Expanded HIV Testing in Low-Prevalence,High-Income Countries: A Cost-Effectiveness Analysis for the United Kingdom

Objective

In many high-income countries with low HIV prevalence, significant numbers of persons living with HIV (PLHIV) remain undiagnosed. Identification of PLHIV via HIV testing offers timely access to lifesaving antiretroviral therapy (ART) and decreases HIV transmission. We estimated the effectiveness and cost-effectiveness of HIV testing in the United Kingdom (UK), where 25% of PLHIV are estimated to be undiagnosed.

Design

We developed a dynamic compartmental model to analyze strategies to expand HIV testing and treatment in the UK, with particular focus on men who have sex with men (MSM), people who inject drugs (PWID), and individuals from HIV-endemic countries.

Methods

We estimated HIV prevalence, incidence, quality-adjusted life years (QALYs), and health care costs over 10 years, and cost-effectiveness.

Results

Annual HIV testing of all adults could avert 5% of new infections, even with no behavior change following HIV diagnosis because of earlier ART initiation, or up to 18% if risky behavior is halved. This strategy costs £67,000–£106,000/QALY gained. Providing annual testing only to MSM, PWID, and people from HIV-endemic countries, and one-time testing for all other adults, prevents 4–15% of infections, requires one-fourth as many tests to diagnose each PLHIV, and costs £17,500/QALY gained. Augmenting this program with increased ART access could add 145,000 QALYs to the population over 10 years, at £26,800/QALY gained.

Conclusions

Annual HIV testing of key populations in the UK is very cost-effective. Additional one-time testing of all other adults could identify the majority of undiagnosed PLHIV. These findings are potentially relevant to other low-prevalence, high-income countries.     

No Correlation between TIMP2 -418 G>C Polymorphism and Increased Risk of Cancer: Evidence from a Meta-Analysis

Aim

Tissue inhibitor of metalloproteinase (TIMP2) is involved in the regulation of matrix metalloproteinase 2 (MMP2) and shown to implicate in cancer development and progression. The results from the published studies based on the association between TIMP2 -418 G>C polymorphism and cancer risk are inconsistent. In this meta-analysis, we aimed to evaluate the potential association between TIMP2 -418 G>C polymorphism and cancer risk.

Methodology

We searched PubMed (Medline) and EMBASE web databases to cover all studies based on relationship of TIMP2 -418 G>C polymorphism and risk of cancer until October 2013. The meta-analysis was performed for selected case-control studies and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all genetic models.

Results

A total of 2225 cancer cases and 2532 controls were included from ten eligible case-control studies. Results from overall pooled analysis suggested no evidence of significant risk between TIMP2 -418 G>C polymorphism and cancer risk in any of the genetic models, such as, allele (C vs. G: OR = 1.293, 95% CI = 0.882 to 1.894, p = 0.188), homozygous (CC vs. GG: OR = 0.940, 95% CI = 0.434 to 2.039, p = 0.876), heterozygous (GC vs. GG: OR = 1.397, 95% CI = 0.888 to 2.198, p = 0.148), dominant (CC+GC vs. GG: OR = 1.387, 95% CI = 0.880 to 2.187, p = 0.159) and recessive (CC vs. GG+GC: OR = 0.901, 95% CI = 0.442 to 1.838, p = 0.774) models. No evidence of publication bias was detected during the analysis.

Conclusions

The present meta-analysis suggests that the TIMP2 -418 G>C polymorphism may not be involved in predisposing risk factor for cancer in overall population. However, future larger studies with group of populations are needed to analyze the possible correlation.     

Influences of yeast extract on specific cellular yield of Ovine growth hormone during fed-batch fermentation of E. coli

In most cases of E. coli high cell density fermentation process, maximizing cell concentration helps in increasing the volumetric productivity of recombinant proteins usually at the cost of lower specific cellular protein yield. In this report, we describe a process for maintaining the specific cellular yield of Ovine growth hormone (oGH) from E. coli by optimal feeding of yeast extract during high cell density fermentation process. Recombinant oGH was produced as inclusion bodies in Escherichia coli. Specific cellular yield of recombinant oGH was maintained by feeding yeast extract along with glucose during fed-batch fermentation. Glucose to yeast extract ratio of 0.75 was found to be optimum for maintaining the specific cellular oGH yield of 66 mg/g of E. coli cells. Continuous feeding of yeast extract along with glucose helped in reducing acetic acid secretion and promoted higher cell growth during fed-batch fermentation. High cell growth of E. coli and high specific yield of recombinant oGH thus helped in achieving high volumetric productivity of the expressed protein. A maximum of 2 g/l of ovine growth hormone was expressed as inclusion bodies in 12 h of fed-batch fermentation.     

Comparative studies on citric acid production by Aspergillus niger and Candida lipolytica using molasses and glucose

Citric acid production by Aspergillus niger NCIM 548 and Candida lipolytica NCIM 3472 has been studied in shake culture using glucose and molasses as carbon sources. Methanol addition (3% v/v) at 40 h of fermentation enhanced the production of citric acid by Aspergillus niger whereas a reduction in citric acid production by Candida lipolytica was observed with addition of methanol. Maximum citric acid concentration of 12 kg/m³ was obtained with Aspergillus niger using molasses in the presence of methanol, while maximum citric acid concentration of 8.4 kg/m³ was obtained with Candida lipolytica using glucose without methanol. It appears that product formation by Aspergillus niger is either non-growth associated or partially growth associated depending on the substrate. Methanol addition changes the nature of product formation in case of Candida lipolytica.     

Preferential binding of adriamycin and nogalamycin to DNase-I hypersensitive sites of Sarcoma-180 chromatin

Binding of nogalamycin and adriamycin with Sarcoma-180 ascites tumor cell chromatin was studied by a spectrofluorometric method. There was significant reduction in the number of available drug binding sites per nucleotide when the chromatin was digested with DNase I for a period which releases only 7% of the chromosomal DNA. Results indicate preferential binding of these drugs with DNase I hypersensitive sites of chromatin. The DNase-I hypersensitive sites of chromatin were shown to correlate to the sequences required for gene expression. Further digestion with DNase I increases availability of drug binding sites, probably due to relaxation of the compact chromatin.     

Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1

ATP binding cassette transporter A1 (ABCA1) is a widely expressed lipid transporter essential for the generation of HDL. ABCA1 is particularly abundant in the liver, suggesting that the liver may play a major role in HDL homeostasis. To determine how hepatic ABCA1 affects plasma HDL cholesterol levels, we treated mice with an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus promoter. Treated mice showed a dose-dependent increase in hepatic ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 x 108 to 1.5 x 109 pfu, with maximal expression observed on Day 3 posttreatment. A selective increase in HDL cholesterol occurred at Day 3 in mice treated with 5 x 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL cholesterol levels. In contrast, total cholesterol, triglycerides, phospholipids, non-HDL cholesterol, and apolipoprotein B levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. At comparable expression levels, bacterial artificial chromosome transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, showed a greater and more specific increase in HDL cholesterol than Ad-ABCA1-treated mice. Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL cholesterol levels.     

Heavy Metals Induce Lipid Peroxidation and Affect Antioxidants in Wheat Leaves

The possible role of Zn and Cr as catalytic inducers of free radicals in wheat leaves was investigated. Treatment of excess heavy metals decreased the chlorophyll and carotenoid content in wheat leaves with the increase in time of excision. A sharp increase in proline accumulation was marked with the increase in metal concentration. Total peroxide content and lipid peroxidation measured as malondialdehyde content showed uniform increase under metal treatment in excised leaves. At almost all concentrations, catalase, guaiacol peroxidase and superoxide dismutase activities decreased with a minor increase in the earlier days of excision. Though glutathione content decreased ascorbate content showed significant increase in wheat leaves under heavy metal treatment. This revised version was published online in July 2006 with corrections to the Cover Date.     

Cell cycle phase dependent productivity of a recombinant Chinese hamster ovary cell line

A Chinese Hamster Ovary cell line, CHO1-15₅₀₀, producing recombinant human tissue type plasminogen activator (tPA) via the dihydrofolate reductase (DHFR) amplification system, was studied in batch culture. In this system both DHFR and tPA are under the control of the strong constitutive viral SV40 early promoter. Employing the cumulative viable cell-hour approach, the specific productivity of tPA had maxima in the lag (0.065 pg cell⁻¹ h⁻¹) and early decline (0.040 pg cell⁻¹ h⁻¹) population growth phases. The viable population was assigned into four subpopulations (G1, S, G2/M phase, and Apoptotic cells) using flow cytometric analysis. As expected, intracellular DHFR was maximally expressed during the S cell cycle phase. The production of tPA, however, was found to be a direct linear function of the G1 phase, with a subpopulation specific productivity of 0.080 pg c-h⁻¹. Productivity maxima in the lag and early decline corroborate the flow cytometric data, indicative that this recombinant tPA production occurs primarily in the G1 cell cycle phase, not the S phase. This suggests that endogenous regulatory mechanisms are important controlling influences on the production of recombinant tPA in this ovarian cell line. Productivity from recombinant cell lines cannot be inferred from either the plasmid construct or the host cell alone. Elucidation of the relationship between expression of recombinant protein and the cell cycle phases of the host cell is a major component of the characterization of the animal cell production system. This information facilitates rational process design, including operating mode, modelling and control, and medium formulation.     

De novo design of peptide immunogens that mimic the coiled coil region of human T-cell leukemia virus type-1 glycoprotein 21 transmembrane subunit for induction of native protein reactive neutralizing antibodies

Peptide vaccines able to induce high affinity and protective neutralizing antibodies must rely in part on the design of antigenic epitopes that mimic the three-dimensional structure of the corresponding region in the native protein. We describe the design, structural characterization, immunogenicity, and neutralizing potential of antibodies elicited by conformational peptides derived from the human T-cell leukemia virus type 1 (HTLV-1) gp21 envelope glycoprotein spanning residues 347-374. We used a novel template design and a unique synthetic approach to construct two peptides (WCCR2T and CCR2T) that would each assemble into a triple helical coiled coil conformation mimicking the gp21 crystal structure. The peptide B-cell epitopes were grafted onto the epsilon side chains of three lysyl residues on a template backbone construct consisting of the sequence acetyl-XGKGKGKGCONH2 (where X represents the tetanus toxoid promiscuous T cell epitope (TT) sequence 580-599). Leucine substitutions were introduced at the a and d positions of the CCR2T sequence to maximize helical character and stability as shown by circular dichroism and guanidinium hydrochloride studies. Serum from an HTLV-1-infected patient was able to recognize the selected epitopes by enzyme-linked immunosorbent assay (ELISA). Mice immunized with the wild-type sequence (WCCR2T) and the mutant sequence (CCR2T) elicited high antibody titers that were capable of recognizing the native protein as shown by flow cytometry and whole virus ELISA. Sera and purified antibodies from immunized mice were able to reduce the formation of syncytia induced by the envelope glycoprotein of HTLV-1, suggesting that antibodies directed against the coiled coil region of gp21 are capable of disrupting cell-cell fusion. Our results indicate that these peptides represent potential candidates for use in a peptide vaccine against HTLV-1.     

Reversible dimer dissociation of tubulin S and tubulin detected by fluorescence anisotropy.

Concentration-dependent dissociation of dimers of goat brain tubulin S and tubulin was studied by fluorescence anisotropy. Upon dilution, assembly-competent fluorescein 5'-maleimide labeled dimers of tubulin S and tubulin show a progressive decrease in fluorescence anisotropy. That this lowering of anisotropy results from the dissociation of tubulin S dimers into monomers was shown by dilution experiments with unlabeled homologous and heterologous proteins. A nonlinear least-squares fit of the data gave a dissociation constant of 7.1 x 10(-8) M for tubulin S compared to 7.2 x 10(-7) M for tubulin at 25 degrees C in 0.1 M PEM buffer, pH 7.0. van't Hoff plots of dimer-monomer dissociation of tubulin S and tubulin also show considerable differences in delta H and delta S. Effects of ionic strength and colchicine on the equilibrium constants are also substantially different for tubulin and tubulin S. The implications of these observations on the influence of C-terminal tails on tubulin structure are discussed.