Advancing agendas: a grounded theory of engagement with interagency meetings

In the UK, the development of integrated children's services over the past six years has led to an increased need for public sector managers to attend strategic, interagency meetings. However, there is little research in this field that can be used to support managers in ensuring positive outcomes from such meetings. The aim of this research was to identify the main concerns of managers attending strategic, interagency meetings and to develop a theoretical framework that can account for the ways in which they resolve these concerns. The research used classic grounded theory, an inductive methodology that results in a set of integrated, conceptual hypotheses that are grounded in the data. Data were obtained primarily from interviews and observation of meetings. The main concern of managers attending interagency meetings was identified as being to achieve the maximum personal value from engagement with the meetings. This main concern is resolved via the core category of 'advancing agendas', which accounts for most of the variation in the behaviour of the participants. The grounded theory of Advancing Agendas explains the social strategic process by which meeting participants: identify a personal agenda, that is, an understanding of what they want to get out of their engagement with the meetings; plan a strategy with which to advance this agenda; engage in the meetings and evaluate the outcomes of their actions. Advancing Agendas provides a framework that can be used by those who are chairing or attending interagency meetings, to support them in achieving the desired outcomes. Specifically, it can be used to understand the impact of meeting participants' differing motivations for attending meetings, to recognise situations in which group members' personal agendas conflict with the intended function of the meetings, and to identify ways of enabling full participation and engagement

Dedicator of cytokinesis 4 : a potential prognostic and predictive biomarker within the metastatic spread of breast cancer to bone

Metastasis to bone occurs in over 70% of patients with advanced breast cancer resulting in skeletal complications, including pathological fractures, hypercalcaemia, and bone pain. Significant advances have been made in the treatment of bone metastases, including the use of antiresorptive drugs, such as bisphosphonates, as well as antibody-based therapies targeting key signalling intermediates within the process of cancer-mediated bone destruction. Despite these advances, treatment is not without side effects, including osteonecrosis of the jaw therefore biomarkers predictive of which patients are at high risk of developing bone spread are required to enable personalized medicine initiatives within this important disease area. We used proteomic analysis to compare the protein expression within (1) a parental triple negative human breast cancer cell line, (2) a fully bone homing cell line and (3) a lung homing cell line. The bone and lung homing cell-lines were derived by intra-cardiac injection of fluorescently labelled cells within immune-compromised mice. Proteomics identified Dedicator of Cytokinesis 4 as a biomarker predictive of bone spread, and this finding was further supported by the observation that high levels of Dedicator of Cytokinesis 4 within primary breast tumours were predictive of breast cancer spread to bone. Here, we provide an overview of this study and put the findings into context

Calculations of parity nonconserving s-d transitions in Cs, Fr, Ba II, and Ra II

We have performed ab initio mixed-states and sum-over-states calculations of parity nonconserving (PNC) electric dipole (E1) transition amplitudes between s-d electron states of Cs, Fr, Ba II, and Ra II. For the lower states of these atoms we have also calculated energies, E1 transition amplitudes, and lifetimes. We have shown that PNC E1 transition amplitudes between s-d states can be calculated to high accuracy. Contrary to the Cs 6s-7s transition, in these transitions there are no strong cancelations between different terms in the sum-over-states approach. In fact, there is one dominating term which deviates from the sum by less than 20%. This term corresponds to an s-p_{1/2} weak matrix element, which can be calculated to better than 1%, and a p_{1/2}-d_{3/2} E1 transition amplitude, which can be measured. Also, the s-d amplitudes are about four times larger than the corresponding s-s transitions. We have shown that by using a hybrid mixed-states/sum-over-states approach the accuracy of the calculations of PNC s-d amplitudes could compete with that of Cs 6s-7s if p_{1/2}-d_{3/2} E1 amplitudes are measured to high accuracy.Comment: 15 pages, 8 figures, submitted to Phys. Rev.

The Pt isotopes: comparing the Interacting Boson Model with Configuration Mixing and the Extended Consistent-Q formalism

The role of intruder configurations in the description of energy spectra and B(E2) values in the Pt region is analyzed. In particular, we study the differences between Interacting Boson Model calculations with or without the inclusion of intruder states in the even Pt nuclei $^{172-194}$Pt. As a result, it shows that for the description of a subset of the existing experimental data, i.e., energy spectra and absolute B(E2) values up to an excitation energy of about 1.5 MeV, both approaches seem to be equally valid. We explain these similarities between both model spaces through an appropriate mapping. We point out the need for a more extensive comparison, encompassing a data set as broad (and complete) as possible to confront with both theoretical approaches in order to test the detailed structure of the nuclear wave functions.Comment: To be published in NP

Genetic determinants of cellular addiction to DNA polymerase theta

Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy

The Approach to Ergodicity in Monte Carlo Simulations

The approach to the ergodic limit in Monte Carlo simulations is studied using both analytic and numerical methods. With the help of a stochastic model, a metric is defined that enables the examination of a simulation in both the ergodic and non-ergodic regimes. In the non-ergodic regime, the model implies how the simulation is expected to approach ergodic behavior analytically, and the analytically inferred decay law of the metric allows the monitoring of the onset of ergodic behavior. The metric is related to previously defined measures developed for molecular dynamics simulations, and the metric enables the comparison of the relative efficiencies of different Monte Carlo schemes. Applications to Lennard-Jones 13-particle clusters are shown to match the model for Metropolis, J-walking and parallel tempering based approaches. The relative efficiencies of these three Monte Carlo approaches are compared, and the decay law is shown to be useful in determining needed high temperature parameters in parallel tempering and J-walking studies of atomic clusters.Comment: 17 Pages, 7 Figure

Comparative safety and health care expenditures among patients with chronic myeloid leukemia initiating first-line imatinib, dasatinib, or nilotinib

PURPOSE Tyrosine kinase inhibitors (TKIs) have dramatically improved survival for patients with chronic myeloid leukemia (CML). No overall survival differences were observed between patients initiating first- and second-generation TKIs in trials; however, real-world safety and cost outcomes are unclear. We evaluated comparative safety and health care expenditures between first-line imatinib, dasatinib, and nilotinib among patients with CML. PATIENTS AND METHODS Eligible patients had one or more fills for imatinib, dasatinib, or nilotinib in the MarketScan Commercial and Medicare Supplemental databases between January 1, 2011, and December 31, 2016 (earliest fill is the index date), 6 months pre-index continuous enrollment, CML diagnosis, and no TKI use in the pre-index period. Hospitalizations or emergency department visits (safety events) were compared across treatment groups using propensity-score-weighted 1-year relative risks (RRs) and subdistribution hazard ratios (HRs). Inflation-adjusted annual health care expenditures were compared using quantile regression. RESULTS Eligible patients included 1,417 receiving imatinib, 1,067 receiving dasatinib, and 647 receiving nilotinib. The 1-year risk of safety events was high: imatinib, 37%; dasatinib, 44%; and nilotinib, 40%, with higher risks among patients receiving dasatinib (RR, 1.17; 95% CI, 1.06 to 1.30) and nilotinib (RR, 1.07; 95% CI, 0.93 to 1.23) compared with those receiving imatinib. Over a median of 1.7 years, the cumulative incidence of safety events was higher among patients receiving dasatinib (HR, 1.23; 95% CI, 1.10 to 1.38) and nilotinib (HR, 1.08; 95% CI, 0.95 to 1.24) than among those receiving imatinib. One-year health care expenditures were high (median, $125,987) and were significantly higher among patients initiating second-generation TKIs compared with those receiving imatinib (difference in medians: dasatinib v imatinib,$22,393; 95% CI, $17,068 to$27,718; nilotinib v imatinib, $19,463; 95$14,689 to $24,236). CONCLUSION Patients receiving imatinib had the lowest risk of hospitalization or emergency department visits and 1-year health care expenditures. Given a lack of significant differences in overall survival, imatinib may represent the ideal first-line therapy for patients, on average

Birth outcomes among adolescent and young adult cancer survivors

IMPORTANCE: Cancer diagnosis and treatment may adversely affect reproductive outcomes among female cancer survivors. OBJECTIVE: To compare the birth outcomes of adolescent and young adult cancer survivors (AYA [diagnosed at ages 15-39 years]) with those of women without a cancer diagnosis. DESIGN, SETTING, AND PARTICIPANTS: The North Carolina Central Cancer Registry (CCR) was used to identify female AYA cancer survivors diagnosed from January 2000 to December 2013; CCR records were linked to statewide birth certificate files from January 2000 to December 2014 to identify postdiagnosis live births to AYA survivors (n = 2598). A comparison cohort of births to women without a recorded cancer diagnosis was randomly selected from birth certificate files (n = 12 990) with frequency matching on maternal age and year of delivery. MAIN OUTCOMES AND MEASURES: Prevalence of preterm birth, low birth weight, small-for-gestational-age births, cesarean delivery, and low Apgar score. RESULTS: Overall, 2598 births to AYA cancer survivors (mean [SD] maternal age, 31 [5] years) were included. Births to AYA cancer survivors had a significantly increased prevalence of preterm birth (prevalence ratio [PR], 1.52; 95% CI, 1.34-1.71), low birth weight (PR, 1.59; 95% CI, 1.38-1.83), and cesarean delivery (PR, 1.08; 95% CI, 1.01-1.14) relative to the comparison cohort of 1299. The higher prevalence of these outcomes was most concentrated among births to women diagnosed during pregnancy. Other factors associated with preterm birth and low birth weight included treatment with chemotherapy and a diagnosis of breast cancer, non-Hodgkin lymphoma, or gynecologic cancers. The prevalence of small-for-gestational-age births and low Apgar score (<7) did not differ significantly between groups. CONCLUSIONS AND RELEVANCE: Live births to AYA cancer survivors may have an increased risk of preterm birth and low birth weight, suggesting that additional surveillance of pregnancies in this population is warranted. Our findings may inform the reproductive counseling of female AYA cancer survivors

Inhibition of somatosensory mechanotransduction by annexin A6

Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron-derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6-deficient mice showed increased sensitivity to mechanical stimuli. Sensory neurons from these mice showed increased activity of the cation channel Piezo2, which mediates a rapidly adapting mechano-gated current linked to proprioception and touch, and a decrease in mechanically activated, slowly adapting currents. Conversely, overexpression of annexin A6 in sensory neurons inhibited rapidly adapting currents that were partially mediated by Piezo2. Furthermore, overexpression of annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis, a disease in which mechanically evoked pain is particularly problematic. These data suggest that annexin A6 can be exploited to inhibit chronic mechanical pain

Neoadjuvant pazopanib and molecular analysis of tissue response in renal cell carcinoma

BACKGROUND. Surgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%–40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib. METHODS. ccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment. RESULTS. Twenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations. CONCLUSION. Neoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response. FUNDING. Support was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study