Screening of endocrine organ-specific humoral autoimmunity in 47,XXY Klinefelter's syndrome reveals a significant increase in diabetes-specific immunoreactivity in comparison with healthy control men.

The aim of this study was to evaluate the frequency of humoral endocrine organ-specific autoimmunity in 47,XXY Klinefelter’s syndrome (KS) by investigating the autoantibody profile specific to type 1 diabetes (T1DM), Addison’s disease (AD), Hashimoto thyroiditis (HT), and autoimmune chronic atrophic gastritis (AG). Sixty-one adult Caucasian 47,XXY KS patients were tested for autoantibodies specific to T1DM (Insulin Abs, GAD Abs, IA-2 Abs, Znt8 Abs), HT (TPO Abs), AD (21-OH Abs), and AG (APC Abs). Thirty-five of these patients were not undergoing testosterone replacement therapy TRT (Group 1) and the remaining 26 patients started TRT before the beginning of the study (Group 2). KS autoantibody frequencies were compared to those found in 122 control men. Six of 61 KS patients (9.8 %) were positive for at least one endocrine autoantibody, compared to 6.5 % of controls. Interestingly, KS endocrine immunoreactivity was directed primarily against diabetes-specific autoantigens (8.2 %), with a significantly higher frequency than in controls (p = 0.016). Two KS patients (3.3 %) were TPO Ab positive, whereas no patients were positive for AD- and AG-related autoantigens. The autoantibody endocrine profile of untreated and treated KS patients was not significantly different. Our findings demonstrate for the first time that endocrine humoral immunoreactivity is not rare in KS patients and that it is more frequently directed against type 1 diabetes-related autoantigens, thus suggesting the importance of screening for organ-specific autoimmunity in clinical practice. Follow-up studies are needed to establish if autoantibody-positive KS patients will develop clinical T1D

Endocrine and metabolic evaluation of classic Klinefelter syndrome and high-grade aneuploidies of sexual chromosomes with male phenotype: are they different clinical conditions?

Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in males. As well as classic KS, less frequent higher-grade aneuploidies (HGAs) are also possible. While KS and HGAs both involve testicular dysgenesis with hypergonadotropic hypogonadism, they differ in many clinical features. The aim of this study was to investigate the endocrinal and metabolic differences between KS and HGAs.Objective: Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in males. As well as classic KS, less frequent higher-grade aneuploidies (HGAs) are also possible. While KS and HGAs both involve testicular dysgenesis with hypergonadotropic hypogonadism, they differ in many clinical features. The aim of this study was to investigate the endocrinal and metabolic differences between KS and HGAs. Design: Cross-sectional, case-control study. Methods: 88 patients with KS, 24 with an HGA and 60 healthy controls. Given the known age-related differences all subjects were divided by age into subgroups 1, 2 and 3. Pituitary, thyroid, gonadal and adrenal functions were investigated in all subjects. Metabolic aspects were only evaluated in subjects in subgroups 2 and 3. Results: FT4 and FT3 levels were significantly higher in HGA than in KS patients in subgroups 1 and 2; in subgroup 3, FT4 was significantly higher in controls than in patients. Thyroglobulin was significantly higher in HGA patients in subgroup 1 than in KS patients and controls. Hypergonadotropic hypogonadism was confirmed in both KS and HGA patients, but was more precocious in the latter, as demonstrated by the earlier increase in gonadotropins and the decrease in testosterone, DHEA-S and inhibin B. Prolactin was significantly higher in HGA patients, starting from subgroup 2. Total and LDL cholesterol were significantly higher in HGA patients than in KS patients and controls, while HDL cholesterol was higher in controls than in patients. Conclusions: KS and HGAs should be considered as two distinct conditions

What is going wrong in health research investment? post-pandemic lessons and the need for change

The emergence of a new dimension of consciousness after the COVID-19 pandemic might provide an opportunity to highlight gaps and inequalities in health research investment and to mobilize scientific and public opinion to change the way things are done. This analysis considers some lessons learned from the pandemic crisis concerning the priority of global health research, research in prevention and well-being, and international research cooperation. The question raised by these issues concerns the unfairness of health research funding, mainly dominated by the pharmaceutical and device industries. However, evidence shows that these companies shifted funding to late-phase clinical trials and away from innovation activity and global health priorities. On the other hand, public institutions continue to invest in basic science, with the majority of funds still focused on basic research and innovation. This direct relationship between industry and biomedical research disrupts the reliability of findings and biases the evidence. Several initiatives and efforts are shaping pathways towards health research independence from industry funding. We can propose the idea of industry funding without a direct relationship with researchers through a common pot managed by an independent international agency. Nevertheless, to promote publicly funded research, the scientific community must strengthen its position compared to industry-funded research through transparency and the scientific value of publications.&nbsp

Prognostic role of aspartate aminotransferase-lymphocyte ratio index in patients with metastatic colorectal cancer: results from the randomized ITACa trial

BACKGROUND: The aim of this study was to investigate the role of pre-treatment aspartate aminotransferase-lynphocyte ratio (ALRI) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT) + bevacizumab (B) or CT alone. PATIENTS AND METHODS: Patients randomly received CT+B or CT alone as first-line therapy. CT consisted of either FOLFOX4 or FOLFIRI at the clinician's discretion. RESULTS: Out of the 284 patients enrolled, increased ALRI levels were associated with shorter PFS and OS (p<0.0001). At baseline, median PFS was 10.3 months (95% CI 9.4-12.0) and 8.0 months (95 % CI 6.8-8.9), and median OS was 25.2 months (95 % CI 21.3-30.2) and 18.8 months (95 % CI 16.6-21.7) for patients with low (<14) and high (≥14) ALRI levels, respectively (HR 1.43, 95% CI 1.12-1.82, p=0.004; HR=1.51, 95% CI 1.17-1.96, p<0.001). Interaction tests on ALRI levels and treatment efficacy in the CT+B and the CT groups were statistically significant for PFS (p=0.0003), but not for OS (p=0.228). CONCLUSION: Our results indicate that ALRI is a good prognostic and predictive marker for mCRC patients candidate for CT+B

Prognostic role of serum concentrations of high-sensitivity C-reactive protein in patients with metastatic colorectal cancer: Results from the ITACa trial

Serum levels of C-reactive protein are (CRP) higher in patients with neoplastic conditions and numerous studies have been performed to clarify the etiologic and prognostic role of the high-sensitivity CRP (hs-CRP) in cancer. Our study was conducted on patients enrolled in the prospective randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" to assess hs-CRP levels and their impact on overall survival (OS) and progression-free survival (PFS). Serum samples from 132 ITACa patients were collected at baseline and 2 months after starting first-line chemotherapy. The supernatant was immediately transferred to cryovials and stored at -80°C. After thawing, hs-CRP was measured with the Cobas c501 analyzer. High levels of hs-CRP (≥ 13.1 mg/L) were associated with poorer median PFS (p < 0.0001) and OS (p < 0.0001) than low hs-CRP levels (< 13.1 mg/L). hs-CRP values in 107 patients were evaluated again after 2 months of therapy, revealing that patients with low hs-CRP levels in both baseline and second serum samples had the best median PFS and OS. Our study confirms the prognostic value of hs-CRP in patients with metastatic colorectal carcinoma

Models for financing the regulation of pharmaceutical promotion

Abstract Pharmaceutical companies spend huge sums promoting their products whereas regulation of promotional activities is typically underfinanced. Any option for financing the monitoring and regulation of promotion should adhere to three basic principles: stability, predictability and lack of (perverse) ties between the level of financing and performance. This paper explores the strengths and weaknesses of six different models. All these six models considered here have positive and negative features and none may necessarily be ideal in any particular country. Different countries may choose to utilize a combination of two or more of these models in order to raise sufficient revenue. Financing of regulation of drug promotion should more than pay for itself through the prevention of unnecessary drug costs and the avoidance of adverse health effects due to inappropriate prescribing. However, it involves an initial outlay of money that is currently not being spent and many national governments, in both rich and poor countries, are unwilling to incur extra costs.</p

Long term effectiveness on prescribing of two multifaceted educational interventions: Results of two large scale randomized cluster trials

Introduction: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. Objectives: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. Methods: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach - TEA, with information materials on osteoporosis or prostatic hyperplasia - and a single drug oriented approach - SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. Results: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. Interpretation: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. Trial Registration: Controlled-Trials.com ISRCTN05866587

Adverse pathophysiological influence of early testosterone therapy on the testes of boys with higher grade sex chromosome aneuploidies (HGAs): a retrospective, cross-sectional study

Purpose: Higher grade aneuploidies (HGAs) of the male sex chromosomes are a rare genetic group of pathologies caused by nondisjunction meiotic events. The aim of this study was to evaluate the impact of early androgenic therapy on the testicular secretory hormone profile, and the pathophysiological implications. Patients and methods: In this cross-sectional study, 18 HGA subjects aged 6–8&nbsp;years were recruited. They were divided into two groups, based on whether or not they had previously undergone testosterone therapy (group 1: 11 untreated subjects; group 2: 7 treated subjects). Serum FSH, LH, testosterone (T), inhibin B (INHB) and anti-Müllerian hormone (AMH) were determined, and auxological parameters were assessed. Five group 1 patients and four group 2 patients were treated with hCG (human chorionic gonadotropin) for inguinal cryptorchidism; their hormone profile and auxological parameters were assessed both pre- and post-hCG treatment. Results: Group 1 subjects showed significantly higher testicular volume and higher levels of AMH and INHB (p &lt; 0.0001). Subjects who had undergone hCG therapy showed a significantly higher testicular volume, penis length (respectively, p = 0.008 and p = 0.0005 for group 1 and p = 0.04 and p = 0.001 for group 2) and T (p = 0.005 for group 1 and p = 0.004 for group 2). Conclusions: HGA patients undergoing early testosterone therapy show an earlier and persistent suppression of testicular secretory function. At this age, the testes are still responsive to stimulation with hCG. The selection of patients to be treated must be accompanied by a thorough clinical and hormonal evaluation

Conceptual frameworks and empirical approaches used to assess the impact of health research: an overview of reviews

<p>Abstract</p> <p>Background</p> <p>How to assess the impact of research is of growing interest to funders, policy makers and researchers mainly to understand the value of investments and to increase accountability. Broadly speaking the term "research impact" refers to the contribution of research activities to achieve desired societal outcomes. The aim of this overview is to identify the most common approaches to research impact assessment, categories of impact and their respective indicators.</p> <p>Methods</p> <p>We systematically searched the relevant literature (PubMed, The Cochrane Library (1990-2009)) and funding agency websites. We included systematic reviews, theoretical and methodological papers, and empirical case-studies on how to evaluate research impact. We qualitatively summarised the included reports, as well the conceptual frameworks.</p> <p>Results</p> <p>We identified twenty-two reports belonging to four systematic reviews and 14 primary studies. These publications reported several theoretical frameworks and methodological approaches (bibliometrics, econometrics, ad hoc case studies). The "payback model" emerged as the most frequently used. Five broad categories of impact were identified: a) advancing knowledge, b) capacity building, c) informing decision-making, d) health benefits, e) broad socio-economic benefits. For each proposed category of impact we summarized a set of indicators whose pros and cons are presented and briefly discussed.</p> <p>Conclusions</p> <p>This overview is a comprehensive, yet descriptive, contribution to summarize the conceptual framework and taxonomy of an heterogeneous and evolving area of research. A shared and comprehensive conceptual framework does not seem to be available yet and its single components (epidemiologic, economic, and social) are often valued differently in different models.</p

Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries

<p>Abstract</p> <p>Background</p> <p>Shifts in clinical trial application rates over time indicate if the attractiveness of a country or region for the conduct of clinical trials is growing or decreasing. The purpose of this observational study was to track changes in drug trial application patterns across several EU countries in order to analyze the medium-term impact of the EU Clinical Trials Directive 2001/20/EC on the conduct of drug trials.</p> <p>Methods</p> <p>Rates of Clinical Trial Applications (CTA) for studies with medicinal products in those six countries in the EU, which authorize on average more than 500 trials per year, were analyzed. Publicly available figures on the number of annually submitted CTA, the distribution of trials per phase and the type of sponsorship were tracked; missing data were provided by national drug agencies.</p> <p>Results</p> <p>Since 2001, the number of CTA in Italy and Spain increased significantly (5.0 and 2.5% average annual growth). For Italy, the gain was driven by a strong increase of applications from academic trial sponsors; Spain's growth was due to a rise in trials run by commercial sponsors. The Netherlands, Germany, France and the UK saw a decline (1.9, 2.3, 3.0 and 5.3% average annual diminution; significant (<it>P </it>< 0.05) except for Germany) in clinical drug trials. The decrease in the UK was caused by a sharp fall in academic trial activities. Across the six analyzed countries, no EU-wide trial-phase-specific patterns or trends were observed.</p> <p>Conclusions</p> <p>The EU Clinical Trials Directive 2001/20/EC did not achieve the harmonization of clinical trial requirements across Europe. Rather, it resulted in the leveling of clinical trial activities caused by a continuing decrease in CTA rates in the Netherlands, Germany, France and the UK. Southern European countries, Italy and Spain, benefited to some extent from policy changes introduced by the Directive. In Italy's case, national funding measures helped to considerably promote the conduct of non-commercial trials. On the other hand, the EU Directive-driven transition from liberal policy environments, based on non-explicit trial approval through notifications, towards red-taped processes of trial authorization, contributed to the decreases in trial numbers in Germany and the UK. In the latter case, national research governance concerns had a share in the country's marked decline. However, different EU member states successfully developed best practices, which a new European legislation should take into consideration to resume Europe's attractiveness and international competitiveness for the conduct of clinical trials.</p