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1.
Clin Infect Dis ; 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38759099

RESUMO

BACKGROUND: Aeromonas virulence may not be entirely dependent on the host immune status. Pathophysiologic determinants of disease progression and severity remain unclear. METHODS: One hundred five patients with Aeromonas infections and 112 isolates were identified, their clinical presentations and outcomes analyzed, and their antimicrobial resistance (AMR) patterns assessed. Two isolates (A and B) from fatal cases of Aeromonas dhakensis bacteremia were characterized using whole genome sequence analysis. Virulence factor- and AMR-encoding genes from these isolates were compared with a well-characterized diarrheal isolate A. dhakensis SSU, and environmental isolate A. hydrophila ATCC_7966T. RESULTS: Skin and soft tissue infections, traumatic wound infections, sepsis, burns, and intraabdominal infections were common. Diabetes, malignancy, and cirrhosis were frequent comorbidities. Male sex, age ≥ 65 years, hospitalization, burns, and intensive care were associated with complicated disease. High rates of AMR to carbapenems and piperacillin-tazobactam were found. Treatment failure was observed in 25.7% of cases. Septic shock and hospital-acquired infections were predictors of treatment failure. All four isolates harbored assorted broad-spectrum AMR genes including blaOXA, ampC, cphA, and efflux pumps. Only clinical isolates possessed both polar and lateral flagellar genes, genes for various surface adhesion proteins, type 3- and -6 secretion systems and their effectors, and toxin genes, including exotoxin A. Both isolates A and B were resistant to colistin and harbored the mobile colistin resistance-3 (mcr-3) gene. CONCLUSIONS: Empirical therapy tailored to local Aeromonas antibiograms may facilitate more favorable outcomes, while advanced diagnostic methods may aid in identifying correct Aeromonas spp. of significant clinical importance.

2.
Occup Med (Lond) ; 74(3): 242-250, 2024 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722211

RESUMO

BACKGROUND: Mental ill health has a high economic impact on society and employers. National and international policy advocates line manager (LM) training in mental health as a key intervention, but little is known about employer training provisions. AIMS: To explore the prevalence and characteristics of organizations that offer LM training in mental health. METHODS: Secondary analysis of existing longitudinal anonymised organizational-level survey data derived from computer-assisted telephone interview surveys collected in four waves (2020:1900 firms, 2021:1551, 2022:1904, 2023:1902) in England, before, during and after a global pandemic. RESULTS: The proportion of organizations offering LM training in mental health increased pre- to post-pandemic (2020:50%, 2023:59%) but 41% do not currently provide it. Logistic regression confirmed that LM training is more likely to be offered by large-sized enterprises, organizations with a larger proportion of employees who are younger (aged 25-49), female, disabled and from ethnic minority communities. Sector patterns were inconsistent, but in 2023, organizations from the 'Hospitality' and 'Business Services' sectors were more likely to provide LM training than other sectors. CONCLUSIONS: Continued efforts are needed to increase the proportion of employers offering LM training in mental health, particularly small- to medium-sized enterprises, and organizations with predominantly male, White and/or older workforces.


Assuntos
Saúde Mental , Humanos , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Inglaterra , COVID-19/epidemiologia , Saúde Ocupacional , Inquéritos e Questionários
3.
Clin Radiol ; 78(9): 671-678, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37336673

RESUMO

AIM: To enhance ultrasound teaching delivery to radiology trainees using a simulation course matched to the 2021 Royal College of Radiologists (RCR) curriculum. MATERIAL AND METHODS: An ultrasound simulation training course was designed for specialty trainees (ST) 1 in radiology, which was based on the 2021 RCR curriculum and covered the top ultrasound training priorities. The course was piloted initially on two occasions in a 1-day format to the August 2021 and the March 2022 ST1 intake trainees. Based on the feedback, a comprehensive 4-day course was developed and delivered between October and December 2022 for the August 2022 ST1 intake, funded by Health Education England. The outcomes measured were subjective trainee feedback using numerical scores and free text. RESULTS: All King's College Hospital NHS Foundation Trust radiology ST1 trainees from the August 2021 to the August 2022 intake participated in ultrasound simulation training. The training matched the RCR curriculum and increased the trainees' confidence and competency in medical ultrasound. CONCLUSIONS: Ultrasound simulation training can be successfully delivered to ST1 trainees to match the 2021 RCR curriculum and enhance training in medical ultrasound for radiologists.


Assuntos
Radiologia , Treinamento por Simulação , Humanos , Londres , Radiologia/educação , Currículo , Radiologistas , Competência Clínica
4.
Occup Med (Lond) ; 73(6): 317-323, 2023 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-37499074

RESUMO

BACKGROUND: Mental ill-health is prevalent in the construction industry, and workers in small- to medium-sized enterprises (SMEs) are at high risk. Knowledge about the implementation of mental health initiatives in construction SMEs is limited. AIMS: To explore enablers and barriers to implementing mental health initiatives within UK SME construction firms from the perspective of the business owners, directors and managers with responsibilities for workplace mental health. METHODS: Qualitative study involving semi-structured interviews conducted with company owners/managers with responsibilities for workforce mental health. Participants were sampled from construction SMEs in the UK. RESULTS: Eleven construction professionals were interviewed (10 men, 1 woman; aged 34-55 years, M = 40.6) representing UK SME construction firms that were micro (<10 employees, n = 8), small (<50 employees, n = 1) and medium (<250 employees, n = 2) sized organizations. Reflexive thematic analysis generated four themes: (i) traditional views and macho culture, identified as barriers to implementation; (ii) mental health awareness, knowledge and education; (iii) valuing good mental health and (iv) a reactive or proactive approach to mental health, which all served as both enablers and barriers depending on perspective and context. CONCLUSIONS: This study sheds light on an under-researched but high-risk category of workers experiencing poor mental health. We provide recommendations for policy and practice with a 'call to action' for SME owners, industry and policymakers to embark on workplace mental health implementation projects in SME settings.


Assuntos
Saúde Mental , Saúde Ocupacional , Masculino , Feminino , Humanos , Indústrias , Local de Trabalho , Comércio
5.
Retina ; 42(11): 2120-2127, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35963006

RESUMO

PURPOSE: To examine the impact of physician face mask use on the rates and outcomes of postinjection endophthalmitis. METHODS: A multicenter retrospective, comparative cohort study comparing endophthalmitis rate and visual acuity of eyes that developed endophthalmitis after antivascular endothelial growth factor injections at Mayo Clinic Rochester (MCR) and at Mayo Clinic Health System sites depending on physician masking. RESULTS: A total of 164,824 injections were performed at MCR and Mayo Clinic Health System sites. Of these, 66,098 injections were in the no mask group and 98,726 injections were in the mask group. Overall, there were no differences in the rates of infectious endophthalmitis in the no mask versus mask cohorts (overall: no mask: 20 cases [0.0303%] vs. mask: 41 cases (0.0415%); P = 0.24; infectious: no mask: 12 cases [0.018%] versus mask: 13 cases [0.0132%]; P = 0.42). At MCR alone, there was a significant reduction in infectious endophthalmitis between the no mask versus mask groups (no mask: 9 cases [0.0297%] versus mask: 2 cases [0.003%]; P < 0.001). Only 2 cases of infectious endophthalmitis occurred at MCR after the face mask policy was implemented (1 in 30,000 injections). At presentation and at 6 months, the average visual acuity was similar for patients who developed endophthalmitis between the no mask versus mask groups. CONCLUSION: Physician face mask use did not affect the rate or outcome of postinjection endophthalmitis. However, there was a significant reduction at MCR after masking along with other quality improvement measures, including performance of injections in a dedicated procedure room and preparation of patients by nurses, that led to a low rate of endophthalmitis.


Assuntos
Endoftalmite , Infecções Oculares Bacterianas , Médicos , Humanos , Injeções Intravítreas , Ranibizumab/uso terapêutico , Bevacizumab/uso terapêutico , Infecções Oculares Bacterianas/epidemiologia , Infecções Oculares Bacterianas/prevenção & controle , Infecções Oculares Bacterianas/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Estudos Retrospectivos , Estudos de Coortes , Máscaras/efeitos adversos , Fatores de Crescimento Endotelial , Fator A de Crescimento do Endotélio Vascular , Endoftalmite/epidemiologia , Endoftalmite/etiologia , Endoftalmite/prevenção & controle
6.
BMC Public Health ; 22(1): 1470, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35915479

RESUMO

BACKGROUND: Regular testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an important strategy for controlling virus outbreaks on university campuses during the COVID-19 pandemic but testing participation rates can be low. The Residence-Based Testing Participation Pilot (RB-TPP) was a novel intervention implemented at two student residences on a large UK university campus over 4 weeks. The aim of the pilot was to increase the frequency of asymptomatic SARS-CoV-2 saliva testing onsite. This process evaluation aimed to determine whether RB-TPP was implemented as planned and identify implementation barriers and facilitators. METHODS: A mixed-methods process evaluation was conducted alongside the RB-TPP. Evaluation participants were students (opting in, or out of RB-TPP) and staff with a role in service provision or student support. Monitoring data were collected from the intervention delivery team and meeting records. Data were collected from students via online survey (n = 152) and seven focus groups (n = 30), and from staff via individual interviews (n = 13). Quantitative data were analysed descriptively and qualitative data thematically. Barriers and facilitators to implementation were mapped to the 'Capability, Opportunity, Motivation-Behaviour' (COM-B) behaviour change framework. RESULTS: Four hundred sixty-four students opted to participate in RB-TPP (98% of students living onsite). RB-TPP was implemented broadly as planned but relaxed social distancing was terminated early due to concerns relating to national escalation of the COVID-19 Delta variant, albeit testing continued. Most students (97.9%) perceived the period of relaxed social distancing within residences positively. The majority engaged in asymptomatic testing (88%); 46% (52% of testers) were fully compliant with pre-determined testing frequency. Implementation was facilitated by convenience and efficiency of testing, and reduction in the negative impacts of isolation through opportunities for students to socialise. Main barriers to implementation were perceived mixed-messages about the rules, ambivalent attitudes, and lack of adherence to COVID-19 protective measures in the minority. CONCLUSIONS: This process evaluation identifies factors that help or hinder the success of university residence-based outbreak prevention and management strategies. RB-TPP led to increased rates of SARS-CoV-2 testing participation among students in university residences. Perceived normalisation of university life significantly enhanced student mental wellbeing. The complexity and challenge generated by multiple lines of communication and rapid adaptions to a changing pandemic context was evident. TRIAL REGISTRATION NUMBER: UKAS 307727-02-01; Pre-results. CLINICALTRIALS: gov Identifier: NCT05045989 ; post-results (first posted, 16/09/21). ETHICAL APPROVAL: Faculty of Medicine & Health Sciences Research Ethics Committee, University of Nottingham (Ref: FMHS 96-0920).


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Teste para COVID-19 , Humanos , Pandemias/prevenção & controle , Reino Unido/epidemiologia , Universidades
7.
BMC Musculoskelet Disord ; 23(1): 1071, 2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36476492

RESUMO

BACKGROUND: Self-management (SM) is a key recommended strategy for managing chronic low back pain (CLBP). However, SM programmes generate small to moderate benefits for reducing pain and disability in patients with CLBP. The benefits of the SM programme can potentially be optimised by identifying specific subgroups of patients who are the best responders. To date, no longitudinal study has examined the predictive relationships between SM and biopsychosocial factors in patients with CLBP. The aim was to determine whether biopsychosocial factors predict SM and its change over time in patients with CLBP. METHODS: In this multi-centre longitudinal cohort study, we recruited 270 working-age patients with CLBP (mean age 43.74, 61% female) who consulted outpatient physiotherapy for their CLBP. Participants completed self-reported validated measures of pain intensity, disability, physical activity, kinesiophobia, catastrophising, depression and SM at baseline and six months. SM constructs were measured using eight subscales of the Health Education Impact Questionnaire (heiQ), including Health Directed Activity (HDA), Positive and Active Engagement in Life (PAEL), Emotional Distress (ED), Self-Monitoring and Insight (SMI), Constructive Attitudes and Approaches (CAA), Skill and Technique Acquisition (STA), Social Integration and Support (SIS) and Health Service Navigation (HSN). Data were analysed using General Linear Model (GLM) regression. RESULTS: Physical activity and healthcare use (positively) and disability, depression, kinesiophobia, catastrophising (negatively) predicted (p < 0.05, R2 0.07-0.55) SM constructs at baseline in patients with CLBP. Baseline depression (constructs: PAEL, ED, SMI, CAA and STA), kinesiophobia (constructs: CAA and HSN), catastrophising (construct: ED), and physical disability (constructs: PAEL, CAA and SIS) negatively predicted a range of SM constructs. Changes over six months in SM constructs were predicted by changes in depression, kinesiophobia, catastrophising, and physical activity (p < 0.05, R2 0.13-0.32). CONCLUSIONS: Self-reported disability, physical activity, depression, catastrophising and kinesiophobia predicted multiple constructs of SM measured using the heiQ subscales in working-age patients with CLBP. Knowledge of biopsychosocial predictors of SM may help triage patients with CLBP into targeted pain management programmes. TRIAL REGISTRATION: The study protocol was registered at ClinicalTrials.gov on 22 December 2015 (ID: NCT02636777).


Assuntos
Dor Lombar , Autogestão , Humanos , Feminino , Adulto , Masculino , Dor Lombar/diagnóstico , Dor Lombar/terapia , Estudos Longitudinais , Exercício Físico
8.
AJR Am J Roentgenol ; 216(5): 1183-1192, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33729875

RESUMO

OBJECTIVE. Coronal tibiofemoral (TF) subluxation has generated interest in the last several years due to newfound clinical implications of its presence. However, controversy within the literature concerning how to measure and calculate coronal TF subluxation on radiographic imaging remains. The purpose of this study was to describe how coronal TF subluxation is being measured and calculated in the literature with the goal of describing a reproducible and validated technique for clinical adoption. MATERIALS AND METHODS. A PubMed literature search was performed in March 2020 according to PRISMA guidelines. The terms "tibiofemoral subluxation" and "tibial femoral subluxation" were included in the search. Criteria of interest included radiographic view and evaluation, anatomic landmarks used, and measurement validity. RESULTS. Review of relevant literature resulted in 744 articles, 16 of which met our inclusion criteria. A wide range of measuring techniques, anatomic landmarks, and radiographic views were used with varying validity. Full-limb radiographic views were the most common. Six studies measured the translation of the mechanical axes of the tibia and femur. Eight studies measured the translation of either femoral condyle in reference to the tibial plateau. Coordinate-based software with the iterative closest point algorithm was used in two studies. Whether coronal TF subluxation should be divided by tibial plateau width to account for knee size was controversial. CONCLUSION. A variety of approaches exist for diagnosing and quantifying coronal TF subluxation because of the lack of clear anatomic landmarks within the TF joint that can be used to measure coronal TF subluxation in the horizontal plane. Even when using the same anatomic landmarks, studies varied on how to measure coronal TF subluxation radiographically and whether knee size should be accounted for. Further studies are necessary to standardize (via inter- and intraobserver validation with a control group) an easy, reproducible, and minimally biased approach to measuring coronal TF subluxation on radiographic imaging. We believe our systematic review succinctly provides the necessary information to either develop such a tool or encourage future studies to compare existing techniques to find the most reliable and clinically useful approach for evaluating coronal TF subluxation.


Assuntos
Luxações Articulares/diagnóstico por imagem , Traumatismos do Joelho/diagnóstico por imagem , Radiografia/métodos , Fêmur/diagnóstico por imagem , Fêmur/lesões , Humanos , Articulação do Joelho/diagnóstico por imagem , Tíbia/diagnóstico por imagem , Tíbia/lesões
9.
Bioorg Med Chem ; 46: 116361, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34411983

RESUMO

Epidermal growth factor receptor (EGFR) is overexpressed in many cancers and therefore serves as an excellent target for prodrug activation. Functionalised trans-cyclooctenes (TCO) were conjugated to an EGFR antibody (cetuximab), providing a reagent for pre-targeting and localisation of the bioorthogonal reagent. The TCOs react with a 4-azidobenzyl carbamate doxorubicin prodrug via a [3 + 2]-cycloaddition and subsequent self-immolation leads to release of doxorubicin (click-and-release). In vitro cell-based assays demonstrated proof-of-concept, that cetuximab conjugated to highly strained TCO (AB-d-TCO) could bind to the EGFR in a melanoma cell line, and selectively activate the doxorubicin prodrug. In a non-EGFR expressing melanoma cell line, no significant prodrug activation was observed. In vivo experiments using this combination of AB-d-TCO and the azido-doxorubicin prodrug in a murine melanoma model revealed no significant anti-tumour activity or increased survival, suggesting there was insufficient prodrug activation and drug release at the tumour site.


Assuntos
Alcenos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Azidas/farmacologia , Doxorrubicina/farmacologia , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Alcenos/química , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Azidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/síntese química , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
10.
Neurosurg Focus ; 50(6): E2, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34062499

RESUMO

OBJECTIVE: The use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in routine anterior cervical fusion (ACF) is controversial. Early reports described high complication rates. A variety of dosing regimens ranging from 0.6 to 2.1 mg per level fused have been reported. The authors hypothesized that the high amounts of rhBMP-2 used in these studies led to the high complication rates observed; therefore, they set out to evaluate the safety and efficacy of low-dose rhBMP-2 for use in ACFs. METHODS: Patient inclusion criteria were 1) age 18 to 70 years; 2) initial stand-alone ACF construct; 3) fusion augmentation with rhBMP-2; and 4) at least 1 year of radiographic follow-up. A successful fusion was defined by either 1) lateral flexion-extension radiographs with less than 1 mm of movement across the fused spinous processes, or 2) bone bridging at least half of the fusion area originally achieved by surgery on fine-cut CT. Patient demographics, perioperative data, and postoperative complications were recorded. RESULTS: A total of 198 patients met the inclusion criteria and were included for analysis. Sixty-two patients (31%) were smokers. The median number of levels fused was 2 (IQR 1.25). The mean dose of rhBMP-2 was 0.50 ± 0.09 mg per level. Twenty-two (11%) patients experienced dysphagia. Eleven (6%) patients experienced cervical swelling. Two (1%) patients returned to the operating room (OR) for postoperative hematoma. One (0.5%) patient returned to the OR for seroma. Two (1%) patients experienced pseudarthrosis requiring a posterior fusion. Three (2%) patients experienced a new postoperative neurological deficit that had recovered by last the follow-up. Overall, 190 (96%) patients experienced solid arthrodesis over an average of 15 months of follow-up. There was no difference in fusion rates between patients who were either smokers or nonsmokers (p = 0.7073). CONCLUSIONS: The use of low-dose rhBMP-2 safely and effectively augmented anterior cervical arthrodesis. The low-dose protocol assessed in this study appeared to significantly reduce complications associated with rhBMP-2 use in ACF compared with the literature. The authors have determined that using low-dose rhBMP-2 in patients who are smokers, those with multilevel ACFs, or others at high risk of developing pseudarthrosis is recommended.


Assuntos
Pseudoartrose , Doenças da Coluna Vertebral , Fusão Vertebral , Adolescente , Adulto , Idoso , Proteína Morfogenética Óssea 2 , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Humanos , Pessoa de Meia-Idade , Fusão Vertebral/efeitos adversos , Adulto Jovem
11.
Am J Physiol Heart Circ Physiol ; 318(4): H778-H786, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142354

RESUMO

Sepsis-induced cardiomyopathy (SIC) is associated with increased patient mortality. At present, there are no specific therapies for SIC. Previous studies have reported increased reactive oxygen species (ROS) and mitochondrial dysfunction during SIC. However, a unifying mechanism remains to be defined. We hypothesized that PKCδ is required for abnormal calcium handling and cardiac mitochondrial dysfunction during sepsis and that genetic deletion of PKCδ would be protective. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) surgery decreased the ejection fraction of wild-type (WT) mice but not PKCδ knockout (KO) mice. Similarly, WT cardiomyocytes exposed to lipopolysaccharide (LPS) demonstrated decreases in contractility and calcium transient amplitude that were not observed in PKCδ KO cardiomyocytes. LPS treatment decreased sarcoplasmic reticulum calcium stores in WT cardiomyocytes, which correlated with increased ryanodine receptor-2 oxidation in WT hearts but not PKCδ KO hearts after sepsis. LPS exposure increased mitochondrial ROS and decreased mitochondrial inner membrane potential in WT cardiomyocytes. This corresponded to morphologic changes consistent with mitochondrial dysfunction such as decreased overall size and cristae disorganization. Increased cellular ROS and changes in mitochondrial morphology were not observed in PKCδ KO cardiomyocytes. These data show that PKCδ is required in the pathophysiology of SIC by generating ROS and promoting mitochondrial dysfunction. Thus, PKCδ is a potential target for cardiac protection during sepsis.NEW & NOTEWORTHY Sepsis is often complicated by cardiac dysfunction, which is associated with a high mortality rate. Our work shows that the protein PKCδ is required for decreased cardiac contractility during sepsis. Mice with deletion of PKCδ are protected from cardiac dysfunction after sepsis. PKCδ causes mitochondrial dysfunction in cardiac myocytes, and reducing mitochondrial oxidative stress improves contractility in wild-type cardiomyocytes. Thus, PKCδ is a potential target for cardiac protection during sepsis.


Assuntos
Cardiomiopatias/genética , Mitocôndrias Cardíacas/metabolismo , Proteína Quinase C-delta/genética , Sepse/complicações , Animais , Sinalização do Cálcio , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Células Cultivadas , Feminino , Deleção de Genes , Lipopolissacarídeos/toxicidade , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Estresse Oxidativo , Proteína Quinase C-delta/metabolismo
12.
J Virol ; 93(11)2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30894463

RESUMO

Central nervous system (CNS) transduction by systemically administered recombinant adeno-associated viral (AAV) vectors requires crossing the blood-brain barrier (BBB). We recently mapped a structural footprint on the AAVrh.10 capsid, which, when grafted onto the AAV1 capsid (AAV1RX), enables viral transport across the BBB; however, the underlying mechanisms remain unknown. Here, we establish through structural modeling that this footprint overlaps in part the sialic acid (SIA) footprint on AAV1. We hypothesized that altered SIA-capsid interactions may influence the ability of AAV1RX to transduce the CNS. Using AAV1 variants with altered SIA footprints, we map functional attributes of these capsids to their relative SIA dependence. Specifically, capsids with ablated SIA binding can penetrate and transduce the CNS with low to moderate efficiency. In contrast, AAV1 shows strong SIA dependency and does not transduce the CNS after systemic administration and, instead, transduces the vasculature and the liver. The AAV1RX variant, which shows an intermediate SIA binding phenotype, effectively enters the brain parenchyma and transduces neurons at levels comparable to the level of AAVrh.10. In corollary, the reciprocal swap of the AAV1RX footprint onto AAVrh.10 (AAVRX1) attenuated CNS transduction relative to that of AAVrh.10. We conclude that the composition of residues within the capsid variable region 1 (VR1) of AAV1 and AAVrh.10 profoundly influences tropism, with altered SIA interactions playing a partial role in this phenotype. Further, we postulate a Goldilocks model, wherein optimal glycan interactions can influence the CNS transduction profile of AAV capsids.IMPORTANCE Understanding how viruses cross the blood-brain barrier can provide insight into new approaches to block infection by pathogens or the ability to exploit these pathways for designing new recombinant viral vectors for gene therapy. In this regard, modulation of virus-carbohydrate interactions by mutating the virion shell can influence the ability of recombinant viruses to cross the vascular barrier, enter the brain, and enable efficient gene transfer to neurons.


Assuntos
Barreira Hematoencefálica/metabolismo , Dependovirus/genética , Ácido N-Acetilneuramínico/metabolismo , Encéfalo/metabolismo , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Sistema Nervoso Central/virologia , Dependovirus/metabolismo , Terapia Genética/métodos , Vetores Genéticos , Células HEK293 , Humanos , Ligação Proteica/genética , Transdução Genética/métodos , Tropismo/genética , Vírion/metabolismo
13.
Mol Ther ; 26(2): 510-523, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29175157

RESUMO

Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile.


Assuntos
Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Dependovirus/fisiologia , Dependovirus/ultraestrutura , Animais , Transporte Biológico , Encéfalo/metabolismo , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Dependovirus/classificação , Expressão Gênica , Técnicas de Transferência de Genes , Engenharia Genética , Vetores Genéticos/administração & dosagem , Humanos , Camundongos , Modelos Moleculares , Miocárdio/metabolismo , Especificidade de Órgãos , Filogenia , Ligação Proteica , Distribuição Tecidual , Transdução Genética , Transgenes
14.
Ultrasound Obstet Gynecol ; 52(6): 784-791, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29882224

RESUMO

OBJECTIVE: To establish the diagnostic test accuracy of two-dimensional (2D) and four-dimensional (4D) transperineal ultrasound (TPUS) for diagnosis of posterior pelvic floor disorders in women with obstructed defecation syndrome (ODS), in order to assess if 4D ultrasound imaging provides additional value. METHODS: This was a prospective cohort study of 121 consecutive women with ODS. Symptoms of ODS and pelvic organ prolapse on clinical examination were assessed using validated methods. All women underwent both 2D- and 4D-TPUS. Imaging analysis was performed by two blinded observers. Posterior pelvic floor disorders were dichotomized into presence or absence, according to predefined cut-off values. In the absence of a reference standard, a composite reference standard was created from a combination of results of evacuation proctography, magnetic resonance imaging and endovaginal ultrasound. Primary outcome measures were diagnostic test characteristics of 2D- and 4D-TPUS for rectocele, enterocele, intussusception and anismus. Secondary outcome measures were interobserver agreement, agreement between the two imaging techniques, and association of severity of ODS symptoms and degree of posterior vaginal wall prolapse with conditions observed on imaging. RESULTS: For diagnosis of all four posterior pelvic floor disorders, there was no difference in sensitivity or specificity between 2D- and 4D-TPUS (P = 0.131-1.000). Good agreement between 2D- and 4D-TPUS was found for diagnosis of rectocele (κ = 0.675) and moderate agreement for diagnoses of enterocele, intussusception and anismus (κ = 0.465-0.545). There was no difference in rectocele depth measurements between the techniques (19.9 mm for 2D vs 19.0 mm for 4D, P = 0.802). Interobserver agreement was comparable for both techniques, although 2D-TPUS had excellent interobserver agreement for diagnosis of enterocele and rectocele depth measurements, while this was only moderate and good, respectively, for 4D-TPUS. Diagnoses of rectocele and enterocele on both 2D- and 4D-TPUS were significantly associated with degree of posterior vaginal wall prolapse on clinical examination (odds ratio (OR) = 1.89-2.72). The conditions observed using either imaging technique were not associated with severity of ODS symptoms (OR = 0.82-1.13). CONCLUSIONS: There is no evidence of superiority of 4D ultrasound acquisition to dynamic 2D ultrasound acquisition for the diagnosis of posterior pelvic floor disorders. 2D- and 4D-TPUS could be used interchangeably to screen women with symptoms of ODS. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.


Assuntos
Imageamento Tridimensional/métodos , Obstrução Intestinal/etiologia , Distúrbios do Assoalho Pélvico/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Obstrução Intestinal/diagnóstico por imagem , Pessoa de Meia-Idade , Variações Dependentes do Observador , Distúrbios do Assoalho Pélvico/complicações , Estudos Prospectivos , Sensibilidade e Especificidade , Ultrassonografia
16.
Public Health ; 156: 34-43, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29366916

RESUMO

OBJECTIVE: There is a need to increase HIV testing rates in the UK. One approach is to increase access to testing through general health checks (GHCs) in the workplace. However, it is unclear whether GHCs are routinely offered by organisations, and employer perceptions of HIV testing are largely unknown. STUDY DESIGN: Online survey to assess attitudes towards and provision of general health checks and HIV testing in the workplace. METHODS: Ninety-eight employers from 25 job sectors completed an online survey. Employers were 61 small and medium-sized enterprises (SME), 37 large organisations; 86% employing mobile workers, 77.6% employing migrant workers and 51.7% of employees were male workers. Items included employer attitudes around workplace health, GHC provision, content and delivery and attitudes towards workplace HIV testing including perceived benefits and barriers to HIV testing. RESULTS: Only one company offered opt-in workplace HIV testing. Seventy-eight companies (80%) did not provide any form of workplace GHC for employees. Decisions about health check provisions were not commonly informed by staff consultation (n = 6) or national guidelines (n = 4). Overall, 100% of companies (n = 98) reported at least one benefit of HIV testing and 68 (69%) believed that HIV testing should be offered in the workplace. Perceived barriers to HIV testing in the workplace were: [a] not having enough knowledge about HIV and testing; [b] not having trained staff to undertake HIV testing; and, [c] not knowing how to access HIV testing kits. Fifty-six companies (57.14%) would consider HIV testing as a future provision at their organisation. Sixty-seven companies (68.37%) would like further guidance on workplace HIV testing. CONCLUSIONS: Few employers offer general health testing for employees, and opt-in HIV testing is exceptionally rare, despite positive attitudes towards it. There is a need to provide evidence-based guidance and support for employers around HIV testing in the workplace.


Assuntos
Atitude Frente a Saúde , Emprego/psicologia , Infecções por HIV/diagnóstico , Programas de Rastreamento/psicologia , Serviços de Saúde do Trabalhador , Exame Físico , Adolescente , Adulto , Emprego/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Migrantes/estatística & dados numéricos , Adulto Jovem
18.
Diabet Med ; 34(3): 328-339, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27472405

RESUMO

AIM: Diabetes is a chronic progressive condition presenting physical, social and psychological challenges that increase the risk of comorbid mental health problems. Cognitive-behavioural therapy (CBT) is effective in treating a variety of psychological disorders, and may potentially improve glycaemic control and psychological outcomes in diabetes. This systematic review and meta-analysis aims to establish the effectiveness of CBT on glycaemic control and comorbid diabetes-related distress, depression, anxiety and quality of life in the short, medium and longer term among adults with diabetes. METHOD: An electronic search was conducted in PubMed, Embase, MEDLINE, PsycINFO, CINAHL, Web of Knowledge, Cochrane Central Register of Controlled Trials and references in reviews. Twelve randomized controlled trials (RCTs) were identified that evaluated the effectiveness of CBT on at least one of: glycaemic control, diabetes-related distress, anxiety, depression or quality of life in adults with Type 1 or Type 2 diabetes. The Cochrane Risk of Bias Tool and Review Manager version 5.3 were used for risk of bias assessment and meta-analysis, respectively. RESULTS: CBT is effective in reducing short-term and medium-term glycaemic control, although no significant effect was found for long-term glycaemic control. CBT improved short- and medium-term anxiety and depression, and long-term depression. Mixed results were found for diabetes-related distress and quality of life. CONCLUSION: CBT is beneficial in improving depression for adults with diabetes. It may have benefits for improving glycaemic control and other aspects of psychological health, although the findings are inconclusive.


Assuntos
Terapia Cognitivo-Comportamental , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Medicina Baseada em Evidências , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Estresse Psicológico/prevenção & controle , Adulto , Ansiedade/complicações , Ansiedade/etiologia , Ansiedade/prevenção & controle , Ansiedade/psicologia , Terapia Combinada/efeitos adversos , Terapia Combinada/psicologia , Efeitos Psicossociais da Doença , Depressão/complicações , Depressão/etiologia , Depressão/prevenção & controle , Depressão/psicologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/psicologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/psicologia , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Estresse Psicológico/complicações , Estresse Psicológico/etiologia , Estresse Psicológico/psicologia
19.
Clin Radiol ; 72(4): 307-315, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28159328

RESUMO

AIM: To compare the preoperative staging accuracy of computed tomography (CT) and 3-T magnetic resonance imaging (MRI) in colon cancer, and to investigate the prognostic significance of identified risk factors. MATERIALS AND METHODS: Fifty-eight patients undergoing primary resection of their colon cancer were prospectively recruited, with 53 patients included for final analysis. Accuracy of CT and MRI were compared for two readers, using postoperative histology as the reference standard. Patients were followed-up for a median of 39 months. Risk factors were compared by modality and reader in terms of metachronous metastases and disease-free survival (DFS), stratified for adjuvant chemotherapy. RESULTS: Accuracy for the identification of T3c+ disease was non-significantly greater on MRI (75% and 79%) than CT (70% and 77%). Differences in the accuracy of MRI and CT for identification of T3+ disease (MRI 75% and 57%, CT 72% and 66%) and N+ disease (MRI 62% and 63%, CT 62% and 56%) were also non-significant. Identification of extramural venous invasion (EMVI+) disease was significantly greater on MRI (75% and 75%) than CT (79% and 54%) for one reader (p=0.029). T3c+ disease at histopathology was the only risk factor that demonstrated a significant difference in rate of metachronous metastases (odds ratio [OR] 8.6, p=0.0044) and DFS stratified for adjuvant therapy (OR=4, p=0.048). CONCLUSION: T3c or greater disease is the strongest risk factor for predicting DFS in colon cancer, and is accurately identified on imaging. T3c+ disease may therefore be the best imaging entry criteria for trials of neoadjuvant treatment.


Assuntos
Neoplasias do Colo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Colo/diagnóstico por imagem , Colo/patologia , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Estadiamento de Neoplasias , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco
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