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1.
PLoS Genet ; 17(3): e1009358, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33661901

RESUMO

The feeling of hunger or satiety results from integration of the sensory nervous system with other physiological and metabolic cues. This regulates food intake, maintains homeostasis and prevents disease. In C. elegans, chemosensory neurons sense food and relay information to the rest of the animal via hormones to control food-related behaviour and physiology. Here we identify a new component of this system, SKN-1B which acts as a central food-responsive node, ultimately controlling satiety and metabolic homeostasis. SKN-1B, an ortholog of mammalian NF-E2 related transcription factors (Nrfs), has previously been implicated with metabolism, respiration and the increased lifespan incurred by dietary restriction. Here we show that SKN-1B acts in two hypothalamus-like ASI neurons to sense food, communicate nutritional status to the organism, and control satiety and exploratory behaviours. This is achieved by SKN-1B modulating endocrine signalling pathways (IIS and TGF-ß), and by promoting a robust mitochondrial network. Our data suggest a food-sensing and satiety role for mammalian Nrf proteins.

3.
Clin Cancer Res ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632927

RESUMO

PURPOSE: While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain. EXPERIMENTAL DESIGN: We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets. RESULTS: The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28-0.79, for F. nucleatum-high vs. -negative category; P trend = 0.0004] and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32-0.85; P trend = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs. CONCLUSIONS: The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.

4.
Viruses ; 13(2)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546185

RESUMO

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG's antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Coronavirus Humano OC43/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Tapsigargina/farmacologia , Animais , Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Coronavirus Humano OC43/fisiologia , Estresse do Retículo Endoplasmático , Humanos , Vírus da Influenza A Subtipo H1N1/fisiologia , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Ribavirina/farmacologia , Tapsigargina/uso terapêutico , Replicação Viral/efeitos dos fármacos
5.
Viruses ; 13(2)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567525

RESUMO

Avian influenza virus (AIV) subtypes H5 and H7 are capable of mutating from low to high pathogenicity strains, causing high mortality in poultry with significant economic losses globally. During 2015, two outbreaks of H7N7 low pathogenicity AIV (LPAIV) in Germany, and one each in the United Kingdom (UK) and The Netherlands occurred, as well as single outbreaks of H7N7 high pathogenicity AIV (HPAIV) in Germany and the UK. Both HPAIV outbreaks were linked to precursor H7N7 LPAIV outbreaks on the same or adjacent premises. Herein, we describe the clinical, epidemiological, and virological investigations for the H7N7 UK HPAIV outbreak on a farm with layer chickens in mixed free-range and caged units. H7N7 HPAIV was identified and isolated from clinical samples, as well as H7N7 LPAIV, which could not be isolated. Using serological and molecular evidence, we postulate how the viruses spread throughout the premises, indicating potential points of incursion and possible locations for the mutation event. Serological and mortality data suggested that the LPAIV infection preceded the HPAIV infection and afforded some clinical protection against the HPAIV. These results document the identification of a LPAIV to HPAIV mutation in nature, providing insights into factors that drive its manifestation during outbreaks.


Assuntos
Vírus da Influenza A Subtipo H7N7/genética , Vírus da Influenza A Subtipo H7N7/patogenicidade , Influenza Aviária/virologia , Doenças das Aves Domésticas/virologia , Animais , Anticorpos Antivirais/sangue , Galinhas , Surtos de Doenças/veterinária , Fazendas , Genoma Viral/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H7N7/classificação , Vírus da Influenza A Subtipo H7N7/imunologia , Influenza Aviária/epidemiologia , Influenza Aviária/patologia , Influenza Aviária/transmissão , Mutação , Filogenia , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/transmissão , Reino Unido/epidemiologia , Eliminação de Partículas Virais/genética
6.
Microsc Res Tech ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33448134

RESUMO

Nanocomposites formed by metal nanoparticles self-assembled in an insulator matrix are of great technological importance. Applications include surface enhanced Raman spectroscopy based biosensors, optical devices, photovoltaic cells, and more. Self-assembling of nanocomposites using low energy ion implantation offers a fast and low cost process. We report here on our work on nanocomposites formed by very low energy ion implantation of gold and platinum nanoparticles into Poly(methyl methacrylate) (PMMA), with description of the nanoparticle evolution as a function of implantation dose. The Au-PMMA and Pt-PMMA nanocomposites were characterized by transmission electron microscopy, thus determining the nanoparticle density, their size distribution, and the distance between particles as a function of implantation dose. A comparison between Au-PMMA and Pt-PMMA reveals substantial differences in the formation processes of the nanoparticles. The results provide insight into basic nanoparticle formation processes, as well as crucial information important for design applications. In addition, the tunneling decay length ξ and the electron affinity ε of the implantation-modified PMMA were obtained using a new and simple approach.

7.
Pathology ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33461799

RESUMO

The recently published 5th edition 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System brings significant changes from the 2010 4th edition. An emphasis on uniformity in nomenclature and grading for tumours across all organ systems is a particular feature of the 5th edition blue book series that is reflected in the gastrointestinal tract (GIT) classification. For example, simplified two tiered grading is reinforced for preinvasive lesions throughout the GIT, with dysplasia at all sites now being considered either low or high grade. Similarly, a uniform approach to classification and grading of GIT neuroendocrine neoplasms has been consolidated, with an emphasis on distinguishing grade 3 neuroendocrine tumours from neuroendocrine carcinomas. In this review, we discuss and critically assess the important and sometimes controversial changes made to the classification of tumours of the lower GIT, comprising the colorectum, vermiform appendix and anal canal. The particularly controversial decision to endorse the term 'sessile serrated lesion' for lesions previously termed 'sessile serrated polyp/adenoma' is explored. The morphological, molecular, and clinical insights behind the substitution of the term 'goblet cell adenocarcinoma' for 'goblet cell carcinoid' are assessed. The evolution of the classification of appendiceal mucinous neoplasms is considered. Inflammatory bowel disease related dysplasia and its evolving subtypes, with major implications for pathologists in routine practice, is explained.

8.
PLoS One ; 16(1): e0244669, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33471840

RESUMO

The mutual dependence of human and animal health is central to the One Health initiative as an integrated strategy for infectious disease control and management. A crucial element of the One Health includes preparation and response to influenza A virus (IAV) threats at the human-animal interface. The IAVs are characterized by extensive genetic variability, they circulate among different hosts and can establish host-specific lineages. The four main hosts are: avian, swine, human and equine, with occasional transmission to other mammalian species. The host diversity is mirrored in the range of the RT-qPCR assays for IAV detection. Different assays are recommended by the responsible health authorities for generic IAV detection in birds, swine or humans. In order to unify IAV monitoring in different hosts and apply the One Health approach, we developed a single RT-qPCR assay for universal detection of all IAVs of all subtypes, species origin and global distribution. The assay design was centred on a highly conserved region of the IAV matrix protein (MP)-segment identified by a comprehensive analysis of 99,353 sequences. The reaction parameters were effectively optimised with efficiency of 93-97% and LOD95% of approximately ten IAV templates per reaction. The assay showed high repeatability, reproducibility and robustness. The extensive in silico evaluation demonstrated high inclusivity, i.e. perfect sequence match in the primers and probe binding regions, established as 94.6% for swine, 98.2% for avian and 100% for human H3N2, pandemic H1N1, as well as other IAV strains, resulting in an overall predicted detection rate of 99% on the analysed dataset. The theoretical predictions were confirmed and extensively validated by collaboration between six veterinary or human diagnostic laboratories on a total of 1970 specimens, of which 1455 were clinical and included a diverse panel of IAV strains.

9.
Emerg Microbes Infect ; 10(1): 148-151, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33400615

RESUMO

Analyses of HPAI H5 viruses from poultry outbreaks across a wide Eurasian region since July 2020 including the Russian Federation, Republics of Iraq and Kazakhstan, and recent detections in migratory waterfowl in the Netherlands, revealed undetected maintenance of H5N8, likely in galliform poultry since 2017/18 and both H5N5 and H5N1. All viruses belong to A/H5 clade 2.3.4.4b with closely related HA genes. Heterogeneity in Eurasian H5Nx HPAI emerging variants threatens poultry production, food security and veterinary public health.

10.
Viruses ; 13(1)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467732

RESUMO

Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.


Assuntos
Doenças Assintomáticas , Modelos Animais de Doenças , /fisiologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , /patologia , Feminino , Furões , Genoma Viral/genética , Mutação , Mucosa Nasal/virologia , RNA Viral/genética , Carga Viral , Eliminação de Partículas Virais
11.
Histopathology ; 78(1): 88-105, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33382496

RESUMO

Most absorption of nutrients takes place in the proximal small intestine, and the most common disorders leading to malabsorption are associated with a morphological abnormality in the duodenal mucosa that is appreciable in histological sections of biopsy specimens. Coeliac disease is the most well-known example, causing intraepithelial lymphocytosis, inflammation and villous atrophy in the duodenum. Remarkably similar inflammatory changes can be induced by other processes, including medications, e.g. angiotensin II receptor blockers and immune checkpoint inhibitors, immune dysregulation disorders, e.g. common variable immunodeficiency and autoimmune enteropathy, infections, collagenous sprue, and tropical sprue. However, there are often subtle histological differences from coeliac disease in the type of inflammatory infiltrate, the presence of crypt apoptosis, and the extent and type of inflammation beyond the duodenum. The clinical setting and serological investigation usually allow diagnostic separation, but some cases remain challenging. Histopathology is also important in assessing the response to treatment, such as the change in villous architecture caused by a gluten-free diet, or the response to cessation of a potentially causative medication. This review examines the practical role that histopathology of duodenal biopsy specimens plays in the assessment and management of inflammatory malabsorptive processes of the proximal small intestine, with a particular emphasis on coeliac disease.

12.
Nucleic Acids Res ; 49(1): 340-353, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33330932

RESUMO

DNA double-strand breaks drive genomic instability. However, it remains unknown how these processes may affect the biomechanical properties of the nucleus and what role nuclear mechanics play in DNA damage and repair efficiency. Here, we have used Atomic Force Microscopy to investigate nuclear mechanical changes, arising from externally induced DNA damage. We found that nuclear stiffness is significantly reduced after cisplatin treatment, as a consequence of DNA damage signalling. This softening was linked to global chromatin decondensation, which improves molecular diffusion within the organelle. We propose that this can increase recruitment for repair factors. Interestingly, we also found that reduction of nuclear tension, through cytoskeletal relaxation, has a protective role to the cell and reduces accumulation of DNA damage. Overall, these changes protect against further genomic instability and promote DNA repair. We propose that these processes may underpin the development of drug resistance.


Assuntos
Núcleo Celular/ultraestrutura , Cromatina/ultraestrutura , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Instabilidade Genômica/genética , Núcleo Celular/efeitos dos fármacos , Células Cultivadas , Cromatina/genética , Cisplatino/farmacologia , Reagentes para Ligações Cruzadas/farmacologia , Citoesqueleto/ultraestrutura , Elasticidade , Células HeLa , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Microscopia de Força Atômica , Imagem Individual de Molécula
13.
J Virol Methods ; 289: 114048, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33358911

RESUMO

We describe the optimisation of a simplified sample preparation method which permits rapid and direct detection of SARS-CoV-2 RNA within saliva, using reverse-transcription loop-mediated isothermal amplification (RT-LAMP). Treatment of saliva samples prior to RT-LAMP by dilution 1:1 in Mucolyse™, followed by dilution in 10 % (w/v) Chelex© 100 Resin and a 98 °C heat step for 2 min enabled detection of SARS-CoV-2 RNA in positive saliva samples. Using RT-LAMP, SARS-CoV-2 RNA was detected in as little as 05:43 min, with no amplification detected in 3097 real-time reverse transcription PCR (rRT-PCR) negative saliva samples from staff tested within a service evaluation study, or for other respiratory pathogens tested (n = 22). Saliva samples can be collected non-invasively, without the need for skilled staff and can be obtained from both healthcare and home settings. Critically, this approach overcomes the requirement for, and validation of, different swabs and the global bottleneck in obtaining access to extraction robots and reagents to enable molecular testing by rRT-PCR. Such testing opens the possibility of public health approaches for effective intervention during the COVID-19 pandemic through regular SARS-CoV-2 testing at a population scale, combined with isolation and contact tracing.


Assuntos
/métodos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Saliva/virologia , Manejo de Espécimes/métodos , Humanos , RNA Viral/análise
14.
J Virol ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268518

RESUMO

Swine influenza A virus (swIAV) infection causes substantial economic loss and disease burden in humans and animals. The 2009 pandemic H1N1 (pH1N1) influenza A virus is now endemic in both populations. In this study we evaluated the efficacy of different vaccines in reducing nasal shedding in pigs following pH1N1 virus challenge. We also assessed transmission from immunized and challenged to naive, directly in-contact pigs. Pigs were immunised with either adjuvanted, whole inactivated virus (WIV) vaccines or viral vectored (ChAdOx1 and MVA) vaccines expressing either the homologous or heterologous influenza A virus hemagglutinin (HA) glycoprotein as well as an influenza viral pseudotype (S-FLU) vaccine expressing heterologous HA. Only two vaccines containing homologous HA, which also induced high hemagglutination inhibitory antibody titers, significantly reduced virus shedding in challenged animals. Nevertheless, virus transmission from challenged to naive, in-contact animals occurred in all groups, although was delayed in groups of vaccinated animals with reduced virus shedding.IMPORTANCE This study was designed to determine whether vaccination of pigs with conventional, WIV or viral-vectored vaccines reduces pH1N1 swine influenza virus shedding following challenge and can prevent transmission to naive in-contact animals. Even when viral shedding was significantly reduced following challenge, infection was transmissible to susceptible co-housed recipients. This knowledge is important to inform disease surveillance and control strategies, and to determine the vaccine coverage required in a population, thereby defining disease moderation or herd protection. WIV or viral-vectored vaccines homologous to the challenge strain significantly reduced virus shedding from directly infected pigs, but vaccination did not completely prevent transmission to co-housed naive pigs.

15.
Viruses ; 12(12)2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33316899

RESUMO

Emerging infectious diseases are of great concern to public health, as highlighted by the ongoing coronavirus disease 2019 (COVID-19) pandemic. Such diseases are of particular danger during mass gathering and mass influx events, as large crowds of people in close proximity to each other creates optimal opportunities for disease transmission. The Hashemite Kingdom of Jordan and the Kingdom of Saudi Arabia are two countries that have witnessed mass gatherings due to the arrival of Syrian refugees and the annual Hajj season. The mass migration of people not only brings exotic diseases to these regions but also brings new diseases back to their own countries, e.g., the outbreak of MERS in South Korea. Many emerging pathogens originate in bats, and more than 30 bat species have been identified in these two countries. Some of those bat species are known to carry viruses that cause deadly diseases in other parts of the world, such as the rabies virus and coronaviruses. However, little is known about bats and the pathogens they carry in Jordan and Saudi Arabia. Here, the importance of enhanced surveillance of bat-borne infections in Jordan and Saudi Arabia is emphasized, promoting the awareness of bat-borne diseases among the general public and building up infrastructure and capability to fill the gaps in public health preparedness to prevent future pandemics.


Assuntos
Quirópteros/virologia , Doenças Transmissíveis Emergentes/epidemiologia , Coronavirus/isolamento & purificação , Saúde Pública , Zoonoses/epidemiologia , Animais , Doenças Transmissíveis Emergentes/virologia , Coronavirus/classificação , Coronavirus/patogenicidade , Surtos de Doenças/prevenção & controle , Humanos , Jordânia , Arábia Saudita , Zoonoses/transmissão , Zoonoses/virologia
16.
Sci Rep ; 10(1): 21894, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318594

RESUMO

The rapid emergence of SARS-CoV-2, the causative agent of COVID-19, and its dissemination globally has caused an unprecedented strain on public health. Animal models are urgently being developed for SARS-CoV-2 to aid rational design of vaccines and therapeutics. Immunohistochemistry and in situ hybridisation techniques that facilitate reliable and reproducible detection of SARS-CoV and SARS-CoV-2 viral products in formalin-fixed paraffin-embedded (FFPE) specimens would be of great utility. A selection of commercial antibodies generated against SARS-CoV spike protein and nucleoprotein, double stranded RNA, and RNA probe for spike genes were evaluated for the ability to detect FFPE infected cells. We also tested both heat- and enzymatic-mediated virus antigen retrieval methods to determine the optimal virus antigen recovery as well as identifying alternative retrieval methods to enable flexibility of IHC methods. In addition to using native virus infected cells as positive control material, the evaluation of non-infected cells expressing coronavirus (SARS, MERS) spike as a biosecure alternative to assays involving live virus was undertaken. Optimized protocols were successfully applied to experimental animal-derived tissues. The diverse techniques for virus detection and control material generation demonstrated in this study can be applied to investigations of coronavirus pathogenesis and therapeutic research in animal models.


Assuntos
Antígenos Virais/imunologia , Imuno-Histoquímica , /isolamento & purificação , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , /virologia , Chlorocebus aethiops , Furões , Hibridização In Situ , Sondas RNA/imunologia , Vírus da SARS/isolamento & purificação , Células Vero
17.
Can Urol Assoc J ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33212008

RESUMO

INTRODUCTION: Across all cancer sites and stages, prostate cancer has one of the greatest median five-year survival rates, highlighting the important focus on survivorship issues following diagnosis and treatment. In the current study, we sought to evaluate the prevalence and predictors of depression in a large, multicenter, contemporary, prospectively collected sample of men with prostate cancer. METHODS: Data from the current study were drawn from the baseline visit of men enrolled in the RADICAL PC study. Men with a new diagnosis of prostate cancer or patients initiating androgen deprivation therapy for prostate cancer for the first time were recruited. Depressive symptoms were evaluated using the nine-item version of the Patient Health Questionnaire (PHQ-9). To evaluate factors associated with depression, a multivariable logistic regression model was constructed, including biological, psychological, and social predictor variables. RESULTS: Data from 2445 patients were analyzed. Of these, 201 (8.2%) endorsed clinically significant depression. Younger age (odds ratio [OR] 1.38; 95% confidence interval [CI] 1.16-1.60 per 10-year decrease), being a current smoker (OR 2.77; 95% CI 1.66-4.58), former alcohol use (OR 2.63; 95% CI 1.33-5.20), poorer performance status (OR 5.01; 95% CI 3.49-7.20), having a pre-existing clinical diagnosis of depression or anxiety (OR 3.64; 95% CI 2.42-5.48), and having high-risk prostate cancer (OR 1.49; 95% CI 1.05-2.12) all conferred independent risk for depression. CONCLUSIONS: Clinically significant depression is common in men with prostate cancer. Depression risk is associated with a host of biopsychosocial variables. Clinicians should be vigilant to screen for depression in those patients with poor social determinants of health, concomitant disability, and advanced disease.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33146440

RESUMO

BACKGROUND: Colitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy. AIMS: To investigate associations between clinical, endoscopic, and histological features with outcomes METHODS: We identified 149 patients from seven institutions with biopsy-proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological-refractory colitis, colectomy or death from colitis). RESULTS: Three mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4-13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1-42.3 P = 0.003). CONCLUSION: Histological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms.

19.
J Am Coll Emerg Physicians Open ; 1(5): 994-999, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33145550

RESUMO

Pediatric head injury is a common presenting complaint in the emergency department (ED), often requiring neuroimaging or ED observation for diagnosis. However, the traditional diagnostic neuroimaging modality, head computed tomography (CT), is associated with radiation exposure while prolonged ED observation impacts patient flow and resource utilization. Recent scientific literature supports abbreviated, or focused and shorter, brain magnetic resonance imaging (MRI) as a feasible and accurate diagnostic alternative to CT for traumatic brain injury. However, this is a relatively new application and its use is not widespread. The aims of this review are to describe the science and applications of abbreviated brain MRI and report a model protocol's development and ED implementation in the evaluation of children with head injury for replication in other institutions.

20.
Shock ; 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32881757

RESUMO

BACKGROUND: Combined burn and traumatic brain injury (TBI) treatment priorities may not align due to opposing fluid resuscitation paradigms used in treating burns and TBI. We developed a porcine model of combined thermal injury/TBI and compared an "aggressive" fluid resuscitation strategy using the Parkland formula and a "restrictive" resuscitation strategy using the modified Brooke formula. METHODS: Twenty eight swine were deeply anesthetized and received a 40% total body surface area full thickness burn injury and TBI. Swine were then randomized to receive restrictive or aggressive resuscitation for eight hours after which time animals were euthanized and necropsy was performed. Volume of brain injury was assessed after analyzing segmental slices of brain tissue. RESULTS: There were no differences between the restrictive and aggressive resuscitation groups in blood pressure, heart rate, central venous pressure, intra-cranial pressure (ICP), or serum lactate levels after 8 hours of resuscitation. Urine output was higher in the aggressive resuscitation group. The restrictive group had a significantly higher serum BUN compared to baseline and compared to the aggressive group. There was no significant difference in size of brain injury between groups. CONCLUSIONS: Both restrictive and aggressive resuscitation demonstrated adequate resuscitation at eight hours post-injury. Increased serum BUN in the restrictive group may be an indicator of early acute kidney injury, despite adequate urine output. Resuscitation strategy did not appear to affect ICP or the size of brain injury.

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