A Cluster Randomized Trial of Routine HIV-1 Viral Load Monitoring in Zambia: Study Design,Implementation, and Baseline Cohort Characteristics

Background

The benefit of routine HIV-1 viral load (VL) monitoring of patients on antiretroviral therapy (ART) in resource-constrained settings is uncertain because of the high costs associated with the test and the limited treatment options. We designed a cluster randomized controlled trial to compare the use of routine VL testing at ART-initiation and at 3, 6, 12, and 18 months, versus our local standard of care (which uses immunological and clinical criteria to diagnose treatment failure, with discretionary VL testing when the two do not agree).

Methodology

Dedicated study personnel were integrated into public-sector ART clinics. We collected participant information in a dedicated research database. Twelve ART clinics in Lusaka, Zambia constituted the units of randomization. Study clinics were stratified into pairs according to matching criteria (historical mortality rate, size, and duration of operation) to limit the effect of clustering, and independently randomized to the intervention and control arms. The study was powered to detect a 36% reduction in mortality at 18 months.

Principal Findings

From December 2006 to May 2008, we completed enrollment of 1973 participants. Measured baseline characteristics did not differ significantly between the study arms. Enrollment was staggered by clinic pair and truncated at two matched sites.

Conclusions

A large clinical trial of routing VL monitoring was successfully implemented in a dynamic and rapidly growing national ART program. Close collaboration with local health authorities and adequate reserve staff were critical to success. Randomized controlled trials such as this will likely prove valuable in determining long-term outcomes in resource-constrained settings.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00929604","term_id":"NCT00929604"}}NCT00929604     

Evaluating the Potential for Harmonized Prediction and Comparison of Disposal‐Stage Greenhouse Gas Emissions for Biomaterial Products

The carbon footprint (CF) of biofuels and biomaterials is a barrier to their acceptance, yet the greenhouse gas emissions associated with disposing of biomaterials are frequently omitted from analyses. This article investigates whether harmonization is appropriate for calculating the importance of biomaterials’ disposal. This research shows that disposal stages could double a biomaterial's CF, or reduce it to the point that it could claim to be zero carbon. Incineration with combined heat and power coupled with on‐site energy production in the biorefinery are identified as prerequisites to being zero carbon. The article assesses the current UK waste infrastructure's ability to support a low‐carbon bio‐based future economy, and finds that presently it only achieves marginal net reductions when compared to landfill and so cannot be said to support low‐carbon biomaterials, though the article challenges the polluter pays principle where low‐carbon disposal infrastructure are not available. Reuse and recycling are shown to have the potential to offset all the emissions caused by landfill of biomaterials. However, the savings are not so great as to offset the biomaterial's upstream emissions. The study explores the ability to overcome the barriers to incorporating disposal into life cycle assessment while identifying limitations of using harmonization as an assessment method. Specifically, data availability and industry consensus are flagged as major barriers. The study also uses sensitivity analysis to investigate the influence of methodological choices, such as allowing additional reuse and recycling stages, classifying biomaterials into different types, and choosing between opposing allocation methods.     

Sampling efficacy for the red imported fire ant Solenopsis invicta (Hymenoptera: Formicidae)

Cost-effective detection of invasive ant colonies before establishment in new ranges is imperative for the protection of national borders and reducing their global impact. We examined the sampling efficiency of food-baits and pitfall traps (baited and nonbaited) in detecting isolated red imported fire ant (Solenopsis invicta Buren) nests in multiple environments in Gainesville, FL. Fire ants demonstrated a significantly higher preference for a mixed protein food type (hotdog or ground meat combined with sweet peanut butter) than for the sugar or water baits offered. Foraging distance success was a function of colony size, detection trap used, and surveillance duration. Colony gyne number did not influence detection success. Workers from small nests (0- to 15-cm mound diameter) traveled no >3 m to a food source, whereas large colonies (>30-cm mound diameter) traveled up to 17 m. Baited pitfall traps performed best at detecting incipient ant colonies followed by nonbaited pitfall traps then food baits, whereas food baits performed well when trying to detect large colonies. These results were used to create an interactive model in Microsoft Excel, whereby surveillance managers can alter trap type, density, and duration parameters to estimate the probability of detecting specified or unknown S. invicta colony sizes. This model will support decision makers who need to balance the sampling cost and risk of failure to detect fire ant colonies.     

Synthesis and in vitro evaluation of palladium(II) salicylaldiminato thiosemicarbazone complexes against Trichomonas vaginalis

Eight mononuclear Pd(II) complexes containing salicylaldiminato thiosemicarbazones (saltsc-R; where R = H (1), 3-OMe (2), 3-^tBu (3) and 5-Cl (4)) as dinegative tridentate ligands were prepared by the reaction of the corresponding thiosemicarbazone with the precursor Pd(L)₂Cl₂ (L = phosphatriazaadamantane or 4-picoline) in the presence of a weak base. These complexes (9-16) were characterised by a range of spectroscopic and analytical techniques including NMR spectroscopy and X-ray diffraction. These complexes along with four other Pd(II) analogues (5-8) were screened for activity in vitro against the Trichomonas vaginalis parasite. Preliminary results show that the type of ancillary ligand as well as the substituents on the aromatic ring of the salicylaldiminato thiosemicarbazone ligand influences the antiparasitic activity of these complexes.     

A theoretical account of cue averaging in the rodent head direction system

Head direction (HD) cell responses are thought to be derived from a combination of internal (or idiothetic) and external (or allothetic) sources of information. Recent work from the Jeffery laboratory shows that the relative influence of visual versus vestibular inputs upon the HD cell response depends on the disparity between these sources. In this paper, we present simulation results from a model designed to explain these observations. The model accurately replicates the Knight et al. data. We suggest that cue conflict resolution is critically dependent on plastic remapping of visual information onto the HD cell layer. This remap results in a shift in preferred directions of a subset of HD cells, which is then inherited by the rest of the cells during path integration. Thus, we demonstrate how, over a period of several minutes, a visual landmark may gain cue control. Furthermore, simulation results show that weaker visual landmarks fail to gain cue control as readily. We therefore suggest a second longer term plasticity in visual projections onto HD cell areas, through which landmarks with an inconsistent relationship to idiothetic information are made less salient, significantly hindering their ability to gain cue control. Our results provide a mechanism for reliability-weighted cue averaging that may pertain to other neural systems in addition to the HD system.     

Assessment of pharmacological activities of two medicinal plant of Bangladesh: Launaea sarmentosa and Aegialitis rotundifolia roxb in the management of pain,pyrexia and inflammation

Background

The current study aims at evaluating the analgesic, anti-pyretic and anti-inflammatory properties of methanolic extract of the stem, bark and leaves of Launaea sarmentosa and Aegialitis rotundifolia roxb.

Results

The AELS and AEAR extract presented a significant (***p < 0.001) dose dependent increase in reaction time in writhing method and showed inhibition of 63.1% and 57.1% respectively at the doses of 400 mg/kg body weight while standard drug showed (P < 0.001) inhibition of 69.23%. In tail immersion method, AELS and AEAR showed maximum time of tail retention at 30 min in hot water i.e. 6.93 sec and 6.54 sec respectively at highest doses of 400 mg/kg body weight than lower dose while standard pentazocine showed reaction time of 7.62 sec. The AELS and AEAR extract also exhibited promising anti-inflammatory effect as demonstrated by statistically significant inhibition of paw volume by 32.48% and 26.75% respectively at the dose of 400 mg/kg body weight while the value at the dose of 200 mg/kg body weight were linear to higher dose at the 3^rd hour of study. On the other hand, Standard indomethacin inhibited 40.13% of inflammation (***P < 0.001). In Cotton-pellet granuloma method, AELS and AEAR extract at the dose of 400 mg/kg body weight exhibited inhibition of inflammation of 34.7% and 29.1% respectively while standard drug showed (P < 0.001) inhibition of 63.22%. Intraperitoneal administration of AELS and AEAR showed dose dependent decrease in body temperature in brewer’s yeast induced hyperthermia in rats at both doses. However, AELS significantly decreased body temperature (***p < 0.001) at 400 mg/kg compared to control.

Conclusions

Present work propose that the methanolic extract of Launaea sarmentosa and Aegialitis rotundifolia roxb possesses dose dependent pharmacological action which supports its therapeutic use in folk medicine possibly mediated through the inhibition or blocking of release of prostaglandin and/or actions of vasoactive substances such as histamine, serotonin and kinins.     

Light brown apple moth (Epiphyas postvittana) (Lepidoptera: Tortricidae) colonization of California

In response to the confirmed detection of the light brown apple moth, Epiphyas postvittana, in California, approximately 53,000 pheromone-baited Jackson traps were deployed and more than 246,000 males were caught (February 2007–February 2010). Approximately 46,000 manually entered catch records were corrected for errors and converted into catch per trap per day. As empty trap data (zeros) were not recorded, we added zeros between first and last catch for each trap based on the stated servicing period (~30,000), before analyzing for trends. Residual data error rate was estimated as 1.5 %. San Francisco and Santa Cruz counties had relatively high trap catches immediately upon trap set, and remained the leading population centers, while most other counties showed a more general trend of a slow build-up in catch over time (12 counties). An exponential increase in trap catch was observed in four counties with sufficient data. The pattern of spread indicated natural, as well as anthropogenic-assisted spread rates, with populations appearing well ahead of the invasion front. This jump dispersal is probably due to movement of host plants, unsurprising since eggs of this polyphagous moth are readily laid on foliage. There was evidence of seasonality in spread, probably linked to the phenology of the insect. There was a positive relationship between catch and known host tree preference, suggesting that trap placement in preferred hosts could add sensitivity to future surveys. Recommendations include the improved provision of data acquisition by telecommunications, standardization of data input, more archiving, and frequent analysis of trap catches. The rapid rate of population growth demonstrated in two counties and spread across many others supports the hypothesis of the recent arrival of E. postvittana in California.     

Application of Balanced Scorecard in the Evaluation of a Complex Health System Intervention: 12 Months Post Intervention Findings from the BHOMA Intervention: A Cluster Randomised Trial in Zambia

Introduction

In many low income countries, the delivery of quality health services is hampered by health system-wide barriers which are often interlinked, however empirical evidence on how to assess the level and scope of these barriers is scarce. A balanced scorecard is a tool that allows for wider analysis of domains that are deemed important in achieving the overall vision of the health system. We present the quantitative results of the 12 months follow-up study applying the balanced scorecard approach in the BHOMA intervention with the aim of demonstrating the utility of the balanced scorecard in evaluating multiple building blocks in a trial setting.

Methods

The BHOMA is a cluster randomised trial that aims to strengthen the health system in three rural districts in Zambia. The intervention aims to improve clinical care quality by implementing practical tools that establish clear clinical care standards through intensive clinic implementations. This paper reports the findings of the follow-up health facility survey that was conducted after 12 months of intervention implementation. Comparisons were made between those facilities in the intervention and control sites. STATA version 12 was used for analysis.

Results

The study found significant mean differences between intervention(I) and control (C) sites in the following domains: Training domain (Mean I:C; 87.5.vs 61.1, mean difference 23.3, p = 0.031), adult clinical observation domain (mean I:C; 73.3 vs.58.0, mean difference 10.9, p = 0.02 ) and health information domain (mean I:C; 63.6 vs.56.1, mean difference 6.8, p = 0.01. There was no gender differences in adult service satisfaction. Governance and motivation scores did not differ between control and intervention sites.

Conclusion

This study demonstrates the utility of the balanced scorecard in assessing multiple elements of the health system. Using system wide approaches and triangulating data collection methods seems to be key to successful evaluation of such complex health intervention.

Trial number

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01942278","term_id":"NCT01942278"}}NCT01942278     

Plk1 Inhibition Causes Post-Mitotic DNA Damage and Senescence in a Range of Human Tumor Cell Lines

Plk1 is a checkpoint protein whose role spans all of mitosis and includes DNA repair, and is highly conserved in eukaryotes from yeast to man. Consistent with this wide array of functions for Plk1, the cellular consequences of Plk1 disruption are diverse, spanning delays in mitotic entry, mitotic spindle abnormalities, and transient mitotic arrest leading to mitotic slippage and failures in cytokinesis. In this work, we present the in vitro and in vivo consequences of Plk1 inhibition in cancer cells using potent, selective small-molecule Plk1 inhibitors and Plk1 genetic knock-down approaches. We demonstrate for the first time that cellular senescence is the predominant outcome of Plk1 inhibition in some cancer cell lines, whereas in other cancer cell lines the dominant outcome appears to be apoptosis, as has been reported in the literature. We also demonstrate strong induction of DNA double-strand breaks in all six lines examined (as assayed by γH2AX), which occurs either during mitotic arrest or mitotic-exit, and may be linked to the downstream induction of senescence. Taken together, our findings expand the view of Plk1 inhibition, demonstrating the occurrence of a non-apoptotic outcome in some settings. Our findings are also consistent with the possibility that mitotic arrest observed as a result of Plk1 inhibition is at least partially due to the presence of unrepaired double-strand breaks in mitosis. These novel findings may lead to alternative strategies for the development of novel therapeutic agents targeting Plk1, in the selection of biomarkers, patient populations, combination partners and dosing regimens.