Rapid pre-screening of cervical smears as a method of internal quality control in a cervical screening programme

Objective:  To evaluate the performance of rapid pre-screening (RPS) as a method of internal quality control in the cytopathological examination of cervical smears for cervical cancer screening.
Methods:  The sample consisted of 6135 cervical smears submitted to RPS and routine screening (RS) methods. The smears classified as negative in RPS and RS were considered final diagnoses, and were not, therefore, submitted to any additional review. The smears identified as suspect or unsatisfactory according to RPS were analysed separately by two different cytologists irrespective of the diagnosis reached in RS. Smears considered abnormal or unsatisfactory at RS were also reviewed. When both cytologists issued concordant diagnoses, this was considered the final diagnosis. Discordant results were analysed by a third cytologist and a consensus meeting was held to define the final diagnosis.
Results:  Taking abnormalities detected by RS as the denominator, RPS had a sensitivity of 63.0% for the detection of all abnormal smears and 96.7% for high grade squamous intraepithelial lesion (HSIL). When compared with the final diagnosis, sensitivity of RPS for all abnormal smears was 74.9% and for HSIL 95.0%. Of the 529 abnormal smears confirmed in the final diagnosis, 2.15% were detected only by the RPS.
Conclusion:  RPS is an effective alternative method of internal quality control with high sensitivity for the detection of more severe lesions. It also permits monitoring of the laboratory rate of false-negative results, and allows constant evaluation of the performance both of the pre-screening and RS cytologists.     

Towards the identification of the allosteric Phe-binding site in phenylalanine hydroxylase

The enzyme phenylalanine hydroxylase (PAH) is defective in the inherited disorder phenylketonuria. PAH, a tetrameric enzyme, is highly regulated and displays positive cooperativity for its substrate, Phe. Whether Phe binds to an allosteric site is a matter of debate, despite several studies worldwide. To address this issue, we generated a dimeric model for Phe–PAH interactions, by performing molecular docking combined with molecular dynamics simulations on human and rat wild-type sequences and also on a human G46S mutant. Our results suggest that the allosteric Phe-binding site lies at the dimeric interface between the regulatory and the catalytic domains of two adjacent subunits. The structural and dynamical features of the site were characterized in depth and described. Interestingly, our findings provide evidence for lower allosteric Phe-binding ability of the G46S mutant than the human wild-type enzyme. This also explains the disease-causing nature of this mutant.     

A Rhizobium tropici DNA region carrying the amino-terminal half of a nodD gene and a nod-box-like sequence confers host-range extension

Rhizobium tropici CIAT899 is a broad-host-range strain that, in addition to Phaseolus, nodulates other plant legumes such as Leucaena and Macroptilium. The narrow-host-range of Rhizobium leguminosarum biovars phaseoli (strain CE3) and trifolii (strain RS1051) can be extended to Leucaena esculents and Phaseolus vulgaris plants, respectively, by the introduction of a DNA fragment 521 bp long, which carries 128 amino acids of the amino-terminal region of a nodD gene from R. tropici, as well as a putative nod-box-like sequence, divergently oriented. The 521 bp fragment, in the presence of L. esculenta or P. vulgaris root exudates, induced a R. leguminosarum bv. viciae nodA-lacZ fusion in either a CE3 or RS1051 background, respectively.     

From food‐dependent statistics to metabolic parameters,a practical guide to the use of dynamic energy budget theory

The standard model of the dynamic energy budget theory for metabolic organisation has variables and parameters that can be quantified using indirect methods only. We present new methods (and software) to extract food‐independent parameter values of the energy budget from food‐dependent quantities that are easy to observe, and so facilitate the practical application of the theory to enhance predictability and extrapolation. A natural sequence of 10 steps is discussed to obtain some compound parameters first, then the primary parameters, then the composition parameters and finally the thermodynamic parameters; this sequence matches a sequence of required data of increasing complexity which is discussed in detail. Many applications do not require knowledge of all parameters, and we discuss methods to extrapolate parameters from one species to another. The conversion of mass, volume and energy measures of biomass is discussed; these conversions are not trivial because biomass can change in chemical composition in particular ways thanks to different forms of homeostasis. We solve problems like “What would be the ultimate reproduction rate and the von Bertalanffy growth rate at a specific food level, given that we have measured these statistics at abundant food?” and “What would be the maximum incubation time, given the parameters of the von Bertalanffy growth curve?”. We propose a new non‐destructive method for quantifying the chemical potential and entropy of living reserve and structure, that can potentially change our ideas on the thermodynamic properties of life. We illustrate the methods using data on daphnids and molluscs.     

Multiple myeloma and occupation: A pooled analysis by the International Multiple Myeloma Consortium

Objective: We investigated occupational risk of multiple myeloma (MM) in a pooled analysis of five international case–control studies. Methods: We calculated the odds ratio and its 95% confidence interval for selected occupations with unconditional regression analysis in 1959 MM cases and 6192 controls, by pooling study-specific risks using random-effects meta-analysis. Exposure to organic solvents was assessed with a job-exposure matrix (JEM). Results: Gardeners and nursery workers combined, most likely exposed to pesticides, showed a 50% increase in risk (OR = 1.50, 95% CI 0.9–2.3), while other farming jobs did not. Metal processors (OR = 1.55, 95% CI 0.9–2.3), female cleaners (OR = 1.32, 95% CI 1.0–1.8), and high level exposure to organic solvents (OR = 1.38, 95% CI 0.96–1.8) also showed moderately increased risks. Conclusions: Additional case–control studies of MM aetiology are warranted to further investigate the nature of the repeatedly reported increase in MM risk in several occupational groups.     

Comparative post-hatching ontogeny of Pseudoplatystoma reticulatum (Eigenmann & Eigenmann 1889) and Leiarius marmoratus (Gill, 1870) and their hybrid

Ontogenetic studies of the eggs and larvae of fish can provide information on the initial life history and biology of a species, are important for taxonomic and evolutionary studies, and for cultivation in captivity. The aim of this study was to analyze and describe the main morphological differences in the larval ontogeny of Pseudoplatystoma reticulatum, Leiarius marmoratus, and its hybrid (♀ P. reticulatum × ♂ L. marmoratus), as well as to identify characteristics that can identify the species and their hybrid at the larvae and juvenile stages. 205 L. marmoratus, 210 P. reticulatum, and 205 hybrid specimens were analyzed, all of which were obtained through induced reproduction. Analyses were performed from hatching to 30 days post-hatching. 19 morphometric and 5 meristic characteristics were evaluated, in addition to chromatophore shape and distribution. The specimens were classified into two life periods: Larval (stages: yolk sac, pre-flexion, flexion, and post-flexion) and Juvenile. Newly hatched larvae were transparent, poorly developed, and had a scarcity of chromatophores. During the early stages of larval development, the three groups showed similarities in appearance and proportional dimensions. However, at both the end of the post-flexion stage and at the juvenile period when individuals were approximately 2 cm long, it was possible to differentiate between hybrids and their parental species by their morphometric, meristic, and pigment characteristics. The hybrid, despite occupying an intermediate position in relationship to its parents, exhibited a shape and size more similar to P. reticulatum, its maternal parent.     

Expanding ART for treatment and prevention of HIV in South Africa: estimated cost and cost-effectiveness 2011-2050

Background

Antiretroviral Treatment (ART) significantly reduces HIV transmission. We conducted a cost-effectiveness analysis of the impact of expanded ART in South Africa.

Methods

We model a best case scenario of 90% annual HIV testing coverage in adults 15–49 years old and four ART eligibility scenarios: CD4 count <200 cells/mm³ (current practice), CD4 count <350, CD4 count <500, all CD4 levels. 2011–2050 outcomes include deaths, disability adjusted life years (DALYs), HIV infections, cost, and cost per DALY averted. Service and ART costs reflect South African data and international generic prices. ART reduces transmission by 92%. We conducted sensitivity analyses.

Results

Expanding ART to CD4 count <350 cells/mm³ prevents an estimated 265,000 (17%) and 1.3 million (15%) new HIV infections over 5 and 40 years, respectively. Cumulative deaths decline 15%, from 12.5 to 10.6 million; DALYs by 14% from 109 to 93 million over 40 years. Costs drop $504 million over 5 years and $3.9 billion over 40 years with breakeven by 2013. Compared with the current scenario, expanding to <500 prevents an additional 585,000 and 3 million new HIV infections over 5 and 40 years, respectively. Expanding to all CD4 levels decreases HIV infections by 3.3 million (45%) and costs by $10 billion over 40 years, with breakeven by 2023. By 2050, using higher ART and monitoring costs, all CD4 levels saves $0.6 billion versus current; other ART scenarios cost $9–194 per DALY averted. If ART reduces transmission by 99%, savings from all CD4 levels reach $17.5 billion. Sensitivity analyses suggest that poor retention and predominant acute phase transmission reduce DALYs averted by 26% and savings by 7%.

Conclusion

Increasing the provision of ART to <350 cells/mm3 may significantly reduce costs while reducing the HIV burden. Feasibility including HIV testing and ART uptake, retention, and adherence should be evaluated.