Mechanistic Investigations of the Asymmetric Hydrogenation of Enamides with Neutral Bis(phosphine) Cobalt Precatalysts

The mechanism of the asymmetric hydrogenation of prochiral enamides by well-defined, neutral bis(phosphine) cobalt(0) and cobalt(II) precatalysts has been explored using(R,R)-iPrDuPhos ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (R,R)-(iPrDuPhos)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl(Z)-α-acetamidocinnamate (MAC), and methyl(Z)-acetamido(4-fluorophenyl)acrylate (4FMAC)) complexes (1-MAA, 1-MAC, and 1-4FMAC), as well as a dinuclear cobalt tetrahydride, [(R,R)-(iPrDuPhos)Co]2(μ2-H)3(H) (2), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (R,R)-(iPrDuPhos)Co(enamide) complexes by X-ray diffraction established the formation of the pro-(R) diastereomers in contrast to the (S)-alkane products obtained from the catalytic reaction. In situ monitoring of the cobalt-catalyzed hydrogenation reactions by UV–visible and freeze-quench electron paramagnetic resonance spectroscopies revealed (R,R)-(iPrDuPhos)Co(enamide) complexes as the catalyst resting state for all the three enamides studied. Variable time normalization analysis kinetic studies of the cobalt-catalyzed hydrogenation reactions in methanol established a rate law that is first order in (R,R)-(iPrDuPhos)Co(enamide) and H2 but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H2/D2 kinetic isotope effect and catalytic hydrogenations with HD, established an irreversible H2 addition step to the bound enamide. Density functional theory calculations support that this step is both rate and selectivity determining. Calculations, as well as HD-labeling studies, provide evidence for two-electron redox cycling involving cobalt(0) and cobalt(II) intermediates during the catalytic cycle. Taken together, these experiments support an unsaturated pathway for the [(R,R)-(iPrDuPhos)Co]-catalyzed hydrogenation of prochiral enamides

A Replication of Failure, Not a Failure to Replicate

Purpose: The increasing role of systematic reviews in knowledge production demands greater rigor in the literature search process. The performance of the Social Work Abstracts (SWA) database has been examined multiple times over the past three decades. The current study is a replication within this line of research. Method: Issue level coverage was examined for the same 33 SWA core journals and the same time period as our 2009 study. Results: The mean percentage of issues missing in the current study was 20%. The mean percentage of issues missing in the current study was significantly greater than the mean percentage of issues missing in the 2009 study. Discussion: The research of other groups, and that of our own, has failed to prompt NASW Press to act. SWA was failing, it is failing and NASW Press has failed to correct those failures

Deconstructing the lesbian, gay, bisexual, transgender victim of sex trafficking: Harm, exceptionality and religion–sexuality tensions

Contrary to widespread belief, sex trafficking also targets lesbian, gay, bisexual, transgender (LGBT) communities. Contemporary social and political constructions of victimhood lie at the heart of regulatory policies on sex trafficking. Led by the US Department of State, knowledge about LGBT victims of trafficking constitutes the newest frontier in the expansion of criminalization measures. These measures represent a crucial shift. From a burgeoning range of preemptive measures enacted to protect an amorphous class of ‘all potential victims’, now policies are heavily premised on the risk posed by traffickers to ‘victims of special interest’. These constructed identities, however, are at odds with established structures. Drawing on a range of literatures, the core task of this article is to confront some of the complexities and tensions surrounding constructions of LGBT trafficking victims. Specifically, the article argues that discourses of ‘exceptional vulnerability’ and the polarized notions of ‘innocence’ and ‘guilt’ inform hierarchies of victimhood. Based on these insights, the article argues for the need to move beyond monolithic understandings of victims, by reframing the politics of harm accordingly

Acceptability, feasibility and cost of point of care testing for sexually transmitted infections among South African adolescents where syndromic management is standard of care

BACKGROUND: Young people (YP) in southern Africa are at substantial risk of HIV and sexually transmitted infections (STIs). Despite the epidemiological and biological link between STIs and HIV transmission and acquisition, infections such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) remain widely undiagnosed. Syndromic STI management is the standard of care in low- and middle-income countries (LMICs) despite a high prevalence of asymptomatic infections. We conducted an observational study to explore the acceptability, feasibility, and cost of a STI test-and-treat service for YP in Cape Town. METHODS: YP attending a mobile clinic (MC) and a youth centre clinic (YC) were offered STI screening. Urine testing for CT and NG using a 90-min molecular point-of-care (POC) test on the GeneXpert platform was conducted and treatment provided. Data were collated on demographics, sexual behaviour, presence of symptoms, uptake of same-day treatment, prevalence of CT/NG, and service acceptability. RESULTS: Three hundred sixty six participants were enrolled (median age 20, 83% female).57% (209/366) of participants tested positive for either CT (126/366, 34%) or NG (57/366, 16%) or co-infection (26/366, 7%). Clinical symptoms were a poor predictor of GeneXpert diagnosed CT or NG, with a sensitivity of 46.8% and 54.0% for CT and NG respectively. Although half of participants initially chose to receive same day results and treatment, only a third waited for results on the day. The majority of participants (91%) rated the service highly via a post-visit acceptability questionnaire. CONCLUSION: Curable STIs are highly prevalent in this population. STI screening using POC testing was feasible and acceptability was high. The study provides further impetus for moving policy beyond syndromic management of STIs in South Africa

The effects of weather and climate change on dengue

There is much uncertainty about the future impact of climate change on vector-borne diseases. Such uncertainty reflects the difficulties in modelling the complex interactions between disease, climatic and socioeconomic determinants. We used a comprehensive panel dataset from Mexico covering 23 years of province-specific dengue reports across nine climatic regions to estimate the impact of weather on dengue, accounting for the effects of non-climatic factors

Toward stronger theory in critical public health: Insights from debates surrounding posthumanism

The “posthumanist turn” in critical theory comprises efforts to recognize and analyze the interdependence of human existence with non-human entities, including other animals, spaces, and technologies. Scholarship aligned to and debating posthumanism pertains to public health, but has yet to be clearly articulated for a public health audience. This commentary and an appended glossary illustrate the relevance of these ideas for enhancing critical theory in public health. Keywords: Social Sciences, Humanities, Technology, Animals, Public HealthCanadian Institutes of Health Researc

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients

EGFR Inhibitor Enhances Cisplatin Sensitivity of Oral Squamous Cell Carcinoma Cell Lines

Epidermal growth factor receptor (EGFR) is involved in multiple aspects of cancer cell biology. EGFR has already been identified as an important target for cancer therapy, with various kinds of EGFR inhibitors currently used in treatment of several human cancers. Recently, EGFR and its downstream signaling pathways were identified as being associated with cisplatin sensitivity. In addition, EGFR inhibitors have shown significant promise for patients who failed cisplatin-based therapy. In this study, we investigated whether treatment with an EGFR inhibitor improves cisplatin sensitivity in oral squamous cell carcinoma (OSCC) cell lines. The effects of a combination of AG1478, a specific EGFR tyrosine kinase inhibitor, with cisplatin were evaluated in cultured OSCC cell lines and cisplatin-resistant sublines. Higher expression of EGFR and p-EGFR was found in the two cisplatin-resistant cell lines compared with the corresponding parental cell lines. In addition, augmented inhibition of OSCC cell growth by the combination of AG1478 with cisplatin was found in both cell lines. These results suggest that the combination of an EGFR inhibitor and cisplatin may be useful as a rational strategy for the treatment of patients with oral cancer with acquired cisplatin resistance