Regulatory Issues in Electronic Health Records for Adolescent HIV Research: Strategies and Lessons Learned.

BACKGROUND: Electronic health records (EHRs) are a cost-effective approach to provide the necessary foundations for clinical trial research. The ability to use EHRs in real-world clinical settings allows for pragmatic approaches to intervention studies with the emerging adult HIV population within these settings; however, the regulatory components related to the use of EHR data in multisite clinical trials poses unique challenges that researchers may find themselves unprepared to address, which may result in delays in study implementation and adversely impact study timelines, and risk noncompliance with established guidance. OBJECTIVE: As part of the larger Adolescent Trials Network (ATN) for HIV/AIDS Interventions Protocol 162b (ATN 162b) study that evaluated clinical-level outcomes of an intervention including HIV treatment and pre-exposure prophylaxis services to improve retention within the emerging adult HIV population, the objective of this study is to highlight the regulatory process and challenges in the implementation of a multisite pragmatic trial using EHRs to assist future researchers conducting similar studies in navigating the often time-consuming regulatory process and ensure compliance with adherence to study timelines and compliance with institutional and sponsor guidelines. METHODS: Eight sites were engaged in research activities, with 4 sites selected from participant recruitment venues as part of the ATN, who participated in the intervention and data extraction activities, and an additional 4 sites were engaged in data management and analysis. The ATN 162b protocol team worked with site personnel to establish the necessary regulatory infrastructure to collect EHR data to evaluate retention in care and viral suppression, as well as para-data on the intervention component to assess the feasibility and acceptability of the mobile health intervention. Methods to develop this infrastructure included site-specific training activities and the development of both institutional reliance and data use agreements. RESULTS: Due to variations in site-specific activities, and the associated regulatory implications, the study team used a phased approach with the data extraction sites as phase 1 and intervention sites as phase 2. This phased approach was intended to address the unique regulatory needs of all participating sites to ensure that all sites were properly onboarded and all regulatory components were in place. Across all sites, the regulatory process spanned 6 months for the 4 data extraction and intervention sites, and up to 10 months for the data management and analysis sites. CONCLUSIONS: The process for engaging in multisite clinical trial studies using EHR data is a multistep, collaborative effort that requires proper advanced planning from the proposal stage to adequately implement the necessary training and infrastructure. Planning, training, and understanding the various regulatory aspects, including the necessity of data use agreements, reliance agreements, external institutional review board review, and engagement with clinical sites, are foremost considerations to ensure successful implementation and adherence to pragmatic trial timelines and outcomes.

Building an HIV Learning Health Care Community for Youth in Florida: Opportunities and Challenges.

In Florida, 33% of new HIV infections among men and 21% of new infections among women are among those younger than 29 years of age. We describe the development of a Learning Health Care Community for youth (Y-LHCC) in Orange County, FL. Its core implementation team (iTeam) was composed of representatives from community agencies and academics, whose work was informed by data from the Florida Department of Health (FDOH) and regional research, in-depth interviews (IDIs) with agency representatives, and a pilot implementation of Tailored Motivational Interviewing (TMI) to improve service provision. IDIs revealed limited programming specifically for youth, significant structural challenges providing them with PrEP, and differences in use of evidence-based behavioral interventions to improve HIV services. FDOH provided data on new HIV infections, linkage to care, viral suppression, and PrEP coverage, however, limitations such as minimal data on PrEP referrals and use, agency level data, and inability to generate data quarterly (which would facilitate program improvement) were encountered. Thirty staff members from five agencies serving youth in Orange County participated in TMI training. About half the agency staff (n = 16) completed at least three of the four online training sessions. MI skills improved from pre- (n = 28; M = 1.96) to post TMI training (n = 11; M = 2.48, SD = 0.57); (t(37) = - 3.14, p = 0.0033). The iTeam held seven remote meetings and two in-person half-day meetings at the end of the study, during which they reassessed areas of focus for improving youth services. They also reiterated their commitment to continuing to meet beyond the study period and to engage other agencies in the newly established coalition. Findings highlight the potential of creating a Y-LHCC in Florida as well as some of the challenges that will need to be overcome to achieve ending the HIV Epidemic goals for young people in the region.

RESUMEN: En Florida, el 33% y 21% de las nuevas infecciones del VIH entre hombres y mujeres, respectivamente, fueron entre personas menores de 29 años de edad. Describimos el desarrollo de una Comunidad de Aprendizaje de Atención Médica para jóvenes (Y-LHCC) en el Condado de Orange, FL. Su equipo central de implementación (iTeam) estuvo compuesto de representantes de agencias comunitarias y académicos, cuyo trabajo se basó en datos del Departamento de Salud de Florida (FDOH) e investigaciones regionales, entrevistas en profundidad con representantes de agencias y un programa piloto de implementación de la Entrevista Motivacional a la Medida (TMI) para mejorar la prestación de servicios. Las entrevistas revelaron poca programación específica para los jóvenes, desafíos estructurales significativos para proporcionarles PrEP, y diferencias en el uso de intervenciones conductuales basadas en evidencia para mejorar los servicios de VIH. El FDOH proporcionó datos sobre nuevas infecciones por el VIH, vinculación con la atención médica, supresión viral y cobertura de PrEP. Sin embargo, se encontraron limitaciones en la data, tales como datos limitados sobre derivaciones u uso de PrEP, falta de datos a nivel de agencia, e incapacidad para generar datos trimestrales (lo que facilitaría la mejora de programas en la agencia). Treinta miembros del personal de cinco agencias que atienden a jóvenes en el Condado de Orange participaron en la capacitación de TMI. Aproximadamente la mitad del personal de la agencia (n = 16) completó al menos tres de las cuatro sesiones de capacitación remota. Las habilidades de MI mejoraron desde antes (n = 28; M = 1.96, SD = .042) hasta después del entrenamiento de TMI (n = 11; M = 2.48, SD = 0.57); (t(37) = − 3.14, p = 0.0033). El iTeam realizó siete reuniones remotas y dos reuniones en persona de medio día al final del estudio, durante las cuales reevaluaron las áreas de enfoque para mejorar los servicios para jóvenes. También reiteraron su compromiso de continuar reuniéndose más allá del período de estudio y de involucrar a otras agencias en la coalición recién establecida. Los hallazgos destacan el potencial de crear un Y-LHCC en Florida, así como algunos de los desafíos que deberán superarse para lograr los objetivos de terminar con la epidemia de VIH para los jóvenes de la región.

Nurses' Perceptions of Telephone Triage in Child and Adolescent Psychiatric Services - An Enhanced Critical Incident Technique Study.

In Sweden, units managed by nurses specialised in counselling and telephone triage, have been developed within the Child and Adolescent Mental Health services (CAMHS). This study has a qualitative design and illuminates the nurses' perceptions of what helps or hinders their assessments and telephone triage. The Enhanced Critical Incident Technique was utilised, eight nurses were interviewed in depth, to identify factors influencing triage. The study is the first to provide a comprehensive description of helpful and hindering factors while performing telephone triage. It illuminates telephone triage in Swedish CAMHS settings and provides insights how to enhance and implement this practice.

Reuniting philosophy and science to advance cancer research.

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

Precision medicine and the problem of structural injustice.

Many countries currently invest in technologies and data infrastructures to foster precision medicine (PM), which is hoped to better tailor disease treatment and prevention to individual patients. But who can expect to benefit from PM? The answer depends not only on scientific developments but also on the willingness to address the problem of structural injustice. One important step is to confront the problem of underrepresentation of certain populations in PM cohorts via improved research inclusivity. Yet, we argue that the perspective needs to be broadened because the (in)equitable effects of PM are also strongly contingent on wider structural factors and prioritization of healthcare strategies and resources. When (and before) implementing PM, it is crucial to attend to how the organisation of healthcare systems influences who will benefit, as well as whether PM may present challenges for a solidaristic sharing of costs and risks. We discuss these issues through a comparative lens of healthcare models and PM-initiatives in the United States, Austria, and Denmark. The analysis draws attention to how PM hinges on-and simultaneously affects-access to healthcare services, public trust in data handling, and prioritization of healthcare resources. Finally, we provide suggestions for how to mitigate foreseeable negative effects.

Slowing down decay: biological clocks in personalized medicine.

This article discusses so-called biological clocks. These technologies, based on aging biomarkers, trace and measure molecular changes in order to monitor individuals' "true" biological age against their chronological age. Drawing on the concept of decay, and building on ethnographic fieldwork in an academic laboratory and a commercial firm, we analyze the implications of the development and commercialization of biological clocks that can identify when decay is "out of tempo." We show how the building of biological clocks rests on particular forms of knowing decay: In the academic laboratory, researchers focus on endo-processes of decay that are internal to the person, but when the technology moves to the market, the focus shifts as staff bracket decay as exo-processes, which are seen as resulting from a person's lifestyle. As the technology of biological clocks travels from the laboratory to the market of online testing of the consumer's biological age, we observe shifting visions of aging: from an inevitable trajectory of decline to a malleable and plastic one. While decay is an inevitable trajectory starting at birth and ending with death, the commercialization of biological clocks points to ways of stretching time between birth and death as individuals "optimize" their biological age through lifestyle changes. Regardless of admitted uncertainties about what is measured and the connection between maintenance and future health outcomes, the aging person is made responsible for their decaying body and for enacting maintenance to slow down decay. We show how the biological clock's way of "knowing" decay turns aging and its maintenance into a life-long concern and highlight the normative implications of framing decay as malleable and in need of intervention.

Understanding implementation completion of tailored motivational interviewing in multidisciplinary adolescent HIV clinics.

Background: Understanding the barriers and facilitators of implementation completion is critical to determining why some implementation efforts fail and some succeed. Such studies provide the foundation for developing further strategies to support implementation completion when scaling up evidence-based practices (EBPs) such as Motivational Interviewing. Method: This mixed-methods study utilized the Exploration, Preparation, Implementation, and Sustainment framework in an iterative analytic design to compare adolescent HIV clinics that demonstrated either high or low implementation completion in the context of a hybrid Type III trial of tailored motivational interviewing. Ten clinics were assigned to one of three completion categories (high, medium, and low) based on percentage of staff who adhered to three components of implementation strategies. Comparative analysis of staff qualitative interviews compared and contrasted the three high-completion clinics with the three low-completion clinics. Results: Results suggested several factors that distinguished high-completion clinics compared to low-completion clinics including optimism, problem-solving barriers, leadership, and staff stress and turnover. Conclusions: Implementation strategies targeting these factors can be added to EBP implementation packages to improve implementation success. Plain Language Summary: While studies have begun to address adherence to intervention techniques, this is one of the first studies to address organizational adherence to implementation strategies. Youth HIV providers from different disciplines completed interviews about critical factors in both the inner and outer context that can support or hinder an organization's adherence to implementation strategies. Compared to less adherent clinics, more adherent clinics reported more optimism, problem-solving, and leadership strengths and less staff stress and turnover. Implementation strategies addressing these factors could be added to implementation packages to improve implementation success.

The practical ethics of repurposing health data: how to acknowledge invisible data work and the need for prioritization.

Throughout the Global North, policymakers invest in large-scale integration of health-data infrastructures to facilitate the reuse of clinical data for administration, research, and innovation. Debates about the ethical implications of data repurposing have focused extensively on issues of patient autonomy and privacy. We suggest that it is time to scrutinize also how the everyday work of healthcare staff is affected by political ambitions of data reuse for an increasing number of purposes, and how different purposes are prioritized. Our analysis builds on ethnographic studies within the Danish healthcare system, which is internationally known for its high degree of digitalization and well-connected data infrastructures. Although data repurposing ought to be relatively seamless in this context, we demonstrate how it involves costs and trade-offs for those who produce and use health data. Even when IT systems and automation strategies are introduced to enhance efficiency and reduce data work, they can end up generating new forms of data work and fragmentation of clinically relevant information. We identify five types of data work related to the production, completion, validation, sorting, and recontextualization of health data. Each of these requires medical expertise and clinical resources. We propose that the implications for these forms of data work should be considered early in the planning stages of initiatives for large-scale data sharing and reuse, such as the European Health Data Space. We believe that political awareness of clinical costs and trade-offs related to such data work can provide better and more informed decisions about data repurposing.

Synthesizing Adaptive Digital Bioethics to Guide the Use of Interactive Communication Technologies in Adolescent Behavioral Medicine: A Systematic Configurative Review.

Despite the continuing integration of digital outreach tools into adolescent preventive services, adaptive guidance for their ethical use remains limited. In this configurative review, we synthesize the ad hoc, applied digital bioethics developed in adolescent human immunodeficiency virus prevention science. By focusing on generalizable technological affordances, while balancing privacy and autonomy, we offer strategies for identifying potential technologically mediated harms that can transcend specific platforms, tools, or the knowledge levels of individual clinicians. Clinical vignettes illustrate the application of these strategies.

A role for cortical dopamine in the paradoxical calming effects of psychostimulants.

Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies using dopamine (DA) transporter (DAT) knockout (KO) mice have suggested that the paradoxical calming effect of psychostimulants might occur through actions on serotonin (5-HT) neurotransmission. However, newer non-stimulant drugs, such as atomoxetine and guanfacine, suggest that targeting the norepinephrine (NE) system in the prefrontal cortex (PFC) might explain this paradoxical calming effect. Thus, we sought to clarify the mechanism of this paradoxical action of psychostimulants. Our ex vivo efflux experiments reveal that the NE transporter (NET) blocker desipramine elevates both norepinephrine (NE) and dopamine (DA), but not 5-HT levels, in PFC tissue slices from wild-type (WT) and DAT-KO, but not NET-KO mice. However, the 5-HT transporter (SERT) inhibitor fluoxetine elevates only 5-HT in all three genotypes. Systemic administration of desipramine or fluoxetine inhibits hyperactivity in DAT-KO mice, whereas local PFC infusion of desipramine alone produced this same effect. In contrast, pharmacological NE depletion and DA elevation using nepicastat also inhibits hyperactivity in DAT-KO mice. Together, these data suggest elevation of PFC DA and not NE or 5-HT, as a convergent mechanism for the paradoxical effects of psychostimulants observed in ADHD therapy.

Precision patients: Selection practices and moral pathfinding in experimental oncology.

This paper addresses selection practices in a Danish phase 1 unit specialised in precision medicine in the field of oncology. Where precision medicine holds the ambition of selecting genetically fit medicine for the patient, we find that precision medicine in the early trial setting is oriented towards selecting clinically and genetically fit patients for available treatment protocols. Investigating how phase 1 oncologists experience and respond to the moral challenges of selecting patients for early clinical trials, we show that inclusion criteria and patient categories are not always transparent to patients. Lack of transparency about inclusion criteria has been interpreted as morally problematic. Yet drawing on social science studies of 'unknowing', we argue that silence and non-transparency in interactions between oncologists and patients are crucial to respect the moral agency of patients at the edge of life and recognise them as belonging to the public of Danish health care. In the discussion, we consider the practice of placing 'unfit' patients on a waiting list for trial participation. Rather than representing an ethical and political problem, we argue, the waiting list can act as a valve enabling oncologists to navigate the scientific and as well as the moral uncertainties in phase 1 oncology.

Plastic diagnostics: The remaking of disease and evidence in personalized medicine.

Politically authorized reports on personalized and precision medicine stress an urgent need for finer-grained disease categories and faster taxonomic revision, through integration of genomic and phenotypic data. Developing a data-driven taxonomy is, however, not as simple as it sounds. It is often assumed that an integrated data infrastructure is relatively easy to implement in countries that already have highly centralized and digitalized health care systems. Our analysis of initiatives associated with the Danish National Genome Center, recently launched to bring Denmark to the forefront of personalized medicine, tells a different story. Through a "meta-taxonomy" of taxonomic revisions, we discuss what a genomics-based disease taxonomy entails, epistemically as well as organizationally. Whereas policy reports promote a vision of seamless data integration and standardization, we highlight how the envisioned strategy imposes significant changes on the organization of health care systems. Our analysis shows how persistent tensions in medicine between variation and standardization, and between change and continuity, remain obstacles for the production as well as the evaluation of genomics-based taxonomies of difference. We identify inherent conflicts between the ideal of dynamic revision and existing regulatory functions of disease categories in, for example, the organization and management of health care systems. Moreover, we raise concerns about shifts in the regulatory regime of evidence standards, where clinical care increasingly becomes a vehicle for biomedical research.

Using Twitter Data Analysis to Understand the Perceptions, Awareness, and Barriers to the Wide Use of Pre-Exposure Prophylaxis in the United States.

User-generated social media posts such as tweets can provide insights about the public's perception, cognitive, and behavioral responses to health-related issues. Pre-Exposure Prophylaxis (PrEP) is one of the most effective ways to reduce the risk of HIV infection. However, its utilization is low in the US, especially among populations disproportionately affected by HIV such as the age group of under 24 years old. It is therefore important to understand the barriers to the wider use of PrEP in the US using social media posts. In this study, we collected tweets from Twitter about PrEP in the past 4 years to identify such barriers by first identifying tweets about personal discussions, and then performing textual analysis using word analysis, UMLS semantic type analysis, and topic modeling. We found that the public often discussed advocacy, risks/benefits, access, pricing, insurance coverage, legislation, stigma, health education, and prevention of HIV. This result is consistent with the literature and can help identify strategies for promoting the use of PrEP, especially among young adults.

The Quest for System-Theoretical Medicine in the COVID-19 Era.

Precision medicine and molecular systems medicine (MSM) are highly utilized and successful approaches to improve understanding, diagnosis, and treatment of many diseases from bench-to-bedside. Especially in the COVID-19 pandemic, molecular techniques and biotechnological innovation have proven to be of utmost importance for rapid developments in disease diagnostics and treatment, including DNA and RNA sequencing technology, treatment with drugs and natural products and vaccine development. The COVID-19 crisis, however, has also demonstrated the need for systemic thinking and transdisciplinarity and the limits of MSM: the neglect of the bio-psycho-social systemic nature of humans and their context as the object of individual therapeutic and population-oriented interventions. COVID-19 illustrates how a medical problem requires a transdisciplinary approach in epidemiology, pathology, internal medicine, public health, environmental medicine, and socio-economic modeling. Regarding the need for conceptual integration of these different kinds of knowledge we suggest the application of general system theory (GST). This approach endorses an organism-centered view on health and disease, which according to Ludwig von Bertalanffy who was the founder of GST, we call Organismal Systems Medicine (OSM). We argue that systems science offers wider applications in the field of pathology and can contribute to an integrative systems medicine by (i) integration of evidence across functional and structural differentially scaled subsystems, (ii) conceptualization of complex multilevel systems, and (iii) suggesting mechanisms and non-linear relationships underlying the observed phenomena. We underline these points with a proposal on multi-level systems pathology including neurophysiology, endocrinology, immune system, genetics, and general metabolism. An integration of these areas is necessary to understand excess mortality rates and polypharmacological treatments. In the pandemic era this multi-level systems pathology is most important to assess potential vaccines, their effectiveness, short-, and long-time adverse effects. We further argue that these conceptual frameworks are not only valid in the COVID-19 era but also important to be integrated in a medicinal curriculum.

Mouse avatars of human cancers: the temporality of translation in precision oncology.

Patient-derived xenografts (PDXs) are currently promoted as new translational models in precision oncology. PDXs are immunodeficient mice with human tumors that are used as surrogate models to represent specific types of cancer. By accounting for the genetic heterogeneity of cancer tumors, PDXs are hoped to provide more clinically relevant results in preclinical research. Further, in the function of so-called "mouse avatars", PDXs are hoped to allow for patient-specific drug testing in real-time (in parallel to treatment of the corresponding cancer patient). This paper examines the circulation of knowledge and bodily material across the species boundary of human and personalized mouse model, historically as well as in contemporary practices. PDXs raise interesting questions about the relation between animal model and human patient, and about the capacity of hybrid or interspecies models to close existing translational gaps. We highlight that the translational potential of PDXs not only depends on representational matching of model and target, but also on temporal alignment between model development and practical uses. Aside from the importance of ensuring temporal stability of human tumors in a murine body, the mouse avatar concept rests on the possibility of aligning the temporal horizons of the clinic and the lab. We examine strategies to address temporal challenges, including cryopreservation and biobanking, as well as attempts to speed up translation through modification and use of faster developing organisms. We discuss how featured model virtues change with precision oncology, and contend that temporality is a model feature that deserves more philosophical attention.

Aging biomarkers and the measurement of health and risk.

Prevention of age-related disorders is increasingly in focus of health policies, and it is hoped that early intervention on processes of deterioration can promote healthier and longer lives. New opportunities to slow down the aging process are emerging with new fields such as personalized nutrition. Data-intensive research has the potential to improve the precision of existing risk factors, e.g., to replace coarse-grained markers such as blood cholesterol with more detailed multivariate biomarkers. In this paper, we follow an attempt to develop a new aging biomarker. The vision among the project consortium, comprising both research and industrial partners, is that the new biomarker will be predictive of a range of age-related conditions, which may be preventable through personalized nutrition. We combine philosophical analysis and ethnographic fieldwork to explore the possibilities and challenges of managing aging through bodily signs that are not straightforwardly linked to symptomatic disease. We document how the improvement of measurement brings about new conceptual challenges of demarcating healthy and unhealthy states. Moreover, we highlight that the reframing of aging as risk has social and ethical implications, as it is generative of normative notions of what constitutes successful aging and good citizenship.

Retrograde Labeling Illuminates Distinct Topographical Organization of D1 and D2 Receptor-Positive Pyramidal Neurons in the Prefrontal Cortex of Mice.

The cortex plays an important role in regulating motivation and cognition, and does so by regulating multiple subcortical brain circuits. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC) are topographically organized in different subregions such as the prelimbic, infralimbic (IL), and orbitofrontal and project to topographically-organized subcortical target regions. Dopamine D1 and D2 receptors are expressed on glutamatergic pyramidal neurons in the PFC. However, it is unclear whether D1 and D2 receptor-expressing pyramidal neurons in the PFC are also topographically organized. We used a retrograde adeno-associated virus (AAVRG)-based approach to illuminate the topographical organization of D1 and D2 receptor-expressing neurons, projecting to distinct striatal and midbrain subregions. Our experiments reveal that AAVRG injection in the nucleus accumbens (NAcc) or dorsal striatum (dSTR) of D1Cre mice labeled distinct neuronal subpopulations in medial orbitofrontal or prelimbic PFC, respectively. However, AAVRG injection in NAcc or dSTR of D2Cre mice labeled medial orbitofrontal, but not medial prelimbic PFC, respectively. Additionally, D2R+ but not D1R+ PFC neurons were labeled on injection of AAVRG in substantia nigra pars compacta (SNpc). Thus, our data are the first to highlight a unique dopamine receptor-specific topographical pattern in the PFC, which could have profound implications for corticostriatal signaling in the basal ganglia.

How to choose your research organism.

Despite August Krogh's famous admonition that a 'convenient' organism exists for every biological problem, we argue that appeals to 'convenience' are not sufficient to capture reasoning about organism choice. Instead, we offer a detailed analysis based on empirical data and philosophical arguments for a working set of twenty criteria that interact with each other in the highly contextualized judgements that biologists make about organism choice. We propose to think of these decisions as a form of 'differential analysis' where researchers weigh multiple criteria for organismal choice against each other, and often utilize multidimensional refinement processes to finalize their choices. The specific details of any one case make it difficult to draw generalizations or to abstract away from specific research situations. However, this analysis of criteria for organismal choice and how these are related in practice allows us to reflect more generally on what makes a particular organism useful or 'good.'