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RESEARCH QUESTION: Can microbes vertically transmit from semen and follicular fluid to embryo culture media during assisted reproductive technology (ART) treatment? DESIGN: Spent embryo culture media (SECM), seminal fluid and follicular fluid samples were collected from 61 couples with infertility undergoing ART treatment at the Prince of Wales Hospital, Hong Kong SAR, China. Metagenomic analysis was conducted using 16s rRNA sequencing to identify the source of microbes in SECM, correlation between the semen microbiome and male infertility, and correlation between the follicular fluid microbiome and female infertility. RESULTS: Microbial vertical transmission into SECM was reported in 82.5% of cases, and semen was the main source of contamination in conventional IVF cases. The increased abundances of Staphylococcus spp. and Streptococcus anginosus in semen had negative impacts on total motility and sperm count, respectively (P < 0.001). Significant increases in abundance of the genera Prophyromonas, Neisseria and Facklamia were observed in follicular fluid in women with anovulation, uterine factor infertility and unexplained infertility, respectively (P < 0.01). No significant correlation was found between the bacteria identified in all sample types and ART outcomes, including fertilization rate, embryo development, number of available embryos, and clinical pregnancy rate. CONCLUSION: Embryo culture media can be contaminated during ART treatment, not only by seminal microbes but also by follicular fluid and other sources of microbes. Strong correlations were found between specific microbial taxa in semen and sperm quality, and between the follicular fluid microbiome and the aetiology of female infertility. However, no significant association was found between the microbiomes of SECM, semen and follicular fluid and ART outcomes.
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Medios de Cultivo , Líquido Folicular , Microbiota , Técnicas Reproductivas Asistidas , Semen , Humanos , Femenino , Masculino , Adulto , Embarazo , Líquido Folicular/microbiología , Semen/microbiología , Técnicas de Cultivo de Embriones , Fertilización In Vitro , Infertilidad Femenina/microbiología , Infertilidad Femenina/terapiaRESUMEN
OBJECTIVE: To establish the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women referred to colposcopy with persistent high-risk human papillomavirus (hrHPV) cytology-negative screening sample according to hrHPV genotype, age at referral and colposcopic performance. DESIGN: Prospective cohort study. SETTING: Single colposcopy clinic linked to a population-based screening programme. POPULATION: Women referred with persistent hrHPV cytology-negative routine screening samples. METHODS: Prospective study with descriptive statistics from a single colposcopy unit between June 2014 and July 2019. MAIN OUTCOME MEASURES: Prevalence of hrHPV genotypes and CIN2+, positive predictive value for colposcopic impression, and inadequate colposcopic examinations. RESULTS: A total of 3107 women were referred. Prevalence of CIN2+ was highest for persistent HPV16 infections (10.7%) compared with HPV18 (3.6%) or HPVO (4.7%). Prevalence of CIN2+ declined with age (25-34 years 14.2% to 55-64 years 1.1%) whereas the percentage of women with an inadequate colposcopic examination increased (25-34 years 0.9% to 55-64 years 29.5%). High-grade colposcopic impression fell over time during the study from 16.1 to 5.1%. The positive predictive value for colposcopic impression of CIN2+ was affected by hrHPV genotype (57.3% for HPV16 versus 32.1% for nonHPV16). The adjunctive use of electrical impedance spectroscopy detected an extra 42 cases of CIN2+, which was irrespective of hrHPV genotype. CONCLUSIONS: Primary hrHPV cervical screening increases detection of CIN2+; however, low specificity results in more women being referred to colposcopy with a low prevalence of CIN2+. Colposcopy performs poorly in some groups, particularly with HPVO infections and women over 50 years of age. An appropriate threshold for referral to colposcopy in primary hrHPV screening has not been established. TWEETABLE ABSTRACT: Low prevalence of CIN2+ in HPV-positive negative cytology samples. HPV genotype, age and prevalence of CIN2+ affect colposcopic performance.
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Colposcopía/normas , Infecciones por Papillomavirus/epidemiología , Displasia del Cuello del Útero/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Adulto , Factores de Edad , Colposcopía/estadística & datos numéricos , Femenino , Humanos , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Prevalencia , Estudios Prospectivos , Sensibilidad y Especificidad , Neoplasias del Cuello Uterino/diagnóstico , Adulto Joven , Displasia del Cuello del Útero/diagnósticoRESUMEN
INTRODUCTION: Primary HPV screening will be implemented into the English Cervical Screening Programme by 2019. Its impact upon women referred to colposcopy, with negative cytology but persistently positive high-risk HPV (hrHPV), remains unreported from UK Sentinel sites. HPV primary screening was introduced in Sheffield, UK in April 2013; this paper reports its impact on the service. METHODS: A retrospective cohort study was performed from June 2014 to July 2016 at the Jessop Wing Colposcopy Unit, Sheffield. UK. Data were obtained from the pathology and colposcopy databases and cross-referenced with case-notes and pathology results for women referred with persistently positive hrHPV, cytology negative samples. Patient demographics, hrHPV genotype, biopsy rates, histological diagnoses, management, and outcomes were collected and baseline statistics performed. RESULTS: During the study 1076 women were seen. Most frequent hrHPV genotypes were: hrHPV other, 41%; and HPV16, 33%. The majority (72%) were found to have normal colposcopy; 28% had an abnormal colposcopic assessment (11% low-grade; 11% high-grade; 6% inadequate). The majority were discharged (83%) and only 5% underwent LLETZ. No cancers were detected. High-grade cervical intraepithelial neoplasia (CIN) was found in 7%; overall risk of CIN2 was 1/29; 1/30 for CIN3. Presence of HPV16 was associated with a significantly higher risk of high-grade CIN; 1/9. CONCLUSION: This is the first study to report results for women referred to colposcopy with cytology negative, persistently positive hrHPV. Disease prevalence is low, although women with HPV16 have a significantly higher likelihood of high-grade disease compared to other HPV subtypes.
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Genotipo , Papillomaviridae/genética , Infecciones por Papillomavirus , Displasia del Cuello del Útero , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Prevalencia , Estudios Retrospectivos , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.
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Síndrome Coronario Agudo/tratamiento farmacológico , Soluciones Cardiopléjicas/administración & dosificación , Ácidos Grasos no Esterificados/sangre , Glucólisis/efectos de los fármacos , Miocardio/metabolismo , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/genética , Anciano , Biomarcadores/sangre , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Femenino , Genotipo , Glucosa/administración & dosificación , Humanos , Insulina/administración & dosificación , Masculino , Persona de Mediana Edad , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Fenotipo , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Potasio/administración & dosificación , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The ability to perform comprehensive profiling of cancers at high resolution is essential for precision medicine. Liquid biopsies using shed exosomes provide high-quality nucleic acids to obtain molecular characterization, which may be especially useful for visceral cancers that are not amenable to routine biopsies. PATIENTS AND METHODS: We isolated shed exosomes in biofluids from three patients with pancreaticobiliary cancers (two pancreatic, one ampullary). We performed comprehensive profiling of exoDNA and exoRNA by whole genome, exome and transcriptome sequencing using the Illumina HiSeq 2500 sequencer. We assessed the feasibility of calling copy number events, detecting mutational signatures and identifying potentially actionable mutations in exoDNA sequencing data, as well as expressed point mutations and gene fusions in exoRNA sequencing data. RESULTS: Whole-exome sequencing resulted in 95%-99% of the target regions covered at a mean depth of 133-490×. Genome-wide copy number profiles, and high estimates of tumor fractions (ranging from 56% to 82%), suggest robust representation of the tumor DNA within the shed exosomal compartment. Multiple actionable mutations, including alterations in NOTCH1 and BRCA2, were found in patient exoDNA samples. Further, RNA sequencing of shed exosomes identified the presence of expressed fusion genes, representing an avenue for elucidation of tumor neoantigens. CONCLUSIONS: We have demonstrated high-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers. A wide range of cancer-derived biomarkers could be detected within the nucleic acid cargo of shed exosomes, including copy number profiles, point mutations, insertions, deletions, gene fusions and mutational signatures. Liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling.
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Biomarcadores de Tumor/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Anciano , Biomarcadores de Tumor/biosíntesis , Exoma/genética , Exosomas/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/biosíntesis , Neoplasias Pancreáticas/patologíaRESUMEN
Accumulation of ß-amyloid (Aß) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (É4 carrier[É4(+)], É4 non-carrier[É4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aß-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aß neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aß positron emission tomography neuroimaging was used to classify participants as Aß(-) or Aß(+). Relative to Aß(-)É4(-), Aß(+)É4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aß(+)É4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aß(-)É4(-) and Aß(-)É4(+) groups. Among Aß(+) individuals, É4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with É4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aß-related cognitive decline. Aß(+)É4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aß(+)É4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aß(-) and Aß(+) É4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.
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Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Trastornos del Conocimiento , Polimorfismo de Nucleótido Simple/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Compuestos de Anilina/metabolismo , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/metabolismo , Femenino , Estudios de Seguimiento , Ingeniería Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Tiazoles/metabolismoRESUMEN
The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) É4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE É4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.
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Trastornos del Conocimiento/epidemiología , Dieta , Anciano , Envejecimiento/genética , Envejecimiento/psicología , Apolipoproteína E4/genética , Australia , Trastornos del Conocimiento/genética , Estudios de Cohortes , Función Ejecutiva , Femenino , Estudios de Seguimiento , Humanos , Modelos Lineales , Masculino , Pruebas Neuropsicológicas , Análisis de Componente Principal , Encuestas y CuestionariosRESUMEN
OBJECTIVE: This study looks at the importance of large loop excision of the transformation zone (LLETZ) excision margins and residual cervical intraepithelial neoplasia (CIN) in women undertaking high-risk human papillomavirus (hrHPV) test of cure (TOC). METHODS: A retrospective cohort study with interval analysis performed June 2007 and June 2012 on all women undertaking treatment for CIN and subsequent hrHPV TOC 6 months post LLETZ. RESULTS: Final analysis group comprised 2093 women treated by LLETZ (1396 completely excised; 697 incompletely excised). 298 out of 1794 women (13%) were hrHPV positive at TOC. Thirty-six women who failed TOC and attended colposcopy had residual CIN. No statistically significant difference existed between the completely and incompletely excised groups with regards to the detection of residual CIN at 6 months post-treatment. There was no correlation of margins of excision with hrHPV status at TOC. The overall cure rate at TOC was 98%. CONCLUSIONS: TOC pathways recommend subsequent follow-up in primary care. This study identified no safety issues with TOC pathways. We can no longer assess histological failure rates at 12 months; we, therefore, recommend that this measure of treatment failure be redefined for post TOC women. It seems time to question the benefits of routine excision margins reporting, in the absence of invasion, for treated CIN. Future reporting needs to be reconsidered by the Royal College of Pathologists.
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Cuello del Útero/patología , Márgenes de Escisión , Infecciones por Papillomavirus/diagnóstico , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Anciano , Cuello del Útero/cirugía , Colposcopía , Citodiagnóstico , Femenino , Humanos , Persona de Mediana Edad , Prueba de Papanicolaou , Papillomaviridae , Embarazo , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía , Adulto Joven , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/cirugíaRESUMEN
Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndromes (ACS). In an Immediate Myocardial Metabolic Enhancement During Initial Assessment And Treatment In Emergency Care (IMMEDIATE) trial's sub-study (n = 318), we explored effects of 132,634 genetic variants on plasma glucose and potassium response to 12-h GIK infusion. Associations between metabolite-associated variants and infarct size (n = 84) were assessed. The 'G' allele of rs12641551, near ACSL1, as well as the 'A' allele of XPO4 rs2585897 were associated with a differential glucose response (P for 2 degrees of freedom test, P2df ⩽ 4.75 × 10(-7)) and infarct size with GIK (P2df < 0.05). Variants within or near TAS1R3, LCA5, DNAH5, PTPRG, MAGI1, PTCSC3, STRADA, AKAP12, ARFGEF2, ADCYAP1, SETX, NDRG4 and ABCB11 modified glucose response, and near CSF1/AHCYL1 potassium response (P2df ⩽ 4.26 × 10(-7)), but not outcomes. Gene variants may modify glucose and potassium response to GIK infusion, contributing to cardiovascular outcomes in ACS.
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Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/genética , Variación Genética/genética , Glucosa/administración & dosificación , Insulina/administración & dosificación , Potasio/administración & dosificación , Alelos , Glucemia/genética , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas/métodos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The mechanistic effects of intravenous glucose, insulin and potassium (GIK) in cardiac ischemia are not well understood. We conducted a genetic sub-study of the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial to explore effects of common and rare glucose and insulin-related genetic loci on initial to 6-h and 6- to 12-h change in plasma glucose and potassium. We identified 27 NOTCH2/ADAM30 and 8 C2CD4B variants conferring a 40-57% increase in glucose during the first 6 h of infusion (P<5.96 × 10(-6)). Significant associations were also found for ABCB11 and SLC30A8 single-nucleotide polymorphisms (SNPs) and glucose responses, and an SEC61A2 SNP with a potassium response to GIK. These studies identify genetic factors that may impact the metabolic response to GIK, which could influence treatment benefits in the setting of acute coronary syndromes (ACS).
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Variación Genética/genética , Glucosa/genética , Insulina/genética , Sitios de Carácter Cuantitativo/genética , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/genética , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Glucosa/uso terapéutico , Humanos , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Potasio/uso terapéutico , Resultado del TratamientoRESUMEN
Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-É4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/complicaciones , Anemia/sangre , Anemia/complicaciones , Disfunción Cognitiva/sangre , Disfunción Cognitiva/complicaciones , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Estudios Transversales , Femenino , Ácido Fólico/sangre , Hemoglobinas/metabolismo , Humanos , Hierro/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Transferrina/metabolismoRESUMEN
Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of ß amyloid (Aß) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aß levels have focused primarily on plasma Aß(1-40) and not on the more pathogenic Aß(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aß levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aß(1-40) and Aß(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aß(1-40); beta=0.208, P=0.017; Aß(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-É4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-É4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Gonadotropinas/metabolismo , Fragmentos de Péptidos/metabolismo , Testosterona/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Apolipoproteínas E/genética , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Estudios de Cohortes , Humanos , Modelos Lineales , Masculino , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/metabolismo , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Estadísticas no Paramétricas , TiazolesRESUMEN
Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Neocórtex/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Compuestos de Anilina , Apolipoproteínas E/genética , Quimiocina CCL3/sangre , Estudios de Cohortes , Proteínas Cullin , Femenino , Humanos , Interleucina-17 , Masculino , Neocórtex/diagnóstico por imagen , Polipéptido Pancreático , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Curva ROC , TiazolesRESUMEN
OBJECTIVE: When the Sheffield screening laboratory changed the high-risk human papillomavirus (hrHPV) platforms from hybrid capture 2(®) (HC2; Digene Ltd) and to cobas 4800(®) (Roche) an unexpected and substantial increase in the number of cytology-negative/hrHPV-positive test-of-cure (ToC) samples after large loop excision of the transformation zone (LLETZ) was noted. We explore the potential reasons for these increased rates and discuss the implications this may have on the English NHS cervical screening programme (CSP). METHODS: A retrospective cohort study with interval analysis between June 2007 and June 2012. RESULTS: ToC was performed on 1530 women with HC2 and 396 with cobas 4800: 95.1% and 92.4% of women had negative cytology at ToC in the HC2 and cobas4800 testing period, respectively. Of these 13.9% and 27.8% tested positive for hrHPV in the HC2 and cobas 4800 group, respectively (P = <0.0001). No clinically significant increase in the number of cases of cervical intraepithelial neolpasia (CIN) was detected by the cobas4800 test in spite of doubling the number of cytology-negative/hrHPV-positive ToC samples. CONCLUSIONS: As far as we are aware, this is the first study reporting potential differences between different HPV platforms currently available in the English programme. The immediate impact of this increase in rates of hrHPV detection with cobas4800 is an increased number of colposcopy referrals to our service. The NHSCSP needs to assess whether this increase is acceptable and, if not, whether specific HPV platforms more suited to screening in a ToC scenario should be recommended.
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Cuello del Útero/patología , ADN Viral/aislamiento & purificación , Electrocirugia , Hibridación de Ácido Nucleico , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/patología , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/patología , Adolescente , Adulto , Anciano , Cuello del Útero/cirugía , Estudios de Cohortes , Colposcopía , Detección Precoz del Cáncer , Inglaterra , Reacciones Falso Negativas , Femenino , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Infecciones por Papillomavirus/diagnóstico , Estudios Retrospectivos , Sensibilidad y Especificidad , Neoplasias del Cuello Uterino/diagnóstico , Adulto Joven , Displasia del Cuello del Útero/diagnósticoRESUMEN
Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-ß (Aß) and Aß brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aß and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aß levels were measured in fasting blood samples. A subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aß1-42/1-40 ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aß from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ε4 carriers. Lower plasma Aß1-42/1-40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.
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Envejecimiento/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Actividad Motora , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Alelos , Péptidos beta-Amiloides/sangre , Apolipoproteína E4/genética , Biomarcadores/sangre , Biomarcadores/metabolismo , Glucemia , Colesterol/sangre , Femenino , Neuroimagen Funcional , Humanos , Insulina/sangre , Estilo de Vida , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: There has been an almost 100% increase in referrals to breast cancer diagnostic clinics in the past decade. Breaching of the two-week cancer referral target is now commonplace, potentially delaying diagnoses of breast malignancy in many women. Almost one in five of these referrals are women with mastalgia, not a symptom linked to breast cancer. The objective of the study was the safe introduction of an advanced nurse practitioner-led telephone service for women with mastalgia to improve the service for women and create capacity for those with "red flag" breast symptoms. METHODS: Referrals to clinic were triaged, women with mastalgia only were directed to a telephone-based assessment clinic and symptoms evaluated using a multidisciplinary created proforma. RESULTS: Within 23 months, 1,427 women were assessed in the breast pain telephone assessment clinic: 863 (61%) were aged over 40 and 564 (39%) aged under 40. A total of 1,238 underwent telephone assessment. Reassurance and discharge only was needed for 365 (26%). The aetiology of pain was identified as musculoskeletal in 1,104/1,238 (89%) of patients, with only 39/1,238 (3.2%) identified as having true breast pain. Additional symptoms were mentioned by 264 women (18%) during the consultation; all immediately redirected back to a diagnostic clinic. Mammography was undertaken in 609 women (43%). Seven women (0.6%) were diagnosed with a breast malignancy. Patient survey indicated that 93% of patients were satisfied with the care received and 97% said they would recommend the service to a family member or friend. CONCLUSIONS: Although face-to-face assessments for breast pain remain the standard practice in many breast units, data indicating the safety of a telephone assessment clinic, along with high levels of patient satisfaction, question whether services can be delivered differently.
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Neoplasias de la Mama , Mastodinia , Enfermeras Practicantes , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Mastodinia/diagnóstico , Mastodinia/etiología , Mastodinia/terapia , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/diagnóstico , Derivación y Consulta , TeléfonoRESUMEN
German chamomile (Matricaria recutita L.), a widely-used herbal medicine, has been reported to have a wide range of biological effects, including smooth muscle relaxation. The aim of this study was to compare the effects of representative compounds from chamomile (apigenin, luteolin, (-)-α-bisabolol, farnesene, umbelliferone; 3-30 µM) on vascular tone using porcine coronary and splenic arteries mounted for isometric tension recording in isolated tissue baths and precontracted with the thromboxane-mimetic U46619. Apigenin, luteolin, and (-)-α-bisabolol produced slow, concentration-dependent relaxations in both the coronary and splenic arteries that were not blocked by inhibition of nitric oxide synthase or potassium channels. Removal of extracellular calcium inhibited the relaxations to all three compounds, and these compounds also inhibited calcium re-addition-evoked contractions, indicating that the relaxation response may be mediated through inhibition of calcium influx. Apigenin and luteolin, but not (-)-α-bisabolol, enhanced the relaxation to the nitric oxide donor sodium nitroprusside, indicating that apigenin and luteolin may act to regulate cyclic GMP levels. Umbelliferone produced a rapid, transient relaxation in the splenic artery, but not the coronary artery, that was inhibited by L-NAME and removal of the endothelium, suggesting an influence on nitric oxide production. Farnesene, at concentrations up to 30 µM, was without effect in either blood vessel. In conclusion, hydroxylated compounds (apigenin, luteolin and (-)-α-bisabolol) found in chamomile all caused a slow relaxation of isolated blood vessels through an effect on calcium influx. Umbelliferone, on the other hand, produced a rapid, transient relaxation dependent upon release of nitric oxide from the endothelium.
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Manzanilla , Vasos Coronarios/efectos de los fármacos , Extractos Vegetales/farmacología , Arteria Esplénica/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Vasos Coronarios/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Técnicas de Cultivo de Órganos , Extractos Vegetales/aislamiento & purificación , Arteria Esplénica/fisiología , Porcinos , Vasoconstrictores/farmacología , Vasodilatación/fisiología , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: The prognostic value of subjective memory complaints (SMCs) in the diagnosis of dementia of the Alzheimer's type is unclear. While some studies have found an association between SMCs and cognitive decline, many have found a stronger association with depression, which raises questions about their diagnostic utility. METHODS: We examined the cross-sectional association between SMC severity (as measured using the MAC-Q, a brief SMC questionnaire) and affect, memory, and Alzheimer's disease (AD) biomarkers (ß-amyloid deposition and the apolipoprotein E ε4 (APOEε4) allele) in healthy elderly controls (HC; M = 78.74 years, SD = 6.7) and individuals with mild cognitive impairment (MCI; M = 72.74 years, SD = 8.8). We analyzed a subset of individuals drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Aging. RESULTS: SMCs were more severe in MCI patients than in HCs. SMC severity was related to affective variables and the interaction between age and group membership (HC/MCI). Within the HC group, SMC severity was related to affective variables only, while severity correlated only with age in the MCI group. SMCs were not related to cognitive variables or AD biomarkers. CONCLUSION: SMCs were related to solely by poorer mood (greater depressive and anxious symptomatology) in the cognitively healthy elderly however mean levels were subclinical. This finding argues for the assessment of affective symptomatology in conjunction with cognitive assessment in elderly memory complainers. Future AIBL research will focus on assessing other AD biomarkers, such as brain atrophy and Aß plasma markers, in relation to complaint severity. Once our 36-month follow-up data are collected, we propose to assess whether SMCs can predict future cognitive decline.
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Envejecimiento , Enfermedad de Alzheimer/complicaciones , Biomarcadores/sangre , Memoria , Afecto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Australia , Estudios de Casos y Controles , Disfunción Cognitiva/diagnóstico , Estudios Transversales , Femenino , Evaluación Geriátrica/métodos , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Pronóstico , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
OBJECTIVES: To assess whether consumption of lean red meat on three exercise training days per week can promote greater improvements than exercise alone in health-related quality of life (HR-QoL) in community-dwelling older adults. DESIGN: This study is a secondary analysis from a 6 month, two-arm, parallel randomized controlled trial conducted in 2014 and 2015. SETTING: Community-dwelling older adults living in metropolitan Melbourne, Australia. PARTICIPANTS: One hundred and fifty-four men and women aged ≥65 years. INTERVENTION: All participants were enrolled in a multi-component, resistance-based exercise program (3 d/week) and randomly allocated to either a group asked to consume lean red meat (2x80g cooked servings/day) on each of the three training days (Ex+Meat, n=77) or a control group asked to consume one serving of carbohydrates (1/2 cup rice/pasta or 1 medium potato; Ex+C, n=77). MEASUREMENTS: HR-QoL was assessed using the Short-Form (SF)-36 health survey. RESULTS: Overall 62% of the participants were female, the mean age was 70.7 years (range 65 to 84 years), approximately 67% of participants were classified as either overweight or obese, and the average number of chronic conditions was two. A total of 145 participants (94%) completed the study. Mean baseline HR-QoL scores were comparable to the mean for the Australian population [Global HR-QoL (mean ± SD): Ex+Meat, 49.99 ± 6.57; Ex+C, 50.49 ± 5.27]. General Linear Mixed Models examining within and between group changes over time revealed that after 6 months, there were no within-group changes in either Ex+Meat or Ex+C nor any between-group differences for any measure of HR-QoL, with the exception that the mental health subscale improved in Ex+C versus Ex+Meat [net difference for change, -2.32 (95% CI), -4.73, 0.09, P=0.048] after adjusting for relevant covariates and the physical function subscale improved in Ex+Meat relative to baseline [mean change (95% CI), 1.88 (0.37, 3.39), P=0.011]. CONCLUSION: A multi-component resistance-based training program performed with and without the provision of lean red meat in line with current Australian dietary guidelines on each of the three training days, did not improve HR-QoL in healthy community-dwelling older adults.
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Carne Roja , Entrenamiento de Fuerza , Masculino , Humanos , Femenino , Anciano , Anciano de 80 o más Años , Calidad de Vida , Australia , Ejercicio FísicoRESUMEN
The secreted products of cells drive many functions in vivo; however, methods to link this functional information to surface markers and transcriptomes have been lacking. By accumulating secretions close to secreting cells held within cavity-containing hydrogel nanovials, we demonstrate workflows to analyze the amount of IgG secreted from single human B cells and link this information to surface markers and transcriptomes from the same cells. Measurements using flow cytometry and imaging flow cytometry corroborate the association between IgG secretion and CD38/CD138. By using oligonucleotide-labeled antibodies we find that upregulation of pathways for protein localization to the endoplasmic reticulum and mitochondrial oxidative phosphorylation are most associated with high IgG secretion, and uncover surrogate plasma cell surface markers (e.g., CD59) defined by the ability to secrete IgG. Altogether, this method links quantity of secretion with single-cell sequencing (SEC-seq) and enables researchers to fully explore the links between genome and function, laying the foundation for discoveries in immunology, stem cell biology, and beyond.