RESUMEN
BACKGROUND: Autoimmune diseases (AIDs) are linked to oropharyngeal cancer (OPC), but the exact nature of this association remains unclear. This study aims to examine the potential causal effect of AIDs on the risk of developing OPC. METHOD: Information regarding AIDs was collected from the UK Biobank dataset and the Finn Gen study. OPC data were sourced from the IEU Open GWAS project. All data were derived from European populations. Inverse variance weighted (IVW) to two-sample Mendelian randomization (MR) was complemented by weighted median and MR Egger validation analyses. RESULT: The development of asthma (AS), multiple sclerosis (MS), and rheumatoid arthritis (RA) influenced the risk of developing OPC. However, the reverse MR analysis did not provide evidence for the impact of OPC on AIDs. Sensitivity analysis using MR corroborated the IVW results. The IVW results indicate OR values of 1.004 for AS, 0.936 for MS, and 1.0002 for RA. CONCLUSION: This MR study supports a causal relationship between asthma and rheumatoid arthritis for OPC in a European population. Multiple sclerosis was protective against OPC.
Asunto(s)
Enfermedades Autoinmunes , Neoplasias Orofaríngeas , Humanos , Análisis de la Aleatorización Mendeliana , Esclerosis Múltiple/genética , Artritis Reumatoide , Asma/epidemiología , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Causalidad , Reino Unido/epidemiología , Masculino , FemeninoRESUMEN
Information on bone loss in treated non-Hodgkin's lymphoma patients is limited. In this study, we used CT to analyze bone loss as well as prevalent and incident fractures. We found severe bone loss, a high rate of fractures, and a novel association between bone loss and the international prognostic index. INTRODUCTION: To investigate bone loss and fracture risk in non-Hodgkin-lymphoma (NHL) patients by (i) comparing treatment-related vertebral density (VD) loss in NHL patients with control subjects and (ii) investigating associations of VD loss versus fracture risk. Further, associations of VD loss and clinical parameters were investigated. METHODS: VD of 123 NHL patients was measured pre- and post-treatment in the L1, L2, and L3 vertebrae in routine computed tomography (CT) scans, performed between Jan 2016 and Mar 2017. Control measurements (n = 52) were obtained from CT colonographies between Sept 2003 and Sept 2017 and their subsequent follow-up-exams (10-137 months). Prevalent and incident (between baseline and follow-up) fractures were assessed in all subjects, and VD loss per year was calculated. Linear regression models were used to (i) compare VD loss between patients and controls and (ii) identify associations between VD loss and clinical parameters. Using logistic regression models, ORs for fractures per SD change in VD were assessed in patients. Analyses were adjusted for age, sex, and contrast application. RESULTS: NHL patients experienced significantly greater VDL1-3 loss than controls (P = 0.003), and greater VDL1-3 loss was associated with a greater likelihood of incident fractures (OR, [95%-CI], P 1.90, [1.03, 3.51], 0.04). Patients with an initial international prognostic index (IPI) of 5 suffered significantly greater VD loss compared with an IPI of 0 (P = 0.01). CONCLUSION: Using VD measurements in routine CT scans, substantial vertebral bone loss in NHL patients could be documented with a high incidence of fractures.
Asunto(s)
Linfoma no Hodgkin , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Densidad Ósea , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/lesiones , Linfoma no Hodgkin/epidemiología , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/etiologíaRESUMEN
BACKGROUND: Food systems are associated with severe and persistent problems worldwide. Governance approaches aiming to foster sustainable transformation of food systems face several challenges due to the complex nature of food systems. SCOPE AND APPROACH: In this commentary we argue that addressing these governance challenges requires the development and adoption of novel research and innovation (R&I) approaches that will provide evidence to inform food system transformation and will serve as catalysts for change. We first elaborate on the complexity of food systems (transformation) and stress the need to move beyond traditional linear R&I approaches to be able to respond to persistent problems that affect food systems. Though integrated transdisciplinary approaches are promising, current R&I systems do not sufficiently support such endeavors. As such, we argue, we need strategies that trigger a double transformation - of food systems and of their R&I systems. KEY FINDINGS AND CONCLUSIONS: Seizing the opportunities to transform R&I systems has implications for how research is done - pointing to the need for competence development among researchers, policy makers and society in general - and requires specific governance interventions that stimulate a systemic approach. Such interventions should foster transdisciplinary and transformative research agendas that stimulate portfolios of projects that will reinforce one another, and stimulate innovative experiments to shape conditions for systemic change. In short, a thorough rethinking of the role of R&I as well as how it is funded is a crucial step towards the development of the integrative policies that are necessary to engender systemic change - in the food system and beyond.
RESUMEN
We demonstrate quantum control of ^{9}Be^{+} ions directly implemented by an optical frequency comb. Based on numerical simulations of the relevant processes in ^{9}Be^{+} for different magnetic field regimes, we demonstrate a wide applicability when controlling the comb's spectral properties. We introduce a novel technique for the selective and efficient generation of a spectrally tailored narrow-bandwidth optical frequency comb near 313 nm. We experimentally demonstrate internal state control and internal-motional state coupling of ^{9}Be^{+} ions implemented by stimulated-Raman manipulation using a spectrally optimized optical frequency comb. Our pulsed laser approach is a key enabling step for the implementation of quantum logic and quantum information experiments in Penning traps.
RESUMEN
An important subgroup of people who inject drugs (PWID) receiving opioid agonist therapy (OAT) cannot be treated in the setting of a hepatology centre and would not regularly ingest their medication when handed to them for self-administration. Our hypothesis was that chronic hepatitis C in these patients could be ideally managed if modern, interferon-free regimens were administered together with OAT under direct observation of a physician or nurse at a low-threshold facility. In this open-label, noninterventional, proof-of-concept study (ClinicalTrials.gov number, NCT02638233), 40 PWID at risk of nonadherence to direct-acting antivirals (DAA) and previously untreated chronic hepatitis C virus genotype 1 infection without cirrhosis were treated with ledipasvir/sofosbuvir for 8 weeks. Patients received antiviral treatment together with OAT under direct observation of a physician or nurse at a low-threshold facility. By following the concept of directly observed therapy, excellent adherence to antiviral therapy was achieved as follows: only 0.16% (95% CI: 0.03-0.47) of scheduled dates for ingestion of the antiviral therapy in combination with OAT were missed by the 40 patients. The rate of sustained virological response 12 weeks after end of therapy was 100% (95% CI: 91.2-100.0). Between week 12 and week 24 of follow-up reinfections were recorded in 2 of 40 patients (5%). Directly observed therapy of chronic hepatitis C is highly effective in PWID at risk of nonadherence to DAA. By this new concept, a group of difficult-to-treat patients can be cured, who could not have been treated in settings of studies published so far.
Asunto(s)
Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Terapia por Observación Directa , Fluorenos/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/administración & dosificación , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Respuesta Virológica Sostenida , Resultado del Tratamiento , Adulto JovenRESUMEN
We found that HIV+/HCV+ women had 7-8% lower areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) at the spine, hip, and radius (p < 0.01) and 5-7% lower volumetric BMD (vBMD) by central quantitative computed tomography (cQCT) at the spine and hip (p < 0.05). These data suggest that true deficits in vBMD may contribute to bone fragility and excess fractures reported in HIV+/HCV+ women. INTRODUCTION: aBMD by DXA is lower in persons coinfected with HIV and HCV (HIV+/HCV+) than with HIV monoinfection (HIV+). However, weight is often also lower with HCV infection, and measurement of aBMD by DXA can be confounded by adiposity; we aimed to determine whether true vBMD is also lower in HIV+/HCV+ coinfection. METHODS: We measured aBMD of the lumbar spine (LS), total hip (TH), femoral neck (FN), and ultradistal radius (UDR) by DXA and vBMD of the spine and hip by cQCT and of the distal radius and tibia by high-resolution peripheral QCT (HRpQCT) in 37 HIV+/HCV+ and 119 HIV+ postmenopausal women. Groups were compared using Student's t tests with covariate adjustment by multiple regression analysis. RESULTS: HIV+/HCV+ and HIV+ women were of similar age and race/ethnicity. HIV+/HCV+ women had lower body mass index (BMI) and trunk fat and were more likely to smoke and less likely to have a history of AIDS. In HIV+/HCV+ women, aBMD by DXA was 7-8% lower at the LS, TH, and UDR (p < 0.01). Similarly, vBMD by cQCT was 5-7% lower at the LS and TH (p < 0.05). Between-group differences in LS aBMD and vBMD remained significant after adjustment for BMI, smoking, and AIDS history. Tibial total vBMD by HRpQCT was 10% lower in HIV+/HCV+ women. CONCLUSION: HIV+/HCV+ postmenopausal women had significantly lower spine aBMD and vBMD. These deficits in vBMD may contribute to bone fragility and excess fractures reported in HIV+/HCV+ women.
Asunto(s)
Coinfección/complicaciones , Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Osteoporosis Posmenopáusica/virología , Absorciometría de Fotón/métodos , Negro o Afroamericano/estadística & datos numéricos , Densidad Ósea/fisiología , Coinfección/etnología , Coinfección/fisiopatología , Femenino , Infecciones por VIH/etnología , Infecciones por VIH/fisiopatología , Hepatitis C/fisiopatología , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/fisiopatología , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/fisiopatología , Persona de Mediana Edad , Grupos Minoritarios/estadística & datos numéricos , Osteoporosis Posmenopáusica/diagnóstico por imagen , Osteoporosis Posmenopáusica/etnología , Osteoporosis Posmenopáusica/fisiopatología , Radio (Anatomía)/diagnóstico por imagen , Radio (Anatomía)/fisiopatología , Tibia/diagnóstico por imagen , Tibia/fisiopatología , Tomografía Computarizada por Rayos X/métodos , Estados Unidos/epidemiologíaRESUMEN
The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.
Asunto(s)
Agorafobia/genética , Agorafobia/metabolismo , Receptores de Glicina/genética , Adulto , Alelos , Ansiedad/complicaciones , Trastornos de Ansiedad/genética , Encéfalo/metabolismo , Encéfalo/fisiología , Estudios de Casos y Controles , Cognición/fisiología , Miedo/fisiología , Miedo/psicología , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Alemania , Humanos , Masculino , Mutación/genética , Trastorno de Pánico/genética , Receptores de Glicina/metabolismo , Reflejo de Sobresalto/genéticaRESUMEN
We investigated the sensitivity of distal bone density, structure, and strength measurements by high-resolution peripheral quantitative computed tomography (HR-pQCT) to variability in limb length. Our results demonstrate that HR-pQCT should be performed at a standard %-of-total-limb-length to avoid substantial measurement bias in population study comparisons and the evaluation of individual skeletal status in a clinical context. INTRODUCTION: High-resolution peripheral quantitative computed tomography (HR-pQCT) measures of bone do not account for anatomic variability in bone length: a 1-cm volume is acquired at a fixed offset from an anatomic landmark. Our goal was to evaluate HR-pQCT measurement variability introduced by imaging fixed vs. proportional volumes and to propose a standard protocol for relative anatomic positioning. METHODS: Double-length (2-cm) scans were acquired in 30 adults. We compared measurements from 1-cm sub-volumes located at the default fixed offset, and the average %-of-length offset. The average position corresponded to 4.0% ± 1.1 mm for radius, and 7.2% ± 2.2 mm for tibia. We calculated the RMS difference in bone parameters and T-scores to determine the measurement variability related to differences in limb length. We used anthropometric ratios to estimate the mean limb length for published HR-pQCT reference data, and then calculated mean %-of-length offsets. RESULTS: Variability between fixed vs. relative scan positions was highest in the radius, and for cortical bone in general (RMS difference Ct.Th = 19.5%), while individuals had T-score differentials as high as +3.0 SD (radius Ct.BMD). We estimated that average scan position for published HR-pQCT reference data corresponded to 4.0% at the radius, and 7.3% at tibia. CONCLUSION: Variability in limb length introduces significant bias to HR-pQCT measures, confounding cross-sectional analyses and limiting the clinical application for individual assessment of skeletal status. We propose to standardize scan positioning using 4.0 and 7.3% of total bone length for the distal radius and tibia, respectively.
Asunto(s)
Densidad Ósea/fisiología , Radio (Anatomía)/diagnóstico por imagen , Tibia/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Anciano , Anciano de 80 o más Años , Puntos Anatómicos de Referencia , Antropometría/métodos , Femenino , Análisis de Elementos Finitos , Antebrazo/anatomía & histología , Humanos , Pierna/anatomía & histología , Masculino , Radio (Anatomía)/fisiología , Reproducibilidad de los Resultados , Tibia/fisiología , Tomografía Computarizada por Rayos X/normasRESUMEN
In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter-operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection ("scout view image") and define the region to be scanned by positioning a "reference line" on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanner's software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter-operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p < 0.001). New trained operators achieved comparable intra-operator reproducibility to experienced operators and lower inter-operator reproducibility (p < 0.001). Precision errors were significantly greater for the radius than for the tibia. CONCLUSION: Operator reference line positioning contributes significantly to in vivo measurement precision and is significantly greater for multi-operator datasets. Inter-operator variability can be significantly reduced using a systematic training platform, now available online ( http://webapps.radiology.ucsf.edu/refline/ ).
Asunto(s)
Competencia Clínica , Osteoporosis/diagnóstico por imagen , Tomografía Computarizada por Rayos X/normas , Anciano , Anciano de 80 o más Años , Puntos Anatómicos de Referencia , Femenino , Humanos , Capacitación en Servicio/métodos , Masculino , Radio (Anatomía)/diagnóstico por imagen , Reproducibilidad de los Resultados , Diseño de Software , Tibia/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodosRESUMEN
Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.
Asunto(s)
Trastorno de Pánico/genética , Receptores de Hormona Liberadora de Corticotropina/genética , Adulto , Alelos , Ansiedad/genética , Trastornos de Ansiedad/genética , Sesgo , Hormona Liberadora de Corticotropina/metabolismo , Miedo , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Genotipo , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Sistema Hipófiso-Suprarrenal/metabolismo , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: Clinico-pathological correlation of thyroid nodules is not routinely performed as until recently there was no objective classification system for reporting thyroid nodules on ultrasound. We compared the Thyroid Imaging Reporting and Data System (TIRADS) of classifying thyroid nodules on ultrasound with the findings on fine-needle aspiration cytology (FNAC) reported using the Bethesda System. METHODS: A retrospective analysis of 100 consecutive cases over 1 year (Jan-Dec 2015) was performed comparing single-surgeon-performed bedside thyroid nodule ultrasound findings based on the TIRADS classification to the FNAC report based on the Bethesda Classification. TIRADS 1 (normal thyroid gland) and biopsy-proven malignancy referred by other clinicians were excluded. Benign-appearing nodules were reported as TIRADS 2 and 3. Indeterminate or suspected follicular lesions were reported as TIRADS 4, and malignant-appearing nodules were classified as TIRADS 5 during surgeon-performed bedside ultrasound. All the nodules were subjected to ultrasound-guided FNAC, and TIRADS findings were compared to Bethesda FNAC Classification. RESULTS: Of the 100 cases, 74 were considered benign or probably benign, 20 were suspicious for malignancy, and 6 were indeterminate on ultrasound. Overall concordance rate with FNAC was 83% with sensitivity and specificity of 70.6 and 90.4%, respectively. The negative predictive value was 93.8%. CONCLUSION: It is essential for clinicians performing bedside ultrasound thyroid and guided FNAC to document their sonographic impression of the nodule in an objective fashion using the TIRADS classification and correlate with the gold standard cytology to improve their learning curve and audit their results.
Asunto(s)
Nódulo Tiroideo/patología , Biopsia con Aguja Fina/métodos , Citodiagnóstico , Humanos , Estudios Retrospectivos , Glándula Tiroides/patología , Nódulo Tiroideo/clasificación , Nódulo Tiroideo/diagnóstico por imagen , UltrasonografíaRESUMEN
Multidrug resistance protein 8 (ABCC11) is an efflux transporter for anionic lipophilic compounds, conferring resistance to antiviral and anticancer agents like 5-fluorouracil (5-FU). ABCC11 missense variants may contribute to variability in drug response but functional consequences, except for the 'earwax variant' c.538G>A, are unknown. Using the 'Screen and Insert' technology, we generated human embryonic kidney 293 cells stably expressing ABCC11 missense variants frequently occurring in different ethnic populations: c.57G>A, c.538G>A, c.950C>A, c.1637C>T, c.1942G>A, c.4032A>G. A series of in silico prediction analyses and in vitro plasma membrane vesicle uptake, immunoblotting and immunolocalization experiments were undertaken to investigate functional consequences. We identified c.1637C>T (T546M), previously associated with 5-FU-related toxicity, as a novel functionally damaging ABCC11 variant exhibiting markedly reduced transport function of 5-FdUMP, the active cytotoxic metabolite of 5-FU. Detailed analysis of 14 subpopulations revealed highest allele frequencies of c.1637C>T in Europeans and Americans (up to 11%) compared with Africans and Asians (up to 3%).
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/metabolismo , Antineoplásicos/metabolismo , Pueblo Asiatico , Transporte Biológico , Población Negra , Línea Celular , Simulación por Computador , Sulfato de Deshidroepiandrosterona/metabolismo , Estrona/análogos & derivados , Estrona/metabolismo , Fluorodesoxiuridilato/metabolismo , Frecuencia de los Genes , Humanos , Desequilibrio de Ligamiento , Mutación Missense , Población BlancaRESUMEN
Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus (HBV) genotype in innate immune responses and investigate whether Toll-like receptor (TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon (Peg-IFN) therapy of HBeAg seroconversion in HBeAg-positive patients. We showed that as early as 4 weeks after initiation of Peg-IFN, future HBeAg seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBeAg seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBeAg proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBeAg-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3Cys. Importantly, the addition of IFN-α to TLR2-stimulated cells cotransfected with an HBeAg expression plasmid reversed HBeAg-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBeAg seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBeAg suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum.
Asunto(s)
Genotipo , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/clasificación , Hepatitis B Crónica/tratamiento farmacológico , Inmunidad Innata , Receptores de Interleucina-1/metabolismo , Receptor Toll-Like 2/metabolismo , Adulto , Antivirales/uso terapéutico , Células Cultivadas , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatocitos/inmunología , Humanos , Interferón-alfa/uso terapéutico , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
We present a compact few-cycle 100 kHz OPCPA system pumped by a CPA-free picosecond Nd:YVO4 solid-state amplifier with all-optical synchronization to an ultra-broadband Ti:sapphire oscillator. This pump approach shows an exceptional conversion rate into the second harmonic of almost 78%. Efficient parametric amplification was realized by a two stage double-pass scheme with following chirped mirror compressor. The amount of superfluorescence was measured by an optical cross-correlation. Pulses with a duration of 8.7 fs at energies of 18 µJ are demonstrated. Due to the peak power of 1.26 GW, this simple OPCPA approach forms an ideal high repetition rate driving source for high-order harmonic generation.
RESUMEN
UNLABELLED: Lower vitamin D and higher parathyroid hormone (PTH) levels are associated with higher volumetric BMD and bone strength at the lumbar spine as measured by central quantitative computed tomography in primary hyperparathyroidism (PHPT), but there are no differences in bone microarchitecture as measured by trabecular bone score (TBS). INTRODUCTION: The purpose of this study was to evaluate the association between 25-hydroxyvitamin D (25OHD) and volumetric bone mineral density (vBMD) and the TBS at the lumbar spine (LS) in PHPT. METHODS: This is a cross-sectional analysis of PHPT patients with and without low 25OHD. We measured vBMD with quantitative computed tomography (cQCT) and TBS by dual-energy X-ray absorptiometry (DXA) at the LS in 52 and 88 participants, respectively. RESULTS: In the cQCT cohort, those with lower vitamin D (<20 vs. 20-29 vs. ≥30 ng/ml) tended to be younger (p = 0.05), were less likely to use vitamin D supplementation (p < 0.01), and had better renal function (p = 0.03). Those with 25OHD <20 ng/ml had 80 and 126 % higher serum PTH levels respectively vs. those with 25OHD 20-29 ng/ml (p = 0.002) and 25OHD ≥30 ng/ml (p < 0.0001). Covariate-adjusted integral and trabecular vBMD were higher in those with 25OHD 20-29 vs. those with 25OHD ≥30 ng/ml, but those with 25OHD <20 did not differ. Because there were few participants with 25OHD deficiency, we also compared those with vitamin D <30 vs. ≥30 ng/ml. Covariate-adjusted integral and trabecular vBMD were 23 and 30 % higher respectively (both p < 0.05) in those with vitamin D <30 vs. ≥30 ng/ml. TBS was in the partially degraded range but did not differ by vitamin D status. CONCLUSION: In mild PHPT, lower 25OHD is associated with higher PTH, but vitamin D deficiency and insufficiency using current clinical thresholds did not adversely affect lumbar spine skeletal health in PHPT. Further work is needed to determine if higher vBMD in those with lower vitamin D is due to an anabolic effect of PTH.
Asunto(s)
Densidad Ósea , Hueso Esponjoso/patología , Hiperparatiroidismo Primario/complicaciones , Deficiencia de Vitamina D/complicaciones , Anciano , Estudios Transversales , Femenino , Humanos , Hiperparatiroidismo Primario/fisiopatología , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Vitamina D/análogos & derivados , Vitamina D/sangre , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
UNLABELLED: Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. INTRODUCTION: The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). METHODS: A total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. RESULTS: Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). CONCLUSION: Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.
Asunto(s)
Biomarcadores/sangre , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , Anciano , Anciano de 80 o más Años , Colágeno Tipo I/sangre , Fuerza Compresiva/fisiología , Femenino , Cuello Femoral/diagnóstico por imagen , Cuello Femoral/fisiología , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/fisiología , Masculino , Osteocalcina/sangre , Fragmentos de Péptidos/sangre , Péptidos/sangre , Procolágeno/sangre , Estudios Prospectivos , Tomografía Computarizada por Rayos XRESUMEN
Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. INTRODUCTION: We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. METHODS: The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. RESULTS: Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. CONCLUSION: This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.
Asunto(s)
Biomarcadores/sangre , Densidad Ósea , Remodelación Ósea , Fracturas Óseas/epidemiología , Anciano , Anciano de 80 o más Años , Femenino , Cuello Femoral/patología , Humanos , Islandia , Estudios Longitudinales , MasculinoRESUMEN
At sufficiently low temperatures, condensed-matter systems tend to develop order. A notable exception to this behaviour is the case of quantum spin liquids, in which quantum fluctuations prevent a transition to an ordered state down to the lowest temperatures. There have now been tentative observations of such states in some two-dimensional organic compounds, yet quantum spin liquids remain elusive in microscopic two-dimensional models that are relevant to experiments. Here we show, by means of large-scale quantum Monte Carlo simulations of correlated fermions on a honeycomb lattice (a structure realized in, for example, graphene), that a quantum spin liquid emerges between the state described by massless Dirac fermions and an antiferromagnetically ordered Mott insulator. This unexpected quantum-disordered state is found to be a short-range resonating valence-bond liquid, akin to the one proposed for high-temperature superconductors: the possibility of unconventional superconductivity through doping therefore arises in our system. We foresee the experimental realization of this model system using ultra-cold atoms, or group IV elements arranged in honeycomb lattices.
RESUMEN
BACKGROUND: Within the context of paediatric chronic pain, parental attitudes are of particular importance given that they have the potential to impact on how parents respond to their child. The current study was designed to assess whether parental attitudes, such as parental confidence and beliefs in their child's ability to function in spite of pain, and parental catastrophising about their child's pain, are associated with parental pain-related behaviours known to be associated with poor child outcomes, such as protectiveness and high levels of monitoring. METHODS: Participants were 138 child-parent dyads recruited from a tertiary chronic pain clinic. Patients were aged 8- to 17-years. Prior to the initial clinic appointment, parents completed validated measures of parental pain catastrophising and parental responses to their child's pain. Patients completed measures of functional disability and pain intensity. RESULTS: Parents who reported lower confidence in their child's ability to cope with the pain engaged in significantly more protective, monitoring and distracting behaviours, even when controlling for the child's recent level of functioning. They also took more days off work due to their child's pain. Parents who catastrophised more about their child's pain engaged in significantly more protective and monitoring behaviours, even when controlling for the child's recent level of functioning. CONCLUSIONS: Parental behaviours in response to their child's pain are significantly related to parental confidence in their child's coping and parental pain-related catastrophising. Clinical interventions may benefit from addressing parental attitudes, especially their confidence in their child's ability to function.
Asunto(s)
Adaptación Psicológica , Catastrofización/psicología , Dolor Crónico/psicología , Responsabilidad Parental/psicología , Padres/psicología , Estrés Psicológico/psicología , Adolescente , Catastrofización/complicaciones , Niño , Toma de Decisiones , Evaluación de la Discapacidad , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Dimensión del Dolor , Relaciones Padres-Hijo , Pronóstico , Estrés Psicológico/etiología , Encuestas y CuestionariosRESUMEN
In the field of health, evidence-based medicine and associated methods like randomised controlled trials (RCTs) have become widely used. RCT has become the gold standard for evaluating causal links between interventions and health results. Originating in pharmacology, this method has been progressively expanded to medical devices, non-pharmacological individual interventions, as well as collective public health interventions. Its use in these domains has led to the formulation of several limits, and it has been called into question as an undisputed gold standard. Some of those limits (e.g. confounding biases and external validity) are common to these four different domains, while others are more specific. This paper describes the different limits, as well as several research avenues. Some are methodological reflections aiming at adapting RCT to the complexity of the tested interventions, and at overcoming some of its limits. Others are alternative methods. The objective is not to remove RCT from the range of evaluation methodologies, but to resituate it within this range. The aim is to encourage choosing between different methods according to the features and the level of the intervention to evaluate, thereby calling for methodological pluralism.