The Impact of Syphilis Screening among Female Sex Workers in China: A Modelling Study

Background

In China, female sex workers (FSWs) are at high risk of syphilis infection, but are hard to reach for interventions. Point-of-care testing introduces opportunities for expanding syphilis control measures. Modelling is used to estimate the impact of using rapid tests to screen FSWs for syphilis. In other settings, modelling has predicted large rebounds in infectious syphilis following screening, which may undermine any impact achieved.

Methods

A deterministic syphilis transmission model among FSWs and clients was fitted to data from Yunnan Province (FSW syphilis prevalence = 7.5%), and used to estimate the impact of rapid syphilis testing and treatment for FSWs. Impact projections were compared for different model structures that included risk heterogeneity amongst FSWs, incoming syphilis infections amongst new FSWs and clients and re-infection from FSWs'' regular non-commercial partners. The rebound in syphilis prevalence after screening ceased was explored.

Results

All model structures suggest yearly syphilis screening could substantially reduce (by 72–88%) syphilis prevalence amongst FSWs in this setting over five years. However, incoming syphilis infections amongst new FSWs and clients or re-infections from regular non-commercial partners of FSWs can considerably reduce (>30%) the proportion of infections averted. Including heterogeneity in risk amongst FSWs had little effect upon the proportion of infections averted. In this setting, the rebound in syphilis prevalence after screening ceased is predicted to be slight, but it could be large in high prevalence settings.

Conclusions

Rapid test screening could dramatically reduce syphilis prevalence amongst hard-to-reach groups, but strategies to reduce re-infection from regular non-commercial partners are needed to maximise impact.     

A Homogeneous,High-Throughput Assay for Phosphatidylinositol 5-Phosphate 4-Kinase with a Novel,Rapid Substrate Preparation

Phosphoinositide kinases regulate diverse cellular functions and are important targets for therapeutic development for diseases, such as diabetes and cancer. Preparation of the lipid substrate is crucial for the development of a robust and miniaturizable lipid kinase assay. Enzymatic assays for phosphoinositide kinases often use lipid substrates prepared from lyophilized lipid preparations by sonication, which result in variability in the liposome size from preparation to preparation. Herein, we report a homogeneous 1536-well luciferase-coupled bioluminescence assay for PI5P4Kα. The substrate preparation is novel and allows the rapid production of a DMSO-containing substrate solution without the need for lengthy liposome preparation protocols, thus enabling the scale-up of this traditionally difficult type of assay. The Z’-factor value was greater than 0.7 for the PI5P4Kα assay, indicating its suitability for high-throughput screening applications. Tyrphostin AG-82 had been identified as an inhibitor of PI5P4Kα by assessing the degree of phospho transfer of γ-³²P-ATP to PI5P; its inhibitory activity against PI5P4Kα was confirmed in the present miniaturized assay. From a pilot screen of a library of bioactive compounds, another tyrphostin, I-OMe tyrphostin AG-538 (I-OMe-AG-538), was identified as an ATP-competitive inhibitor of PI5P4Kα with an IC₅₀ of 1 µM, affirming the suitability of the assay for inhibitor discovery campaigns. This homogeneous assay may apply to other lipid kinases and should help in the identification of leads for this class of enzymes by enabling high-throughput screening efforts.     

Dietary patterns,abdominal visceral adipose tissue,and cardiometabolic risk factors in African Americans: The Jackson heart study

Objective:

To examine the relative association of abdominal visceral adipose tissue (VAT) with cardiometabolic risk factors between African and European Americans.

Design and Methods:

We conducted a cross‐sectional study of 2035 African Americans from Jackson Heart Study (JHS) and 3170 European Americans from Framingham Heart Study (FHS) who underwent computed tomography assessment of VAT and subcutaneous adipose tissue (SAT). The FHS participants were weighted to match the age distribution of the JHS participants and the metabolic risk factors were examined by study groups in relation to VAT.

Results:

JHS participants had higher rates of obesity, hypertension, diabetes and metabolic syndrome than FHS participants (all p = 0.001). The associations were weaker in JHS women for VAT with blood pressure, triglycerides, HDL‐C, and total cholesterol (p_interaction = 0.03 to 0.001) than FHS women. In contrast, JHS men had stronger associations for VAT with high triglycerides, low HDL, and metabolic syndrome (all p_interaction = 0.001) compared to FHS men. Similar associations and gender patterns existed for SAT with most metabolic risk factors.

Conclusions:

The relative association between VAT and cardiometabolic risk factors is weaker in JHS women compared to FHS women, whereas stronger association with triglycerides and HDL were observed in JHS men.     

Anti-tumoral,anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2

Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody (Ang-2-VEGF-TAvi6) targeting VEGF-A with 2 arms based on bevacizumab (Avastin®), and targeting Ang-2 with 2 arms based on a novel anti-Ang-2 antibody (LC06). The two Ang-2-targeting single-chain variable fragments are disulfide-stabilized and fused to the C-terminus of the heavy chain of bevacizumab. Treatment with Ang-2-VEGF-A-TAvi6 led to a complete abrogation of angiogenesis in the cornea micropocket assay. Metastatic spread and tumor growth of subcutaneous, orthotopic and anti-VEGF-A resistant tumors were also efficiently inhibited. These data further establish Ang-2-VEGF bispecific antibodies as a promising anti-angiogenic, anti-metastatic and anti-tumor agent for the treatment of cancer.     

Motor Adaptations to Pain during a Bilateral Plantarflexion Task: Does the Cost of Using the Non-Painful Limb Matter?

During a force-matched bilateral task, when pain is induced in one limb, a shift of load to the non-painful leg is classically observed. This study aimed to test the hypothesis that this adaptation to pain depends on the mechanical efficiency of the non-painful leg. We studied a bilateral plantarflexion task that allowed flexibility in the relative force produced with each leg, but constrained the sum of forces from both legs to match a target. We manipulated the mechanical efficiency of the non-painful leg by imposing scaling factors: 1, 0.75, or 0.25 to decrease mechanical efficiency (Decreased efficiency experiment: 18 participants); and 1, 1.33 or 4 to increase mechanical efficiency (Increased efficiency experiment: 17 participants). Participants performed multiple sets of three submaximal bilateral isometric plantarflexions with each scaling factor during two conditions (Baseline and Pain). Pain was induced by injection of hypertonic saline into the soleus. Force was equally distributed between legs during the Baseline contractions (laterality index was close to 1; Decreased efficiency experiment: 1.16±0.33; Increased efficiency experiment: 1.11±0.32), with no significant effect of Scaling factor. The laterality index was affected by Pain such that the painful leg contributed less than the non-painful leg to the total force (Decreased efficiency experiment: 0.90±0.41, P<0.001; Increased efficiency experiment: 0.75±0.32, P<0.001), regardless of the efficiency (scaling factor) of the non-painful leg. When compared to the force produced during Baseline of the corresponding scaling condition, a decrease in force produced by the painful leg was observed for all conditions, except for scaling 0.25. This decrease in force was correlated with a decrease in drive to the soleus muscle. These data highlight that regardless of the overall mechanical cost, the nervous system appears to prefer to alter force sharing between limbs such that force produced by the painful leg is reduced relative to the non-painful leg.     

Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice

Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI^-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI^-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI^-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.     

Midpoint attractors and species richness: Modelling the interaction between environmental drivers and geometric constraints

We introduce a novel framework for conceptualising, quantifying and unifying discordant patterns of species richness along geographical gradients. While not itself explicitly mechanistic, this approach offers a path towards understanding mechanisms. In this study, we focused on the diverse patterns of species richness on mountainsides. We conjectured that elevational range midpoints of species may be drawn towards a single midpoint attractor – a unimodal gradient of environmental favourability. The midpoint attractor interacts with geometric constraints imposed by sea level and the mountaintop to produce taxon‐specific patterns of species richness. We developed a Bayesian simulation model to estimate the location and strength of the midpoint attractor from species occurrence data sampled along mountainsides. We also constructed midpoint predictor models to test whether environmental variables could directly account for the observed patterns of species range midpoints. We challenged these models with 16 elevational data sets, comprising 4500 species of insects, vertebrates and plants. The midpoint predictor models generally failed to predict the pattern of species midpoints. In contrast, the midpoint attractor model closely reproduced empirical spatial patterns of species richness and range midpoints. Gradients of environmental favourability, subject to geometric constraints, may parsimoniously account for elevational and other patterns of species richness.