Predictors of antiretroviral therapy initiation in eThekwini (Durban), South Africa: Findings from a prospective cohort study

Despite expanded antiretroviral therapy (ART) eligibility in South Africa, many people diagnosed with HIV do not initiate ART promptly, yet understanding of the reasons is limited. Using data from an 8-month prospective cohort interview study of women and men newly-diagnosed with HIV in three public-sector primary care clinics in the eThekwini (Durban) region, South Africa, 2010–2014, we examined if theoretically-relevant social-structural, social-cognitive, psychosocial, and health status indicators were associated with time to ART initiation. Of 459 diagnosed, 350 returned to the clinic for their CD4+ test results (linkage); 153 (33.3%) were ART-eligible according to treatment criteria at the time; 115 (75.2% of those eligible) initiated ART (median = 12.86 weeks [95% CI: 9.75, 15.97] after linkage). In adjusted Cox proportional hazard models, internalized stigma was associated with a 65% decrease in the rate of ART initiation (Adjusted hazard ratio [AHR] 0.35, 95% CI: 0.19–0.80) during the period less than four weeks after linkage to care, but not four or more weeks after linkage to care, suggesting that stigma-reduction interventions implemented shortly after diagnosis may accelerate ART uptake. As reported by others, older age was associated with more rapid ART initiation (AHR for 1-year age increase: 1.04, 95% CI: 1.01–1.07) and higher CD4+ cell count (≥300μL vs. <150μL) was associated with a lower rate of initiation (AHR 0.38, 95% CI: 0.19–0.80). Several other factors that were assessed prior to diagnosis, including stronger belief in traditional medicine, higher endorsement of stigma toward people living with HIV, food insecurity, and higher psychological distress, were found to be in the expected direction of association with ART initiation, but confidence intervals were wide and could not exclude a null finding

Ipl1/aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis

Cells coordinate spindle formation with DNA repair and morphological modifications to chromosomes prior to their segregation to prevent cell division with damaged chromosomes. Here we uncover a novel and unexpected role for Aurora kinase in preventing the formation of spindles by Clb5-CDK (S-CDK) during meiotic prophase I and when the DDR is active in budding yeast. This is critical since S-CDK is essential for replication during premeiotic S-phase as well as double-strand break induction that facilitates meiotic recombination and, ultimately, chromosome segregation. Furthermore, we find that depletion of Cdc5 polo kinase activity delays spindle formation in DDR-arrested cells and that ectopic expression of Cdc5 in prophase I enhances spindle formation, when Ipl1 is depleted. Our findings establish a new paradigm for Aurora kinase function in both negative and positive regulation of spindle dynamics

Selection for Replicases in Protocells

PMCID: PMC3649988This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Syndromic Recognition of Influenza A Infection in a Low Prevalence Community Setting

BACKGROUND: With epidemics of influenza A virus infection, people and medical professionals are all concerned about symptoms or syndromes that may indicate the infection with influenza A virus. METHODOLOGY/PRINCIPAL FINDINGS: A prospective study was performed at a community clinic of a metropolitan area. Throat swab was sampled for 3-6 consecutive adult patients with new episode (<3 days) of respiratory tract infection every weekday from Dec. 8, 2005 to Mar. 31, 2006. Demographic data, relevant history, symptoms and signs were recorded. Samples were processed with multiplex real time PCR for 9 common respiratory tract pathogens and by virus culture. Throat swab samples were positive for Influenza A virus with multiplex real time PCR system in 12 of 240 patients. The 12 influenza A positive cases were with more clusters and chills than the other 228. Certain symptoms and syndromes increased the likelihood of influenza A virus infection. The syndrome of high fever plus chills plus cough, better with clustering of cases in household or workplace, is with the highest likelihood (positive likelihood ratio 95; 95% CI 12-750). Absence of both cluster and chills provides moderate evidence against the infection (negative likelihood ratio 0.51; 95% CI 0.29-0.90). CONCLUSIONS/SIGNIFICANCE: Syndromic recognition is not diagnostic but is useful for discriminating between influenza A infection and common cold. In addition to relevant travel history, confirmatory molecular test can be applied to subjects with high likelihood when the disease prevalence is low

Increased risk of phosphorus limitation at higher temperatures for Daphnia magna

Invertebrate herbivores frequently face growth rate constraints due to their high demands for phosphorus (P) and nitrogen (N). Temperature is a key modulator of growth rate, yet the interaction between temperature and P limitation on somatic growth rate is scarcely known. To investigate this interaction, we conducted a study on the somatic growth rate (SGR) of the cladoceran Daphnia magna, known to be susceptible to P-limitation. We determined the SGR across a broad range of dietary P content of algae (carbon (C):P ratios (125–790), and at different temperatures (10–25°C). There was a strong impact of both temperature and C:P ratio on the SGR of D. magna, and also a significant interaction between both factors was revealed. The negative effect of dietary C:P on growth rate was reduced with decreased temperature. We found no evidence of P limitation at lowest temperature, suggesting that enzyme kinetics or other measures of food quality overrides the demands for P to RNA and protein synthesis at low temperatures. These findings also indicate an increased risk of P limitation and thus reduced growth efficiency at high temperatures

Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction

BACKGROUND: Hepatocelluar carcinoma (HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro. METHODS: RNA interference was performed by transfecting siRNA to specifically knock down Mcl-1 expression in HCC cells. Mcl-1 expression was measured by quantitative real-time PCR and Western blot. Induction of apoptosis and caspase activity after treatment with chemotherapeutic drugs and different targeted therapies were measured by flow cytometry and fluorometric analysis, respectively. RESULTS: Here we demonstrate that Mcl-1 expressing HCC cell lines show low sensitivity towards treatment with a panel of chemotherapeutic drugs. However, treatment with the anthracycline derivative epirubicin resulted in comparatively high apoptosis rates in HCC cells. Inhibition of the kinase PI3K significantly increased apoptosis induction by chemotherapy. RNA interference efficiently downregulated Mcl-1 expression in HCC cells. Mcl-1 downregulation sensitized HCC cells to different chemotherapeutic agents. Sensitization was accompanied by profound activation of caspase-3 and -9. In addition, Mcl-1 downregulation also increased apoptosis rates after treatment with PI3K inhibitors and, to a lower extent, after treatment with mTOR, Raf I and VEGF/PDGF kinase inhibitors. TRAIL-induced apoptosis did not markedly respond to Mcl-1 knockdown. Additionally, knockdown of Mcl-1 efficiently enhanced apoptosis sensitivity towards combined treatment modalities: Mcl-1 knockdown significantly augmented apoptosis sensitivity of HCC cells towards chemotherapy combined with PI3K inhibition. CONCLUSION: Our data suggest that specific downregulation of Mcl-1 by RNA interference is a promising approach to sensitize HCC cells towards chemotherapy and molecularly targeted therapies

Estimating the Cost of Type 1 Diabetes in the U.S.: A Propensity Score Matching Method

Diabetes costs represent a large burden to both patients and the health care system. However, few studies that examine the economic consequences of diabetes have distinguished between the two major forms, type 1 and type 2 diabetes, despite differences in underlying pathologies. Combining the two diseases implies that there is no difference between the costs of type 1 and type 2 diabetes to a patient. In this study, we examine the costs of type 1 diabetes, which is often overlooked due to the larger population of type 2 patients, and compare them to the estimated costs of diabetes reported in the literature.Using a nationally representative dataset, we estimate yearly and lifetime medical and indirect costs of type 1 diabetes by implementing a matching method to compare a patient with type 1 diabetes to a similar individual without the disease. We find that each year type 1 diabetes costs this country $14.4 billion (11.5-17.3) in medical costs and lost income. In terms of lost income, type 1 patients incur a disproportionate share of type 1 and type 2 costs. Further, if the disease were eliminated by therapeutic intervention, an estimated$10.6 billion (7.2-14.0) incurred by a new cohort and $422.9 billion (327.2-519.4) incurred by the existing number of type 1 diabetic patients over their lifetime would be avoided.We find that the costs attributed to type 1 diabetes are disproportionately higher than the number of type 1 patients compared with type 2 patients, suggesting that combining the two diseases when estimating costs is not appropriate. This study and another recent contribution provides a necessary first step in estimating the substantial costs of type 1 diabetes on the U.S

Initiation of V(D)J Recombination by Dβ-Associated Recombination Signal Sequences: A Critical Control Point in TCRβ Gene Assembly

T cell receptor (TCR) β gene assembly by V(D)J recombination proceeds via successive Dβ-to-Jβ and Vβ-to-DJβ rearrangements. This two-step process is enforced by a constraint, termed beyond (B)12/23, which prohibits direct Vβ-to-Jβ rearrangements. However the B12/23 restriction does not explain the order of TCRβ assembly for which the regulation remains an unresolved issue. The initiation of V(D)J recombination consists of the introduction of single-strand DNA nicks at recombination signal sequences (RSSs) containing a 12 base-pairs spacer. An RSS containing a 23 base-pairs spacer is then captured to form a 12/23 RSSs synapse leading to coupled DNA cleavage. Herein, we probed RSS nicks at the TCRβ locus and found that nicks were only detectable at Dβ-associated RSSs. This pattern implies that Dβ 12RSS and, unexpectedly, Dβ 23RSS initiate V(D)J recombination and capture their respective Vβ or Jβ RSS partner. Using both in vitro and in vivo assays, we further demonstrate that the Dβ1 23RSS impedes cleavage at the adjacent Dβ1 12RSS and consequently Vβ-to-Dβ1 rearrangement first requires the Dβ1 23RSS excision. Altogether, our results provide the molecular explanation to the B12/23 constraint and also uncover a ‘Dβ1 23RSS-mediated’ restriction operating beyond chromatin accessibility, which directs Dβ1 ordered rearrangements