Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: a meta-analysis of randomized trials

BACKGROUND & AIMS Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB on HCC by performing a systematic review with meta-analyses of randomized trials. METHODS Electronic and manual searches were combined. Authors were contacted for unpublished data. Included trials assessed NSBB for patients with cirrhosis; the control group could receive any other intervention than NSBB. Fixed and random effects meta-analyses were performed with I(2) as a measure of heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate heterogeneity, bias and the robustness of the results after adjusting for multiple testing. RESULTS Twenty-three randomized trials on 2618 patients with cirrhosis were included, of which 12 reported HCC incidence and 23 reported HCC mortality. The mean duration of follow-up was 26 months (range 8-82). In total, 47 of 694 patients randomized to NSBB developed HCC vs 65 of 697 controls (risk difference -0.026; 95% CI-0.052 to -0.001; number needed to treat 38 patients). There was no heterogeneity (I(2) = 7%) or evidence of small study effects (Eggers P = 0.402). The result was not confirmed in sequential analysis, which suggested that 3719 patients were needed to achieve the required information size. NSBB did not reduce HCC-related mortality (RD -0.011; 95% CI -0.040 to 0.017). CONCLUSIONS Non-selective beta-blockers may prevent HCC in patients with cirrhosis.

Outcome discrepancies and selective reporting: impacting the leading journals?

BACKGROUND Selective outcome reporting of either interesting or positive research findings is problematic, running the risk of poorly-informed treatment decisions. We aimed to assess the extent of outcome and other discrepancies and possible selective reporting between registry entries and published reports among leading medical journals. METHODS Randomized controlled trials published over a 6-month period from July to December 31st, 2013, were identified in five high impact medical journals: The Lancet, British Medical Journal, New England Journal of Medicine, Annals of Internal Medicine and Journal of American Medical Association were obtained. Discrepancies between published studies and registry entries were identified and related to factors including registration timing, source of funding and presence of statistically significant results. RESULTS Over the 6-month period, 137 RCTs were found. Of these, 18% (n = 25) had discrepancies related to primary outcomes with the primary outcome changed in 15% (n = 20). Moreover, differences relating to non-primary outcomes were found in 64% (n = 87) with both omission of pre-specified non-primary outcomes (39%) and introduction of new non-primary outcomes (44%) common. No relationship between primary or non-primary outcome change and registration timing (prospective or retrospective; P = 0.11), source of funding (P = 0.92) and presence of statistically significant results (P = 0.92) was found. CONCLUSIONS Discrepancies between registry entries and published articles for primary and non-primary outcomes were common among trials published in leading medical journals. Novel approaches are required to address this problem.

Aberrant association of misfolded SOD1 with Na+/K+ATPase-α3 impairs its activity and contributes to motor neuron vulnerability in ALS.

Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific antibody B8H10 which recognizes a misfolded state of SOD1 (misfSOD1) to longitudinally identify its interactome during early disease stage in SOD1G93A mice. This strategy identified a direct isozyme-specific association of misfSOD1 with Na+/K+ATPase-α3 leading to the premature impairment of its ATPase activity. Pharmacological inhibition of Na+/K+ATPase-α3 altered glutamate receptor 2 expression, modified cholinergic inputs and accelerated disease pathology. After mapping the site of direct association of misfSOD1 with Na+/K+ATPase-α3 onto a 10 amino acid stretch that is unique to Na+/K+ATPase-α3 but not found in the closely related Na+/K+ATPase-α1 isozyme, we generated a misfSOD1 binding deficient, but fully functional Na+/K+ATPase-α3 pump. Adeno associated virus (AAV)-mediated expression of this chimeric Na+/K+ATPase-α3 restored Na+/K+ATPase-α3 activity in the spinal cord, delayed pathological alterations and prolonged survival of SOD1G93A mice. Additionally, altered Na+/K+ATPase-α3 expression was observed in the spinal cord of individuals with sporadic and familial ALS. A fraction of sporadic ALS cases also presented B8H10 positive misfSOD1 immunoreactivity, suggesting that similar mechanism might contribute to the pathology.

The role of vulnerability factors in individuals with an at-risk mental state of psychosis

Background Several indicators of heightened vulnerability to psychosis and relevant stressors have been identified. However, it has rarely been studied prospectively to what extent these vulnerability factors are in fact more frequently present in individuals with an at-risk mental state for psychosis. Moreover, it remains unknown whether any of these contribute to the prediction of psychosis onset in at-risk mental state individuals. Methods There were 28 healthy controls, 86 first-episode psychosis patients and 127 at-risk mental state individuals recruited within the Basel “Früherkennung von Psychosen” project. Relative frequencies of selected vulnerability factors for psychosis were compared between healthy controls, psychosis patients, those at-risk mental state individuals with subsequent psychosis onset (n = 31) and those without subsequent psychosis onset (n = 55). Survival analyses were applied to determine associations between time to transition to psychosis and vulnerability factors in all 127 at-risk mental state individuals. Results The vulnerability factors/indicators such as “difficulties during school education or vocational training”, “difficulties during employment”, “being single”, “difficulties with intimate relationships” and “being burdened with specific stressful situations” were more commonly found in the at-risk mental state and first-episode psychosis group than in healthy controls. Conclusions At-risk mental state and first-episode psychosis individuals more frequently present with vulnerability factors. Individual vulnerability factors appear, however, not to be predictive for an onset of psychosis.

Automatic assessment of time-resolved OCT images for selective retina therapy

Purpose In recent years, selective retina laser treatment (SRT), a sub-threshold therapy method, avoids widespread damage to all retinal layers by targeting only a few. While these methods facilitate faster healing, their lack of visual feedback during treatment represents a considerable shortcoming as induced lesions remain invisible with conventional imaging and make clinical use challenging. To overcome this, we present a new strategy to provide location-specific and contact-free automatic feedback of SRT laser applications. Methods We leverage time-resolved optical coherence tomography (OCT) to provide informative feedback to clinicians on outcomes of location-specific treatment. By coupling an OCT system to SRT treatment laser, we visualize structural changes in the retinal layers as they occur via time-resolved depth images. We then propose a novel strategy for automatic assessment of such time-resolved OCT images. To achieve this, we introduce novel image features for this task that when combined with standard machine learning classifiers yield excellent treatment outcome classification capabilities. Results Our approach was evaluated on both ex vivo porcine eyes and human patients in a clinical setting, yielding performances above 95 % accuracy for predicting patient treatment outcomes. In addition, we show that accurate outcomes for human patients can be estimated even when our method is trained using only ex vivo porcine data. Conclusion The proposed technique presents a much needed strategy toward noninvasive, safe, reliable, and repeatable SRT applications. These results are encouraging for the broader use of new treatment options for neovascularization-based retinal pathologies.

Selective sampling during catastrophic disruption: Mapping the location of reaccumulated fragments in the original parent body

In this paper, we simulate numerically the catastrophic disruption of a large asteroid as a result of a collision with a smaller projectile and the subsequent reaccumulation of fragments as a result of their mutual gravitational attractions. We then investigate the original location within the parent body of the small pieces that eventually reaccumulate to form the largest offspring of the disruption as a function of the internal structure of the parent body. We consider four cases that may represent the internal structure of such a body (whose diameter is fixed at 250 km) in various early stages of the Solar System evolution: fully molten, half molten (i.e., a 26 km-deep outer layer of melt containing half of the mass), solid except a thin molten layer (8 km thick) centered at 10 km depth, and fully solid. The solid material has properties of basalt. We then focus on the three largest offspring that have enough reaccumulated pieces to consider. Our results indicate that the particles that eventually reaccumulate to form the largest reaccumulated bodies retain a memory of their original locations in the parent body. Most particles in each reaccumulated body are clustered from the same original region, even if their reaccumulations take place far away. The extent of the original region varies considerably depending on the internal structure of the parent. It seems to shrink with the solidity of the body. The fraction of particles coming from a given depth is computed for the four cases, which can give constraints on the internal structure of parent bodies of some meteorites. As one example, we consider the ureilites, which in some petrogenetic models are inferred to have formed at particular depths within their parent body. (C) 2014 Elsevier Ltd. All rights reserved.