Ventricular pacing or dual-chamber pacing for sinus-node dysfunction

BACKGROUND Dual-chamber (atrioventricular) and single-chamber (ventricular) pacing are alternative treatment approaches for sinus-node dysfunction that causes clinically significant bradycardia. However, it is unknown which type of pacing results in the better outcome. METHODS We randomly assigned a total of 2010 patients with sinus-node dysfunction to dual-chamber pacing (1014 patients) or ventricular pacing (996 patients) and followed them for a median of 33.1 months. The primary end point was death from any cause or nonfatal stroke. Secondary end points included the composite of death, stroke, or hospitalization for heart failure; atrial fibrillation; heart-failure score; the pacemaker syndrome; and the quality of life. RESULTS The incidence of the primary end point did not differ significantly between the dual-chamber group (21.5 percent) and the ventricular-paced group (23.0 percent, P=0.48). In patients assigned to dual-chamber pacing, the risk of atrial fibrillation was lower (hazard ratio, 0.79; 95 percent confidence interval, 0.66 to 0.94; P=0.008), and heart-failure scores were better (P CONCLUSIONS In sinus-node dysfunction, dual-chamber pacing does not improve stroke-free survival, as compared with ventricular pacing. However, dual-chamber pacing reduces the risk of atrial fibrillation, reduces signs and symptoms of heart failure, and slightly improves the quality of life. Overall, dual-chamber pacing offers significant improvement as compared with ventricular pacing

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The Computerized test of information processing (CTIP) Offers an alternative to the PASAT for assessing cognitive processing speed in individuals with multiple sclerosis

Objective: To compare the ability of the Computerized Test of Information Processing (CTIP) to detect impaired cognitive processing speed in patients with multiple sclerosis (MS) with a traditional 3.0 second Paced Auditory Serial Addition Test (PASAT) and the Adjusting-PASAT which allows for calculation of a speed score. Background: A primary cognitive deficit in MS is an impaired ability to process information quickly. Unfortunately, relatively few clinical tests effectively measure information processing speed. Of these, the PASAT is generally acknowledged to be the most sensitive, but use of this test is constrained by several factors. Methods: All tests were administered to 30 adults with relapsing-remitting MS and 30 control participants. Results: A series of analysis of variances revealed MS participants performed significantly worse than controls on the CTIP and the 3.0 second PASAT, whereas no significant difference was observed for the Adjusting-PASAT. Conclusions: The results suggest the CTIP can detect deficits in the speed at which people with MS process information. Thus, the CTIP offers an alternative means to the 3.0 second PASAT included in the Multiple Sclerosis Functional Composite for assessing such impairment. Copyrigh

Reaction time: An alternative method for assessing the effects of multiple sclerosis on information processing speed

The ability of a newly developed measure of information processing to detect deficits in cognitive functioning associated with multiple sclerosis (MS) was investigated. The Computerized Tests of Information Processing (CTIP; Tombaugh, T., & Rees, L. (1999). Computerized Tests of Information Processing (CTIP). Unpublished test. Ottawa, Ontario, Canada: Carleton University) was administered to 60 clinically definite MS patients and 60 healthy controls. MS patients responded significantly slower than controls on the reaction time tests composing the CTIP. Moreover, as the CTIP tests became more difficult (i.e. as processing demands increased), the difference between the performances of the two groups progressively increased. These results suggest the CTIP is sensitive to the cognitive deficits observed in MS and that this measure has the potential to serve as a viable alternative to traditional measures of information processing speed currently in use with MS patients

Cognitive fatigue in individuals with multiple sclerosis undergoing immunoablative therapy and hematopoietic stem cell transplantation

Background Fatigue presents as a significant problem in multiple sclerosis (MS). Cognitive fatigue (CF) can be defined as a decrease in, or inability to maintain task performance throughout the duration of a continuous cognitive task. CF was evaluated using the Paced Auditory Serial Addition Test (PASAT) both pre- and post-immunoablation and hematopoietic stem cell transplantation (IA-HSCT) over a 3-year follow-up period. The magnitude of CF was examined and the impact of scoring methodology was evaluated. Methods Twenty-three individuals with rapidly progressive MS and poor prognosis underwent high dose immunosuppression and subsequent HSCT. Individuals completed the 3″ and 2″ PASAT at baseline and every 6 months thereafter over a period of 36 months. As scoring methodology can impact its sensitivity to CF, the PASAT was s

fMRI investigation of disinhibition in cognitively impaired patients with multiple sclerosis

Although deficits in executive functioning are well known cognitive sequelae of multiple sclerosis (MS), less is known about patients' performance on response inhibition tasks in particular. Behavioural observation of cognitively impaired MS patients often reveals impulsivity. However, knowledge about associated neural activity during response inhibition measurable with functional magnetic resonance imaging (fMRI) is lacking. In the current study the performance and fMRI activation patterns of patients with MS on a response inhibition task (Go/No-Go) were investigated. Methods: Ten cognitively impaired patients with MS (with little or no physical disability) and 10 sex-, age- and education-matched healthy controls performed a Go/No-Go task while in the MR scanner. Results: MS patients had significantly more commission errors than controls but did not demonstrate longer reaction times. Controlling for this difference, whole brain random effects analyses revealed that patients demonstrated more activation than controls in the fusiform gyrus, cingulate gyrus (including the anterior cingulate gyrus), cerebellum and putamen. Patients demonstrated less activity than controls in the supramarginal gyrus. Conclusions: MS patients exhibited significant neural compensation during response inhibition when compared with controls. The specific results provide new insight into the neural processing underlying the impulsivity often observed in cognitively impaired individuals with MS

Tests of information processing speed: What do people with multiple sclerosis think about them?

Reduction in information processing speed (IPS) is a key deficit in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and Computerized Test of Information Processing (CTIP) are used to measure IPS. Both the PASAT and SDMT are sensitive to deficits in IPS. The CTIP, a newer task, also shows promise. The PASAT has several limitations, and it is often perceived negatively by patients. Yet little supporting quantitative evidence of such perceptions has been presented. Therefore, in this study, subjective ratings of likeability, difficulty, and appropriateness of the PASAT, CTIP, and SDMT were obtained. Ratings were compared between MS patients and healthy controls. It was hypothesized that ratings of the PASAT would differ significantly from those of the SDMT and CTIP. The relationship between subjective ratings and objective performance was evaluated. Sixty-nine MS patients and 68 matched controls rated the three tests in terms of likeability, difficulty, and appropriateness for capturing cognitive deficits often associated with MS using a Likert scale. Both groups rated the PASAT as most difficult and least likeable. The MS group rated the PASAT and SDMT as more appropriate for measuring MS-related deficits than the CTIP. Subjects who performed better on the PASAT were more likely to rate it as easier. Ratings of the SDMT and CTIP did not vary consistently with performance. The findings lend quantitative support to the common belief that the PASAT is perceived as unpleasant. Other tests are available that are similarly sensitive to deficits in IPS and more palatable to the patient