Total synthesis and biological evaluation of the tetramic acid based natural product harzianic acid and its stereoisomers

Financial support for this project was provided by Cancer Research UK (Grant No. C21383/A6950)The bioactive natural product harzianic acid was prepared for the first time in just six steps (longest linear sequence) with an overall yield of 22%. The identification of conditions to telescope amide bond formation and a Lacey-Dieckmann reaction into one pot proved important. The three stereoisomers of harzianic acid were also prepared, providing material for comparison of their biological activity. While all of the isomers promoted root growth, improved antifungal activity was unexpectedly associated with isomers in the enantiomeric series opposite that of harzianic acid.Publisher PDFPeer reviewe

The Rachel Carson Letters and the Making of Silent Spring

Environment, conservation, green, and kindred movements look back to Rachel Carson’s 1962 book Silent Spring as a milestone. The impact of the book, including on government, industry, and civil society, was immediate and substantial, and has been extensively described; however, the provenance of the book has been less thoroughly examined. Using Carson’s personal correspondence, this paper reveals that the primary source for Carson’s book was the extensive evidence and contacts compiled by two biodynamic farmers, Marjorie Spock and Mary T. Richards, of Long Island, New York. Their evidence was compiled for a suite of legal actions (1957-1960) against the U.S. Government and that contested the aerial spraying of dichlorodiphenyltrichloroethane (DDT). During Rudolf Steiner’s lifetime, Spock and Richards both studied at Steiner’s Goetheanum, the headquarters of Anthroposophy, located in Dornach, Switzerland. Spock and Richards were prominent U.S. anthroposophists, and established a biodynamic farm under the tutelage of the leading biodynamics exponent of the time, Dr. Ehrenfried Pfeiffer. When their property was under threat from a government program of DDT spraying, they brought their case, eventually lost it, in the process spent US$100,000, and compiled the evidence that they then shared with Carson, who used it, and their extensive contacts and the trial transcripts, as the primary input for Silent Spring. Carson attributed to Spock, Richards, and Pfeiffer, no credit whatsoever in her book. As a consequence, the organics movement has not received the recognition, that is its due, as the primary impulse for Silent Spring, and it is, itself, unaware of this provenance

Community collective efficacy is associated with reduced physical intimate partner violence (IPV) incidence in the rural province of Mpumalanga, South Africa: Findings from HPTN 068

Background Intimate partner violence (IPV) is a human rights violation and is associated with a variety of adverse physical and mental health outcomes. Collective efficacy, defined as mutual trust among community members and willingness to intervene on the behalf of the common good, has been associated with reduced neighbourhood violence. Limited research has explored whether community collective efficacy is associated with reduced incidence of IPV. This is of particular interest among adolescent girls and young women (AGYW) in sub-Saharan Africa, where the burden of HIV is greatest and IPV is common. Methods We collected longitudinal data among 2533 AGYW (ages 13-20) enrolled in the HPTN 068 cohort in Mpumalanga province, South Africa between 2011 and 2016. We included participants from 26 villages where community surveys were collected during the HPTN 068 study. Collective efficacy was measured at the village level via two population-based cross-sectional surveys in 2012 and 2014. Multivariable Poisson generalised estimating equation regression models estimated the relative risk ratio (RR) between village collective efficacy scores and subsequent physical IPV 12 month incidence, adjusting for village-level clustering and covariates. Results Thirty-eight per cent of the cohort (n=950) reported at least one episode of recent physical IPV during follow-up. For every SD higher level of collective efficacy, there was a 6% lower level of physical IPV incidence (adjusted RR: 0.94;95% CI 0.89 to 0.98) among AGYW after adjusting for covariates. Conclusions Community-level interventions that foster the development of collective efficacy may reduce IPV among AGYW

Multilevel Gender-Equitable Norms and Risk of HIV and Herpes Simplex Virus Type 2 Acquisition Among Young South African Women: A Longitudinal Analysis of the HIV Prevention Trials Network 068 Cohort

Purpose: Adolescent girls and young women (AGYW) in South Africa experience a disproportionately high burden of HIV acquisition. National HIV prevalence among AGYW increases nearly three-fold during the transition from late teenage years to their early twenties. We investigated whether beliefs about gender equity influence subsequent HIV acquisition among AGYW in South Africa. Methods: We used data from the HIV Prevention Trials Network 068, a longitudinal conditional cash transfer study of AGYW in Mpumalanga Province, South Africa. Gender-equitable beliefs were measured at the level of the individual and summarized among school peers and adults in the community using the Gender Equitable Men's Scale (GEMS). Generalized estimating equation regression was used to assess the association between individual, peer and community GEMS and HIV incidence, herpes simplex virus type 2 (HSV-2) incidence, and other HIV risk factors while accounting for repeated observations and clustering. Results: A total of 2,533 AGYW were followed up for up to 5 years. Adjusting for potential confounders, a unit increase in peer GEMS scores (i.e. more equitable) were significantly protective against subsequent HIV acquisition (risk difference = −.019; 95% confidence interval: −.032, −.006) and subsequent HSV-2 acquisition (risk difference = −.020; 95% confidence interval: −.040, −.000). Low individual and community GEMS scores were associated with multiple HIV risk factors but not with HIV or HSV-2 incidence directly. Conclusion: School-level peer endorsement of gender equity may be protective against HIV and HSV-2 incidence among AGYW. Interventions that increase gender equity at the individual level and at the level of the social environment, particularly among school peers, have the potential for protective effects on the health of AGYW

Basic Subsistence Needs and Overall Health Among Human Immunodeficiency Virus-infected Homeless and Unstably Housed Women

Some gender differences in the progression of human immunodeficiency virus (HIV) infection have been attributed to delayed treatment among women and the social context of poverty. Recent economic difficulties have led to multiple service cuts, highlighting the need to identify factors with the most influence on health in order to prioritize scarce resources. The aim of this study was to empirically rank factors that longitudinally impact the health status of HIV-infected homeless and unstably housed women. Study participants were recruited between 2002 and 2008 from community-based venues in San Francisco, California, and followed over time; marginal structural models and targeted variable importance were used to rank factors by their influence. In adjusted analysis, the factor with the strongest effect on overall mental health was unmet subsistence needs (i.e., food, hygiene, and shelter needs), followed by poor adherence to antiretroviral therapy, not having a close friend, and the use of crack cocaine. Factors with the strongest effects on physical health and gynecologic symptoms followed similar patterns. Within this population, an inability to meet basic subsistence needs has at least as much of an effect on overall health as adherence to antiretroviral therapy, suggesting that advances in HIV medicine will not fully benefit indigent women until their subsistence needs are met

CD4+ T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa

Background: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally. Methods: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitor-based regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/µl in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years. Results: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150/µl was 529/µl [95% confidence interval (CI): 517-541] in North America, 494/µl (95% CI: 429-559) in West Africa, 515/µl (95% CI: 508-522) in Southern Africa, 503/µl (95% CI: 478-528) in Asia and 437/µl (95% CI: 425-449) in East Africa. Conclusions: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional leve

Effectiveness of an HIV Prevention Program for Women Visiting Their Incarcerated Partners: The HOME Project

Having an incarcerated partner presents a unique HIV risk for women, particularly low-income women of color. We developed a population-specific risk reduction intervention for women visiting men in prison that was peer educator-based and included individual and community-level intervention components. Women who were assessed prior to the intervention period had a positive association between the number of unprotected penetrative intercourse (UPI) episodes prior to their partners’ incarceration and the number of UPI episodes following partners’ release from prison. However, this association was negated among women assessed during the intervention. Intervention participants also were more likely to be tested for HIV, to have partners who got tested, and to talk with their partners about significantly more HIV-related topics. Conducting intervention and evaluation activities with women visiting incarcerated men is feasible and is a useful model for reaching more at-risk women

The Safety Attitudes Questionnaire: psychometric properties, benchmarking data, and emerging research

BACKGROUND: There is widespread interest in measuring healthcare provider attitudes about issues relevant to patient safety (often called safety climate or safety culture). Here we report the psychometric properties, establish benchmarking data, and discuss emerging areas of research with the University of Texas Safety Attitudes Questionnaire. METHODS: Six cross-sectional surveys of health care providers (n = 10,843) in 203 clinical areas (including critical care units, operating rooms, inpatient settings, and ambulatory clinics) in three countries (USA, UK, New Zealand). Multilevel factor analyses yielded results at the clinical area level and the respondent nested within clinical area level. We report scale reliability, floor/ceiling effects, item factor loadings, inter-factor correlations, and percentage of respondents who agree with each item and scale. RESULTS: A six factor model of provider attitudes fit to the data at both the clinical area and respondent nested within clinical area levels. The factors were: Teamwork Climate, Safety Climate, Perceptions of Management, Job Satisfaction, Working Conditions, and Stress Recognition. Scale reliability was 0.9. Provider attitudes varied greatly both within and among organizations. Results are presented to allow benchmarking among organizations and emerging research is discussed. CONCLUSION: The Safety Attitudes Questionnaire demonstrated good psychometric properties. Healthcare organizations can use the survey to measure caregiver attitudes about six patient safety-related domains, to compare themselves with other organizations, to prompt interventions to improve safety attitudes and to measure the effectiveness of these interventions

Mechanistic Insights into a Novel Exporter-Importer System of Mycobacterium tuberculosis Unravel Its Role in Trafficking of Iron

Elucidation of the basic mechanistic and biochemical principles underlying siderophore mediated iron uptake in mycobacteria is crucial for targeting this principal survival strategy vis-à-vis virulence determinants of the pathogen. Although, an understanding of siderophore biosynthesis is known, the mechanism of their secretion and uptake still remains elusive.Here, we demonstrate an interplay among three iron regulated Mycobacterium tuberculosis (M.tb) proteins, namely, Rv1348 (IrtA), Rv1349 (IrtB) and Rv2895c in export and import of M.tb siderophores across the membrane and the consequent iron uptake. IrtA, interestingly, has a fused N-terminal substrate binding domain (SBD), representing an atypical subset of ABC transporters, unlike IrtB that harbors only the permease and ATPase domain. SBD selectively binds to non-ferrated siderophores whereas Rv2895c exhibits relatively higher affinity towards ferrated siderophores. An interaction between the permease domain of IrtB and Rv2895c is evident from GST pull-down assay. In vitro liposome reconstitution experiments further demonstrate that IrtA is indeed a siderophore exporter and the two-component IrtB-Rv2895c system is an importer of ferrated siderophores. Knockout of msmeg_6554, the irtA homologue in Mycobacterium smegmatis, resulted in an impaired M.tb siderophore export that is restored upon complementation with M.tb irtA.Our data suggest the interplay of three proteins, namely IrtA, IrtB and Rv2895c in synergizing the balance of siderophores and thus iron inside the mycobacterial cell