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In the last decade, the market for new psychoactive substances has been enriched by numerous psychedelic phenethylamines, which mimic the psychoactive effect of lysergic acid diethylamide (LSD). In particular, the -NBOMe series, which are more potent than their 2C compounds analogs, are considered worthy substitutes for LSD by users. The purpose of this study was to assess the effects of 25

Fentanyl derivatives (FENS) belongs to the class of Novel Synthetic Opioids that emerged in the illegal drug market of New Psychoactive Substances (NPS). These substances have been implicated in many cases of intoxication and death with overdose worldwide. Therefore, the aim of this study is to investigate the pharmaco-dynamic profiles of three fentanyl (FENT) analogues: Acrylfentanyl (ACRYLF), Ocfentanyl (OCF) and Furanylfentanyl (FUF). In vitro, we measured FENS opioid receptor efficacy, potency, and selectivity in calcium mobilization studies performed in cells coexpressing opioid receptors and chimeric G proteins and their capability to promote the interaction of the mu receptor with G protein and β-arrestin 2 in bioluminescence resonance energy transfer (BRET) studies. In vivo, we investigated the acute effects of the systemic administration of ACRYLF, OCF and FUF (0.01-15 mg/kg i.p.) on mechanical and thermal analgesia, motor impairment, grip strength and cardiorespiratory changes in CD-1 male mice. Opioid receptor specificity was investigated in vivo using naloxone (NLX; 6 mg/kg i.p) pre-treatment. In vitro, the three FENS were able to activate the mu opioid receptor in a concentration dependent manner with following rank order potency: FUF FENT=OCF ACRYLF. All compounds were able to elicit maximal effects similar to that of dermorphin, with the exception of FUF which displayed lower maximal effects thus behaving as a partial agonist. In the BRET G-protein assay, all compounds behaved as partial agonists for the β-arrestin 2 pathway in comparison with dermorphin, whereas FUF did not promote β-arrestin 2 recruitment, behaving as an antagonist. In vivo, all the compounds increased mechanical and thermal analgesia with following rank order potency ACRYLF = FENT FUF OCF and impaired motor and cardiorespiratory parameters. Among the substances tested, FUF showed lower potency for cardiorespiratory and motor effects. These findings reveal the risks associated with the use of FENS and the importance of studying the pharmaco-dynamic properties of these drugs to better understand possible therapeutic interventions in the case of toxicity.

Introduction: The anterior cingulate cortex (ACC) has shown to play a role in impulsivity, fear, and anxiety. Considering, its high glutamate receptor density, it was chosen as a region of interest to investigate the role of glutamate transmission in drug dependance. We investigated the correlations between personality trait scores and glutamate-to-glutamine (Glx) ratio concentrations in the ACC in order to evaluate if (1) personality traits may increase the probability of drug use and (2) drug use can modify cerebral metabolic pattern contributing to addictive behaviors. Materials and Methods: Glx ratio concentrations in the ACC region were measured with high-resolution multivoxel proton magnetic resonance spectroscopy (1H-MRS). Personality traits were evaluated utilizing Cloninger's TCI-revised test. Bivariate correlations between personality scores of 28 teens cannabis users (males, mean age = 18.54 ± 2.80) were evaluated. Results: In the ACC, we observed negative correlation between GG concentrations (r = −0.44, P = 0.05) and co-operativeness values (CO), choline (cho), and novelty seeking (NS) values (r = −0,45, P = 0.05). Low levels of glutamate and high levels of cho in the ACC were closely related to the CO and NS personality traits. Conclusions: Metabolic and personality patterns seems to be related to the risk of substance predisposition in adolescents. Our data contribute a possible support to the “top-down” control of the ACC on brain metabolism, due to the particular cerebral metabolic pattern found in “drug-using” adolescents.

MT-45 is a synthetic opioid that was developed in the 1970s as an analgesic compound. However, in recent years MT-45 has been associated with multiple deaths in Europe and has been included in the class of novel psychoactive substances known as novel synthetic opioids (NSOs). Little is known about the pharmaco-toxicological effects of MT-45. Therefore, we used a dynamic mass redistribution (DMR) assay to investigate the pharmacodynamic profile of this NSO in vitro compared with morphine. We then used in vivo studies to investigate the effect of the acute systemic administration of MT-45 (0.01–15 mg/kg i.p.) on motor and sensorimotor (visual, acoustic and tactile) responses, mechanical and thermal analgesia, muscle strength and body temperature in CD-1 male mice. Higher doses of MT-45 (6–30 mg/kg i.p.) were used to investigate cardiorespiratory changes (heart rate, respiratory rate, SpO2 saturation and pulse distention). All effects of MT-45 were compared with those of morphine. In vitro DMR assay results demonstrated that at human recombinant opioid receptors MT-45 behaves as a potent selective mu agonist with a slightly higher efficacy than morphine. In vivo results showed that MT-45 progressively induces tail elevation at the lowest dose tested (0.01 mg/kg), increased mechanical and thermal antinociception (starting from 1 to 6 mg/kg), decreased visual sensorimotor responses (starting from 3 to 6 mg/kg) and reduced tactile responses, modulated motor performance and induced muscle rigidity at higher doses (15 mg/kg). In addition, at higher doses (15–30 mg/kg) MT-45 impaired the cardiorespiratory functions. All effects were prevented by the administration of the opioid receptor antagonist naloxone. These findings reveal the risks associated with the ingestion of opioids and the importance of studying these drugs and undertaking more clinical studies of the current molecules to better understand possible therapeutic interventions in the case of toxicity.

MDPV is a synthetic cathinone illegally marketed and consumed for its psychostimulant effects, which are similar to those produced by cocaine, amphetamines, and MDMA. Clinical reports indicate that MDPV produces euphoria, increases alertness, and at high doses causes agitation, psychosis, tachycardia and hypertension, hallucinations, delirium, hyperthermia, rhabdomyolysis, and even death. In rodents, MDPV reproduces the typical physiological effects of psychostimulant drugs, demonstrating greater potency than cocaine. Nevertheless, its role in aggressive behavior has been reported but not yet experimentally confirmed. Therefore, the aim of this study was to evaluate the effects of acute and repeated MDPV (0.01–10 mg/kg i.p.) administration on aggressive behavior in mice and to compare them with those of cocaine (0.01–10 mg/kg i.p.) administration. To this purpose, the resident–intruder test in isolated mice and the spontaneous and stimulated aggressiveness tests for group-housed mice were employed. The present study shows for the first time that MDPV enhances aggressive behavior and locomotion in mice with greater potency and efficacy than cocaine treatment. Moreover, the aggressive and locomotor responses are enhanced after repeated administration, indicating that a sensitization mechanism comes into play. These results, although from preclinical investigation, are suggestive that human MDPV intake could be a problem for public health and the criminal justice system. Thus, investigation by police officers and medical staff is needed to prevent interpersonal violence induced by the consumption of synthetic cathinones.

JWH-250 and JWH-073 are two synthetic cannabinoid agonists with nanomolar affinity at CB1 and CB2 receptors. They are illegally marketed within "herbal blend" for theirs psychoactive effects greater than those produced by Cannabis. Recently, we analyzed an "herbal" preparation containing a mixture of both JWH-250 and JWH-073. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of JWH-250 and JWH-073 in male CD-1 mice. In vitro competition binding experiments performed on mouse and human CB1 and CB2 receptors revealed a nanomolar affinity and potency of the JWH-250 and JWH-073. In vivo studies showed that JWH-250 and JWH-073, administered separately, induced a marked hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promote aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of JWH-250 and JWH-073 stimulated dopamine release in the nucleus accumbens in a dose-dependent manner. Behavioral, neurological and neurochemical effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM 251. Co-administration of ineffective doses of JWH-250 and JWH-073 impaired visual sensorimotor responses, improved mechanical pain threshold and stimulated mesolimbic DA transmission in mice, living unchanged all other behavioral and physiological parameters. For the first time the present study demonstrates the overall pharmacological effects induced by the administration of JWH-250 and JWH-073 in mice and it reveals their potentially synergistic action suggesting that co-administration of different synthetic cannabinoids may potentiate the detrimental effects of individual compounds increasing their dangerousness and abuse potential.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the clinical effectiveness and safety of the combined Antiretroviral Treatment containing ABC relative to ABC‐sparing cART. A subgroup comparison will be performed in studies comparing Antiretroviral Treatment containing ABC relative to TDF containing cART.

Objectives: The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine. Several randomized clinical trials (RCTs) investigated the effectiveness and safety of abacavir/lamivudine and tenofovir/emtricitabine combined antiretroviral treatment (cART) and we have reviewed the available evidence. Design: Systematic review and meta-analysis of RCTs using standard Cochrane Collaboration methodologies. Methods: We calculated risk ratios (RRs) with 95% CIs. The primary outcome was the rate of patients with viral load (VL) below the pre-defined cut-off at 48 weeks and/or at 96 weeks. Where available, results were analysed according to VL screening levels (,100000 or .100000 copies/mL) with conventional meta-analytical pooling by subgroups and meta-regression. Results:Meta-analytical pooling of RCTs with a direct comparisonof abacavir/lamivudine and tenofovir/emtricitabine according to baseline VL at 48 weeks (six trials, 4118 patients) showed that the proportions of subjects with VL ,50 copies/mL were similar in the overall comparison (RR 0.98; 95% CI 0.94‐1.03), in the low baseline VL strata (RR 1.01; 95% CI 0.99‐1.03) and in the high baseline VL strata (RR 0.96; 95% CI 0.90‐1.03). Meta-regression analysis at 48 weeks confirms the results of subgroup analysis. Similar virological results were found at 96 weeks (four trials, 2003 patients). Differences in the occurrence of adverse events requiring discontinuation of treatment favoured tenofovir recipients (RR 1.26; 95% CI 0.99‐1.61), but this difference, mostly related to suspected abacavir hypersensitivity reaction, was not statistically significant. Conclusions: Ourcumulative, cross-sectional data suggest a similar virological efficacy of abacavir/lamivudine and tenofovir/emtricitabine regardless of the baseline VL.

Drug abuse assessment methods based on measuring illicit substances in waste waters are consolidated. The approach of ambient air monitoring looks questionable, nonetheless it can be explored if the variables determining the drug burdens are accounted for, or suitable co-contaminants are adopted to normalize concentrations to environmental and human contours. The general approach linking the airborne drug concentrations to consumption is presented and the case of cocaine is discussed according to measurements conducted in Italy. The cocaine/nicotine concentration ratio, identified as the most suitable tool, fitted well with anti-drug Police operations and people noticed for drug-related crimes, and with the abuse prevalence estimated in the cities investigated. According to that, the conversion factors of drug concentrations into prevalence estimates seem assessable, provided sufficient databases over space and time are collected. Further investigations are necessary to understand if airborne drugs cause adverse sanitary effects.© 2013 Elsevier Ltd. All rights reserved.

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, “dark net”) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society (UNODC, World Drug Report, 2014; EMCDDA, European Drug Report 2014: Trends and developments). The chemical structure (phenethylamines, piperazine, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%)(WDR, 2014). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone and MDMA analogues). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with “Spice” use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.

It is well known that an impairment of learning and memory function is one of the major physiological effects caused by natural or synthetic cannabinoid consumption in rodents, nonhuman primates and in humans. JWH-018 and its halogenated derivatives (JWH-018-Cl and JWH-018-Br) are synthetic CB 1 /CB 2 cannabinoid agonists, illegally marketed as “Spice” and “herbal blend” for their Cannabis-like psychoactive effects. In the present study the effects of acute exposure to JWH-018, JWH-018-Cl, JWH-018-Br (JWH-018-R compounds) and Δ 9 -THC (for comparison) on Novel Object Recognition test (NOR) has been investigated in mice. Moreover, to better characterize the effects of JWH-018-R compounds on memory function, in vitro electrophysiological and neurochemical studies in hippocampal preparations have been performed. JWH-018, JWH-018-Cl and JWH-018-Br dose-dependently impaired both short- and long-memory retention in mice (respectively 2 and 24 h after training session). Their effects resulted more potent respect to that evoked by Δ 9 -THC. Moreover, in vitro studies showed as JWH-018-R compounds negatively affected electrically evoked synaptic transmission, LTP and aminoacid (glutamate and GABA) release in hippocampal slices. Behavioral, electrophysiological and neurochemical effects were fully prevented by CB 1 receptor antagonist AM251 pretreatment, suggesting a CB 1 receptor involvement. These data support the hypothesis that synthetic JWH-018-R compounds, as Δ 9 -THC, impair cognitive function in mice by interfering with hippocampal synaptic transmission and memory mechanisms. This data outline the danger that the use and/or abuse of these synthetic cannabinoids may represent for the cognitive process in human consumer.

A key issue in the prevention and control of Sexually Transmitted Diseases (STD) is to provide access to health centres, and in diagnosing and treating STD. The present study is aimed to assess the prevalence of sexually transmitted diseases (STDs) and Hepatitis C virus (HCV) in a population of immigrant female sex workers (FSWs). We conducted a cross sectional survey of FSWs working in Verona, North-eastern Italy. Screening test included serology for STDs [including Human Immunodeficiency Virus (HIV), syphilis and Hepatitis B virus (HBV)] and hepatitis C virus (HCV). Sixteen out of 345 (4.6%) street FSWs screened during 1999-2007 resulted positive for HIV, 12 (3.5%) were positive for HBsAg, 7 (2.0%) were positive for syphilis serological test, and 3 (0.9%) were positive for HCV. Comparison of the prevalence data between women from Africa (286/345, 82.8%) and other countries showed no statistical difference for HIV infection (R.R. 1.44; 95% CI, 0.34-6.19) and for presence of HBsAg (R.R. 2.27; 95% CI, 0.30-17.24). The positivity of syphilis serologic tests had a lower prevalence among African FSWs (mostly coming from Nigeria) than among FSWs from Eastern Europe (57/345, 16.5%). This difference was statistically significant (R.R. 0.03; 95% CI, 0.00-0.28). The prevalence of HIV infection increased with age (p=0.04, by chi2 for trend analysis), but not with the time worked as sex workers in Italy. Moreover, the presence of any of the screened infections was predictable by both age and earlier time of immigration by way of logistic multivariable regression. The prevalence of HIV and HBsAg was higher in the whole analyzed cohort compared to the general population; prevalence of syphilis was significantly higher in FSWs from Eastern Europe than in FSWs from Africa. HCV prevalence remains low among non intravenous drug abuser FSWs. The data offers a starting point to address targeted intervention that would prevent FSWs acquiring and transmitting STDs.

A B S T R A C T A novel method based on microemulsion electrokinetic chromatography (MEEKC) with diode array detection (DAD) for rapid determination of caffeine in commercial and clandestine stimulants, known as ‘‘energy drinks’’ and ‘‘smart drugs’’, is described. Separations were carried out in 50 cm � 50 mm (ID) uncoated fused silica capillaries. The optimized buffer electrolyte was composed of 8.85 mM sodium tetraborate pH 9.5, SDS 3.3% (w/v), n-hexane 1.5% (v/v) and 1-butanol 6.6% (v/v). Separations were performed at a voltage of 20 kV. Sample injection conditions were 0.5 psi, 3 s. Diprofilline was used as internal standard. The determination of the analytes was based on the UV signal recorded at 275 nm, corresponding to the maximum wavelength of absorbance of caffeine, whereas peak identification and purity check was performed on the basis of the acquisition of UV radiation between 200 and 400 nm wavelengths. Under the described conditions, the separation of the compounds was achieved in 6 min without any interference from the matrix. Linearity was assessed within a caffeine concentration range from 5 to 100 mg/mL. The intra-day and inter-day precision values were below 0.37% for migration times and below 9.86% for peak areas. The present MEEKC method was successfully applied to the direct determination of caffeine in smart drugs and energy drinks.

Propofol is a short-acting hypnotic agent that is commonly used to induce and maintain anesthesia. Propofol abuse and its involvement in suicide deaths have increased in recent years, especially among healthcare personnel. An example is the suicide of a 61-year-old nurse found with a propofol drip in his left arm. We describe the postmortem concentration of propofol in various tissues (femoral and cardiac blood, bile, urine, brain, and liver) and in the drip. The toxicological analyses were performed through two analytical methods, differing in derivatization reaction and in instrumentation: silylation for gas chromatograph–mass spectrometer (GC–MS), as routinely performed in our laboratory for this kind of analyses (lower limits of quantification–LLOQ–in urine and blood: 0.3 and 5 ng/ml); for liquid chromatograph–tandem mass spectrometer (LC–MS/MS) an innovative azo-coupling derivatization (LLOQ: 0.0004 and 0.1 ng/ml). This latter produces an azo-derivative (molecular composition: C 18 H 22 ON 2 ; molecular weight: 282 Da) highly ionizable in electro-spray ion source, both in negative and positive ionizations. These two methods were compared to evaluate the effectiveness of this new LC–MS/MS analysis. An acidic hydrolysis (HCl 6 N, 100 °C, and 1 h) was performed for the biological samples (1 ml or 1 g) irrespective of the analytical method applied. The drip content was extracted adding phosphate buffer (pH 8) and a dichloromethane/ethylacetate 8:2 (v:v) mixture. Derivatization steps were: silylation with N , O -bis(trimethylsilyl)trifluoroacetamide (BSTFA) + tetramethylammonium hydroxide (TMAH) for GC–MS; regarding LC–MS/MS, azo-coupling reaction with the aryl-diazonium salt (0–5 °C, and 30 min). The analyses were achieved in selected-ion monitoring for GC–MS ( m/z , 235,250,73 propofol”; m/z , 252,267,27 propofol-d17) and in multiple reaction monitoring ([M−H] − : m/z 283→241,77, azo-propofol; m/z 299→251,77, azo-propofol-d17) for LC–MS/MS. Autopsy showed no significant findings. Propofol concentrations were (LC–MS/MS vs GC–MS, respectively): 15.1 vs 14.5 mg/ml, drip content; 7.11 vs 6.07 μg/ml, cardiac blood; 9.50 vs 7.19 μg/ml, femoral blood; 0.64 vs 1.07 μg/ml, bile; 0.042 vs 0.051 μg/ml urine; 4.93 vs 5.89 μg/g, brain; and 7.88 vs 6.80 μg/g, liver. These values are comparable with the ones described in literature for death by acute propofol intoxication; the drip content is compatible with a diluted formulation of propofol available in Italy (20 mg/ml injectable emulsion). The comparison shows an excellent fitting of the data (R 2 : 0.9362). Toxicological results proved the cause of death as acute propofol intoxication. Furthermore, the new LC–MS/MS method showed an excellent effectiveness and reliability when compared to the routinely used GC–MS method.

In a meta-analysis of 10 studies, the BACTEC 960/MGIT and BACTEC 460 systems showed a sensitivity and specificity in detecting mycobacteria (1,381 strains from 14,745 clinical specimens) of 81.5 and 99.6% and 85.8 and 99.9%, respectively. Combined with solid media, the sensitivity of the two systems increased to 87.7 and 89.7%, respectively.

Sputum induction is a simple and noninvasive procedure for Pneumocystis carinii pneumonia (PCP) diagnosis in human immunodeficiency virus-1-positive patients, although less sensitive than bronchoalveolar lavage (BAL). In order to obtain an overview of the diagnostic accuracy of sputum induction, a systematic review and meta-analysis of studies reporting the comparative sensitivity and specificity of BAL (the "gold standard") and sputum induction was performed. The odds ratio and related 95% confidence interval were calculated using summary receiving operating characteristic curves as well as fixed-effect and random-effect models. Based on pooled data, the negative and positive predictive values were calculated for a range of PCP prevalence using a Bayesian approach. Seven prospective studies assessed the comparative accuracy of BAL and sputum induction. On the whole, sputum induction demonstrated 55.5% sensitivity and 98.6% specificity. The sensitivity of sputum induction was significantly higher with immunofluorescence than with cytochemical staining (67.1 versus 43.1%). In settings of 25-60% prevalence of PCP, the positive and negative predictive values ranged 86-96.7 and 66.2-89.8, respectively, with immunofluorescence, and 79-94.4 and 53-83.5% with cytochemical staining. In conclusion, in a setting of low prevalence of Pneumocystis carinii pneumonia, sputum induction, particularly with immunostaining, appears to be adequate for clinical decision-making.

JWH-018 is a synthetic CB1 and CB2 agonist illegally marketed as products named “Spice” or “herbal blend” for its psychoactive effects which are much higher than those produced by cannabis. In the last year, the European Monitoring Centre for Drugs and Drug Addiction reported to the Italian National Early Warning System the seizure of plant material containing new halogenated derivatives of JWH-018 (JWH-018 Cl and JWH-018 Br). The present study aimed to investigate the in vitro and in vivo activity of these two new synthetic cannabinoids in mice. In vitro competition binding experiments performed on mouse and human CB1 receptors revealed a high affinity and potency of the halogenated compounds. Synthetic cannabinoids (0.01–6 mg/kg i.p.) impaired motor activity and induced catalepsy in mice and their effects were more severe with respect to those evoked by Δ9-THC. Moreover, they increased the mechanical and thermal pain threshold and induced a marked hypothermia. It is interesting to note that whereas high doses of JWH-018 cause seizures, myoclonia and hyperreflexia, the halogenated compounds, in particular JWH-018Br, were less effective. Behavioral and neurological changes were prevented by the selective CB1 receptor antagonist AM 251. These data demonstrate for the first time that JWH-018 Cl and JWH-018 Br act similarly to JWH-018 while inducing less convulsive episodes and myoclonias. These data support the hypothesis that the halogenated compounds may have been introduced onto market to produce similar intoxicating effects as JWH-018 while causing less side effects.

To assess if the relative infectiousness of patients with tuberculosis is enhanced by coinfection with human immunodeficiency virus type 1 (HIV-1), data from 6 studies of 1240 health care workers who had contact with tuberculosis patients were analyzed. Overall rates of tuberculin skin test conversion were similar regardless of HIV-1 positivity of tuberculosis patients (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.23-1.84). However, when only 3 studies during nosocomial outbreaks of multidrug-resistant Mycobacterium tuberculosis were analyzed, rates of skin test conversion were higher among contacts of HIV-1-positive index cases (OR, 2.85; 95% CI, 1.85-3.85; P = .0002). A second meta-analysis included data from 11 studies of 10,714 household contacts of tuberculosis patients. Prevalence of both skin test positivity (OR, 0.45; 95% CI, 0.20-1.03) and active disease (OR, 1.17; 95% CI, 0.78-1.56) were similar regardless of HIV-1 positivity of index cases. These data suggest that tuberculosis patients with HIV-1 infection are not intrinsically more infectious to their contacts than are HIV-1-negative tuberculosis patients.

BACKGROUND Regimen simplification can be defined as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy may be considered candidates for a simplification strategy and, among them, those who have achieved virologic suppression. Several clinical trials have evaluated the efficacy of triple nucleoside combination as a simplification therapy in patients who achieved virologic suppression OBJECTIVES The aim of this review is to combine randomised, controlled trials to examine whether in patients with undetectable viraemia on a Protease inhibitor (PI) based regimen simplification treatment with abacavir (ABC)-based triple-nucleoside combinations has similar rates of efficacy and tolerability compared with a PI regimen or simplification with a NNRTIs (efavirenz-EFV- or nevirapine-NVP) containing regimen. Studies were included if they had at least two of the three interventions, including one 3NRTI arm. SEARCH METHODS Electronic databases and conference proceedings were searched (1996-2012) with relevant search terms without limits to language. SELECTION CRITERIA Randomised controlled trials (RCTs) only are included in this review. Patients population is represented by HIV-infected adult patients treated with a PI-containing regimen (PI or boosted PI), with undetectable viral load. Patients on a PI-containing regimen had three possibilities: continue the PI regimen or switch to a simplification maintenance regimen, including switch to a NNRTI (EFV or NVP) containing regimen, or switch to a triple-NRTI regimen (ABC-zidovudine-lamivudine) DATA COLLECTION AND ANALYSIS The primary outcomes were: proportion of patients discontinuing or switching antiretroviral therapy due to virologic failure or to adverse events; death (all cause) and AIDS defining illness; occurrence of myocardial infarction and cardiovascular disease. Secondary outcomes were: proportion of patients maintaining an undetectable viral load (e.g. HIV-RNA

Electronic health record systems (EHRs) play an increasingly important role in opioid agonist treatment. In Italy, an EHR called the Multi Functional Platform (MFP) is in use in 150 opioid-agonist treatment facilities in 8 of Italy’s 23 regions. This report describes MFP and presents 2010 data from 65 sites that treated 8,145 patients, of whom 72.3% were treated with methadone and 27.7% with buprenorphine. Patients treated with buprenorphine compared to methadone were more likely to be male (p < 0.01) and younger (p < 0.001). Methadone compared to buprenorphine patients had a higher percentage of opioid-positive urine tests (p < 0.001) and longer mean length of stay (p = 0.004). MFP has been implemented widely in Italy and has been able to track patient outcomes across treatment facilities. In the future, this EHR system can be used for performance improvement initiatives.

Drug addiction can be a devastating and chronic relapsing disorder with social, psychological and physical consequences, and more effective treatment options are needed. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has been assessed in a growing number of studies for its therapeutic potential in treating addiction. This review paper offers an overview on the current state of clinical research in treating drug addiction with rTMS. Because of the limited research in this area, all studies (including case reports) that evaluated the therapeutic use of rTMS in nicotine, alcohol or illicit drug addiction were included in this review. Papers published prior to December 2012 were found through an NCBI PubMed search (http://www.ncbi.nlm.nih.gov). A total of eleven studies were identified that met review criteria. There is nascent evidence that rTMS could be effective in reducing cocaine craving, and nicotine and alcohol craving and consumption, and might represent a potential therapeutic tool for treating addiction. Further studies are needed to identify the optimal parameters of stimulation for the most effective treatment of drug addiction, to improve our comprehension of the treatment neurophysiological effects, and to conduct rigorous, controlled efficacy studies with adequate power.

For the first time a capillary separation based on micellar electrokinetic chromatography (MEKC) with diode array detection (DAD) was developed and validated for the rapid determination of synthetic cannabinoids in herbal blends. Separations were carried out on a 30 μm (ID) × 40 cm uncoated fused silica capillaries. The optimized buffer electrolyte was composed of 25 mM sodium tetraborate pH 8.0, 30 mM SDS and n-propanol 20% (v/v). Separations were performed at 30 kV. Sample injection conditions were 0.5 psi, 10 s. Diazepam and JWH-015 were used as internal standards. The determination of the analytes was based on the UV signal recorded at 220 nm, corresponding to the maximum wavelength of absorbance of the molecules, whereas peak identification and purity check were also performed on the basis of the acquisition of UV spectra between 200 and 400 nm wavelengths. Under the described conditions, the separation of the compounds was achieved in 25 min without any significant interference from the matrix. Linearity was assessed within a concentration range from 5 to 100 μg/mL. The intra-day and inter-day imprecision values were below 2.45% for relative migration times and below 10.75% for relative peak areas. The present method was successfully applied to the direct determination of synthetic cannabinoids in 15 different herbal blend samples requiring only sample dilution. In addition, the developed MEKC separation was also applied to estimate the octanol/water partition coefficients (log P) of these new and poorly known molecules.

Since 2004, a number of herbal blends containing different synthetic compounds mimicking the pharmacological activity of cannabinoids and displaying a high toxicological potential have appeared in the market. Their availability is mainly based on the so-called "e-commerce", being sold as legal alternatives to cannabis and cannabis derivatives. Although highly selective, sensitive, accurate, and quantitative methods based on GC-MS and LC-MS are available, they lack simplicity, rapidity, versatility and throughput, which are required for product monitoring. In this context, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) offers a simple and rapid operation with high throughput. Thus, the aim of the present work was to develop a MALDI-TOF MS method for the rapid qualitative direct analysis of herbal blend preparations for synthetic cannabinoids to be used as front screening of confiscated clandestine preparations. The sample preparation was limited to herbal blend leaves finely grinding in a mortar and loading onto the MALDI plate followed by addition of 2 µl of the matrix/surfactant mixture [α-cyano-4-hydroxy-cinnamic acid/cetyltrimethylammonium bromide (CTAB)]. After drying, the sample plate was introduced into the ion source for analysis. MALDI-TOF conditions were as follows: mass spectra were analyzed in the range m/z 150-550 by averaging the data from 50 laser shots and using an accelerating voltage of 20 kV. The described method was successfully applied to the screening of 31 commercial herbal blends, previously analyzed by GC-MS. Among the samples analyzed, 21 contained synthetic cannabinoids (namely JWH-018, JWH-073, JWH-081, JWH-250, JWH-210, JWH-019, and AM-694). All the results were in agreement with GC-MS, which was used as the reference technique.

New Italian legislation on driving under the influence of drugs considers oral fluid (OF) as a possible alternative drug testing matrix. On this basis, the present research was carried out to evaluate the applicability of four commercial on-site OF drug screening devices, namely DDS ® , Drugtest 5000 ® , Drugwipe 5+ ® and RapidSTAT ® , in a real operative context. Preliminarily trained police officers tested randomly stopped drivers with two different kits side-by-side during roadside patrols. A central laboratory confirmed on-site kits' results by UHPLC–MS/MS analysis of the saliva specimen remaining after the screening analysis. 1025 drivers were submitted to the OF tests: 11.6% were positive for cocaine and metabolites, 11.1% for THC, 6% for amphetamines and amphetamine-type designer drugs and 2.3% for ketamine. The sensitivities of the kits were 81% (RapidSTAT ® ), 82% (DDS ® ), 90% (Drugwipe 5+ ® ) and 97% (Drugtest 5000 ® ) for cocaine and 38% (DDS ® ), 47% (Drugwipe 5+ ® ), 72% (RapidSTAT ® ) and 92% (Drugtest 5000 ® ) for THC. Drugtest 5000 was the only kit showing an acceptable sensitivity for on-site application. Only Drugtest 5000 ® and RapidSTAT ® could be evaluated for amphetamines and methamphetamines: Drugtest 5000 ® showed a sensitivity of 100% in the case of amphetamines and 86% for methamphetamines, while RapidSTAT ® 90% and 76% respectively. Nowadays, ketamine is not included in the target analytes of any on-site devices, but it was systematically included in the UHPLC–MS/MS confirmatory analysis. To ensure adequate reliability, MS confirmation of on-site OF screening tests is anyway always necessary, due to the presence of a significant number of false positive results even when using the commercial kit with the best performance.

Background The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease in some cohort studies. However, no excess risk of myocardial infarction (MI) with ABC therapy has been observed in individual randomized clinical trials (RCTs) and in the aggregated clinical trials database maintained by the manufacturer of ABC. Objective To combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on MI and overall major cardiovascular events (CVEs). Methods Primary outcomes included MI, CVE, adverse events requiring discontinuation of treatment, and overall mortality. We used a conventional Mantel-Haenszel method, with risk ratio and 95% confidence intervals (CIs) or, in the presence of heterogeneity, a random-effect model. Results Data were from 28 primary RCTs (9233 participants) comparing ABC-containing cART (4376 participants) to other regimens not containing ABC (4857 controls). MI data were available from 18 trials (31 episodes in 7054 patients) and CVE data from 20 trials (79 episodes in 7899 patients). Compared to the controls, ABC use did not increase significantly the occurrence of MI (risk ratio 0.73, 95% CI 0.39-1.35; P = 0.31), CVE (risk ratio 0.95, 95% CI 0.62-1.44; P = 0.80), overall mortality (risk ratio 1.20, 95% CI 0.63-2.27; P = 0.58), and adverse events requiring discontinuation of treatment (risk ratio 0.82, 95% CI 0.67-1.00; P = 0.05). Conclusion This meta-analysis of RCTs does not support the hypothesis that ABC-containing cART regimens carry a greater risk of MI or major cardiovascular events relative to comparator cART.

We performed a meta-analysis to determine whether antifungal prophylaxis decreases infectious morbidity and mortality in liver transplant patients. We searched for randomized trials dealing with prophylaxis with systemic antifungal agents. We used a fixed effect model, with risk ratio (RR) and 95% confidence interval (CI); we assessed study quality for heterogeneity and publication bias. Six studies (5 double-blind), for a total of 698 patients, compared fluconazole, itraconazole, or liposomal amphotericin to placebo (5 studies) or oral nystatin. Prophylaxis reduced colonization (RR, 0.45; CI, 0.37-0.55), total proven fungal infections (RR, 0.31; CI, 0.21-0.46), which included both superficial (RR, 0.27; CI, 0.16-0.45) and invasive (RR, 0.33; CI, 0.18-0.59) infections, and mortality attributable to fungal infection (RR, 0.30; CI, 0.12-0.75). Prophylaxis did not affect overall mortality (RR, 1.06; CI, 0.69-1.64) or empiric treatment for suspected fungal infection (RR, 0.80; CI, 0.39-1.67). The beneficial effect of antifungal prophylaxis was predominantly associated with the reduction of Candida albicans infection and mortality attributable to C. albicans. Compared to controls, however, patients receiving prophylaxis experienced a higher proportion of episodes of non-albicans Candida, and in particular of C. glabrata. No beneficial effect on invasive Aspergillus infection was observed. In conclusion, our analysis shows a clear, though limited, beneficial effect of antifungal prophylaxis in liver transplant patients. Concerns about the selection of triazole-resistant Candida strains, however, are realistic, and the potential disadvantages of prophylaxis should be weighed against the established benefits.

The Parasight-F test is a device for the rapid diagnosis of Plasmodium falciparum malaria. In a number of field studies rather wide disparities in the performance of the test have been reported. To provide an evaluation of the quality of available reports and an overall summary of diagnostic accuracy of the Parasight-F test, we have performed a systematic review.Systematic review and meta-analysis of controlled studies evaluating the diagnostic accuracy of Parasight-F test in comparison with light microscopy.15,359 subjects (4,119 with falciparum malaria) studied with the Parasight-F test as reported in 32 studies from 29 publications.Summary receiving operator characteristic (SROC) curve as well as odds ratio calculated by the fixed effect model and the random effect model. Based on pooled data, the predictive values were calculated for a range of P. falciparum prevalence through a Bayesian approach.Overall, the Parasight-F test demonstrated 0.90 (95%, confidence intervals 0.88-0.93) sensitivity and 0.94 (0.92-0.96) specificity. Both sensitivity and specificity were significantly higher in the non-resident than in the resident population. The post-test probability indicates that in settings of low malaria prevalence, a negative test almost absolutely excludes infection, while in settings of high prevalence, the same result still gives a substantial chance of infection being present.The Parasight-F test is a simple and accurate test for the diagnosis of P. falciparum infection. The test could be of particular value in the diagnosis of malaria in travelers returning from endemic areas.

Background Over the last two decades, the proportion of people who inject drugs among newly reported HIV cases in Italy has been continuously declining. This trend is reflected in the prevalence of HIV infection among problem drug users followed in drug treatment services. We report nationwide trends in the prevalence of HIV and HCV among tested clients in charge to drug addiction services from 2005 to 2011. Methods Data on the prevalence of HIV and HCV among drug users from public drug treatment services across Italy were collected and analyzed for the period from 2005 to 2011. Prevalence of HIV and HCV were compared between clients returning to treatment and those entering treatment for the first time, and by gender. Due to the high percentage of missing data, the “inverse probability weight” method was used. Trends in testing uptake were also analysed. Results A significant decrease of HIV and HCV prevalence is observed among all PDUs entering treatment (from 14.7% to 11.1% and from 61.6% to 50%, respectively, in 2005–2011). By contrast, among those entering the services for the first time, after an initial decline the prevalence of HIV infection steadily increased in both sexes, from 2.2% in 2009 to 5.3% in 2011. Self-reported injecting rates in this group decreased over time, and in 2011 the proportion reporting drug injecting was lower among new clients than in people returning to services (14.5 vs. 34.4%). We also observed a progressive and significant reduction in HIV and HCV testing in drug treatment services. Conclusions Changes in injection practice and type of drugs used, coupled with a concurrent reduction in HCV prevalence, do not support drug injection as the main explanation for an increased HIV transmission in people entering drug treatment services for the first time. While reductions in testing rates raise concerns over data quality, the possibility of increased sexual transmission needs to be considered.