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OBJECTIVES: To characterize and elucidate the spread of amikacin-resistant Enterobacteriaceae isolates from environmental samples on a pig farm in the UK, following the previous identification of index Salmonella isolates harbouring the rmtB gene, a 16S rRNA methylase. METHODS: Environmental samples were collected during two visits to a pig farm in the UK. Isolates were recovered using selective media (amikacin 128 mg/L) followed by real-time PCR and WGS to analyse rmtB-carrying Salmonella and Escherichia coli isolates. RESULTS: Salmonella and E. coli isolates harbouring the rmtB gene were detected at both farm visits. All Salmonella isolates were found to be monophasic S. enterica serovar Typhimurium variant Copenhagen of ST34. rmtB-harbouring E. coli isolates were found to be one of three STs: ST4089, ST1684 and ST34. Long-read sequencing identified the rmtB gene to be chromosomally located in Salmonella isolates and on IncFII-type plasmids in E. coli isolates. The results showed the rmtB gene to be flanked by IS26 elements and several resistance genes. CONCLUSIONS: We report on the occurrence of rmtB-harbouring Enterobacteriaceae on a pig farm in the UK. rmtB confers resistance to multiple aminoglycosides and this work highlights the need for surveillance to assess dissemination and risk.
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Antibacterianos , Escherichia coli , Granjas , Metiltransferasas , Salmonella , Animales , Porcinos/microbiología , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/aislamiento & purificación , Escherichia coli/clasificación , Antibacterianos/farmacología , Reino Unido , Salmonella/genética , Salmonella/efectos de los fármacos , Salmonella/aislamiento & purificación , Salmonella/clasificación , Metiltransferasas/genética , Pruebas de Sensibilidad Microbiana , Amicacina/farmacología , Secuenciación Completa del Genoma , Plásmidos/genética , Farmacorresistencia Bacteriana/genética , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/veterinaria , Enfermedades de los Porcinos/microbiología , Proteínas de Escherichia coli/genéticaRESUMEN
INTRODUCTION: Disparities in the health of Indigenous people and in the health of rural populations are well described. University Departments of Rural Health (UDRHs) in Australia are federally funded under a program to address ongoing challenges with health workforce distribution for rural and remote areas. They have a significant role in research in regional, rural and remote areas, including research related to Indigenous health. However, a comprehensive analysis of their contributions to original Indigenous health related to Indigenous health is lacking. OBJECTIVE: This study examines the contributions of UDRHs to Indigenous issues through analysis of publications of UDRHs focused on Indigenous health during the period 2010-2021. DESIGN: This paper examines a database of UDRH Indigenous-related publications from 2010 to 2021. FINDINGS: A total of 493 publications to which UDRHs contributed were analysed, including 354 original research articles. Health services research was the most common category, followed by epidemiology and papers exploring Indigenous culture and health. While health services research substantially increased over the period, the numbers of original research papers specifically focused on Indigenous workforce issues, whether related to Indigenous people, students or existing workforce was relatively small. DISCUSSION: This broad overview shows the nature and trends in Indigenous health research by UDRHs and makes evident a substantial contribution to Indigenous health research, reflecting their commitment to improving the health and well-being of Indigenous communities. CONCLUSIONS: The analysis can help direct future efforts, and future analyses should delve deeper into the impact of this research and further engage Indigenous researchers.
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Abstract. BACKGROUND: Chronic muscle diseases (MD) are progressive and cause wasting and weakness in muscles and are associated with reduced quality of life (QoL). The ACTMuS trial examined whether Acceptance and Commitment Therapy (ACT) as an adjunct to usual care improved QoL for such patients as compared to usual care alone. METHODS: This two-arm, randomised, multicentre, parallel design recruited 155 patients with MD (Hospital and Depression Scale ⩾ 8 for depression or ⩾ 8 for anxiety and Montreal Cognitive Assessment ⩾ 21/30). Participants were randomised, using random block sizes, to one of two groups: standard medical care (SMC) (n = 78) or to ACT in addition to SMC (n = 77), and were followed up to 9 weeks. The primary outcome was QoL, assessed by the Individualised Neuromuscular Quality of Life Questionnaire (INQoL), the average of five subscales, at 9-weeks. Trial registration was NCT02810028. RESULTS: 138 people (89.0%) were followed up at 9-weeks. At all three time points, the adjusted group difference favoured the intervention group and was significant with moderate to large effect sizes. Secondary outcomes (mood, functional impairment, aspects of psychological flexibility) also showed significant differences between groups at week 9. CONCLUSIONS: ACT in addition to usual care was effective in improving QoL and other psychological and social outcomes in patients with MD. A 6 month follow up will determine the extent to which gains are maintained.
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Terapia de Aceptación y Compromiso , Humanos , Calidad de Vida , Enfermedad Crónica , Encuestas y Cuestionarios , Músculos , Análisis Costo-BeneficioRESUMEN
BACKGROUND: One in five children with an intellectual disability in the UK display behaviours that challenge. Despite associated impacts on the children themselves, their families, and services, little research has been published about how best to design, organise, and deliver health and care services to these children. The purpose of this study was to describe how services are structured and organised ("service models") in England for community-based health and care services for children with intellectual disability who display behaviours that challenge. METHODS: Survey data about services were collected from 161 eligible community-based services in England. Staff from 60 of these services were also interviewed. A combination of latent class and descriptive analysis, coupled with consultation with family carers and professionals was used to identify and describe groupings of similar services (i.e., "service models"). RESULTS: The latent class analysis, completed as a first step in the process, supported a distinction between specialist services and non-specialist services for children who display behaviours that challenge. Planned descriptive analyses incorporating additional study variables were undertaken to further refine the service models. Five service models were identified: Child and Adolescent Mental Health Services (CAMHS) (n = 69 services), Intellectual Disability CAMHS (n = 28 services), Children and Young People Disability services (n = 25 services), Specialist services for children who display behaviours that challenge (n = 27 services), and broader age range services for children and/or adolescents and adults (n= 12 services). CONCLUSIONS: Our analysis led to a typology of five service models for community health and care services for children with intellectual disabilities and behaviours that challenge in England. Identification of a typology of service models is a first step in building evidence about the best provision of services for children with intellectual disabilities who display behaviours that challenge. The methods used in the current study may be useful in research developing service typologies in other specialist fields of health and care. STUDY REGISTRATION: Trial Registration: Current Controlled Trials ISRCTN88920546, Date assigned 05/07/2022.
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Discapacidad Intelectual , Adulto , Adolescente , Humanos , Niño , Discapacidad Intelectual/terapia , Discapacidad Intelectual/psicología , Servicios de Salud Comunitaria , Inglaterra , Cuidadores/psicología , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Paratuberculosis, commonly known as Johne's disease, is a chronic granulomatous infection of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP). Clinical signs, including reduced milk yields, weight loss and diarrhoea, are typically absent until 2 to 6 years post exposure. OBJECTIVES: To identify metabolomic changes profiles of MAP challenged Holstein-Friesian (HF) cattle and correlate identified metabolites to haematological and immunological parameters. METHODS: At approximately 6 weeks of age, calves (n = 9) were challenged with 3.8 × 109 cells of MAP (clinical isolate CIT003) on 2 consecutive days. Additional unchallenged calves (n = 9) formed the control group. The study used biobanked serum from cattle sampled periodically from 3- to 33-months post challenge. The assessment of sera using flow infusion electrospray high resolution mass spectrometry (FIE-HRMS) for high throughput, sensitive, non-targeted metabolite fingerprinting highlighted differences in metabolite levels between the two groups. RESULTS: In total, 25 metabolites which were differentially accumulated in MAP challenged cattle were identified, including 20 which displayed correlation to haematology parameters, particularly monocyte levels. CONCLUSION: The targeted metabolites suggest shifts in amino acid metabolism that could reflect immune system activation linked to MAP and as well as differences in phosphocholine levels which could reflect activation of the Th1 (tending towards pro-inflammatory) immune response. If verified by future work, selected metabolites could be used as biomarkers to diagnose and manage MAP infected cattle.
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Enfermedades de los Bovinos , Mycobacterium avium subsp. paratuberculosis , Paratuberculosis , Aminoácidos , Animales , Bovinos , Enfermedades de los Bovinos/diagnóstico , Sistema Inmunológico/metabolismo , Metabolómica , Paratuberculosis/diagnóstico , Paratuberculosis/microbiologíaRESUMEN
Mycobacterium avium subspecies paratuberculosis (MAP) is the causative organism of Johne's disease, a chronic granulomatous enteritis of ruminants. We have previously used naturally MAP-infected heifer calves to document metabolomic changes occurring in MAP infections. Herein, we used experimentally MAP-inoculated heifer calves to identify biomarkers for MAP infections. At 2-weeks of age, 20 Holstein-Friesian (HF) calves were experimentally inoculated with MAP. These calves, along with 20 control calves, were sampled biweekly up to 13-months of age and then monthly up to 19-months of age. Sera were assessed using flow infusion electrospray high-resolution mass spectrometry (FIE-HRMS) on a Q Exactive hybrid quadrupole-Orbitrap mass spectrometer for high throughput, sensitive, non-targeted metabolite fingerprinting. Partial least squares-discriminate analysis (PLS-DA) and hierarchical cluster analysis (HCA) discriminated between MAP-inoculated and control heifer calves. Out of 34 identified metabolites, six fatty acyls were able to differentiate between experimental groups throughout the study, including 8, 11, 14-eicosatrienoic acid and cis-8, 11, 14, 17-eicosatetraenoic acid which were also detected in our previous study and so further suggested their value as biomarkers for MAP infection. Pathway analysis highlighted the role of the alpha-linoleic acid and linoleic acid metabolism. Within these pathways, two broad types of response, with a rapid increase in some saturated fatty acids and some n-3 polyunsaturated fatty acids (PUFAs) and later n-6 PUFAs, became predominant. This could indicate an initial anti-inflammatory colonisation phase, followed by an inflammatory phase. This study demonstrates the validity of the metabolomic approach in studying MAP infections. Nevertheless, further work is required to define further key events, particularly at a cell-specific level.
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Enfermedades de los Bovinos , Mycobacterium avium subsp. paratuberculosis , Paratuberculosis , Animales , Biomarcadores , Bovinos , Enfermedades de los Bovinos/microbiología , Eicosanoides , Ácidos Grasos Insaturados , Femenino , Ácidos Linoleicos , Mycobacterium avium subsp. paratuberculosis/fisiología , Paratuberculosis/diagnóstico , Paratuberculosis/microbiologíaRESUMEN
OBJECTIVES: To determine the prevalence of 16S rRNA methyltransferase- (16S RMTase-) producing Gram-negative bacteria in patients in the UK and to identify potential risk factors for their acquisition. METHODS: A 6 month prospective surveillance study was conducted from 1 May to 31 October 2016, wherein 14 hospital laboratories submitted Acinetobacter baumannii, Enterobacterales and Pseudomonas aeruginosa isolates that displayed high-level amikacin resistance according to their testing methods, e.g. no zone of inhibition with amikacin discs. Isolates were linked to patient travel history, medical care abroad, and previous antibiotic exposure using a surveillance questionnaire. In the reference laboratory, isolates confirmed to grow on Mueller-Hinton agar supplemented with 256 mg/L amikacin were screened by PCR for 16S RMTase genes armA, rmtA-rmtH and npmA, and carbapenemase genes (blaKPC, blaNDM, blaOXA-48-like and blaVIM). STs and total antibiotic resistance gene complement were determined via WGS. Prevalence was determined using denominators for each bacterial species provided by participating hospital laboratories. RESULTS: Eighty-four isolates (44.7%), among 188 submitted isolates, exhibited high-level amikacin resistance (MIC >256 mg/L), and 79 (94.0%) of these harboured 16S RMTase genes. armA (54.4%, 43/79) was the most common, followed by rmtB (17.7%, 14/79), rmtF (13.9%, 11/79), rmtC (12.7%, 10/79) and armA + rmtF (1.3%, 1/79). The overall period prevalence of 16S RMTase-producing Gram-negative bacteria was 0.1% (79/71â063). Potential risk factors identified through multivariate statistical analysis included being male and polymyxin use. CONCLUSIONS: The UK prevalence of 16S RMTase-producing Gram-negative bacteria is low, but continued surveillance is needed to monitor their spread and inform intervention strategies.
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Farmacorresistencia Bacteriana , Bacterias Gramnegativas , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Bacterias Gramnegativas/genética , Humanos , Masculino , Metiltransferasas/genética , Pruebas de Sensibilidad Microbiana , Prevalencia , Estudios Prospectivos , ARN Ribosómico 16S/genética , Reino Unido/epidemiología , beta-Lactamasas/genéticaRESUMEN
BACKGROUND: Improving health outcomes for Indigenous people by providing person-centred, culturally safe care is a crucial challenge for the health sector, both in Australia and internationally. Many cancer providers and support services are committed to providing high quality care, yet struggle with providing accessible, culturally safe cancer care to Indigenous Australians. Two Australian cancer services, one urban and one regional, were identified as particularly focused on providing culturally safe cancer care for Indigenous cancer patients and their families. The article explores the experiences of Indigenous cancer patients and their families within the cancer services and ascertains how their experiences of care matches with the cancer services' strategies to improve care. METHODS: Services were identified as part of a national study designed to identify and assess innovative services for Indigenous cancer patients and their families. Case studies were conducted with a small number of identified services. In-depth interviews were conducted with Indigenous people affected by cancer and hospital staff. The interviews from two services, which stood out as particularly high performing, were analysed through the lens of the patient experience. RESULTS: Eight Indigenous people affected by cancer and 23 hospital staff (Indigenous and non-Indigenous) were interviewed. Three experiences were shared by the majority of Indigenous cancer patients and family members interviewed in this study: a positive experience while receiving treatment at the cancer service; a challenging time between receiving diagnosis and reaching the cancer centre; and the importance of family support, while acknowledging the burden on family and carers. CONCLUSIONS: This article is significant because it demonstrates that with a culturally appropriate and person-centred approach, involving patients, family members, Indigenous and non-Indigenous staff, it is possible for Indigenous people to have positive experiences of cancer care in mainstream, tertiary health services. If we are to improve health outcomes for Indigenous people it is vital more cancer services and hospitals follow the lead of these two services and make a sustained and ongoing commitment to strengthening the cultural safety of their service.
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Servicios de Salud del Indígena , Neoplasias , Australia , Hospitales , Humanos , Nativos de Hawái y Otras Islas del Pacífico , Neoplasias/terapia , Calidad de la Atención de SaludRESUMEN
A phenotype is emerging for the proximal pair of G-dark bands in 11q (11q14.1 and q14.3) but not yet for the distal pair (11q22.1 and q22.3). A mother and daughter with the same directly transmitted 12.3-Mb interstitial deletion of 11q21q22.3 (GRCh37: 93,551,765-105,817,723) both had initial feeding difficulties and failure to thrive, speech delay, learning difficulties, and mild dysmorphism. Among 17 patients with overlapping deletions, developmental or speech delay, dysmorphism, hypotonia, intellectual disability or learning difficulties, short stature, and coloboma were each found in 2 or more. These results may provide the basis for a consistent phenotype for this region. Among the 53 deleted and additional breakpoint genes, CNTN5, YAP1, and GRI4 were the most likely candidates. Non-penetrance of haploinsufficient genes and dosage compensation among related genes may account for the normal cognition in the mother and variable phenotypes that can extend into the normal range.
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Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Anomalías Múltiples/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Contactinas/genética , Femenino , Humanos , Fenotipo , Receptores AMPA/genética , Factores de Transcripción/genética , Proteínas Señalizadoras YAPRESUMEN
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
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Inmunidad Adaptativa/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia , Melanoma/terapia , Modelos Biológicos , Anciano , Anciano de 80 o más Años , Biomarcadores , Linfocitos T CD8-positivos/citología , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Análisis Multivariante , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Resultado del TratamientoRESUMEN
Mutants with enhanced growth in the presence of an antibiotic are more difficult to identify than mutants where the antibiotic's MIC increases, because they are not amenable to lethal selection in vitro We report that activatory mutations in the CreC signal sensor enhance growth of Escherichia coli in the presence of cefoxitin, cefotaxime, and meropenem, without increasing their MICs. Enhanced growth is dependent on overproduction of the inner membrane cre regulon protein CreD.
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Antibacterianos/farmacología , Carbapenémicos/farmacología , Cefalosporinas/farmacología , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Proteínas Quinasas/genética , Cefoxitina/farmacología , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Regulón/genética , beta-Lactamasas/genéticaRESUMEN
BACKGROUND: Indigenous Australians are under-represented in the health workforce, with large disparities between rates of Indigenous and non-Indigenous people in every health profession, including nurses, medical practitioners and all allied health professionals. Yet Indigenous people have long requested to have Indigenous practitioners involved in their health care, with this increasing the likelihood of culturally safe care. To address the shortage of Indigenous health professionals, it is important to not only recruit more Indigenous people into health courses, but also to support them throughout their studies so that they graduate as qualified health professionals. The aim of this systematic literature review was two-fold: to identify the factors affecting the retention of Indigenous students across all tertiary health disciplines, and to identify strategies that support Indigenous students to remain with, and successfully complete, their studies. METHODS: Eight electronic databases were systematically searched between July and September 2018. Articles were screened for inclusion using pre-defined criteria and assessed for quality using the Mixed Methods Assessment Tool and the Joanna Briggs Institute Checklist for Text and Opinion. RESULTS: Twenty-six articles met the criteria for inclusion. Key factors reported by students as affecting retention were: family and peer support; competing obligations; academic preparation and prior educational experiences; access to the Indigenous Student Support Centre; financial hardship; and racism and discrimination. The most successful strategies implemented by nursing, health and medical science faculties to improve retention were multi-layered and included: culturally appropriate recruitment and selection processes; comprehensive orientation and pre-entry programs; building a supportive and enabling school culture; appointing Indigenous academics; embedding Indigenous content throughout the curriculum; developing mentoring and tutoring programs; flexible delivery of content; partnerships with the Indigenous Student Support Centre; providing social and financial support; and 'leaving the university door open' for students who leave before graduation to return. CONCLUSIONS: Universities have an important role to play in addressing inequities in the Indigenous health workforce. A suite of measures implemented concurrently to provide support, starting with recruitment and pre-entry preparation programs, then continuing throughout the student's time at university, can enable talented Indigenous people to overcome adversities and graduate as health professionals.
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Nativos de Hawái y Otras Islas del Pacífico/psicología , Abandono Escolar/estadística & datos numéricos , Estudiantes del Área de la Salud/psicología , Australia , Humanos , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Factores de Riesgo , Estudiantes del Área de la Salud/estadística & datos numéricosRESUMEN
BACKGROUND: Indigenous peoples in developed countries have reduced life expectancies, particularly from chronic diseases. The lack of access to and take up of palliative care services of Indigenous peoples is an ongoing concern. OBJECTIVES: To examine and learn from published studies on provision of culturally safe palliative care service delivery to Indigenous people in Australia, New Zealand (NZ), Canada and the United States of America (USA); and to compare Indigenous peoples' preferences, needs, opportunities and barriers to palliative care. METHODS: A comprehensive search of multiple databases was undertaken. Articles were included if they were published in English from 2000 onwards and related to palliative care service delivery for Indigenous populations; papers could use quantitative or qualitative approaches. Common themes were identified using thematic synthesis. Studies were evaluated using Daly's hierarchy of evidence-for-practice in qualitative research. RESULTS: Of 522 articles screened, 39 were eligible for inclusion. Despite diversity in Indigenous peoples' experiences across countries, some commonalities were noted in the preferences for palliative care of Indigenous people: to die close to or at home; involvement of family; and the integration of cultural practices. Barriers identified included inaccessibility, affordability, lack of awareness of services, perceptions of palliative care, and inappropriate services. Identified models attempted to address these gaps by adopting the following strategies: community engagement and ownership; flexibility in approach; continuing education and training; a whole-of-service approach; and local partnerships among multiple agencies. Better engagement with Indigenous clients, an increase in number of palliative care patients, improved outcomes, and understanding about palliative care by patients and their families were identified as positive achievements. CONCLUSIONS: The results provide a comprehensive overview of identified effective practices with regards to palliative care delivered to Indigenous populations to guide future program developments in this field. Further research is required to explore the palliative care needs and experiences of Indigenous people living in urban areas.
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Atención a la Salud/métodos , Servicios de Salud del Indígena/normas , Cuidados Paliativos/métodos , Australia , Canadá , Atención a la Salud/normas , Humanos , Nueva Zelanda , Cuidados Paliativos/estadística & datos numéricos , Estados UnidosRESUMEN
Leri-Weill dyschondrosteosis is a pseudoautosomal dominantly-inherited skeletal dysplasia ascribed to haploinsufficiency of the SHOX gene caused by deletions, point mutations, or partial duplications of the gene, or to heterozygous deletions upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements that show enhancer activity. Recently, two SHOX conserved non-coding element duplications, one upstream and one downstream, were reported in patients referred with idiopathic short stature. To further evaluate the role of these duplications in SHOX-related disorders, we describe seven patients (five with Leri-Weill dyschondrosteosis and two with short stature) all of whom have duplications of part of the upstream or downstream conserved non-coding element regions, identified by multiplex ligation-dependent probe amplification. In addition, we show data from 32 patients with an apparently identical downstream duplication that includes a proposed putative regulatory element (identified by multiplex ligation-dependent probe amplification or array comparative genome hybridization), which results in a variable phenotype from normal to mild Leri-Weill dyschondrosteosis. These additional data provide further evidence that duplications of upstream and downstream long range cis-regulatory DNA elements can result in a SHOX-related phenotype.
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Duplicación Cromosómica , Enanismo/diagnóstico , Enanismo/genética , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Proteínas de Homeodominio/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Hibridación Genómica Comparativa , Femenino , Haplotipos , Humanos , Masculino , Mutación , Linaje , Fenotipo , Proteína de la Caja Homeótica de Baja Estatura , Adulto JovenRESUMEN
There is currently minimal data on fertility outcomes in premenopausal women undergoing autologous stem cell transplant (ASCT) with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. A retrospective analysis of fertility outcomes in premenopausal females aged between 18 and 40 yr who underwent BEAM/ASCT for lymphoma between 1995 and 2011 was performed at four transplant centres. Of 41 premenopausal women who underwent BEAM conditioning, 25 met the inclusion criteria with the main exclusion criterion being inadequate documentation. Eighteen had Hodgkin lymphoma, and seven had non-Hodgkin lymphoma. Median number of chemotherapy regimens pretransplant was 2 (1-3). Seventeen women (68%) with a median age at transplant of 25 yr (range 17-33) recovered their menses. The comparative group without recovery was older with a median age of 34 yr (range 20-40) (P = 0.007). Ten patients, with a median age at transplant of 22 yr (range 17-30), had 15 naturally conceived pregnancies. Chemotherapy regimens and lymphoma type did not obviously influence the incidence of menses recovery or conception. The incidence of recovery of menses and fertility in premenopausal women undergoing BEAM/ASCT for lymphoma is substantial. Younger age at transplant correlates with superior fertility outcomes.
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Fertilidad , Trasplante de Células Madre Hematopoyéticas , Premenopausia , Acondicionamiento Pretrasplante , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carmustina/efectos adversos , Carmustina/uso terapéutico , Citarabina/efectos adversos , Citarabina/uso terapéutico , Femenino , Fertilidad/efectos de los fármacos , Humanos , Linfoma/terapia , Melfalán/efectos adversos , Melfalán/uso terapéutico , Podofilotoxina/efectos adversos , Podofilotoxina/uso terapéutico , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Adulto JovenRESUMEN
Clinical experience with the impact of serum biomarkers for invasive fungal disease (IFD) varies markedly in hemato-oncology. Invasive pulmonary aspergillosis (IPA) is the most common manifestation, so we evaluated biomarkers in bronchoalveolar lavage (BAL) fluid. An Aspergillus-specific lateral-flow device (LFD), quantitative real-time PCR (qPCR), and the galactomannan (GM) test were used with 32 BAL fluid samples from 32 patients at risk of IPA. Eight patients had proven IPA, 3 had probable IPA, 6 had possible IPA, and 15 patients had no IPA by European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group/Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (EORTC/MSG) criteria. The diagnostic accuracies of the tests were evaluated, and pairwise agreement between biomarkers was calculated. The diagnostic performance of the EORTC/MSG criteria was evaluated against the test(s) identified to be the most useful for IPA diagnosis. Using the EORTC/MSG criteria, the sensitivities of qPCR and LFD were 100% and the sensitivity of the GM test was 87.5% (GM test index cutoff, >0.8), with the tests having specificities of between 66.7 and 86.7%. The agreement between the results of qPCR and LFD was almost perfect (Cohen's kappa coefficient = 0.93, 95% confidence interval, 0.81 to 1.00). LFD and qPCR combined had a sensitivity of 100% and a specificity of 85.7%. Calcofluor staining and culture of all BAL fluid samples were negative for fungal infection. The median time from the start of mold-active antifungal therapy to the time of collection of BAL fluid was 6 days. Reversing roles and using dual testing by LFD and qPCR to classify cases, the EORTC/MSG criteria had a sensitivity of 83.3%. All three tests are useful for the diagnosis of IPA in BAL fluid samples. Despite the significant delays between the start of antifungal therapy and bronchoscopy, unlike microscopy and culture, the biomarkers remained informative. In particular, the combination of LFD and qPCR allows the sensitive and specific detection of IPA.
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Biomarcadores/análisis , Líquido del Lavado Bronquioalveolar/microbiología , Cromatografía de Afinidad/métodos , Aspergilosis Pulmonar Invasiva/diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Adulto , Antígenos Fúngicos/análisis , Antígenos Fúngicos/inmunología , ADN de Hongos/análisis , ADN de Hongos/genética , Humanos , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors.
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Anomalías Múltiples/genética , Cromosomas Humanos Par 8/genética , Discapacidades del Desarrollo/genética , Duplicación de Gen/genética , Adolescente , Niño , Preescolar , Deleción Cromosómica , Femenino , Factor de Transcripción GATA4/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Masculino , SíndromeRESUMEN
BACKGROUND: The optimal reduction of immunosuppressive therapy (IST) in renal transplant patients with post-transplant lymphoproliferative disorders (PTLDs) is uncertain. As chemotherapy is immunosuppressive, IST may be stopped during this time without compromising graft function. Subsequent long-term reduction of IST reduces relapse risk, but may increase risk of graft rejection. METHODS: We performed a retrospective, matched cohort study of adult renal transplant patients in whom IST was ceased during chemotherapy and resumed at lower dose (calcineurin inhibitor at 50%, prednisolone ≤10 mg daily, no third agent) approximately 6 weeks after chemotherapy. Outcomes were compared with those of renal transplant patients without PTLD, matched for creatinine at equivalent time post-transplant that PTLD was diagnosed in cases, as well as for age, gender and year of transplant. RESULTS: Twenty-four cases of PTLD occurring at a median of 9.2 years post-transplant were compared with 83 matched controls. PTLD cases were followed for a median of 11.9 years. Using competing risks analysis, time to 25% increase in serum creatinine was not significantly different between the two groups [adjusted hazard ratio (HR) 1.8, 95% confidence interval (CI) 0.89-3.6]. Similar results were obtained using multivariable Cox regression analysis (HR 1.19, 95% CI 0.44-3.23). Only one PTLD case experienced a ≥25% increase in creatinine <6 months after IST cessation in the setting of progressive PTLD and death. Three cases recommenced dialysis, compared with three controls (HR 2.5, 95% CI 0.47-13.00). Five-year patient survival rates for cases and controls were 70 and 94%, respectively (P = 0.01). CONCLUSIONS: IST can be safely ceased during chemotherapy for PTLD in renal transplant patients. Furthermore, long-term reduction in IST is not associated with a significant difference in renal function deterioration. Prospective trials are needed to address the optimal reduction of IST in PTLDs.
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Antineoplásicos/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/administración & dosificación , Trasplante de Riñón/efectos adversos , Trastornos Linfoproliferativos/tratamiento farmacológico , Privación de Tratamiento , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Rechazo de Injerto/etiología , Rechazo de Injerto/mortalidad , Humanos , Tolerancia Inmunológica , Huésped Inmunocomprometido , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: The term severe acute respiratory infection (SARI) encompasses a heterogeneous group of respiratory illnesses. Grading the severity of SARI is currently reliant on indirect disease severity measures such as respiratory and heart rate, and the need for oxygen or intensive care. With the lungs being the primary organ system involved in SARI, chest radiographs (CXRs) are potentially useful for describing disease severity. Our objective was to develop and validate a SARI CXR severity scoring system. METHODS: We completed validation within an active SARI surveillance project, with SARI defined using the World Health Organization case definition of an acute respiratory infection with a history of fever, or measured fever of ≥ 38 °C; and cough; and with onset within the last 10 days; and requiring hospital admission. We randomly selected 250 SARI cases. Admission CXR findings were categorized as: 1 = normal; 2 = patchy atelectasis and/or hyperinflation and/or bronchial wall thickening; 3 = focal consolidation; 4 = multifocal consolidation; and 5 = diffuse alveolar changes. Initially, four radiologists scored CXRs independently. Subsequently, a pediatrician, physician, two residents, two medical students, and a research nurse independently scored CXR reports. Inter-observer reliability was determined using a weighted Kappa (κ) for comparisons between radiologists; radiologists and clinicians; and clinicians. Agreement was defined as moderate (κ > 0.4-0.6), good (κ > 0.6-0.8) and very good (κ > 0.8-1.0). RESULTS: Agreement between the two pediatric radiologists was very good (κ = 0.83, 95% CI 0.65-1.00) and between the two adult radiologists was good (κ = 0.75, 95% CI 0.57-0. 93). Agreement of the clinicians with the radiologists was moderate-to-good (pediatrician:κ = 0.65; pediatric resident:κ = 0.69; physician:κ = 0.68; resident:κ = 0.67; research nurse:κ = 0.49, medical students: κ = 0.53 and κ = 0.56). Agreement between clinicians was good-to-very good (pediatrician vs. physician:κ = 0.85; vs. pediatric resident:κ = 0.81; vs. medicine resident:κ = 0.76; vs. research nurse:κ = 0.75; vs. medical students:κ = 0.63 and 0.66). Following review of discrepant CXR report scores by clinician pairs, κ values for radiologist-clinician agreement ranged from 0.59 to 0.70 and for clinician-clinician agreement from 0.97 to 0.99. CONCLUSIONS: This five-point CXR scoring tool, suitable for use in poorly- and well-resourced settings and by clinicians of varying experience levels, reliably describes SARI severity. The resulting numerical data enables epidemiological comparisons of SARI severity between different countries and settings.
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Radiografía Torácica/normas , Infecciones del Sistema Respiratorio/diagnóstico por imagen , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: The clinical features, management, and prognosis of stage I-II diffuse large B-cell lymphoma of the bone (PB-DLBCL) included in an international database of 499 lymphoma patients with skeletal involvement were reviewed. METHODS: HIV-negative patients (n = 161) with diffuse large B-cell lymphoma of the bone (PB-DLBCL) after complete staging workup were considered. The primary objective of this study was to identify the most effective treatment modality; the secondary objectives were to define the contribution of irradiation fields and doses and the pattern of relapse. RESULTS: Median age was 55 years (range, 18-99 years), with a male/female ratio of 1:2; 141 (87%) patients had stage I, 14 (9%) had B symptoms, 37 (23%) had bulky lesion, 54 (33%) showed elevated lactate dehydrogenase serum levels, and 25 (15%) had fracture. Thirteen (8%) patients received chemotherapy alone, 23 (14%) received radiotherapy alone, and 125 (78%) received both treatments. The response to the first-line treatment was complete in 131 of 152 assessed patients (complete response rate, 86%; 95% confidence interval [CI], 81%-91%) and partial in 7, with an overall response rate of 91% (95% CI, 87%-95%). At a median follow-up of 54 months (range, 3-218), 107 (67%) patients remained relapse-free, with a 5-year progression-free survival of 68% (SE: 4). Four (2.5%) patients had meningeal relapse; 119 patients were alive (113 disease-free), with a 5-year overall survival of 75% (SE: 4). Patients managed with primary chemotherapy, whether followed by radiotherapy or not, had a significantly better outcome than patients treated with primary radiotherapy, whether followed by chemotherapy or not. The addition of consolidative radiotherapy after primary chemotherapy was not associated with improved outcome; doses >36 Gy and the irradiation of the whole affected bone were not associated with better outcome. CONCLUSION: Patients with PB-DLBCL exhibit a favorable prognosis when treated with primary anthracycline-based chemotherapy whether followed by radiotherapy or not. In patients treated with chemoradiotherapy, the use of larger radiation fields and doses is not associated with better outcome. Central nervous system dissemination is a rare event in PB-DLBCL patients.