Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis

BACKGROUND: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. METHODS: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. FINDINGS: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10(-10)), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10(-36)) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. INTERPRETATION: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom

Individual Rights, Economic Transactions, and Recognition: A Legal Approach to Social Economics

Modernity brought the idea of individual property rights as a com- plex phenomenon. However, economics adopted a simplistic view of property as a fundamental institution, understating the complex interaction of different rights and obligations that frame the legal environment of economic processes with an insufficiently elaborated tool. Here, a more elaborate view of legal elements will be propose

Osseous metaplasia in an ulcerating tubular adenoma of the colon: a case report

<p>Abstract</p> <p>Introduction</p> <p>Heterotopic bone is rarely found in the gastrointestinal tract. Here we report a rare case of metaplastic ossification within a benign ulcerating adenoma and review the literature concerning the aetiology.</p> <p>Case presentation</p> <p>A 63-year-old woman, who presented with a history of melaena, was found at colonoscopy to have a pedunculated ulcerating polyp. Histological examination demonstrated multiple areas of osseous metaplasia within the polyp stroma.</p> <p>Conclusion</p> <p>Heterotopic ossification in colonic adenomas is a particularly rare phenomenon, with the majority of cases occurring within malignant lesions. The suggested mechanisms for its aetiology still remain unclear.</p

The GuideLine Implementability Appraisal (GLIA): development of an instrument to identify obstacles to guideline implementation

BACKGROUND: Clinical practice guidelines are not uniformly successful in influencing clinicians' behaviour toward best practices. Implementability refers to a set of characteristics that predict ease of (and obstacles to) guideline implementation. Our objective is to develop and validate a tool for appraisal of implementability of clinical guidelines. METHODS: Indicators of implementability were identified from the literature and used to create items and dimensions of the GuideLine Implementability Appraisal (GLIA). GLIA consists of 31 items, arranged into 10 dimensions. Questions from 9 of the 10 dimensions are applied individually to each recommendation of the guideline. Decidability and Executability are critical dimensions. Other dimensions are Global, Presentation and Formatting, Measurable Outcomes, Apparent Validity, Flexibility, Effect on Process of Care, Novelty/Innovation, and Computability. We conducted a series of validation activities, including validation of the construct of implementability, expert review of content for clarity, relevance, and comprehensiveness, and assessment of construct validity of the instrument. Finally, GLIA was applied to a draft guideline under development by national professional societies. RESULTS: Evidence of content validity and preliminary support for construct validity were obtained. The GLIA proved to be useful in identifying barriers to implementation in the draft guideline and the guideline was revised accordingly. CONCLUSION: GLIA may be useful to guideline developers who can apply the results to remedy defects in their guidelines. Likewise, guideline implementers may use GLIA to select implementable recommendations and to devise implementation strategies that address identified barriers. By aiding the design and operationalization of highly implementable guidelines, our goal is that application of GLIA may help to improve health outcomes, but further evaluation will be required to support this potential benefit

Academic freedom: in justification of a universal ideal

This paper examines the justification for, and benefits of, academic freedom to academics, students, universities and the world at large. The paper surveys the development of the concept of academic freedom within Europe, more especially the impact of the reforms at the University of Berlin instigated by Wilhelm von Humboldt. Following from this, the paper examines the reasons why the various facets of academic freedom are important and why the principle should continue to be supported

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Quality of care for older adults with chronic obstructive pulmonary disease and asthma based on comparisons to practice guidelines and smoking status

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to describe the prevalence of respiratory diseases in older adults and compare the demographic, health and smoking characteristics of those with and without these diseases. Furthermore, we evaluate the association between smoking status and patterns in health care and how concordant this care is with guidelines.</p> <p>Methods</p> <p>Using a nationally representative sample of 29,902 older adults who participated in the Medicare Current Beneficiary Survey (1992–2002), we compared guideline recommendations on the treatment and prevention of chronic obstructive pulmonary disease and asthma with survey utilization data, including the use of bronchodilators, spirometry and influenza vaccine.</p> <p>Results</p> <p>26% to 30% of older adults were diagnosed with or self-reported chronic respiratory diseases; however 69% received no pharmacological treatment and 30% of patients reporting use of pharmacological treatments did not receive short-acting bronchodilator inhalers. Current smokers appeared to receive significantly less care for respiratory diseases than non-smokers or former smokers.</p> <p>Conclusion</p> <p>Disparities between recommended and actual care for older adults with chronic lung disease require further research. The needs of older adults with co-morbidities and nicotine addiction deserve special attention in care as well as guideline development and implementation.</p

The influence of personality and ability on undergraduate teamwork and team performance

The ability to work effectively on a team is highly valued by employers, and collaboration among students can lead to intrinsic motivation, increased persistence, and greater transferability of skills. Moreover, innovation often arises from multidisciplinary teamwork. The influence of personality and ability on undergraduate teamwork and performance is not comprehensively understood. An investigation was undertaken to explore correlations between team outcomes, personality measures and ability in an undergraduate population. Team outcomes included various self-, peer- and instructor ratings of skills, performance, and experience. Personality measures and ability involved the Five-Factor Model personality traits and GPA. Personality, GPA, and teamwork survey data, as well as instructor evaluations were collected from upper division team project courses in engineering, business, political science, and industrial design at a large public university. Characteristics of a multidisciplinary student team project were briefly examined. Personality, in terms of extraversion scores, was positively correlated with instructors’ assessment of team performance in terms of oral and written presentation scores, which is consistent with prior research. Other correlations to instructor-, students’ self- and peer-ratings were revealed and merit further study. The findings in this study can be used to understand important influences on successful teamwork, teamwork instruction and intervention and to understand the design of effective curricula in this area moving forward

Academic detailing to increase colorectal cancer screening by primary care practices in Appalachian Pennsylvania

<p>Abstract</p> <p>Background</p> <p>In the United States, colorectal cancer (CRC) is the third most frequently diagnosed cancer and second leading cause of cancer death. Screening is a primary method to prevent CRC, yet screening remains low in the U.S. and particularly in Appalachian Pennsylvania, a largely rural area with high rates of poverty, limited health care access, and increased CRC incidence and mortality rates. Receiving a physician recommendation for CRC screening is a primary predictor for patient adherence with screening guidelines. One strategy to disseminate practice-oriented interventions is academic detailing (AD), a method that transfers knowledge or methods to physicians, nurses or office staff through the visit(s) of a trained educator. The objective of this study was to determine acceptability and feasibility of AD among primary care practices in rural Appalachian Pennsylvania to increase CRC screening.</p> <p>Methods</p> <p>A multi-site, practice-based, intervention study with pre- and 6-month post-intervention review of randomly selected medical records, pre- and post-intervention surveys, as well as a post-intervention key informant interview was conducted. The primary outcome was the proportion of patients current with CRC screening recommendations and having received a CRC screening within the past year. Four practices received three separate AD visits to review four different learning modules.</p> <p>Results</p> <p>We reviewed 323 records pre-intervention and 301 post-intervention. The prevalence of being current with screening recommendation was 56% in the pre-intervention, and 60% in the post-intervention (p = 0. 29), while the prevalence of having been screened in the past year increased from 17% to 35% (p < 0.001). Colonoscopies were the most frequently performed screening test. Provider knowledge was improved and AD was reported to be an acceptable intervention for CRC performance improvement by the practices.</p> <p>Conclusions</p> <p>AD appears to be acceptable and feasible for primary care providers in rural Appalachia. A ceiling effect for CRC screening may have been a factor in no change in overall screening rates. While the study was not designed to test the efficacy of AD on CRC screening rates, our evidence suggests that AD is acceptable and may be efficacious in increasing recent CRC screening rates in Appalachian practices which could be tested through a randomized controlled study.</p

Synaptic Reorganization in the Adult Rat's Ventral Cochlear Nucleus following Its Total Sensory Deafferentation

Ablation of a cochlea causes total sensory deafferentation of the cochlear nucleus in the brainstem, providing a model to investigate nervous degeneration and formation of new synaptic contacts in the adult brain. In a quantitative electron microscopical study on the plasticity of the central auditory system of the Wistar rat, we first determined what fraction of the total number of synaptic contact zones (SCZs) in the anteroventral cochlear nucleus (AVCN) is attributable to primary sensory innervation and how many synapses remain after total unilateral cochlear ablation. Second, we attempted to identify the potential for a deafferentation-dependent synaptogenesis. SCZs were ultrastructurally identified before and after deafferentation in tissue treated for ethanolic phosphotungstic acid (EPTA) staining. This was combined with pre-embedding immunocytochemistry for gephyrin identifying inhibitory SCZs, the growth-associated protein GAP-43, glutamate, and choline acetyltransferase. A stereological analysis of EPTA stained sections revealed 1.11±0.09 (S.E.M.)×109 SCZs per mm3 of AVCN tissue. Within 7 days of deafferentation, this number was down by 46%. Excitatory and inhibitory synapses were differentially affected on the side of deafferentation. Excitatory synapses were quickly reduced and then began to increase in number again, necessarily being complemented from sources other than cochlear neurons, while inhibitory synapses were reduced more slowly and continuously. The result was a transient rise of the relative fraction of inhibitory synapses with a decline below original levels thereafter. Synaptogenesis was inferred by the emergence of morphologically immature SCZs that were consistently associated with GAP-43 immunoreactivity. SCZs of this type were estimated to make up a fraction of close to 30% of the total synaptic population present by ten weeks after sensory deafferentation. In conclusion, there appears to be a substantial potential for network reorganization and synaptogenesis in the auditory brainstem after loss of hearing, even in the adult brain