Early changes in bone turnover and inflammatory biomarkers and clinically significant bone mineral density loss over 48 weeks among HIV-infected patients with virological failure of a standard first-line antiretroviral therapy regimen in the SECOND-LINE study.

OBJECTIVES: We assessed whether changes at week 12 in markers of bone turnover, inflammation, and immune activation were associated with clinically important (≥ 5%) bone mineral density (BMD) loss from baseline to week 48 at the proximal femur (hip) and lumbar spine in the SECOND-LINE study. METHODS: We measured concentrations of procollagen type 1 pro-peptide (P1NP), carboxyl-terminal collagen crosslinks (CTX), high-sensitivity C-reactive protein (hs-CRP), D-dimer, interleukin (IL)-6, tumor necrosis factor (TNF), neopterin, and soluble CD14 and 163 at weeks 0, 12, and 48 in 123 SECOND-LINE dual-energy X-ray absorptiometry (DXA) substudy participants. Linear regression was used to compare changes in biomarkers. Predictors of ≥ 5% BMD loss were examined using multivariable regression. RESULTS: The mean age was 38 years, the mean CD4 T-cell count was 252 cells/µL and the mean viral load was 4.2 log HIV-1 RNA copies/mL; 56% of participants were female and 47% were randomized to receive a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI]-based regimen [91% (53/58) were randomized to receive a tenofovir disoproxil fumarate (TDF)-containing regimen]. Over 48 weeks, 71% in the N(t)RTI arm experienced ≥ 5% hip BMD loss vs. 29% in the raltegravir arm (P = 0.001). Week 12 changes in P1NP and CTX were significantly greater among patients experiencing ≥ 5% hip BMD loss, patients randomized to N(t)RTI, and male patients. Predictors of ≥ 5% hip BMD loss at week 48 were P1NP increase [odds ratio (OR) 5.0; 95% confidence interval (CI) 1.1-27; P < 0.043]; N(t)RTI randomization (OR 6.7; 95% CI 2.0-27.1; P < 0.003), being African, higher baseline CD4 T cell count , and smoking. CONCLUSIONS: In a diverse cohort of viraemic HIV-infected patients, switching to second-line antiretroviral therapy (ART) was associated with clinically significant BMD loss, which was correlated with an early increase in P1NP. Measurement of P1NP may facilitate timely interventions to reduce rapid BMD loss among at-risk patients.

Rapid initiation of antiretroviral therapy at HIV diagnosis: definition, process, knowledge gaps.

Initiating antiretroviral therapy (ART) as early as the day of HIV diagnosis is a strategy of increasing global interest to control the HIV epidemic and optimize the health of people living with HIV (PLWH). No detrimental effects of rapid-start ART have been identified in randomized controlled trials undertaken in low- or middle-income countries, or in cohort studies performed in high-income countries. Rapid-start ART may be a key approach in reaching the 2020 Joint United Nations Programme on HIV/AIDS goal of 90% of all PLWH knowing their status, 90% of those diagnosed receiving sustained ART, and 90% of those receiving ART achieving viral suppression; it may also be important for achieving the suggested fourth "90%" goal: improving health-related quality-of-life in PLWH. Presently there is insufficient broad evidence for guidelines to recommend universal test-and-treat strategies for all people, in all settings, at HIV diagnosis; consequently, there is a pressing need to conduct high-quality studies that investigate immediate ART initiation. This article evaluates global evidence regarding rapid-start ART, including same-day start, with particular focus on the implementation of this strategy in high-income countries.

Contaminated sites from the past: experience of the US Environmental Protection Agency.

The purpose of this paper is to provide an overview of the experience of the US Environmental Protection Agency (EPA) in cleaning up radioactively contaminated sites. In the USA, EPA regulates the radiological clean-up of uranium mill tailings sites, some Department of Energy legacy sites within the US nuclear weapons complex, and Superfund National Priorities List sites. The approach to site remediation decisions, including the determination of clean-up levels, varies according to the enabling legislation granting EPA these authorities. Past practices that gave rise to many of the existing exposure situations at legacy sites were permissible before the advent of environmental clean-up legislation. The Uranium Mill Tailings Radiation Control Act of 1978 authorised EPA to set applicable radioactivity concentration standards for soil clean-up at inactive uranium mill sites and vicinity properties. For the other categories of sites mentioned above, remediation goals are typically based on not exceeding a target excess cancer risk range established under the Comprehensive Environmental Response, Compensation, and Liability Act (also known as 'Superfund'). EPA's regulations for cleaning up various contaminated sites in existing exposure situations often result in residual doses that are typical of optimised doses in planned exposure situations. Although the clean-up levels selected may differ from those adopted in other countries, recommendations from the International Commission on Radiological Protection are reflected in the exposure assessment methodologies used in their establishment.

Adaptation of red blood cell lysis represents a fundamental breakthrough that improves the sensitivity of Salmonella detection in blood.

AIMS: Isolation of Salmonella Typhi from blood culture is the standard diagnostic for confirming typhoid fever but it is unavailable in many developing countries. We previously described a Microwave Accelerated Metal Enhanced Fluorescence (MAMEF)-based assay to detect Salmonella in medium. Attempts to detect Salmonella in blood were unsuccessful, presumably due to the interference of erythrocytes. The objective of this study was to evaluate various blood treatment methods that could be used prior to PCR, real-time PCR or MAMEF to increase sensitivity of detection of Salmonella. METHODS AND RESULTS: We tested ammonium chloride and erythrocyte lysis buffer, water, Lymphocyte Separation Medium, BD Vacutainer(®) CPT(™) Tubes and dextran. Erythrocyte lysis buffer was the best isolation method as it is fast, inexpensive and works with either fresh or stored blood. The sensitivity of PCR- and real-time PCR detection of Salmonella in spiked blood was improved when whole blood was first lysed using erythrocyte lysis buffer prior to DNA extraction. Removal of erythrocytes and clotting factors also enabled reproducible lysis of Salmonella and fragmentation of DNA, which are necessary for MAMEF sensing. CONCLUSIONS: Use of the erythrocyte lysis procedure prior to DNA extraction has enabled improved sensitivity of Salmonella detection by PCR and real-time PCR and has allowed lysis and fragmentation of Salmonella using microwave radiation (for future detection by MAMEF). SIGNIFICANCE AND IMPACT OF THE STUDY: Adaptation of the blood lysis method represents a fundamental breakthrough that improves the sensitivity of DNA-based detection of Salmonella in blood.

A comparison of computational models with and without genotyping for prediction of response to second-line HIV therapy.

OBJECTIVES: We compared the use of computational models developed with and without HIV genotype vs. genotyping itself to predict effective regimens for patients experiencing first-line virological failure. METHODS: Two sets of models predicted virological response for 99 three-drug regimens for patients on a failing regimen of two nucleoside/nucleotide reverse transcriptase inhibitors and one nonnucleoside reverse transcriptase inhibitor in the Second-Line study. One set used viral load, CD4 count, genotype, plus treatment history and time to follow-up to make its predictions; the second set did not include genotype. Genotypic sensitivity scores were derived and the ranking of the alternative regimens compared with those of the models. The accuracy of the models and that of genotyping as predictors of the virological responses to second-line regimens were compared. RESULTS: The rankings of alternative regimens by the two sets of models were significantly correlated in 60-69% of cases, and the rankings by the models that use a genotype and genotyping itself were significantly correlated in 60% of cases. The two sets of models identified alternative regimens that were predicted to be effective in 97% and 100% of cases, respectively. The area under the receiver-operating curve was 0.72 and 0.74 for the two sets of models, respectively, and significantly lower at 0.55 for genotyping. CONCLUSIONS: The two sets of models performed comparably well and significantly outperformed genotyping as predictors of response. The models identified alternative regimens predicted to be effective in almost all cases. It is encouraging that models that do not require a genotype were able to predict responses to common second-line therapies in settings where genotyping is unavailable.

Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study.

BACKGROUND: Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen. METHODS: We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463. FINDINGS: We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI -4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal. INTERPRETATION: The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy. FUNDING: University of New South Wales, Merck, AbbVie, the Foundation for AIDS Research.

Predictors of clinical progression in HIV-1-infected adults initiating combination antiretroviral therapy with advanced disease in the Asia-Pacific region: results from the TREAT Asia HIV observational database.

The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm(3) in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings.

A regulatory perspective on whether the system of radiation protection is fit for purpose.

The system of radiation protection has its origins in the early efforts to protect people from x rays and radium. It was at the Second International Congress of Radiology in Stockholm in 1928 where the first radiation protection recommendations were adopted. The system of protection steadily evolved as new sources of exposure arose and understanding of radiation-related health risks improved. Safeguarding against these risks has required regulators to set enforceable (i.e. measurable) standards. From erythema dose to tolerance dose, critical organ dose to effective dose equivalent, and now effective dose, the units used to set these limits have evolved along with the science underpinning them. Similarly, the definition of the person or group being protected has changed - from Standard Man to Reference Man to Reference Person, with age and gender differences now considered explicitly. As regulators look towards implementing the changes in the 2007 Recommendations of the International Commission on Radiological Protection (ICRP), there remain questions about how to translate an optimisation-based system of constraints and reference levels into the more familiar regime of enforceable limits. Nevertheless, as the new ICRP Recommendations are refinements of a system that did the job it was designed to do more than adequately, so too will the new system of radiation protection be fit for purpose.

Effect of nucleoside reverse transcriptase inhibitors on CD4 T-cell recovery in HIV-1-infected individuals receiving long-term fully suppressive combination antiretroviral therapy.

OBJECTIVE: The aim of the study was to determine the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on CD4 recovery in HIV-1-infected individuals receiving long-term suppressive combination antiretroviral therapy (cART). METHODS: A retrospective cohort study was carried out. The mean time-weighted CD4 change from baseline was determined at weeks 48, 96 and 144: its associations with exposure to NRTIs were assessed using linear regression. RESULTS: One hundred and five patients were included. Their median baseline CD4 count was 225 (interquartile range 91-362) cells/microL. A trend of greater CD4 change from baseline was observed for individuals who at baseline had CD4 counts >200 cells/microL (138 vs. 113, 176 vs. 134 and 204 vs. 173 cells/microL), or were 0.05. Lower CD4 increases were observed in patients exposed to didanosine (ddI) or a combination of ddI and stavudine, although the difference was not statistically significant. For patients that commenced cART with CD4 count

Predictive factors for immunological and virological endpoints in Thai patients receiving combination antiretroviral treatment.

BACKGROUND: Routine CD4 count and HIV viral load monitoring is a financial barrier in developing countries. METHODS: We assessed factors associated with CD4 counts < or =200 cells/microL and detectable viral load in Thai HIV-infected patients receiving antiretroviral therapy (ART) at the HIV Netherlands Australia Thailand Research Collaboration and the Thai Red Cross AIDS Research Centre (HIV-NAT). Univariate and multivariate Cox proportional hazards models for multiple treatment failures were used to determine factors related to CD4 counts < or =200 cells/microL and detectable viral load. Multivariate Cox proportional hazards models for CD4 counts < or =200 cells/microL were developed with and without viral load in order to build models applicable to contexts in which viral load is not available. RESULTS: Four hundred and seventeen patients were included in the study. Fifty-four per cent were male, and the median CD4 count and log(10) viral load at baseline were 283 cells/microL and 4.3 log(10) HIV-1 RNA copies/mL, respectively. Independent factors related to CD4 count < or =200 cells/microL were CD4 count at baseline [hazards ratio (HR) 0.20/100 cells/microL; 95% confidence interval (CI) 0.17-0.23] and changes in CD4 count (HR 0.22/100 cells/microL; 95% CI 0.17-0.28). Factors in multivariate models (in which viral load was considered for inclusion) were CD4 count at baseline (HR 0.21/100 cells/microL; 95% CI 0.18-0.24), changes in CD4 count (HR 0.25/100 cells/microL; 95% CI 0.19-0.32) and detectable viral load (HR 1.94; 95% CI 1.20-3.13). Predictive factors (independent of viral load) were triple ART or highly active antiretroviral therapy (HAART) (HR 0.28; 95% CI 0.22-0.36) and detectable viral load at baseline (HR 2.96; 95% CI 2.24-3.91). Conclusions CD4 count at baseline and changes in CD4 count were important in predicting CD4 counts < or =200 cells/microL. Triple ART and detectable viral load at baseline were important in predicting detectable viral load.

Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009.

OBJECTIVE: Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity. METHODS: Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat. RESULTS: Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved. CONCLUSIONS: IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.

Social constructs of curricular change.

The adoption of problem-based approaches to teaching and learning in dental and medical education requires educators to consider a significantly different role and responsibilities as teacher from what they have experienced previously. This qualitative study explored how some educators experienced and interpreted changes in the newly merged dental and medical curriculum at the University of British Columbia. Our findings present how educators explained and dealt with change. In-depth interviews provided considerable insight into factors influencing the resistance or acceptance to change. The educators' beliefs about teaching and learning and their understanding of the development and implementation process of change mediated these factors. Findings from this study should help administrators, faculty developers, and educators themselves to understand better how curricular change is experienced and to plan effective and appropriate faculty development.

Partner notification for chlamydial infections among private sector clinicians in Seattle-King County: a clinician and patient survey.

BACKGROUND & OBJECTIVES: To describe partner notification practices for chlamydial infections among private sector clinicians. STUDY DESIGN: Telephone interviews of clinicians and patients identified through public health case reports in Seattle-King County, August-October 1998. RESULTS: Clinicians reported advising 135 of 150 (90%) patients to notify their sex partners, but knew that all partners of only 26 (17%) patients received treatment. While 71 (57%) clinicians acknowledged ever providing medicine-to a patient to give to a partner, only 6 (4%) so treated a patient about whom they were interviewed. Most (87%) clinicians believed the health department should routinely contact all patients about partner notification. Almost all patients (72/76-95%) reported that their provider had advised them to notify their partners and 59 (78%) stated they did so. Most patients (11/17-65%) who did not notify all of their partners would have been willing to allow their clinician or the heath department to do it for them. CONCLUSION: Private sector clinicians and their patients are generally unaware of chlamydial partner notification outcomes but are receptive to expanded partner notification services.

Use of discriminant and regression analyses to modify a clinical certification board examination.

The National Dental Examining Board of Canada (NDEB) conducts mandatory, high stakes, pass/fail, certification examinations for dental licensure. One of these examinations was a seven-part, simulated clinical examination in which candidates were required to perform procedures on typodonts. These requirements were two intracoronal and two extracoronal preparations, an amalgam restoration, a provisional crown, and a diagnostic wax-up. Feedback from candidates and examiners indicated that one or more of the requirements may not have been contributing effectively to the overall evaluation of candidates. The NDEB's Clinical Examination Committee therefore requested that an in-depth statistical analysis be performed to identify potential areas of concern and to provide a basis for modifying the examinations. The results of two examination sessions with a total of 168 candidates were subjected to both a discriminant and a logistic regression analysis. Every candidate had results for each of the seven requirements, and no candidate participated in both sessions of the examination. The discriminant analysis revealed that six of the seven requirements could be used to reliably assign examinees according to their true pass/fail classifications. Stepwise discriminant analysis resulted in a 98.81 percent classification success rate with a corresponding 2.50 percent false-positive classification error rate. The logistic regression analysis showed that five components correctly predicted 99.40 percent with a 1.25 percent false-positive rate. The Clinical Examination Committee concluded that one requirement (diagnostic wax-up) should be eliminated and that a second requirement (PFM preparation) be significantly modified and reevaluated. This study demonstrates the usefulness of statistical methods in the analysis and modification of a clinical certification board examination.