Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures

Abstract Aims Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects. Methods A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance. Results The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9) −1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L). Discussion Elevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism

Achieving the Middle Ground in an Age of Concentrated Extremes: Mixed Middle-Income Neighborhoods and Emerging Adulthood

This paper focuses on stability and change in “mixed middle-income” neighborhoods. We first analyze variation across nearly two decades for all neighborhoods in the U.S. and the Chicago area. We then analyze a new longitudinal study of almost 700 Chicago adolescents over an 18-year span, including their neighborhood income experiences during the transition to young adulthood. The concentration of income extremes is highly persistent among neighborhoods, whereas mixed middle-income neighborhoods are more fluid. Persistence dominates among individuals too, although Latino-Americans are much more likely than African-Americans or whites to be exposed to mixed middle-income neighborhoods in the first place and to transition into them over time, adjusting for immigrant status, education, income, and residential mobility. The results enhance our knowledge of the course of income inequality at the neighborhood level, and the endurance of concentrated extremes suggests that policies seeking to promote mixed-income neighborhoods face greater odds than commonly thought.Sociolog

Investigation of optical coherence micro-elastography as a method to visualize micro-architecture in human axillary lymph nodes

This project is supported with funding from the Australian Research Council; and Cancer Council WA, which allowed us to develop the technology; Department of Health of Western Australia, National Breast Cancer Foundation (Australia); and the National Health and Medical Research Council, Australia, which allowed us to design and implement the clinical protocol, and to perform the clinical measurements.Background : Evaluation of lymph node involvement is an important factor in detecting metastasis and deciding whether to perform axillary lymph node dissection (ALND) in breast cancer surgery. As ALND is associated with potentially severe long term morbidity, the accuracy of lymph node assessment is imperative in avoiding unnecessary ALND. The mechanical properties of malignant lymph nodes are often distinct from those of normal nodes. A method to image the micro-scale mechanical properties of lymph nodes could, thus, provide diagnostic information to aid in the assessment of lymph node involvement in metastatic cancer. In this study, we scan axillary lymph nodes, freshly excised from breast cancer patients, with optical coherence micro-elastography (OCME), a method of imaging micro-scale mechanical strain, to assess its potential for the intraoperative assessment of lymph node involvement. Methods : Twenty-six fresh, unstained lymph nodes were imaged from 15 patients undergoing mastectomy or breast-conserving surgery with axillary clearance. Lymph node specimens were bisected to allow imaging of the internal face of each node. Co-located OCME and optical coherence tomography (OCT) scans were taken of each sample, and the results compared to standard post-operative hematoxylin-and-eosin-stained histology. Results : The optical backscattering signal provided by OCT alone may not provide reliable differentiation by inspection between benign and malignant lymphoid tissue. Alternatively, OCME highlights local changes in tissue strain that correspond to malignancy and are distinct from strain patterns in benign lymphoid tissue. The mechanical contrast provided by OCME complements the optical contrast provided by OCT and aids in the differentiation of malignant tumor from uninvolved lymphoid tissue. Conclusion : The combination of OCME and OCT images represents a promising method for the identification of malignant lymphoid tissue. This method shows potential to provide intraoperative assessment of lymph node involvement, thus, preventing unnecessary removal of uninvolved tissues and improving patient outcomes.Publisher PDFPeer reviewe

Optical coherence tomography in the assessment of acute changes in cutaneous vascular diameter induced by heat stress.

There are limited imaging technologies available that can accurately assess or provide surrogate markers of the in vivo cutaneous microvessel network in humans. In this study, we establish the use of optical coherence tomography (OCT) as a novel imaging technique to assess acute changes in cutaneous microvessel area density and diameter in humans. OCT speckle decorrelation images of the skin on the ventral side of the forearm up to a depth of 500 μm were obtained prior to and following 20-25 mins of lower limb heating in eight healthy males (30.3±7.6 yrs). Skin red blood cell flux was also collected using laser Doppler flowmetry probes immediately adjacent to the OCT skin sites, along with skin temperature. OCT speckle decorrelation images were obtained at both baseline and heating time points. Forearm skin flux increased significantly (0.20±0.15 to 1.75±0.38 CVC, P<0.01), along with forearm skin temperature (32.0±1.2 to 34.3±1.0°C, P<0.01). Quantitative differences in the automated calculation of vascular area densities (26±9 to 49±19%, P<0.01) and individual microvessel diameters (68±17 to 105±25 μm, P<0.01) were evident following the heating session. This is the first in vivo within-subject assessment of acute changes in the cutaneous microvasculature in response to heating in humans and highlights the use of OCT as an exciting new imaging approach for skin physiology and clinical research

Depression and its associated factors among people living with HIV in the Volta region of Ghana

Depression among people living with HIV/AIDS in higher-income countries is associated with suboptimal adherence to antiretroviral therapy and though counterintuitive. Yet, less is known regarding how depression, social support, and other sociodemographic factors influence outcomes among people living with HIV, particularly in resource-limited settings like Ghana. In view of this gap, this study investigated factors associated with depressive symptoms among people living with HIV in the Volta region of Ghana. A total of 181 people living with HIV from a local antiretroviral clinic was purposively sampled for the study. The questionnaire included the Center for Epidemiologic Studies Depression Scale, the Internalized Stigma of HIV/AIDS Tool, and the Interpersonal Support Evaluation List-12. An independent student t-test, one-way analysis of variance, and chi-square test were conducted to ascertain the associations among the variables of interest. The magnitude of association was evaluated with multiple linear regression. The average depression score among the participants was 9.1±8.8 and 20.4% reported signs of depression. Majority (78%) of participants who were depressed were male compared to females (p = 0.031). In the multiple linear regression, every one-year increase in age was significantly associated with an estimated 0.012 standard deviation increase in depression scores (95% CI: 0.002–0.021) after adjusting for all other variables in the model. Every unit standard deviation increase in social support was significantly associated with an estimated 0.659 standard deviation increase in depression scores (95% CI:0.187–1.132), after adjusting for all other variables in the model. We found a high prevalence of depressive symptoms among people living with HIV especially among males. An increase in age and social support was associated with an increase in depressive symptoms among people living with HIV in this study. We recommend further study using longitudinal approach to understand this unexpected association between depression and social support among people living with HIV in Ghana

Socially Disorganized Rural Communities

The article talks about the social disorganization of rural communities in the U.S. It is stated that family farming has been on the decline for decades, with the numbers of farmers dropping by 16 million since 1950 and farms decreasing by over 4 million during the past century. It is inferred that a part of a community\u27s history and way of life are being forfeited when local business are closing. According to the author, the theory of social disorganization emphasizes social integration and stability as necessary conditions for community. It offers some of the disadvantages of disorganized communities, such as the lack of collective efficacy

Application of Dyes in Nonlinear Optical Materials

An outline of some azobenzene derivatives which are being used in ICI as the basis for new nonlinear optical materials is presented

Electrode-stress-induced nanoscale disorder in Si quantum electronic devices

Disorder in the potential-energy landscape presents a major obstacle to the more rapid development of semiconductor quantum device technologies. We report a large-magnitude source of disorder, beyond commonly considered unintentional background doping or fixed charge in oxide layers: nanoscale strain fields induced by residual stresses in nanopatterned metal gates. Quantitative analysis of synchrotron coherent hard x-ray nanobeam diffraction patterns reveals gate-induced curvature and strains up to 0.03% in a buried Si quantum well within a Si/SiGe heterostructure. Electrode stress presents both challenges to the design of devices and opportunities associated with the lateral manipulation of electronic energy levels