Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials.

Liver metastases have long been known to indicate an unfavourable disease course in breast cancer (BC). However, a small subset of patients with liver metastases alone who were treated with pre-taxane chemotherapy regimens was reported to have longer survival compared with patients with liver and metastases at other sites. In the present study, we examined the clinical outcome of breast cancer patients with liver metastases alone in the context of two phase III European Organisation for Research and Treatment of Cancer (EORTC) trials which compared the efficacy of doxorubicin (A) versus paclitaxel (T) (trial 10923) and of AC (cyclophosphamide) versus AT (trial 10961), given as first-line chemotherapy in metastatic BC patients. The median follow-up for the patients with liver metastases was 90.5 months in trial 10923 and 56.6 months in trial 10961. Patients with liver metastases alone comprised 18% of all patients with liver metastases, in both the 10923 and 10961 trials. The median survival of patients with liver metastases alone and liver plus other sites of metastases were 22.7 and 14.2 months (log rank test, P=0.002) in trial 10923 and 27.1 and 16.8 months (log rank test, P=0.19) in trial 10961. The median TTP (time to progression) for patients with liver metastases alone was also longer compared with the liver plus other sites of metastases group in both trials: 10.2 versus 8.8 months (log rank test, P=0.02) in trial 10923 and 8.3 versus 6.7 months (log rank test, P=0.37) in trial 10961. Most patients with liver metastases alone have progression of their disease in their liver again (96 and 60% of patients in trials 10923 and 10961, respectively). Given the high prevalence of breast cancer, improved detection of liver metastases, encouraging survival achieved with currently available cytotoxic agents and the fact that a significant portion of patients with liver metastases alone have progression of their tumour in the liver again, a more aggressive multimodality treatment approach through prospective clinical trials seems worth exploring in this specific subset of women.

Multi-centre research in Australia:analysis of a recent National Health and Medical Research Council-funded project

BACKGROUND AND OBJECTIVE: Human research ethics committees provide essential review of research projects to ensure the ethical conduct of human research. Several recent reports have highlighted a complex process for successful application for human research ethics committee approval, particularly for multi-centre studies. Limited resources are available for the execution of human clinical research in Australia and around the world.

METHODS: This report overviews the process of ethics approval for a National Health and Medical Research Council-funded multi-centre study in Australia, focussing on the time and resource implications of such applications in 2007 and 2008.

RESULTS: Applications were submitted to 16 hospital and two university human research ethics committees. The total time to gain final approval from each committee ranged between 13 and 77 days (median = 46 days); the entire process took 16 months to complete and the research officer's time was estimated to cost $A34 143.

CONCLUSIONS: Obstacles to timely human research ethics committee approval are reviewed, including recent, planned and potential initiatives that could improve the ethics approval of multi-centre research.

Posterior partially edentulous jaws, planning a rehabilitation with dental implants

To discuss important characteristics of the use of dental implants in posterior quadrants and the rehabilitation planning. An electronic search of English articles was conducted on MEDLINE (PubMed) from 1990 up to the period of March 2014. The key terms were dental implants and posterior jaws, dental implants/treatment planning and posterior maxilla, and dental implants/treatment planning and posterior mandible. No exclusion criteria were used for the initial search. Clinical trials, randomized and non randomized studies, classical and comparative studies, multicenter studies, in vitro and in vivo studies, case reports, longitudinal studies and reviews of the literature were included in this review. One hundred and fifty-two articles met the inclusion criteria of treatment planning of dental implants in posterior jaw and were read in their entirety. The selected articles were categorized with respect to their context on space for restoration, anatomic considerations (bone quantity and density), radiographic techniques, implant selection (number, position, diameter and surface), tilted and pterygoid implants, short implants, occlusal considerations, and success rates of implants placed in the posterior region. The results derived from the review process were described under several different topic headings to give readers a clear overview of the literature. In general, it was observed that the use of dental implants in posterior region requires a careful treatment plan. It is important that the practitioner has knowledge about the theme to evaluate the treatment parameters. The use of implants to restore the posterior arch presents many challenges and requires a detailed treatment planning.

Nosocomial infection: A risk factor for a complicated course in children with respiratory syncytial virus infection - Results from a prospective multicenter German surveillance study

BACKGROUND: Nosocomially acquired respiratory syncytial virus infections (RSV-NI) may cause serious problems in hospitalized paediatric patients. Hitherto, prospectively collected representative data on RSV-NI from multicenter studies in Germany are limited. METHODS: The DMS RSV Ped database was designed for the prospective multicenter documentation and analysis of clinically relevant aspects of the management of inpatients with RSV-infection. The study covered six consecutive seasons (1999-2005); the surveillance took place in 14 paediatric hospitals in Germany. RESULTS: Of the 1568 prospectively documented RSV-infections, 6% (n=90) were NI and 94% (n=1478) were community acquired (CA). A significantly higher proportion in the NI group displayed additional risk factors like prematurity, chronic lung disease, mechanical ventilation (med. history), congenital heart disease, and neuromuscular impairment. Of all NI, 55% occurred in preterms (30.6% of all RSV-infections in preterms with severe chronic lung disease of prematurity were NI). Illness severity as well as the total mortality, but not the attributable mortality was significantly higher in the NI group. In the multivariate analysis, NI was significantly associated with the combined outcome 'complicated course of disease'. CONCLUSION: This is the first prospective multicenter study from Germany, which confirms the increased risk of a severe clinical course in nosocomially acquired RSV-infection. Of great concern is the high rate of (preventable) NI in preterms, in particular in those with severe chronic lung disease or with mechanical ventilation due to other reasons.

Safety and efficacy of the combination of trastuzumab with docetaxel for HER2-positive women with advanced breast cancer : a review of the existing clinical trials and results of the expanded access programme in the UK

Trastuzumab is a humanised monoclonal antibody against the extracellular domain of HER2 (human epidermal growth factor receptor-2) that is overexpressed in about 25% of human breast cancers. It has shown clinical benefit in HER2-positive breast cancer cases when used alone or in combination with chemotherapy. Trastuzumab increases the response rate to chemotherapy and prolongs survival when used in combination with taxanes. In this article, we review the clinical trials where trastuzumab has been administered together with docetaxel, and we present the results of the trastuzumab expanded access programme (EAP) in the UK. Combination of trastuzumab with docetaxel results in similar response rates and time-to-progression with the trastuzumab/paclitaxel combinations. The toxicity of the combination and the risk of heart failure are low. The clinical data for the docetaxel/trastuzumab combination indicate a favourable profile from both the efficacy and the safety point of view and confirm the feasibility and safety of trastuzumab administration both as monotherapy and in combination with docetaxel. © 2004 Blackwell Publishing Ltd.

Groteski suomalaisessa kirjallisuudessa : Neljä tapaustutkimusta

The grotesque in Finnish literature. Four case studies The topic of the dissertation is the grotesque in Finnish literature. The dissertation is twofold. Firstly, it focuses on the genre tradition of the grotesque, especially its other main branch, which has been named, following in Bakhtin s footsteps, subjective ( chamber ) grotesque, to be distinguished from carnivalistic ( public square ) grotesque. Secondly, the dissertation analyses and interprets four fictional literary works within the context of the grotesque genre, constructed on the basis of previous research and literature. These works are the novel Rakastunut rampa (1922) by Joel Lehtonen, the novel Prins Efflam (1953, transl. into Finnish as Kalastajakylän prinssi) by Sally Salminen, the short story Orjien kasvattaja (1965) by Juhani Peltonen, and the novel Veljeni Sebastian (1985) by Annika Idström. What connects these stirring novels, representing early or full modernism, is the supposition that they belong to the tradition of the subjective grotesque, not only due to occasional details, but also in a more comprehensive manner. The premises are that genre is a significant part of the work and that reading a novel in the context of the genre tradition adds something essential to the interpretation of individual texts and reveals meanings that might otherwise go unnoticed. The main characteristic of the grotesque is breaking the norm. This is accomplished through different means: degradation, distortion, inversion, combination, exaggeration and multiplication. The most significant strategy for breaking the norm is incongruence: the grotesque combines conflicting or mutually exclusive categories and elements on different levels. Simultaneously, the grotesque unravels categorisations and questions our way of perceiving the world. The grotesque not only poses a threat to one s identity, but can also pose a threat to the cognitive process. An analysis of the fictional works is presented as case studies of each chosen work as a whole. The analysis is based on the method of close reading, which draws on both classical and postclassical narratology, and the analysis and interpretation are expanded within the genre tradition of the grotesque. The grotesque is also analysed in terms of its relationship to the neighbouring categories and genre traditions, such as the tragic, the sublime, the horror story and the coming-of-age story. This dissertation shows how the grotesque is constructed repeatedly on deviations from the norm as well as on incongruence, also in the works analysed, and how it stratifies in these novels on and between different levels, such as the story, text, narration, composition and the world of the novels. In all the works analysed, the grotesque reduces and subverts. Again and again it reveals different sides of humanity stripped of idealisation and glorification. The dissertation reveals that Finnish literature is not a solitary island, even regarding the grotesque, for it continues and offers variations of the common tradition of grotesque literature, and likewise draws on grotesque visual arts. This dissertation is the first monograph in Finnish literature research focusing on the subjective grotesque.

A genome-wide association study of sleep habits and insomnia

Several aspects of sleep behavior such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of six sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317, 370, and 610K arrays and the SNPs in common between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the third intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (P = 1.3 x 10(-)(6)). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (P = 0.73). We have identified several other suggestive associations that await replication in an independent sample. We did not replicate the results from previous genome-wide analyses of self-reported sleep phenotypes after correction for multiple testing.

A variant in LIN28B is associated with 2D:4D finger-length ratio, a putative retrospective biomarker of prenatal testosterone exposure

The ratio of the lengths of an individual's second to fourth digit (2D:4D) is commonly used as a noninvasive retrospective biomarker for prenatal androgen exposure. In order to identify the genetic determinants of 2D:4D, we applied a genome-wide association approach to 1507 11-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in whom 2D:4D ratio had been measured, as well as a sample of 1382 12- to 16-year-olds from the Brisbane Adolescent Twin Study. A meta-analysis of the two scans identified a single variant in the LIN28B gene that was strongly associated with 2D:4D (rs314277: p = 4.1 x 10(-8)) and was subsequently independently replicated in an additional 3659 children from the ALSPAC cohort (p = 1.53 x 10(-6)). The minor allele of the rs314277 variant has previously been linked to increased height and delayed age at menarche, but in our study it was associated with increased 2D:4D in the direction opposite to that of previous reports on the correlation between 2D:4D and age at menarche. Our findings call into question the validity of 2D:4D as a simplistic retrospective biomarker for prenatal testosterone exposure.

Genomewide significant linkage to migrainous headache on chromosome 5q21

Familial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23-90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs (130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine.

Evaluating intra-articular drug delivery for the treatment of osteoarthritis in a rat model.

Osteoarthritis (OA) is a degenerative joint disease that can result in joint pain, loss of joint function, and deleterious effects on activity levels and lifestyle habits. Current therapies for OA are largely aimed at symptomatic relief and may have limited effects on the underlying cascade of joint degradation. Local drug delivery strategies may provide for the development of more successful OA treatment outcomes that have potential to reduce local joint inflammation, reduce joint destruction, offer pain relief, and restore patient activity levels and joint function. As increasing interest turns toward intra-articular drug delivery routes, parallel interest has emerged in evaluating drug biodistribution, safety, and efficacy in preclinical models. Rodent models provide major advantages for the development of drug delivery strategies, chiefly because of lower cost, successful replication of human OA-like characteristics, rapid disease development, and small joint volumes that enable use of lower total drug amounts during protocol development. These models, however, also offer the potential to investigate the therapeutic effects of local drug therapy on animal behavior, including pain sensitivity thresholds and locomotion characteristics. Herein, we describe a translational paradigm for the evaluation of an intra-articular drug delivery strategy in a rat OA model. This model, a rat interleukin-1beta overexpression model, offers the ability to evaluate anti-interleukin-1 therapeutics for drug biodistribution, activity, and safety as well as the therapeutic relief of disease symptoms. Once the action against interleukin-1 is confirmed in vivo, the newly developed anti-inflammatory drug can be evaluated for evidence of disease-modifying effects in more complex preclinical models.

Ventricular conduction and long-term heart failure outcomes and mortality in African Americans: insights from the Jackson Heart Study.

BACKGROUND: QRS prolongation is associated with adverse outcomes in mostly white populations, but its clinical significance is not well established for other groups. We investigated the association between QRS duration and mortality in African Americans. METHODS AND RESULTS: We analyzed data from 5146 African Americans in the Jackson Heart Study stratified by QRS duration on baseline 12-lead ECG. We defined QRS prolongation as QRS≥100 ms. We assessed the association between QRS duration and all-cause mortality using Cox proportional hazards models and reported the cumulative incidence of heart failure hospitalization. We identified factors associated with the development of QRS prolongation in patients with normal baseline QRS. At baseline, 30% (n=1528) of participants had QRS prolongation. The cumulative incidences of mortality and heart failure hospitalization were greater with versus without baseline QRS prolongation: 12.6% (95% confidence interval [CI], 11.0-14.4) versus 7.1% (95% CI, 6.3-8.0) and 8.2% (95% CI, 6.9-9.7) versus 4.4% (95% CI, 3.7-5.1), respectively. After risk adjustment, QRS prolongation was associated with increased mortality (hazard ratio, 1.27; 95% CI, 1.03-1.56; P=0.02). There was a linear relationship between QRS duration and mortality (hazard ratio per 10 ms increase, 1.06; 95% CI, 1.01-1.12). Older age, male sex, prior myocardial infarction, lower ejection fraction, left ventricular hypertrophy, and left ventricular dilatation were associated with the development of QRS prolongation. CONCLUSIONS: QRS prolongation in African Americans was associated with increased mortality and heart failure hospitalization. Factors associated with developing QRS prolongation included age, male sex, prior myocardial infarction, and left ventricular structural abnormalities.

The Olympic Games and urban displacement: the case of Beijing

Urban spectacles such as the Olympic Games have been long perceived as being able to impose desired effects in the city that act as host. This kind of urban boost may include the creation of new jobs and revenue for local community, growth in tourism and convention business, improvements to city infrastructure and environment, and the stimulation of broad reform in the social, political and institutional realm. Nevertheless at the other end of the debate, the potentially detrimental impacts of Olympic urban development, particularly on disadvantaged and vulnerable groups, have also been increasingly noticed in recent years and subsequently cited by a number of high profile anti-Olympic groups to campaign against Olympic bids and awards. The common areas of concern over Olympic-related projects include the cost and debts risk, environmental threat, the occurrence of social imbalance, and disruption and disturbance of existing community life. Among these issues, displacement of low income households and squatter communities resulting from Olympic-inspired urban renewal are comparatively under-explored and have emerged as an imperative area for research inquiry. This is particularly the case where many other problems have become less prominent. Changing a city’s demographic landscape, particularly displacing lower income people from the area proposed for a profitable development is a highly contentious matter in its own right. Some see it as a natural and inevitable outgrowth of the process of urban evolution, without which cities cannot move towards a more attractive location for consumption-based business. Others believe it reflects urban crises and conflicts, highlighting the market failures, polarization and injustice. Regardless of perception,these phenomena are visible everywhere in post-industrial cities and particularly cannot be ignored when planning for the Olympic Games and other mega-events. The aim of this paper is to start the process of placing the displacement issue in the context of Olympic preparation and to seek a better understanding of their interrelations. In order to develop a better understanding of this issue in terms of cause, process, influential factors and its implication on planning policy, this paper studies the topic from both theoretic and empirical angles. It portrays various situations where the Olympics may trigger or facilitate displacement in host cities during the preparation of the Games, identifies several major variables that may affect the process and the overall outcome, and explores what could be learnt in generic terms for planning Olympic oriented infrastructure so that ill-effects to the local community can be effectively controlled. The paper concludes that the selection of development sites, the integration of Olympic facilities with the city’s fabric, the diversity of housing type produced for local residents and the dynamics of the new socioeconomic structure.

Adherence to hand hygiene and risk factors for poor adherence in 13 Ontario acute care hospitals

Multicenter studies assessing hand hygiene adherence and risk factors for poor performance are scarce. In an observational study involving 13 hospitals across Ontario, Canada, we found a mean adherence rate of 31.2%, and that adherence was positively associated with nurses, single rooms, contact precautions, and the availability of alcohol hand rub dispensers. Copyright © 2011 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Next-generation sequencing: a change of paradigm in molecular diagnostic validation

Next-generation sequencing (NGS) is beginning to show its full potential for diagnostic and therapeutic applications. In particular, it is enunciating its capacity to contribute to a molecular taxonomy of cancer, to be used as a standard approach for diagnostic mutation detection, and to open new treatment options that are not exclusively organ-specific. If this is the case, how much validation is necessary and what should be the validation strategy, when bringing NGS into the diagnostic/clinical practice? This validation strategy should address key issues such as: what is the overall extent of the validation? Should essential indicators of test performance such as sensitivity of specificity be calculated for every target or sample type? Should bioinformatic interpretation approaches be validated with the same rigour? What is a competitive clinical turnaround time for a NGS-based test, and when does it become a cost-effective testing proposition? While we address these and other related topics in this commentary, we also suggest that a single set of international guidelines for the validation and use of NGS technology in routine diagnostics may allow us all to make a much more effective use of resources.