezing in children, and countries with westernized lifestyles were especially at risk of higher food allergy rates . Julia e2.5 exposure and asthma as well as between NO2 exposure and eczema (Early life exposure to particulate matter (PM) or other pollutants may influence the development of both allergy and neurodevelopmental disorders. There is strong evidence to support the link between environmental PM and allergic disorders, as demonstrated in various studies –80. A red eczema . Exposurd eczema . Mercuryd eczema . In the d eczema .The link between PM exposure and ADHD was similarly discussed in a review by Myhre et al. . PrenataEnterobacter and decreased levels of commensal Bifidobacteria and Lactobacillus, contributing to an overall increase in inflammatory state  and reduced production of energy in the form of adenosine triphosphate (ATP), which is essential for cellular metabolism and function. The malfunctioning is driven by oxidative stress and reactive oxygen species (ROS) production, and malfunctioning mitochondria alter the bioenergetics and metabolic profile of the cell to favor systemic inflammation that plays a central role in the pathogenesis of chronic diseases, e.g., allergy and neurodevelopmental disorders , 117.c expression and activity and decreased lung ATP levels was observed in ovalbumin (OVA)-induced experimental allergic asthma mice, and anti-inflammatory IL-4 antibody treatment was able to reverse the mitochondrial dysfunction, indicating a link between mitochondrial dysfunction and inflammation in allergic asthma (Raby et al. reported a significant association between mitochondrial haplotype and total serum IgE levels and that haplogroup U carriers had greater skin prick test reactivity and higher rate of AD . A recenc asthma . Moreovec asthma .In a study involving eight children with ASD and eight controls aged 4–10 years, significantly lower ETC complex activities were observed in the cerebellum, frontal cortex, and temporal cortex of the ASD group . The redCollectively, mitochondrial dysfunction may bridge the gap for understanding how allergy and neurodevelopmental disorders are related .The epidemiological link between allergy and neurodevelopmental disorders such as ADHD and ASD has been established in multiple cross-sectional and longitudinal studies , 32, 34.We also discussed common factors that contribute to the development of both allergy and neurodevelopmental disorders, and they included maternal depression and anxiety –46, GDM in vivo studies are required to examine the methylation pattern and ETC complex activities in animal models that are reflective of the conditions.With emerging evidence on the possible links between allergy and neurodevelopment disorders, it is important to understand the underlying mechanisms so as to identify new treatment and therapeutic targets. To further elucidate the role of epigenetics , 114 andIn this narrative review, we have discussed the association between allergic diseases and neurodevelopmental disorders such as ADHD and ASD, that both start early in life. Early prevention would be of utmost importance as both disorders pose a serious burden and impact on quality of life. Recent studies reported several factors such as maternal depression and anxiety, GDM, maternal allergic status, diet, exposure to environmental pollutants, microbiome dysbiosis, and sleep disturbances that influence the development of both allergy and neurodevelopmental disorders. Moreover, apart from inflammation, epigenetics and gene expression and mitochondrial dysfunction have emerged as possible underlying mechanisms in the pathogenesis of these conditions. The exploration and understanding of these shared factors and possible mechanisms may enable us to elucidate the link in the comorbidity .RC, MT, and DO performed literature search and wrote the manuscript. KS, ET, LS, and MM critically reviewed and revised the manuscript. EL conceptualized the ideas, critically reviewed, and wrote the manuscript. All authors contributed to the article and approved the submitted version.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.


This resource list could serve to orient those interested in global surgery and could be supplemented with resources advocating for global surgery from clinical, population health, or policy perspectives. The most useful resource reported was Global Surgery 2030, along with other publications, data collection tools, books and training manuals, and a documentary.This list could serve as a starting point for individuals interested in global surgery and be supplemented with resources advocating for global surgery from clinical, population health, or policy perspectives. Global surgery is defined asan area of study, research, practice, and advocacy that seeks to improve health outcomes and achieve health equity for all people who need surgical and anesthesia care, with a special emphasis on underserved populations and populations in crisis.–The need is great. Surgical disease is among the top 15 causes of disability, and surgical conditions account for up to 30% of total disability-adjusted life years (DALYs) lost worldwide—with the greatest need in low- and middle-income countries (LMICs).,,–The transition from the Millennium Development Goals to the Sustainable Development Goals has usheredin a new era for the global surgery community. Sustain-able Development Goal 3, to “ensure healthy lives and promote well-being at all ages,” emphasizes health system strengthening and universal health coverage.,As a result, the emerging field of global surgery has increased in priority among health practitioners, including nonphysician surgeons and anesthetists, researchers, and students. Evidence of this prioritization includes a shift toward incorporating surgical care as an integral part of global health systems strengthening in LMICs that has occurred and will likely continue to grow in importance within global health agendas.Because of the growing interest in global surgery, momentum in this emerging field, and the importance of global surgery in the training of health professionals, we aimed to summarize the top resources in global surgery to orient readers to the field. We undertook a 2-stage process to identify and select the top 10 resources in global surgery.In the first stage, we convened a team of global surgery leaders, including persons with decades of experience in global surgery and emerging leaders. The team included 6 global surgeons from a variety of surgical specialties and training and 2 public health professionals. A diverse authorship team was deliberately selected so that the nominated resources would transcend disciplines, career stages, and setting. The authorship team also included representation from varying career stages, including 2 students, 2 residents, 3 practicing surgeons, and 2 academic researchers. Lastly, the team included leaders from LMICs and high-income countries (HICs). Twenty-one resources were nominated de novo, including 10 peer-reviewed articles, 4 books or monographs, 3 data collection tools, 2 development manuals, and 2 advocacy pieces, comprising a documentary film and a newspaper opinion-editorial article.The second stage involved a collaborative crowdsourcing initiative using social media and email distribution lists over a 1-month period. Using the social media and email platforms, we aimed to collect information from persons involved in global surgery from several perspectives, including surgeons, anesthesiologists and anesthetists, obstetricians, and public health students. We created a short survey that contained the 21 resources from stage 1 and asked participants to select their top 10 resources from this list. Participants were also asked to nominate other resources related to global surgery through short-answer responses. After the 1-month period, ratings and open-ended responses were compiled and tabulated, resulting in the nominated top 10 resources in global surgery.The top 10 resources included a wide variety of items including 3 publications, 3 data collection tools, 3 books or manuals, and 1 documentary film .Surgery and Global Health: A View from Beyond the OR (2008) is widely regarded as the impetus for global surgery to become a major global health emphasis.Global Surgery 2030, a report by The Lancet Commission on Global Surgery (2015), repeatedly topped lists as the most useful and impactful resource.Cost-Effectiveness of Surgery in Low- and Middle-Income Countries: A Systematic Review to evaluate the cost-effectiveness of surgical interventions that could be available at district hospitals in LMICs.In 2014, Grimes and colleagues wrote WHO Surgical Safety Checklist was created to assist surgical teams in reducing avoidable surgical site infections and preventable deaths.,,As part of the Safe Surgery Saves Lives initiative formed by the World Alliance for Patient Safety and WHO, the Global Burden of Disease (GBD) data (2017) repository and visualization tools.The second data collection tool resource is the online Lancet Commission report that were incorporated in the World Bank Development Indicators in 2015.The final data collection tool resource includes the 6 core indicators reported by the Disease Control Priorities (DCP3) series provides “the most up-to-date evidence on cost-effective interventions to address the burden of disease in low-resource settings.”DCP3 is dedicated to Essential Surgery and evaluates 44 emergency and essential surgical procedures.The third edition of the Global Surgery: An Introduction, a booklet written by Dr. Dominique Vervoort in 2017, provides an introduction on the basic concepts, history, and future steps of global surgery and related topics, targeting an audience new to the field of global surgery.Surgical Care Systems Strengthening: Developing National Surgical, Obstetric, and Anaesthesia Plans to highlight the importance of NSOAPs and the progress made in selected countries around the world.Lastly, following the movement toward National Surgical, Obstetric, and Anesthesia Plans (NSOAPs) in some sub-Saharan African countries and the launch of Zambia’s NSOAP, the WHO produced the Finally, The Checklist Effect, a 2015 documentary by the Lifebox Foundation directed by Lauren Anders Brown, follows surgical health professionals in Haiti, Uganda, Mongolia, Guatemala, and Moldova.Due to the increased interest in global surgery among academic institutions and LMIC health care professionals, there is not only the need for a collection of first-step resources in the field but also the need for thoughtful guidelines to improve surgical care in LMICs and low-resource settings through multidisciplinary approaches.There are many additional resources, including publications, partnerships, training tools, and ongoing studies on global surgery that are moving the field forward in tremendous ways. This list is not meant to be comprehensive or final, but rather a starting point for students, professionals, clinicians, and others interested in global surgery. Initially, the focus of interest in global surgery has solely been on providing clinical care to persons with surgical conditions. However, the field has broadened to include public health, health economics, health services, and policy research perspectives, thus promoting the need for global surgery resources to encompass both the individual-level and population-level needs, while contextually incorporating locally-driven viewpoints. Building upon the top 10 resources, other key supplementary resources from a socioecological viewpoint are described below .Primary Sur-gery, Principles of Reconstructive Surgery in Africa, Paediatric Surgery: A Comprehensive Textbook for Africa, SUGAR PEARLS , and many more.–Global Surgery and Anesthesia Manual and Non-Technical Skills for Surgeons System Handbook have also been made available to health practitioners in LMICs.,On a clinical level, the field of global surgery is seeing momentum build around clinical guidelines for care in resource-constrained settings that are relevant to practitioners in LMICs. Some clinical practice resource examples include Additional effects toward trauma care improvement, including prehospital and emergency room care, have also been emphasized from a full health care system perspective.As a recommendation for the development of future resources, international collaborative efforts and partnerships (whether researchers in both HICs and LMICs or researchers in LMICs among themselves) can guide the creation of global surgery resources that cater to the needs of local stakeholders among practitioners in LMICs. Trainees and surgeons in LMICs must be fully involved in these endeavors and their need for more specific and targeted clinical resources addressed as well. Though already exposed to care in resource-constrained settings, trainees in LMICs need clinical guidelines such as those previously cited as they prepare to care for patients in their local low-resource settings. Reciprocity with collaborative partners must be ensured, sharing clinical experience from HICs and learning new approaches to surgical disease already practiced by local surgeons.On a population health level, collaborative efforts resulting in the collection of primary epidemiologic data are needed. Several large, multinational cohort studies on surgery, such as GlobalSurg, Global PaedSurg, COVIDSurg and other national and international databases on trauma care, neurosurgery, pediatric surgery, and other specialty areas, continue to collect primary data in LMICs, which has resulted in several profound publications highlighting the global surgery need from an epidemiologic standpoint.In addition to the longitudinal cohort studies, there are several data collection tools available for population-level data collection, including the aforementioned tools used in the Global Burden of Disease tools and the World Bank Development Indicators. Other data collection tools include the Surgeons Overseas Assessment of Surgical Need, the Surgeons Overseas PIPES—Personnel, Infra-structure, Procedure, Equipment, and Supplies—Assessment tool, Surgeons Overseas Pediatric PIPES, the Global Assessment of Pediatric Surgery, and the World Health Organization Tool for Situational Analysis to Assess Emergency and Essential Surgical Care.Recommendations for future resources from a population health perspective include additional longitudinal studies that are contextually applicable to specific populations. Validated questionnaires assessing a more granular approach to measure the burden of surgical conditions, facility-level tools to measure quality of care, and qualitative data collection tools aimed at overcoming barriers to surgical care are a few examples of further tools to be developed.Strong support for strengthening emergency and essential surgical and anesthesia care has been advocated as an essential component of universal health coverage and was recognized by the World Health Assembly (WHA) as resolution WHA68:15. In 2017, another resolution was passed (WHA70.22) that requires member nations to provide biennial reports on the strengthening of emergency and essential surgical care and anesthesia as a component of universal health coverage as requested in resolution WHA69:11. This series of global events at the policy level of health care highlight the role that policy makers and advocates of global surgery have on the international health agenda.,The promotion of recommendations to develop national surgical plans have propelled many countries to engage local stakeholders at various levels of health care and policy to begin formulating NSOAPs. Many organizations and institutions have been involved in engaging key stakeholders to advocate for the surgical patient. As an example, the G4 Alliance, comprising over 80 organizations in more than 160 countries, has played a strong role in advocacy, policy implementation, and strategic planning for global surgery as outlined in their forthcoming Global Action Plan for Surgery.We identified key resources as relevant to practitioners from various specialties and stages of their careers and listed the top 10 resources relevant to individuals across all groups. We hope that this list will serve as a starting point for individuals interested in global surgery and aid in promoting global surgery awareness, scholarship, and collaboration toward a world in which safe surgical and anesthesia care is a reality for all.


Brucellosis not only represents an important health restraint on livestock but also causes high economic losses in many developing countries worldwide. Despite considerable efforts made for the control of brucellosis, the disease is still spreading in many regions (such as the Middle East) where it represents one of the most important health hazards impacting both animals and humans. The present review aims to investigate the efficacy of veterinary control programs regarding brucellosis, with a special focus on current prevention, control, and eradication approaches. The reasons for unsuccessful control programs such as the absence of highly effective vaccines and non-certified bulls are also debated, to understand why the prevalence of brucellosis in livestock is not decreasing in many areas despite considerable efforts taken to date. The importance of governmental and regional investment in brucellosis control remains one of the main limiting factors owing to the limited budget allocated to tackle this disease. In this context, one health concept has generated novel comprehensive approaches with multiple economic implications across the livestock industry and public health. However, the implementation of such global preventive strategies appears to be a key issue for many endemic and low-income countries. According to the collected data, epidemiological contexts including management and trade systems along with well-defined agro-ecological zones should be evaluated in brucellosis endemic countries to improve milk production and to enhance the sustainability of the livestock sector at both national and regional levels. The family Brucellaceae comprises the genus Brucella and six further genera, including Ochrobactrum, Daeguia, Crabtreella, Mycoplana, Pseudochrobactrum, and Paenochrobactrum which are phylogenetically members of the order Rhizobiales within the class Alphaproteobacteria , B. melitensis (goats and sheep), B. ovis (rams), B. canis (dogs), B. suis (pigs), and B. neotomae . The most important pathogenic species in man are known as B. melitensis, B. suis, and B. abortus , and B. pinnipedialis  have been reported from marine mammal hosts according to their pathogenicity and preferred hosts     is associated with pathogenicity of Brucella which has been described in the genome of B. canis , ribosomal protein L7L12, bacterioferritin (BFR) P39, and lumazine synthase BLS have been characterized , along with production of gamma interferon (IFN-γ) by natural killer (NK) cells and T cells  along with an early Th1 response , brucellosis is classified as one of the seven neglected zoonotic disease involved in a high portion of poverty in developing countries  was carried out. It was shown that having a history of reactor cattle to brucellosis and sharing of water sources for cattle with and within outside farms are important risk factors for Brucella infection  and immunological methods such as indirect Enzyme Linked Immunosorbent Assay (i-ELISA), that represent the conventional and most available approaches to indirectly confirm the contamination of milk with Brucella spp.  , and B.abortus RB51 is a rapid and specific diagnostic tool for early and direct identification of Brucella in clinical specimens  could effectively detect lk Nimri . This se8.Brucella infections. The consumption of contaminated raw milk, cheese and butter could also transmit this disease  in dairy cattle due to infertility and abortion particularly in the second lactation , for sheep and goat, and Brucella abortus strain 19 (S19) and B. abortus strain RB51 (RB51) for cattle have been applied successfully in different countries , was confirmed in milk samples of dairy cattle by bacteriological test and a PCR technique (Zowghi et al. Brucella infections has been reported in dairy farms (Wareth et al. The prevalence study on vaccinated herds is required to obtain a comprehensive understanding of the 11.Brucella to develop management and prevention of brucellosis at local, national, regional and global levels (Plumb et al. Brucella infection, whereas environmental drivers such as the seasonal variations, animal group size, behavior and host density may influence the transmission trends of brucellosis (Schumaker Brucella spp. transmission may be deeply complicated because they are impacted by different factors such as livestock and wildlife population sizes, location, disease prevalence in wildlife, the susceptibility of livestock, and seasonal frequency of spatiotemporal interactions (Plumb et al. Brucella transmission and epidemiology dynamics in different systems, modification of brucellosis prevalence under different control options, economic evaluation of brucellosis on public health and livestock, different control strategies for improvement economic benefits in the animal and human populations could help to the cost assessment of brucellosis in livestock (McDermott et al. Beside the extensive control programs from veterinary organization, it is thought that brucellosis remains a considerable issue amongst rural and small-scale livestock farmers in the world (Lindahl et al. Therefore, international standards to balance reporting, testing, vaccines, as well as control and prevention measures for protecting animal and human health, is an important factor in acceptable and transparent brucellosis management processes. However, specific multidisciplinary ‘One Health’ actions could provide further value regarding conventional or one-disciplinary health activities (Buttigieg et al. 12.Brucellosis is considered as one of the most important and widespread zoonotic diseases worldwide. Milk production shows a permanent increase due to the increasing demand for milk and growing population. However, the farmers’ knowledge about the zoonotic preventive practices is still limited. This review aimed at defining how brucellosis control programs could improve dairy production, in terms both of quality and of quantity.Brucella infections. According to our investigations, multiple factors influence the epidemiology of brucellosis among dairy herds, including management and trade systems, climatic conditions, and agro-ecological zones. All potential risk factors need to be carefully identified and their individual and combined impacts on milk production evaluated in order to design adequate preventive strategies and control programs to improve milk production process in endemic regions. Furthermore, governmental bodies such as veterinary organization and public health authorities should collaborate to manage brucellosis in dairy farms and to reduce the risk of human exposure. In addition, vaccine-based control programs including calf, sheep and goat vaccination appeared to be crucial in endemic areas.The critical role that can play the implementation of appropriate regulatory practices to control the transmission of the disease and to reduce multiple risks factors associated with brucellosis in dairy farms has been described in detail. Considering the potential public health implication and important economic losses associated with this widespread zoonotic diseases, strict preventive programs should be performed to protect the cattle population from An ‘One Health’ strategy including the development of veterinary capacities/services and the expansion of health education has proved remarkably effective in the control of brucellosis. Furthermore, governmental organisations and regulatory authorities should make efforts to inform farmers about the risks of the replacement of heifers and the introduction of semen from not certified farms. Thus, we recommend control programs within the ‘One Health’ principles to significantly reduce the burden of brucellosis in dairy farms through national vaccination, brucellosis testing and prevention education, while improving public health capacities and international collaborations across endemic regions.


Per- and polyfluoroalkyl substances (PFAS) constitute a large class of environmentally persistent chemicals used in industrial and consumer products. Human exposure to PFAS is extensive, and PFAS contamination has been reported in drinking water and food supplies as well as in the serum of nearly all people. The most well-studied member of the PFAS class, perfluorooctanoic acid (PFOA), induces tumors in animal bioassays and has been associated with elevated risk of cancer in human populations. GenX, one of the PFOA replacement chemicals, induces tumors in animal bioassays as well. Using the Key Characteristics of Carcinogens framework for cancer hazard identification, we considered the existing epidemiological, toxicological and mechanistic data for 26 different PFAS. We found strong evidence that multiple PFAS induce oxidative stress, are immunosuppressive, and modulate receptor-mediated effects. We also found suggestive evidence indicating that some PFAS can induce epigenetic alterations and influence cell proliferation. Experimental data indicate that PFAS are not genotoxic and generally do not undergo metabolic activation. Data are currently insufficient to assess whether any PFAS promote chronic inflammation, cellular immortalization or alter DNA repair. While more research is needed to address data gaps, evidence exists that several PFAS exhibit one or more of the key characteristics of carcinogens. Per- and polyfluoroalkyl substances (PFAS) are human-made fluorinated chemicals that have become pervasive contaminants in people and the environment. Since the 1950s, thousands of different PFAS have been produced for use in industrial and consumer products. The use of PFAS in firefighting foams and presence in industrial discharges has resulted in extensive contamination worldwide. Currently, PFAS are detectable in nearly all humans, with exposures beginning during fetal development. As detailed in this article, a growing body of research suggests that exposure to PFAS at contaminated sites and in the general population can adversely impact human health. One well-studied PFAS, perfluorooctanoic acid (PFOA) was reviewed by the International Agency for Research on Cancer (IARC) in 2016 and classified as group 2B, a possible human carcinogen ,4. Recently, the Key Characteristics of Carcinogens framework was developed in order to facilitate the organization and characterization of mechanistic data for cancer hazard identification ,6. UsingIncorporation of a key characteristic analysis into risk assessments is increasingly utilized by U.S. and international government agencies including IARC , the IntThis state-of-the-science review summarizes the available data for several PFAS for each of the key characteristics of carcinogens and evaluates the strength of evidence for each characteristic. We adapt the framework to include the findings from epidemiological studies. This article addresses PFOA as the most studied member of the PFAS group; long-chain PFAS that have a carbon chain length of eight or more for perfluoroalkyl carboxylic acids and six or more for perfluoroalkane sulfonates; and short-chain PFAS for which data are available for at least one of the key characteristics of carcinogens. In addition, data gaps are identified where additional research is needed. Human biomonitoring for PFAS has been conducted by U.S. Centers for Disease Control and Prevention (CDC), by the American Red Cross , the staFor the general population, the majority of PFAS intake has been attributed to food. Drinking water, indoor air and dust, and consumer products provide additional sources of PFAS exposure . ConsumpPFAS interactions with biological tissues and organisms are distinct from those of other environmentally persistent halogenated synthetic chemicals. Unlike organochlorine aromatic compounds such as polychlorinated biphenyls, chlorinated dioxins and dichlorodiphenyltrichloroethane (DDT), PFAS are not lipophilic and do not accumulate in adipose tissue . In vivoWhile hundreds of research studies have been published on the health harms due to individual PFAS, significant data gaps remain, particularly with respect to PFAS other than PFOA and PFOS, and for PFAS mixtures. For example, in Wilmington, North Carolina where PFAS contaminated water supplies, over 30 unique PFAS have been identified in the watershed , yet limHuman epidemiologic studies have linked occupational, community, and general population exposure to PFOS and PFOA with an elevated risk of cancer. Prior reviews have focused on all cancers ,30, and In the C8 Health Project, comprised of individuals who lived or worked in the mid-Ohio Valley where drinking water was contaminated with PFOA, elevated PFOA levels in the body were associated with greater risk of non-Hodgkin lymphoma and kidney, testicular, prostate, and ovarian cancers . In a geLimitations in these epidemiologic studies include differences in reporting disease  and different approaches for estimating PFAS exposure . In addition, small numbers of rare cancer types, such as pancreatic cancer, in individual cohorts limit the statistical power of the published analyses. Nevertheless, several studies have reported a significant association of PFOA and/or PFOS exposure with kidney and prostate or testicular cancer ,38. Due Two-year carcinogenicity bioassays in rats have been conducted for PFOA ,42 PFOS Here, we assemble, organize and evaluate the peer-reviewed literature on PFAS through the lens of the key characteristics of carcinogens. Previous systematic reviews for toxicity data have been performed for several PFAS, such as the Agency for Toxic Substances and Disease Registry (ATSDR) toxicological profiles  and EPA Strong evidence was designated if at least two types of evidence  had consistent findings for multiple representative PFAS within a group, with more data-limited group members having positive evidence from one study type. If only one type of evidence provided positive findings, or if findings for distinct PFAS were inconsistent, then the overall evidence was considered Suggestive. If two types of evidence had studies limited in number and/or design or reported largely inconsistent findings, the data were considered Insufficient to make an assessment. For epidemiological literature, we utilized a qualitative assessment of evidence based on the presence or lack of a significant finding. For a given key characteristic, we evaluated whether the reviewed literature indicated strong evidence, suggestive evidence, no association or insufficient data for PFOA, other long-chain PFAS, and short-chain PFAS. A unifying characteristic of PFAS is their resistance to biodegradation, resulting from the chemical stability of the carbon-fluorine bond. This stability renders the PFAS family of chemicals non electrophilic, relatively metabolically inert and resistant to metabolic activation . Most PFGenotoxicity is a well-studied mechanism of environmental carcinogenesis. PFAS, primarily PFOA and PFOS, have been evaluated and reviewed for genotoxicity. Prior reviews reported that PFAS are not directly mutagenic and suggested that the DNA damage observed in some assays is likely a secondary event resulting from oxidative damage . Recent In addition to direct genotoxicity, xenobiotics can contribute to changes in DNA through alteration of DNA replication or repair . These aChanges in DNA methylation is a form of epigenetic regulation of gene expression implicated in the development of disease . Site-spPFAS, primarily PFOA and PFOS, can induce both hypo- and hypermethylation of specific gene regions and the genome globally. Guerrero-Preston et al. (2010)  analyzedSimilarly, Kingsley and colleagues examined a cohort of 44 mother–child pairs and reported no correlation between PFOA exposure during pregnancy and global DNA methylation in offspring cord blood but identified 20 PFOA specific differentially methylated CpG sites in genes involved in cell growth . In maleIn a cohort of 652 highly exposed adults from the C8 Health Project, serum PFOS concentrations, but not PFOA, PFNA or PFHxS, were associated with greater LINE-1 DNA methylation in peripheral blood leukocytes . A crossA limited number of studies investigated DNA methylation changes associated with PFAS exposure in vitro while evidence in animal studies is sparse. Mice exposed to PFOS during gestation exhibited decreased global DNA methylation in the liver as well as increased methylation of the glutathione-S-transferase Pi (GSTp) promoter . SimilarChanges in DNA methylation following PFAS exposure represent one form of epigenetic regulation. Other epigenetic changes such as histone modifications, nucleosome positioning and expression of non-coding microRNAs also occur in cancer , and addOxidative stress is defined as an imbalance between the production of reactive oxygen species (ROS) and their elimination by cellular defense mechanisms. ROS can cause damage to lipids, proteins, and DNA, and contribute to the pathology observed in chronic inflammatory conditions, such as aging and cancer . OxidatiMetabolomics has been used to study human responses to internal and external stressors such as disease, and environmental exposures . In a stA significant body of data from both in vivo and in vitro studies, including mammalian and wildlife species, have confirmed that PFAS are capable of inducing ROS and/or a condition of oxidative stress. Oxidative stress has been most extensively studied for PFOA and PFOS. In the HepG2 human hepatoma cell line, oxidative DNA damage  and ROS levels increased following exposure to PFOA and PFOS at 400 nM and higher ,87. HoweRissa tridactyla), six of 20 long-chained PFAS  were detected and assessed for their ability to modulate plasma biomarkers of oxidative stress, [As PFAS are ubiquitous in the environment, the impact of PFAS has been evaluated in wildlife species. In a comprehensive study in male Arctic seabirds , while activation of the immune system (key characteristic 7) can result in chronic inflammation. Recent animal and in vitro studies have reported PFAS-related inflammation that can promote a disbalance of overall immune homeostasis. Long-chain PFAS exposure  in mice cause an allergic inflammatory response ,115. PFOOverall, there is somewhat suggestive evidence from epidemiological, animal and in vitro studies that PFOA, PFOS, PFDA and PFUnA may promote chronic inflammation, yet the number of studies are limited and biomarkers of chronic inflammation and identification of inflammatory diseases which are specific to PFAS exposures are needed to more fully characterize the relationship between exposure, chronic inflammation and risk for cancer development . Data avImmunotoxicity is a sensitive endpoint for PFAS toxicity, with implications for children’s health and for lifetime cancer risk (reviewed in ). Both iRegulatory agencies typically rely on the T cell-dependent antibody response (TDAR) assay in laboratory animals to evaluate immunosuppression . This asAllergies are classified as Type I hypersensitivity reactions that can be monitored in humans by the presence of increased serum levels of IgE. While prospective studies of birth cohorts did not reveal a consistent association of PFAS exposure and Type I hypersensitivity reactions in children or serum IgE levels , analysiRodent studies have demonstrated that both PFOA and PFOS are capable of suppressing the TDAR, with lower bound benchmark dose estimates of 1.75 mg/kg/day, which supports the epidemiologic findings that these PFAS elicit immunosuppression ,131,132.Animal studies on PFAS-mediated immunoenhancement are limited. In a mouse model of asthma involving dermal exposure to ovalbumin (OVA) as the antigenic trigger, PFOA did not increase serum IgE levels but increased the OVA-mediated hypersensitivity response . In contThe National Toxicology Program evaluated the immunotoxicity potential for PFOA and PFOS and concluded that the evidence for suppression of antibody responses was high for experimental animals and moderate in humans . StudiesAlterations in cellular receptor signaling and subsequent changes in genomic and metabolic pathways controlled by those receptors have a profound influence on the development, and function of cells, tissues and organisms as well as on the risk of cancer and other diseases ,142,143.Here we review epidemiological, toxicological and mechanistic data that help elucidate how PFAS substances modulate receptor-mediated effects, with a primary focus on recent studies and early life exposures because of children’s greater susceptibility to the effects of endocrine disruptors , and chiIn a Danish cohort of men exposed to PFAS in utero, maternal PFOA serum levels (median = 3.8 ng/mL), but not PFOS was associated with reduced sperm concentration and count, and increased levels of luteinizing hormone and follicle stimulating hormone . In a JaA study of 18–22-year-old men in the PFAS-contaminated Veneto region of Italy, observed reduced testicular volume in males and increased circulating levels of luteinizing hormone and testosterone, and shorter AGD compared to controls . In two PFAS exposure also affected birth outcomes controlled by thyroid hormone  and incrSimilar to human studies, animal studies consistently documented impact on receptor-mediated pathways such as changes in circulating hormone levels and potential anti-androgen effects. Toxicological studies of PFOA in laboratory rats observed decreases in serum testosterone and increases in estradiol . SimilarIn female mice, PFOA delayed mammary gland development in dams as well as female offspring ,170 at cAnalysis of PFOA activity in high-throughput screening assays from the ToxCast and Tox21 programs identified that PFOA induced activity in four different estrogen receptor assays, seven peroxisome proliferator activated receptors (PPAR) and retinoid X receptor assays, one androgen receptor assay, as well as several metabolic enzyme assays . PFNA, PIn estrogen receptor alpha binding assays, eight PFAS—PFOA, PFOS, PFHxS, PFHxA, PFBS, PFBA, 6:2 FTOH and 4:2 FTOH—had a higher affinity for the human receptor compared to the rat receptor which was increased in longer chain compounds relative to shorter chains with IC50s ranging from 16.72 to 74.27 µM . EstrogeNotably, two studies examined several PFAS chemicals used in food packing materials including fluorotelomer alcohols, 4:2 FTOH, 6:2 FTOH, 8:2 FTOH, and polyfluorinated alkyl phosphate esters, 8:2 monoPAP, 8:2 diPAP, 8:2 triPAP, 10:2 diPAP and reported increased estradiol, decreased testosterone production and estrogen receptor activation but no effect on PPARα or androgen receptor ,185. PFOA and other PFAS may modulate hormonal signaling and endogenous circulating hormone levels through interaction with serum proteins that facilitate the transport of various endogenous and exogenous substances, including hormones and xenobiotic compounds ,187. ForOverall, the epidemiologic evidence suggests that long-chain PFAS exposure  can modulate circulating levels of several hormones. In animal bioassays, PFAS-associated male reproductive toxicity and impact on thyroid hormones are consistently reported. Finally, mechanistic data indicate that several PFAS activate PPARα, weakly activate estrogen receptor, antagonize androgen receptor and bind thyroid hormone transport proteins. Of the 26 PFAS reviewed here, 22 exhibited receptor mediated effects in vitro for at least one receptor and nine, including both long-chain and short-chain PFAS have support from multiple lines of evidence . TherefoImmortalization of cancerous cells through inhibition of normal cellular senescence and unlimited replicative potential results in uncontrolled proliferation and facilitates both the formation of macroscopic tumors and tumor metastasis . As noteBoth telomere length and mitochondrial DNA content are sensitive to environmental stressors and contaminants ,196. To The data are insufficient to determine how PFAS may impact immortalization due to the limited number of studies available. Further research is needed to provide information on the mechanisms by which PFAS impact telomeres and how those changes may contribute to cellular immortalization and cancer development. It is possible that other key characteristics such as induction of oxidative stress and chronic inflammation may contribute to this type of cellular transformation.Lack of normal cell cycle control, uncontrolled proliferation and ultimately metastasis represent a hallmark of cancer promotion and progression, which, in turn, has stimulated interest in targeting cell cycle regulatory proteins for cancer therapeutics . AdditioIn vitro, the ability of PFAS to influence cell proliferation, particularly in assays of breast and other endocrine mediated cells and tissues has been assessed. PFOA and PFOS both increased proliferation, cell migration and invasion of normal human breast epithelial cells and altered the expression of proteins involved in cell cycle regulation, including cyclin dependent kinase 4 ,203. SimIn vitro, PFOA induced cell migration and invasion in human endometrial  and ovarInformation for this key characteristic can be gathered from pathological assessments of tissues from exposed laboratory animals using tissue hyperplasia is an indicator of cell proliferation. After 28 day exposure in rats, PFOA induced hyperplasia of the olfactory and respiratory epithelium. Impact on olfactory tissue were also observed for PFHxA, PFBS and PFHxS. In addition, PFBS and PFNA induced hyperplasia in the forestomach epithelium ,62. Increased cell proliferation has been observed in vitro for PFOA, PFOS, 6:2 and 8:2 FTOH and in vivo for PFOA, PFOS, PFHxA, PFBS, PFHxS and PFNA providing suggestive evidence that both long and short-chain PFAS are associated with this key characteristic . As yet,Here, we present a novel review of PFAS utilizing the Key Characteristics of Carcinogens framework. Our state-of-the-science review incorporates data from epidemiological studies with supporting information from animal toxicological studies and in vitro mechanistic studies and includes data from 26 different PFAS compounds including long- and short-chain perfluoroalkyl carboxylates and sulfonates, fluorotelomer alcohols, polyfluoroalkyl phosphate esters and fluoropolyether carboxylates . OverallAs this is a hazard-based approach, exposure dose was not one of the key factors in the strength of evidence assessment. Future research on specific key characteristics and effects at environmentally relevant doses  will be particularly important for risk assessment. More research is also needed to address the mechanistic links between the KCs and the combination of KCs and their relationship to the carcinogenic potency of chemicals that exhibit specific key characteristics. Additionally, differences in evidence strength and conclusions for the groups of PFAS evaluated here may be due to limited data availability rather than toxicological differences. The strength of evidence assessments for PFAS are based on the published, peer-reviewed studies. The number of such studies is significant for PFOA and PFOS, moderate for other long-chain PFAS, and limited for short-chain PFAS and certain structural functional groups such as fluorotelemers (FTOHs) and flouralkyl phosphate esters (PAPs). However, while perfluroalkyl acids are not metabolized, the PAPs and FTOHs are biotransformed in the body and environment to their corresponding carboxylates of the same chain length. Therefore, it may be appropriate to evaluate this group of PFAS by their biotransformation products. Importantly over 600 different PFAS were reported in active use over the past decade, yet for the majority of those compounds there is no toxicological information available. The present work can assist in addressing those data gaps with respect to cancer pathways that are likely to be impacted by PFAS. Future research into the key characteristics of carcinogens may elucidate how combinations of key characteristics influence cancer risk. In a study of 86 agents known to cause cancer in humans, on average, each agent exhibited four key characteristics . This isEvidence exists that multiple PFAS exhibit several of the key characteristics of carcinogens with each of 26 chemicals identified in our review exhibiting at least one characteristic, particularly receptor-mediated effects. Well-studied PFAS, including PFOA and PFAS, exhibit up to five key characteristics which can serve as research priorities for less-studied PFAS as well as sources of information for potential application of read-across approaches to unstudied endpoints for other PFAS class members. Despite the existing data gaps, both in human epidemiology and mechanistic aspects of PFAS toxicity, development of a systematic framework for understanding the PFAS class can be facilitated with the key characteristics approach and may be useful for categorizing the carcinogenic hazards of PFAS that have not undergone systematic testing.


As the population ages, potentially inappropriate prescribing (PIP) in the older adults may become increasingly prevalent. This undermines patient safety and creates a potential source of major morbidity and mortality. Understanding the factors that influence prescribing behaviour may allow development of interventions to reduce PIP. The aim of this study is to apply the Theoretical Domains Framework (TDF) to explore barriers to effective prescribing for older adults in the ambulatory setting.A scoping review was performed based on the five-stage methodological framework developed by Arksey and O’Malley. From 30 Aug 2018 to 5 Sep 2018, we conducted our search on PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, and Web of Science. We also searched five electronic journals, Google and Google Scholar to identify additional sources and grey literature. Two reviewers applied eligibility criteria to the title and abstract screening, followed by full text screening, before systematically charting the data.A total of 5731 articles were screened. Twenty-nine studies met the selection criteria for qualitative analysis. We mapped our results using the 14-domain TDF, eventually identifying 10 domains of interest for barriers to effective prescribing. Of these, significant domains include physician-related factors such as “Knowledge”, “Skills”, and “Social/Professional Role and Identity”; issues with “Environmental Context and Resources”; and the impact of “Social Influences” and “Emotion” on prescribing behaviour.The TDF elicited multiple domains which both independently and collectively lead to barriers to effective prescribing for older adults in the ambulatory setting. Changing the prescribing climate will thus require interventions targeting multiple stakeholders, including physicians, patients and hospital/clinic systems. Further work is needed to explore individual domains and guide development of frameworks to aid guide prescribing for older adults in the ambulatory setting.The online version contains supplementary material available at 10.1186/s12877-020-01766-7. The aging population brings with it an increasing number of older adults (aged 65 years and above) living with chronic disease and taking medications on a regular basis. Compared to younger individuals, older adults are at increased risk for developing drug-related complications due to a multitude of reasons including frailty, multi-morbidity, altered drug pharmacokinetics and pharmacodynamics, as well as a higher proportion of polypharmacy . This prPIP describes the use of medications where the actual or potential harms of therapy outweigh the benefits, and encompasses both potentially inappropriate medications (PIMs) and potential prescribing omission (PPOs) . PIP incDespite these tools, PIP remains a significant problem worldwide, with studies estimating the prevalence of PIP in older adults between 31 and 73% –8. AlthoThe prescribing framework in Singapore has long-centred on the physician as the key source of prescribing and medication review in both the inpatient and ambulatory care settings. In 2018, Singapore launched the National Collaborative Prescribing Programme , a threeThis study thus aims to explore barriers to effective physician prescribing for older adults in the ambulatory setting. This review also serves as part of a proof-of-concept study in Phase 1 of an extended 3-phase project to improve prescribing for older adults at outpatient clinics in public hospitals in Singapore.To capture barriers reported by physicians without placing a limit on the scope or nature of studies, a scoping review was selected over a systematic review. In line with the goals of scoping reviews, quality of evidence and risk of bias were not assessed . We adopOur aim is to map barriers experienced by physicians when they are prescribing for older adults with multi-morbidity. As the results will eventually help to inform formulation of an outpatient collaborative care intervention, we focused our search on studies conducted in the ambulatory setting including both primary care and specialty ambulatory care . Hence, our research question was finalized as:What are the key barriers to appropriate prescribing for older adults receiving ambulatory care?JBI’s three-step search strategy was adapted , with anIn the second step of the search, our full search strategy was applied across the following databases from 30 Aug 2018 to 5 Sep 2018: PubMed, The Cochrane Database of Systematic Reviews (CDSR), Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature (CINAHL). The full search strategy for the peer-reviewed databases is provided in Additional file Grey literature searches were conducted using Google and Google Scholar to capture non peer-reviewed publications on the subject. We reviewed the first 50 titles/websites that were displayed, sorted by relevance and limiting the publication date from 1998 onwards. In addition, we also searched electronic databases of the following five journals relevant to our topic, using limited key words: Age and Aging, Archives of Gerontology and Geriatrics, BMC Geriatrics, Gerontology Series A and Journal of the American Geriatrics Society. In addition, reference lists of the included studies were also searched. This last step was recommended in JBI’s three-step search strategy .Two reviewers (SL and DYY) who are practicing clinicians independently completed the first stage title and abstract screening, resulting in a total of 45 eligible studies for the second-stage full text screening. Twenty-nine studies were found to be eligible for inclusion, following full text screening by the same reviewers. Conflicts were resolved through discussion. The two-stage screening process was managed in Covidence , an onliStudies which involved patients aged less than 65 years or only non-physician prescribers were automatically excluded from this scoping review. We included one study by Carthy et al.  which diOne of the reviewers (SL) performed data extraction, charting the following information: Authors, year, country of origin, aims and purposes of the study, study population, sample size, methods of the studies and key findings on barriers identified by physicians. The second reviewer (DYY) validated the extracted data and made suggestions for changes and additions, with agreement from the first reviewer (SL).Barriers identified in the studies were mapped to the Theoretical Domains Framework (TDF) proposed by Michie and colleagues . The TDFThe barriers were extracted and first mapped to the 14 domains in the TDF by the first reviewer (SL). The second reviewer (DYY) cross-checked and made suggestions, which was then discussed and agreed on with the first reviewer (SL). The results were subsequently shared and discussed with the rest of the authors, and finalised after several rounds of iterations. The flow of the process is reported using the PRISMA flow diagram .Our search yielded 5731 abstracts, of which 45 full-text articles were assessed for eligibility, and an eventual 29 articles were included in the qualitative synthesis  is less likely to be associated with the more positive domains such as optimism and goals.The identified domains were further subdivided based on their respective stakeholders  where appropriate so as to more effectively target interventions. Table Our scoping review identified three major stakeholders which influence effective prescribing in older adults – namely the patient, the physician, and the healthcare system at large. By crystallising the barriers into discrete stakeholder profiles, we can shift our perspectives accordingly, highlight specific areas of concern, and help direct further work targeting individual intervention groups. For patients, major themes include poor healthcare literacy, incorrect or misinformed expectations and beliefs, and socioeconomic factors. For physicians, we need to help prescribers navigate the medical complexities in this particular group of patients, equip them with skills on deprescribing in older adults, address concerns regarding interprofessional relationships and role dilemmas, as well as put in place proper safeguards for issues pertaining to negative consequences . For the healthcare system, frameworks need to be developed to balance time and resource constraints, improve coordination of care, and establish funding for further research in this area. These findings are summarised in Table The TDF elicited multiple domains which both independently and collectively lead to barriers to effective prescribing in older adults in the ambulatory setting, including significant factors pertaining to Knowledge, Skills, Social/Professional Role and Identity, Social Influences and Environmental Context and Resources. We recognise that older adults remain a unique population owing to their medical complexity, multimorbidity and frailty, and this can prove challenging for physicians who lack the knowledge and skillsets to effectively manage this group of patients , 49. PatBeyond usual evidence-based guidelines which may be more easily applicable in younger patient groups, there is a constant need to weigh the risks and benefits of each recommendation based on individual patient context in the older adult, and thus no ‘one size fits all’ solution. With increased specialisation and fragmentation of care, physicians have also highlighted concerns regarding inter-professional relationships, hesitancy to interfere with recommendations from secondary or tertiary care, and also fears surrounding adverse outcomes or medicolegal consequences , 51. WitChanging the prescribing climate will thus require interventions targeting multiple stakeholders, including patients, physicians, ambulatory clinic systems and healthcare policy makers. At the level of the community, we need to work towards correcting the misconception that ‘more medications constitute better treatment’, that deprescribing does not equate to ‘giving up on the patient’, and gently reinforce the importance of medication review. Healthcare and social policies need to target the issue of healthcare financing, provision of adequate subsidies and ensuring equal access to healthcare . For phyThis scoping review distinguishes itself from existing literature in its focus on older adults receiving ambulatory care, which has its own unique set of challenges compared to hospital or residential-based care, as shown in the barriers identified above. Indeed, the original reason for this focus was the anticipation that certain barriers related to environmental context and resources  may be more prominent in this setting –59. MoreHowever, because we sought to understand general barriers to prescribing rather than disease-specific or drug-specific considerations, the exclusion of studies that focused on either may have limited the number of studies included in this review. The authors also acknowledge that contextual factors  may not be applicable across all healthcare settings, and may need to be interpreted in accordance to each population’s unique needs.In conclusion, there exist multiple barriers to effective prescribing which will require multipronged interventions targeting patients, physicians and the healthcare system at large in order to reduce PIP and improve care in older adults. Moving forward, the study team will take findings from this scoping review into a modified Delphi study to explore the significance of the identified TDF domains in Singapore’s context, bearing in mind the potential for cultural and healthcare framework differences between Singapore and the studies included in this review. Building upon empiric evidence for pharmacist involvement in medication reviews, which has demonstrated improvements in prescribing practices and reduction in PIP –63, our Additional file 1. Search strategy for peer-reviewed data bases