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The etiology of sirenomelia is currently unknown. Data are limited in comparing external and internal abnormalities using modern imaging technologies and molecular genetic analysis. The purpose of the current study was designed to compare external and internal anatomical defects in two cases of sirenomelia and Potter's sequence. Considered rare, Potter's sequence is a fetal disorder with characteristic features of bilateral renal agenesis, obstructive uropathy, atypical facial appearance, and limb malformations. The internal and external malformations of two term fetuses with sirenomelia and Potter's sequence were compared using assessment of external features, radiography and MRI on internal structures, and molecular genetic studies on sex determination. Data reveal that both fetuses were male and manifested with an overlapping but distinct spectrum of abnormalities. Principal differences were noted in the development of the ears, brain, urogenital system, lower limbs, pelvis, and vertebral column. Defects of the axial mesoderm are likely to underlie the abnormalities seen in both fetuses. The first one, which had only caudal defects, was found to have a spectrum of abnormalities most similar to those associated with more severe forms of the small pelvic outlet syndrome, although the structure and orientation of the sacrum and iliae were different from previously reported cases. The other had both caudal and cranial defects, and was most similar to those described in the axial mesodermal dysplasia syndrome. Defects associated with sirenomelia can be evaluated with standard gross anatomy examination, radiology, MRI, and modified PCR techniques to determine anatomical abnormalities and the sex of preserved specimens, respectively. Evidence indicated that sirenomelia could be developed via various etiologies.
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Ectromelia , Humanos , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico por imagen , Ectromelia/genética , Ectromelia/diagnóstico por imagen , Ectromelia/patología , Feto/anomalías , Feto/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
Across a range of neurodevelopmental conditions, a diagnosis of attention deficit hyperactivity disorder (ADHD) has been shown to be associated with executive function impairment. However, the DSM-V emphasis upon viewing psychological characteristics as existing on a continuous distributed quantitative dimension has enabled the opportunity to consider the influence of sub-diagnostic or sub-referral levels of these psychological characteristics upon cognitive function. This study adopted a continuum approach to the consideration of this ADHD influence and examined the extent to which the difference in parental reported executive functions between children with Tourette syndrome (TS) or typically developing children could be mediated by a concurrent group difference in the possession of sub-referral levels of ADHD-like characteristics. A total of 146 children, 58 with reported TS diagnosis, participated. Parental report measures of ecological executive functioning, the Child Executive Functioning Inventory, and the Vanderbilt ADHD Diagnostic Parent Rating Scale were employed. The analyses with a full sample and a sub-referral sample revealed significant group differences in most of the key measures. In addition, these measures were highly correlated even when controlling for age and gender. A series of mediation analyses indicated that in all models, the ADHD-like measures significantly mediated the group difference in executive function. These results suggest that sub-referrals levels of ADHD-like characteristics continue to contribute to executive challenges in TS. Future intervention research targeting these executive functions should consider the presence of ADHD-like characteristics at sub-referral levels of possession.
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Trastorno por Déficit de Atención con Hiperactividad , Síndrome de Tourette , Niño , Humanos , Trastorno por Déficit de Atención con Hiperactividad/psicología , Síndrome de Tourette/complicaciones , Función Ejecutiva , Cognición , PadresRESUMEN
Objectives: The present study aims to evaluate existing policy and practice relating to the use of pharmacological treatments with patients suffering from paraphilic disorders who are at risk of committing further sexual offences.Methods: A systematic literature search was conducted to document current legal policies across 26 different countries. In addition, a questionnaire assessing the practice of pharmacological treatment was sent to practitioners involved in the treatment of patients with paraphilic disorders.Results: Legal policies concerning the preconditions of using pharmacological treatments differ considerably between countries, and for most jurisdictions do not exist. Drawing on the responses of 178 practitioners, pharmacological agents are a useful addition to psychotherapeutic interventions, especially with those patients classified as medium or high risk for sexually violent behaviours. It would appear that most patients are medically examined, are informed of the risks and possible side effects before treatment commences and are also obliged to sign a consent form.Conclusions: Although pharmacological agents can be seen as an intrusion into a patients' sexual self determination, results indicate that ethical and clinical standards are being met in the majority of cases. However, further promotion of current WFSBP treatment guidelines would help to standardise practice across North American and European countries.
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Quimioterapia/normas , Política de Salud/legislación & jurisprudencia , Trastornos Parafílicos/tratamiento farmacológico , Delitos Sexuales/prevención & control , Humanos , Internacionalidad , Masculino , Guías de Práctica Clínica como Asunto , Conducta Sexual/efectos de los fármacosRESUMEN
Objective This paper describes the 4-year journey of Hunter and New England HealthPathways - a password-protected web-based portal designed to provide localised evidence-informed clinical and referral information to support general practice at the point of care. Methods A process evaluation was conducted in 2013, with a case study comparison performed in 2014 to assess impact of HealthPathways on patient referral and access to specialist care, followed by a review in 2016 of utilisation of the online portal to assess whether healthcare providers continued to access HealthPathways. Results Increased utilisation was correlated with an increase in the number of pathways published online. Clinical leadership and the process of developing pathways built relationships between primary care and specialist teams. Case studies indicated that a comprehensive approach to pathway implementation accompanied by service redesign resulted in higher pathway use and improved access to specialist care. Senior management support and a formal partnership between major health care providers led to strong governance of HealthPathways and the delivery of other integrated care initiatives. There was significant growth in utilisation over the 4 years, increasing to an average of 6679 sessions per month in 2016 and more general practices reported use of HealthPathways. Conclusions HealthPathways is a vehicle for building strong foundations to support system change and integrated care. The critical elements for acceptability, growth and sustainability are the strong relationships between primary care and specialist clinicians, as well as formal partnerships that are built from the processes used to develop HealthPathways. What is known about the topic? HealthPathways and similar web-based evidence-informed guidelines aimed at improving system integration are increasing in Australia. There are few published papers that describe approaches to inform the ongoing implementation of such programs. What does this paper add? This paper describes iterative methodology for evaluating complex programs, such as HealthPathways, that identifies the critical factors required to build sustainable models of integrated care. What are the implications for practitioners? The 4-year experience of Hunter and New England HealthPathways provides an approach to improve the implementation, sustainability and spread of similar programs and associated integrated care initiatives.
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Actitud del Personal de Salud , Prestación Integrada de Atención de Salud/métodos , Médicos Generales/psicología , Accesibilidad a los Servicios de Salud , Pautas de la Práctica en Medicina , Derivación y Consulta , Práctica Clínica Basada en la Evidencia , Medicina General , Humanos , Internet , Relaciones Interprofesionales , Nueva Gales del Sur , Estudios de Casos Organizacionales , Pautas de la Práctica en Medicina/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Practice variations in insulin management and glycemic adverse events led nine Dignity Health hospitals to initiate a collaborative effort to improve hypoglycemia, uncontrolled hyperglycemia, and glycemic control. METHODS: Non-critical care adult inpatients with ≥4 point-of-care blood glucose (BG) readings in a ≥2-day period were included. Balanced glucometric goals for each hospital were individualized to improve performance by 10%-20% from baseline or achieve top performance derived from Society of Hospital Medicine (SHM) benchmarking studies. Baseline measures (2011) were compared to mature results (postintervention, 2014). Protocols for insulin management and hypoglycemia prevention were piloted at one facility and were then spread to the cohort. Interventions included standardized order sets, education, mentoring from physician experts, feedback of metrics, and measure-vention (coupling measurement of patients "off protocol" with concurrent intervention to correct lapses in care). RESULTS: The day-weighted mean BG for the cohort improved by 11.4 mg/dL (95% confidence interval [CI]: 11.0-11.8]; all nine sites improved. Eight of the sites reduced severe hyperglycemic days, and the percentage of patient-days with any BG > 299 mg/dL for the total cohort improved from 11.6% to 8.8% (relative risk, 0.76 [95% CI: 0.74-0.78]). The percentage of patient-days with any BG < 70 mg/dL remained unchanged at 3.6%. Eight of the sites either reduced hypoglycemia by 20% or achieved SHM best-quartile rates. CONCLUSION: Multihospital improvements in glycemic control and severe hyperglycemia without significant increases in hypoglycemia are feasible using portable low-cost toolkits and metrics.
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Glucemia/metabolismo , Hospitalización , Hiperglucemia/tratamiento farmacológico , Hipoglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Adulto , Humanos , Hiperglucemia/sangre , Pacientes Internos , Sistemas de Entrada de Órdenes Médicas , Mejoramiento de la CalidadRESUMEN
OBJECTIVE: Safely improve glycemic control in the critical care units of nine hospitals. METHODS: Critical care adult inpatients from nine hospitals with ≥4 point-of-care blood glucose (BG) readings over ≥2 days were targeted by collaborative improvement efforts to reduce hyper- and hypoglycemia. Balanced glucometric goals for each hospital were set targeting improvement from baseline or goals deemed desirable from Society of Hospital Medicine (SHM) benchmarking data. Collaborative interventions included standardized insulin infusion protocols, hypoglycemia prevention bundles, audit and feedback, education, and measure-vention (coupling measurement of patients "off protocol" with concurrent interventions to correct suboptimal care). RESULTS: All sites improved glycemic control. Six reached prespecified levels of improvement of the day-weighted mean BG. The day-weighted mean BG for the cohort decreased by 7.7 mg/dL (95% confidence interval [CI], 7.0 mg/dL to 8.4 mg/dL) to 151.3 mg/dL. Six of nine sites showed improvement in the percent intensive care unit (ICU) days with severe hyperglycemia (any BG >299 mg/dL). ICU severe hyperglycemic days declined from 8.6 to 7.2% for the cohort (relative risk, 0.84; 95% CI, 0.80 to 0.88). Patient days with any BG <70 mg/dL were reduced by 0.4% (95% CI, 0.06% to 0.6%), from 4.5 to 4.1%, for a small but statistically significant reduction in hypoglycemia. Seven of nine sites showed improvement. CONCLUSION: Multihospital improvements in ICU glycemic control, severe hyperglycemia, and hypoglycemia are feasible. Balanced goals for glycemic control and hypoglycemia in the ICU using SHM benchmarks and metrics enhanced successful improvement efforts with good staff acceptance and sustainability. ABBREVIATIONS: BG = blood glucose CMI = case-mix index CY = calendar year DKA = diabetic ketoacidosis EMR = electronic medical record GBMF = Gordon and Betty Moore Foundation ICU = intensive care unit IIP = insulin infusion protocol SHM = Society of z Hospital Medicine.
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Glucemia/metabolismo , Hiperglucemia/sangre , Hiperglucemia/prevención & control , Hipoglucemia/sangre , Hipoglucemia/prevención & control , Sistemas de Atención de Punto/normas , Adulto , Anciano , Anciano de 80 o más Años , California , Conducta Cooperativa , Cuidados Críticos , Femenino , Hospitales , Humanos , Insulina/administración & dosificación , Insulina/efectos adversos , Sistemas de Infusión de Insulina , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Mejoramiento de la CalidadRESUMEN
Cytogenetics can inform risk stratification in pediatric acute myeloid leukemia (AML). We describe the first case of a newborn with leukemia cutis found to have AML harboring a cryptic insertional t(8;16)(p11.2;p13.3) with associated KAT6A/CREBBP fusion identified exclusively by fluorescence in situ hybridization (FISH). Expectant management resulted in spontaneous leukemia resolution. The identification of t(8;16)(p11.2;p13.3) may serve as a biomarker for spontaneous remission in congenital AML. FISH for this translocation is warranted in congenital AML with a normal karyotype, and patients with KAT6A/CREBBP fusion should be conservatively managed. While 50% of spontaneously remitting congenital AML with t(8;16)(p11.2;p13.3) may recur, high salvage rates are attained with standard therapy.
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Proteína de Unión a CREB/genética , Histona Acetiltransferasas/genética , Leucemia Mieloide Aguda/congénito , Leucemia Mieloide Aguda/genética , Regresión Neoplásica Espontánea/genética , Translocación Genética/genética , Cromosomas Humanos Par 8/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipo , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Acute leukemia in adults is usually associated with a myeloid phenotype, and less commonly presents as an acute lymphocytic leukemia. Rarely, the leukemic blast cells express more than one lineage phenotype and satisfy the diagnostic criteria for an acute leukemia of ambiguous lineage (ALAL), further subclassified as mixed phenotype acute leukemia (MPAL). Near-tetraploidy is an unusual presentation of acute leukemia where the blasts contain 80-104 chromosomes. More commonly associated with acute lymphocytic leukemia, near-tetraploidy has been described in only a limited number of cases of acute myeloid leukemias, and near-tetraploid ALAL is rare. We describe the first report of near-tetraploid MPAL, B/myeloid, not otherwise specified.
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Childhood obesity is a growing health concern, associated with significant physical and psychological morbidity. Childhood obesity is known to have a strong genetic component, with mutations in the melanocortin-4 receptor (MC4R) gene being the most common monogenetic cause of obesity. Over 166 different MC4R mutations have been identified in persons with hyperphagia, severe childhood obesity, and increased linear growth. However, it is unclear whether the MC4-R deficiency phenotype is due to haploinsufficiency or dominant-negative effects by the mutant receptor. We report the case of a four-and-a-half-year-old boy with an interstitial deletion involving the long arm of chromosome 18 (46,XY,del(18)(q21.32q22.1)) encompassing the MC4R gene. This patient presented with tall stature and hyperphagia within his first 18 months of life leading to significant obesity. This case supports haploinsufficiency of MC4-R as it describes a MC4-R deficiency phenotype in a patient heterozygous for a full MC4R gene deletion. The intact functional allele with MC4-R haploinsufficiency has the potential to favor a therapeutic response to gastric surgery. Currently, small molecule MC4-R agonists are under development for pharmacologic therapy.
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PURPOSE: The authors report on a 7-year-old male, designated FR, who has severe sensorineural hearing loss. Features include a round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns regarding FR, all but his speech delay resolved when he was placed in an educational program that accommodated his hearing loss. Genetic studies were performed to investigate genetic causes for his hearing loss. METHOD: History, physical examination, audiologic assessment, and imaging were performed according to usual practice. FMR1,GJB2,GJB6, and POU3F4 genes were sequenced. Chromosomal studies consisted of karyotyping and breakpoint analysis by fluorescence in situ hybridization (FISH). RESULTS: Results from FMR1,GJB2,GJB6, and POU3F4 sequencing and echocardiography, electrocardiogram, and abdominal ultrasound were normal. A computed tomography (CT) scan revealed a large fundus of the internal auditory canals and absence of the bony partition between the fundus and the adjacent cochlear turns, with a widened modiolus bilaterally. FR's CT findings were consistent with those described in persons with X-linked deafness-2 (DFNX2) hereditary deafness. FR's karyotype was 46,inv(X)(q13q24),Y.ish inv(X)(XIST+)mat. FISH refined the breakpoints to inv(X)(q21.1q22.3). The Xq21.1 breakpoint was narrowed to a 25-kb region 450 kb centromeric to the DFNX2 gene, POU3F4. There are rare case reports of DFNX2 patients with chromosomal rearrangements positioned centromeric to POU3F4 and no mutations within the gene. CONCLUSION: Authors hypothesized that FR's hearing loss was caused by dysregulation of POU3F4 due to separation from regulatory elements affected by the inversion.
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Inversión Cromosómica , Cromosomas Humanos X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pérdida Auditiva Conductiva/genética , Pérdida Auditiva Sensorineural/genética , Factores del Dominio POU/genética , Niño , Conexina 26 , Conexinas , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Genotipo , Pérdida Auditiva Conductiva/fisiopatología , Pérdida Auditiva Sensorineural/fisiopatología , Humanos , Masculino , FenotipoRESUMEN
High-quality nursing care is not delivered consistently to the millions of Americans treated for invasive cancer in the United States. As part of its quality initiative, the Oncology Nursing Society (ONS) developed and tested nursing-sensitive quality measures for breast cancer care. Findings from the pilot testing suggested significant knowledge and practice gaps that could be addressed through member education.
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Educación Continua en Enfermería/organización & administración , Relaciones Enfermero-Paciente , Enfermería Oncológica , Mejoramiento de la Calidad , Educación Continua en Enfermería/normas , Proyectos Piloto , Recursos HumanosRESUMEN
This study aimed to explore the professional and personal impact that a clinical Masters program of manipulative therapy education had on the lives of individuals who had undertaken the course and was a follow-on study of participants' career pathways following Masters education (Green et al., 2008). Seven graduates from the program took part in a focus group. The narrative data obtained was independently verified prior to two researchers conducting a systematic, thematic content analysis. Three key themes were identified and the 'knowledge acquisition model' developed. Findings revealed that studying at Master's level is a 'life changing' and rewarding experience that develops individuals in three key domains; professionally, personally and intellectually. During Masters education students described a journey of multi-compartmental development whereby their knowledge-base was challenged and their existing cognitive framework deconstructed. Progression through the program resulted in the development of a new, clearer framework for thinking and understanding that extended, universally, into all aspects of their lives; clinically, managerially, emotionally, politically and intellectually. Participants also described two cultures for career progression in the UK National Health Service (NHS). Findings could help students considering undertaking Masters level education, employers and clinical mentors of these practitioners and academic educators.
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Educación Continua/organización & administración , Educación Profesional/métodos , Manipulaciones Musculoesqueléticas/educación , Competencia Clínica , Educación , Femenino , Grupos Focales , Humanos , Masculino , Modelos Educacionales , Evaluación de Programas y Proyectos de Salud , Control de Calidad , Reino UnidoRESUMEN
BACKGROUND: The majority of cardiac atrial neoplasms represent benign myxomas. Rarely, malignant cardiac neoplasms are encountered and can include primary cardiac neoplasms, as well as secondary tumors involving the heart. As many cardiac neoplasms lack pathognomonic clinical features, histopathologic diagnosis is crucial for classification and appropriate treatment of these neoplasms. Molecular investigation is critical to begin to catalogue genomic changes that correlate with these malignancies. METHODS: A 60-year-old man presented with superior vena cava syndrome, and computed tomographic scan revealed an infiltrative mass of the right atrium that nearly filled the atrial chamber and partially occluded superior vena cava flow. Urgent surgical resection revealed a soft mass with the appearance of "fish flesh." Histologic, immunochistochemical, cytogenetic, and detailed molecular investigations were carried out. RESULTS: Histologic examination revealed complete replacement of the atrial wall by diffuse sheets of pleomorphic lymphoid cells with occasional smaller plasmacytoid cells. The predominant lymphoid population was immunoreactive for CD45, CD20, CD79a, BCL-2, BCL-6, Ki-67, CD10, p53, and light chain restricted for IgM lambda. A diagnosis of primary cardiac diffuse large B-cell lymphoma with plasmacytoid differentiation was established and was supported by cytogenetic studies demonstrating the presence of a t(14;18)(q32;q21) translocation in addition to other chromosomal abnormalities. Fluorescence in situ hybridization revealed no evidence of a C-MYC translocation. CONCLUSION: In this single case, comparative genomic hybridization analysis using both bacterial artificial chromosome and oligonucleotide arrays correlated well with cytogenetic findings and allows for the cataloguing of more subtle genomic events.
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Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Neoplasias Cardíacas/genética , Hibridación Fluorescente in Situ/métodos , Linfoma/genética , Biomarcadores de Tumor/metabolismo , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , ADN de Neoplasias/análisis , Neoplasias Cardíacas/metabolismo , Neoplasias Cardíacas/patología , Neoplasias Cardíacas/cirugía , Humanos , Procesamiento de Imagen Asistido por Computador , Linfoma/metabolismo , Linfoma/patología , Linfoma/cirugía , Masculino , Persona de Mediana Edad , Translocación GenéticaRESUMEN
In response to concerns over provision of care for people with dementia, NICE and the Social Care Institute for Excellence (SCIE) developed a national guideline on supporting patients and carers. The clinical and support issues raised below are based on the NICE/SCIE (2006a) guidance on dementia. The guidance specifies nurses are key professionals in dementia care. Whether they work in mental health or elsewhere all nurses need to understand the guidance to enable sound implememtation across all caer settings.
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Demencia/diagnóstico , Demencia/enfermería , Diagnóstico Precoz , Necesidades y Demandas de Servicios de Salud , Humanos , Memoria , Reino UnidoRESUMEN
This two-part unit discusses the NICE and Social Care Institute for Excellence (SCIE) dementia guideline (2006). Part 1 outlines the clinical issue of dementia and can be used as a learning tool to aid recognition of signs of dementia and its risk factors.
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Demencia/diagnóstico , Demencia/epidemiología , Demencia/fisiopatología , Humanos , Pronóstico , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
PURPOSE: Follicular lymphoma is a common lymphoma of adults. Although its course is often indolent, a substantial proportion of patients have a poor prognosis, often due to rapid progression or transformation to a more aggressive lymphoma. Currently available clinical prognostic scores, such as the follicular lymphoma international prognostic index, are not able to optimally predict transformation or poor outcome. EXPERIMENTAL DESIGN: Gene expression profiling was done on primary lymphoma biopsy samples. RESULTS: Using a statistically conservative approach, predictive interaction analysis, we have identified pairs of interacting genes that predict poor outcome, measured as death within 5 years of diagnosis. The best gene pair performs >1,000-fold better than any single gene or the follicular lymphoma international prognostic index in our data set. Many gene pairs achieve outcome prediction accuracies exceeding 85% in extensive cross-validation and noise sensitivity computational analyses. Many genes repeatedly appear in top-ranking pairs, suggesting that they reproducibly provide predictive capability. CONCLUSIONS: The evidence reported here may provide the basis for an expression-based, multi-gene test for predicting poor follicular lymphoma outcomes.
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Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Over the last decade there has been potential for manual therapists to extend their roles and develop their careers. In order to explore the career pathways of a group of postgraduate manual therapists and to identify the influence of Master's education on those careers, a postal questionnaire was sent to all graduates from a clinically based programme (response rate 62.3%, n=48, with representation from each year over a 10-year period). All the respondents were still working in physiotherapy and the majority had a clinical element to their role (83%). The new career framework, which seeks to enable therapists to progress their careers and retain a clinical work load is demonstrated within this sample, with 6.2% achieving Consultant Therapist roles, 14.4% in Extended Scope Practitioner posts and 16.6% working as Clinical Specialists. Positive contributions from Master's education were the status of the qualification, improved clinical skills and increased confidence. Negative factors were less clinical 'hands-on' within their roles, lack of time and an increase in management responsibilities. Findings suggest that Master's education has enabled the participants to take on the new roles that have resulted from a raft of political imperatives but further work could explore the issues around positive and negative drivers.
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Movilidad Laboral , Educación de Postgrado , Manipulaciones Musculoesqueléticas/educación , Encuestas de Atención de la Salud , Humanos , Rol Profesional , Estudios Retrospectivos , Medicina Estatal , Reino UnidoRESUMEN
22q11.2 microduplications of a 3-Mb region surrounded by low-copy repeats should be, theoretically, as frequent as the deletions of this region; however, few microduplications have been reported. We show that the phenotype of these patients with microduplications is extremely diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. This diversity will make ascertainment difficult and will necessitate a rapid-screening method. We demonstrate the utility of four different screening methods. Although all the screening techniques give unique information, the efficiency of real-time polymerase chain reaction allowed the discovery of two 22q11.2 microduplications in a series of 275 females who tested negative for fragile X syndrome, thus widening the phenotypic diversity. Ascertainment of the fragile X-negative cohort was twice that of the cohort screened for the 22q11.2 deletion. We also report the first patient with a 22q11.2 triplication and show that this patient's mother carries a 22q11.2 microduplication. We strongly recommend that other family members of patients with 22q11.2 microduplications also be tested, since we found several phenotypically normal parents who were carriers of the chromosomal abnormality.
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Cromosomas Humanos Par 22 , Duplicación de Gen , Variación Genética , Anomalías Múltiples/genética , Adulto , Niño , Preescolar , Femenino , Síndrome del Cromosoma X Frágil/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Repeticiones de Microsatélite , Reacción en Cadena de la Polimerasa , SíndromeRESUMEN
Mutations of the RET proto-oncogene are found in the majority of patients with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). A minority of cases, however, have no detectable RET mutation and there is considerable phenotypic variation within and among MEN 2 families with the same RET mutation, suggesting a role for other loci in this disease. A candidate for such a gene is glial cell line-derived neurotrophic factor receptor alpha 4 (GFRA4), which encodes a cell surface-bound co-receptor (GFR alpha 4) required for interaction of RET with its ligand persephin. The GFRA4 gene has multiple alternative splices leading to three distinct protein isoforms that are prominently expressed in thyroid. We postulated that mutations of GFRA4 contribute to MEN 2 in the absence of RET mutations or modify the RET mutation phenotype. We screened patients with MEN 2 or MEN 2-like phenotypes, with and without RET mutations, for variants of GFRA4. We identified 10 variants, one of which was over represented in, and two of which were found exclusively in, our patient populations. One of these was a single-base substitution upstream of the GFR alpha 4 coding region, where it may alter gene expression. The second was a 7 bp insertion, which results in a change in reading frame for all three GFR alpha 4 isoforms. This would cause a relative shift in membrane bound and soluble forms of GFR alpha 4, which would significantly alter the formation of RET signalling complexes. Our data suggest a model of wild-type GFR alpha 4 isoform expression that includes both activating and inhibiting co-receptors for RET.
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Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/farmacología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2b/genética , Receptores de Factor de Crecimiento Nervioso/genética , Secuencia de Aminoácidos , Regulación de la Expresión Génica , Pruebas Genéticas , Genotipo , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Humanos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso , Reacción en Cadena de la Polimerasa , Isoformas de Proteínas , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/farmacología , Proteínas Proto-Oncogénicas c-ret , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/farmacología , Transducción de SeñalRESUMEN
Evaluation of six pilot schemes using specialist GPs to provide ENT services in the community suggests these innovations are popular with patients and have the potential to reduce waiting times. Waiting times in one area, where a specialist GP had been in post for three years, were down to 24 days. The schemes need champions in primary and secondary care and must fit well with the strategy of the local health economy.