Adult patients with pulmonary arterial hypertension due to congenital heart disease: a review on advanced medical treatment with bosentan

Pulmonary arterial hypertension (PAH) is a progressive disease with poor survival outcome. PAH is classified by the 2009 updated clinical classification of pulmonary hypertension and a major subgroup is PAH due to congenital heart disease (CHD) with systemic-to-pulmonary shunt. CHD-PAH is a result of systemic-to-pulmonary shunting and chronic increased flow that ultimately results in adaptations of pulmonary vasculature and endothelial dysfunction. The advanced stage is called Eisenmenger syndrome which forms a small percentage (1%) of all CHD patients. Therapies targeted on PAH symptoms are called primary therapy for PAH, but most CHD-PAH patients progress to advanced therapy which is directed at the PAH itself. In CHD-PAH, advanced therapies are extensively investigated for all three major pathways: endothelin-1 receptor antagonists such as bosentan, prostanoids such as epoprostenol and phosphodiesterase 5 inhibitors such as sildenafil. Endpoints in most trials were catheterization hemodynamics, World Health Organization functional class, six-minute walking distance and patient-focused outcomes, based on quality of life questionnaires and Borg dyspnea index. The BREATHE-5 and EARLY study were two important randomized controlled trials showing efficacy of bosentan at short follow-up. Moreover in patients with Eisenmenger syndrome, one recent survival retrospective study with majority of patients on bosentan showed strong survival benefit over conservative therapy. A diversity of prospective cohort and retrospective studies were performed but all with limited data, due to small numbers and heterogeneity of underlying CHD diagnoses. Further larger studies are needed to determine optimal treatment for adults with CHD-PAH. This review focuses on bosentan in CHD-PAH. In particular, we discuss outcome of various clinical trials and compare efficacy and safety of bosentan to other advanced therapies

Arterial CO2 pressure changes during hypercapnia are associated with changes in brain parenchymal volume

The Monro-Kellie hypothesis (MKH) states that volume changes in any intracranial component (blood, brain tissue, cerebrospinal fluid) should be counterbalanced by a co-occurring opposite change to maintain intracranial pressure within the fixed volume of the cranium. In this feasibility study, we investigate the MKH application to structural magnetic resonance imaging (MRI) in observing compensating intracranial volume changes during hypercapnia, which causes an increase in cerebral blood volume. Seven healthy subjects aged from 24 to 64 years (median 32), 4 males and 3 females, underwent a 3-T three-dimensional T1-weighted MRI under normocapnia and under hypercapnia. Intracranial tissue volumes were computed. According to the MKH, the significant increase in measured brain parenchymal volume (median 6.0 mL; interquartile range 4.5, 8.5; p = 0.016) during hypercapnia co-occurred with a decrease in intracranial cerebrospinal fluid (median -10.0 mL; interquartile range -13.5, -6.5; p = 0.034). These results convey several implications: (i) blood volume changes either caused by disorders, anaesthesia, or medication can affect outcome of brain volumetric studies; (ii) besides probing tissue displacement, this approach may assess the brain cerebrovascular reactivity. Future studies should explore the use of alternative sequences, such as three-dimensional T2-weighted imaging, for improved quantification of hypercapnia-induced volume changes

On the Origin of Regioselectivity in Palladium-Catalyzed Oxidation of Glucosides

The palladium-catalyzed oxidation of glucopyranosides has been investigated using relativistic density functional theory (DFT) at ZORA-BLYP−D3(BJ)/TZ2P. The complete Gibbs free energy profiles for the oxidation of secondary hydroxy groups at C2, C3, and C4 were computed for methyl β-glucoside and methyl carba-β-glucoside. Both computations and oxidation experiments on carba-glucosides demonstrate the crucial role of the ring oxygen in the C3 regioselectivity observed during the oxidation of glucosides. Analysis of the model systems for oxidized methyl β-glucoside shows that the C3 oxidation product is intrinsically favored in the presence of the ring oxygen. Subsequent energy decomposition analysis (EDA) and Hirschfeld charge analysis reveal the role of the ring oxygen: it positively polarizes C1/C5 by inductive effects and disfavors any subsequent buildup of positive charge at neighboring carbon atoms, rendering C3 the most favored site for the β-hydride elimination

Six-Minute Walk Test in Patients With Down Syndrome:Validity and Reproducibility

Contains fulltext : 81543.pdf (publisher's version ) (Closed access)OBJECTIVES: To examine the validity of the six-minute walk test (6MWT) as a tool to evaluate functional exercise performance in patients with Down syndrome (DS). DESIGN: Comparison of the six-minute walk distance (6MWD) in 2 distinct groups of DS patients: with and without severe cardiac disease. To test reproducibility, a group of patients with DS performed the 6MWT twice. SETTING: Tertiary referral centers for patients with congenital heart defects and outpatient clinics for people with intellectual disabilities. PARTICIPANTS: Adult patients with DS with (n=29) and without (n=52) severe cardiac disease categorized by cardiac echocardiography. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Distance walked on the 6MWT. RESULTS: The mean 6MWD in the group with severe cardiac disease was 289+/-104 m and in the group without severe cardiac disease 280+/-104 m (P=.70). Older age, female sex, and severe level of intellectual disability were all found to be independently and significantly correlated with a lower 6MWD (r=.67, P<.001). The paired 6MWD was not significantly different (310+/-88 m vs 317+/-85 m; P=.40) in patients who performed the 6MWT twice. The coefficient of variation was 11%. CONCLUSIONS: The 6MWD between the 2 groups was not significantly different. However, the walking distance inversely correlated with the level of intellectual disability. Therefore, the 6MWT is not a valid test to examine cardiac restriction in adult patients with DS

ExploreASL: an image processing pipeline for multi-center ASL perfusion MRI studies

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Fast CSF MRI for brain segmentation; Cross-validation by comparison with 3D T1-based brain segmentation methods

OBJECTIVE: In previous work we have developed a fast sequence that focusses on cerebrospinal fluid (CSF) based on the long T2 of CSF. By processing the data obtained with this CSF MRI sequence, brain parenchymal volume (BPV) and intracranial volume (ICV) can be automatically obtained. The aim of this study was to assess the precision of the BPV and ICV measurements of the CSF MRI sequence and to validate the CSF MRI sequence by comparison with 3D T1-based brain segmentation methods. MATERIALS AND METHODS: Ten healthy volunteers (2 females; median age 28 years) were scanned (3T MRI) twice with repositioning in between. The scan protocol consisted of a low resolution (LR) CSF sequence (0:57min), a high resolution (HR) CSF sequence (3:21min) and a 3D T1-weighted sequence (6:47min). Data of the HR 3D-T1-weighted images were downsampled to obtain LR T1-weighted images (reconstructed imaging time: 1:59 min). Data of the CSF MRI sequences was automatically segmented using in-house software. The 3D T1-weighted images were segmented using FSL (5.0), SPM12 and FreeSurfer (5.3.0). RESULTS: The mean absolute differences for BPV and ICV between the first and second scan for CSF LR (BPV/ICV: 12±9/7±4cc) and CSF HR (5±5/4±2cc) were comparable to FSL HR (9±11/19±23cc), FSL LR (7±4, 6±5cc), FreeSurfer HR (5±3/14±8cc), FreeSurfer LR (9±8, 12±10cc), and SPM HR (5±3/4±7cc), and SPM LR (5±4, 5±3cc). The correlation between the measured volumes of the CSF sequences and that measured by FSL, FreeSurfer and SPM HR and LR was very good (all Pearson's correlation coefficients >0.83, R2 .67-.97). The results from the downsampled data and the high-resolution data were similar. CONCLUSION: Both CSF MRI sequences have a precision comparable to, and a very good correlation with established 3D T1-based automated segmentations methods for the segmentation of BPV and ICV. However, the short imaging time of the fast CSF MRI sequence is superior to the 3D T1 sequence on which segmentation with established methods is performed

All CSF measurements for all methods in each subject.

<p>One slice from subject 8 from A) the HR T₁-weighted image (downsampled images have the same in-plane resolution); B) 3D T₁-weighted FSL HR; C) 3D T₁-weighted SPM HR; D) postprocessed CSF LR; E) postprocessed CSF HR. No image is presented for FreeSurfer, because FreeSurfer uses the determinant of the transformation matrix to estimate ICV rather than distinguishing the skull from peripheral CSF.</p