Economic Evaluation of Community-Based HIV Prevention Programs in Ontario: Evidence of Effectiveness in Reducing HIV Infections and Health Care Costs

Investments in community-based HIV prevention programs in Ontario over the past two and a half decades are assumed to have had an impact on the HIV epidemic, but they have never been systematically evaluated. To help close this knowledge gap, we conducted a macro-level evaluation of investment in Ontario HIV prevention programs from the payer perspective. Our results showed that, from 1987 to 2011, province-wide community-based programs helped to avert a total of 16,672 HIV infections, saving Ontario’s health care system approximately $6.5 billion Canadian dollars (range 4.8–7.5B). We also showed that these community-based HIV programs were cost-saving: from 2005 to 2011, every dollar invested in these programs saved about $5. This study is an important first step in understanding the impact of investing in community-based HIV prevention programs in Ontario and recognizing the impact that these programs have had in reducing HIV infections and health care costs.     

News of Biomedical Advances in HIV: Relationship to Treatment Optimism and Expected Risk Behavior in US MSM

HIV treatment optimism and the ways in which news of HIV biomedical advances in HIV is presented to the most at-risk communities interact in ways that affect risk behavior and the incidence of HIV. The goal of the current study was to understand the relationships among HIV treatment optimism, knowledge of HIV biomedical advances, and current and expected increased risk behavior as a result of reading hypothetical news stories of further advances. Most of an online-recruited sample of MSM were quite knowledgeable about current biomedical advances. After reading three hypothetical news stories, 15–24% of those not living with HIV and 26–52% of those living with HIV reported their condom use would decrease if the story they read were true. Results suggest the importance of more cautious reporting on HIV biomedical advances, and for targeting individuals with greater treatment optimism and those living with HIV via organizations where they are most likely to receive their information about HIV.     

Criterion validity of the Duke Activity Status Index for assessing functional capacity in patients with chronic obstructive pulmonary disease

PURPOSE: This study evaluated the concurrent criterion validity of the Duke Activity Status Index (DASI) with respect to standard physiologic work capacity indices in patients with chronic obstructive pulmonary disease (COPD) and compared its performance with similar surrogates. METHODS: 119 patients with moderate to severe COPD (86 men, 33 women) completed medical and smoking histories, physical examination, pulmonary function testing (PFT), cycle ergometry (CE), arm ergometry (AE), and 6-minute walk distance (6MWD), DASI, the Sickness Impact Profile-68 (SIP-68) and the Chronic Respiratory Disease Questionnaire (CRDQ). Correlation methods were used to assess the validity of the potential surrogates DASI and the domain scores for SIP-68 and CRDQ, with the standards CE, AE, PFT, and 6MWD (as a standard). RESULTS: The mean DASI score was 33.4 +/- 13.0. Significant Pearson correlations (P <.01) were observed between the DASI and PFT outcomes maximum voluntary ventilation (r =.28); peak expiratory flow (r =.21); diffusion capacity of lung for carbon monoxide (r =.30). For CE, the correlations with DASI were oxygen consumption (VO(2))(r =.34); minute ventilation (r =.25); watts (r =.37). For AE, the correlations with DASI were VO(2) (r=.38); watts (r =.47). For 6MWD, the correlation was r =.53. Higher correlations were obtained for the distance completed during the first minute of the 6MWD and ergometric indices as well as DASI scores: watts(AE) (r =.39); VO(2AE) (r =.45); watts(CE) (r =.50); VO(2CE) (r =.44). Correlation coefficients for all SIP-68 and CRDQ domain and total scores were lower than corresponding correlations obtained for the DASI. Regression analysis demonstrated that the DASI and 6MWD were important (P <.05) for predicting VO(2) or work for CE while DASI and SIP range or CRDQ dyspnea entered for AE, when gender, age, BMI, and the FEV1 were forced into the model. In forward stepwise analyses, DASI entered first for AE, and 6MWD entered first for CE. The DASI was selected in 3 of 4 models with R(2) values ranging from.47 to.70. SIP-68 and CRDQ subscores were significant as additional predictors. CONCLUSIONS: DASI has high criterion validity for predicting CE and/or AE outcomes in the COPD population. It is warranted in addition to the 6MWD, and its predictive significance and simplicity recommends it over several other self-administered instruments for evaluating functional capacity.     

Platelets modulate the proteolysis of factor VIII:C protein by plasmin

Factor VIII coagulant protein (VIII:C) functions as a critical cofactor with factor IXa, calcium ions, and phospholipid during the activation of factor X. In the course of this reaction, the activity of VIII:C is first increased and then is destroyed by one or more serine proteases that are part of the coagulation sequence. In this study, we have investigated the influence of platelets on the inactivation of VIII:C by plasmin. Platelets were separated from plasma proteins in the presence of granule release inhibitors and were incubated with plasmin and isolated VIII:C or the complex of purified VIII:C/von Willebrand factor (vWF); VIII:C activity and antigen levels were assessed over time. In the presence of platelets, the isolated VIII:C showed an initial increase in VIII:C activity that was not present when platelets were absent, and the VIII:C/vWF showed an increase in VIII:C activity over that seen when platelets were absent. In addition, platelets stabilized VIII:C activity over a one-hour time course when compared with buffer. The VIII:C antigen did not increase and decreased slowly whether platelets were present or absent. Preincubating the platelets with ristocetin, collagen, or plasmin did not alter the results, and experiments using platelets from a patient with severe von Willebrand's disease also showed a pattern similar to that seen with normal platelets. Experiments using fixed platelets or phospholipid vesicles showed that they did not support the activation reaction or delay the inactivation reaction. These studies demonstrate that platelets modulate the activation and inactivation of VIII:C by plasmin, apparently by a mechanism that is independent of the platelet release reaction.     

Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

Currently, the methods available for preimplantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo single-nucleotide and short indel mutations, which have been shown to cause a large fraction of genetic diseases. Detection of all these types of mutations requires whole-genome sequencing (WGS). In this study, advanced massively parallel WGS was performed on three 5- to 10-cell biopsies from two blastocyst-stage embryos. Both parents and paternal grandparents were also analyzed to allow for accurate measurements of false-positive and false-negative error rates. Overall, >95% of each genome was called. In the embryos, experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false-positive rate of about one error per Gb, resulting in fewer than 10 such errors per embryo. This represents a ∼100-fold lower error rate than previously published from 10 cells, and it is the first demonstration that advanced WGS can be used to accurately identify these de novo mutations in spite of the thousands of false-positive errors introduced by the extensive DNA amplification required for deep sequencing. Using haplotype information, we also demonstrate how small de novo deletions could be detected. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease-causing mutations and to reduce the incidence of genetic diseases.Worldwide, more than 5 million babies (Ferraretti et al. 2013) have been born through in vitro fertilization (IVF) since the birth of the first in 1978 (Steptoe and Edwards 1978). Exact numbers are difficult to determine, but it has been estimated that currently 350,000 babies are born yearly through IVF (de Mouzon et al. 2009, 2012; Centers for Disease Control and Prevention 2011; Ferraretti et al. 2013). That number is expected to rise, as advanced maternal age is associated with decreased fertility rates and women in developed countries continue to delay childbirth to later ages. In 95% of IVF procedures, no diagnostic testing of the embryos is performed (https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0). Couples with prior difficulties conceiving or those wishing to avoid the transmission of highly penetrant heritable diseases often choose to perform preimplantation genetic diagnosis (PGD). PGD involves the biopsy of one cell from a 3-d embryo or the recently more preferred method, due to improved implantation success rates (Scott et al. 2013b), of up to 10 cells from a 5- to 6-d blastocyst-stage embryo. Following biopsy, genetic analysis is performed on the isolated cell(s). Currently this is an assay for translocations and the correct chromosome copy number (Hodes-Wertz et al. 2012; Munne 2012; Yang et al. 2012; Scott et al. 2013a; Yin et al. 2013), a unique test designed and validated for each specific heritable disease (Gutierrez-Mateo et al. 2009), or a combination of both (Treff et al. 2013). Importantly, none of these approaches can detect de novo mutations.Advanced maternal age has long been associated with an increased risk of producing aneuploid embryos (Munne et al. 1995; Crow 2000; Hassold and Hunt 2009) and giving birth to a child afflicted with Down syndrome or other diseases resulting from chromosomal copy number alterations. Conversely, children of older fathers have been shown to have an increase in single base and short multibase insertion/deletion (indels) de novo mutations (Kong et al. 2012). Many recent large-scale sequencing studies have found that de novo variations spread across many different genes are likely to be the cause of a large fraction of autism cases (Michaelson et al. 2012; O’Roak et al. 2012; Sanders et al. 2012; De Rubeis et al. 2014; Iossifov et al. 2014), severe intellectual disability (Gilissen et al. 2014), epileptic encephalopathies (Epi4K Consortium and Epilepsy Phenome/Genome Project 2013), and many other congenital disorders (de Ligt et al. 2012; Veltman and Brunner 2012; Yang et al. 2013; Al Turki et al. 2014). Additionally rare and de novo variations have been suggested to be prevalent in patients with schizophrenia (Fromer et al. 2014; Purcell et al. 2014), and Michaelson et al. (2012) found that single base de novo mutations affect conserved regions of the genome and essential genes more often than regions of unknown function. Current targeted approaches to PGD would miss many of these important functional changes within the embryonic DNA sequence, and even a whole-genome sequencing (WGS)–based carrier screen of both parents would not enable comprehensive preimplantation or prenatal diagnoses due to de novo mutations. As more parents delay childbirth into their mid-30s and later, these studies suggest we should try to provide better diagnostic tests for improving the health of newborns. In this study, we demonstrate the use of an advanced WGS process that provides an accurate and phased genome sequence from about 10 cells, allowing highly sensitive and specific detection of single base de novo mutations from IVF blastocyst biopsies.