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1.
Nature ; 591(7850): 451-457, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33561864

RESUMEN

All coronaviruses known to have recently emerged as human pathogens probably originated in bats1. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801-an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials-markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/prevención & control , Citidina/análogos & derivados , Hidroxilaminas/administración & dosificación , Hidroxilaminas/uso terapéutico , Administración Oral , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/virología , Animales , COVID-19/inmunología , Quimioprevención , Quirópteros/virología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Citidina/administración & dosificación , Citidina/uso terapéutico , Citocinas/inmunología , Células Epiteliales/virología , Femenino , Xenoinjertos , Humanos , Inmunidad Innata , Interferón Tipo I/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Trasplante de Pulmón , Masculino , Ratones , Profilaxis Posexposición , Profilaxis Pre-Exposición , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Replicación Viral
2.
J Interprof Care ; 37(1): 29-38, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-34723716

RESUMEN

Workplace-based interprofessional education (IPE) offers opportunities for pre-registration students to interact with patients in authentic settings. Senior dietetic, medical, nursing, physiotherapy and radiation therapy students took part in a workplace IPE initiative on cancer and palliative care informed by experiential learning theory and run by clinical tutors. Research was undertaken to gauge students and tutors' experiences of the initiative. The mixed methods approach included: Pre and post-administration of the University of West England Interprofessional questionnaire 'Communication and Teamwork Scale, 'Interprofessional Learning Scale,' 'Interprofessional Interaction Scale.' Two questions were added relating to cancer and palliative care. Separate focus group interviews were held with students and tutors. There was a positive shift in the Communication and Teamwork scale based on students' pre and post questionnaires, but no change in the other two scales. Analysis of student and tutor focus group data showed that both affirmed the IPE initiative for a range of reasons. A brief experiential, theory-informed IPE initiative with a focus on cancer and palliative care was well received by both students and clinical tutors. The mixed method approach highlighted some discrepancies between quantitative and qualitative results but when synthesized were explicable, demonstrating the value of using a mixed methods approach to research.


Asunto(s)
Relaciones Interprofesionales , Neoplasias , Humanos , Cuidados Paliativos , Educación Interprofesional , Estudiantes , Neoplasias/terapia , Lugar de Trabajo , Actitud del Personal de Salud
3.
J Biol Chem ; 295(41): 14189-14202, 2020 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-32788210

RESUMEN

Autophagy is a conserved process that recycles cellular contents to promote survival. Although nitrogen limitation is the canonical inducer of autophagy, recent studies have revealed several other nutrients important to this process. In this study, we used a quantitative, high-throughput assay to identify potassium starvation as a new and potent inducer of autophagy in the yeast Saccharomyces cerevisiae We found that potassium-dependent autophagy requires the core pathway kinases Atg1, Atg5, and Vps34, and other components of the phosphatidylinositol 3-kinase complex. Transmission EM revealed abundant autophagosome formation in response to both stimuli. RNA-Seq indicated distinct transcriptional responses: nitrogen affects transport of ions such as copper, whereas potassium targets the organization of other cellular components. Thus, nitrogen and potassium share the ability to influence molecular supply and demand but do so in different ways. Both inputs promote catabolism through bulk autophagy, but result in distinct mechanisms of cellular remodeling and synthesis.


Asunto(s)
Autofagia , Potasio/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Fosfatidilinositol 3-Quinasas Clase III/genética , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
4.
Neuropediatrics ; 51(6): 421-424, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32198741

RESUMEN

We report a case of a 9-year-old boy who presented with altered mental status and ataxia following 3 days of vomiting. Shortly after arrival to our emergency department, he declined and required intubation. The following day, he recovered and was successfully extubated. He was found to be positive for methadone on his urine drug screen. Brain imaging demonstrated a pattern of acute cerebellitis. Following extubation, the patient returned to his normal mental status; however, he began to have consistently elevated blood pressure and bradycardia and subsequent brain imaging showed supratentorial changes that were related to atypical posterior reversible encephalopathy syndrome. Through medical management including high-dose steroids and antihypertensive medications, the patient's blood pressure normalized, and he was eventually discharged home without further complications.


Asunto(s)
Encefalitis/diagnóstico , Metadona/efectos adversos , Síndrome de Leucoencefalopatía Posterior/diagnóstico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Niño , Encefalitis/inducido químicamente , Humanos , Masculino , Síndrome de Leucoencefalopatía Posterior/inducido químicamente
5.
Sex Abuse ; 30(1): 43-62, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26787299

RESUMEN

Cognitive distortions are often referred to as attitudes toward rape in theory, research, and clinical practice pertaining to sexual aggression. In the social-psychological literature, however, attitudes are typically defined as evaluations; thus, in this context, attitudes toward rape are considered evaluations of rape (e.g., rape is negative vs. positive). The purpose of the current study was to explore whether a widely used measure of cognitive distortions (RAPE Scale; Bumby, 1996) assesses evaluation of rape, and, if not, whether evaluation of rape and the cognitions assessed by the RAPE Scale are independently associated with sexually aggressive behavior. Participants (660 male undergraduate students) completed the RAPE Scale as well as measures of evaluation of rape and sexually aggressive behavior. An exploratory factor analysis revealed that the RAPE Scale items formed a correlated but distinct factor from the Evaluation of Rape Scale items. Regression analyses indicated that the Evaluation of Rape Scale and the RAPE Scale had small to moderate independent associations with self-report measures of sexually aggressive behavior. Our results suggest that evaluation of rape may be distinct from cognitive distortions regarding rape, and both evaluation and cognitive distortions may be relevant for understanding sexual violence.


Asunto(s)
Agresión/psicología , Actitud , Cognición/fisiología , Violación/psicología , Delitos Sexuales/psicología , Conducta Sexual/psicología , Adolescente , Adulto , Humanos , Masculino , Estudiantes/psicología , Adulto Joven
6.
World J Gastroenterol ; 30(27): 3284-3289, 2024 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-39086746

RESUMEN

Inflammatory bowel disease (IBD) is the consequence of a complex interplay between environmental factors, like dietary habits, that alter intestinal microbiota in response to luminal antigens in genetically susceptible individuals. Epigenetics represents an auspicious area for the discovery of how environmental factors influence the pathogenesis of inflammation, prognosis, and response to therapy. Consequently, it relates to gene expression control in response to environmental influences. The increasing number of patients with IBD globally is indicative of the negative effects of a food supply rich in trans and saturated fats, refined sugars, starches and additives, as well as other environmental factors like sedentarism and excess bodyweight, influencing the promotion of gene expression and increasing DNA hypomethylation in IBD. As many genetic variants are now associated with Crohn's disease (CD), new therapeutic strategies targeting modifiable environmental triggers, such as the implementation of an anti-inflammatory diet that involves the removal of potential food antigens, are of growing interest in the current literature. Diet, as a strong epigenetic factor in the pathogenesis of inflammatory disorders like IBD, provides novel insights into the pathophysiology of intestinal and extraintestinal inflammatory disorders.


Asunto(s)
Metilación de ADN , Dieta , Epigénesis Genética , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/inmunología , Dieta/efectos adversos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Conducta Alimentaria , Predisposición Genética a la Enfermedad
7.
Am J Nurs ; 124(3): 42-49, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38386834

RESUMEN

LOCAL PROBLEM: In 2019 and the first half of 2020, our facility experienced an increase in the number and severity of hospital-acquired pressure injuries (HAPIs) among our cardiothoracic surgery population. Fifty percent of these HAPIs occurred within 72 hours of surgery. A review of the literature revealed that alternating pressure overlays (APOs) have been successfully used to prevent HAPIs in surgical patients. PURPOSE: The primary purpose of our quality improvement (QI) project was to measure perioperative HAPI rates in cardiothoracic surgery patients after the addition of APOs to our HAPI prevention protocol. Our secondary purpose was to identify common factors among those patients who developed HAPIs. METHODS: This QI project collected both pre- and postintervention data and compared the findings. A nurse-led team was responsible for measuring HAPI rates during the intervention-from July through October 2020-which involved placing an APO under cardiothoracic surgery patients during the 72-hour perioperative period. APOs were placed on all operating room (OR) tables and remained with the patients following surgery. Bed linens and skin care products were standardized for consistency. Lifts were used to reduce friction during repositioning. RESULTS: During preintervention data collection, we identified 10 patients who developed HAPIs (seven out of 1,174 cardiothoracic surgery patients in 2019, for a HAPI rate of 0.6%, and three out of 333 patients in the first half of 2020, for a HAPI rate of 0.9%). During the four-month intervention period, in which APOs were used in 331 patients undergoing cardiothoracic surgery, no HAPIs developed. CONCLUSION: Use of an APO in cardiothoracic ORs and critical care units may help reduce HAPI rates.


Asunto(s)
Ropa de Cama y Ropa Blanca , Úlcera por Presión , Humanos , Recolección de Datos , Unidades de Cuidados Intensivos , Pacientes , Úlcera por Presión/prevención & control
8.
J Cell Biol ; 223(4)2024 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-38334983

RESUMEN

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to lipogenesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride after fatty acid pulse-chase. This LD size phenotype was rescued by chimeric APOE that targets only LDs. Like APOE depletion, APOE4-expressing astrocytes form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 causes aberrant LD composition and morphology. Our study contributes to accumulating evidence that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation, which could contribute to Alzheimer's disease risk.


Asunto(s)
Enfermedad de Alzheimer , Apolipoproteínas E , Astrocitos , Gotas Lipídicas , Triglicéridos , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Astrocitos/metabolismo , Ácidos Grasos/metabolismo , Gotas Lipídicas/metabolismo , Triglicéridos/metabolismo
9.
bioRxiv ; 2024 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-38260395

RESUMEN

Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.

10.
bioRxiv ; 2023 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-37162939

RESUMEN

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to neutral lipid synthesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the ER lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs containing more unsaturated triglyceride. This LD size distribution phenotype was rescued by chimeric APOE that targets only LDs. APOE4 - expressing astrocytes also form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the larger LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 is a toxic gain of function variant that causes aberrant LD composition and morphology. We propose that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation or lipotoxicity, which could contribute to Alzheimer's disease risk. Summary: Windham et al . discover that APOE in astrocytes can traffic to lipid droplets (LDs), where it modulates LD composition and size. Astrocytes expressing the Alzheimer's risk variant APOE4 form large LDs with impaired turnover and increased peroxidation sensitivity.

11.
iScience ; 26(5): 106645, 2023 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-37182104

RESUMEN

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved, ubiquitously expressed nucleic acid-binding protein that regulates DNA/RNA metabolism. Genetics and neuropathology studies have linked TDP-43 to several neuromuscular and neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under pathological conditions, TDP-43 mislocalizes to the cytoplasm where it forms insoluble, hyper-phosphorylated aggregates during disease progression. Here, we optimized a scalable in vitro immuno-purification strategy referred to as tandem detergent-extraction and immunoprecipitation of proteinopathy (TDiP) to isolate TDP-43 aggregates that recapitulate those identified in postmortem ALS tissue. Moreover, we demonstrate that these purified aggregates can be utilized in biochemical, proteomics, and live-cell assays. This platform offers a rapid, accessible, and streamlined approach to study ALS disease mechanisms, while overcoming many limitations that have hampered TDP-43 disease modeling and therapeutic drug discovery efforts.

12.
J Org Chem ; 77(5): 2368-81, 2012 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-22288783

RESUMEN

A "2 + 2" strategy for synthesizing adj-dicarbaporphyrinoid systems has been developed. In a model study, an azulenylmethylpyrrole dialdehyde was condensed with a dipyrrylmethane in the presence of HCl, followed by oxidation with ferric chloride, to give a modest yield of an azuliporphyrin. Fulvene aldehydes were prepared by reacting an indene-derived enamine with azulene aldehydes in the presence of Bu(2)BOTf, and azulene dialdehydes similarly reacted to give fulvene dialdehydes. The dialdehydes were condensed with dipyrrylmethanes in TFA/dichloromethane to afford good to excellent yields of dicarbaporphyrinoids with adjacent indene and azulene subunits. These 22-carbaazuliporphyrins exhibited significant diatropic character, and this property was magnified upon protonation. These characteristics are attributed to tropylium-containing resonance contributors that possess 18π electron delocalization pathways. Protonation studies demonstrated that C-protonation readily occurred at the interior indene carbon, but deuterium exchange also occurred at the internal azulene CH as well as at the meso-positions with TFA-d. Reaction of a carbaazuliporphyrin with silver(I) acetate in methanol or ethanol solutions also gave unusual nonaromatic dialkoxy derivatives.


Asunto(s)
Aldehídos/química , Aldehídos/síntesis química , Azulenos/química , Porfirinas/síntesis química , Estructura Molecular , Porfirinas/química , Estereoisomerismo
13.
J Interpers Violence ; 37(3-4): 1933-1959, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-32517562

RESUMEN

The current study examined the extent to which evaluative attitudes toward sexual aggression (i.e., positive or negative evaluative judgments about sexually aggressive behavior) mediate the association between injunctive norms (i.e., extent to which peers approve or disapprove of sexually aggressive behavior) and self-reported sexual aggression against women. Participants were 200 male undergraduate students. Approximately one in four males reported engaging in at least one sexually aggressive act since the age of 16. Participants with a history of sexual aggression also reported the highest likelihood of engaging in sexually aggressive behavior in the future. We tested two separate mediation models to examine the extent to which evaluative attitudes account for the link between injunctive norms and sexual aggression: one model with self-reported history of sexual aggression as the outcome and the other with likelihood of engaging in sexually aggressive behavior as the outcome. Results showed that more positive evaluative attitudes toward sexual aggression accounted for the association between injunctive norms and self-reported history of sexual aggression. Similarly, evaluative attitudes accounted for the link between injunctive norms and self-reported likelihood of engaging in sexually aggressive behavior in the future. Overall, these findings are consistent with theoretical and empirical explanations of sexual offending and general criminal behavior; however, this is the first study to explore the relationship between injunctive norms and evaluative attitudes in the context of explaining sexually aggressive behavior. If more rigorous research establishes a causal relationship between injunctive norms, evaluative attitudes, and sexually aggressive behavior, this would suggest that targeting these factors in prevention programs may reduce sexual aggression by male undergraduate students.


Asunto(s)
Agresión , Actitud , Femenino , Humanos , Masculino , Grupo Paritario , Conducta Sexual , Estudiantes
14.
Sci Adv ; 8(13): eabm9718, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35363522

RESUMEN

Cystic fibrosis (CF) is characterized by abnormal transepithelial ion transport. However, a description of CF lung disease pathophysiology unifying superficial epithelial and submucosal gland (SMG) dysfunctions has remained elusive. We hypothesized that biophysical abnormalities associated with CF mucus hyperconcentration provide a unifying mechanism. Studies of the anion secretion-inhibited pig airway model of CF revealed elevated SMG mucus concentrations, osmotic pressures, and SMG mucus accumulation. Human airway studies revealed hyperconcentrated CF SMG mucus with raised osmotic pressures and cohesive forces predicted to limit SMG mucus secretion/release. Using proline-rich protein 4 (PRR4) as a biomarker of SMG secretion, CF sputum proteomics analyses revealed markedly lower PRR4 levels compared to healthy and bronchiectasis controls, consistent with a failure of CF SMGs to secrete mucus onto airway surfaces. Raised mucus osmotic/cohesive forces, reflecting mucus hyperconcentration, provide a unifying mechanism that describes disease-initiating mucus accumulation on airway surfaces and in SMGs of the CF lung.


Asunto(s)
Fibrosis Quística , Animales , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Moco/metabolismo , Sistema Respiratorio/metabolismo , Esputo/metabolismo , Porcinos
15.
J Consult Clin Psychol ; 89(4): 350-363, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33734722

RESUMEN

OBJECTIVE: We quantitatively reviewed the construct validity evidence for all cognitively based indirect measures of sexual interest in prepubescent children (pedophilic interest) and pubescent children (hebephilic interest) using meta-analysis. METHOD: Studies were included if they presented scores on a cognitively based indirect measure of pedohebephilic interest for a sample of adolescent or adult males who had committed a sexual offense against a child 16 years of age or younger, or who reported sexual interest in children, and for a comparison group. Studies were also included if they reported on the strength of association between scores on an indirect measure and an independent indicator of pedohebephilic interest in a sample of males. We used meta-analysis with robust variance estimation to summarize effect sizes and metaregression to test potential moderators. RESULTS: Cognitively based indirect measures of pedohebephilic interest showed a moderate difference between pedohebephilic (n = 2,552) and nonpedohebephilic males (n = 2,434), d = 0.61, 95% CI [0.46, 0.76], k = 39. A small-to-moderate correlation was also observed between indirect measures and independent indicators of pedohebephilic interest, r = .23, 95% CI [0.17, 0.28], k = 23, n = 3,623. These effects were qualified by substantial heterogeneity; however, most moderators we tested did not account for a significant amount of heterogeneity. CONCLUSIONS: Findings suggest that publication bias did not substantially distort the results. However, the lack of significant moderators suggests more research is needed to understand the conditions under which indirect measures best reflect pedohebephilic interest. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Asunto(s)
Pedofilia/psicología , Pruebas Psicológicas , Adolescente , Adulto , Nivel de Alerta , Cognición , Modificador del Efecto Epidemiológico , Humanos , Masculino , Reproducibilidad de los Resultados
16.
Res Sq ; 2020 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-32995766

RESUMEN

All known recently emerged human coronaviruses likely originated in bats. Here, we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV, SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronaviruses. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats harbor endogenous coronaviruses capable of direct transmission into humans. Further detailed analysis of pandemic SARS-CoV-2 in vivo infection of LoM human lung tissue showed predominant infection of human lung epithelial cells, including type II pneumocytes present in alveoli and ciliated airway cells. Acute SARS-CoV-2 infection was highly cytopathic and induced a robust and sustained Type I interferon and inflammatory cytokine/chemokine response. Finally, we evaluated a pre-exposure prophylaxis strategy for coronavirus infection. Our results show that prophylactic administration of EIDD-2801, an oral broad spectrum antiviral currently in phase II clinical trials for the treatment of COVID-19, dramatically prevented SARS-CoV-2 infection in vivo and thus has significant potential for the prevention and treatment of COVID-19.

18.
Clin Teach ; 16(5): 519-524, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30560577

RESUMEN

BACKGROUND: Cancer care is typically delivered by a range of health professionals, and is frequently a uniprofessional pre-registration clinical placement. A workplace-based, 6-hour interprofessional education (IPE) pilot on cancer care, led by clinical tutors, was undertaken in a New Zealand hospital, accompanied by an external evaluation. The pilot involved a cohort of 21 dietetic, medicine, pharmacy, physiotherapy and radiation therapy students. The aim of the evaluation was to determine student and tutor reactions to IPE, and any changes in perceptions and attitudes. METHODS: The evaluation used focus groups to collect data: two student groups and one tutor group. Focus groups were audio-recorded, transcribed; the content was coded and then analysed. RESULTS: Both students and tutors reported benefits from having IPE in the workplace environment, with cancer care seen as a suitable topic. Students reported a better understanding of professional roles, skills and the provision of collaborative care, and suggested other professions should be included in future IPE. Patient selection needed to be better tailored for physiotherapy students to ensure uniform relevance. As a result of competing demands, tutors found that they needed an 18-month lead time to establish the IPE programme. Tutors felt that the programme had gone relatively smoothly and that they had benefitted from forming closer interpersonal relationships, but noted considerable unanticipated and unremunerated preparation time. DISCUSSION: This short workplace-based IPE programme elicited a positive student and tutor response, but highlighted the need for improvements: broadening the topic area, targeted patient selection, including more professions and providing administrative support for tutors. Cancer care was generally seen as a suitable topic.


Asunto(s)
Relaciones Interprofesionales , Oncología Médica/educación , Evaluación Educacional , Grupos Focales , Humanos , Comunicación Interdisciplinaria , Oncología Médica/métodos , Neoplasias/terapia , Estudiantes de Medicina/psicología
19.
J AOAC Int ; 102(6): 1689-1694, 2019 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-31239007

RESUMEN

Changing weather conditions have heightened the risk of growth of mycotoxigenic molds on crops and various agricultural commodities. Mycotoxins, which are linked to carcinogenic and nephrotoxic effects in animals and humans, have been traditionally analyzed by immunoassays, gas, and LC techniques with spectrophotometric detectors. This review discusses the current techniques and challenges in commercial settings associated with the analysis of mycotoxins in unique matrices such as animal feeds, herbal products, and dietary supplements containing botanicals. Because of the advantages and growing acceptance of LC-tandem MS (MS/MS) over traditional approaches, discussion is mainly based on LC-MS/MS-based approaches. Considering the impact of sample preparation on accuracy of quantitative results, discussion about pros and cons of recently introduced sample preparation techniques is integrated with analytical methods. A section of the review explains the importance and availability of reference materials for mycotoxins. The present discussion provides good insight into the current challenges and developments during mycotoxin analysis of feed and botanicals and addresses the need for researchers in terms of an official MS-based method.


Asunto(s)
Contaminación de Alimentos/análisis , Micotoxinas/análisis , Alimentación Animal/análisis , Cromatografía Liquida/métodos , Micotoxinas/normas , Preparaciones de Plantas/análisis , Estándares de Referencia , Espectrometría de Masas en Tándem/métodos
20.
Exp Hematol Oncol ; 7: 12, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29774169

RESUMEN

BACKGROUND: The current standard of care for classical Hodgkin lymphoma (HL) is multiagent chemotherapy with or without radiation. In patients who relapse or fail to respond, additional high-dose chemotherapy with autologous hematopoietic stem cell transplantation (AHSCT) can improve progression-free survival (PFS). Novel therapies are required for patients refractory to chemotherapy and AHSCT. The mammalian target of rapamycin inhibitor everolimus has shown preliminary activity in preclinical models of HL and promising efficacy in patients with relapsed or refractory HL. METHODS: This was an open-label, two-stage, phase 2 study that enrolled 57 patients aged ≥ 18 years with classic HL that had progressed after standard therapy. Patients received everolimus 10 mg daily until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was overall response rate; secondary endpoints included PFS, overall survival, time to response, duration of response, and safety. RESULTS: Overall response rate was 45.6% (95% confidence interval [CI] 32.4-59.3%); five patients (8.8%) experienced a complete response and 21 patients had a partial response (36.8%). Median PFS was 8.0 months (95% CI 5.1-11.0 months). Seven patients (12%) were long-term responders (≥ 12 months). The most common study drug-related adverse events were thrombocytopenia (45.6%), fatigue (31.6%), anemia (26.3%), rash (24.6%), and stomatitis (22.8%). CONCLUSIONS: Everolimus 10 mg/day demonstrated favorable results in patients with heavily pretreated, relapsed, or refractory classical HL. These findings support the further evaluation of everolimus in this indication.Trial registration ClinicalTrials.gov NCT01022996. Registered November 25, 2009.

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