Geographic variation and evolutionary history of Dipodomys nitratoides (Rodentia: Heteromyidae), a species in severe decline

We examined geographic patterns of diversification in the highly impacted San Joaquin kangaroo rat, Dipodomys nitratoides, throughout its range in the San Joaquin Valley and adjacent basins in central California. The currently recognized subspecies were distinct by the original set of mensural and color variables used in their formal diagnoses, although the Fresno kangaroo rat (D. n. exilis) is the most strongly differentiated with sharp steps in character clines relative to the adjacent Tipton (D. n. nitratoides) and short-nosed (D. n. brevinasus) races. The latter two grade more smoothly into one another but still exhibit independent, and different, character clines within themselves. At the molecular level, as delineated by mtDNA cytochrome b sequences, most population samples retain high levels of diversity despite significant retraction in the species range and severe fragmentation of local populations in recent decades due primarily to landscape conversion for agriculture and secondarily to increased urbanization. Haplotype apportionment bears no relationship to morphologically defined subspecies boundaries. Rather, a haplotype network is shallow, most haplotypes are single-step variants, and the time to coalescence is substantially more recent than the time of species split between D. nitratoides and its sister taxon, D. merriami. The biogeographic history of the species within the San Joaquin Valley appears tied to mid-late Pleistocene expansion following significant drying of the valley resulting from the rain shadow produced by uplift of the Central Coastal Ranges

Self-harm in primary school-aged children: Prospective cohort study

Introduction No prospective studies have examined the prevalence, antecedents or concurrent characteristics associated with self-harm in non-treatment-seeking primary school-aged children. Methods In this cohort study from Melbourne, Australia we assessed 1239 children annually from age 8–9 years (wave 1) to 11–12 years (wave 4) on a range of health, social, educational and family measures. Past-year self-harm was assessed at wave 4. We estimated the prevalence of self-harm and used multivariable logistic regression to examine associations with concurrent and antecedent factors. Results 28 participants (3% of the 1059 with self-harm data; 18 girls [3%], 10 boys [2%]) reported self-harm at age 11–12 years. Antecedent (waves 1–3) predictors of self-harm were: persistent symptoms of depression (sex-age-socioeconomic status adjusted odds ratio [aOR]: 7.8; 95% confidence intervals [CI] 2.6 to 24) or anxiety (aOR: 5.1; 95%CI 2.1 to 12), frequent bullying victimisation (aOR: 24.6; 95%CI 3.8 to 158), and recent alcohol consumption (aOR: 2.9; 95%CI 1.2 to 7.1). Concurrent (wave 4) associations with self-harm were: having few friends (aOR: 8.7; 95%CI 3.2 to 24), poor emotional control (aOR: 4.2; 95%CI 1.9 to 9.6), antisocial behaviour (theft—aOR: 3.1; 95%CI 1.2 to 7.9; carrying a weapon—aOR: 6.9; 95%CI 3.1 to 15), and being in mid-puberty (aOR: 6.5; 95%CI 1.5 to 28) or late/post-puberty (aOR: 14.4; 95%CI 2.9 to 70)

A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007)

Objective: Rectal microbicides are needed to reduce the risk of HIV acquisition associated with unprotected receptive anal intercourse. The MTN-007 study was designed to assess the safety (general and mucosal), adherence, and acceptability of a new reduced glycerin formulation of tenofovir 1% gel. Methods: Participants were randomized 1:1:1:1 to receive the reduced glycerin formulation of tenofovir 1% gel, a hydroxyethyl cellulose placebo gel, a 2% nonoxynol-9 gel, or no treatment. Each gel was administered as a single dose followed by 7 daily doses. Mucosal safety evaluation included histology, fecal calprotectin, epithelial sloughing, cytokine expression (mRNA and protein), microarrays, flow cytometry of mucosal T cell phenotype, and rectal microflora. Acceptability and adherence were determined by computer-administered questionnaires and interactive telephone response, respectively. Results: Sixty-five participants (45 men and 20 women) were recruited into the study. There were no significant differences between the numbers of ≥ Grade 2 adverse events across the arms of the study. Likelihood of future product use (acceptability) was 87% (reduced glycerin formulation of tenofovir 1% gel), 93% (hydroxyethyl cellulose placebo gel), and 63% (nonoxynol-9 gel). Fecal calprotectin, rectal microflora, and epithelial sloughing did not differ by treatment arms during the study. Suggestive evidence of differences was seen in histology, mucosal gene expression, protein expression, and T cell phenotype. These changes were mostly confined to comparisons between the nonoxynol-9 gel and other study arms. Conclusions: The reduced glycerin formulation of tenofovir 1% gel was safe and well tolerated rectally and should be advanced to Phase 2 development. Trial Registration: ClinicalTrials.gov NCT01232803

An assessment of intermediary roles in payments for ecosystem services schemes in the context of catchment management: An example from South West England

Payments for Ecosystems Services (PES) schemes are an underdeveloped component of the policy mix for catchment management in many countries. The importance of intermediaries to such schemes is acknowledged in the literature but few studies go beyond theory to evaluate practice. This paper analyses generic intermediary functions for PES. It then evaluates an innovative example from southwest England that provides illustrations, and some lessons regarding necessary capabilities and characteristics for intermediaries, and understanding of their form, functions and modalities. The ‘UpStream Thinking’ project was co-developed by a private water company and an environmental charity. The former translated effective demand from shareholders and water customers for improved raw water quality into finance, whilst the latter had capabilities for catchment-scale on-farm delivery and trusted acceptance as an intermediary. While any sector can potentially provide a PES intermediary, the value driven, not-for-profit and politically neutral voluntary sector proves to be a good fit. Such ‘boundary organisations’ are also well placed for horizontal coordination of catchment management authorities and actions

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

The devil is in the details: Genomics of transmissible cancers in Tasmanian devils

Cancer poses one of the greatest human health threats of our time. Fortunately, aside from a few rare cases of cancer transmission in immune-suppressed organ transplant recipients or a small number of transmission events from mother to fetus, cancers are not spread from human to human. However, transmissible cancers have been detected in vertebrate and invertebrate animals, sometimes with devastating effects. Four examples of transmissible cancers are now known: 1) canine transmissible venereal tumor (CTVT) in dogs, 2) a tumor in a laboratory population of Syrian hamsters that is no longer cultured, 3) infectious neoplasias in at least four species of bivalve mollusks, and 4) two independently derived transmissible cancers (devil facial tumor disease [DFTD]) in Tasmanian devils (Fig 1A and 1B). The etiologic agents of CTVT, the bivalve cancers, and DFTDare the transplants (allografts) of the neoplastic cells themselves, but the etiologic agent is unknown for the hamster tumor.The effects of these transmissible cancers on their respective host populations vary. CTVT is spread in dogs through sexual contact and is at least 11,000 years old, placing the timing of its origin close to that of the domestication of dogs. Although genomic analyses of the tumor suggest evasion of multiple components of the dog immune system, dogs most commonly survive and often show evidence of spontaneous tumor regression within a year of initial diagnosis. For the infectious bivalve neoplasias, which have existed for at least 40 years, population effects vary from enzootic infections with no noticeable effects on population sizes to evidence of a catastrophic population decline. In Tasmanian devils (Fig 1A), the first infectious tumor discovered (DFT1; Fig 1B) has spread across approximately 95% of the geographic range of Tasmanian devils since 1996 (Fig 1C). DFTD is almost always fatal (Fig 1B), with >90% declines in infected localities and an overall species-wide decline exceeding 80%. Transmission dynamics appear consistent with frequency dependence, with DFTD spread by biting during social interactions, resulting in predictions of extinction from standard epidemiological models. Despite these predictions, long-infected devil populations persist at reduced densities, suggesting that individual-level variability in fecundity and tumor growth rate in infected individuals are key for understanding epidemiological dynamics. Additionally, the origin of the second, independent lineage of DFTD (i.e., DFT2) within 20 years of the discovery of DFT1 suggests that transmissible cancers may be a recurring part of the Tasmanian devils' evolutionary history, without causing extinction

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

The politicisation of evaluation: constructing and contesting EU policy performance

Although systematic policy evaluation has been conducted for decades and has been growing strongly within the European Union (EU) institutions and in the member states, it remains largely underexplored in political science literatures. Extant work in political science and public policy typically focuses on elements such as agenda setting, policy shaping, decision making, or implementation rather than evaluation. Although individual pieces of research on evaluation in the EU have started to emerge, most often regarding policy “effectiveness” (one criterion among many in evaluation), a more structured approach is currently missing. This special issue aims to address this gap in political science by focusing on four key focal points: evaluation institutions (including rules and cultures), evaluation actors and interests (including competencies, power, roles and tasks), evaluation design (including research methods and theories, and their impact on policy design and legislation), and finally, evaluation purpose and use (including the relationships between discourse and scientific evidence, political attitudes and strategic use). The special issue considers how each of these elements contributes to an evolving governance system in the EU, where evaluation is playing an increasingly important role in decision making