Every new HIV infection is preventable and every HIV-related death is avoidable. As many jurisdictions around the world endeavour to end HIV as an epidemic, missed HIV prevention and treatment opportunities must be regarded as public health emergencies, and efforts to quickly fill gaps in service provision for all people living with and vulnerable to HIV infection must be prioritized.We present a novel, comprehensive, primary and secondary HIV prevention continuum model for the United States as a conceptual framework to identify key steps in reducing HIV incidence and improving health outcomes among those vulnerable to, as well as those living with, HIV infection. We further discuss potential approaches to address gaps in data required for programme planning, implementation and evaluation across the elements of the HIV prevention continuum.Our model conceptualizes opportunities to monitor and quantify primary HIV prevention efforts and, importantly, illustrates the interplay between an outcomes-oriented primary HIV prevention process and the HIV care continuum to move aggressively forward in reaching ambitious reductions in HIV incidence. To optimize the utility of this outcomes-oriented HIV prevention continuum, a key gap to be addressed includes the creation and increased coordination of data relevant to HIV prevention across sectors. The HIV care continuum has become a highly visual, accessible and reproducible model to improve health outcomes and minimize transmission risk among those living with the virus . Viral lAn HIV prevention continuum, like the care continuum, is potentially valuable to identify opportunities at key steps in an HIV incidence- and health outcomes-oriented process. Such a model affords the opportunity to: 1) define best biomedical, behavioural and ancillary support practices, including those that foster integration of HIV prevention with broader primary care, wellness promotion and sexual and reproductive health services; 2) further articulate and refine the metrics of success; 3) identify gaps in provider/intervention access and utilization; 4) inform the allocation of human and financial resources; 5) establish implementation science priorities; and 6) generate and support advocacy for the highest impact HIV prevention activities.Primary HIV prevention continua and similar heuristics have been developed by others. These include a generalized, population-based approach ; an infeRecognizing inherent challenges, we present a novel continuum model for the United States as a conceptual framework for addressing individualized primary HIV prevention needs to achieve population-level reductions in HIV acquisition risk and to illustrate the critical link between a comprehensive primary prevention process and the care continuum to further improve health outcomes and minimize transmission risk among those who are infected with HIV. To bolster stakeholder interest in this model, particularly among U.S. public health departments, we discuss potential approaches to address gaps in data required for programme planning, implementation, and evaluation across the elements of the primary HIV prevention continuum.Our model, shown in A unique feature of the proposed model is a depiction of the link between the primary HIV prevention continuum and the HIV care continuum and the critical interplay of both in maximizing health outcomes and minimizing ongoing spread of the virus. For example, an HIV-negative individual who seroconverts while engaged in a prevention programme featuring regular HIV testing may quickly be linked to and engaged in HIV care and, thereby, benefit from early antiretroviral therapy, including reduction in further onward HIV transmission.HIV testing is the entry point in the HIV prevention cycle, as it generally provides a critical point of contact with the healthcare and service delivery systems for individuals who are HIV negative but are vulnerable to the infection, as well as being a gateway to treatment for people diagnosed with HIV infection. The cycle is repeated for as long as an individual remains at risk for HIV acquisition. In effect, 100% of people at risk for HIV infection who test seronegative at the beginning and end of one cycle should re-enter the cycle and be retested at least annually –10, coupAs part of a comprehensive prevention strategy, following a negative HIV test, people vulnerable to HIV infection should receive risk and needs assessments. These can best ensure linkage to medical and other service providers capable of providing or coordinating evidence-based interventions and social services appropriate for that individual. The cyclical framework of our model, with HIV retesting as a central indicator, allows for repeated risk and needs assessments to meet an individual's changing HIV prevention requirements.For those testing for HIV in acute care (e.g. emergency departments) or non-healthcare settings (e.g. community-based organizations (CBOs)), minimum assessments may include knowledge of and eligibility for a range of risk-reduction strategies, including PrEP, in accordance with U.S. Centers for Disease Control and Prevention (CDC) recommendations, and healthcare provider and insurance status navigation needs . For vulFor individuals tested for HIV and having undergone comprehensive risk and needs assessments in primary care settings, linkage may include referrals to specialized medical, mental health and substance abuse services and CBO-provided psychosocial and ancillary services  ,13. For The final element in the primary prevention cycle addresses uptake of, engagement in and adherence to optimal, high quality HIV prevention and risk-reduction interventions. These include PrEP; post-exposure prophylaxis (PEP); syringe exchange programmes (SEPs) and substance abuse treatment; mental health services; housing assistance; sexual health services; and behavioural change interventions. To help optimize engagement in HIV prevention programmes and related systems of care, the use of culturally competent case managers, patient navigators and/or other client-centred services should be considered –18.In contrast to the relatively straightforward data elements used to assess outcomes along the HIV care continuum, the metrics required to populate a primary HIV prevention continuum involving different systems of service delivery, interventions and outcome measures are incredibly complex and often without adequate or complete population-based data sources. Here we discuss two potential approaches to address the gaps in data required for programmatic planning, implementation and evaluation across the elements of the prevention cycle.One strategy involves coordinating existing HIV prevention-related data. For example, the U.S. CDC, utilizing data from the National Health and Nutrition Examination Survey, the National Survey on Drug Use and Health and the National Survey of Family Growth, has estimated the number of U.S. adults with indications for PrEP based on behavioural risk factors for HIV and the 2014 U.S. Public Health Service's PrEP clinical practice guideline to be 1,232,000  ,20. ThisA similar large-scale effort to identify and validate data sources for mid-cycle elements of the HIV prevention continuum, such as rates of health insurance coverage, linkage to service providers and utilization of evidence-based interventions, has not yet been undertaken. One potential data source for this work might be the National HIV Prevention Program Monitoring and Evaluation (NHM&E) system, which collects current and prior HIV testing data, referrals to specific HIV prevention activities and “intervention completion” each time a client enrols in or completes an intervention after HIV testing at a CDC directly funded CBO . AvailabA second approach includes leveraging extant, robust HIV surveillance data among individuals who tested positive for the virus. Since the early days of the U.S. epidemic, such data pertaining to transmission risk among individuals testing positive for HIV have been used to inform HIV prevention planning and funding.Each new infection continues to represent a missed opportunity for primary HIV prevention. In the setting of expanded prevention options available to those vulnerable to HIV infection, there is a need for renewed and strategic use of HIV surveillance data on new diagnoses to systematically understand prevention gaps and missed prevention opportunities, with rapid translation to “reverse engineer” primary HIV prevention continuum element priorities. Other areas of public health, including efforts to prevent maternal mortality, have employed similar approaches and have benefited from studying “near misses” in order to inform population-level best practices and implementation strategies –27.Current CDC data systems allow for the collection of information to make some inferences about an individual's attributable risk factor(s) for HIV acquisition and to track linkages to appropriate services after receiving a positive diagnosis. However, not enough surveillance data are gathered following diagnosis to learn about missed HIV prevention opportunities inherent in every new HIV infection. Treating each new infection as an sentinel health event is necessary to understand exactly where gaps in the primary HIV prevention continuum are occurring, especially as PrEP and PEP implementation is ramping up in many jurisdictions. Examples of probable gaps include the following: lack of knowledge regarding the symptoms of, and high transmission risk during, acute HIV infection; lack of awareness or availability of PrEP, PEP, SEP or other interventions; poor retention in or adherence to prevention services; and structural barriers to affordable health insurance, adequate medical care, safe housing or other supportive services. A fundamental assumption in the reverse engineering approach is that people vulnerable to HIV infection will have similar characteristics and risk factors to those who were recently diagnosed, such that extrapolation of data between populations is valid. Local programmes targeted at increasing early or immediate treatment following HIV testing, such as the University of California, San Francisco's RAPID programme , are welOur proposed model provides a standardized roadmap for moving aggressively forward in reaching national HIV incidence and care targets by: 1) conceptualizing primary HIV prevention as a repeating, comprehensive and outcomes-oriented process that is applicable to vulnerable populations comprised of individuals with fluctuating risks and intervention needs; and 2) illustrating the value of HIV retesting as both a metric to continuously gauge the effectiveness of the primary HIV prevention cycle and an opportunity to streamline successful linkage, engagement and viral load suppression through the HIV care continuum. A limitation of our model is the absence of the complete data required to test the proposed primary HIV prevention continuum steps, which will be necessary indicators of success. An obstacle to model validation is the lack of a robust and coordinated HIV prevention monitoring system, which is sorely needed to help guide the implementation of key modalities of HIV prevention, such as PrEP and PEP. Our hope is that, in suggesting a way forward, we can catalyze an effort to address these limitations, which have stymied the promulgation of a meaningful primary HIV prevention continuum to date.Given the current state of data collection infrastructure in the United States, efforts to vitalize HIV prevention will need to focus on increasing coordination between existing systems, including those not specifically focused on HIV, to prioritize the reporting of data for people vulnerable to HIV infection. The need for these data, however, must be weighed against efforts to decrease federal data collection and reporting burdens among health departments and CBOs as well as the need for increased resources required to more fully support these surveillance activities. Creating new primary prevention-focused variables in existing data collection tools, as well as conducting more analyses of current variables, will inform regional, state and national public health evaluation of prevention service coverage, identify gaps and facilitate advocacy for scale-up of highly effective prevention services in the United States.


Background: This paper explores telemonitoring/mhealth approaches as a promising real time and contextual strategy in overhauling HIV and TB interventions quality access and uptake, retention,adherence and coverage impact in endemic and prone-epidemic prevention and control in sub-Sahara Africa.Methods: The scoping review method was applied in acknowledged journals indexing platforms including Medline, Embase, Global Health, PubMed, MeSH PsycInfo, Scopus and Google Scholar to identify relevant articles pertaining to telemonitoring as a proxy surrogate method in reinforcing sustainability of HIV/TB prevention/treatment interventions in sub-Saharan Africa. Full papers were assessed and those selected that fosters evidence on telemonitoring/mhealth diagnosis, treatment approaches and strategies in HIV and TB prevention and control were synthesized and analyzed.Results: We found telemonitoring/mhealth approach as a more efficient and sustained proxy in HIV and TB risk reduction strategies for early diagnosis and prompt quality clinical outcomes. It can significantly contribute to decreasing health systems/patients cost, long waiting time in clinics, hospital visits, travels and time off/on from work. Improved integrated HIV and TB telemonitoring systems sustainability hold great promise in health systems strengthening including patient centered early diagnosis and care delivery systems, uptake and retention to medications/services and improving patients’ survival and quality of life.Conclusion: Telemonitoring/mhealth acceptability, access and uptake are crucial in monitoring and improving uptake, retention,adherence and coverage in both local and national integrated HIV and TB programs and interventions. Moreover, telemonitoring is crucial in patient-providers-health professional partnership, real-time quality care and service delivery, antiretroviral and anti-tuberculous drugs improvement, susceptibility monitoring and prescription choice, reinforcing cost effective HIV and TB integrated therapy model and survival rate. Sub-Saharan Africa needs innovative technology applications and tools  that facilitate effective and efficient epidemiologic, clinical and behavioral surveillance data collection for evidence-based health systems thereby reengineering resilient behavioural improvements. Digital and social media innovations such as mobile phones electronic and internet chatting, televideo and messaging integrated into primary healthcare policies of safety and precautionary measures, awareness, consultations and counseling can ease open access and enhance patient care, treatment, adherence, monitoring as well as open access to patient-data sharing amongst professionals and providers thereby improving quality of health, life and productivity.5This has restricted the integration of telemonitoring strategies to enhance HIV and TB sustained interventions uptake, compliance and coverage to empower positive behavioural changes in most settingsa.8 whereas only few pilot studies have been conducted in selected Africa countries.9 The impact of telemonitoring is unequivocal in these settings.8 It may be helpful in expansion and scaling up healthcare services delivery, revamping community health workers and allied workforce performance and efficiency, reaching remote and hard to reach communities. Likewise, assists in increasing mutual dialogue and participation between patient and care provider and health professionals, thus, lessening the challenges of traditional healthcare face to face and onsite, as well as distant counseling and diagnosis, treatment of patients by health care providers.10 Telemonitoring has been proven as a cheap, potential and sustained health care delivery process when compared to traditional standards.10 For example, telemonitoring has been found to reduce hospital saving from €40 397.00 per patient to less than €36 802.97 among cystic fibrosis patients.10Telemonitoring expatiated as the use of mhealth or ehealth approaches  to access, monitor and improve uptake, retention adherence and coverage of HIV and TB programs effectiveness remain valuable expedite tool in health systems strengthening. This has been used in various settings to monitor and improve patient outcomes accounting in significant reductions in patients waiting time in hospital settings,This paper therefore explored the promising of real-time and contextual telemonitoring systems in revamping HIV, TB and national immunization access, retention, adherence and coverage programs in sub-Saharan Africa settings and other endemic-prone countries.To ascertain the importance of telemonitoring approaches in reinforcing sustainability of HIV/TB prevention/treatment interventions in sub-Saharan Africa, authors used various journal indexing platforms to access articles describing electronic and messaging health technology that enhances patient curative care, quality of care and healthcare policies relevant to African settings. The scoping review design-method was applied to synthesize the information extracted from indexed journal research hubs. Medline, Pubmed, MeSH PsycInfo, Scopus and Google Scholar journal indexing bodies were used to assess and identify the relevant telemonitoring articles. The search terms used in locating relevant articles were “Telemedicine community engagement HIV/TB, or telemonitoring community engagement HIV/TB or mhealth community engagement HIV/TB or electronic messaging community engagement HIV/TB” tactics in social behavioural changes. The reference articles were those published in English and French languages only.12 Building the enabling environment, community partnership and participatory community engagement (PCE) are essential for long-term access, trust and uptake of innovative HIV/TB telemedicine approaches and interventions as shown in Understanding the local context, cultural norms and ecological issues and challenges can play a significant role in the design and integration of HIV and TB telemonitoring programs. The spectrum of cultural and socio-ecological engagement can lead to integrating HIV/TB prevention into the community life style.12 The local socio-cultural ecological cascades in this context are trusted community delivery platforms that are policy-driven and ensure HIV and TB prevention and treatment interventions in reaching the target populations. These may include the access and uptake coverage to quality programs and strategies coupled with ownership, shared accountability and transparency.The prevention cascade can be achieved by targeting the entire cultural and socio-ecological framework cascade that reduces risk perception/awareness and enhances acceptability and adoption of the prevention/treatment approaches.13 Hence, contextual evidence-based premises such as PCE are cost effective and essential entry points that support and addresses health interventions uptake at various levels of the ecological framework, compared to the existing conventional methods of care delivery.11 For example, local ecological cascade has been used in addressing programs among hard to reach men who have sex with men in resistant communities.14 Based on the PCE ecological model, community interventions have been found associated with greater awareness and healthier behavioral outcomes.15There is an urgent need to increase collective community engagement in adoption, acceptability and sustained telemonitoring uptake approaches that initiate and expand early HIV and TB prevention and treatment programs. Community dialogue and PCE have been vindicated and proven as programs to support integrated HIV/AIDS and TB telemonitoring platforms.15 Therefore, an effective uptake and treatment of TB and HIV or immunization program coverage is a function of innovative and sustained stakeholders’ engagement and leadership. The increase sensitization, awareness, participation and motivation of stakeholders in PCE16 play a significant role especially in designing quality-driven programs, recruitment and programs implementation. For example, the use of mobile phones and social media are common communication technological phenomenon in Africa today. More to that, in sub-Saharan Africa there is hardly no family without a mobile or social media facility3 which can be adapted and used in mobile health monitoring. Several mobile health technology platform including android/smartphones or iPads-enabled devices using Open Data Kit (ODK) software format such as video, audio, visual and text messaging may be helpful in modifying the disease surveillance and monitoring.9 To ensure the effectiveness, appropriateness and acceptability of the integrated HIV/TB telemonitoring, PCE must be properly planned with coordinated implementation.3 Therefore, strengthening community engagement uptake and retention toward ownership processes must be implemented with proper culturally dignified approach, local trust and accountability. The use of PCE can act as pathway to systematic evaluation of process indicators, outcomes and impact of HIV and TB treatment and prevention programs. For example, coverage and uptake of HIV and TB surveillance and monitoring depends on the sustained uptake and adoption of the intervention at various stages of the stakeholder engagement.16 This depends on the PCE fidelity, integrity, honesty, community respect/trust and the delivery of the program.Implementing telemonitoring approaches, framework and interventions of HIV and TB prevention holds great promises and opportunities in strengthening HIV and TB prevention and subsequently healthier communities’ lifestyles.17 In such PCE environment, the stigma and other structural factors including the questions on what the HIV and TB intervention is all about, and how it will be implemented and structured and the involvement of the community are discussed. Moreover, the functions and resources including benefits, time and dissemination of findings are also discussed in PCE.14 Implementing PCE can promote ethical and legal conduct on how interventions can be implemented successfully in local context including retention and adherence.18The engagement of communities with stigmatized diseases such as HIV and TB in health promotion programs is not an easy process. It requires appropriate and culturally improved communication skills as well as thought and buy-in planning. This is embedded in a constituted awareness and motivation meetings with diverse stakeholders including health officials, local community health workers, local and international non-profit organizations (NGOs), community leaders, faith-based organizations, stakeholders-policy makers, gate keepers, local women/ men association. This framework is based on trust and legal structures that enhances and maximizes programme strength, improvement as well as sustainability. Thus, such an engagement may increase public perception and altitude against fear and myth on HIV and TB co-infections using PCE strategy.18 unlike the social determinants of health within which education is driven in one direction leading to better health outcomes. As previously demonstrated the individuals with higher level of education may be associated with both lower and higher levels of vaccine acceptance.20 The limiting factors that hinder immunization coverage across the globe and predominantly in Africa are majorly from hesitancy determinants matrix that encompass; (1) contextual influences- of historic, socio-cultural, environmental, health system/institutional, economic or political factors, (2) ecological influences arising from personal perception of the vaccine or social/peer environment and (3) fear and misconception related to vaccine and vaccination specific issues, such as polio immunization linked infertility issue in Northern Nigeria.18 Some other barriers may include vaccination schedule, mode of administration and reliability and/or the source of vaccine and/or vaccine related equipment drawbacks.21 Thus, HIV and TB teledata-sharing platform has the capacity to enhance the patient and providers awareness through constructive debates and taming out the patients and communities for hesitancy risk impact in attaining the global HIV/AIDS and End TB goals.1 With this background, fostering the benefit of integrated HIV and TB telemonitoring platform, policy and interventions is crucial to prevent new infections, increasing community resilience and programs ownership in early diagnosis and care seeking, packages uptake and quality life outcomes.25 Telemonitoring approaches implementation in integrated HIV and TB programs for provides real-time and immense opportunities in improving primary healthcare access and treatment adherence, as well. Improving treatment adherence may diminish the rising trend of new infections and multidrug resistance in urban and rural remote settings in sub-Saharan Africa.25It is critical to note that vaccine hesitancy determinants  like education and socio-economic status do not influence hesitancy in only one direction,25 Furthermore, there is a growing body of evidence for raising the new HIV infections rate which may probably due to unsafe sexual intercourse and drug users, gender inequities in family and society disparities, cultural practices including child marriage, polygamy/concubine and condom user non satisfaction that exacerbate the spread of HIV and hindered health and socio-economic development. These contributions are poorly documented and unclear in several settings in Africa and require further operational investigations.25 In addition, strengthening quality access and care uptake interventions including modern contraceptive methods amongst female sex workers and tattooing, detainees, drugs abuse and men who inject non-sterile needles, male homosexuals is crucial. Boosting community engagement, awareness and empowerment on social, ecological and cultural-related aspects of exposure and vulnerability factors and promoters which are associated with persistent transmission dynamics is important in escalating the benefits of future health and economic programs.There is increasing concern on the rising new infections pattern and trend in the region which requires more proactive policy and action in scaling-up HIV and TB surveillance which may be helpful in access to preventive measures .15 Coordinated, appropriate and sustained efforts are needed to reduce drug use-related risk behaviors, including risky injection practices and unsafe sex, transactional sex, trading sex for drugs, sharing contaminated needles/blades in tattooing, homosexuality, and circumcision.25Tackling the new trend and pattern of HIV and TB infections, drug and multiresistance emerging from social and behavioural, economic and cultural barriers and challenges to access, uptake and retention requires developing and scaling up new tactics capitalizing on effective early access to and use of mobile health and social media telemonitoring surveillance and control programs. Moreover, increasing the rate of pre-exposure prophylaxis (PrEP) and antiretroviral treatment (ART) intervention activities aiming at prevention or reduction of new HIV infection and opportunistic illnesses are in line with the global HIV agenda, 2030.20 Timely access of comprehensive and coherent HIV/TB barriers and challenges data and information is core for improvement and guiding evidence-based policies, programs and services formulation and implementation. Likewise, improved integrated HIV/TB advocacy and care programs implementation that to support telemedicine and socio-behavioral programs and services such as early family planning, reproductive and sexual education and awareness, counseling pre and post HIV testing, HIV home-based and personalized care and/or follow-up care management, and psychosocial and legal services.Furthermore, promoting antimicrobial resistance stewardship in inappropriate use of antiretroviral and anti TB drugs as well as increasing adherence to treatment and preventive measures may help easy reaction against adverse ART. In addition, strengthening patients and their families in nosocomial TB preventive measures by health workers may be a good practice. The other best practices to prevent the HIV and TB-associated risks are increasing public awareness and free mental health telecounseling services, reducing the laboratory tests cost and the out of pocket medication as well as prohibiting stigmatization and discrimination of people living with HIV/AIDS and TB through social support systems.(a) Investing real-time and contextual mobile health and social media HIV and TB open access surveillance and monitoring approaches in revamping sustainability of national TB immunization effectiveness and improving PrEP, as well as access to effective programs and interventions in endemic-prone settings.(b) Promoting research and development (R&D) nvestment in telemonitoring technologies and applications innovations as key indicators for early monitoring of treatment failure and patient triage for appropriate and personalized intervention prioritization.(c) Promoting national and regional integrated HIV and TB telemedicine and telemonitoring programs advocated and supported by African governments and local stakeholders.(d) Strengthening telemonitoring capability ito improve the patients and care providers quality of life.(e) Addressing telemonitoring implementation barriers and challenges that include patient privacy and confidentiality, data sharing, digital literacy and language barriers, unreliable connectivity and telecommunication coverage aimed accelerating patient and providers’ telemonitoring technologies, applications and approaches for diagnosis in clinical sectors.Telemonitoring and mhealth approaches are hold immerse future in real-time and promising array of opportunities in improving primary healthcare especially increasing access and long-term uptake of preventive and treatment including HIV/TB in Sub-Saharan Africa. Fostering telemonitoring science and practice adoption and implementation in chronic and emerging infectious diseases threat and epidemics including retention, adherence and sustained programs is imperative in increasing the quality and performance of service delivery in rural and urban settings. Therefore, investing in simple, cost-effective and reliable telemonitoring science and practice approach implementation is vital to promote and scale up acceptability, trust and performance in health systems strengthening, regulatory compliance, patient-health professional and care providers dialogue and feedback. Other areas include boosting social security such as medical insurance, billing and reimbursement scheme integrated into routine telemonitoring primary care and practices in sub Saharan Africa.Not applicable.The authors declare no conflict of interest.ET conceived the idea and performed the initial literature and manuscript draft. ET, CSY and CKW supported with additional information. ET, CSY, CKW, GM and JYN provided further inputs. ET critically revised the manuscript. All authors read and approved the final manuscript.The review does not reflect the official views or policies of any institution or body nor its planned design and construct but the views of the authors.We are grateful to the valuable discussions and inputs from our field staff and students.


File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material,  DISEASE diagnosis, one of the primary goals of medicine, is a process to discover the origin or nature of disease in a particular patient. Without an accurate diagnosis, we can neither identify the cause nor design an effective treatment strategy to suppress or ameliorate the condition. Many patients with rare conditions undergo a “diagnostic odyssey,” a long and frustrating journey to obtain an accurate diagnosis. Several organizations have estimated that ∼80% of these undiagnosed diseases have a genetic origin .Advanced technology is increasingly important for diagnosis and has been transformative for rare Mendelian disorders , made clear the priority that model organism research should have in biomedical research.Studying human genomic variants in model organisms is facilitated by collaboration between clinicians and model organism researchers (Drosophila and zebrafish (Undiagnosed Diseases Network (UDN) with its centralized Model Organisms Screening Center (MOSC) (the Centers for Mendelian Genomics (CMG) (Canadian Rare Diseases Models and Mechanisms Network (RDMM) provide exciting opportunities for model organism researchers, human geneticists, and clinicians to collaborate to determine the potential pathogenicity of disease-linked rare variants, gain deeper pathophysiological understanding of diseases, and discover potential treatments and therapies for patients and families. Lessons learned from these complementary projects will likely lead to the establishment of an efficient framework for facilitating the diagnosis and study of rare diseases.In this article, we show how model organism research can be integral to unraveling the molecular mechanisms of disease. We begin this discussion with illustrative examples that document the value model organisms have brought to human disease research, including Mendelian diseases and cancer. We highlight three approaches for engaging model organism laboratories with the expanding list of human genes and variants requiring functional annotation. We primarily focus on two model organisms—ebrafish —and highBiologists often focus on differences among organisms. Indeed, the diversity of life is staggering. Our first impulse is to assume that this diversity arises from different developmental mechanisms, and that these processes must rely on different genes, signaling pathways, and molecular events. For example, it is difficult to comprehend that a fruit fly or a fish could share many genes and signaling pathways with humans. They differ in so many morphological features, and their physiology seems so different, that we tend to imagine there are no or very few commonalities. It was therefore surprising when it became apparent in the 1980s and 1990s that numerous genes are conserved across species and are used repeatedly in many different contexts.Aplysia , and identification of conserved developmental genes and pathways  had major impacts on biomedical research. Basic knowledge obtained from model organism research is now being translated to mammalian contexts with remarkable speed. For example, control of organ growth and size was shown to be regulated by genes of the Hippo signaling pathway in flies in 2003  (ROR2 (DVL1 (DVL3 (dishevelled gene) cause Robinow syndrome. Thus, although flies do not have an endoskeleton like in vertebrates, conserved genetic machinery that regulates wing patterning in Drosophila is responsible for skeletal and craniofacial defects in humans. This parsimony arises because evolutionarily conserved molecular pathways are reused in different cellular contexts and tissues.Flies and fish have tissues and organs that are specific to their phyla. One may wonder if wings of flies or dorsal fins in fish can teach us something that is directly relevant to human development or physiology. Mutations that affect the development of wings in flies pioneered the characterization of key developmental pathways such as the Notch  and Wingless (Wnt) signaling pathways. Interestingly, pathogenic variants in many genes in the Wnt pathway in humans cause Robinow syndrome—a severe skeletal dysplasia with short stature, short limbs and digits, dysmorphic facial features, and a variety of other problems including cardiac anomalies . Pathogenic variants in C. elegans genes that mutate to cause a high frequency of male offspring. While the phenotypes in humans (breast cancer) and worms  do not appear related, they derive from common underlying genetic defects (subset of genes involved in DNA damage response). Once these nonobvious relationships are documented, then additional genetic links can be made between models and humans  can be replaced by their human counterparts  gene. Studies in the 1960s identified a nonphototaxic fly mutant with a distinct electroretinogram phenotype , loss-of-function (LOF) or modulation -of-function mechanisms. The most extreme disease is caused by TRPV4 (brachyolmias type 3 (MIM# 113500), which is characterized by short trunk, short stature, and scoliosis, as well as a series of more severe skeletal dysplasias, is due to GOF missense mutations in TRPV4 that causes the channels to be activated by stimuli to which they would not normally respond  and Charcot-Marie-Tooth disease type 2C (MIM# 606071) (Drosophila.One of the earliest examples of a henotype . Subsequhenotype . TRP chahenotype . Insight 606071) . HeterozResearch on zebrafish complements research on flies because zebrafish share vertebrate-specific features with human, such as similar organ structures. Zebrafish offer a number of experimental advantages for investigation of human disease mechanisms and therapeutic strategies . Chief aBRAF gene is the most frequent mutation driving human melanomas, but mutations in other genes are required for metastasis  that cooperates with V600EBRAF to drive melanoma formation and growth , such as the anti-inflammatory drug leflunomide, as suppressors of neural crest development and melanoma formation  as an example of Mendel’s laws operating in humans (vs. 17.5% for adults (Online Mendelian Inheritance in Man (OMIM) reveals 8487 human disease phenotypes with suspected Mendelian basis, of which 6017 (70.9%) have a known molecular basis.The study of Mendelian disorders has yielded many significant insights into human biology, starting with the recognition of n humans , 1923. TCMGs  produced discoveries of 956 genes, including 375 not previously associated with human disease  has funded several sequencing centers to use next-generation sequencing techniques, primarily whole-exome sequencing, to identify and describe as many Mendelian disorders as possible , caused a later onset retinal phenotype not previously seen with CRX variants. Such a finding is often referred to as a “phenotypic expansion” of a known disease-linked gene. In another example, a novel disease gene whose biological function was poorly characterized (ANKLE2) was discovered to be linked to autosomal recessive primary microcephaly 16 (MIM# 616681). Within 2 years of the publication of the screen of these 153 fly genes, an additional ∼15% of the genes have become linked to Mendelian diseases. A key insight from this study led to the realization that essential genes in Drosophila with more than one human homolog are eight times more likely to be associated with Mendelian diseases, allowing the prioritization of disease candidate genes  and TANGO2  and EMC1 (Harel-Yoon syndrome (MIM# 617183) and ATAD3A  and KATNB1 (steroid-resistant nephrotic syndrome (MIM# 615573) and ADCK4      and INTU in ciliopathy syndromes  with Texas Children’s Hospital, Vanderbilt University Medical Center, Duke Medicine with Columbia University Medical Center, Harvard Teaching Hospitals  and NIH], two Sequencing Cores , one Model Organisms Screening Center , one Metabolomics Core , and one Coordination Center  (NR5A1 in human sex determination (ASXL2 and Shashi-Pena syndrome (MIM# 617190)  (The successes of the UDP continued after expansion to the UDN ( School) . Recent Given its approach as a network providing in-depth clinical evaluation for the most difficult to diagnose cases, the UDN faces several challenges. For example, genomic discovery in single patients is dramatically hampered by the lack of statistical power. In this context, the need for the UDN to functionally validate candidate gene variants is paramount. Therefore, extensive phenotyping , precise genotyping (performed by the Sequencing Cores), functional exploration of candidate genes and variants (performed by the MOSC) and integration of this information (performed by the Coordination Center) are all key aspects of such a patient-centered effort.ExAC (Exome Aggregation Consortium) browser (de novo missense variant in the nucleus accumbens associated 1 (NACC1) gene as one of several candidates for the child’s disorder. Very little gene and protein function information was available to aid in determining whether the NACC1 variant might be disease-causing. Working with the MOSC, a resulting collaboration between the UDN and the CMG, posting of the gene on GeneMatcher, and identification of additional cases in clinical laboratories including Baylor Genetics and UCLA Clinical Genomics Center, demonstrated a clear role for this de novo variant in the patient’s phenotype. The combined data of these efforts led from the initial “n = 1” to identification of a total of seven individuals from seven independent families, all with the same de novo missense variant in NACC1 and presenting with the same disease phenotypes  automates most of these searches and allows anyone to quickly retrieve the relevant information in a simple comprehensive format  are assigned to the Drosophila Core, and the remaining (∼35%) genes are assigned to the Zebrafish Core. Occasionally, variants identified in diseases that affect vertebrate specific organ systems such as bone and neural crest derived structures are also assigned to the fish core.Next, genes are assigned to the enotypes . Genes tDrosophila Core, experiments are tailored to each gene and variant using diverse genetic strategies. One strategy depends on the versatile engineered transposable element, MiMIC (Minos-mediated integration cassette)  may be available or rescue with human cDNA may not always be successful  and Cas9 mRNA or protein into one-cell zebrafish embryos, where gene editing occurs during early cleavage divisions of the embryo. This results in large clones of mutant cells, several of which almost invariably enter the germline. To increase throughput, the Core combines multiple gRNAs targeting different genes in the same injection (de novo variants in EBF3 using Drosophila (de novo variant of unknown significance in EBF3 (Early B-Cell Factor 3), the MOSC identified two additional patients with de novo variants altering the same amino acid of the EBF3 protein through collaborative database searches. In addition, using a MiMIC insertion line in the fly EBF3 ortholog knot—a gene that was well-studied in the context of neural development—the MOSC showed that a reference human EBF3 cDNA can rescue the lethality of the fly knot LOF mutation, showing that human EBF3 can functionally replace the Drosophila ortholog. The missense de novo variants found in the patient abolished the ability of human EBF3 to rescue mutant flies  via knowledge of a disease gene pathway; and (4) establishment of longer term collaborations between basic scientists and clinicians that will lead to basic or applied research.In Canada, a series of rare disease gene discovery projects, including FORGE (Finding of Rare Disease Genes)  ]; Italy (Telethon Undiagnosed Diseases Program); and Australia and New Zealand [Undiagnosed Diseases Program—Australia and New Zealand  and the International Rare Diseases Research Consortium (IRDiRC), is beginning to facilitate interactions and information exchange among undiagnosed disease researchers worldwide. Patient advocate organizations such as National Organization for Rare Disorders (NORD) and European Organization for Rare Diseases (EURORDIS) collaborate with these consortia to facilitate diagnoses and research of rare diseases. In the absence of functional data, much of the current efforts are focused around identifying a second patient with overlapping phenotypes and genotypes to try to solve the more difficult “n = 1” cases. Considering that functional information of genes and variants will be necessary for most new disease genes and variants of unknown significance that are discovered through these efforts, we foresee that an international network of model organism researchers will boost the pace of disease gene discovery and downstream mechanistic studies necessary for understanding pathogenesis.A number of institutes and organizations around the world are actively engaged in undiagnosed rare diseases research: Japan [The drive to assess the function of human genes based on model organism research will continue to increase. As our knowledge deepens, understanding the role of human genes will greatly benefit from this knowledge base. Several general themes are emerging that will pave the way forward.TRPV4 locus with different mutations causing distinct diseases, as described earlier. Therefore, the key role of model organisms to facilitate understanding of the many functions of a pleiotropic gene cannot be overstated.Pleiotropy is the phenomenon of mutations in the same gene causing multiple phenotypes. This can be due to a gene being used in different tissues or at different stages of development, or encoding a protein that has more than one molecular function. Insights from human genome sequencing efforts provided several examples of pleiotropy. For instance, sequencing often uncovers a known disease gene in a patient with undiagnosed disease, and, in retrospect, the variant is diagnostic. However, the gene might not have been considered initially because the patient did not precisely match what was previously understood about the clinical phenotype of the disease; in retrospect, the patient’s symptoms extended beyond what were previously recognized as the core clinical features. This realization of “phenotypic expansion” is a product of limited clinical descriptions and the inherent pleiotropy of many human genes (microRNA-140 (miR-140) regulates palate formation in zebrafish , then gene knockdown or overexpression in model organisms may be productive , ExAC and its expansion project gnomAD (Genome Aggregation Database) (Geno2MP (the DiscovEHR Collaboration (Matchmaker Exchange (MME)   Patient Archive are connected to one another, thereby supporting queries of data from >20,000 unrelated patients, and facilitating prioritization of genes and variants.Genetic diagnoses have greatly benefitted from information in numerous human databases. Efforts to use human genomics for diagnosis depend on comparing candidate variants to other variants at the locus found in other databases. The success of efforts, such as Saccharomyces Genome Database , Pombase (fission yeast), C. elegans)WormBase FlyBase , Mouse Genome Informatics , and Rat Genome Database , are critical to mine, organize, and curate biological information required to prioritize candidate disease genes. Although databases and mining tools integrating information from multiple key model organism databases and corresponding human genes are being developed by the Alliance of Genome Resources, the Monarch Initiative, and other efforts such as MARRVEL and Gene2Function, specific model organism databases will continue to play a critical role because they curate and annotate organism-specific datasets that are seminal to their respective research communities. For example, FlyBase  consortium Bloomington , Caenorhabditis Genetics Center (CGC), Zebrafish International Resource Center (ZIRC), Mutant Mouse Resource and Research Centers (MMRRC), and Mouse Mutant Resource (MMR) that assist in the maintenance of these and other useful mutant and transgenic resources depend upon continued support by the NIH, international research community, and end-users. By combining these resources, and the genotype to phenotype information obtained from human patients, one can more rapidly study the LOF phenotype, test whether the molecular function of the human and model organism genes are conserved, determine whether a variant of unknown significance is functional, study the expression pattern and subcellular localization of the protein of interest, identify physical interaction partners, and understand the function of the gene in the organ system and cell type of interest  approach and the distributive (RDMM) approach may ultimately be the best way to study candidate variants in model organisms. A potential workflow would be first to engage a primary center where genome biologists check variants against other human genomic datasets, chose the ideal model organism, select the best technologies, efficiently and economically generate the reagents, and rapidly test candidate variants. The acquired information and reagents could then be distributed to expert colleagues who wish to pursue the biology of the gene and disease in depth. Structuring multi-organism teams in the face of rapidly expanding lists of candidate variants and genes is a challenge that requires clinicians, human geneticists, bioinformaticians, and model organism investigators to work together. This collaboration allows rapid translation of knowledge obtained in one species to another and avoids duplication of effort. Integrating and acknowledging the strengths of each model organism is required to accelerate discoveries that identify pathogenic mechanisms and lead to development of novel therapeutic strategies.Click here for additional data file.


Hispanics are the largest minority group in the USA. They contribute to the economy, cultural diversity, and health of the nation. Assessing their health status and health needs is key to inform health policy formulation and program implementation. To this end, we conducted a scoping review of the literature and national statistics on Hispanic health in the USA using a modified social-ecological framework that includes social determinants of health, health disparities, risk factors, and health services, as they shape the leading causes of morbidity and mortality. These social, environmental, and biological forces have modified the epidemiologic profile of Hispanics in the USA, with cancer being the leading cause of mortality, followed by cardiovascular diseases and unintentional injuries. Implementation of the Affordable Care Act has resulted in improved access to health services for Hispanics, but challenges remain due to limited cultural sensitivity, health literacy, and a shortage of Hispanic health care providers. Acculturation barriers and underinsured or uninsured status remain as major obstacles to health care access. Advantageous health outcomes from the “Hispanic Mortality Paradox” and the “Latina Birth Outcomes Paradox” persist, but health gains may be offset in the future by increasing rates of obesity and diabetes. Recommendations focus on the adoption of the Health in All Policies framework, expanding access to health care, developing cultural sensitivity in the health care workforce, and generating and disseminating research findings on Hispanic health.The online version of this article (doi:10.1186/s40985-016-0043-2) contains supplementary material, which is available to authorized users. Hispanics are the largest ethnic minority in the USA; in 2014, Hispanics comprised 17.4% of the US population (55.4 million), and this percentage is expected to increase to 28.6% (119 million) by 2060. Hispanics in the USA include native-born and foreign-born individuals immigrating from Latin America, the Caribbean, and Spain  an opportunity to identify existing health risks in women and to prevent future health problems for women and their children” .An unanswered question is whether the ACA and enhanced Medicaid perinatal care programs are having an effect on birth outcomes . InitialNonetheless, the main reasons for Hispanic women not being able to access care are (1) not being “poor enough” to qualify for Medicaid without any structured perinatal care on which to rely on; (2) unable to afford coverage offered by the ACA; and (3) born outside the USA and may not qualify for Medicaid coverage depending on their legal status and the state they live in, as there are differences in eligibility and perinatal coverage among states . It thusThe Hispanic Mortality Paradox refers to lower mortality rates and better health outcomes among foreign-born, newly arrived, and thus less acculturated Hispanics as compared to native-born Hispanics or to NHWs. Reasons for this paradox may be that migrants and first-generation Hispanics may represent a self-selected healthier population. Also, undocumented or un-acculturated Hispanics may leave the country if unhealthy or their negative health outcomes may be underreported due to lack of access to health services. Lower rates of smoking seem to be at the heart of the Hispanic Mortality Paradox; however, the obesity and diabetes epidemics, together with higher levels of inflammatory biomarkers and increasing social and environmental stressors, may offset the health advantages of Hispanics in the future , 136.The social response to health needs is implemented through health policy and programs, generically called “health services.” Typical health service indicators include access, coverage, utilization, costs and expenditures, and quality and performance. In the case of Hispanics, health literacy and cultural competence play important roles.The implementation of the ACA has increased access to health care for Hispanics; a recent survey showed that 87% of US-born Hispanics have health insurance, compared to 78% of those born outside the USA . The ACAAn analysis of four national health surveys reported higher rates (41.5%) of uninsured Hispanics ages 18–64 years  compared with 15.1% of NHWs of the same age. Moreover, foreign-born Hispanics 18–64 years were over twice as likely to be uninsured than US-born individuals . About 15.5% of Hispanics reported delayed or lack of medical care because of cost concerns compared to just 13.6% of NHWs and 12.5% did not obtain needed prescription drugs because of cost compared to just 9.5% of NHWs [Hispanics use fewer health screenings, have less follow-up care, and face more economic and cultural barriers to health care. Hispanics are 28% less likely to be screened for colorectal cancer than are NHWs. Hispanic women have less access to breast cancer and cervical cancer screening , 158.Hispanics are more likely than NHWs to receive mental health care through emergency departments rather than self-referral or outpatient services . They arThe number of Hispanic health care professionals does not mirror the total percentage of Hispanics in the USA (17.4%). Hispanic professionals have been historically underrepresented in the health professions in the USA: pharmacists make up 3.4%, physicians 5%, physician assistants 3.7%, licensed registered nurses 1.7%, and dentists 3.3% of health professionals . In 2015Hispanics comprise about 14% of the total US workforce in the USA. About 50% of the 22 million Hispanic workers in the USA are immigrants. Immigrant workers are often employed in high-risk jobs where they bear a high burden of occupational injuries, often holding temporary jobs with no health benefits. They are also often geographically mobile, thus unable to have a usual care provider and obtain continuity of care . UndocumThis scoping review provides an updated account of the social determinants of health, health inequalities, and risk factors shaping Hispanic morbidity and mortality trends in the one hand and the organized social response by health services in the other. Our review considers recent information on Hispanic subpopulation types: Hispanics born in the USA, foreign-born, undocumented, and migrant and seasonal farm workers (MSFW). The increasing heterogeneity of the Hispanic population in the USA by country of origin is also taken into account. Additionally, we provide brief updates on the Hispanic Mortality Paradox and the Latina Birth Outcomes Paradox.A multilevel, multifaceted approach, from social policy to health services, is needed to improve the health of Hispanics in the USA. We identified three priority policy and programmatic areas to be pursued.Social, environmental, and biological forces have modified the epidemiologic profile of Hispanics in the USA . Health Initiatives like those proposed by the Social Determinants of Health Work Group at the CDC offer a roadmap to address SDHs and health inequalities through five key domains: (1) economic stability, (2) education, (3) health and health care, (4) neighborhood and built environment, and (5) social community context. They identify national, state, and local resources and point out national experiences of interventions to improve social determinants of health .Intersectoral actions are key to address the diversity of social determinants of health and also involve partnering with communities to engage them and increase the pertinence of interventions. The interconnected nature of determinants of health, health inequalities, and risk factors herein presented require equally comprehensive initiatives that would not only target and help Hispanics but other ethnic and vulnerable populations sharing similar contexts, through multidisciplinary, multisectoral programs aiming at generating sustainable local capacities .The integrated approach presented in our conceptual framework reflects the opportunity for the different social sectors to share information and collaborate with direct actions targeting the different social determinants of health within their area of responsibility. For example, health authorities can collaborate with housing, urban development counterparts to generate comprehensive programs focusing on improving local housing and the built environment, as well as indoor environmental conditions. Table Unequal health insurance markets have created a variegated array of health care access for Hispanics in the USA. It is unclear how the final implementation and shape of Medicaid eligibility provided by the ACA will benefit Hispanics. Major obstacles to health care access for Hispanics should be addressed, particularly those originating from substandard employment with limited health benefits, limited number of Hispanic health care providers, cultural sensitivity, geographic mobility, and undocumented status. These barriers result in Hispanics using fewer therapeutic and preventive health services even with increased access to, and utilization of, health services through the ACA , 168.The underrepresentation of Hispanic health care workers in health professions programs must be addressed through pipeline education programs, affirmative action admissions, diversity requirements for school accreditation, tuition loan repayment programs and federal, and scholarship funding to support diversity enrichment programs. Similar Hispanic representation must be accomplished at all levels of decision-making and services, following the Health in All Policies framework outlined above, to respond to the changing demographic and health profiles of Hispanics in the USA .Enhancing cultural sensitivity and health literacy is needed to increase Hispanics’ access to and utilization of health services, particularly for controlling chronic diseases, fostering healthy lifestyles, obesity prevention, workplace safety, and utilization of preventive and screening services . SpanishMigration forces to the USA are diverse; multilateral country collaborations between migrant sender and recipient communities are needed to develop health care programs for Hispanics. Immigrants’ access to health services varies among states according to legal status, country of origin, and cultural and linguistic issues. For example, Puerto Ricans have citizenship rights in the USA and refugees and asylees in the USA are granted Medicaid coverage in the USA . UndocumEfforts should continue to disseminate the results of health disparities research and promotion and risk prevention strategies among Hispanics. Research must capture and interpret the sociocultural factors to explain Hispanic health inequalities by improving the terminology to identify Hispanics  and incrThe complexity of factors impinging on Hispanic health requires addressing the social determinants of health related to the quality of the social and physical environment where Hispanics live and work, including neighborhoods, housing, transportation, and environmental and employment conditions.The changing profile of Hispanic morbidity and mortality offers new opportunities to further address the main morbidity and mortality causes and further the health outcomes underlying the Hispanic and Latina Birth Outcomes Paradoxes by curbing the obesity epidemic, expanding antenatal and perinatal care, preventing and ceasing smoking, and decreasing workplace hazards.Limited cultural sensitivity, health illiteracy, and a shortage of Hispanic health care providers remain as the main barriers to access to health services for Hispanics. Even for those with access to health care services, underutilization of preventive care is still a challenge. Migrant and undocumented workers are disproportionately exposed to health risks in the workplace, with limited access to health services.Multiple gaps are evident regarding knowledge needed to improve Hispanic health. The weight of the evidence on Hispanic health is mostly from cross-sectional studies that offer nationwide averages, obscuring focalized health disparities and inequalities. The health of Hispanics in the USA differs by demographic, ethnic, and cultural subgroups. Understanding and addressing Hispanic health issues in a comprehensive way requires a targeted approach to country of origin and idiosyncrasy.The framework and scoping methodology guiding this review allow a comprehensive approach to assessing and monitoring Hispanic health in the USA and may be replicated at the state and local levels to evaluate the impact of social and health policies.Additional file 1:Supplemental Material. Review papers on Hispanic Health cited in PubMed from 2006 through September 2016. (DOCX 36 kb)


During the United States economic recession of 2008–2011, the number of homeless and unstably housed people in the United States increased considerably. Homeless adult women and unaccompanied homeless youth make up the most marginal segments of this population. Because homeless individuals are a hard to reach population, research into these marginal groups has traditionally been a challenge for researchers interested in substance abuse and mental health. Network analysis techniques and research strategies offer means for dealing with traditional challenges such as missing sampling frames, variation in definitions of homelessness and study inclusion criteria, and enumeration/population estimation procedures. This review focuses on the need for, and recent steps toward, solutions to these problems that involve network science strategies for data collection and analysis. Research from a range of fields is reviewed and organized according to a new stress process framework aimed at understanding how homeless status interacts with issues related to substance abuse and mental health. Three types of network innovation are discussed: network scale-up methods, a network ecology approach to social resources, and the integration of network variables into the proposed stress process model of homeless substance abuse and mental health. By employing network methods and integrating these methods into existing models, research on homeless and unstably housed women and unaccompanied young people can address existing research challenges and promote more effective intervention and care programs. During the United States economic recession of 2008–2011, poverty levels increased substantially, as did the number of “doubled-up” households, foreclosures, those on welfare and homeless adults and children [Homeless and unstably housed youth [HUHY] make up one of the most vulnerable populations in the U.S. They often are victims of caretaker physical and sexual abuse –5], fam, fam5], i.e., HIV+ samples, in-treatment/clinical samples). Although HA women are one of the fastest growing segments of the homeless population in the United States  women remain a significantly understudied population. Perhaps because women make up a lower percentage of homeless adults, studies of HA women are relatively scarce in comparison to both general studies of HA and studies of male HA. What few studies exist of specifically female HA are characterized by small sample sizes and restricted to a single location in predominantly large coastal cities. There are few regional or longitudinal studies of HA women in the United States. Of the few studies of female HA, a significant number focus only on specific subpopulations of HA women .Understanding the size and distribution of the full spectrum of HUHY and HA women housing needs is critical. The most recent estimates of the number HUHY range from 380,000  to 1,500Beyond housing status, there is consensus that HUHY tend to cluster by identity and/or subsistence strategies, , furtherFor all these reasons, reaching the full spectrum of HUHY is crucial, and delays in doing so are costly in both personal and social terms. There is plentiful evidence that the number and length of homeless episodes are central factors in risk for victimization and stress . There iet al.  and and69] aet al. ). Yet boet al. –80]..et al. . Th. Th84]. et al. noted more than a decade ago . R. R109]. lter use  and redulter use . As theslter use . This inTo make matters worse, most studies of homeless youth have not provided adequate comparison groups among those marginally housed and those currently experiencing an episode of homelessness who may be co-participants in many of the same activities or behaviors. As noted above, the relationship between HIV/HepC risk  and the range of housing statuses remains murky; while it may be well known in some places  114], i, i114], Both stress and substance abuse/dependence disorders (SAD) are disproportionately high among homeless adult populations. Available evidence indicates that homeless adults experience significantly more stressors than other populations, including low-income housed adults . In partHomeless women encounter more stressors and strains on average than housed women. They are more likely to be victims of violence  and sexuet al.’s study , a, a123], ’s study  comparin’s study  128], a, aet al.et al. ’s risk amplification model [These factors can be captured under a single model that combines a classic stress process model  130] wi wi130] won model  to consiThus, for example, it could be that HA women who engage in higher levels of substance use and/or have substance abuse and dependence disorders often experience more stressors (path B), whose manifestation is perpetuated by their substance abuse/dependence (path A). These together can perpetuate homeless outcomes  that later contribute to failed efforts to exit homelessness though failures of program compliance. Examples of such simultaneous cause/effect/cause relationships are well documented in the literature: for example, being under the influence of drugs or alcohol places homeless people on the street at higher risk of being victimized , which iThis model also takes into account the role of prior stressors. Women’s experiences prior to becoming homeless, including during childhood, are often predictive of both later homelessness and SAD (path C). Stressors in childhood such as child maltreatment have been associated with risk for adult alcohol use disorders . CompareResearch on the topic of homeless women and substance use/abuse is timely given recent economic changes that have increased the homeless population in suburban and rural areas. Nationally, between 2007 and 2010, the number of homeless families is estimated to have increased by 20% and the number of those families using shelters increased by 57% . A recenApparent ethnic/racial differences among HA women may mask more salient social differences related to broad political economic changes, particularly in the aftermath of the social transformations that have taken place in the last several years. No current or previous study has examined how racial/ethnic outcomes may be related to differing levels of social capital and social network access in a rapidly changing rural political economy. Shelter populations in mid-size Central US cities now contain women from longstanding, historically urban African American populations, newly arrived white women displaced by changes in agricultural economies, Hispanic women who have immigrated more recently to work in the emerging rural economy, and Native American women who move between reservation and urban margins. Together, they represent a significant departure from past populations. Such personal historical differences necessarily provide different levels of social support that significantly impact both the ability to transcend homeless and deal with substance use/abuse issues.In the Central US, the housing crisis may have both masked and accelerated ongoing rural social changes  149]. M. M149]. In this view, racial and ethnic differences in homeless trajectories  would be seen as closely related to differences in the social networks of support and influence, which themselves are products of markedly distinct roles that women of different ethnic and racial groups play in the emerging rural economy of the Central US. For white women in the region, rural economic decline has, for some, meant a descent into poverty and resulting strained family ties, internal migration, and new forms of welfare dependency. In contrast, Hispanic migrant women, many of whom lack legal documentation, can draw on little support when domestic or economic changes overwhelm personal resources. African American women in the region are primarily urban, and many are able to retain social networks despite tenuous economic status . And Native American women often move in and out of social networks as conditions in home reservation communities prompt circular patterns of migration into and out of regional urban areas.In each case, individual social networks reflect these historical differences, and are reflected in individual histories of housing instability and homelessness. If different groups, seemingly identifiable by racial or ethnic background, draw on very different networks of support, then their differential paths out of homelessness would likely be very different. To the extent that homelessness itself is a recognized vector for both substance abuse and health deterioration, the ability to tailor programs to specific needs (toward and from desired and undesired influences) represents an important step forward in our ability to meet the needs of what, on the surface, may seem a uniformly needy population.i.e., selecting substance using network members) as well as by damaging relationships with prosocial members (path G). These networks then may be an important mediator in the substance use-to-stress association.Network considerations can be added as mediators and moderators of the new stress process model shown in At stake in such a network-enabled model is the ability to better predict homeless outcomes. Being homeless often necessitates adaptive behaviors as survival mechanisms, including sex work and deviant subsistence strategies (path H). SAD may also facilitate negative behaviors associated with abuse/addiction, such as risky sexual behaviors and deviant subsistence strategies (path I). In a study of homeless young people in four cities, being unemployed and having drug problems increased the odds of engaging in risky survival strategies . FurtherContextualizing this entire model is the larger question of ethnic/racial differences in homeless outcomes (dashed circle). These differences may appear in any of the relationships in the model. For instance, distributions of stress and adversity may be highest among African Americans , which mThere are clear payoffs from defining network actors and ties more broadly: chiefly, in this model people are not only seen as sources of resources, they are also seen as sources of resource competition . Given tThis review argues that network techniques can play an important role in understanding substance abuse and HIV/hepatitis risk among two segments of the US homeless population: homeless adult women and homeless and unstably housed youth. In the last three decades, the use of network techniques has grown significantly public health research. We have discussed evidence that supports the greater use of network data collection and analysis in three areas: 1) population enumeration of the homeless and unstably housed, especially homeless youth , 2) a sociometric approach to homeless adult resource use and competition (using a network ecology approach), and 3) the integration of network factors into existing stress process models aimed at understanding substance abuse and mental health interactions (using a network-enhanced stress process model shown above). Together these elements hold out promise for greater integration of existing research findings, which in turn can help intervention planners to more successfully meet the needs of a group that has grown in both size and complexity over the last decade.


Substance use–related communication for drug use promotion and its prevention is widely prevalent on social media. Social media big data involve naturally occurring communication phenomena that are observable through social media platforms, which can be used in computational or scalable solutions to generate data-driven inferences. Despite the promising potential to utilize social media big data to monitor and treat substance use problems, the characteristics, mechanisms, and outcomes of substance use–related communications on social media are largely unknown. Understanding these aspects can help researchers effectively leverage social media big data and platforms for observation and health communication outreach for people with substance use problems.The objective of this critical review was to determine how social media big data can be used to understand communication and behavioral patterns of problematic use of prescription drugs. We elaborate on theoretical applications, ethical challenges and methodological considerations when using social media big data for research on drug abuse and addiction. Based on a critical review process, we propose a typology with key initiatives to address the knowledge gap in the use of social media for research on prescription drug abuse and addiction.First, we provided a narrative summary of the literature on drug use–related communication on social media. We also examined ethical considerations in the research processes of (1) social media big data mining, (2) subgroup or follow-up investigation, and (3) dissemination of social media data-driven findings. To develop a critical review-based typology, we searched the PubMed database and the entire e-collection theme of “infodemiology and infoveillance” in the Journal of Medical Internet Research / JMIR Publications. Studies that met our inclusion criteria  were reviewed for knowledge synthesis. User characteristics, communication characteristics, mechanisms and predictors of such communications, and the psychological and behavioral outcomes of social media use for problematic drug use–related communications are the dimensions of our typology. In addition to ethical practices and considerations, we also reviewed the methodological and computational approaches used in each study to develop our typology.We developed a typology to better understand non-medical, problematic use of prescription drugs through the lens of social media big data. Highly relevant studies that met our inclusion criteria were reviewed for knowledge synthesis. The characteristics of users who shared problematic substance use–related communications on social media were reported by general group terms, such as adolescents, Twitter users, and Instagram users. All reviewed studies examined the communication characteristics, such as linguistic properties, and social networks of problematic drug use–related communications on social media. The mechanisms and predictors of such social media communications were not directly examined or empirically identified in the reviewed studies. The psychological or behavioral consequence  of engaging with and being exposed to social media communications regarding problematic drug use was another area of research that has been understudied.We offer theoretical applications, ethical considerations, and empirical evidence within the scope of social media communication and prescription drug abuse and addiction. Our critical review suggests that social media big data can be a tremendous resource to understand, monitor and intervene on drug abuse and addiction problems. User-generated content and user interactions related to drug use  are prevalent and are rapidly emerging forms of communication across social media platforms ,2. SociaAlthough well-established resources in the United States such as the Drug Abuse Warning Network and the National Survey on Drug Use and Health offer critical information about substance abuse practices, these traditional platforms are known to lag in time in terms of data availability to the public for possible use in research . On the Along with advances in information and communication technologies, seeking health information, disclosing personal health concerns, and exchanging social support are pervasive forms of human communications on social media ,11-20. IDue to the analogous and reflective nature of one’s social media world to one’s own real world, user-generated social media big data are increasingly being embraced and analyzed to observe and predict psychological states and collective human behavior ,22. For With a growing line of empirical evidence demonstrating social media’s usefulness for observing and predicting health behaviors, social media data on drug use–related communications are being analyzed to address various research inquiries, including temporal trends of problematic substance use ,34, markOur conceptualization classifies the communication on drug use problems that is evident on social media into 4 key dimensions: (1) user characteristics, (2) communication characteristics, (3) mechanisms and predictors of problematic substance use–related communications on social media, and (4) psychological and behavioral consequences of these social media communications at an individual and a societal level.First, understanding user characteristics  permits in-depth subgroup or moderator analyses of the drug-related communications and related risks . More spSecond, identifying the communication features of target social media big data can offer insights into temporal, linguistic, and psychological patterns associated with self-disclosed social media communications about problematic use of prescription drugs . For exaAs emphasized in a recent study incorporating machine learning techniques on Twitter feeds for a mental health diagnosis, analyzing linguistic properties of self-disclosed communication on social media regarding substance use problems provides a novel opportunity to identify communication themes and unmet needs among people with substance use problems . UnderstThird, investigating why and in which contexts people use social media to communicate about substance use–related problems reveals the mechanisms of various unsolicited behaviors . Identifying this mechanism of communication behavior through analyzing social media big data, along with user interviews and self-reported surveys, can inform a strategic mediating construct for investigators when developing social media-based prevention or intervention programs .Fourth, understanding the psychological effects  and behavioral outcomes  that such unsolicited uses of social media communications have on the self and others has received increased public attention . HoweverIntegrating these 4 themes into a multidimensional framework enables systematic observation of factors and conditions explaining pervasive uses of social media for drug use–related communications. Development of this multiconceptual framework can also help researchers and clinicians explore the predictive and mechanistic values of social media-based communications in delivering state-of-the-art drug abuse recovery support and engagement systems. Furthermore, learning outcomes relevant to this multidimensional framework will offer data-driven strategies for leveraging social media data, features, and platforms for health promotion , as well as for understanding the nature of human communications concerning time-sensitive health issues.In this work, we begin by reviewing the current use of social media for problematic drug use–related communications. Then, we highlight ethical challenges and methodological considerations when using social media big data for research on drug abuse and addiction. Lastly, based on these 4 conceptual dimensions and ethical considerations, we provide a narrative summary of the literature on social media-based drug communications and propose a typology with key initiatives aimed at addressing knowledge gaps in the use of social media for research on problematic and nonmedical use of prescription drugs.User-generated content that promotes substance use  is prev, adolescents who reported seeing pictures of peers using substances on social media were more likely to use substances than were those who had never seen this peer-generated content on social media [Moreno and colleagues ,49 foundal media .Social psychology and media communication theories explain this link between content exposure and an increased willingness to engage in the behavior being promoted. For example, cultivation theory ,53 positSocial media communication platforms allow substance users to connect with a wide array of social networks and readily accessible substance use–related content. A news feed on a social media site can become a platform that constantly provides both personalized and socially infused content for social modeling and mimicry. These socially mediated learning processes on social media underscore the importance of considering the consequences  of routine exposure to content that is positively framed for and, indirectly or directly, promotes problematic drug use.While content that promotes substance use is prevalent on social media, use of social media networks and online communities to explore recovery support for drug addiction problems is an increasingly popular form of communication . Social Compared with their application in the drug addiction context, the values of peer support and user engagement on social media platforms have been leveraged in health interventions for other health contexts, such as smoking cessation  and weigA national report released by the US Centers for Disease Control and Prevention stated that almost 48,000 deaths in the United States in 2014 were induced by potent substance poisoning, surpassing the number of deaths caused by motor vehicle accidents . The US The proliferation of substance use prevention and addiction recovery support communications among social media users provides empirical resources to systematically analyze naturalistic, real-time communications data and to gain time-sensitive insights into substance use risk factors, behavioral patterns, and prevention and recovery processes. Applying big data informatics—the process of examining large unstructured data to discover hidden patterns and useful information —to substWith these clinical implications and opportunities for understanding and enhancing a sensitive health problem, the social media data that contain various levels of user information  and users’ expectations and nuances embedded in social media contexts require cautionary attention to ethical boundaries and practices. In the following section, we discuss key ethical principles, challenges, and considerations applicable in this novel research setting when incorporating user-centered social media communication data for behavioral health research.The use of social media big data for informatics can provide population-level inferences, such as pattern or trend recognition  and natuThroughout the process of mining and retrieving social media big data, it is important to balance an understanding of data privacy from the user’s perspective beyond the needs of researchers who are interested in the data to provide broader public health benefits. Taking a user’s perspective  can be a useful practice for ethical considerations. Perspective taking is an other-centered social cognitive process that involves simulation of and making inference about the target counterpart’s mind and cognitive state . AccuratTo protect users’ privacy and understand their expectations on the use of their potentially sensitive social media content, such as drug use–related communications, we also encourage researchers to construct guidelines for case-specific scenarios concerning potential ethical issues. For example, a research program at Harvard University published a guideline booklet that reviews ethical norms, case reports, and concrete guidance to help researchers who use social media sites for patient recruitment and contact . The guiAs demonstrated in Harvard’s guideline for social media use for recruitment research, scenario-specific solutions for ethical challenges on social media-based observational studies can be implemented through “cognitive rehearsals” (or scenario planning) prospectively, rather than retrospectively. Cognitive rehearsal is a cognitive behavioral technique that allows individuals to develop an effective set of responses to a critical event. A cognitive rehearsal approach ,75 is baResearchers’ responsibilities extend to maintaining data confidentiality and protection, and ensuring the transparency of research activities. These activities include not only data mining and analysis, but also subgroup analysis or follow-up investigation . Investigators may need to conduct follow-up surveys or interventions to address questions raised by big data–driven findings. Electronic data are track-(back)-able and technological advances can allow deidentified social media data to be reidentified. Therefore, failures in confidentiality or lack of transparency during the follow-up processes can cause great concern among users if their data were aggregated from social media without their prior consent. The ethical implications and social consequences of contacting individuals who were attributes of the big data–driven findings should be recognized by researchers and policy makers in relation to data protection and human autonomy issues in big data research, even as the attributes of individuals were imperceptible to the aggregate level of big data–driven knowledge ,76. BefoEmerging technologies and big data have ethical implications beyond those identified in accomplishing research aims. Researchers are also responsible for ethically disseminating the findings extracted from social media big data . Even ifEthical principles, including the fundamental rights of “autonomy, protection, safety, maximization of benefits and minimization of harm, and respect for beneficence” , We developed a typology based on a critical review process . The strJournal of Medical Internet Research and articles in other JMIR journals indexed with this topic (http://www.jmir.org/themes/69). The search keywords were “prescription drug abuse,” “nonmedical drug use,” “social media,” “social network sites,” “big data,” “data mining,” “social media data,” “informatics,” “machine learning,” “Twitter,” “Instagram,” and “Facebook.” The same researcher (SJK) then evaluated the titles and abstracts of published studies based on their topical relevance  and included studies that used social media communication data and computational analytic methods .In our critical review, 1 researcher (SJK) independently searched for relevant literature within the PubMed database and the entire e-collection theme of “infodemiology and infoveillance” of JMIR Publications which includes the Journal of Medical Internet Research, we reviewed findings from 8 highly relevant studies that met all the inclusion criteria. We report empirical evidence from the studies in relation to the 4 research inquiries, the methodological and computational approaches, and ethical practices and considerations discussed in each study , problematic use of other substances , or noncomputational analytic methods  , contextual (abusive vs therapeutic), and thematic  aspects of social media communications regarding problematic use of prescription drugs . In a pThere was limited work on directly examining moderating or mechanistic factors of drug abuse–related social media communications. The predictors and mechanisms of social media communications for nonmedical use of prescription drugs  were not directly investigated in the studies we reviewed, and thus remain largely underexplored. Applying use and gratification theory of media can shed light on what motivates individuals to share or engage with such content on social media and what kinds of media use gratification  these media activities provide for people with substance use problems ,87. UndeThe psychological and behavioral consequences  of engaging with and being exposed to social media communications regarding problematic drug use is another area of research that has been understudied. This dimension was not directly examined or empirically identified in the reviewed studies. However, the importance of understanding the varied aspects of these outcomes was discussed in some studies ,33. For Understanding short-term and long-term effects of media exposure and engagement for problematic drug use–related communications may require population-level-based surveys or longitudinal follow-up investigation in addition to social media big data analytics. By examining the psychological and behavioral effects of using social media for drug promotional or prevention- and control-related purposes, investigators can be well positioned to improve their ability to develop theoretical and methodological models when harnessing social media platforms for health promotion targeting public health problems, such as nonmedical and problematic use of prescription drugs. Investigating the outcome dimension will also help researchers understand the clinical implications and the utility of social media as behavioral intervention platforms.For the data mining process, some studies developed and tested their own social media data monitoring and crawling systems. For example, Cameron and colleagues developed the Prescription Drug Abuse Online Surveillance and Epidemiology (PREDOSE) infrastructure to extract and analyze entities and sentiments of unstructured social media text data regarding prescription drug abuse ,89. DataWith the exception of 2 studies conducted by Correia and colleagues , who useAmong the reviewed studies, 4 reported that an institutional review board (IRB) approved their study ,33,83. TThe detrimental consequences of substance use highlight the urgent need for research to understand the drug epidemic in a scalable, systematic manner. Performing big data analytics on social media content allows researchers to generate data-informed insights into the phenomena of interest, such as the promotional communication of problematic substance use shared on social media platforms. The use of social media data to monitor and observe problematic use of prescription drugs, such as nonmedical use of analgesic opioid drugs, is as yet an unexplored area of biomedical research. In our reviewed studies reported in a typology, the communication properties were used to identify high-risk events , indicatIn this paper, we propose a multilevel framework and ethical considerations that are applicable to social media communication data to understand problematic drug use phenomena. Based on the 4 dimensions in the framework, along with methodological and ethical domains, we conducted a critical, narrative review of empirical findings that were based on social media communication data involving problematic use of prescription drugs. The 4 primary conceptual dimensions are (1) understanding characteristics of users who share their data  about nonmedical substance use on social media; (2) the communication characteristics of such self-disclosed data; (3) predictors and underlying mechanisms of social media communications on problematic use of prescription drugs; and (4) the psychological and behavioral consequences that social media use for problematic drug use–related communications may have for users themselves  or others . The state of social media uses among people with substance use problems is receiving increased attention. We designed an evidence-based, multiconceptual framework in our typology to inform potential future research directions, which may also offer insights into public health outreach strategies, as well as the development of social media-based substance use prevention and recovery intervention programs.Advances in communication technology and informatics offer novel opportunities for understanding substance use problems through naturally occurring, self-disclosed communications on social media. This research requires multidisciplinary collaborative efforts between data scientists, social scientists, and clinicians to systematically structure and identify the ongoing substance abuse problems observable through problematic drug use–related communications on social media. Various social media features and characteristics , automated analytic approaches at scale, and the prevalence of sharing and engaging user activities for such communications underscore the benefits of harnessing social media platforms and data to study drug use trends, patterns, and the underlying psychology and subsequent outcomes. Social media big data on the nationwide public health problem of nonmedical use of prescription drugs in the United States can also have a practical impact at the individual level , as well as at the societal level . Although a different and extended set of ethical challenges exists in the realm of social media big data research, we expect that principle-guided, multidisciplinary, and iterative processes will soon start to converge for this topic. We also raise the importance of the precision and sensitivity of social media big data that can be prone to type I error . ForWe acknowledged a lack of theoretical frameworks that are applicable to social media big data for substance use monitoring and observational systems . To bridIn this paper, we aimed to offer key conceptual applications, ethical considerations, social media data-based empirical evidence, and a typology framework within the scope of dominant public health issues centered on nonmedical and problematic prescription drug use. As proposed in the novel typology, integrating the 4 conceptual dimensions and multidisciplinary research efforts may advance our knowledge on this nationwide crisis of prescription drug use problems in the United States. Future research may use the proposed conceptual framework and the perspectives delivered in this paper as a leverage in advancing scientific scholarship on this important topic.