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1.
Nature ; 625(7996): 760-767, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38092039

RESUMO

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.


Assuntos
Fator 15 de Diferenciação de Crescimento , Hiperêmese Gravídica , Náusea , Vômito , Animais , Feminino , Humanos , Camundongos , Gravidez , Talassemia beta/sangue , Talassemia beta/metabolismo , Feto/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Fator 15 de Diferenciação de Crescimento/metabolismo , Hormônios/sangue , Hormônios/metabolismo , Hiperêmese Gravídica/complicações , Hiperêmese Gravídica/metabolismo , Hiperêmese Gravídica/prevenção & controle , Hiperêmese Gravídica/terapia , Náusea/sangue , Náusea/complicações , Náusea/metabolismo , Placenta/metabolismo , Vômito/sangue , Vômito/complicações , Vômito/metabolismo
2.
PLoS Pathog ; 19(3): e1011155, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36857394

RESUMO

RNA viruses can exchange genetic material during coinfection, an interaction that creates novel strains with implications for viral evolution and public health. Influenza A viral genetic exchange can occur when genome segments from distinct strains reassort in coinfected cells. Predicting potential genomic reassortment between influenza strains has been a long-standing goal. Experimental coinfection studies have shed light on factors that limit or promote reassortment. However, determining the reassortment potential between diverse Influenza A strains has remained elusive. To address this challenge, we developed a high throughput genotyping approach to quantify reassortment among a diverse panel of human influenza virus strains encompassing two pandemics (swine and avian origin), three specific epidemics, and both circulating human subtypes A/H1N1 and A/H3N2. We found that reassortment frequency (the proportion of reassortants generated) is an emergent property of specific pairs of strains where strain identity is a predictor of reassortment frequency. We detect little evidence that antigenic subtype drives reassortment as intersubtype (H1N1xH3N2) and intrasubtype reassortment frequencies were, on average, similar. Instead, our data suggest that certain strains bias the reassortment frequency up or down, independently of the coinfecting partner. We observe that viral productivity is also an emergent property of coinfections, but uncorrelated to reassortment frequency; thus viral productivity is a separate factor affecting the total number of reassortants produced. Assortment of individual segments among progeny and pairwise segment combinations within progeny generally favored homologous combinations. These outcomes were not related to strain similarity or shared subtype but reassortment frequency was closely correlated to the proportion of both unique genotypes and of progeny with heterologous pairwise segment combinations. We provide experimental evidence that viral genetic exchange is potentially an individual social trait subject to natural selection, which implies the propensity for reassortment is not evenly shared among strains. This study highlights the need for research incorporating diverse strains to discover the traits that shift the reassortment potential to realize the goal of predicting influenza virus evolution resulting from segment exchange.


Assuntos
Coinfecção , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Influenza Humana , Infecções por Orthomyxoviridae , Animais , Humanos , Suínos , Vírus da Influenza A/genética , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H1N1/genética , Vírus Reordenados/genética
3.
Emerg Infect Dis ; 30(8): 1721-1723, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38914418

RESUMO

Examining the persistence of highly pathogenic avian influenza A(H5N1) from cattle and human influenza A(H1N1)pdm09 pandemic viruses in unpasteurized milk revealed that both remain infectious on milking equipment materials for several hours. Those findings highlight the risk for H5N1 virus transmission to humans from contaminated surfaces during the milking process.


Assuntos
Indústria de Laticínios , Vírus da Influenza A Subtipo H1N1 , Virus da Influenza A Subtipo H5N1 , Influenza Humana , Leite , Animais , Leite/virologia , Bovinos , Humanos , Indústria de Laticínios/instrumentação , Influenza Humana/transmissão , Influenza Humana/virologia , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/virologia
4.
Int J Behav Nutr Phys Act ; 21(1): 40, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627708

RESUMO

BACKGROUND: Actigraphy is often used to measure sleep in pediatric populations, despite little confirmatory evidence of the accuracy of existing sleep/wake algorithms. The aim of this study was to determine the performance of 11 sleep algorithms in relation to overnight polysomnography in children and adolescents. METHODS: One hundred thirty-seven participants aged 8-16 years wore two Actigraph wGT3X-BT (wrist, waist) and three Axivity AX3 (wrist, back, thigh) accelerometers over 24-h. Gold standard measures of sleep were obtained using polysomnography (PSG; Embletta MPRPG, ST + Proxy and TX Proxy) in the home environment, overnight. Epoch by epoch comparisons of the Sadeh (two algorithms), Cole-Kripke (three algorithms), Tudor-Locke (four algorithms), Count-Scaled (CS), and HDCZA algorithms were undertaken. Mean differences from PSG values were calculated for various sleep outcomes. RESULTS: Overall, sensitivities were high (mean ± SD: 91.8%, ± 5.6%) and specificities moderate (63.8% ± 13.8%), with the HDCZA algorithm performing the best overall in terms of specificity (87.5% ± 1.3%) and accuracy (86.4% ± 0.9%). Sleep outcome measures were more accurately measured by devices worn at the wrist than the hip, thigh or lower back, with the exception of sleep efficiency where the reverse was true. The CS algorithm provided consistently accurate measures of sleep onset: the mean (95%CI) difference at the wrist with Axivity was 2 min (-6; -14,) and the offset was 10 min (5, -19). Several algorithms provided accurate measures of sleep quantity at the wrist, showing differences with PSG of just 1-18 min a night for sleep period time and 5-22 min for total sleep time. Accuracy was generally higher for sleep efficiency than for frequency of night wakings or wake after sleep onset. The CS algorithm was more accurate at assessing sleep period time, with narrower 95% limits of agreement compared to the HDCZA (CS:-165 to 172 min; HDCZA: -212 to 250 min). CONCLUSION: Although the performance of existing count-based sleep algorithms varies markedly, wrist-worn devices provide more accurate measures of most sleep measures compared to other sites. Overall, the HDZCA algorithm showed the greatest accuracy, although the most appropriate algorithm depends on the sleep measure of focus.


Assuntos
Actigrafia , Sono , Criança , Adolescente , Humanos , Reprodutibilidade dos Testes , Polissonografia , Algoritmos
5.
J Am Chem Soc ; 145(21): 11530-11536, 2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37192402

RESUMO

Because of its impressive ability to promote pharmaceutical activity, the introduction of trifluoromethylacyl (CF3CO) functionality into organic compounds has become an important and growing research area. Although various protocols have been developed to access trifluoroketones, the use of trifluoroacetyl radicals remains virtually undeveloped. Herein, we disclose a novel method for trifluoroacetylation through an umpolung reagent, thereby transforming an electrophilic radical into a nucleophilic radical. The applicability of this transformation is highlighted by large-scale, late-stage reactions of complex bioactive molecules sclareolide and loratadine. Furthermore, the direct transformation of trifluoromethyl ketones into various fluorinated analogues illustrates the potential synthetic application of our developed method.

6.
Climacteric ; 26(6): 625-631, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37751773

RESUMO

OBJECTIVE: Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Cognitive symptoms during natural menopause transition are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, we explored the cognitive experiences of women within 24 months post BSO. METHODS: This observational cross-sectional sub-study is part of a larger project, the Early Menopause and Cognition Study (EM-COG). We investigated perceived cognitive experiences in Australian women (n = 16) who underwent risk-reducing BSO using qualitative interviews. Thematic analysis was undertaken to identify key themes. RESULTS: Fifteen out of 16 participants (93.75%) reported changes to cognition within 24 months post BSO. The key cognitive symptoms reported were brain fog, memory and retrieval difficulties, slower processing speed as well as attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. CONCLUSION: Findings from this study suggest that women experience subjective cognitive changes within 24 months post BSO. This period could be a vulnerable time for women's cognitive health. While these findings need to be confirmed by a large prospective study, our research indicates that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.


Assuntos
Doenças dos Genitais Femininos , Neoplasias Ovarianas , Feminino , Humanos , Salpingo-Ooforectomia , Estudos Prospectivos , Estudos Transversais , Austrália , Menopausa/psicologia , Neoplasias Ovarianas/cirurgia , Ovariectomia
7.
Vet Pathol ; 60(2): 185-189, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36541627

RESUMO

Sebaceous carcinomas of the human ocular adnexa commonly exhibit pagetoid spread, mutations in tumor-suppressor genes, and protooncogene copy number gain. Sebaceous carcinomas are rarely reported in other species, and while the Meibomian gland (MG) represents the most common ocular adnexal structure of the canine eyelid to develop neoplasia, most are clinically and histologically benign. The objective of this study was to compare molecular features of canine MG carcinomas and adenomas. Two retrospectively identified MG carcinomas were subject to immunohistochemistry and qPCR. When compared with normal glands, MYC was upregulated in benign and malignant MG neoplasms. Aberrant p53 expression was restricted to the nuclei of intraepithelial neoplastic cells in MG carcinomas. Adipophilin expression was diminished in MG neoplasms compared with the normal MG. Our findings, if confirmed in a larger cohort of cases, could suggest that MG oncogenesis in a dog may exhibit similar molecular features as their human counterparts.


Assuntos
Adenoma , Carcinoma Basocelular , Doenças do Cão , Neoplasias das Glândulas Sebáceas , Neoplasias Cutâneas , Humanos , Cães , Animais , Glândulas Tarsais/metabolismo , Glândulas Tarsais/patologia , Proteína Supressora de Tumor p53 , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/química , Neoplasias das Glândulas Sebáceas/metabolismo , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sebáceas/veterinária , Neoplasias Cutâneas/veterinária , Carcinoma Basocelular/veterinária , Transformação Celular Neoplásica , Adenoma/patologia , Adenoma/veterinária , Mutação
8.
Phys Rev Lett ; 128(13): 132002, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35426724

RESUMO

The first measurement of lepton-jet momentum imbalance and azimuthal correlation in lepton-proton scattering at high momentum transfer is presented. These data, taken with the H1 detector at HERA, are corrected for detector effects using an unbinned machine learning algorithm (multifold), which considers eight observables simultaneously in this first application. The unfolded cross sections are compared with calculations performed within the context of collinear or transverse-momentum-dependent factorization in quantum chromodynamics as well as Monte Carlo event generators.

9.
Anim Cogn ; 25(5): 1331-1343, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35430682

RESUMO

Environmental condition, such as environmental complexity or stocking density, can directly or indirectly influence animal emotion and ultimately, affective state. Affective states of animals can be assessed through judgement bias tests, evaluating responses to ambiguous situations. In this study, we aimed to determine whether environmental complexity and stocking density impacted rainbow trout affective state. Rainbow trout (n = 108) were housed in recirculating aquaculture systems under commercial conditions while trained at tank-level to discriminate between a positively reinforced chamber (feed) in one location and a negative chamber (positive punishment; chase by net for 1 s) in the opposing location. Fish from successful tanks (two out of five tanks) were then housed in treatment tanks of either high- or low- environmental complexity at either high (165 fish/m3) or low (69 fish/m3) stocking density. Trained fish were tested for latencies to approach three intermediate, ambiguous chambers. Fish housed in high-density tanks were faster to enter all chambers than those housed in low-density tanks (8.5 s vs. 15.2 s; P = 0.001), with faster entries into the positive (7.4 s vs. 15.2 s; P = 0.02) and near-negative chambers (10.2 s vs. 17.4 s; P = 0.006), suggesting that these fish were more optimistic to receive a feed reward. Tank complexity did not affect test outcomes. No differences between treatments were observed between body weight, length, and plasma cortisol. Overall, rainbow trout are capable of discriminating between cues during a judgement bias test and fish housed in high-density environments respond more optimistically in ambiguous situations compared to fish in low-density environments.


Assuntos
Oncorhynchus mykiss , Animais , Oncorhynchus mykiss/fisiologia , Aquicultura , Emoções
10.
Hum Reprod ; 36(11): 2840-2847, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34536006

RESUMO

STUDY QUESTION: Using time-lapse data, can the current consensus for the timing of fertilisation assessment of oocytes, cultured in standard incubation, be optimised? SUMMARY ANSWER: The optimum time to perform fertilisation assessment for oocytes cultured in standard incubation is 16.5 ± 0.5 h post-insemination (hpi), and the current consensus requires modification in order to minimise the chance of fertilisation being missed. WHAT IS KNOWN ALREADY: Time-lapse incubation allows the embryologist to retrospectively review collated images of oocytes and embryos to capture important embryological observations that may otherwise be missed in standard incubation. According to expert consensus, the optimum time to perform the assessment of fertilisation is 17 ± 1 hpi. STUDY DESIGN, SIZE, DURATION: A retrospective, multicentre analysis utilised data obtained from 54 746 ICSI-derived embryos and 23 602 IVF-derived embryos cultured in time-lapse incubation between January 2011 and November 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using time-lapse imaging (TLI), the precise time of pronuclei appearance and disappearance was recorded, where applicable, and the number of oocytes with two pronuclei observable during 10 30-min intervals from 15 hpi to 20 hpi was determined. MAIN RESULTS AND THE ROLE OF CHANCE: Between 15 and 17.5 hpi, the average number of oocytes exhibiting normal fertilisation, elicited as two pronuclei, was 98.19% with the highest proportion of oocytes having visible pronuclei at 16-16.5 hpi (98.32%). At 18-18.5 hpi, the number of visible pronuclei reduced to 95.53% and continued to fall to 87.02% at 19.5-20 hpi. LIMITATIONS, REASONS FOR CAUTION: The authors' expectation is that these findings are transferable to other settings, however it is possible that, with alternative culture media and incubation environments, calibration of this timing may be required. As data cannot readily be recorded for pronuclear appearance for IVF-derived embryos, it is not possible to determine the optimum time to perform the fertilisation assessment for IVF-derived embryos. WIDER IMPLICATIONS OF THE FINDINGS: By fine-tuning the time at which fertilisation assessment takes place the accuracy of the assessment can be increased to maximise the number of fertilised oocytes identified, thereby increasing the number of usable embryos for the patient. Without TLI and following current consensus guidelines, over 11% (n = 3000) of oocytes would have been marked as unfertilised within this cohort. Further to this, depending on the time of a standard fertilisation assessment, up to 300 embryos which resulted in live births could have been categorised as unfertilised, as they presented no visible pronuclei at the conventional assessment time-point. STUDY FUNDING/COMPETING INTEREST(S): A.C. is a minor shareholder in CARE Fertility Limited. Validated algorithmic time-lapse embryo selection is offered to patients at CARE Fertility at an additional charge as an adjuvant treatment option. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Fertilização in vitro , Oócitos , Feminino , Fertilização , Humanos , Estudos Retrospectivos , Imagem com Lapso de Tempo
11.
Rev Sci Tech ; 40(2): 469-481, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34542100

RESUMO

Animal welfare is an essential component of the future of sustainable agriculture and the United Nations Sustainable Development Goals. There is growing global recognition of the importance of animal welfare, which must always be considered as part of the decision-making around food and nutrition security. Veterinary Services, encompassing public and private veterinarians and para-veterinarians, are custodians of animal welfare and key players in future actions to improve it. The welfare of animals is everyone's responsibility, from the individual farmer and practitioner to policymakers at the national and intergovernmental level. In this paper, after providing background information about current animal welfare issues and identifying animal welfare risks, the authors make a number of recommendations for action at the institutional and individual level. They do so because while the former is essential to generate change at scale and effective resourcing, the latter can create immediate action at a local level and drive change from the ground up. Without coordinated action from Veterinary Services, opportunities to improve animal welfare, alongside human and environmental health and well-being, may very well be lost, and animal welfare may fail to improve or even be at risk of decline.


L'accélération de la perturbation numérique depuis quelques années est spectaculaire, transformant tous les secteurs de l'économie, y compris la production animale, la santé animale et le bien-être des animaux. Les auteurs s'intéressent à certaines technologies numériques de pointe qui pourraient influencer le devenir des Services vétérinaires. Toutes ces technologies sont orientées données et trouvent leur illustration dans trois exemples qui se répartissent dans les catégories suivantes : a) les technologies sans fil et mobiles appliquées au suivi de la santé animale, à la surveillance des maladies, aux notifications des foyers et à l'échange d'informations ; b) les technologies avancées de traitement des données, dont les mégadonnées et l'analytique de données qui servent à mettre en évidence des structures sous-jacentes, à extraire des schémas prédictifs, à relever des corrélations et à générer d'autres informations ; c) des technologies prometteuses comme les applications « blockchain ¼ (chaînes de blocs) utilisées pour une gestion efficace et efficiente de diverses chaînes d'approvisionnement en intrants. Les auteurs résument brièvement les défis actuels associés au recours accru à ces technologies dans le secteur de la santé animale et en font ressortir certaines répercussions sur les Services vétérinaires. Les technologies numériques vont profondément affecter les modalités de la prestation des services de santé animale ainsi que la gestion des systèmes de santé animale. Par conséquent, il est crucial que les Services vétérinaires anticipent cette évolution et s'adaptent à la transformation numérique en cours. L'investissement dans les nouvelles technologies et les efforts visant à doter les professionnels vétérinaires actuels et futurs des compétences et des connaissances numériques nécessaires pour rester informés et au centre de l'innovation numérique dans le domaine de la santé animale doivent être les priorités des prochaines années.


El bienestar animal es un componente esencial de la agricultura sostenible del futuro y de los Objetivos de Desarrollo Sostenible fijados por las Naciones Unidas. Su importancia está cada vez más clara en todo el mundo. El bienestar de los animales debe ser siempre tenido en cuenta en los procesos decisorios que tocan a la seguridad alimentaria y nutricional. Los Servicios Veterinarios, que comprenden tanto a los veterinarios públicos y privados como al personal paraveterinario, son custodios del bienestar animal y agentes clave de toda acción futura encaminada a mejorarlo. Para lograr que el bienestar animal mejore desde ahora mismo, allí donde haga falta, y asegurar que siga un rumbo de constante progreso en el futuro, es preciso que todos los interlocutores, desde los productores y cuidadores hasta los planificadores de políticas de ámbito nacional e intergubernamental, hagan suya esta responsabilidad. Tras presentar información básica sobre los actuales problemas de bienestar animal y señalar los riesgos existentes en la materia, los autores formulan una serie de recomendaciones para actuar tanto desde las instituciones como a título individual, sabedores de que el primer nivel es fundamental para inducir cambios a gran escala y movilizar recursos eficazmente, mientras que el segundo puede generar inmediatamente acciones a escala local e impulsar desde ahí cambios en sentido ascendente. A falta de una labor coordinada de los Servicios Veterinarios, es muy posible que se pierdan oportunidades para mejorar el bienestar animal, junto con la salud y el bienestar de personas y ecosistemas, y que los niveles de bienestar animal no mejoren o, incluso, corran peligro de deterioro.


Assuntos
Médicos Veterinários , Medicina Veterinária , Agricultura , Bem-Estar do Animal , Animais , Fazendeiros , Humanos
12.
HIV Med ; 21(7): 418-428, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32168418

RESUMO

OBJECTIVES: Combination antiretroviral therapy has largely restored the lifespan of persons living with HIV. Data suggest early comorbidities of aging in this population. Past studies focused on men; limited data exist regarding the prevalence of dyslipidaemia in women living with HIV (WLWH). We investigated the prevalence of cardiometabolic abnormalities among WLWH and HIV-negative women in the Children and Women: Antiretrovirals and Markers of Aging (CARMA) cohort, and their relationships to cellular aging markers. METHODS: We conducted a cross-sectional analysis of nonpregnant female patients (156 WLWH and 133 HIV-negative controls, aged 12-69 years) enrolled in CARMA between 2013 and 2017. The Framingham risk score (FRS) and the prevalences of hypertension, diabetes, metabolic syndrome and dyslipideamia were determined using self-report, anthropometrics, chart review and laboratory data. Cellular aging was determined by assessing leukocyte telomere length and blood mitochondrial DNA content. Diagnoses were based on current Canadian guidelines and definitions. RESULTS: HIV-infected status was associated with dyslipidaemia [odds ratio (OR) 2.89; 95% confidence interval (CI) 1.69-5.01], but not diabetes, higher FRS, hypertension or metabolic syndrome. The median age was 43.5 [interquartile range (IQR) 36.8-50.9] years in WLWH and 46.2 (IQR 30.3-54.9) years in HIV-negative controls. WLWH were less likely to be menopausal or use alcohol, and more often had hepatitis C virus infection or a current or past smoking history. Lower mitochondrial DNA content was associated with metabolic syndrome; no other associations were noted between cardiometabolic abnormalities and markers of cellular aging. CONCLUSIONS: Despite their relatively young age, almost two-thirds of WLWH had dyslipidaemia, a significantly greater proportion than in controls. Strategies to address dyslipidaemia and decrease smoking rates may improve long-term outcomes among WLWH.


Assuntos
Antirretrovirais/uso terapêutico , Dislipidemias/epidemiologia , Infecções por HIV/tratamento farmacológico , Adolescente , Adulto , Idoso , Canadá/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Prevalência , Fatores de Risco , Homeostase do Telômero , Adulto Jovem
13.
Int J Legal Med ; 134(4): 1451-1455, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31811378

RESUMO

Evidence presented within a courtroom should be clear so that the members of the jury can understand it. The presentation of distressing images, such as human remains, can have a negative effect on the jury since photographic images may evoke emotional responses. Therefore, it is important to understand how other visual mediums may improve comprehension, bias, or distress individuals. For this study, 91 individuals were randomly assigned one of three visual evidence formats in a mock courtroom exercise. These included photographs, 3D visualisations, or a 3D-printed model. The results show that the use of 3D imaging improves the juror's understanding of technical language used within a courtroom, which in turn better informs the juror's in their decision-making.


Assuntos
Recursos Audiovisuais , Compreensão , Tomada de Decisões , Prova Pericial , Ciências Forenses , Adulto , Direito Penal , Feminino , Humanos , Imageamento Tridimensional , Masculino , Fotografação , Impressão Tridimensional
14.
Am J Transplant ; 19(1): 62-76, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29766641

RESUMO

Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4ß7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.


Assuntos
Inflamação/imunologia , Intestinos/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th1/citologia , Animais , Adesão Celular , Movimento Celular , Proliferação de Células , Quimiocina CXCL10/metabolismo , Epigênese Genética , Feminino , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Integrinas/metabolismo , Interleucina-12/imunologia , Masculino , Camundongos , Fenótipo , Receptores CCR/metabolismo , Receptores CXCR3/metabolismo , Timo/imunologia
15.
J Antimicrob Chemother ; 74(1): 1-5, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30307507

RESUMO

Protein synthesis inhibitor antibiotics inhibit synthesis of new proteins, including exotoxins and other important virulence determinants in Staphylococcus aureus. A summary of the literature regarding the use of adjunctive protein synthesis inhibitors for toxin suppression in the setting of S. aureus infections is presented.


Assuntos
Antibacterianos/administração & dosagem , Toxinas Bacterianas/biossíntese , Inibidores da Síntese de Proteínas/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Toxinas Bacterianas/antagonistas & inibidores , Humanos , Inibidores da Síntese de Proteínas/farmacologia
17.
Anaesthesia ; 74(6): 758-764, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30793278

RESUMO

Demand for critical care among older patients is increasing in many countries. Assessment of frailty may inform discussions and decision making, but acute illness and reliance on proxies for history-taking pose particular challenges in patients who are critically ill. Our aim was to investigate the inter-rater reliability of the Clinical Frailty Scale for assessing frailty in patients admitted to critical care. We conducted a prospective, multi-centre study comparing assessments of frailty by staff from medical, nursing and physiotherapy backgrounds. Each assessment was made independently by two assessors after review of clinical notes and interview with an individual who maintained close contact with the patient. Frailty was defined as a Clinical Frailty Scale rating > 4. We made 202 assessments in 101 patients (median (IQR [range]) age 69 (65-75 [60-80]) years, median (IQR [range]) Acute Physiology and Chronic Health Evaluation II score 19 (15-23 [7-33])). Fifty-two (51%) of the included patients were able to participate in the interview; 35 patients (35%) were considered frail. Linear weighted kappa was 0.74 (95%CI 0.67-0.80) indicating a good level of agreement between assessors. However, frailty rating differed by at least one category in 47 (47%) cases. Factors independently associated with higher frailty ratings were: female sex; higher Acute Physiology and Chronic Health Evaluation II score; higher category of pre-hospital dependence; and the assessor having a medical background. We identified a good level of agreement in frailty assessment using the Clinical Frailty Scale, supporting its use in clinical care, but identified factors independently associated with higher ratings which could indicate personal bias.


Assuntos
Cuidados Críticos/métodos , Fragilidade/diagnóstico , Avaliação Geriátrica/métodos , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Escócia , Índice de Gravidade de Doença , País de Gales
18.
Soc Psychiatry Psychiatr Epidemiol ; 54(12): 1505-1518, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31123787

RESUMO

BACKGROUND: Self-harm is common, debilitating and associated with completed suicide and increased all-cause mortality, but there is uncertainty about its causal risk factors, limiting risk assessment and effective management. Neuroticism is a stable personality trait associated with self-harm and suicidal ideation, and correlated with coping styles, but its value as an independent predictor of these outcomes is disputed. METHODS: Prior history of hospital-treated self-harm was obtained by record-linkage to administrative health data in Generation Scotland:Scottish Family Health Study (N = 15,798; self-harm cases = 339) and by a self-report variable in UK Biobank (N = 35,227; self-harm cases = 772). Neuroticism in both cohorts was measured using the Eysenck Personality Questionnaire-Short Form. Associations of neuroticism with self-harm were tested using multivariable regression following adjustment for age, sex, cognitive ability, educational attainment, socioeconomic deprivation, and relationship status. A subset of GS:SFHS was followed-up with suicidal ideation elicited by self-report (n = 3342, suicidal ideation cases = 158) and coping styles measured by the Coping Inventory for Stressful Situations. The relationship of neuroticism to suicidal ideation, and the role of coping style, was then investigated using multivariable logistic regression. RESULTS: Neuroticism was positively associated with hospital-associated self-harm in GS:SFHS (per EPQ-SF unit odds ratio 1.2 95% credible interval 1.1-1.2, pFDR 0.0003) and UKB (per EPQ-SF unit odds ratio 1.1 95% confidence interval 1.1-1.2, pFDR 9.8 × 10-17). Neuroticism, and the neuroticism-correlated coping style, emotion-oriented coping (EoC), were also associated with suicidal ideation in multivariable models. CONCLUSIONS: Neuroticism is an independent predictor of hospital-treated self-harm risk. Neuroticism and emotion-orientated coping styles are also predictive of suicidal ideation.


Assuntos
Neuroticismo , Comportamento Autodestrutivo/psicologia , Ideação Suicida , Adaptação Psicológica , Adolescente , Adulto , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Regressão , Fatores de Risco , Escócia , Autorrelato , Estresse Psicológico/psicologia , Reino Unido , Adulto Jovem
19.
Subst Use Misuse ; 54(7): 1067-1074, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30849925

RESUMO

BACKGROUND: The community reinforcement approach (CRA) is an evidence-based practice for the treatment of substance use disorders and achieving and maintaining abstinence, but few studies have systematically explored the effect of CRA on secondary, yet also important outcomes, such as social functioning. OBJECTIVES: The purpose of this study was to examine whether an internet-based version of the CRA plus contingency management is associated with improved social functioning of individuals seeking substance use disorder treatment in a multi-site clinical effectiveness trial. METHODS: Social functioning was measured using the 54-item Social Adjustment Scale assessing role performance in six domains (work, social and leisure activities, extended family relationships, marital relationship, parenting, and immediate family). Generalized linear mixed models tested the effects of treatment, time, sex, baseline abstinence, baseline social functioning and baseline psychological distress on overall social functioning and across social functioning subscales at the end of the 12-week treatment phase and 3 and 6 months post treatment. RESULTS: Results showed no significant association between treatment and total social functioning score or any subscale scores. Being male was significantly associated with better social functioning overall at the end of treatment (p = .024). Higher levels of psychological distress at baseline predicted significantly worse social functioning at the end of treatment overall (p = .037). CONCLUSIONS: The addition of an internet-based version of the CRA was not associated with greater improvements in social functioning compared to standard outpatient care after 12 weeks of treatment. Implications for internet-delivered CRA are discussed.


Assuntos
Internet , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Adulto , Terapia Comportamental/métodos , Feminino , Humanos , Masculino , Reforço Psicológico , Ajustamento Social , Transtornos Relacionados ao Uso de Substâncias/terapia , Terapia Assistida por Computador , Resultado do Tratamento , Adulto Jovem
20.
Allergy ; 73(5): 1141-1144, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29319887

RESUMO

Allergic rhinitis (AR) is associated with significant decreases in quality of life and productivity losses. We hypothesized that symptoms of AR may differentially associate with lost productivity due to AR. We performed a cross-sectional cohort study of 105 prospectively recruited patients with persistent AR. AR control, severity of depressed mood, and sinonasal symptoms were assessed with the Rhinitis Control Assessment Test (RCAT), Patient Health Questionnaire (PHQ-2), and the 22-item Sinonasal Outcome Test (SNOT-22), respectively. Lost productivity was assessed by asking the number of days of work/school missed due to AR in the last 3 months. Patients missed a mean of 1.5 days (SD:2.9) of work or school. Lost productivity was associated with PHQ-2 (adjusted linear regression coefficient [ß] = .68, 95% CI: 0.20-1.15, P = .007) analysis but not SNOT-22 or RCAT scores. Productivity losses due to AR are associated with severity of depressed mood rather than classic nasal or extra-nasal symptoms of AR.


Assuntos
Absenteísmo , Depressão/etiologia , Eficiência , Rinite Alérgica/psicologia , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários
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