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BACKGROUND AND OBJECTIVES: Intraventricular drug delivery enables the delivery of therapeutics to the central nervous system, while minimizing peripheral drug exposure and toxicity. However, currently used delivery devices cannot be controlled externally to adjust their output during delivery. Here, the authors investigated the performance of a conceptually novel device designed to metronomically deliver a drug to the cerebrospinal fluid in a manner that can be adjusted wirelessly from an external controller. METHODS: Six sheep were subcutaneously implanted in the shoulder region with a drug delivery pump and a catheter connecting to the brain ventricles. Three groups of 2 sheep received low, medium, and high dosages of metronomic methotrexate (MTX) over several weeks, while kept mobile outdoors in a pen. MTX dosages were adjusted from a wireless external controller, and intraventricular MTX concentrations were measured in regular intervals with an Ommaya reservoir. RESULTS: Over the course of this 12-week study, sheep showed no signs of toxicity. MTX measurements in the cerebrospinal fluid confirmed that the pump remained responsive to external control and able to deliver drug in an adjustable, metronomic fashion. CONCLUSION: This implantable pump system enables external control of drug output, so that the resulting intraventricular drug concentrations can continuously be maintained within the therapeutic range.
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Introduction: Asian and Pacific Islander (API), African, and Caribbean immigrant groups in the U.S. are disproportionately impacted by chronic hepatitis B and hepatocellular carcinoma (primary liver cancer). Creating educational communication campaigns about hepatitis B and liver cancer for these communities is necessary to increase disease-related awareness and prompt health-promoting behaviors. Identifying interpersonal communication (IPC) preferences within diverse communities for integration into an educational campaign that emphasizes the link between hepatitis B and liver cancer can ultimately promote uptake of screening, vaccination and linkage to appropriate care. Methods: Fifteen focus groups and two key informant interviews were conducted with participants from Micronesian, Chinese, Hmong, Nigerian, Ghanaian, Vietnamese, Korean, Somali, Ethiopian, Filipino, Haitian, and Francophone West African communities. Data were analyzed using thematic coding and analysis. Results: Findings demonstrate that all communities preferred that materials be offered in both English and native languages and emphasized that campaigns highlight the connection between hepatitis B and liver cancer. Educational sessions should take place in settings where communities feel safe, including community-based organizations, religious establishments, and healthcare offices, and should be facilitated by trusted messengers, including patient navigators, doctors and faith leaders. Presenting accurate information and dispelling myths and misconceptions around hepatitis B, liver cancer, and their connection were the biggest needs identified across all focus groups. Discussion: This study provides insight into community-specific preferences for learning about hepatitis B and liver cancer through IPC methods. The findings from this study can be used to design multi-platform, culturally and linguistically appropriate health education campaigns to facilitate improved diagnosis, prevention, and management of hepatitis B and liver cancer among heavily impacted communities in the U.S.
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Grupos Focales , Hepatitis B , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/prevención & control , Femenino , Masculino , Persona de Mediana Edad , Adulto , Hepatitis B/prevención & control , Comunicación , Emigrantes e Inmigrantes/psicología , Estados Unidos , Carcinoma Hepatocelular/prevención & control , Competencia CulturalRESUMEN
Well plates are widely used in biological experiments, particularly in pharmaceutical sciences and cell biology. Its popularity stems from its versatility to support a variety of fluorescent markers for high throughput monitoring of cellular activities. However, using fluorescent markers in traditional well plates has its own challenges, namely, they can be potentially toxic to cells, and thus, may perturb their biological functions; and it is difficult to monitor multiple analytes concurrently and in real-time inside each well. This paper presents a fully instrumented microphysiological system with integrated sensors (IMSIS) with a similar well format. Each well in the microphysiological system has a set of sensors for monitoring multiple metabolic analytes in real-time. The IMSIS platform is supported by integrated bioelectronic circuits and a graphical user interface for easy user configuration and monitoring. The system has integrated microfluidics to maintain its microphysiological environment within each well. The IMSIS platform currently incorporates O2, H2O2, and pH sensors inside each well, allowing up to six wells to perform concurrent measurements in real-time. Furthermore, the architecture is scalable to achieve an even higher level of throughput. The miniaturized design ensures portability, suitable for small offices and field applications. The IMSIS platform was successfully used to monitor in real-time the mitochondrial functions of live bovine embryos in O2 consumption, H2O2 release as an indication of ROS production, and extracellular acidity changes before and after the introduction of external substrates.
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Técnicas Biosensibles , Diseño de Equipo , Sistemas Microfisiológicos , Animales , Humanos , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Peróxido de Hidrógeno/análisis , Concentración de Iones de Hidrógeno , Dispositivos Laboratorio en un Chip , Mitocondrias/metabolismo , Oxígeno/metabolismo , Oxígeno/análisisAsunto(s)
COVID-19 , Vacunas contra Papillomavirus , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Vacunas contra Papillomavirus/administración & dosificación , Estados Unidos/epidemiología , Estudios de Cohortes , Vacunación , Infecciones por Papillomavirus/prevención & control , SARS-CoV-2/inmunología , Bases de Datos Factuales , Femenino , Virus del Papiloma HumanoRESUMEN
HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
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VIH-1 , Inmunidad Innata , Macrófagos , Proteínas Proto-Oncogénicas , Transactivadores , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/virología , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/metabolismo , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/genética , VIH-1/fisiología , VIH-1/inmunología , Transactivadores/metabolismo , Transactivadores/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/genética , Células HEK293 , Virión/metabolismo , Proteínas Serina-Treonina QuinasasRESUMEN
Excessive exposure to ultraviolet radiation (UVR) causes harmful effects on human skin. Pre-exposure application of sunscreen can be protective, but not after damage already has occurred. There is a need for agents that can be applied post-UVR exposure to repair the damage. We investigated a novel compound, NEO400, that appears to meet this medicinal need. NEO400 was created by conjugating linoleic acid to perillyl alcohol. UVR was repeatedly administered to the skin of mice over several weeks, where it caused the typical signs of UV damage, including scaling of the skin, DNA damage, and elevated levels of inflammatory cytokines. However, when NEO400 was applied immediately post-UVR, it triggered the appearance of markers for dermal stem cell proliferation, and no signs of skin damage emerged. Furthermore, when NEO400 was applied to skin that already had incurred significant damage, it accelerated skin healing. When applied individually, linoleic acid and perillyl alcohol were ineffective, indicating that they had to be conjugated in order to exert therapeutic efficacy. None of these skin-protective effects could be achieved with Aloe vera gel, a popular and widely used post-exposure remedy. Our study suggests that NEO400 holds potential as a regenerative treatment for excessively UVR-exposed skin.
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Background: Immigrant groups from Southeast Asia, the Pacific Islands, sub-Saharan Africa, and the Caribbean bear the heaviest burden of chronic hepatitis B and primary liver cancer in the United States. Educational campaigns to increase knowledge about these diseases and their connection are necessary to promote protective health behaviors within these communities, to ultimately reduce the burden of disease, lessen stigma, and eliminate health disparities. Objectives: This project sought to engage groups within highly impacted communities to identify existing gaps in hepatitis B- and liver cancer-related knowledge, in order to inform future health education programming that will aim to reduce stigma and promote liver cancer prevention and early detection behaviors within and across groups. Methods: Fifteen focus groups and two key informant interviews were conducted virtually with participants from Micronesian, Chinese, Hmong, Nigerian, Ghanaian, Vietnamese, Korean, Somali, Ethiopian, Filipino, Haitian, and Francophone West African communities. Qualitative data were analyzed using thematic coding. Results: There are large gaps in knowledge and awareness of hepatitis B and liver cancer, and the link between these two diseases among Asian, Pacific Islander, African and Haitian immigrant communities. This limited knowledge and misinformation, exacerbated by stigma, hinder these groups' utilization of hepatitis B and liver cancer diagnostic and preventative healthcare services. Conclusion: To reduce hepatitis B and liver cancer health disparities within heavily burdened groups, health education needs to be community-informed, culturally sensitive, and actionable. Study results can guide the development of culturally and linguistically appropriate education programs that focus on the link between hepatitis B and liver cancer and the need for vaccination and routine screening, and that are responsive to the knowledge gaps and misperceptions of diverse communities. The results also provide valuable insights for healthcare providers to improve the knowledge gaps of the diverse patient populations that they serve.
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Background: The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR). Patients with such tumors receive very little, if any, benefit from TMZ. We are developing a novel molecule, NEO212 (TMZ conjugated to NEO100), that harbors the potential to overcome these limitations. Methods: We used mouse models that were orthotopically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Animals received NEO212 (or TMZ for comparison) without or with RT. Overall survival was recorded, and histology studies quantified DNA damage, apoptosis, microvessel density, and impact on bone marrow. Results: In all tumor models, replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved a strikingly superior extension of survival, especially in TMZ-resistant and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity. Conclusions: NEO212 is a candidate drug to potentially replace TMZ within the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.
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Asian, Pacific Islander, African, and Caribbean communities in the U.S. are heavily impacted by chronic hepatitis B (HBV) and hepatocellular carcinoma (HCC). Educating these groups about the link between the two diseases is imperative to improve screening rates and health outcomes. This study aims to identify and incorporate preferred mediated communication methods into community-specific educational campaigns which emphasize the connection between the conditions, to promote uptake of prevention and management behaviors for HBV and HCC. Fifteen focus groups and two key informant interviews were conducted with Micronesian, Chinese, Hmong, Nigerian, Ghanaian, Vietnamese, Korean, Somali, Ethiopian, Filipino, Haitian, and Francophone West African communities. Data were analyzed using thematic coding and analysis. Findings demonstrate that all communities preferred materials be offered in both English and native languages and requested that materials highlight the connection between HBV and HCC. Delivery channel preferences and messaging themes varied by group. This study provides insight into community-specific preferences for learning about HBV and HCC. The findings can be used to design culturally and linguistically tailored, multi-platform, health education campaigns to facilitate improved HBV screening and vaccination rates and increase knowledge about HCC risk among highly impacted communities in the U.S.
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Grupos Focales , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/etnología , Femenino , Masculino , Comunicación en Salud/métodos , Adulto , Disparidades en el Estado de Salud , Persona de Mediana Edad , Carcinoma Hepatocelular/etnología , Carcinoma Hepatocelular/prevención & control , Estados Unidos , Hepatitis B/prevención & control , Hepatitis B/etnología , Hepatitis B Crónica/etnología , Hepatitis B Crónica/prevención & control , Competencia Cultural , Investigación Cualitativa , Etnicidad/estadística & datos numéricos , Etnicidad/psicología , Disparidades en Atención de Salud/etnologíaRESUMEN
Previous research has explored theories regarding the vertical transmission of human papillomavirus (HPV) infection and its association with adverse pregnancy and perinatal outcomes. However, the impact of maternal HPV infection on congenital anomalies (CAs) in offspring remains relatively understudied. We conducted a population-based cohort study linking the Taiwan Birth Registry, Taiwan Death Registry, and National Health Insurance Research Database, in which newborns born in Taiwan between 2009 and 2015 were included. We established a maternal HPV infection cohort comprising 37 807 newborns and matched them with a comparison group of 151 228 newborns at a 1:4 ratio based on index year, age, and sex. The study examined a composite outcome and subgroups of different types of congenital malformations. Differences in cumulative incidence of CAs were assessed using Kaplan-Meier curves and log-rank tests. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazard regressions. No significant association was found between HPV infection and the broad spectrum of CAs (aHR: 1.04, 95% confidence interval [CI]: 0.98-1.10; log-rank test p = 0.14). However, we observed a 19% increased risk of musculoskeletal CAs in the maternal HPV infection group (aHR: 1.19; 95% CI: 1.05-1.34) compared to those without maternal HPV exposure. Other factors, including the type of HPV (aHR: 0.65; 95% CI: 0.16-2.63), the timing of exposure (during or before pregnancy), and maternal age (aHR for <30 years: 1.02, 95% CI: 0.94-1.1; aHR for 30-39 years: 1.05, 95% CI: 0.99-1.11; aHR for ≥40 years: 0.88, 95% CI: 0.67-1.17), did not significantly affect the risk for any CA. In conclusion, gestation detection of HPV infection was associated with musculoskeletal CAs but not other major CAs. Prospective studies are warranted to elucidate the necessity of prenatal screening in populations at risk.
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Infecciones por Papillomavirus , Embarazo , Femenino , Humanos , Recién Nacido , Adulto , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Estudios de Cohortes , Estudios Prospectivos , Investigación , Taiwán/epidemiología , Factores de RiesgoRESUMEN
Epithelial cells create barriers that protect many different components in the body from their external environment. The gut in particular carries bacteria and other infectious agents. A healthy gut epithelial barrier prevents unwanted substances from accessing the underlying lamina propria while maintaining the ability to digest and absorb nutrients. Increased gut barrier permeability, better known as leaky gut, has been linked to several chronic inflammatory diseases. Yet understanding the cause of leaky gut and developing effective interventions are still elusive due to the lack of tools to maintain tissue's physiological environment while elucidating cellular functions under various stimuli ex vivo. This paper presents a microphysiological system capable of recording real-time barrier permeability of mouse gut tissues in a realistic physiological environment over extended durations. Key components of the microphysiological system include a microfluidic chamber designed to hold the live tissue explant and create a sufficient microphysiological environment to maintain tissue viability; proper media composition that preserves a microbiome and creates necessary oxygen gradients across the barrier; integrated sensor electrodes and supporting electronics for acquiring and calculating transepithelial electrical resistance (TEER); and a scalable system architecture to allow multiple chambers running in parallel for increased throughput. The experimental results demonstrate that the system can maintain tissue viability for up to 72 hours. The results also show that the custom-built and integrated TEER sensors are sufficiently sensitive to distinguish differing levels of barrier permeability when treated with collagenase and low pH media compared to control. Permeability variations in tissue explants from different positions in the intestinal tract were also investigated using TEER revealing their disparities in permeability. Finally, the results also quantitatively determine the effect of the muscle layer on total epithelial resistance.
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The Epstein-Barr virus (EBV) is accepted as a primary risk factor for certain nasopharyngeal carcinoma (NPC) subtypes, where the virus persists in a latent stage which is thought to contribute to tumorigenesis. Current treatments are sub-optimal, and recurrence occurs in many cases. An alternative therapeutic concept is aimed at triggering the lytic cycle of EBV selectively in tumor cells as a means to add clinical benefit. While compounds able to stimulate the lytic cascade have been identified, their clinical application so far has been limited. We are developing a novel anticancer molecule, NEO212, that was generated by covalent conjugation of the alkylating agent temozolomide (TMZ) to the naturally occurring monoterpene perillyl alcohol (POH). In the current study, we investigated its potential to trigger the lytic cycle of EBV in NPC cells in vitro and in vivo. We used the established C666.1 cell line and primary patient cells derived from the brain metastasis of a patient with NPC, both of which harbored latent EBV. Upon treatment with NEO212, there was an increase in EBV proteins Zta and Ea-D, key markers of the lytic cycle, along with increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum (ER) stress, followed by the activation of caspases. These effects could also be confirmed in tumor tissue from mice implanted with C666.1 cells. Towards a mechanistic understanding of these events, we used siRNA-mediated knockdown of CHOP and inclusion of anti-oxidant compounds. Both approaches blocked lytic cycle induction by NEO212. Therefore, we established a sequence of events, where NEO212 caused reactive oxygen species (ROS) production, which triggered ER stress and elevated the levels of CHOP, which was required to stimulate the lytic cascade of EBV. Inclusion of the antiviral agent ganciclovir synergistically enhanced the cytotoxic impact of NEO212, pointing to a potential combination treatment for EBV-positive cancers which should be explored further. Overall, our study establishes NEO212 as a novel agent able to stimulate EBV's lytic cycle in NPC tumors, with implications for other virus-associated cancers.
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Our previous research studies have demonstrated the role of microRNA133b (miR133b) in healing the contused spinal cord when administered either intranasally or intravenously 24 h following an injury. While our data showed beneficial effects of exogenous miR133b delivered within hours of a spinal cord injury (SCI), the kinetics of endogenous miR133b levels in the contused spinal cord and rostral/caudal segments of the injury were not fully investigated. In this study, we examined the miR133b dysregulation in a mouse model of moderate unilateral contusion injury at the fifth cervical (C5) level. Between 30 min and 7 days post-injury, mice were euthanized and tissues were collected from different areas of the spinal cord, ipsilateral and contralateral prefrontal motor cortices, and off-targets such as lung and spleen. The endogenous level of miR133b was determined by RT-qPCR. We found that after SCI, (a) most changes in miR133b level were restricted to the injured area with very limited alterations in the rostral and caudal parts relative to the injury site, (b) acute changes in the endogenous levels were predominantly specific to the lesion site with delayed miR133b changes in the motor cortex, and (c) ipsilateral and contralateral hemispheres responded differently to unilateral SCI. Our results suggest that the therapeutic window for exogenous miR133b therapy begins earlier than 24 h post-injury and potentially lasts longer than 7 days.
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Médula Cervical , Contusiones , MicroARNs , Traumatismos de la Médula Espinal , Animales , Ratones , Contusiones/metabolismo , Modelos Animales de Enfermedad , MicroARNs/metabolismo , MicroARNs/uso terapéutico , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/terapia , Médula Cervical/lesionesRESUMEN
Obesity is a growing concern in human and equine populations, predisposing to metabolic pathologies and reproductive disturbances. Cellular lipid accumulation and mitochondrial dysfunction play an important role in the pathologic consequences of obesity, which may be mitigated by dietary interventions targeting these processes. We hypothesized that obesity in the mare promotes follicular lipid accumulation and altered mitochondrial function of oocytes and granulosa cells, potentially contributing to impaired fertility in this population. We also predicted that these effects could be mitigated by dietary supplementation with a combination of targeted nutrients to improve follicular cell metabolism. Twenty mares were grouped as: Normal Weight [NW, n = 6, body condition score (BCS) 5.7 ± 0.3], Obese (OB, n = 7, BCS 7.7 ± 0.2), and Obese Diet Supplemented (OBD, n = 7, BCS 7.7 ± 0.2), and fed specific feed regimens for ≥ 6 weeks before sampling. Granulosa cells, follicular fluid, and cumulus-oocyte complexes were collected from follicles ≥ 35 mm during estrus and after induction of maturation. Obesity promoted several mitochondrial metabolic disturbances in granulosa cells, reduced L-carnitine availability in the follicle, promoted lipid accumulation in cumulus cells and oocytes, and increased basal oocyte metabolism. Diet supplementation of a complex nutrient mixture mitigated most of the metabolic changes in the follicles of obese mares, resulting in parameters similar to NW mares. In conclusion, obesity disturbs the equine ovarian follicle by promoting lipid accumulation and altering mitochondrial function. These effects may be partially mitigated with targeted nutritional intervention, thereby potentially improving fertility outcomes in the obese female.
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Oocitos , Folículo Ovárico , Humanos , Caballos , Animales , Femenino , Folículo Ovárico/metabolismo , Oocitos/metabolismo , Líquido Folicular , Obesidad/metabolismo , Lípidos , Suplementos DietéticosRESUMEN
Ertapenem, a carbapenem-type beta-lactam antibiotic, demonstrates broad-spectrum efficacy against a wide range of Gram-positive and Gram-negative bacteria, including aerobes and anaerobes. Importantly, it demonstrates resistance to virtually all beta-lactamases, including the extended spectrum beta-lactamases (ESBLs). Haematologic complications such as thrombocytosis, haemolysis, anaemia, and neutropenia are infrequent side effects associated with this drug. In this report, we present a rare case of ertapenem-induced thrombocytosis in a 62-year-old female patient who was admitted for a complicated urinary tract infection caused by Escherichia coli. LEARNING POINTS: Ertapenem was identified as the most likely cause of thrombocytosis.Discontinuing ertapenem normalised the platelet count.It is crucial for physicians to identify and address causes of thrombocytosis, particularly when related to medications, to avoid inadvertent complications and to ensure effective patient care.
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IMPORTANCE: Medication nonadherence leads to worse health outcomes, increased healthcare service utilization, and increased overall healthcare costs. OBJECTIVE: To determine whether a discharge pharmacy located in the Emergency Department (ED) reduces ED revisits and hospitalizations. DESIGN: This is a cohort study where we extracted data from our electronic medical records with adult encounters between 12/2019-10/2021. For the purpose of this study, we defined a revisit to the ED as within 7 days and an admission within 30 days from prior initial ED visit. SETTING: The University of Chicago Medicine is an academic medical center located in Chicago's South Side. PARTICIPANTS: Between dates of 12/2019-11/2021, we had 78,660 adult distinct encounters. We created 5 different groups: no medications prescribed, ED discharge pharmacy only, e-prescriptions to outside pharmacies, combination of ED pharmacy and e-prescription sent elsewhere, and printed prescriptions with or without any e-prescriptions. EXPOSURE: Our ED pharmacy is located within the adult ED, serving only patients seen and discharged from the adult ED. MAIN OUTCOME(S) AND MEASURE(S): Our primary endpoint is to evaluate if prescribing and dispensing prescriptions from only our ED pharmacy is associated with decreased ED revisits within 7 days and reduced hospitalizations within 30 days of initial ED visit. RESULTS: When comparing patients who received prescriptions only from the ED discharge pharmacy, patients who received no prescriptions were 31.6% (P < 0.001) more likely to revisit our ED, and patients who received e-prescriptions sent to other pharmacies were 10.4% (P = 0.017) more likely to revisit. Patients who received e-prescriptions from other pharmacies were 29.2% (P < 0.001) more likely to be hospitalized and mixture of e-prescriptions were 59.5% (P < 0.001) more likely to be hospitalized compared to the ED pharmacy only group. CONCLUSIONS AND RELEVANCE: We believe having a pharmacy providing medications to patients being discharged from the ED reduces barriers like cost, transportation, and pharmacy access patients face trying to fill prescriptions at their local pharmacy. All of these reductions in barriers provides an easier and more convenient method for patients to obtain their medications at discharge from the ED, reducing the risk of a repeat ED visit and subsequent hospital admission.
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Farmacias , Farmacia , Adulto , Humanos , Alta del Paciente , Estudios de Cohortes , Hospitalización , Servicio de Urgencia en HospitalRESUMEN
The linear production and consumption of plastics today is unsustainable. It creates large amounts of unnecessary and mismanaged waste, pollution and carbon dioxide emissions, undermining global climate targets and the Sustainable Development Goals. This Perspective provides an integrated technological, economic and legal view on how to deliver a circular carbon and plastics economy that minimizes carbon dioxide emissions. Different pathways that maximize recirculation of carbon (dioxide) between plastics waste and feedstocks are outlined, including mechanical, chemical and biological recycling, and those involving the use of biomass and carbon dioxide. Four future scenarios are described, only one of which achieves sufficient greenhouse gas savings in line with global climate targets. Such a bold system change requires 50% reduction in future plastic demand, complete phase-out of fossil-derived plastics, 95% recycling rates of retrievable plastics and use of renewable energy. It is hard to overstate the challenge of achieving this goal. We therefore present a roadmap outlining the scale and timing of the economic and legal interventions that could possibly support this. Assessing the service lifespan and recoverability of plastic products, along with considerations of sufficiency and smart design, can moreover provide design principles to guide future manufacturing, use and disposal of plastics.
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Contaminación Ambiental , Objetivos , Plásticos , Reciclaje , Desarrollo Sostenible , Biomasa , Dióxido de Carbono/análisis , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Contaminación Ambiental/economía , Contaminación Ambiental/legislación & jurisprudencia , Contaminación Ambiental/prevención & control , Contaminación Ambiental/estadística & datos numéricos , Combustibles Fósiles , Calentamiento Global/prevención & control , Gases de Efecto Invernadero/análisis , Plásticos/síntesis química , Plásticos/economía , Plásticos/metabolismo , Plásticos/provisión & distribución , Reciclaje/economía , Reciclaje/legislación & jurisprudencia , Reciclaje/métodos , Reciclaje/tendencias , Energía Renovable , Desarrollo Sostenible/economía , Desarrollo Sostenible/legislación & jurisprudencia , Desarrollo Sostenible/tendencias , Tecnología/economía , Tecnología/legislación & jurisprudencia , Tecnología/métodos , Tecnología/tendenciasRESUMEN
HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
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OBJECTIVE: Malignancies of the CNS are difficult to treat because the blood-brain barrier (BBB) prevents most therapeutics from reaching the intracranial lesions at sufficiently high concentrations. This also applies to chimeric antigen receptor (CAR) T cells, for which systemic delivery is inferior to direct intratumoral or intraventricular injection of the cells. The authors previously reported on a novel approach to safely and reversibly open the BBB of mice by applying intra-arterial (IA) injections of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol. The authors hypothesized that this method would enable enhanced brain entry and therapeutic activity of intravenously delivered CAR T cells, which the authors tested in a mouse model of CNS lymphoma. METHODS: Human Raji lymphoma cells were implanted into the brains of immune-deficient mice. After tumor uptake was confirmed with bioluminescent imaging, 0.3% NEO100 was injected intra-arterially, which was followed by intravenous (IV) delivery of CD19-targeted CAR T cells. After this single intervention, tumor growth was monitored with imaging, long-term survival of mice was recorded, and select mice were euthanized to analyze the distribution of CAR T cells in brain tissue. RESULTS: Intravenously injected CAR T cells could be readily detected in brain tumor areas after IA injection of NEO100 but not after IA injection of the vehicle (without NEO100). Although all untreated control animals died within 3 weeks, all mice that received IA NEO100 followed by IV CAR T cells survived and thrived for 200 days, when the experiment was terminated. Of the mice that received IV CAR T cells without prior IA NEO100, 3 died within 3 weeks and 2 survived long-term. CONCLUSIONS: BBB opening by IA NEO100 facilitates brain entry of intravenously delivered CD19 CAR T cells. The long-term survival of all mice with CNS lymphoma, along with the disappearance of the tumor as determined with imaging, suggests that this one-time therapeutic intervention was curative. BBB opening by IA NEO100 may offer a novel option to increase brain access by CAR T cells.
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Inmunoterapia Adoptiva , Inyecciones Intraarteriales , Receptores Quiméricos de Antígenos , Animales , Ratones , Inmunoterapia Adoptiva/métodos , Modelos Animales de Enfermedad , Barrera Hematoencefálica , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/inmunología , Línea Celular Tumoral/trasplante , Linfoma/terapia , Linfoma/inmunología , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/inmunología , Linfocitos T/inmunología , Linfocitos T/trasplante , Ratones SCIDRESUMEN
Objective: Venous thromboembolic event (VTE) after spine surgery is a rare but potentially devastating complication. With the advent of machine learning, an opportunity exists for more accurate prediction of such events to aid in prevention and treatment. Methods: Seven models were screened using 108 database variables and 62 preoperative variables. These models included deep neural network (DNN), DNN with synthetic minority oversampling technique (SMOTE), logistic regression, ridge regression, lasso regression, simple linear regression, and gradient boosting classifier. Relevant metrics were compared between each model. The top four models were selected based on area under the receiver operator curve; these models included DNN with SMOTE, linear regression, lasso regression, and ridge regression. Separate random sampling of each model was performed 1000 additional independent times using a randomly generated training/testing distribution. Variable weights and magnitudes were analyzed after sampling. Results: Using all patient-related variables, DNN using SMOTE was the top-performing model in predicting postoperative VTE after spinal surgery (area under the curve [AUC] =0.904), followed by lasso regression (AUC = 0.894), ridge regression (AUC = 0.873), and linear regression (AUC = 0.864). When analyzing a subset of only preoperative variables, the top-performing models were lasso regression (AUC = 0.865) and DNN with SMOTE (AUC = 0.864), both of which outperform any currently published models. Main model contributions relied heavily on variables associated with history of thromboembolic events, length of surgical/anesthetic time, and use of postoperative chemoprophylaxis. Conclusions: The current study provides promise toward machine learning methods geared toward predicting postoperative complications after spine surgery. Further study is needed in order to best quantify and model real-world risk for such events.