A scintillator attenuation spectrometer for intense gamma-rays.

A new type of compact high-resolution high-sensitivity gamma-ray spectrometer for short-pulse intense gamma-rays (250 keV to 50 MeV) has been developed by combining the principles of scintillators and attenuation spectrometers. The first prototype of this scintillator attenuation spectrometer (SAS) was tested successfully in Trident laser experiments at LANL. Later versions have been used extensively in the Texas Petawatt laser experiments in Austin, TX, and more recently in OMEGA-EP laser experiments at LLE, Rochester, NY. The SAS is particularly useful for high-repetition-rate laser applications. Here, we give a concise description of the design principles, capabilities, and sample preliminary results of the SAS.

In vivo evidence that the cannabinoid receptor 2-63 RR variant is associated with the acquisition and/or expansion of HIV infection.

OBJECTIVES: The aim of the study was to investigate whether the rs35761398 variants of the cannabinoid receptor 2 (CB2) gene may influence the acquisition of HIV infection and the clinical presentation of HIV/hepatitis C virus (HCV) coinfection. METHODS: We compared 166 HIV/HCV-coinfected patients with 186 HCV-monoinfected patients, all with biopsy-proven chronic hepatitis (using the Ishak scoring system), naïve for anti-HCV treatment and tested for the CB2 rs35761398 polymorphism (using the TaqMan assay). RESULTS: The HIV/HCV-coinfected patients were more frequently male (P < 0.002), were younger (P < 0.001), and had lower median BMI (P < 0.001) and HCV RNA (P < 0.05) and higher median aspartate aminotransferase (AST; P < 0.001), alanine aminotransferase (ALT; P < 0.001) and gamma glutamyl transferase (GGT; P < 0.001) levels than the HCV-monoinfected patients. The CB2 RR variant predominated in HIV/HCV-coinfected patients (45.8% vs. 31.2% in HCV-monoinfected patients; P < 0.001) and the CB2 QR variant in HCV-monoinfected patients (57.5% vs. 38.6% in HIV/HCV-coinfected patients; P < 0.00001), and the CB2 QQ variant was equally distributed. Focusing on patients with the CB2 QQ variant, the 26 HIV/HCV-coinfected patients, compared with the 21 HCV-monoinfected patients, showed less severe liver necroinflammation [lower histological activity index (HAI)] (P < 0.05). Of the patients with the CB2 RR variant, the 76 HIV/HCV-coinfected patients, compared with the 58 HCV-monoinfected patients, were more frequently male (P < 0.05), were younger (P < 0.001), and had a lower median body mass index (BMI; P < 0.001), a higher median AST level (P < 0.001), a higher mean HAI score (P < 0.05) and a higher rate of cases with severe steatosis (P = 0.05). In an analysis of variance (anova) of HCV/HIV-coinfected and HCV-monoinfected patient data, those with the CB2 RR variant (P = 0.003) and of male sex (P = 0.002) were more prevalent in the HCV/HIV-coinfected group. CONCLUSIONS: There is the suggestion of a positive effect of the CB2 RR variant on HIV acquisition and/or spread, which is in accordance with previous in vitro observations.

The albumin-bilirubin grade uncovers the prognostic relationship between hepatic reserve and immune dysfunction in HIV-associated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of liver-related mortality in people living with HIV, where co-infection with hepatotropic viruses accelerates the course of chronic liver disease. AIM: To evaluate whether the albumin-bilirubin (ALBI) grade, a more accurate marker of liver dysfunction in HCC, might identify patients with progressive liver dysfunction in the context of HIV/hepatitis co-infection. METHODS: Using uni- and multi-variable analyses, we studied the albumin-bilirubin grade as a predictor of overall survival (OS) in a large, multi-center cohort of patients with HIV-associated HCC recruited from 44 centres in 9 countries within the Liver Cancer in HIV study group. Patients who underwent liver transplantation were excluded. RESULTS: A total of 387 patients, predominantly HCV co-infected (78%) with balanced representation of all Barcelona Clinic Liver Cancer (BCLC) stages (A = 33%, B = 18%, C = 37%, D = 12%) were recruited. At HCC diagnosis, 84% had been on anti-retrovirals for a median duration of 8.8 years. The albumin-bilirubin grade identified significant differences in median survival of 97 months for grade 1 (95% CI 13-180 months), 17 months for grade 2 (95% CI 11-22 months) and 6 months for grade 3 (95% CI 4-9 months, P < .001). A more advanced albumin-bilirubin grade correlated with lower CD4 counts (464/373/288 cells/mm3 for grades 1/2/3) and higher HIV viraemia (3.337/8.701/61.845 copies/mL for grades 1/2/3, P < .001). CONCLUSIONS: In this large, multi-center retrospective study, the albumin-bilirubin grade highlights the interplay between liver reserve and immune dysfunction as prognostic determinants in HIV-associated HCC.

Walking the tightrope-perspectives on local politicians' role in implementing a national social care policy on evidence-based practice.

BACKGROUND: Despite national policy recommending evidence-based practice (EBP), its application in social care has been limited. While local politicians can affect the process, little is known about their knowledge, attitudes and roles regarding EBP. The aim here is twofold: to explore the role of local politicians in the implementation of EBP in social care from both their own and a management perspective; and to examine factors politicians perceive as affecting their decisions and actions concerning the implementation of EBP policy. METHODS: Local politicians (N = 13) and managers (N = 22) in social care were interviewed. Qualitative thematic analysis with both inductive and deductive codes was used. RESULTS: Politicians were rather uninformed regarding EBP and national policy. The factors limiting their actions were, beside the lack of awareness, lack of ability to question existing working methods, and a need for support in the steering of EBP. Thus, personal interest played a significant part in what role the politicians assumed. This resulted in some politicians taking a more active role in steering EBP while others were not involved. From the managers' perspective, a more active steering by politicians was desired. Setting budget and objectives, as well as active follow-up of work processes and outcomes, were identified as means to affect the implementation of EBP. However, the politicians seemed unaware of the facilitating effects of these actions. CONCLUSIONS: Local politicians had a possibility to facilitate the implementation of EBP, but their role was unclear. Personal interest played a big part in determining what role was taken. The results imply that social care politicians might need support in the development of their steering of EBP. Moving the responsibility for EBP facilitation upwards in the political structure could be an important step in developing EBP in social care.

Treatment of severe recurrent hepatitis C after liver transplantation in HIV infected patients using sofosbuvir-based therapy.

BACKGROUND: For liver transplant recipients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection, recurrence after LT is associated with a higher risk of graft loss than for HCV mono-infected patients. Prior HCV treatment options were limited by side effects and drug-drug interactions. AIM: To evaluate treatment outcomes with sofosbuvir (SOF)-based therapy among HIV/HCV coinfected liver transplant recipients. METHODS: Access to SOF and ribavirin (RBV) prior to regulatory approval was attained via an international compassionate access program for transplant recipients with a life expectancy of 1 year or less in the absence of HCV treatment. This report focuses on the short and longer term outcomes in HCV-HIV co-infected liver transplant recipients. RESULTS: Twenty patients were treated, nine with early severe recurrence and 11 with cirrhosis. Eleven patients received SOF and RBV, one SOF, RBV and Peg-interferon, three SOF, RBV and simeprevir and five SOF, RBV and daclatasvir. Of the 18 patients who completed treatment, 16 (89%) achieved sustained virological response 12 weeks after the end of treatment (SVR12). Liver function tests (including bilirubin and albumin) improved significantly over time. Nineteen serious adverse events occurred in eight (40%) patients, none of them related to SOF. Two patients died during treatment and another, 1 year after the end of therapy, due to progressive end-stage liver disease. Importantly, HIV suppression was not compromised. No significant drug-drug interactions were reported. CONCLUSIONS: Sofosbuvir-based regimens are safe, well-tolerated and provide high rates of SVR in HCV-HIV co-infected patients with severe recurrence after-liver transplant.

Impact of PNPLA3 variants on liver histology of 168 patients with HIV infection and chronic hepatitis C.

This study analysed the impact of PNPLA3 variants on liver histology of 168 HIV/hepatitis C virus (HCV)-coinfected patients who were naïve for HCV treatment. A athologist unaware of the patients' condition graded liver fibrosis and necroinflammation (Ishak) and steatosis (Kleiner). Patients were tested for PNPLA3 variants and genotyped for the PNPLA3 rs738409 C to G variant underlying the I148M substitution. All were hepatitis B surface antigen negative and stated no alcohol abuse. The mean age was 40.6 (37.6-44.1) years, 72.6% were males, 42% had HCV genotype 3, 38.9% HCV genotype 1 and 79.2% were receiving highly active antiretroviral therapy. The 79 patients with the PNPLA3 p.148I/M or M/M variants more frequently showed severe steatosis (score 3-4) than the 89 with PNPLA3 p.148I/I (43% vs. 24.7%, p 0.001), whereas no difference was observed in the degree of necroinflammation or fibrosis. Compared with 112 patients with lower scores, 56 with severe steatosis showed higher body mass index (p 0.03), higher rate of HCV genotype 3 (55.6% vs. 35.2%, p 0.01), PNPLA3 p.148I/M or M/M (60.7% vs. 39.3%, p 0.01) and lower CD4(+) cells/mm(3) (514.00 (390.5-673.0) vs. 500.00 (399.0-627.0); p 0.002). At multivariate analysis, body mass index (p 0.01), HCV genotype 3 (p 0.006), CD4(+) cell count (p 0.005) and PNPLA3 p.148I/M or M/M variants (p 0.01) were found to be independent predictors of severe liver steatosis. The PNPLA3 p.148 I/M or M/M variants and CD4(+) cell count were the only independent predictors of severe steatosis in patients with HCV non-3 genotypes. This is the first study to show that among HIV/HCV-coinfected patients the PNPLA3 p.148I/M or M/M variant have substantially less impact on steatosis for those with HCV genotype 3 than non-genotype 3.

Distribution of natural resistance to NS3 protease inhibitors in hepatitis C genotype 1a separated into clades 1 and 2 and in genotype 1b of HIV-infected patients.

Naturally occurring resistance-associated variants (RAVs) within the protease domain of hepatitis C virus (HCV) genotype (G) 1a separated into clades 1 and 2, and G1b were investigated in 59 HIV/HCV coinfected patients. RAVs were detected in 10/23 G1a/clade 1 and 1/19 G1b (p 0.0059). A similar frequency of RAVs was found when comparing G1a/clade 2 and G1b (p 0.1672). A cross-resistance to the macrocyclic compounds simeprevir and paritaprevir was detected in two G1a/clade 2 and 1 G1b sequences and none of G1a/clade 1 sequences. The simultaneous characterization of subtype and natural RAVs by population analysis of the NS3 domain by may add important information for anti-HCV treatment strategies including protease inhibitors.

Evidence-informed policy formulation and implementation: a comparative case study of two national policies for improving health and social care in Sweden.

BACKGROUND: Evidence has come to play a central role in health policymaking. However, policymakers tend to use other types of information besides research evidence. Most prior studies on evidence-informed policy have focused on the policy formulation phase without a systematic analysis of its implementation. It has been suggested that in order to fully understand the policy process, the analysis should include both policy formulation and implementation. The purpose of the study was to explore and compare two policies aiming to improve health and social care in Sweden and to empirically test a new conceptual model for evidence-informed policy formulation and implementation. METHODS: Two concurrent national policies were studied during the entire policy process using a longitudinal, comparative case study approach. Data was collected through interviews, observations, and documents. A Conceptual Model for Evidence-Informed Policy Formulation and Implementation was developed based on prior frameworks for evidence-informed policymaking and policy dissemination and implementation. The conceptual model was used to organize and analyze the data. RESULTS: The policies differed regarding the use of evidence in the policy formulation and the extent to which the policy formulation and implementation phases overlapped. Similarities between the cases were an emphasis on capacity assessment, modified activities based on the assessment, and a highly active implementation approach relying on networks of stakeholders. The Conceptual Model for Evidence-Informed Policy Formulation and Implementation was empirically useful to organize the data. CONCLUSIONS: The policy actors' roles and functions were found to have a great influence on the choices of strategies and collaborators in all policy phases. The Conceptual Model for Evidence-Informed Policy Formulation and Implementation was found to be useful. However, it provided insufficient guidance for analyzing actors involved in the policy process, capacity-building strategies, and overlapping policy phases. A revised version of the model that includes these aspects is suggested.

High e+/e- Ratio Dense Pair Creation with 10(21)W.cm(-2) Laser Irradiating Solid Targets.

We report results of new pair creation experiments using ~100 Joule pulses of the Texas Petawatt Laser to irradiate solid gold and platinum targets, with intensities up to ~1.9 × 10(21) W.cm(-2) and pulse durations as short as ~130 fs. Positron to electron (e+/e-) ratios >15% were observed for many thick disk and rod targets, with the highest e+/e- ratio reaching ~50% for a Pt rod. The inferred pair yield was ~ few ×10(10) with emerging pair density reaching ~10(15)/cm(3) so that the pair skin depth becomes < pair jet transverse size. These results represent major milestones towards the goal of creating a significant quantity of dense pair-dominated plasmas with e+/e- approaching 100% and pair skin depth ≪ pair plasma size, which will have wide-ranging applications to astrophysics and fundamental physics.

Age- and sex-related characteristics of tonic GABA currents in the rat substantia nigra pars reticulata.

Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4ß3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved.

Post-stroke depression and functional independence: a conundrum.

OBJECTIVES: People who suffer a stroke are at risk of developing post-stroke depression (PSD). Not only does this lower their quality of life but it also increases their risk of another stroke or death. This study aimed to investigate the factors associated with PSD in order to better direct rehabilitation efforts aimed at cutting the incidence of PSD. MATERIAL AND METHODS: This study was based on all patients admitted to the stroke unit of a hospital in southern Sweden from 1 October 2003 to 30 November 2005. The total number of patients involved was 181. Measures were collected at 2 ± 1 weeks after discharge from hospital, 3 ± 0.5 months after the occurrence of the stroke and 12 ± 1 months after the occurrence of the stroke. Information collected was results from the Center of Epidemiologic Studies Depression Scale and the Barthel Index together with demographic data including age, sex, time since stroke and relationship status. RESULTS: Those patients involved in the study were mainly men (58-59%) and generally those either married or cohabiting (53-57%). The age of respondents ranged from 32 to 92 years with a mean age of 74.0 (95%CI 72.37-75.63) at 2 ± 1 weeks after discharge. The Barthel Index scores ranged from 15 to 100 with means of between 88.7 and 91.7. Between 15% and 19% of the group were clinically depressed during the time frame of the study. The Barthel Index, measuring functional independence in terms of need for assistance with personal activities of daily living (P-ADL), was consistently associated with PSD. CONCLUSIONS: The differences found in levels of depression between those with lower functional independence after a stroke compared to those more independent in P-ADL, raise the possibility that attention should be paid to therapeutic rehabilitation for stroke patients to help them recover as much functional independence as possible in order to improve their quality of life and lower their chances of developing PSD.

Factors associated with high use of a workplace web-based stress management program in a randomized controlled intervention study.

In web-based health promotion programs, large variations in participant engagement are common. The aim was to investigate determinants of high use of a worksite self-help web-based program for stress management. Two versions of the program were offered to randomly selected departments in IT and media companies. A static version of the program including health screening tool, diary and information about stress was offered to the control group. Additional materials, i.e. interactive, cognitive-based and classical stress management exercises and a chat room, were offered to the intervention group. Baseline data regarding participants' demographics, health (self-ratings and biological measures), lifestyle, work-related factors and group membership were analyzed to study determinants of employees' participation in the program during a period of 12 months. Multiple logistic regression analysis was used and found intervention group membership, being a woman, having at most a secondary education, regular physical exercise habits and having positive expectations of the program were significant predictors of high use. The findings demonstrate that the interactivity of a web-based program is an important factor for determining participation in a web-based worksite stress management program. Implications for those developing and implementing future web-based health promotion activities are discussed.

The International Caries Detection and Assessment System (ICDAS): an integrated system for measuring dental caries.

This paper describes early findings of evaluations of the International Caries Detection and Assessment System (ICDAS) conducted by the Detroit Center for Research on Oral Health Disparities (DCR-OHD). The lack of consistency among the contemporary criteria systems limits the comparability of outcomes measured in epidemiological and clinical studies. The ICDAS criteria were developed by an international team of caries researchers to integrate several new criteria systems into one standard system for caries detection and assessment. Using ICDAS in the DCR-OHD cohort study, dental examiners first determined whether a clean and dry tooth surface is sound, sealed, restored, crowned, or missing. Afterwards, the examiners classified the carious status of each tooth surface using a seven-point ordinal scale ranging from sound to extensive cavitation. Histological examination of extracted teeth found increased likelihood of carious demineralization in dentin as the ICDAS codes increased in severity. The criteria were also found to have discriminatory validity in analyses of social, behavioral and dietary factors associated with dental caries. The reliability of six examiners to classify tooth surfaces by their ICDAS carious status ranged between good to excellent (kappa coefficients ranged between 0.59 and 0.82). While further work is still needed to define caries activity, validate the criteria and their reliability in assessing dental caries on smooth surfaces, and develop a classification system for assessing preventive and restorative treatment needs, this early evaluation of the ICDAS platform has found that the system is practical; has content validity, correlational validity with histological examination of pits and fissures in extracted teeth; and discriminatory validity.

Evaluation of an educational "toolbox" for improving nursing staff competence and psychosocial work environment in elderly care: results of a prospective, non-randomized controlled intervention.

BACKGROUND: Lack of professional development opportunities among nursing staff is a major concern in elderly care and has been associated with work dissatisfaction and staff turnover. There is a lack of prospective, controlled studies evaluating the effects of educational interventions on nursing competence and work satisfaction. OBJECTIVES: The aim of this study was to evaluate the possible effects of an educational "toolbox" intervention on nursing staff ratings of their competence, psychosocial work environment and overall work satisfaction. DESIGN: The study was a prospective, non-randomized, controlled intervention. PARTICIPANTS AND SETTINGS: Nursing staff in two municipal elderly care organizations in western Sweden. METHODS: In an initial questionnaire survey, nursing staff in the intervention municipality described several areas in which they felt a need for competence development. Measurement instruments and educational materials for improving staff knowledge and work practices were then collated by researchers and managers in a "toolbox." Nursing staff ratings of their competence and work were measured pre and post-intervention by questionnaire. Staff ratings in the intervention municipality were compared to staff ratings in the reference municipality, where no toolbox was introduced. RESULTS: Nursing staff ratings of their competence and psychosocial work environment, including overall work satisfaction, improved significantly over time in the intervention municipality, compared to the reference group. Both competence and work environment ratings were largely unchanged among reference municipality staff. Multivariate analysis revealed a significant interaction effect between municipalities over time for nursing staff ratings of participation, leadership, performance feedback and skills' development. Staff ratings for these four scales improved significantly in the intervention municipality as compared to the reference municipality. CONCLUSIONS: Compared to a reference municipality, nursing staff ratings of their competence and the psychosocial work environment improved in the municipality where the toolbox was introduced.

Home-based chemically-induced whitening of teeth in adults.

BACKGROUND: During the last decade tooth whitening products have become widely available in the USA for sale over-the-counter or dispensed by dentists for use at home. With the current rapid growth in demand for tooth whitening it is imperative that the dental community base its recommendations to patients on sound scientific evaluations conducted in well-designed and independent studies. OBJECTIVES: To evaluate the effectiveness (versus a placebo or another active product) and side effects of over-the-counter or dentist-dispensed chemically-based tooth whitening products designed for home use. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 3); MEDLINE (January 1966 to September week 2 2005); and EMBASE (1988 to week 39 2005). The tables of content of selected dental journals published since 1995 were searched for additional references. Written requests for additional studies and information were mailed to experts in this area of research. After a final set of studies was identified, the list of references reported in the included reports was reviewed to identify additional studies. Studies published in English and non-English were considered in this review. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials of dentist-dispensed or over-the-counter tooth whitening products with a chemical action (rather than abrasive action), for home use. DATA COLLECTION AND ANALYSIS: Screening of titles and abstracts, data extraction and quality assessment were undertaken independently and in duplicate. MAIN RESULTS: A total of 416 articles were identified, 25 of which met the inclusion criteria and presented data that could be used in the analysis. All included trials measured effectiveness immediately after 2 weeks of product application. Only 13 studies reported outcome data 1 week after the 2-week application period, and of those only six reported outcome data after 1 month or longer. Four of the included trials were assessed as at moderate risk of bias and the remainder at high risk of bias. All trials were sponsored by the manufacturers of tooth whitening products. Six trials compared different whitening products (gel in trays, paint-on films and whitening strips) with placebo/no treatment and all analyses showed the products to be effective, although most comparisons were based on single trials. Nineteen trials compared different whitening products with each other. There was only one meta-analysis which included more than one trial which showed statistically significant differences between the different whitening products. Strips (5.5% to 6.5% hydrogen peroxide(HP)) are more effective than gel in tray at 10% carbamide peroxide (CP) mean difference 1.82 (95% confidence interval (CI) 0.26 to 3.38). All of these trials were assessed as of high risk of bias. 'Mild' to 'moderate' tooth sensitivity and gingival irritation were the most common side effects. The whitening strips and products with high concentrations of HP caused more users to complain from tooth sensitivity. The protocols for preparation of participants prior to bleaching were inconsistent among the studies. Data on baseline scores of whiteness were not reported by the majority of the studies. The current evidence base on tooth whitening products suffers from methodological and publication biases. AUTHORS' CONCLUSIONS: There is evidence that whitening products work when compared with placebo/no treatment. There are differences in efficacy between the products, mainly due to the levels of active ingredients, hydrogen peroxide and carbamide peroxide. All trials were however short term and the majority of the studies were judged to be at high risk of bias and were either sponsored or conducted by the manufacturers. There is a need for pragmatic long-term and independent clinical studies that include participants representing diverse populations. There is also a need to evaluate long-term harms. Several studies reported (where measured) the common side effects of tooth sensitivity and gingival irritation, and people should be informed of this.

Osteoprotegerin and bone turnover markers in heavily pretreated HIV-infected patients.

OBJECTIVES: To characterize osteoprotegerin (OPG) levels, bone remodelling and bone mineral density (BMD) in heavily pretreated HIV-infected patients on antiretroviral therapy, and to evaluate the clinical factors associated with bone density decline. METHODS: Heavily pretreated (> 5 years) HIV-positive patients were enrolled in this cross-sectional, observational study, which was based on a total body bone densitometry examination and a comprehensive evaluation of bone and mineral parameters. RESULTS: Sixty-eight patients (55 male and 13 female) with a median age of 41 years (range 25-60 years) were included in the study. Their antiretroviral treatment lasted for 82 months. On the basis of the World Health Organization criteria, nine patients (13.2%) were osteoporotic [T-score < -2.5 standard deviation (SD)] and 19 patients (27.9%) were osteopenic (T-score between -1 and -2.5). The principal outcomes associated with the presence of a low BMD were high OPG and lysylpyridinoline/creatinine ratio (Dpd) values. Most of the patients (39 of 48; 81.25%) showed vitamin D insufficiency [Vitamin D (25(OH)D) < 18 ng/mL] with secondary hyperparathyroidism (13 of 50 patients: 26%), which proved to be correlated to osteocalcin (BGP) levels [parathyroid hormone (PTH) vs. BGP: r = 0.34; P < 0.01]. There was an inverse correlation between T-scores and serum osteocalcin and alkaline phosphatase (AP) levels, on one hand, and Dpd, on the other. High AP and Dpd values were associated with relative risks of 4.1 [95% confidence interval (CI) = 1.01-17.6] and 7.2 (95% CI = 1.67-31.03), respectively, of a pathological T-score. Multivariate analysis revealed that the factors associated with the presence of osteopenia or osteoporosis were older age and lower body mass index. CONCLUSIONS: About 40% of our heavily pretreated subjects with advanced HIV infection had a low BMD, and 56% (24 of 44 patients) showed a high bone turnover rate with marked osteoclast activation. High OPG levels may protect against bone resorption.

Lopinavir/ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation.

OBJECTIVES: To evaluate the risk factors for lopinavir/ritonavir (LPV/r)-related liver enzyme elevation (LEE) in HIV antiretroviral-experienced patients. METHODS: An open prospective observational study was carried out to analyse the incidence and time of LEE development during LPV/r treatment, and to determine whether LEE development was correlated with epidemiological, clinical and biochemical data, immune and virological profiles, concomitant hepatic diseases, antiretroviral therapy, or histological and ultrasonography liver examination results. A diagnosis of LEE was considered when LEE symptoms occurred after LPV/r introduction and was confirmed by a second control within 2 weeks. RESULTS: A total of 782 HIV-positive outpatients have been enrolled in six different Infectious Diseases Departments in Northern Italy since August 2000. Of these patients, 71 (9.1%) developed LEE within 115+/-85 days (mean+/-standard deviation); 13 of these subjects discontinued LPV/r and four were hospitalized. Of the patients with LEE, 74.6% and 25.4% had grade 2 and > or =3 toxicity, respectively. No correlation between LEE and sex, baseline CD4 cell count, viral load, HIV stage, triglyceride values, histological and ultrasonography liver examination results, nevirapine use, or increase in CD4 cell count was observed. Higher baseline alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) values (P < 0.0001 and P=0.004, respectively), younger age (P=0.008), previous hepatitis B virus (HBV) infection (P=0.012), efavirenz use (P=0.04), and hepatitis C virus (HCV) and/or HBV coinfection (P < 0.0001, relative risk 4.78) were significantly related to LEE. No correlations between LEE and the same risk factors as investigated in the whole study population were found in subgroups of patients with HCV and/or HBV infection. CONCLUSIONS: HCV and HBV testing and measurement of baseline ALT values are essential for screening subjects at risk of LEE before starting LPV/r. Strict monitoring of clinical and biochemical parameters should be performed in these patients.

The introduction of the fusion inhibitors in the HAART-regimens.

Interference with HIV entry into target cells provides a novel approach to the treatment of HIV infection. The inhibition of virus fusion with the co-receptor substrate seems the most specific and potentially best way to interfere with HIV infection and replication. The efficacy of the first compound available (enfuvirtide) is evident after the pre-registrative phase II and III studies showing also that the presence of anti gp 41 antibodies in the plasma of the treated patients does not interfere with drug activity. In the failing enfuvirtide treated patients resistant virus was detected in 7/7 after > one year of treatment with genotypic mutations in the HR env domain, however no interclass cross resistance was evidenced. Mutants selected in vivo demonstrated a slight reduction of replication capacity.

Resistance and replicative capacity of HIV-1 strains selected in vivo by long-term enfuvirtide treatment.

Enfuvirtide is the prototype member of a new class of anti HIV-1 agents, the fusion inhibitors (FI). In recent clinical trials, the compound has shown its efficacy in combination with other antiretroviral agents in vivo. However mutant strains resistant to the action of the drug arise quite rapidly in vitro and in vivo. To analyze the process of selection and evolution of HIV-1 strains resistant to enfuvirtide in vivo and to evaluate the impact of resistance on viral fitness, 12 HIV-1 infected subjects treated with T20 (enfuvirtide) for at least one year were included in the study. Gp41-coding sequences were amplified from plasma samples of these subjects at baseline and at different time points during treatment. Seven of the 12 subjects showed selection of gp41 mutations under the selective pressure of enfuvirtide. In particular, these mutations clustered in two distinct regions: (i) a mutational hot-spot localized, as previously described, in the first residues of the N-HR domain, with position number 38 as the most heavily mutated, but including also a G36V, a N42D/T, a N43D, a L44M and a L45M; (ii) other mutations were localized further downstream, within N-HR/C-HR junction and in the C-HR. A recombinant assay specifically designed for the determination of HIV-1 phenotype to FI was developed and validated. Using this assay, we observed that all of the 7 mutated clones displayed substantially reduced susceptibility to T20, IC50 ranging from 0.6 to12.8 microg/ml (>100 fold change). The residues whose mutation was associated with a potent reduction in susceptibility were V38, N42, and N43, other positions such as G36, N44 and L45 playing a minor role. None of the mutant HIV isolates showed cross-resistance to T-1249. By the same method, the HIV-1 replicative capacity of the recombinant clones was tested in the absence of drugs, and for each subject, pre-therapy clones were compared to post-therapy ones. In 3/7 subjects a significant decrease in replicative capacity of the recombinant clones was observed. The phenotypic data from this study suggest that the secondary additional mutations, could be associated with improved resistance or recovery of replicative capacity (compensatory mutations).