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.

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.

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.

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.

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

Intrarenal mechanisms of salt retention after bile duct ligation in rats.

In order to study renal salt-retaining mechanisms during the early stages of ascites formation, rats were subjected to bile duct ligation. After this procedure, plasma volumes were found to be reduced and hematocrits slightly increased. The whole-kidney glomberular filtration rate and plasma flows were reduced to 59 and 57% of control values, but the filtration fraction was unchanged. Absolute sodium excretion, as well as the fraction of the filtered sodium load excreted, was also significantly reduced. When micropuncture techniques were used to examine the function of single superficial nephrons, the glomerular filtration rate in these nephrons was found to be reduced to 70% of controlled values, and fractional reabsorption was found to be increased at all accessible sites along the nephron. Filtration by intermediate and juxtamedullary nephrons, determined by Hanssen's technique, was reduced to 55 and 48% of control values. By the use of radioactive microspheres, it was demonstrated that blood flow to superficial, intermediate, and juxtamedullary nephrons was reduced to 49, 59, and 73% of control values. Filtration by superficial nephrons decreased much more than plasma flow--a finding which suggests that the measured increase in fractional reabsorption was associated with an increase in the superficial nephron filtration fraction. From this study, it appears that two factors play an important part in the sodium retention observed in the initial stages of ascites formation following bile duct ligation in rats: (a) a decrease in the filtered sodium load and (b) increased fractional reabsorption by the superficial nephrons--the nephrons which show the least decrease in filtration.

Phase I-II trial of high-dose epirubicin in patients with lymphoma.

High-dose doxorubicin has shown considerable activity in both previously treated and previously untreated patients with lymphoma. Because of the toxicities of doxorubicin at high dose, we elected to study a new anthracycline at doses comparable to doxorubicin at high dose, to assess response and toxicity. Epirubicin was administered at doses of 120 mg/m2, 150 mg/m2, and 180 mg/m2 every 3 weeks (maximum four doses) to groups of six patients with previously treated intermediate- and high-grade lymphoma. Sixteen of the patients had received significant prior therapy with an anthracycline and/or anthracenedione. At all dose levels, myelosuppression was severe, with median granulocyte nadirs less than 504/mm3. Hematological recovery occurred by day 21 at the 120 mg/m2 and 150 mg/m2 dose levels, allowing for the next cycle of therapy. However, at the 180 mg/m2 dose level, the majority of patients failed to have hematological recovery by the day of the next scheduled therapy. Forty-two % of patients (eight patients) had fever/neutropenia, and required antibiotics. One treatment-related septic death occurred (at 150 mg/m2). Alopecia (68%), fever immediately following treatment (63%), mild/moderate stomatitis (58%), and nausea/vomiting (53%) were the most common nonhematological toxicities. These toxicities were independent of the dose levels and were not dose limiting. A significant change (greater than or equal to 0.10) in the radionuclide ejection (EF) was seen in seven patients. The median of the entire group of patients fell from 0.63 to 0.56. No patient developed clinical or radiological evidence of congestive heart failure. A response rate of 58% (two complete responses, nine partial responses) was achieved with a median duration of 5 months (range, 1-15+). High-dose epirubicin can be successfully utilized in patients with previously treated lymphoma. The only dose-limiting toxicity observed at these dose levels was the lack of hematological recovery by day 21 with 180 mg/m2. Since epirubicin at high dose will be incorporated into high-dose anthracycline regimens in previously untreated patients utilizing a 3-week treatment cycle, 150-180 mg/m2 may be the maximally tolerated dose for such studies.

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.

Phase II study of aclarubicin in acute myeloblastic leukemia.

Aclarubicin is a new anthracycline antibiotic that produces substantially less cardiotoxicity in animals that does doxorubicin. Based upon prior Phase I and II trials in leukemia, a Phase II study in acute myeloblastic leukemia was developed to assess the response rate and toxicity in previously treated patients. Forty patients received aclarubicin 100 mg/m2 per day X 3 with repeated course on days 14-16 if marrow hypoplasia was not produced. Complete responses were achieved in 27.5% (11/40) with durations of 1.5, 2, 2, 2, 3, 3+, 4, 5+, 32+, 33+, and 34+ months. Toxic effects of this therapy included severe neutropenia and thrombocytopenia, nausea/vomiting, mucositis, and diarrhea. No patient developed significant changes in the left ventricular ejection fraction, as measured by radionuclide angiography, or any clinical cardiac symptoms. Alopecia was minimal. Aclarubicin can produce a significant response rate in previously treated patients with acute myeloblastic leukemia and should be considered for study in initial therapy.

A correlation study of diet, oral hygiene and dental caries in 457 Canadian children.

The interrelationship of diet, oral hygiene and caries was evaluated. Of the sample size of 457 children, 234 were in grade 1 and 223 grade 7. Five-day diet surveys were obtained, followed by clinical examinations for oral hygiene and caries. One examiner, using mouth mirror, explorer and extraoral light, conducted the caries examination. From the diet surveys, refined and total carbohydrate consumption was calculated per day; between meals, at meals, and totaled for the day. Five-day totals, which included one weekend, were recorded along with frequency of eating per day and for the 5-day periods. Computer analysis revealed no significant correlation between the diet variables and caries or oral hygiene indices and caries. The children with high caries indices did not have the poorest oral hygiene nor consume the most carbohydrates. Similarly, the children with low caries indices did not have the cleanest teeth nor consume lesser amounts of carbohydrates.

Curricular trends in North America.

Curricular changes in North America are at present being stimulated by changing disease patterns, changes in the needs of the patients attending dental schools, the desire to broaden educational experience without overloading the curriculum and overstressing the students. Curricula are changing in their content, their format, in the methodology used and in the targets that students are set. The evaluation of curricula and the planning of change are processes that are themselves undergoing revision.

Primary and secondary care integration.

Integration of primary and secondary health care is a goal of the 1993 New Zealand health reforms. Focus groups were selected to raise options and stimulate improved integration between primary and secondary care in the Auckland metropolitan and rural areas. Cooperation, communication, coordination, were considered relevant. Several detailed recommendations were produced. They fell into six groups; (1) liaison committees or meetings, (2) communication, (3) referral admission discharge, (4) joint ventures, (5) horizontal integration and (6) general. A key recommendation was that regional health authorities should fund liaison committees or functions to promote inter provider integration. The findings of the focus groups are placed in context of the wider requirements for integration. These are integrated funding, integrated information systems, integrated purchasing and utilisation management.

A performance evaluation of bare alpha track detectors.

Bare alpha track detectors are sensitive to radon progeny as well as to radon gas. This paper reports the test results for two brands of bare alpha track detectors that received several radon exposures at three progeny concentrations. The results show a relationship that is a linear combination of both the radon gas and the radon progeny concentrations. The reported radon concentration depended on the equilibrium factor assumed by the processor. The sensitivity of bare alpha track detectors increases with altitude, but this is a minor, correctable effect compared to the equilibrium factor.

Curriculum focus: traditional dental education confronts the new biology and social responsibility.

The traditional dental education base does not suggest that graduates are prepared only for private general practice. It promises much, much more. It is the beginning of what any graduate may wish or want it to be. In fact it is necessary for new graduates contemplating private practice to seek more in the way of practice management if they plan to be successful in that model. Such is also the case for additional study if one wants to pursue a specialty; further training in the scientific method to undertake research; or further study in education for a teaching career. The predoctoral program promises to be just a beginning, but a sound and sensible beginning. The current foundation model of the predoctoral curriculum continues to serve society and the profession very well. It provides the necessary grounding in the fundamentals of basic medical sciences, clinical biological sciences, and behavioral sciences upon which any graduate can build and pursue a career beyond what is thought to be the traditional role model of the private practice of general dentistry. Faculty members and dental programs can choose, if they desire, to tailor mission statements to reflect a changing emphasis. This could help dental applicants become more thoughtful and self-selective in considering one of many different career options available. Given the emerging demographic profile and trends in needs, the curriculum emphasis could be altered to encourage a change in the balance or proportion of graduates who undertake career options in a postdoctoral experience, in public health, research, teaching, administration, the military, hospital, or specialty practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of immediate introduction of indirect vision on performance and posture.

When students are taught psychomotor skills in the mandibular arch and transfer to the maxillary arch, there is a continued desire to depend upon direct vision, which results in early acquisition of poor postural habits. This study examined differences in psychomotor performance between dental students beginning with direct and indirect vision exercises. The investigation was conducted in a preclinical Performance Simulation Laboratory that allowed a high degree of accuracy in the evaluation of operator posture. No significant differences in performance were found between the groups. Within group variances indicated that there was a more uniform transition from maxillary to mandibular preparations than from the lower to upper arch preparations. Analysis of the postural data showed no significant relationship to the quality of cavity preparation, but indicated that student posture was better for the arch in which they first learned. The study was unable to substantiate the assumption that mirror management is better taught after direct vision skills are learned.

First-year experience with a performance simulation system.

Providing a preclinical learning environment for the undergraduate dental student that is realistic and representative of the clinical setting has been a concern to dental teachers. This article describes a system that provides consistency in the optimal relationship of the operator and patient while emphasizing a balanced postural position. The dental simulator provides an approach that is transferable to all aspects of clinical dental treatment. The student is involved in a learning experience that serves as a basis for future behavior that is consistent with comfort and efficiency in the delivery of dental care.

A structured interview for dental school admissions.

The Dental Admission Test Committee of the Canadian Dental Association developed a structured interview instrument for use in the admission process in Canadian dental schools. The interview was structured to elicit standardized information concerning a candidate's personality with regard to motivation, self-appraisal, maturity, ability to relate, adaptability, principles (ethics), sense of responsibility, and personal reaction. In a pilot study for the 1980 admission cycle, the interview was used in the admission process at the University of British Columbia and the University of Alberta. Interrater reliability was established and factor analysis performed. All subsections of the interview loaded on the same factor, indicating that the use of a composite score is preferable to the use of subscores in the assessment process. Validity studies will be performed when the accepted candidates have progressed in their dental careers.

The impact of the differences in the decline of dental school applicants in the United States and Canada.

The number of individuals writing the Canadian Dental Association Dental Aptitude Test and the American Dental Association Dental Admissions Test for the first time is used as a measure of the number of new additions to the dental school applicant pool in each of the past 15 years. Dramatic changes have occurred during that period. Comparisons are made and similarities noted between the situations in the United States and Canada. A discussion of the probable causes of the differences highlights the changing government programs in the two countries, the perceptions of potential applicants, and the attitudes of members of the dental profession. Some suggestions for future action are proposed.