The feasibility of wildlife immersion experiences for Veterans with PTSD.

Introduction: Animal-assisted interventions (AAI) offer potential physical and psychological health benefits that may assist Veterans with post-traumatic stress disorder. However, more feasibility studies are needed regarding intervention details, adverse events, reasons for study withdrawal, and animal welfare. Methods: This mixed methods feasibility trial involved a modified crossover study in which Veterans with PTSD/PTSD symptoms were provided a series of 8 nature and wildlife immersion experiences to evaluate feasibility and preliminary efficacy. The sample included 19 Veterans with PTSD/PTSD symptoms who were followed for a mean of 15.1 weeks. The intervention was comprised of a baseline forest walk, assisting with wildlife rehabilitation, observation in a wildlife sanctuary, and bird watching. Post study bird feeders were provided for sustainability. Results: This AAI nature/wildlife immersion intervention was feasible, acceptable, and safe to administer to Veterans with PTSD/PTSD symptoms with appropriate support. Logistical and relational facilitators were identified that supported the wildlife immersion activities. Participants reported greatly enjoying the activities. Attention to animal welfare and care was an important ethical foundation that also contributed to feasibility. Discussion: AAI immersion experiences with wildlife are feasible and can safely be administered to Veterans with PTSD/PTSD symptoms. Logistical and relational facilitators are important to support nature and wildlife immersion activities.

Sharing the space of the creature: Intersubjectivity as a lens toward mutual human-wildlife dignity.

Human-wildlife coexistence is critical for sustainable and healthy ecosystems as well as to prevent human and wildlife suffering. In this paper, an intersubjective approach to human-wildlife interactions is proposed as a lens toward human decentering and emergent mutual evolution. The thesis is developed through a secondary data analysis of a research study on wildlife care and philosophical analysis using the work of Bernard Lonergan and Edmund Husserl. The study was conducted using the theory of transcendent pluralism, which is grounded in human and ecological dignity, including the dignity of beyond-human beings. Deeper interpretation of the original data suggests that human-wildlife interactions are mutually conscious, embodied, and hold spatial-temporal dimensions. The affective realm is an integral dimension of human-wildlife intersubjectivity. These findings inform an approach toward human-wildlife relations in which human persons and the beyond-human multitude can all flourish in dignity.

Policy education in a research-focused doctoral nursing program: Power as knowing participation in change.

Nurses have moral obligations incurred by membership in the profession to participate knowingly in health policy advocacy. Many barriers have historically hindered nurses from realizing their potential to advance health policy. The contemporary political context sets additional challenges to policy work due to polarization and conflict. Nursing education can help nurses recognize their role in advancing health through political advocacy in a manner that is consistent with disciplinary knowledge and ethical responsibilities. In this paper, the authors describe an exemplar of Elizabeth Barrett's "Power as Knowing Participation in Change" theory as a disciplinary lens within a doctoral nursing health policy course. Barrett (radically) emphasizes "power as freedom" instead of "power as control." This approach is congruent with nursing disciplinary values and enhances awareness of personal freedom and building collaborative relationships in the policy process. The theory was used in concert with other traditional policy content and frameworks from nursing and other disciplines. We discuss the role of nursing ethics viewed as professional responsibility for policy action, an overview of Barrett's theory, and the design of the course. Four student reflections on how the course influenced their thinking about policy advocacy are included. While not specific to policymaking, Barrett's theory provides a disciplinary grounding to increase students' awareness of freedom and choices in political advocacy participation. Our experience suggests that Barrett's work can be fruitful for enhancing nurses' awareness of choices to participate in change across settings.

Depletion of Bone Marrow Hematopoietic Cells in Ebolavirus-Infected Rhesus Macaques: A Possible Cause of Hematologic Abnormalities in Ebolavirus Disease.

The pathophysiology of long-recognized hematologic abnormalities in Ebolavirus (EBOV) disease (EVD) is unknown. From limited human sampling (of peripheral blood), it has been postulated that emergency hematopoiesis plays a role in severe EVD, but the systematic characterization of the bone marrow (BM) has not occurred in human disease or in nonhuman primate models. In a lethal rhesus macaque model of EVD, 18 sternal BM samples exposed to the Kikwit strain of EBOV were compared to those from uninfected controls (n = 3). Immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy showed that EBOV infects BM monocytes/macrophages and megakaryocytes. EBOV exposure was associated with severe BM hypocellularity, including depletion of myeloid, erythroid, and megakaryocyte hematopoietic cells. These depletions were negatively correlated with cell proliferation (Ki67 expression) and were not associated with BM apoptosis during disease progression. In EBOV-infected rhesus macaques with terminal disease, BM showed marked hemophagocytosis, megakaryocyte emperipolesis, and the release of immature hematopoietic cells into the sinusoids. Collectively, these data demonstrate not only direct EBOV infection of BM monocytes/macrophages and megakaryocytes but also that disease progression is associated with hematopoietic failure, notably in peripheral cytopenia. These findings inform current pathophysiologic unknowns and suggest a crucial role for BM dysfunction and/or failure, including emergency hematopoiesis, as part of the natural history of severe human disease.

Ebola Virus Disease Features Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in the Rhesus Macaque Model.

BACKGROUND: Ebola virus (EBOV) disease (EVD) is one of the most severe and fatal viral hemorrhagic fevers and appears to mimic many clinical and laboratory manifestations of hemophagocytic lymphohistiocytosis syndrome (HLS), also known as macrophage activation syndrome. However, a clear association is yet to be firmly established for effective host-targeted, immunomodulatory therapeutic approaches to improve outcomes in patients with severe EVD. METHODS: Twenty-four rhesus monkeys were exposed intramuscularly to the EBOV Kikwit isolate and euthanized at prescheduled time points or when they reached the end-stage disease criteria. Three additional monkeys were mock-exposed and used as uninfected controls. RESULTS: EBOV-exposed monkeys presented with clinicopathologic features of HLS, including fever, multiple organomegaly, pancytopenia, hemophagocytosis, hyperfibrinogenemia with disseminated intravascular coagulation, hypertriglyceridemia, hypercytokinemia, increased concentrations of soluble CD163 and CD25 in serum, and the loss of activated natural killer cells. CONCLUSIONS: Our data suggest that EVD in the rhesus macaque model mimics pathophysiologic features of HLS/macrophage activation syndrome. Hence, regulating inflammation and immune function might provide an effective treatment for controlling the pathogenesis of acute EVD.

Evaluation of a panel of therapeutic antibody clinical candidates for efficacy against SARS-CoV-2 in Syrian hamsters.

The COVID-19 pandemic spurred the rapid development of a range of therapeutic antibody treatments. As part of the US government's COVID-19 therapeutic response, a research team was assembled to support assay and animal model development to assess activity for therapeutics candidates against SARS-CoV-2. Candidate treatments included monoclonal antibodies, antibody cocktails, and products derived from blood donated by convalescent patients. Sixteen candidate antibody products were obtained directly from manufacturers and evaluated for neutralization activity against the WA-01 isolate of SARS-CoV-2. Products were further tested in the Syrian hamster model using prophylactic (-24 h) or therapeutic (+8 h) treatment approaches relative to intranasal SARS-CoV-2 exposure. In vivo assessments included daily clinical scores and body weights. Viral RNA and viable virus titers were quantified in serum and lung tissue with histopathology performed at 3d and 7d post-virus-exposure. Sham-treated, virus-exposed hamsters showed consistent clinical signs with concomitant weight loss and had detectable viral RNA and viable virus in lung tissue. Histopathologically, interstitial pneumonia with consolidation was present. Therapeutic efficacy was identified in treated hamsters by the absence or diminution of clinical scores, body weight loss, viral loads, and improved semiquantitative lung histopathology scores. This work serves as a model for the rapid, systematic in vitro and in vivo assessment of the efficacy of candidate therapeutics at various stages of clinical development. These efforts provided preclinical efficacy data for therapeutic candidates. Furthermore, these studies were invaluable for the phenotypic characterization of SARS CoV-2 disease in hamsters and of utility to the broader scientific community.

Longitudinal analyses using 18F-Fluorodeoxyglucose positron emission tomography with computed tomography as a measure of COVID-19 severity in the aged, young, and humanized ACE2 SARS-CoV-2 hamster models.

This study compared disease progression of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in three different models of golden hamsters: aged (≈60 weeks old) wild-type (WT), young (6 weeks old) WT, and adult (14-22 weeks old) hamsters expressing the human-angiotensin-converting enzyme 2 (hACE2) receptor. After intranasal (IN) exposure to the SARS-CoV-2 Washington isolate (WA01/2020), 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography with computed tomography (18F-FDG PET/CT) was used to monitor disease progression in near real time and animals were euthanized at pre-determined time points to directly compare imaging findings with other disease parameters associated with coronavirus disease 2019 (COVID-19). Consistent with histopathology, 18F-FDG-PET/CT demonstrated that aged WT hamsters exposed to 105 plaque forming units (PFU) developed more severe and protracted pneumonia than young WT hamsters exposed to the same (or lower) dose or hACE2 hamsters exposed to a uniformly lethal dose of virus. Specifically, aged WT hamsters presented with a severe interstitial pneumonia through 8 d post-exposure (PE), while pulmonary regeneration was observed in young WT hamsters at that time. hACE2 hamsters exposed to 100 or 10 PFU virus presented with a minimal to mild hemorrhagic pneumonia but succumbed to SARS-CoV-2-related meningoencephalitis by 6 d PE, suggesting that this model might allow assessment of SARS-CoV-2 infection on the central nervous system (CNS). Our group is the first to use (18F-FDG) PET/CT to differentiate respiratory disease severity ranging from mild to severe in three COVID-19 hamster models. The non-invasive, serial measure of disease progression provided by PET/CT makes it a valuable tool for animal model characterization.

Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses.

Humanity has faced three recent outbreaks of novel betacoronaviruses, emphasizing the need to develop approaches that broadly target coronaviruses. Here, we identify 55 monoclonal antibodies from COVID-19 convalescent donors that bind diverse betacoronavirus spike proteins. Most antibodies targeted an S2 epitope that included the K814 residue and were non-neutralizing. However, 11 antibodies targeting the stem helix neutralized betacoronaviruses from different lineages. Eight antibodies in this group, including the six broadest and most potent neutralizers, were encoded by IGHV1-46 and IGKV3-20. Crystal structures of three antibodies of this class at 1.5-1.75-Å resolution revealed a conserved mode of binding. COV89-22 neutralized SARS-CoV-2 variants of concern including Omicron BA.4/5 and limited disease in Syrian hamsters. Collectively, these findings identify a class of IGHV1-46/IGKV3-20 antibodies that broadly neutralize betacoronaviruses by targeting the stem helix but indicate these antibodies constitute a small fraction of the broadly reactive antibody response to betacoronaviruses after SARS-CoV-2 infection.

Broadly neutralizing antibodies target the coronavirus fusion peptide.

The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha- and betacoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures of COV44-62 and COV44-79 antigen-binding fragments with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine residue at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.

Broadly neutralizing antibodies target the coronavirus fusion peptide.

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence Summary: Rare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

Expanded Histopathology and Tropism of Ebola Virus in the Rhesus Macaque Model: Potential for Sexual Transmission, Altered Adrenomedullary Hormone Production, and Early Viral Replication in Liver.

The pathogenesis of Ebola virus disease (EVD) is still incomplete, in spite of the availability of a nonhuman primate modelfor more than 4 decades. To further investigate EVD pathogenesis, a natural history study was conducted using 27 Chinese-origin rhesus macaques. Of these, 24 macaques were exposed intramuscularly to Kikwit Ebola virus and euthanized at predetermined time points or when end-stage clinical disease criteria were met, and 3 sham-exposed macaques were euthanized on study day 0. This study showed for the first time that Ebola virus causes uterine cervicitis, vaginitis, posthitis, and medullary adrenalitis. Not only was Ebola virus detected in the interstitial stromal cells of the genital tract, but it was also present in the epididymal and seminal vesicular tubular epithelial cells, ectocervical and vaginal squamous epithelial cells, and seminal fluid. Furthermore, as early as day 3 after exposure, Ebola virus replicative intermediate RNA was detected in Kupffer cells and hepatocytes. These findings in the nonhuman model provide additional insight into potential sexual transmission, possible disruption of sympathetic hormone production, and early virus replication sites in human EVD patients.

Participatory research in Northwest Atlanta's Proctor Creek Watershed: Using photovoice to explore environmental health risks at the water's edge.

In this study we used a participatory research method, photovoice, to explore community perceptions about environmental health risks, community assets, and strengths in and around an urban, degraded watershed in Northwest Atlanta, Georgia. This watershed, formed by Proctor Creek, is a focal point for redevelopment and infrastructure investments for years to come. Using a community-based participatory research approach, 10 Proctor Creek residents (watershed researchers), and a university partner, engaged in data collection; participatory data analysis; internal discussions; translation of research findings into watershed restoration, community revitalization, remedial action, and policy solutions; and dissemination of results to fellow watershed residents, stakeholders, and decision makers. We present a conceptual model linking the watershed researchers' understanding of urban policies and practice in the Proctor Creek Watershed to environmental, neighborhood and housing conditions and their influence on health outcomes and quality of life. Engaging community members in defining their own community environmental health challenges and assets yielded the following primary themes: 1) threats to the natural environment, 2) built environment stressors that influence health, 3) blight and divestment of public resources, and 4) hope for the future. Residents' vision for the future of the watershed - a restored creek, revitalized neighborhoods, and restored people - is fueled by a strong connection to history, memory, and sense of place. We demonstrate the value of local knowledge in identifying previously unaddressed environmental health risks in the Proctor Creek Watershed as well as solutions to reduce or eliminate them.

Kikwit Ebola Virus Disease Progression in the Rhesus Monkey Animal Model.

Ongoing Ebola virus disease outbreaks in the Democratic Republic of the Congo follow the largest recorded outbreak in Western Africa (2013-2016). To combat outbreaks, testing of medical countermeasures (therapeutics or vaccines) requires a well-defined, reproducible, animal model. Here we present Ebola virus disease kinetics in 24 Chinese-origin rhesus monkeys exposed intramuscularly to a highly characterized, commercially available Kikwit Ebola virus Filovirus Animal Non-Clinical Group (FANG) stock. Until reaching predetermined clinical disease endpoint criteria, six animals underwent anesthesia for repeated clinical sampling and were compared to six that did not. Groups of three animals were euthanized and necropsied on days 3, 4, 5, and 6 post-exposure, respectively. In addition, three uninfected animals served as controls. Here, we present detailed characterization of clinical and laboratory disease kinetics and complete blood counts, serum chemistries, Ebola virus titers, and disease kinetics for future medical countermeasure (MCM) study design and control data. We measured no statistical difference in hematology, chemistry values, or time to clinical endpoint in animals that were anesthetized for clinical sampling during the acute disease compared to those that were not.

Filoviruses Infect Rhesus Macaque Synoviocytes in Vivo and Primary Human Synoviocytes in Vitro.

The most commonly reported symptom of post-Ebola virus disease syndrome in survivors is arthralgia, yet involvement of the joints in acute or convalescent Ebola virus infection is not well characterized in human patients or animal models. Through immunohistochemistry, we found that the lining synovial intima of the stifle (knee) is a target for acute infection by Ebola virus/Kikwit, Ebola virus/Makona-C05, and Marburg virus/Angola in the rhesus macaque model. Furthermore, histologic analysis, immunohistochemistry, RNAscope in situ hybridization, and transmission electron microscopy showed that synoviocytes of the stifle, shoulder, and hip are a target for mouse-adapted Ebola virus/Yambuku-Mayinga infection during acute disease in rhesus macaques. A time course of infection study with Ebola virus/Kikwit found that the large joint synovium became immunopositive beginning on postinfection day 6. In total, the synovium of 28 of 30 rhesus macaques with terminal filovirus disease had evidence of infection (64 of 96 joints examined). On the basis of immunofluorescence, infected cell types included CD68+ type A (macrophage-like) synoviocytes and CD44+ type B (fibroblast-like) synoviocytes. Cultured primary human fibroblast-like synoviocytes were permissive to infection with Ebola and Marburg viruses in vitro. Because synovial joints include immune privileged sites, these findings are significant for future investigations of filovirus pathogenesis and persistence as well as arthralgias in acute and convalescent filovirus disease.

Peripheral Neuronopathy Associated With Ebola Virus Infection in Rhesus Macaques: A Possible Cause of Neurological Signs and Symptoms in Human Ebola Patients.

Neurological signs and symptoms are the most common complications of Ebola virus disease. However, the mechanisms underlying the neurologic manifestations in Ebola patients are not known. In this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to Ebola virus (EBOV) disease from 5 to 8 days post exposure. Ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients.

A Community-Academic Partnership for School-Based Nonviolence Education: The Healthy Power Program.

BACKGROUND: Youth violence is a significant problem affecting community health. Community-academic partnerships can advance youth nonviolence education by synergizing the strengths of collaborators while working toward a common goal. We describe a collaboration between an urban public middle school, community nonprofit, and university-based graduate school of nursing in implementing and evaluating the Healthy Power program, a school-based youth nonviolence program for middle-school boys. METHODS: A participatory program evaluation approach was used to plan and implement evaluation of the Healthy Power program with a cohort of 8 students. Collaborative planning allowed for the selection of measures that reflected program objectives and were of value to community partners while also scientifically sound. A mixed-methods approach included a focus group and a pretest-posttest with quantitative items and open-ended questions. RESULTS: While the quantitative pre-posttest did not show any significant change, the open-ended questions and focus group suggested that students had advanced their understanding and application of conflict resolution skills. CONCLUSIONS: The findings support the usefulness of community-academic partnerships for peace/conflict resolution education and program evaluation. Such programs may benefit from mixed methods of evaluation.

Realizing the Focus of the Discipline: Facilitating Humanization in PhD Education: A Student Exemplar Integrating Nature and Health.

Doctorally prepared nurses must be able to represent the unique nursing perspective within interdisciplinary teams to address contemporary health challenges. This article provides a student exemplar applying the unifying focus of facilitating humanization as described by Willis, Grace, and Roy to science on nature and health. As scientific knowledge becomes more complex, nurses must be skilled in translating information through the nursing lens to support individuals in realizing meaning, choice, quality of life, and healing in living and dying. In order for doctoral students to shepherd the discipline, they must first integrate nursing's philosophical underpinnings into their practice.

Clinical Characterization of Host Response to Simian Hemorrhagic Fever Virus Infection in Permissive and Refractory Hosts: A Model for Determining Mechanisms of VHF Pathogenesis.

Simian hemorrhagic fever virus (SHFV) causes a fulminant and typically lethal viral hemorrhagic fever (VHF) in macaques (Cercopithecinae: Macaca spp.) but causes subclinical infections in patas monkeys (Cercopithecinae: Erythrocebus patas). This difference in disease course offers a unique opportunity to compare host responses to infection by a VHF-causing virus in biologically similar susceptible and refractory animals. Patas and rhesus monkeys were inoculated side-by-side with SHFV. Unlike the severe disease observed in rhesus monkeys, patas monkeys developed a limited clinical disease characterized by changes in complete blood counts, serum chemistries, and development of lymphadenopathy. Viral RNA was measurable in circulating blood 2 days after exposure, and its duration varied by species. Infectious virus was detected in terminal tissues of both patas and rhesus monkeys. Varying degrees of overlap in changes in serum concentrations of interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 were observed between patas and rhesus monkeys, suggesting the presence of common and species-specific cytokine responses to infection. Similarly, quantitative immunohistochemistry of livers from terminal monkeys and whole blood flow cytometry revealed varying degrees of overlap in changes in macrophages, natural killer cells, and T-cells. The unexpected degree of overlap in host response suggests that relatively small subsets of a host's response to infection may be responsible for driving hemorrhagic fever pathogenesis. Furthermore, comparative SHFV infection in patas and rhesus monkeys offers an experimental model to characterize host⁻response mechanisms associated with viral hemorrhagic fever and evaluate pan-viral hemorrhagic fever countermeasures.

Ethical challenges experienced by clinical research nurses:: A qualitative study.

BACKGROUND:: Clinical investigation is a growing field employing increasing numbers of nurses. This has created a new specialty practice defined by aspects unique to nursing in a clinical research context: the objectives (to implement research protocols and advance science), setting (research facilities), and nature of the nurse-participant relationship. The clinical research nurse role may give rise to feelings of ethical conflict between aspects of protocol implementation and the duty of patient advocacy, a primary nursing responsibility. Little is known about whether research nurses experience unique ethical challenges distinct from those experienced by nurses in traditional patient-care settings. RESEARCH OBJECTIVES:: The purpose of the study was to describe the nature of ethical challenges experienced by clinical research nurses within the context of their practice. RESEARCH DESIGN:: The study utilized a qualitative descriptive design with individual interviews. PARTICIPANTS AND RESEARCH CONTEXT:: Participating nurses (N = 12) self-identified as having experienced ethical challenges during screening. The majority were Caucasian (90%), female (83%), and worked in outpatient settings (67%). Approximately 50% had > 10 years of research experience. ETHICAL CONSIDERATIONS:: The human subjects review board approved the study. Written informed consent was obtained. FINDINGS:: Predominant themes were revealed: (1) the inability to provide a probable good, or/do no harm, and (2) dual obligations (identity as a nurse vs a research nurse). The following patterns and subthemes emerged: conflicted allegiances between protocol implementation, needs of the participant, desire to advance science, and tension between the nurse-patient therapeutic relationship versus the research relationship. DISCUSSION:: Participants described ethical challenges specific to the research role. The issues are central to the nurse-participant relationship, patient advocacy, the nurse's role in implementing protocols, and/or advancing science. CONCLUSION:: Ethical challenges related to the specialized role of clinical research nurses were identified. More research is warranted to fully understand their nature and frequency and to identify support systems for resolution.