Multianalyte LC-MS-based methods in doping control: what are the implications for doping athletes?

Over the last 50 years, the list of doping substances and methods has been progressively expanding, being regularly reviewed by the international antidoping authorities (formerly the Medical Commission of the International Olympic Committee, and afterward, following its constitution in 1999, the World Anti-Doping Agency [WADA]). New substances/classes of substances have been periodically included in the list, keeping the pace with more advanced and sophisticated doping trends. At present, and apart from the prohibited performance enhancing and masking methods (e.g., blood transfusions and tampering strategies), the list comprises several hundreds of biologically active substances, with broad differences in their physicochemical properties (i.e., molecular weight, polarity and acid-basic properties) [1]. As a consequence, the ‘one class – one procedure’ approach, which had been followed by nearly all accredited antidoping laboratories worldwide until the turn of the millennium, is no longer sustainable. The need to minimize the overall number of independent analytical procedures, and, in parallel, to reduce the analytical costs, stimulated the development of multitargeted methods, aimed to increase the overall ratio of ‘target analytes: procedure’ [2–6]. The above evolution has not always been a straight forward process. The need to comply with the WADA technical requirements (both in terms of identification criteria and of minimum required performance limits [7,8]) and with the reduction of the reporting time (a constraint that becomes even more critical during international sport events, where the daily workload also drastically increases) has imposed a thorough re-planning of the analytical procedures. The development of an antidoping analytical method requires the appropriate knowledge not only of the biophysicochemical properties of the target analyte, but also of its PK profile. Historically, immunological methods and GC-based techniques were applied in antidoping science, as preferential screening methods for the detection of prohibited substances, which were originally limited to nonendogenous stimulants and narcotics. In the 1980s, GC–MS became the reference analytical platform for the detection and quantification of the majority of the low molecular weight doping substances [3–6]. In the following two decades, with the inclusion in the Prohibited List of new classes of low molecular weight, hydrophilic, thermolabile, nonvolatile analytes (including, but not limited to, glucocorticoids and designer steroids) and simultaneously of peptide hormones, scientists were obliged to design, develop, validate and apply techniques based on LC–MS/MS

Studio e implementazione di un Profilo SAML per Trait-based Identity Management System nel Session Initiation Protocol

Il primo capitolo rappresenta un'introduzione al VoIP e al relativo protocollo di segnalazione (Session Initiation Protocol), accennando ai problemi sulla gestione delle identità. Il secondo capitolo presenta in maniera dettagliata il Session Initiation Protocol e le sue funzionalità al servizio dell'Identity Management, dalla fase di registrazione dell'utente alla fase di esecuzione di una chiamata. Nel terzo capitolo si affronta il problema delle identità in maniera più diretta, descrivendo l'infrastruttura logica del Trait-based Identity Management System analizzandone anche requisiti e funzionalità. Il quarto capito è dedicato alla descrizione dell'implementazione della soluzione proposta. Nel quinto capitolo, oltre alle conclusioni, si offrono spunti per eventuali sviluppi futuri dell'infrastruttura. Il sesto capitolo raccoglie due appendici, una in cui si descrive il processo di firma digitale in XML e l'altra, fondamentale, in cui sono tracciate e descritte le fasi da seguire per un setup architetturale corretto per il testing del Trait-based Identity Management System

Non-targeted LC-MS based metabolomics analysis of the urinary steroidal profile

The urinary steroidal fraction has been extensively explored as non-invasive alternative to monitor pathological conditions as well as to unveil the illicit intake of pseudo-endogenous anabolic steroids in sport. However, the majority of previous approaches involved the a priori selection of potentially relevant target analytes. Here we describe the non-targeted analysis of the urinary steroidal profiles. The workflow includes minimal sample pretreatment and normalization according to the specific gravity of urine, a 20 min reverse phase ultra-performance liquid chromatographic separation hyphenated to electrospray time-of-flight mass spectrometry. As initial validation, we analyzed a set of quality control urines spiked with glucurono- and sulfo-conjugated steroids at physiological ranges. We then applied the method for the analysis of samples collected after single transdermal administration of testosterone in hypogonadal men. The method allowed profiling of approximately three thousand metabolic features, including steroids of clinical and forensic relevance. It successfully identified metabolic pathways mostly responsible for groups clustering even in the context of high inter-individual variability and allowed the detection of currently unknown metabolic features correlating with testosterone administration. These outcomes set the stage for future studies aimed at implementing currently monitored urinary steroidal markers both in clinical and forensic analysis

Prognostic factors influencing infectious complications after cytoreductive surgery and HIPEC. Results from a tertiary referral center

Background. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) showed promising results in selected patients. High morbidity restrains its wide application. The aim of this study was to report postoperative infectious complications and investigate possible correlations with preoperative nutritional status and other prognostic factors in patients with peritoneal metastases treated with CRS and HIPEC. Methods. For the study we reviewed the clinical records of all patients with peritoneal metastases from different primary cancers and treated by CRS and HIPEC in our Institution from November 2000 to December 2017. Patients were divided according to their nutritional status (SGA) in group A (well-nourished), B/C (mild or severely malnourished). Possible statistical correlations between risk factors and postoperative complications rates have been investigated by univariate and multivariate analysis. Results. Two hundred patients were selected and underwent CRS and HIPEC during the study period. Postoperative complications occurred in 44% of the patients, 35.3% in SGA-A patients and 53% in SGA-B /C patients. Cause of complications was infective in 42, non-infective in 37 and HIPEC related in 9 patients. Infectious complications occurred more frequently in SGA-B /C patients (32.6% vs. 9.8% of SGA-A patients). The most frequent sites of infection were Surgical Site Infections (SSI, 35.7%) and Central Line Associated BloodStream Infections (CLABSI, 26.2%). The most frequent isolated species was Candida (22.8%). ASA score, blood loss, performance status, PCI, large bowel resection, postoperative serum albumin levels and nutritional status correlated with higher risk for postoperative infectious complications. Conclusions. Malnourished patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are more prone to post-operative infectious complications and adequate perioperative nutritional support should be considered, including immune-enhancing nutrition. Sequential monitoring of common sites of infection, antifungal prevention of candidiasis, and careful patient selection should be implemented to reduce complications rate

Statistical sampling applied to the radiological characterization of historical waste

International audienceThe evaluation of the activity of radionuclides in radioactive waste is required for its disposal in final repositories. Easy-to-measure nuclides, like g-emitters and high-energy X-rays, can be measured via non-destructive nuclear techniques from outside a waste package. Some radionuclides are difficult-to-measure (DTM) from outside a package because they are a-or b-emitters. The present article discusses the application of linear regression, scaling factors (SF) and the so-called "mean activity method" to estimate the activity of DTM nuclides on metallic waste produced at the European Organization for Nuclear Research (CERN). Various statistical sampling techniques including simple random sampling, systematic sampling, stratified and authoritative sampling are described and applied to 2 waste populations of activated copper cables. The bootstrap is introduced as a tool to estimate average activities and standard errors in waste characterization. The analysis of the DTM Ni-63 is used as an example. Experimental and theoretical values of SFs are calculated and compared. Guidelines for sampling historical waste using probabilistic and non-probabilistic sampling are finally given

Smoking cessation interventions in nurses and other health care workers

Introduction: Tobacco smoking can be considered an old and a new challenge for public health. The aim of this review was to analyse different smoking cessation interventions aiming at health care workers.Methods: A literature search of electronic journal databases for studies on smoking cessation interventions among health care workers was performed according to PRISMA criteria, using the MEDLINE and Scopus databases.Results: Smoking restriction policies shouldn’t be considered as actual interventions, being ineffective, unpopular and reducing willingness to quit smoking in many subjects. Even though pharmacological therapies based on bupropion SR and transdermal nicotine patches grant significant results on the short-term (weeks and months), smoking recurrence rates are high and individualised interventions should be preferred or integrated since they seem to grant better results on the longterm (years).Conclusions: There is evidence that smoking cessation interventions among health care workers can be effective. This is of particular interest both for reducing tobacco smoking prevalence among this type of workers and for helping them to be useful model for the general population

Rapid screening of beta-adrenergic agents and related compounds in human urine for anti-doping purpose using capillary electrophoresis with dynamic coating

This paper presents a capillary electrophoresis method, developed for the detection, in human urine, of beta-adrenergic agents and phenolalkylamines. The electrophoretic separation is achieved in less than 10 min and is based on the use of CEofix kit, for the dynamic capillary coating. The effects of accelerator buffer pH and separation voltage were investigated. The optimum buffer pH was found to be 2.5 for beta2-agonists and 6.2 for beta-blockers and phenoalkylamines with a separation voltage of 15 IN. Urine samples spiked with the compounds here studied were treated according to the standard procedure (SPE and evaporation to dryness) and analyzed by CE interfaced with an UV diode-array, set at 195 and 210 nm. The quantitative validation results, obtained analyzing samples at three different concentrations, show a good precision of peak areas that do not exceed 5% for intra-day assays and 10% for inter-day assays. Good linearity (r(2) > 0.995) was obtained within the 50-500 ng/mL concentration range. The qualitative validation data show a relative migration times (MTs) variation lower than 1%. The analytes were clearly distinguishable in urine, with LOD and LOQ in the range of 10-80 and 40-100 ng/mL, respectively

The role of technology on adherence to physical activity programs in patients with chronic diseases experiencing fatigue: a systematic review

Background The beneficial role of physical activity (PA) to manage the health condition of patients with chronic diseases is well known. However, adherence to PA guidelines in this group is still low. Monitoring and user-interface technology could represent a significant tool to increase exercise adherence to those particular groups who experience difficulties in adhering to regular and substantial physical activity, and could be supportive in increasing the success of PA programs and interventions. This systematic review aimed at evaluating the effect of physical activity monitoring technology in improving adherence to a PA program in patients with chronic diseases experiencing fatigue. Methods This systematic review was conducted according to PRISMA guidelines. The literature search was performed in Embase, Medline, Biosis, Scopus, and SPORTDiscus. We filtered the literature according to the question: “Does monitoring technology affect adherence to physical activity and exercise programs in patients with chronic diseases perceiving fatigue?”. Results The search resulted in 1790 hits; finally, eight studies were included, with a total number of 205 patients. Study quality was moderate except for one study of high quality. Only three disease types emerged, COPD, HF, and cancer. PA programs were rather short (from 8 to 13 weeks) except for one 3-year-long study. Five studies employed pedometers and two an activity monitor. Three studies based their adherence on steps, the remaining studies focused on active minutes. Adherence was explicitly reported in two studies, and otherwise derived. Four studies showed high adherence levels (85% week-10, 89% week-8, 81% week-13, 105% week-13, 83% average week-1–12) and three low levels (56% week-12, 41% year-2, 14 year-3). Conclusion The small number of studies identified did not allow to establish whether the use of monitoring technology could improve adherence to PA programs in patients with chronic diseases experiencing fatigue, but the current evidence seems to suggest that this is a field warranting further study, particularly into how monitoring technology can help to engage patients to adhere to PA programs

The use of cytochrome P450 inhibitors in sport. A new generation of doping masking agents?

The activity of the CYP450 enzymes responsible for the phase I metabolism of most of the compounds included in the World Anti-Doping Agency (WADA) list of prohibited substances and methods could be strongly modified by the combined administration of other drugs such as, for example, the antidepressant, the antifungal and the H2 receptor antagonist agents. These compounds act as inhibitors of the CYP450 isoforms and it has been demonstrated that their co-administration with a drug that is also a CYP450 substrate may lead to a substantial alteration of the latter drug bioavailability, metabolism and excretion kinetics. In sports some classes of non-banned drugs, and primarily among them antidepressants, antifungals and the H2 receptor antagonists are extensively used, according to the information available on the doping control forms. Athletes may intentionally combine the CYP450 inhibitors with doping agents to modify in urine the time window of detection of the selected marker(s) of drug abuse, especially in those cases where the parent drugs are extensively metabolized

Efficacy of adalimumab in young children with juvenile idiopathic arthritis and chronic uveitis: A case series

Background: Juvenile idiopathic arthritis is a relatively common chronic disease of childhood, and is associated with persistent morbidity and extra-articular complications, one of the most common being uveitis. The introduction of biologic therapies, particularly those blocking the inflammatory mediator tumor necrosis factor-α, provided a new treatment option for juvenile idiopathic arthritis patients who were refractory to standard therapy such as non-steroidal anti-inflammatory drugs, corticosteroids and/or methotrexate. Case presentations. The first case was a 2-year-old girl with juvenile idiopathic arthritis and uveitis who failed to respond to treatment with anti-inflammatories, low-dose corticosteroids and methotrexate, and had growth retardation. Adalimumab 24 mg/m2 every 2 weeks and prednisone 0.5 mg/kg/day were added to methotrexate therapy; steroid tapering and withdrawal started after 1 month. After 2 months the patient showed good control of articular and ocular manifestations, and she remained in remission for 1 year, receiving adalimumab and methotrexate with no side effects, and showing significant improvement in growth. Case 2 was a 9-year-old boy with an 8-year history of juvenile idiopathic arthritis and uveitis that initially responded to infliximab, but relapse occurred after 2 years off therapy. After switching to adalimumab, and adjusting doses of both adalimumab and methotrexate based on body surface area, the patient showed good response and corticosteroids were tapered and withdrawn after 6 months; the patient remained in remission taking adalimumab and methotrexate. The final case was a 5-year-old girl with juvenile idiopathic arthritis for whom adalimumab was added to methotrexate therapy after three flares of uveitis. The patient had two subsequent episodes of uveitis that responded well to local therapy, but was then free of both juvenile idiopathic arthritis and uveitis symptoms, allowing methotrexate and then adalimumab to be stopped; the patient remained in drug-free remission. Conclusion: This report includes the first published case of the use of adalimumab in a child aged <3 years. Our clinical experience further supports the use of biologic therapy for the management of juvenile idiopathic arthritis and uveitis in children as young as two years of age. © 2014 La Torre et al.; licensee BioMed Central Ltd