RESUMEN
Cross jurisdictional collaboration efforts and emergency vaccine plans that are consistent with Tribal sovereignty are essential to public health emergency preparedness. The widespread adoption of clearly written federal, state, and local vaccine plans that address fundamental assumptions in vaccine distribution to Tribal nations is imperative for future pandemic response.
Asunto(s)
Vacunas , Humanos , Planificación en Desastres , Gobierno Federal , Indígenas Norteamericanos , Gobierno Estatal , Estados Unidos , Vacunas/provisión & distribuciónAsunto(s)
COVID-19 , Crup , Infecciones del Sistema Respiratorio , Crup/diagnóstico , Crup/terapia , Humanos , SARS-CoV-2RESUMEN
In 2004 and 2005, the first clinical trials were launched to investigate the use of tenofovir for HIV prevention in Cambodia,Cameroon, Nigeria and Thailand. Controversies erupted over the ethical integrity of the research protocol. We reflect on the events that ledto the controversies and identified that scientific and ethical concerns raised by members of local communities at each of these sites wereerased by trialists, causing crisis that led to premature shut down the early PrEP trials. In the aftermath of these trials, the World HealthOrganisation, UNAIDS, and AVAC developed ethics guidelines intended to recognize the concerns as authentic, and developed guidelines toimprove researchers' engagement of communities in biomedical HIV prevention trial design and implementation. Our findings suggest thatthe ethics guidelines are limited in its ability to address power inequalities that leads to voice erasures and non-recognition of localcompetencies. Rather the ethical documents enabled trialists to gain a new sense of authority through the interpretations of ethical researchconduct enabling trialists regain power that can further entrench inequality and voice erasures. To address concerns with what seems anintractable problem, we suggested models of engagement for off-shored research may be the option.
RESUMEN
Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2-Hc0 H2d H2-T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5def mice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5def mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31-bp deletion in the Insr gene in the B10.D2-Hc0 H2d H2-T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5cont and C5def mice, indicating an insulin-sensitizing function of C5.
Asunto(s)
Complemento C5/deficiencia , Complemento C5/genética , Intolerancia a la Glucosa/genética , Enfermedades por Deficiencia de Complemento Hereditario/patología , Adenoviridae/genética , Animales , Complemento C5/fisiología , Modelos Animales de Enfermedad , Metabolismo Energético/genética , Metabolismo Energético/inmunología , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Enfermedades por Deficiencia de Complemento Hereditario/genética , Resistencia a la Insulina/genética , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Endogámicos NOD , Ratones Transgénicos , Transducción de Señal/genética , Transducción GenéticaRESUMEN
In 2004, the first ever multi-sited clinical trials studied the prospect of HIV biomedical prevention (referred to as pre-exposure prophylaxis-'PrEP'). The trials were implemented at several international sites, but many officially closed down before they completed. At most sites, both scientists and community AIDS advocates raised concerns over the ethics and scientific rationales of the trial. Focusing on the Nigerian trial site, we detail the controversy that emerged among mostly Nigerian research scientists who scrutinized the research design and protocol. While some of the disputes, especially those pertaining to community engagement mechanisms, were ultimately resolved in international fora and implemented in later PrEP trials, concerns over science rationales and assumptions were never addressed. We argue that scientific rationales should be treated as ethical concerns and suggest that such concerns should be deliberated at host sites before the trial protocol is finalized.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Investigación Biomédica/ética , Análisis Ético , Infecciones por VIH/prevención & control , Profilaxis Pre-Exposición , Investigadores/ética , Tenofovir/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Participación de la Comunidad , Disentimientos y Disputas , Ética en Investigación , VIH , Humanos , Nigeria , Defensa del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/ética , Proyectos de Investigación , Pensamiento/éticaRESUMEN
Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Expresión Génica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Enfermedades Metabólicas/tratamiento farmacológico , Preparaciones Farmacéuticas/administración & dosificación , Humanos , Macrófagos/inmunología , Enfermedades Metabólicas/inmunología , Terapia Molecular DirigidaRESUMEN
OBJECTIVE: Obesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function. Our study aimed to determine whether normalizing the number of AT eosinophils in obese mice, to those of lean healthy mice, would reduce obesity and/or improve metabolic fitness. METHODS: C57BL/6J mice fed a high fat diet (HFD) were simultaneously given recombinant interleukin-5 (rIL5) for 8 weeks to increase AT eosinophils. Metabolic fitness was tested by evaluating weight gain, AT inflammation, glucose, lipid, and mixed-meal tolerance, AT insulin signaling, energy substrate utilization, energy expenditure, and white AT beiging capacity. RESULTS: Eosinophils were increased â¼3-fold in AT of obese HFD-fed mice treated with rIL5, and thus were restored to levels observed in lean healthy mice. However, there were no significant differences in rIL5-treated mice among the above listed comprehensive set of metabolic assays, despite the increased AT eosinophils. CONCLUSIONS: We have shown that restoring obese AT eosinophils to lean healthy levels is not sufficient to allow for improvement in any of a range of metabolic features otherwise impaired in obesity. Thus, the mechanisms that identified eosinophils as positive regulators of AT function, and therefore systemic health, are more complex than initially understood and will require further study to fully elucidate.
Asunto(s)
Tejido Adiposo/patología , Eosinófilos/efectos de los fármacos , Obesidad/patología , Tejido Adiposo/efectos de los fármacos , Animales , Metabolismo Energético , Insulina/metabolismo , Interleucina-5/farmacología , Interleucina-5/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológicoRESUMEN
OBJECTIVE: The prevalence of obesity continues to rise, and it is understood that regulation of white adipose tissue (WAT) function is important to systemic metabolic homeostasis. Immune cells play a central role in the maintenance of WAT, and their compositions change in number and inflammatory phenotype with the progression of obesity. Because of its energy-burning capabilities, brown adipose tissue (BAT) has become a focus of obesity research. Although novel studies have focused on the function of brown adipocytes in thermogenesis, the tissue as a whole has not been immunologically characterized. METHODS: BAT immune cell populations were analyzed by flow cytometry and immunohistochemistry in mice with diet-induced obesity (3, 8, or 16 weeks of diet) and in aged mice (1, 6-7, and 10-15 months). RESULTS: The data confirmed the presence of macrophages and eosinophils, as previously reported, and showed that 20% to 30% of the immune cells in BAT were B cells. The number of B cells and eosinophils increased with diet-induced obesity, whereas macrophages decreased. There was no change in number of any immune cell quantified with age. CONCLUSIONS: These studies reveal a novel finding of B220 + B cells in BAT and show that BAT immune cell populations change in response to diet-induced obesity.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Linfocitos B/metabolismo , Obesidad/patología , Animales , Linfocitos B/patología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The global interest in developing therapies for Ebola infection management and its prevention is laudable. However the plan to conduct an emergency immunization program specifically for healthcare workers using experimental vaccines raises some ethical concerns. This paper shares perspectives on these concerns and suggests how some of them may best be addressed. DISCUSSION: The recruitment of healthcare workers for Ebola vaccine research has challenges. It could result in coercion of initially dissenting healthcare workers to assist in the management of EVD infected persons due to mistaken beliefs that the vaccine offers protection. It could also affect equity and justice. For example, where people who are not skilled health care professionals but who provide care to patients infected with Ebola (such as in home care settings) are not prioritized for vaccination. The possibility of study participants contracting Ebola infection despite the use of experimental vaccine, and the standard of care they would receive, needs to be addressed clearly, transparently and formalized as part of the ethics review process. Future access to study products in view of current status of the TRIPS agreement needs to be addressed. Finally, broad stakeholder engagement at local, regional and international levels needs to be promoted using available communication channels to engage local, regional and international support. These same concerns are applicable for current and future epidemics. Successful Ebola vaccine development research requires concerted efforts at public dialogue to address misconceptions, equity and justice in participant selection, and honest discussions about risks, benefits and future access. Public dialogue about Ebola vaccine research plans is crucial and should be conducted by trusted locals and negotiated between communities, researchers and ethics committees in research study sites.
Asunto(s)
Investigación Biomédica/ética , Urgencias Médicas , Fiebre Hemorrágica Ebola/prevención & control , Programas de Inmunización/ética , Terapias en Investigación/ética , Vacunación , Vacunas Virales , Descubrimiento de Drogas , Ebolavirus , Epidemias , Ética en Investigación , Personal de Salud , Fiebre Hemorrágica Ebola/epidemiología , Fiebre Hemorrágica Ebola/virología , Humanos , Sujetos de Investigación , Vacunas Virales/normasRESUMEN
The recent wave of the Ebola Virus Disease (EVD) in Western Africa and efforts to control the disease where the health system requires strengthening raises a number of ethical challenges for healthcare workers practicing in these countries. We discuss the implications of weak health systems for controlling EVD and limitations of the ethical obligation to provide care for patients with EVD using Nigeria as a case study. We highlight the right of healthcare workers to protection that should be obligatorily provided by the government. Where the national government cannot meet this obligation, healthcare workers only have a moral and not a professional obligation to provide care to patients with EVD. The national government also has an obligation to adequately compensate healthcare workers that become infected in the course of duty. Institutionalisation of policies that protect healthcare workers are required for effective control of the spread of highly contagious diseases like EVD in a timely manner.
Asunto(s)
Planificación en Salud Comunitaria/ética , Atención a la Salud/ética , Brotes de Enfermedades , Personal de Salud/ética , Fiebre Hemorrágica Ebola , Obligaciones Morales , África Occidental/epidemiología , Códigos de Ética , Compensación y Reparación , Atención a la Salud/economía , Ética Médica , Personal de Salud/economía , Fiebre Hemorrágica Ebola/epidemiología , Fiebre Hemorrágica Ebola/terapia , Fiebre Hemorrágica Ebola/transmisión , Humanos , Nigeria/epidemiología , Política Pública , Responsabilidad SocialRESUMEN
Between 2004 and 2005, the first multi-sited clinical trial tested whether an existing, marketed antiretroviral drug, Tenofovir (TDF), could prevent HIV transmission. Referred to as pre-exposure prophylaxis (PrEP), most of these trial sites prematurely closed down. Two sites located in Cambodia and Cameroon received international media attention. But little attention was drawn to sites in Malawi and Nigeria, where university ethicists and research scientists extensively debated PrEP. This article focuses on events that took place in Malawi where there was a prolonged dispute over the scientific rationales of PrEP and not trial specific ethics referred to as 'bioethics'. Specifically, the article discusses debates pertaining to three PrEP trial protocols that were refused ethics approval in Malawi between 2004 and 2009. It is argued that HIV science debates in Malawi are embedded in postcolonial politics--geopolitical histories and state and household economic dispossessions that have created the structural possibilities for Malawi to become an offshore destination for HIV clinical research. As such, ethics in this case does not pertain to trial or bioethical 'failures'. Rather, ethics is located at the scale of imperial relations that give rise to multiple, often invisible, research concerns and constraints.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Ensayos Clínicos como Asunto/ética , Infecciones por VIH , Profilaxis Pre-Exposición , Insuficiencia del Tratamiento , Antropología Médica , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/etnología , Infecciones por VIH/prevención & control , Humanos , MalauiRESUMEN
BACKGROUND: HIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND). In this study, we used micropositron emission tomography (PET) imaging to quantify neuroinflammation in HIV-1 transgenic rat (Tg), a small animal model of HIV, known to develop neurological and behavioral problems. METHODS: Dynamic [(18)F]DPA-714 PET imaging was performed in Tg and age-matched wild-type (WT) rats in three age groups: 3-, 9-, and 16-month-old animals. As a positive control for neuroinflammation, we performed unilateral intrastriatal injection of quinolinic acid (QA) in a separate group of WT rats. To confirm our findings, we performed multiplex immunofluorescent staining for Iba1 and we measured cytokine/chemokine levels in brain lysates of Tg and WT rats at different ages. RESULTS: [(18)F]DPA-714 uptake in HIV-1 Tg rat brains was generally higher than in age-matched WT rats but this was not statistically significant in any age group. [(18)F]DPA-714 uptake in the QA-lesioned rats was significantly higher ipsilateral to the lesion compared to contralateral side indicating neuroinflammatory changes. Iba1 immunofluorescence showed no significant differences in microglial activation between the Tg and WT rats, while the QA-lesioned rats showed significant activation. Finally, cytokine/chemokine levels in brain lysates of the Tg rats and WT rats were not significantly different. CONCLUSION: Microglial activation might not be the primary mechanism for neuropathology in the HIV-1 Tg rats. Although [(18)F]DPA-714 is a good biomarker of neuroinflammation, it cannot be reliably used as an in vivo biomarker of neurodegeneration in the HIV-1 Tg rat.
Asunto(s)
Lesiones Encefálicas/virología , Encefalitis/diagnóstico por imagen , Fluorodesoxiglucosa F18/farmacocinética , VIH-1/metabolismo , Tomografía de Emisión de Positrones , Pirazoles/farmacocinética , Pirimidinas/farmacocinética , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/diagnóstico por imagen , Mapeo Encefálico , Citocinas/metabolismo , Encefalitis/etiología , Fluorodesoxiglucosa F18/sangre , Lateralidad Funcional , VIH-1/genética , Masculino , Pirazoles/sangre , Pirimidinas/sangre , Ácido Quinolínico/toxicidad , Ratas , Ratas Endogámicas F344 , Ratas Transgénicas , Factores de TiempoRESUMEN
BACKGROUND: The current Ebola Virus Disease (EVD) outbreak in West Africa is the largest in history. As of February 18(th) 2015, 23,258 cases of EVD have been cumulatively reported from Nigeria, Senegal, Guinea, Liberia, Mali, Sierra Leone, Spain, the United Kingdom and the United States of America resulting in more than 9,000 deaths. It is therefore exigent to develop prevention and treatment therapies for EVD. DISCUSSION: Several new EVD treatments are in clinical development at this time. Based on lessons learned, four critical processes need to be implemented before clinical trials begin. First, all global EVD research need to be coordinated to promote data sharing and synergistic overlap, while reducing unnecessary duplication of efforts. The World Health Organization is well-placed to undertake such an endeavor. Second, governments of affected nations where trials are being proposed need to lead discussions regarding immediate access to any proven medications for epidemics. Also, governments need to leverage international resources to support and expand existing national expertise to jointly conduct high-caliber clinical research; and resources must be used to enhance local technical skills and expand existing personnel. Third, ethics committees must review protocols, monitor the research process, and work closely with research scientists to insure the ethical integrity of research throughout the trials. Fourth, community advisory boards (CAB) need to be formed, linked with existing community leadership structures and organized in conjunction with trial implementation. These community structures should work together with ethics committees to facilitate the study design, informed consent process, and study implementation. We must facilitate communication and mutual understanding between trial communities and research teams, and promote positive collaborations between all stakeholders engaged in EVD research. The community engagement process for EVD research is crucial to address myths and misconceptions, and to promote study volunteers' understanding of the research details. The collaboration between all stakeholders is crucial for continued long term partnership to address EVD outbreak and none of the stakeholders should be left behind in ongoing efforts to develop EVD therapies.
Asunto(s)
Investigación Biomédica/organización & administración , Fiebre Hemorrágica Ebola/epidemiología , Área sin Atención Médica , África Occidental/epidemiología , Antivirales/farmacología , Antivirales/uso terapéutico , Brotes de Enfermedades/prevención & control , Ebolavirus/efectos de los fármacos , Epidemias , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Fiebre Hemorrágica Ebola/prevención & control , Humanos , Cooperación InternacionalRESUMEN
OBJECTIVE: To determine the incidence and cost of medications dispensed despite discontinuation (MDDD) of the medications in the electronic medical record within an integrated health care organization. SETTING: Dean Health System, with medical clinics and pharmacies linked by an electronic medical record, and a shared health plan and pharmacy benefits management company. PRACTICE DESCRIPTION: Pharmacist-led quality improvement project using retrospective chart review. PRACTICE INNOVATION: Electronic medical records, pharmacy records, and prescription claims data from patients 18 years of age or older who had a prescription filled for a chronic condition from June 2012 to August 2013 and submitted a claim through the Dean Health Plan were aggregated and cross-referenced to identify MDDD. MAIN OUTCOME MEASURES: Descriptive statistics were used to characterize demographics and MDDD incidence. Fisher's exact test and independent samples t tests were used to compare MDDD and non-MDDD groups. Wholesale acquisition cost was applied to each MDDD event. RESULTS: 7,406 patients met inclusion criteria. For 223 (3%) patients with MDDD, 253 independent events were identified. In terms of frequency per category, antihypertensive agents topped the list, followed, in descending order, by anticonvulsants, antilipemics, antidiabetics, and anticoagulants. Nine medications accounted for 59% (150 of 253) of all MDDD events; these included (again in descending order): gabapentin, atorvastatin, simvastatin, hydrochlorothiazide, lisinopril, warfarin, furosemide, metformin, and metoprolol. Mail-service pharmacies accounted for the highest incidence (5.3%) of MDDD, followed by mass merchandisers (4.6%) and small chains (3.9%). The total cost attributable to MDDD was $9,397.74. CONCLUSION: Development of a technology-based intervention to decrease the incidence of MDDD may be warranted to improve patient safety and decrease health care costs.
Asunto(s)
Costos de los Medicamentos/estadística & datos numéricos , Registros Electrónicos de Salud , Planes de Sistemas de Salud/economía , Prescripción Electrónica/economía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mejoramiento de la CalidadRESUMEN
Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron-handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity.
Asunto(s)
Tejido Adiposo/metabolismo , Hierro/metabolismo , Macrófagos/fisiología , Adipocitos/metabolismo , Animales , Homeostasis/fisiología , Humanos , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/metabolismo , Síndrome Metabólico/epidemiología , Síndrome Metabólico/metabolismo , Obesidad/epidemiología , Obesidad/metabolismoRESUMEN
HIV prevention is a critical health issue in Nigeria; a country that has one of the worst HIV epidemic profiles in the world. With 270,000 new infections in 2012, Nigeria is a prime site for HIV prevention research. One effect of the HIV epidemic has been to revolutionalise ethical norms for the conduct of research: it is now considered unethical to design and implement HIV related studies without community engagement. Unfortunately, there is very little commensurate effort in building the capacity of local persons to engage actively with researchers, and there is no existing platform to facilitate dialogue between researchers and communities engaged in research in Nigeria. In an effort to address this gap, we undertook a series of three community dialogues (Phase One) and two community-researcher interface meetings (Phase Two) in Nigeria. This paper aims to give an empirical account of the dialogue from these community engagement processes and provide a resulting critique of the implementation of research ethics practices in Nigeria. It is anticipated that the outputs will: (i) support researchers in designing community-based research protocols; (ii) inform ethics committees of key considerations during research protocol reviews from a community perspective; and (iii) inform policy makers and research sponsors about issues of primary concern to communities with respect to HIV research.
Asunto(s)
Investigación Biomédica/ética , Infecciones por VIH/prevención & control , Política de Salud , Investigación Biomédica/organización & administración , Participación de la Comunidad , Comunicación en Salud , Humanos , NigeriaRESUMEN
The Ebola Virus Disease (EVD) in West Africa has stimulated investments in EVD research. While these research efforts are most welcome, we are concerned about the potential to ignore effective community ethics engagement programmes and critical government regulatory agencies in light of the urgency to conduct clinical trials for EVD therapies and vaccines. We discuss the reasons why community engagement with various research stakeholders is essential, how community engagement should be conducted, and the potential consequences of failing to engage both communities and regulatory agencies by drawing on past experiences in the field of HIV research. We highlight the importance of a) capacity building to enable local researchers design and implement EVD research for future epidemics, b) the need to support community research literacy, and c) the need to build the competency of research regulatory agencies on the continent to address EVD therapy and vaccine research.