Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naive or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naive group (p <0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naive group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function. (C) 2015 The Authors. Published by Elsevier B.V

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Valuing unfamiliar Mediterranean deep-sea ecosystems using visual Q-methodology

Monetary valuation of non-market environmental goods and services such as marine ecosystems is a difficult task, usually approached by stated preference methods. Valuation results are often unstable since preferences for unfamiliar, often highly abstract and complex environmental goods depend on the level of previous knowledge of the participant stakeholders and the information provided to them. In this paper, Q methodology has been applied to explore subjective perspectives on Mediterranean deep-sea, which is among the least explored environment in the world. The participant sample consisted in eight Ph.D. students, half of which with a Marine Life Sciences degree. They were asked to perform a Q sorting experiment, and rank a Q sample of thirty-six underwater photographs of the marine wildlife, landscapes, and ecosystems in the Mediterranean deep sea. Photographs were sorted by each topic according to a subjective priority relative to: a) a personal overall view; b) their perception of the potential interest for fishermen; and c) as if they were fishermen. The study revealed three distinct discourses on the subjective importance of deep-sea ecosystems in the Mediterranean Sea: “Noah's Ark Fans”, “Ecosystem Functions Supporters” and “Deep Coral Lovers”. Data analysis showed that the main differences between factors could be related to the experience and the cultural background of the participants. This study improved our knowledge about individuals’ perceptions on Mediterranean deep-sea ecosystems and represents a preliminary step for their monetary valuation

Estimating preferences for Mediterranean deep-sea ecosystem services: a discrete choice experiment

The deep sea represents Earth’s largest (but least explored) biome. It is increasingly affected by anthropogenic stressors and climate change, which threaten the provision of essential ecosystem services. The monetary value of these benefits has rarely been assessed. High biodiversity is hosted in the deep sea and, more generally, in the oceans. This paper uses a hypothetical choice experiment to investigate Italian households’ preferences for deep- sea ecosystem services. The data show wide heterogeneity of the preferences for preserving the Mediterranean deep sea. Many respondents indicate that they would refuse to pay to support the protection of biodiversity and scientific research in this remote and unfamiliar environment. Overall, global warming was of little concern for most respondents, who would not be willing to pay to limit the increase in global temperatures. High income and formal education positively influenced the willingness of the respondents to donate to Non-Governmental Organization’s initiatives to support the Mediterranean deep sea. Deep-water corals appear more ‘charismatic’ to respondents than submarine canyons among deep-sea habitats

A single center study: Aβ42/p-Tau181 CSF ratio to discriminate AD from FTD in clinical setting

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice

GreyGuide, GreyNet’s web access portal and lobby for change in Grey Literature

In December 2013, the GreyGuide was formerly launched as an online forum and repository of good practice in grey literature. The project partners then turned to the acquisition of both proposed and published good practices. During this same timeframe, GreyNet – one of the project partners – welcomed far reaching developments in its infrastructure. Three new committees were established alongside its Program Committee in line with GreyNet’s fourfold mission dedicated to research, publication, open access, and education in the field of grey literature. In the process of coordinating and facilitating the work of these new committees, it became clear that a multitude of web-based content that is currently maintained on GreyNet’s website and conference site - accessible on diverse webpages in PDF format - could better be made accessible via a web portal. This would allow for browse, search, and retrieval across resources and collections. The GreyGuide was tested for this purpose and it was then decided to select from GreyNet’s range of content and commence with migration to the GreyGuide. While the web origins of three such collections were soon identified – namely, the GreySource Index1, Who’s Who in Grey Literature2 , and Conference Proposals issuing from the GL-Series – still other collections, resources, and in-house publications would also deserve future consideration. The work of defining the metadata for these collections, their subsequent data entry, and additional cross-linking indicated the work that was to be undertaken during the months leading up to GL16. It was anticipated that just as GL15 provided the occasion for the launch of the GreyGuide Repository, GL16 would demonstrate its enhanced function as a web access portal. From the perspective of the GreyGuide, this paper renders an ongoing log, while from the perspective of GreyNet it renders a case study in innovative change in the management of information resources.Includes: Conference preprint, Powerpoint presentation, Abstract and Biographical notesXAInternationa

Development and Use of Gene Therapy Orphan Drugs—Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society

Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15–20 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings

Lessons learned: The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance. Background: This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. Methods: Open-label phase Ia/b study comprising 3+3 dose-limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28-day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. Results: Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment-emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment-related TEAEs. The most common grade ≥3 treatment-related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 μg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression-free survival was 3.3 months (95% confidence interval [CI]: 1.6-4.4). Median overall survival was 8.9 months (95% CI: 3.5-12.7). There were no associations between genetic alterations and efficacy. Conclusion: Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC

Policy Development for Grey Literature Resources. An Assessment of the Pisa Declaration

In the spring of 2014, a workshop took place at the Italian National Council of Research in Pisa. The topic of this event dealt with policy development for grey literature resources. Some seventy participants from nine countries took an active part in the workshop – the outcome of which produced what is today known as the Pisa Declaration. This fifteen point document arising from the input of those who attended the workshop sought to provide a roadmap that would help to serve diverse communities involved in research, publication and the management of grey literature both in electronic and print formats. The Pisa Declaration has been translated and published in some twenty languages. They are all accessible online via the GreyGuide Repository and Portal. Currently, 140 information professionals from renowned organizations worldwide have endorsed this document. In an effort to assess the impact that the Pisa Declaration has had during the last two years on the policy development for grey literature resources, an online survey among those who endorsed the document was carried out and their responses were analysed. Descriptive statistics and short summaries are used to describe the basic features of the data collected. They are combined with simple graphics that offer easier visual representation of the results achieved. Specific results of the survey analysis indicate those points in the Pisa Declaration that in varying degrees are of relevance and importance to grey literature, as well as points that need further attention and work. Although integral part of library and information management practice grey literature has its own peculiarities and needs that require special attention in order to reach its deserved level of importance in today’s research and other activitiesIncludes: Conference preprint, Powerpoint presentation, Abstract and Biographical notesXAInternationa

Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics

Expansion of data-driven research in the 21st century has posed challenges in the evolution of the international agreed framework of research ethics. The World Medical Association (WMA)’s Declaration of Helsinki (DoH) has provided ethical principles for medical research involving humans since 1964, with the last update in 2013. To complement the DoH, WMA issued the Declaration of Taipei (DoT) in 2016 to provide additional principles for health databases and biobanks. However, the ethical principles for secondary use of data or material obtained in research remain unclear. With such a perspective, the Working Group on Ethics (WGE) of the International Federation of Associations of Pharmaceutical Physicians and Pharmaceutical Medicine (IFAPP) suggests a closer scientific linkage in the DoH to the (Declaration of Taipei) DoT focusing specifically on areas that will facilitate data-driven research, and to further strengthen the protection of research participants