RESUMO
BACKGROUND: Cognitive behavioural therapy (CBT) is an empirically supported treatment for generalized anxiety disorder (GAD). Little is known about the effectiveness of CBT for GAD in real-world treatment settings. AIM: This study investigated the effectiveness of group CBT and predictors of treatment response in an out-patient hospital clinic. METHOD: Participants (n = 386) with GAD participated in 12 sessions of group CBT at an out-patient clinic. Of those who provided at least partial data (n = 326), 84.5% completed treatment. Most questionnaires were completed at pre- and post-treatment; worry severity was assessed weekly. RESULTS: Group CBT led to improvements in chronic worry (d = -0.91, n = 118), depressive symptoms (d = -1.22, n = 172), GAD symptom severity (d = -0.65, n = 171), intolerance of uncertainty (IU; d = -0.46, n = 174) and level of functional impairment (d = -0.35, n = 169). Greater pre-treatment GAD symptom severity (d = -0.17, n = 293), chronic worry (d = -0.20, n = 185), functional impairment (d = -0.12, n = 292), and number of comorbid diagnoses (d = -0.13, n = 299) predicted greater improvement in past week worry over treatment. Biological sex, age, depression symptom severity, number of treatment sessions attended, and IU did not predict change in past week worry over time. DISCUSSION: These findings provide support for the effectiveness of group CBT for GAD and suggest the outcomes are robust and are either not impacted or are slightly positively impacted by several demographic and clinical factors.
Assuntos
Transtornos de Ansiedade , Terapia Cognitivo-Comportamental , Psicoterapia de Grupo , Humanos , Terapia Cognitivo-Comportamental/métodos , Masculino , Feminino , Transtornos de Ansiedade/terapia , Transtornos de Ansiedade/psicologia , Psicoterapia de Grupo/métodos , Adulto , Pessoa de Meia-Idade , Resultado do Tratamento , Inquéritos e Questionários , Pacientes Ambulatoriais , IdosoRESUMO
Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.
Assuntos
Membrana Celular/metabolismo , Hidrolases/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Proteínas ras/metabolismo , Proliferação de Células , Células Cultivadas , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Promielocítica Aguda/patologia , Lipoilação , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura MolecularRESUMO
BACKGROUND: Soccer is a high-speed contact sport with risk of injury. Despite long-standing concern, evidence to date remains inconsistent as to the association between playing professional-level soccer and lifelong musculoskeletal consequences. AIMS: The objectives were to assess risk of osteoarthritis in former professional soccer players compared to matched general population controls, and subsequently assess associated musculoskeletal disorders which may contribute to, or result from, osteoarthritis-specifically meniscal injury and joint replacement. METHODS: We conducted a retrospective cohort study using national electronic health records (EHRs) on a cohort of 7676 former professional soccer players aged 40 or over at recruitment, matched on year of birth, sex (all male) and socio-economic status with 23 028 general population controls. Outcomes of interest were obtained by utilizing individual-level record linkage to EHRs from general hospital inpatient and day-case admissions. RESULTS: Compared to controls, former soccer players showed a greater risk of hospital admission for osteoarthritis (hazard ratio [HR] 3.01; 95% confidence interval [CI] 2.80-3.25; Pâ <â 0.001). This increased risk appeared age dependant, normalizing over age 80 years and reflective of increased risk of lower limb osteoarthritis. Further, risk of hospital admissions for meniscal injury (HR 2.73; 95% CI 2.42-3.08; Pâ <â 0.001) and joint replacement (HR 2.82; 95% CI 2.23-3.57; Pâ <â 0.001) were greater among former soccer players. CONCLUSIONS: We report an increased risk of lower limb osteoarthritis in former soccer players when compared with matched population controls. The results of this research add data in support of lower limb osteoarthritis among former soccer players representing a potential industrial injury.
Assuntos
Osteoartrite , Futebol , Humanos , Masculino , Futebol/lesões , Estudos Retrospectivos , Osteoartrite/epidemiologia , Osteoartrite/etiologia , Extremidade Inferior , Fatores de RiscoRESUMO
PURPOSE: Secretory carcinoma (SC) of the salivary gland, formerly known as mammary analogue secretory carcinoma, is an uncommon and fairly newly described low grade malignant neoplasm of the salivary gland. Given the small number of cases reported in the literature to date, treatment guidelines are scarce. This study aimed to describe the clinical characteristics of SC, discuss prior management strategies, and provide recommendations for future treatment. METHODS: We performed a systematic review of all the cases of SC reported in the literature since it was first recognized in 2010. Using Pubmed, Crossref, and Google Scholar, we identified all articles reporting cases of SC. RESULTS: We identified 657 cases of SC in 109 articles. In addition, we provided 2 new cases, for a total of 659 cases in 110 articles. To our knowledge, this is the largest review of cases of SC in the literature to date. We summarized the clinical characteristics of SC, as well as the nodal status, clinical management, recurrence rate, and death rate. CONCLUSIONS: SC occurs on average in middle age (with a large age range), presents most often initially as localized disease without metastasis, and has a low but not insignificant recurrence rate. Deaths have been reported. The generalized recommendations for treatment of SC are in line with those of other low-grade salivary gland malignancies.
Assuntos
Neoplasias da Mama , Carcinoma , Carcinoma Secretor Análogo ao Mamário , Neoplasias das Glândulas Salivares , Feminino , Humanos , Pessoa de Meia-Idade , Glândulas SalivaresRESUMO
Complicated phylogenetic histories benefit from diverse sources of inference. Pseudacris crucifer (spring peeper) spans most of eastern North America and comprises six mtDNA lineages that form multiple contact zones. The putative Miocene or early Pliocene origins of the oldest lineages within Pseudacris crucifer imply sufficient time for species-level divergence. To understand why this species appears unified while congeners have radiated, we analyze and compare male advertisement calls, mitochondrial, and nuclear markers and speak to the complex processes that have potentially influenced its contemporary patterns. We find extensive geographic and topological mitonuclear discordance, with three nuclear lineages containing 6 more-structured mtDNA lineages, and nuclear introgression at some contact zones. Male advertisement call differentiation is incongruent with the genetic structure as only one lineage appears differentiated. Occupying the Interior Highlands of the central United States, this Western lineage also has the most concordant mitochondrial and nuclear geographic patterns. Based on our findings we suggest that the antiquity of common ancestors was not as important as the maintenance of allopatry in the divergence in P. crucifer genetic lineages. We use multiple lines of evidence to generate hypotheses of isolation, reticulation, and discordance within this species and to expand our understanding of the early stages of speciation.
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Anuros/genética , Núcleo Celular/genética , Variação Genética , Animais , Sequência de Bases , DNA Mitocondrial/genética , Geografia , Modelos Lineares , Masculino , Mitocôndrias/genética , América do Norte , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Especificidade da EspécieRESUMO
OBJECTIVES: To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC). METHODS: A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS. RESULTS: 175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/- radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11-3.52, and HR = 0.90, 95%CI 0.22-3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS. CONCLUSIONS: Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made.
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Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Linfonodo Sentinela/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/diagnóstico , Quimiorradioterapia Adjuvante , Intervalo Livre de Doença , Neoplasias do Endométrio/diagnóstico , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
S-Palmitoylation is a reversible post-translational lipid modification that regulates protein trafficking and signaling. The enzymatic depalmitoylation of proteins is inhibited by the beta-lactones Palmostatin M and B, which have been found to target several serine hydrolases. In efforts to better understand the mechanism of action of Palmostatin M, we describe herein the synthesis, chemical proteomic analysis, and functional characterization of analogs of this compound. We identify Palmostatin M analogs that maintain inhibitory activity in N-Ras depalmitoylation assays while displaying complementary reactivity across the serine hydrolase class as measured by activity-based protein profiling. Active Palmostatin M analogs inhibit the recently characterized ABHD17 subfamily of depalmitoylating enzymes, while sparing other candidate depalmitoylases such as LYPLA1 and LYPLA2. These findings improve our understanding of the structure-activity relationship of Palmostatin M and refine the set of serine hydrolase targets relevant to the compound's effects on N-Ras palmitoylation dynamics.
Assuntos
Lactonas/análise , Propiolactona/análogos & derivados , Proteômica , Sulfonas/análise , Proteínas ras/metabolismo , Humanos , Lactonas/metabolismo , Lactonas/farmacologia , Estrutura Molecular , Propiolactona/análise , Propiolactona/metabolismo , Propiolactona/farmacologia , Sulfonas/metabolismo , Sulfonas/farmacologia , Proteínas ras/antagonistas & inibidores , Proteínas ras/químicaRESUMO
AIMS: We examined the effectiveness of a service innovation, Three Dimensions for Diabetes (3DFD), that consisted of a referral to an integrated mental health, social care and diabetes treatment model, compared with usual care in improving biomedical and health economic outcomes. METHODS: Using a non-randomized control design, the 3DFD model was offered in two inner-city boroughs in London, UK, where diabetes health professionals could refer adult residents with diabetes, suboptimal glycaemic control [HbA1c ≥ 75 mmol/mol (≥ 9.0%)] and mental health and/or social problems. In the usual care group, there was no referral pathway and anonymized data on individuals with HbA1c ≥ 75 mmol/mol (≥ 9.0%) were collected from primary care records. Change in HbA1c from baseline to 12 months was the primary outcome, and change in healthcare costs and biomedical variables were secondary outcomes. RESULTS: 3DFD participants had worse glycaemic control and higher healthcare costs than control participants at baseline. 3DFD participants had greater improvement in glycaemic control compared with control participants [-14 mmol/mol (-1.3%) vs. -6 mmol/mol (-0.6%) respectively, P < 0.001], adjusted for confounding. Total follow-up healthcare costs remained higher in the 3DFD group compared with the control group (mean difference £1715, 95% confidence intervals 591 to 2811), adjusted for confounding. The incremental cost-effectiveness ratio was £398 per mmol/mol unit decrease in HbA1c , indicating the 3DFD intervention was more effective and costed more than usual care. CONCLUSIONS: A biomedical, psychological and social criteria-based referral system for identifying and managing high-cost and high-risk individuals with poor glycaemic control can lead to improved health in all three dimensions.
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Atenção à Saúde/organização & administração , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Transtornos Mentais/terapia , Serviços de Saúde Mental/organização & administração , Serviço Social/organização & administração , Adulto , Idoso , Atenção à Saúde/economia , Diabetes Mellitus Tipo 1/economia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/psicologia , Diabetes Mellitus Tipo 2/economia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/psicologia , Feminino , Hemoglobinas Glicadas/metabolismo , Custos de Cuidados de Saúde , Serviços de Saúde/economia , Administração de Serviços de Saúde , Humanos , Londres , Masculino , Transtornos Mentais/psicologia , Serviços de Saúde Mental/economia , Pessoa de Meia-Idade , Projetos Piloto , Serviço Social/economia , População UrbanaRESUMO
Natural killer T (NKT) cells respond to a variety of CD1d-restricted antigens (Ags), although the basis for Ag discrimination by the NKT cell receptor (TCR) is unclear. Here we have described NKT TCR fine specificity against several closely related Ags, termed altered glycolipid ligands (AGLs), which differentially stimulate NKT cells. The structures of five ternary complexes all revealed similar docking. Acyl chain modifications did not affect the interaction, but reduced NKT cell proliferation, indicating an affect on Ag processing or presentation. Conversely, truncation of the phytosphingosine chain caused an induced fit mode of TCR binding that affected TCR affinity. Modifications in the glycosyl head group had a direct impact on the TCR interaction and associated cellular response, with ligand potency reflecting the t(1/2) life of the interaction. Accordingly, we have provided a molecular basis for understanding how modifications in AGLs can result in striking alterations in the cellular response of NKT cells.
Assuntos
Antígenos CD1d/imunologia , Epitopos , Células T Matadoras Naturais/imunologia , Animais , Sequência de Carboidratos , Linhagem Celular , Proliferação de Células , Glicolipídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Dados de Sequência Molecular , Células T Matadoras Naturais/citologia , Receptores de Células Matadoras Naturais/imunologiaRESUMO
BACKGROUND: BRCA1/2 mutation status has increasing relevance for ovarian cancer treatments, making traditional coordination of genetic testing by genetic services unsustainable. Consequently alternative models of genetic testing have been developed to improve testing at the initial diagnosis for all eligible women. METHODS: A training module to enable mainstreamed genetic testing by oncology healthcare professionals was developed by genetic health professionals. Oncology healthcare professionals completed questionnaires before and 12 months post-training to assess perceived skills, competence and barriers to their coordinating genetic testing for women with high-grade non-mucinous epithelial ovarian cancer. Genetic health professionals were surveyed 12 months post-training to assess perceived barriers to implementation of mainstreaming. RESULTS: 185 oncology healthcare professionals were trained in 42 workshops at 35 Australasian hospitals. Of the 273 tests ordered by oncology healthcare professionals post-training, 241 (93.1%) met national testing guidelines. The number of tests ordered by genetic health professionals reduced significantly (z = 45.0, p = 0.008). Oncology healthcare professionals' perceived barriers to mainstreamed testing decreased from baseline to follow-up (t = 2.39, p = 0.023), particularly perceived skills, knowledge and attitudes. However, only 58% reported either 'always' or 'nearly always' having ordered BRCA testing for eligible patients at 12 months, suggesting oncology healthcare professionals' perceived barriers were not systematically addressed through training. CONCLUSIONS: Oncology healthcare professionals have demonstrated a willingness to be involved in the provision of genetic testing in a mainstreaming model. If oncology services are to hold responsibility for coordinating genetic testing, their readiness will require understanding of barriers not addressed by training alone to inform future intervention design.
Assuntos
Carcinoma Epitelial do Ovário/genética , Testes Genéticos/métodos , Genética/educação , Oncologia/educação , Neoplasias Ovarianas/genética , Adolescente , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Educação Médica Continuada , Feminino , Pessoal de Saúde/educação , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE: Standard treatment for retained products of conception (RPOC) is dilation and curettage (D&C), however, this brings a risk of intrauterine synechiae and subsequent fertility issues. A treatment strategy to avoid D&C is medical management with misoprostol. The justification for misoprostol in this setting is extrapolated from miscarriage and termination literature, however, no studies have looked specifically in the setting of RPOC. The purpose of this study is to determine the efficacy of misoprostol as definitive management of RPOC. MATERIALS AND METHODS: A retrospective cohort study was conducted from January 2016 to March 2017 at an Early Pregnancy Assessment Clinic. Patients diagnosed with RPOC with clinical symptoms and ultrasound findings of endometrial mass and/or doppler flow treated expectantly, medically with vaginal misoprostol or with a suction D&C underwent a chart review. Primary outcome was resolution of RPOC without surgical intervention. RESULTS AND CONCLUSIONS: Of 1743 unique pregnancies, 189 women were diagnosed with RPOC. 34% (65/178) chose misoprostol for management of RPOC. Baseline demographics between the three treatment modalities (expectant, medical, surgical) were comparable. 65% (42/65) of patients who took misoprostol avoided D&C. Misoprostol is most effective (76%) in the setting of RPOC if the primary treatment for miscarriage was expectant management, with less success with primary medical management (44%) and primary surgical management (40%).
Assuntos
Abortivos não Esteroides/uso terapêutico , Aborto Espontâneo/tratamento farmacológico , Misoprostol/uso terapêutico , Aborto Espontâneo/diagnóstico por imagem , Estudos de Coortes , Feminino , Feto/diagnóstico por imagem , Humanos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Primeiro Trimestre da Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND: Alternative reproductive tactics (ARTs) are taxonomically pervasive strategies adopted by individuals to maximize reproductive success within populations. Even for conditionally-dependent traits, consensus postulates most ARTs involve both genetic and environmental interactions (GEIs), but to date, quantifying genetic variation underlying the threshold disposing an individual to switch phenotypes in response to an environmental cue has been a difficult undertaking. Our study aims to investigate the origins and maintenance of ARTs within environmentally disparate populations of the microscopic bulb mite, Rhizoglyphus robini, that express 'fighter' and 'scrambler' male morphs mediated by a complex combination of environmental and genetic factors. RESULTS: Using never-before-published individual genetic profiling, we found all individuals across populations are highly inbred with the exception of scrambler males in stressed environments. In fact within the poor environment, scrambler males and females showed no significant difference in genetic differentiation (Fst) compared to all other comparisons, and although fighters were highly divergent from the rest of the population in both poor or rich environments (e.g., Fst, STRUCTURE), fighters demonstrated approximately three times less genetic divergence from the population in poor environments. AMOVA analyses further corroborated significant genetic differentiation across subpopulations, between morphs and sexes, and among subpopulations within each environment. CONCLUSION: Our study provides new insights into the origin of ARTs in the bulb mite, highlighting the importance of GEIs: genetic correlations, epistatic interactions, and sex-specific inbreeding depression across environmental stressors. Asymmetric reproductive output, coupled with the purging of highly inbred individuals during environmental oscillations, also facilitates genetic variation within populations, despite evidence for strong directional selection. This cryptic genetic variation also conceivably facilitates stable population persistence even in the face of spatially or temporally unstable environmental challenges. Ultimately, understanding the genetic context that maintains thresholds, even for conditionally-dependent ARTs, will enhance our understanding of within population variation and our ability to predict responses to selection.
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Sinais (Psicologia) , Meio Ambiente , Variação Genética , Modelos Biológicos , Reprodução/genética , Acaridae/genética , Animais , Feminino , Masculino , Fenótipo , Caracteres SexuaisRESUMO
Children and young people are increasingly likely to receive information regarding inherited health risks relevant to their genetic relatives and themselves. We reviewed the literature to determine what children and young people (21 years and younger) understand about inherited conditions and their attitudes towards genetic testing. We screened 1815 abstracts to identify 20 studies representing the perspectives of 1811 children and young people between the ages of 6 and 21 years (1498 children or young people at general population-level risk from 9 studies, 313 affected/at risk from 15 studies). Children and young people at general population-level risk demonstrated a basic understanding that disease predisposition can be inherited within families. Those affected by or at risk of genetic conditions inferred their genetic status from observable, relational characteristics within their family and the results of personal genetic testing if it had occurred, but some misunderstandings of important genetic concepts were evident. Children and young people expressed interest in and a willingness to undertake personal genetic testing, but also articulated concerns about the limitations and risks of testing. Paediatric patients require developmentally-sensitive genetic counselling and support in navigating the unique landscape of their condition.
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Aconselhamento Genético/tendências , Doenças Genéticas Inatas/genética , Testes Genéticos/tendências , Conhecimentos, Atitudes e Prática em Saúde , Adolescente , Adulto , Criança , Bases de Dados Genéticas , Feminino , Doenças Genéticas Inatas/epidemiologia , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Numerous studies of dental antibiotic prescribing show that overprescribing is a worldwide occurrence. The aim of this study was to assess prescribing practices of general dentists in Australia for antibiotics, analgesics and anxiolytics and to determine the extent to which prescribing is in accordance with current guidelines. METHODS: A structured questionnaire was sent to 1468 dentists in Victoria and Queensland in July-August 2018. The questionnaire covered demographics, clinical conditions where dentists prescribe antibiotics, non-clinical factors which influence prescribing, and medicines for anxiolysis and pain relief. Responses were scored using a system based on the current Australian therapeutic guidelines. Logistic regression was used to determine the relative importance of independent variables on inappropriate prescribing. RESULTS: Three hundred eighty-two responses were received. Overall, 55% of overprescribing of antibiotics was detected, with a range of 13-88% on a routine or occasional basis depending on the scenario. Between 16 and 27% of respondents inappropriately preferenced analgesics over anti-inflammatories for dental pain; 46% of those who prescribed anxiolytic medicines did so inappropriately, with varying regimens and choices outside the guidelines. Years of practice was the main demographic factor influencing prescribing, with recent graduates (0-5 years) generally scoring better than their colleagues for antibiotic prescribing (p < 0.05). CONCLUSIONS: Future interventions could be directed towards the appropriate role and use of antibiotics, shortfalls in knowledge and appropriate choices of medicines for pain relief and anxiolysis. Given that the most overprescribing occurred for localised swellings (88%), this area could be focused on in continuing education as well as ensuring it is addressed in undergraduate teaching. Continuing education on the appropriate use of medicines can be targeted at more experienced dentists as well as patients, especially those who expect antibiotics instead of treatment. TRIAL REGISTRATION: University of Melbourne Human Ethics Sub-Committee; ID: 1750768.1 .
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Antibacterianos , Odontólogos , Padrões de Prática Odontológica , Antibacterianos/uso terapêutico , Feminino , Humanos , Masculino , Queensland , Inquéritos e Questionários , VitóriaRESUMO
Mouse type I natural killer T cell receptors (iNKT TCRs) use a single V alpha 14-J alpha 18 sequence and V beta s that are almost always V beta 8.2, V beta 7, or V beta 2, although the basis of this differential usage is unclear. We showed that the V beta bias occurred as a consequence of the CDR2 beta loops determining the affinity of the iNKT TCR for CD1d-glycolipids, thus controlling positive selection. Within a conserved iNKT-TCR-CD1d docking framework, these inherent V beta-CD1d affinities are further modulated by the hypervariable CDR3 beta loop, thereby defining a functional interplay between the two iNKT TCR CDR beta loops. These V beta biases revealed a broadly hierarchical response in which V beta 8.2 > V beta 7 > V beta 2 in the recognition of diverse CD1d ligands. This restriction of the iNKT TCR repertoire during thymic selection paradoxically ensures that each peripheral iNKT cell recognizes a similar spectrum of antigens.
Assuntos
Antígenos CD1d/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Animais , Antígenos CD1d/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Timo/imunologiaRESUMO
Interprofessional collaborative care has been shown to improve patient outcomes. Physicians' views on collaboration with pharmacists give an insight into what contributes to a well-functioning team. Little is known about these views from low and âmiddle-income countries and nothing from the United Arab Emirates (UAE). The purpose of this study is to investigate physicians' opinions on collaborative relationships with community pharmacists in the UAE. Semi-structured individual interviews and group discussions are conducted with a purposive sample of physicians. Thematic analysis based on the framework approach is used to generate themes. A total of 53 physicians participated. Three themes about collaboration emerged: perceived benefits of collaboration, facilitators of collaboration and perceived barriers to collaboration. Perceived benefits include reducing the burden on physicians, having the pharmacist as an extra safety check within the system, having the pharmacist assist patients to manage their medications: coping with side effects, reducing drug waste and costs, and attaining professional and health-system gains. Perceived facilitators included awareness and trust building, professional role definition, pharmacists' access to patient records and effective communication. Perceived barriers included patient and physician acceptance, logistic and financial issues and perceived pharmacist competence. This study has, for the first time, provided useful information to inform the future development of pharmacist-physician collaboration in the UAE and other countries with similar healthcare systems.
Assuntos
Relações Interprofissionais , Farmacêuticos/organização & administração , Médicos/organização & administração , Papel Profissional , Atitude do Pessoal de Saúde , Serviços Comunitários de Farmácia/organização & administração , Comportamento Cooperativo , Humanos , Emirados Árabes UnidosRESUMO
Reproductive barriers and divergence in species' mate recognition systems underlie major models of speciation. However, hybridization between divergent species is common, and classic mechanisms to explain permeable reproductive barriers rarely consider how an individual may attain reproductive success. Alternative mating tactics (AMTs) exist in various forms across animal taxa. Such tactics may allow poorer quality individuals to gain mating opportunities and facilitate introgression either through asymmetrical positive selection or by circumventing female choice altogether in areas of secondary contact. One such tactic is satellite behaviour in frogs, where silent males perch near advertisers in an attempt to intercept females. To test whether such satellite male tactics are context-dependent and favoured by hybrids, we genotyped and quantified the morphology of 80 male spring peeper (Pseudacris crucifer) individuals involved in caller-satellite associations from a secondary contact zone between two intraspecific mitochondrial lineages. Irrespective of population, satellite behaviour was best predicted by size but not body condition. Within the contact zone, pure individuals showed a significantly greater probability of being active callers, whereas hybrids of one lineage were more likely to adopt the satellite tactic. We suggest that satellite behaviour in P. crucifer promotes introgression, breaks down reproductive isolating barriers and contributes to asymmetrical introgression in this secondary contact zone. AMTs may thus be an underexplored but important alternative to oft-discussed causes of genetic discordance found in hybrid zones.
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Anuros , Hibridização Genética , Reprodução , Animais , Comportamento de Escolha , Feminino , Genótipo , Masculino , Comportamento Sexual AnimalRESUMO
PURPOSE: We aim to describe a mechanism of failure in magnetically controlled growth rods which are used for the correction of the early onset scoliosis. METHODS: This retrieval study involved nine magnetically controlled growth rods, of a single design, revised from five patients for metal staining, progression of scoliosis, swelling, fractured actuator pin, and final fusion. All the retrieved rods were radiographed and assessed macroscopically and microscopically for material loss. Two implants were further analysed using micro-CT scanning and then sectioned to allow examination of the internal mechanism. No funding was obtained to analyse these implants. There were no potential conflicts interests. RESULTS: Plain radiographs revealed that three out of nine retrieved rods had a fractured pin. All had evidence of surface degradation on the extendable telescopic rod. There was considerable corrosion along the internal mechanism. CONCLUSIONS: We found that a third of the retrieved magnetically controlled growth rods had failed due to pin fracture secondary to corrosion of the internal mechanism. We recommend that surgeons consider that any inability of magnetically controlled growth rods to distract may be due to corrosive debris building up inside the mechanism, thereby preventing normal function.
Assuntos
Pinos Ortopédicos , Remoção de Dispositivo , Falha de Prótese , Escoliose/cirurgia , Criança , Corrosão , Feminino , Humanos , Fenômenos Magnéticos , Masculino , Microscopia Eletrônica de Varredura , Estudos Retrospectivos , Coluna Vertebral/crescimento & desenvolvimento , Coluna Vertebral/cirurgia , Microtomografia por Raio-XRESUMO
BACKGROUND: The decision for families to proceed with botulinum toxin-A (BoNT-A) injections for managing childhood conditions involving hypertonia can be complex. Family-centred care is a service model that facilitates supporting families in this decision-making process. Understanding families' experiences of services is critical to developing family-centred care. The aim of this project was therefore to increase understanding of the experiences of families of children attending a BoNT-A service in order to improve the service and its family-centred approach to care. METHOD: Sixteen staff of a BoNT-A service participated in a patient journey mapping exercise. Nine families of the service participated in in-depth interviews. Interviews were audio-recorded and transcribed verbatim. Data from the staff session and interviews were analysed independently using grounded, hermeneutic thematic analysis. RESULTS: Staff sessions revealed 5 core themes that related to impacting on the family experience. Family interviews revealed 4 core themes, with 7 subthemes and 1 latent theme. CONCLUSIONS: Areas of importance identified by families relating to BoNT-A treatment included acknowledgement of individual needs, care coordination, empowerment of families and patients, consistency in service delivery, and the distressing nature of appointment and decision-making. Comparison of the data from the staff patient journey mapping and family interviews suggested that staff have a good but incomplete understanding of the factors important to families, highlighting the need for consumer engagement in establishing family-centred care. The themes identified can guide the provision of family-centred BoNT-A injection clinics.
Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Serviços de Saúde da Criança/normas , Prestação Integrada de Cuidados de Saúde/normas , Fármacos Neuromusculares/uso terapêutico , Relações Profissional-Família , Melhoria de Qualidade , Adaptação Psicológica , Adolescente , Atitude do Pessoal de Saúde , Atitude Frente a Saúde , Criança , Serviços de Saúde da Criança/organização & administração , Pré-Escolar , Feminino , Humanos , Masculino , New South Wales , Estresse Psicológico/etiologiaRESUMO
BACKGROUND: Cancer incidence and mortality projections are important for understanding the evolving landscape for cancer risk factors as well as anticipating future burden on the health service. METHODS: We used an age-period-cohort model with natural cubic splines to estimate cancer cases and deaths from 2015 to 2035 based on 1979-2014 UK data. This was converted to rates using ONS population projections. Modified data sets were generated for breast and prostate cancers. RESULTS: Cancer incidence rates are projected to decrease by 0.03% in males and increase by 0.11% in females yearly between 2015 and 2035; thyroid, liver, oral and kidney cancer are among the fastest accelerating cancers. 243 690 female and 270 261 male cancer cases are projected for 2035. Breast and prostate cancers are projected to be the most common cancers among females and males, respectively in 2035. Most cancers' mortality rate is decreasing; there are notable increases for liver, oral and anal cancer. For 2035, there are 95 961 female deaths projected and 116 585 male deaths projected. CONCLUSIONS: These findings stress the need to continue efforts to address cancer risk factors. Furthermore, the increased burden of the number of cancer cases and deaths as a result of the growing and ageing population should be taken into consideration by healthcare planners.