Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal

BACKGROUND: The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. METHODS: We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a "rare ADEs" category. RESULTS: During a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkin's lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]). CONCLUSIONS: In the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management.

Transcutaneous electrostimulation for osteoarthritis of the knee

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Transcutaneous electrical nerve stimulation (TENS), interferential current stimulation and pulsed electrostimulation are used widely to control both acute and chronic pain arising from several conditions, but some policy makers regard efficacy evidence as insufficient. OBJECTIVES: To compare transcutaneous electrostimulation with sham or no specific intervention in terms of effects on pain and withdrawals due to adverse events in patients with knee osteoarthritis. SEARCH STRATEGY: We updated the search in CENTRAL, MEDLINE, EMBASE, CINAHL and PEDro up to 5 August 2008, checked conference proceedings and reference lists, and contacted authors. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared transcutaneously applied electrostimulation with a sham intervention or no intervention in patients with osteoarthritis of the knee. DATA COLLECTION AND ANALYSIS: We extracted data using standardised forms and contacted investigators to obtain missing outcome information. Main outcomes were pain and withdrawals or dropouts due to adverse events. We calculated standardised mean differences (SMDs) for pain and relative risks for safety outcomes and used inverse-variance random-effects meta-analysis. The analysis of pain was based on predicted estimates from meta-regression using the standard error as explanatory variable. MAIN RESULTS: In this update we identified 14 additional trials resulting in the inclusion of 18 small trials in 813 patients. Eleven trials used TENS, four interferential current stimulation, one both TENS and interferential current stimulation, and two pulsed electrostimulation. The methodological quality and the quality of reporting was poor and a high degree of heterogeneity among the trials (I(2) = 80%) was revealed. The funnel plot for pain was asymmetrical (P < 0.001). The predicted SMD of pain intensity in trials as large as the largest trial was -0.07 (95% CI -0.46 to 0.32), corresponding to a difference in pain scores between electrostimulation and control of 0.2 cm on a 10 cm visual analogue scale. There was little evidence that SMDs differed on the type of electrostimulation (P = 0.94). The relative risk of being withdrawn or dropping out due to adverse events was 0.97 (95% CI 0.2 to 6.0). AUTHORS' CONCLUSIONS: In this update, we could not confirm that transcutaneous electrostimulation is effective for pain relief. The current systematic review is inconclusive, hampered by the inclusion of only small trials of questionable quality. Appropriately designed trials of adequate power are warranted.

One-year outcomes of repeated adjunctive photodynamic therapy during periodontal maintenance: a proof-of-principle randomized-controlled clinical trial

BACKGROUND: Single photodynamic therapy (PDT) has been effective in initial periodontal therapy, but only improved bleeding on probing (BoP) in maintenance patients after a single use. Repeated PDT has not been addressed. OBJECTIVES: To study the possible added benefits of repeated adjunctive PDT to conventional treatment of residual pockets in patients enrolled in periodontal maintenance. MATERIAL AND METHODS: Ten maintenance patients with 70 residual pockets [probing pocket depth (PPD)>or=5 mm] were randomly assigned for treatment five times in 2 weeks (Days 0, 1, 2, 7, 14) with PDT (test) or non-activated laser (control) following debridement. The primary outcome variable was PPD, and the secondary variables were clinical attachment level (CAL) and BoP. These were assessed at 3, 6 and 12 months following the interventions. RESULTS: Greater PPD reductions were observed in the test (-0.67 +/- 0.34; p=0.01) compared with the control patients (-0.04 +/- 0.33; NS) after 6 months. Significant CAL gain (+0.52 +/- 0.31; p=0.01) was noted for the test, but not in the control (-0.27 +/- 0.52; NS) patients after 6 months. BoP percentages decreased significantly in test (97-64%, 67%, 77%), but not control patients after 3, 6 and 12 months. CONCLUSIONS: Repeated (five times) PDT adjunctive to debridement yielded improved clinical outcomes in residual pockets in maintenance patients. The effects were best documented after 6 months.

Randomized controlled trial comparing a variable-thread novel tapered and a standard tapered implant: interim one-year results

STATEMENT OF PROBLEM: A tapered implant with continuously changing threads purported to provide stable tissue support and allow immediate function has been developed. Treatment success and stabilization of supporting tissues over time require documentation. PURPOSE: The purpose of this prospective, randomized, controlled, multicenter study was to evaluate changes in bone level and soft tissue behavior between the novel implant (NobelActive/NA) and a standard tapered implant (NobelReplace Tapered Groovy/NR) with regard to immediate function. MATERIAL AND METHODS: A total of 177 patients randomly allocated to 3 treatment groups (2 different test implant groups: NA Internal (n=117; internal connection) and External (n=82), and 1 standard treatment group, NR (n=126)) received 325 implants. Implants were placed into healed sites, and all but 6 implants were immediately nonocclusally loaded. Clinical and radiographic evaluations of treatment success, crestal bone levels, and soft tissue changes were performed at the time of placement and after 3, 6, and 12 months. Log-Rank test was used to analyze the differences in survival rate. Marginal bone level was compared using the Kruskal-Wallis test and Mann-Whitney U-test (alpha=.05). RESULTS: One-year cumulative survival rates were comparable (96.6% for NA Internal; 96.3% for NA External; 97.6% for NR; P=.852; Log-Rank). Mean (SD) change in bone level was -0.95 mm (1.37) for NA Internal, -0.64 mm (0.97) for NA External, and -0.63 mm (1.18) for NR (P=.589; Kruskal-Wallis). Stable soft tissues and significantly increased papilla scores (P<.001; Wilcoxon signed-rank) were observed for all implant types. CONCLUSIONS: The novel implants showed high survival rates as well as stable bone and soft tissue levels after 1 year, and may be recommended for clinical use, even under immediate function.

A Combinatorial Approach to the Variable Selection in Multiple Linear Regression: Analysis of Selwood et al Data set -A Case Study.

A combinatorial protocol (CP) is introduced here to interface it with the multiple linear regression (MLR) for variable selection. The efficiency of CP-MLR is primarily based on the restriction of entry of correlated variables to the model development stage. It has been used for the analysis of Selwood et al data set [16], and the obtained models are compared with those reported from GFA [8] and MUSEUM [9] approaches. For this data set CP-MLR could identify three highly independent models (27, 28 and 31) with Q2 value in the range of 0.632-0.518. Also, these models are divergent and unique. Even though, the present study does not share any models with GFA [8], and MUSEUM [9] results, there are several descriptors common to all these studies, including the present one. Also a simulation is carried out on the same data set to explain the model formation in CP-MLR. The results demonstrate that the proposed method should be able to offer solutions to data sets with 50 to 60 descriptors in reasonable time frame. By carefully selecting the inter-parameter correlation cutoff values in CP-MLR one can identify divergent models and handle data sets larger than the present one without involving excessive computer time.

Erosion Damage Mapping: Assessing Current Soil Erosion Damage in Switzerland

Within the scope of a comprehensive assessment of the degree of soil erosion in Switzerland, common methods have been used in the past including test plot measurements, artificial rainfall simulation, and erosion modelling. In addition, mapping guidelines for all visible erosion features have been developed since the 1970s and are being successfully applied in many research and soil conservation projects. Erosion damage has been continuously mapped over a period of 9 years in a test region in the central Bernese plateau. In 2005, two additional study areas were added. The present paper assesses the data gathered and provides a comparison of the three study areas within a period of one year (from October 2005 to October 2006), focusing on the on-site impacts of soil erosion. During this period, about 11 erosive rainfall events occurred. Average soil loss rates mapped at each study site amounted to 0.7 t ha-1, 1.2 t ha-1 and 2.3 t ha-1, respectively. About one fourth of the total arable land showed visible erosion damage. Maximum soil losses of about 70 t ha-1 occurred on individual farm plots. Average soil erosion patterns are widely used to underline the severity of an erosion problem (e.g. impacts on water bodies). But since severe rainfall events, wheel tracks, headlands, and other “singularities” often cause high erosion rates, analysis of extreme erosion patterns such as maximum values led to a more differentiated understanding and appropriate conclusions for planning and design of soil protection measures. The study contains an assessment of soil erosion in Switzerland, emphasizing questions about extent, frequency and severity. At the same time, the effects of different types of land management are investigated in the field, aiming at the development of meaningful impact indicators of (un-)sustainable agriculture/soil erosion risk as well as the validation of erosion models. The results illustrate that conservation agriculture including no-till, strip tillage and in-mulch seeding plays an essential role in reducing soil loss as compared to conventional tillage.

On the detection of dynamic responses in a drought-perturbed tropical rainforest in Borneo

The dynamics of aseasonal lowland dipterocarp forest in Borneo is influenced by perturbation from droughts. These events might be increasing in frequency and intensity in the future. This paper describes drought-affected dynamics between 1986 and 2001 in Sabah, Malaysia, and considers how it is possible, reliably and accurately, to measure both coarse- and fine-scale responses of the forest. Some fundamental concerns about methodology and data analysis emerge. In two plots forming 8 ha, mortality, recruitment, and stem growth rates of trees ≥10 cm gbh (girth at breast height) were measured in a ‘pre-drought’ period (1986–1996), and in a period (1996–2001) including the 1997–1998 ENSO-drought. For 2.56 ha of subplots, mortality and growth rates of small trees (10–<50 cm gbh) were found also for two sub-periods (1996–1999, 1999–2001). A total of c. 19 K trees were recorded. Mortality rate increased by 25% while both recruitment and relative growth rates increased by 12% for all trees at the coarse scale. For small trees, at the fine scale, mortality increased by 6% and 9% from pre-drought to drought and on to ‘post-drought’ sub-periods. Relative growth rates correspondingly decreased by 38% and increased by 98%. Tree size and topography interacted in a complex manner with between-plot differences. The forest appears to have been sustained by off-setting elevated tree mortality by highly resilient stem growth. This last is seen as the key integrating tree variable which links the external driver (drought causing water stress) and population dynamics recorded as mortality and recruitment. Suitably sound measurements of stem girth, leading to valid growth rates, are needed to understand and model tree dynamic responses to perturbations. The proportion of sound data, however, is in part determined by the drought itself.

Plurality of tree species responses to drought perturbation in Bornean tropical rain forest

Drought perturbation driven by the El Niño Southern Oscillation (ENSO) is a principal stochastic variable determining the dynamics of lowland rain forest in S.E. Asia. Mortality, recruitment and stem growth rates at Danum in Sabah (Malaysian Borneo) were recorded in two 4-ha plots (trees ≥ 10 cm gbh) for two periods, 1986–1996 and 1996–2001. Mortality and growth were also recorded in a sample of subplots for small trees (10 to <50 cm gbh) in two sub-periods, 1996–1999 and 1999–2001. Dynamics variables were employed to build indices of drought response for each of the 34 most abundant plot-level species (22 at the subplot level), these being interval-weighted percentage changes between periods and sub-periods. A significant yet complex effect of the strong 1997/1998 drought at the forest community level was shown by randomization procedures followed by multiple hypothesis testing. Despite a general resistance of the forest to drought, large and significant differences in short-term responses were apparent for several species. Using a diagrammatic form of stability analysis, different species showed immediate or lagged effects, high or low degrees of resilience or even oscillatory dynamics. In the context of the local topographic gradient, species’ responses define the newly termed perturbation response niche. The largest responses, particularly for recruitment and growth, were among the small trees, many of which are members of understorey taxa. The results bring with them a novel approach to understanding community dynamics: the kaleidoscopic complexity of idiosyncratic responses to stochastic perturbations suggests that plurality, rather than neutrality, of responses may be essential to understanding these tropical forests. The basis to the various responses lies with the mechanisms of tree-soil water relations which are physiologically predictable: the timing and intensity of the next drought, however, is not. To date, environmental stochasticity has been insufficiently incorporated into models of tropical forest dynamics, a step that might considerably improve the reality of theories about these globally important ecosystems.

A Cooperative and Adaptive Variable Neighborhood Search for the Multi Depot Vehicle Routing Problem with Time Windows

In this paper we propose two cooperation schemes to compose new parallel variants of the Variable Neighborhood Search (VNS). On the one hand, a coarse-grained cooperation scheme is introduced which is well suited for being enhanced with a solution warehouse to store and manage the so far best found solutions and a self-adapting mechanism for the most important search parameters. This makes an a priori parameter tuning obsolete. On the other hand, a fine-grained scheme was designed to reproduce the successful properties of the sequential VNS. In combination with the use of parallel exploration threads all of the best solutions and 11 out of 20 new best solutions for the Multi Depot Vehicle Routing Problem with Time Windows were found.

Expression Analysis of the Theileria parva Subtelomere-Encoded Variable Secreted Protein Gene Family

Background The intracellular protozoan parasite Theileria parva transforms bovine lymphocytes inducing uncontrolled proliferation. Proteins released from the parasite are assumed to contribute to phenotypic changes of the host cell and parasite persistence. With 85 members, genes encoding subtelomeric variable secreted proteins (SVSPs) form the largest gene family in T. parva. The majority of SVSPs contain predicted signal peptides, suggesting secretion into the host cell cytoplasm. Methodology/Principal Findings We analysed SVSP expression in T. parva-transformed cell lines established in vitro by infection of T or B lymphocytes with cloned T. parva parasites. Microarray and quantitative real-time PCR analysis revealed mRNA expression for a wide range of SVSP genes. The pattern of mRNA expression was largely defined by the parasite genotype and not by host background or cell type, and found to be relatively stable in vitro over a period of two months. Interestingly, immunofluorescence analysis carried out on cell lines established from a cloned parasite showed that expression of a single SVSP encoded by TP03_0882 is limited to only a small percentage of parasites. Epitope-tagged TP03_0882 expressed in mammalian cells was found to translocate into the nucleus, a process that could be attributed to two different nuclear localisation signals. Conclusions Our analysis reveals a complex pattern of Theileria SVSP mRNA expression, which depends on the parasite genotype. Whereas in cell lines established from a cloned parasite transcripts can be found corresponding to a wide range of SVSP genes, only a minority of parasites appear to express a particular SVSP protein. The fact that a number of SVSPs contain functional nuclear localisation signals suggests that proteins released from the parasite could contribute to phenotypic changes of the host cell. This initial characterisation will facilitate future studies on the regulation of SVSP gene expression and the potential biological role of these enigmatic proteins.

Diversification in the South American Pampas: the genetic and morphological variation of the widespread Petunia axillaris complex (Solanaceae)

Understanding the spatiotemporal distribution of genetic variation and the ways in which this distribution is connected to the ecological context of natural populations is fundamental for understanding the nature and mode of intraspecific and, ultimately, interspecific differentiation. The Petunia axillaris complex is endemic to the grasslands of southern South America and includes three subspecies: P.a.axillaris, P.a.parodii and P.a.subandina. These subspecies are traditionally delimited based on both geography and floral morphology, although the latter is highly variable. Here, we determined the patterns of genetic (nuclear and cpDNA), morphological and ecological (bioclimatic) variation of a large number of P.axillaris populations and found that they are mostly coincident with subspecies delimitation. The nuclear data suggest that the subspecies are likely independent evolutionary units, and their morphological differences may be associated with local adaptations to diverse climatic and/or edaphic conditions and population isolation. The demographic dynamics over time estimated by skyline plot analyses showed different patterns for each subspecies in the last 100000years, which is compatible with a divergence time between 35000 and 107000years ago between P.a.axillaris and P.a.parodii, as estimated with the IMa program. Coalescent simulation tests using Approximate Bayesian Computation do not support previous suggestions of extensive gene flow between P.a.axillaris and P.a.parodii in their contact zone.