Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial

BACKGROUND: Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. METHODS: In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. FINDINGS: The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. INTERPRETATION: Our results suggest that carvedilol extends survival compared with metoprolo

Clinical outcome of prophylactic oophorectomy in BRCA1/BRCA2 mutation carriers and events during follow-up

A retrospective study was performed to assess the histopathologic findings in high-risk women undergoing bilateral prophylactic (salpingo)-oophorectomy. The medical files of BRCA1 or BRCA2 mutation carriers and members of a hereditary breast/ovarian cancer (HBOC) family, who had undergone prophylactic surgery, were reviewed. In all, 38 women underwent a bilateral oophorectomy (26 BRCA1, three BRCA2 and nine HBOC, respectively). A total of 90 women underwent bilateral salpingo-oophorectomy (58 BRCA1, six BRCA2, one BRCA1 and 2, 25 HBOC, respectively). At the time of salpingo-oophorectomy, five of 58 BRCA1 carriers (8.6%) were diagnosed with an occult carcinoma: two fallopian tube carcinomas, two ovarian carcinomas and one case was defined as a fallopian tube/ovarian carcinoma. No occult carcinomas were found in the other groups. Of the 38 patients, who underwent a bilateral oophorectomy (mean follow-up 45 months), three of 26 BRCA1 mutation carriers (3.4 in 100 women-years) developed peritoneal papillary serous carcinoma (PPSC) during follow-up. So far, no PPSC have occurred in the 90 women, who underwent a salpingo-oophorectomy (mean follow-up 12 months), including 58 BRCA1 carriers (0 in 60 in women-years). These results contribute to the thesis that BRCA1 germline mutation carriers are not only at risk for ovarian cancer, but also for fallopian tube carcinoma and peritoneal papillary serous carcinoma. Our data suggest that PPSC risk among BRCA2 carriers is lower than among BRCA1 carrier

Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty

A randomised trial of 367 patients with acute myocardial infarction was performed to determine whether an invasive strategy combining thrombolysis with recombinant tissue-type plasminogen activator (rTPA), heparin, and acetylsalicylic acid, and immediate percutaneous transluminal coronary angioplasty (PTCA) would be superior to a noninvasive strategy with the same medical treatment but without immediate angiography and PTCA. Intravenous infusion of 100 mg rTPA was started within 5 h after onset of symptoms (median 156 min). Angiography was performed 6-165 min later in 180 out of 183 patients allocated to the invasive strategy; 184 patients were allocated to the non-invasive strategy. Immediate PTCA reduced the percentage stenosis of the infarc

Discovery of New Molecular Subtypes in Oesophageal Adenocarcinoma

A large number of patients suffering from oesophageal adenocarcinomas do not respond to conventional chemotherapy; therefore, it is necessary to identify new predictive biomarkers and patient signatures to improve patient outcomes and therapy selections. We analysed 87 formalin-fixed and paraffin-embedded (FFPE) oesophageal adenocarcinoma tissue samples with a reverse phase protein array (RPPA) to examine the expression of 17 cancer-related signalling molecules. Protein expression levels were analysed by unsupervised hierarchical clustering and correlated with clinicopathological parameters and overall patient survival. Proteomic analyses revealed a new, very promising molecular subtype of oesophageal adenocarcinoma patients characterised by low levels of the HSP27 family proteins and high expression of those of the HER family with positive lymph nodes, distant metastases and short overall survival. After confirmation in other independent studies, our results could be the foundation for the development of a Her2-targeted treatment option for this new patient subgroup of oesophageal adenocarcinoma

White Matter and Cognition in Adults Who Were Born Preterm

BACKGROUND AND PURPOSE: Individuals born very preterm (before 33 weeks of gestation, VPT) are at risk of damage to developing white matter, which may affect later cognition and behaviour. METHODS: We used diffusion tensor MRI (DT-MRI) to assess white matter microstructure (fractional anisotropy; FA) in 80 VPT and 41 term-born individuals (mean age 19.1 years, range 17-22, and 18.5 years, range 17-22 years, respectively). VPT individuals were part of a 1982-1984 birth cohort which had been followed up since birth; term individuals were recruited by local press advertisement. General intellectual function, executive function and memory were assessed. RESULTS: The VPT group had reduced FA in four clusters, and increased FA in four clusters relative to the Term group, involving several association tracts of both hemispheres. Clusters of increased FA were associated with more severe neonatal brain injury in the VPT group. Clusters of reduced FA were associated with lower birth weight and perinatal hypoxia, and with reduced adult cognitive performance in the VPT group only. CONCLUSIONS: Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function

Neonatal Brain Injury and Neuroanatomy of Memory Processing following Very Preterm Birth in Adulthood: An fMRI Study

Altered functional neuroanatomy of high-order cognitive processing has been described in very preterm individuals (born before 33 weeks of gestation; VPT) compared to controls in childhood and adolescence. However, VPT birth may be accompanied by different types of adverse neonatal events and associated brain injury, the severity of which may have differential effects on brain development and subsequent neurodevelopmental outcome. We conducted a functional magnetic resonance imaging (fMRI) study to investigate how differing degrees of neonatal brain injury, detected by neonatal ultrasounds, affect the functional neuroanatomy of memory processing in VPT young adults. We used a verbal paired associates learning task, consisting of four encoding, four cued-recall and four baseline condition blocks. To further investigate whether differences in neural activation between the groups were modulated by structural brain changes, structural MRI data were also collected. We studied 12 VPT young adults with a history of periventricular haemorrhage with associated ventricular dilatation, 17 VPT individuals with a history of uncomplicated periventricular haemorrhage, 12 individuals with normal ultrasonographic findings, and 17 controls. Results of a linear trend analysis demonstrated that during completion of the paired associates learning task right frontal and right parietal brain activation decreased as the severity of neonatal brain injury increased. There were no statistically significant between-group differences in on-line task performance and participants' intelligence quotient (IQ) at assessment. This pattern of differential activation across the groups was observed particularly in the right middle frontal gyrus during encoding and in the right posterior cingulate gyrus during recall. Structural MRI data analysis revealed that grey matter volume in the right superior temporal gyrus, right cerebellum, left middle temporal gyrus, right globus pallidus and right medial frontal gyrus decreased with increasing severity of neonatal brain injury. However, the significant between-group functional neuroanatomical differences were not directly attributable to the detected structural regional differences

Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial

Hans Verhoef and colleagues report findings from a randomized trial conducted among Tanzanian children at high risk for malaria. Children in the trial received either daily oral supplementation with either zinc alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. The investigators did not find evidence from this study that zinc or multi-nutrients protected against malaria episodes

Co-chaperones are limiting in a depleted chaperone network

To probe the limiting nodes in the chaperoning network which maintains cellular proteostasis, we expressed a dominant negative mutant of heat shock factor 1 (dnHSF1), the regulator of the cytoplasmic proteotoxic stress response. Microarray analysis of non-stressed dnHSF1 cells showed a two- or more fold decrease in the transcript level of 10 genes, amongst which are the (co-)chaperone genes HSP90AA1, HSPA6, DNAJB1 and HSPB1. Glucocorticoid signaling, which requires the Hsp70 and the Hsp90 folding machines, was severely impaired by dnHSF1, but fully rescued by expression of DNAJA1 or DNAJB1, and partially by ST13. Expression of DNAJB6, DNAJB8, HSPA1A, HSPB1, HSPB8, or STIP1 had no effect while HSP90AA1 even inhibited. PTGES3 (p23) inhibited only in control cells. Our results suggest that the DNAJ co-chaperones in particular become limiting in a depleted chaperoning network. Our results also suggest a difference between the transcriptomes of cells lacking HSF1 and cells expressing dnHSF1