Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension

In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH). 43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-μg increments from 200 μg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 μg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results. A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7- -12.2; p=0.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect. Our results encourage the further investigation of selexipag for the treatment of PAH.     

Serial dependence in time and numerosity perception is dimension-specific

The perception of a visual event (e.g., a flock of birds) at the present moment can be biased by a previous perceptual experience (e.g., the perception of an earlier flock). Serial dependence is a perceptual bias whereby a current stimulus appears more similar to a previous one than it actually is. Whereas serial dependence emerges within several visual stimulus dimensions, whether it could simultaneously operate across different dimensions of the same stimulus (e.g., the numerosity and the duration of a visual pattern) remains unclear. Here we address this question by assessing the presence of serial dependence across duration and numerosity, two stimulus dimensions that are often associated and can bias each other. Participants performed either a duration or a numerosity discrimination task, in which they compared a constant reference with a variable test stimulus, varying along the task-relevant dimension (either duration or numerosity). Serial dependence was induced by a task-irrelevant inducer, that is, a stimulus presented before the reference and always varying in both duration and numerosity. The results show systematic serial dependencies only within the task-relevant stimulus dimension, that is, stimulus numerosity affects numerosity perception only, and duration affects duration perception only. Additionally, at least in the numerosity condition, the task-irrelevant dimension of the inducer (duration) had an opposite, repulsive effect. These findings thus show that attractive serial dependence operates in a highly specific fashion and does not transfer across different stimulus dimensions. Instead, the repulsive influence, possibly reflecting perceptual adaptation, can transfer from one dimension to another.     

Enteral stenting versus gastrojejunostomy for palliation of malignant gastric outlet obstruction

Background and aims

Endoscopic placement of enteral self-expandable metallic stents is an alternative to surgical gastrojejunostomy (GJ) for palliation of malignant gastric outlet obstruction (GOO). Factors associated with clinical outcomes are not known. The aims of this study are to compare the overall complication rate and effectiveness (duration of oral intake) between endoscopic stenting (ES) and GJ in patients with GOO and identify predictors of clinical outcomes.

Patients and methods

This was a retrospective cohort study at a single tertiary academic center. Patients who underwent ES or GJ for treatment of GOO between 1/2001 and 12/2010 were identified using an institutional claims database. The electronic medical records for each patient were reviewed. Univariate and multivariate logistic regression analyses were performed to study the association of treatment outcomes with patient factors and cancer therapy.

Results

120 patients had ES while 227 had GJ. Technical success was higher for GJ (99 vs. 96 %, p = 0.004). Complication rates were higher in the GJ group (22.10 vs. 11.66 %, p = 0.02). Reintervention was more common with ES [adjusted odds ratio (OR) 9.18, p < 0.0001]. Mean length of hospital stay (LOHS) was shorter (adjusted p = 0.005) in the ES compared with the GJ group. However, mean hospital charges, including reinterventions, were greater in the ES group (US $34,250 vs. US $27,599, p = 0.03). ES and GJ had comparable reintervention-free time in patients who had reintervention (88 vs. 106 days, respectively, p = 0.79). Chemotherapy [adjusted hazard ratio (HR) 3 > 0.57, p = 0.04] and radiation therapy (adjusted HR 0.35, p = 0.03) were associated with significantly longer duration of oral intake after ES or GJ.

Conclusion

ES is associated with fewer complications, shorter LOHS, but higher reintervention rates and overall charges.     

Endoscopic ultrasound (EUS)-guided fiducial placement allows localization of small neuroendocrine tumors during parenchymal-sparing pancreatic surgery

Background

Parenchymal-sparing pancreatic surgery is ideal for lesions such as small pancreatic neuroendocrine tumors (PanNET). However, precise localization of these small tumors at surgery can be difficult. The placement of fiducials under endoscopic ultrasound (EUS) guidance (EUS-F) has been used to direct stereotactic radiation therapy for pancreatic adenocarcinoma. This report describes two cases in which placement of fiducials was used to guide surgical resection. This study aimed to assess the feasibility, safety, and efficacy of using EUS-F for intraoperative localization of small PanNETs.

Methods

A retrospective study analyzed two consecutive patients with small PanNETs who underwent EUS-F followed by enucleation in a tertiary-care referral hospital. The following features were examined: technical success and complication rates of EUS-F, visibility of the fiducial at the time of surgery, and fiducial migration.

Results

In the study, EUS-F was performed for two female patients with a 7-mm and a 9-mm PanNET respectively in the uncinate process and neck of the pancreas. In both patients, EUS-F was feasible with two Visicoil fiducials (Core Oncology, Santa Barbara, CA, USA) placed either within or adjacent to the tumors using a 22-gauge Cook Echotip needle. At surgery, the fiducials were clearly visible on intraoperative ultrasound, and both the tumor and the fiducials were successfully enucleated in both cases. No complications were associated with EUS-F, and no evidence of pancreatitis was shown either clinically or on surgical pathology. This investigation had the limitations of a small single-center study.

Conclusions

For patients undergoing enucleation, EUS-F is technically feasible and safe and aids intraoperative localization of small PanNETs.     

Prevention and Treatment Of Heterotopic Ossification After Spinal Cord Injury

Abstract

Background/Objectives: Heterotopic ossification (HO) is a frequent, irreversible complication afterspinal cord injury (SCI). The objective of this article is to explain the etiology of HO; present new advances in prevention, diagnosis, and management of this complication; and provide a suggested algorithm for clinical management.

Etiology: Although still hypothetical, trauma and overexpression of bone morphogenic protein(s) in traumatized soft tissue appear to play important roles as initiating factors of HO.

Prevention: Preventive use of nonsteroidal antiinflammatory agents (NSAIDs) reduces the incidence of HO by a magnitude of 2 to 3.

Management: Early determination of serum creatine phosphokinase may have a diagnostic value in predicting the onset and severity of HO, and an NSAID may be added to etidronate therapy in the initial inflammatory phase of HO formation until C-reactive protein Ieveis return to normal range. Surgery is indicated in a subset of patients, and a regimenthat includes radiation therapy may prevent postoperative recurrence.

Conclusion: Significant progress has been made in the early prevention and management of HO. Further studies are needed to elucidate the etiology.     

Mediastinitis in open heart surgery: a systematic review and meta-analysis of risk factors

Abstract

Objective. We aimed to summarize the evidence from observational studies examining the risk factors of the incidence of mediastinitis in open heart surgery. Design. The study was a systematic review and meta-analysis of cohorts and case-control studies. Material and methods. We searched the literature and 74 studies with at least one risk factor were identified. Both fixed and random effects models were used. Heterogeneity between studies was examined by subgroup and meta-regression analysis. Publication bias or small study effects were evaluated and corrected by limit meta-analysis. Results. When correcting for small study effect, presence of obesity as estimated from 43 studies had Odds Ratio OR = 2.26. (95% CI: 2.17–2.36). This risk was increasing with decreasing latitude of study place. Presence of diabetes mellitus from 63 studies carried an OR = 1.90 (95% CI: 1.59–2.27). Presence of Chronic Obstructive Pulmonary Disease (COPD) from 30 studies had an OR = 2.59 (95% CI: 2.22–2.85). Presence of bilateral intramammary graft (BIMA) from 23 studies carried an OR = 2.54 (95% CI: 2.07–3.13). This risk was increasing with increasing frequency of female patients in the study population. Conclusion. Evidence from this study showed the robustness of the risk factors in the pathogenesis of mediastinitis. Preventive measures can be implemented for reducing obesity, especially in lower latitude countries. Furthermore, it is mandatory to monitor perioperative hyperglycemias with continuous insulin infusion. Use of skeletonized BIMA carries higher risk of mediastinitis especially in female patients without evidence of beneficial effect on survival for the time being.     

Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals

Introduction

Human APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. The clinical relevance is still inconclusive. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART).

Methods

In 88 HIV-1-positive individuals, drug resistance genotyping was carried out in plasma virus and provirus by population sequencing. Hypermutations were determined by three different approaches using Hypermut 2.0 software, cluster analysis and APOBEC3G-mediated defectives indices. Clinical and demographic characteristics of these individuals were studied in relation to these hypermutations.

Results

hA3G/F-mediated hypermutated sequences in proviral DNA, but not in plasma virus, were identified in 11.4% (10/88) subjects. Proviral hypermutations were observed more frequently in patients with ART failure than in ART-naïve individuals (p=0.03). In therapy failure patients, proviral hypermutation were associated with greater intra-compartmental genetic diversity (p<0.001). In therapy-naïve individuals, hypermutated proviral DNA with M184I and M230I mutations due to the editing of hA3G, had stop codons in the open reading frames and the same mutations were absent in the plasma virus. Only a limited concordance was found between the drug resistance mutations in plasma RNA and proviral DNA.

Conclusions

hA3G lethal hypermutation was significantly associated with ART failure in Indian HIV-1 subtype C patients. It is unlikely that viral variants, which exhibit hypermutated sequences and M184I and/or M230I, will mature and expand in vivo.     

The translational repressor eIF4E-binding protein 2 (4E-BP2) correlates with selective delayed neuronal death after ischemia

Transient brain ischemia induces an inhibition of translational rates and causes delayed neuronal death in selective regions and cognitive deficits, whereas these effects do not occur in resistant areas. The translational repressor eukaryotic initiation factor (eIF) 4E-binding protein-2 (4E-BP2) specifically binds to eIF4E and is critical in the control of protein synthesis. To link neuronal death to translation inhibition, we study the eIF4E association with 4E-BP2 under ischemia reperfusion in a rat model of transient forebrain ischemia. Upon reperfusion, a selective neuronal apoptosis in the hippocampal cornu ammonis 1 (CA1) region was induced, while it did not occur in the cerebral cortex. Confocal microscopy analysis showed a decrease in 4E-BP2/eIF4E colocalization in resistant cortical neurons after reperfusion. In contrast, in vulnerable CA1 neurons, 4E-BP2 remains associated to eIF4E with a higher degree of 4E-BP2/eIF4E colocalization and translation inhibition. Furthermore, the binding of a 4E-BP2 peptide to eIF4E induced neuronal apoptosis in the CA1 region. Finally, pharmacological-induced protection of CA1 neurons inhibited neuronal apoptosis, decreased 4E-BP2/eIF4E association, and recovered translation. These findings documented specific changes in 4E-BP2/eIF4E association during ischemic reperfusion, linking the translation inhibition to selective neuronal death, and identifying 4E-BP2 as a novel target for protection of vulnerable neurons in ischemic injury.