Shear stress fluctuations in the granular liquid and solid phases

We report on experimentally observed shear stress fluctuations in both granular solid and fluid states, showing that they are non-Gaussian at low shear rates, reflecting the predominance of correlated structures (force chains) in the solidlike phase, which also exhibit finite rigidity to shear. Peaks in the rigidity and the stress distribution's skewness indicate that a change to the force-bearing mechanism occurs at the transition to fluid behaviour, which, it is shown, can be predicted from the behaviour of the stress at lower shear rates. In the fluid state stress is Gaussian distributed, suggesting that the central limit theorem holds. The fibre bundle model with random load sharing effectively reproduces the stress distribution at the yield point and also exhibits the exponential stress distribution anticipated from extant work on stress propagation in granular materials.Comment: 11 pages, 3 figures, latex. Replacement adds journal reference and addresses referee comment

Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer

Objective The therapeutic benefits of poly(ADP-ribose) polymerase inhibitors highlight the need to evaluate BRCA1/2 defects in tubal/ovarian cancer (OC). We sought to determine the pattern and disease characteristics associated with tumor BRCA1/2 mutations and BRCA1 methylation in women with OC. Methods We obtained 111 OC specimens from 2 university hospitals and assessed BRCA1/2 mutations and BRCA1 methylation in tumor DNA. The frequency and pattern of BRCA1/2 defects were examined. Associations between patient/disease characteristics and BRCA1/2 defects were ascertained (Fisher’s exact test). Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) based on the underlying BRCA1/2 defect were determined (Kaplan-Meier analysis [log-rank test]). Results We observed a BRCA1/2 dysfunction rate of 40% (28/70) in high-grade serous tubal/ovarian cancer (HGSC), including 14.3% BRCA1 methylation (n=10), 7.1% BRCA1 mutation (n=5), and 18.6% BRCA2 mutation (n=13). Defects in BRCA1/2 genes were associated with stage III/IV HGSC (BRCA1 methylation: P=0.005 [stage III/IV] and P=0.004 [HGSC]; BRCA1/2 mutation: P=0.03 [stage III/IV] and P<0.001 [HGSC]). Patients with BRCA1/2-mutated cancers showed improved OS (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43–0.99; P=0.045) and a trend toward improved PFI (HR, 0.48; 95% CI, 0.22–1.06; P=0.07) and PFS (HR, 0.72; 95% CI, 0.51–1.03; P=0.07). No survival differences were observed between BRCA1-methylated and BRCA1/2 wild-type non-BRCA1-methylated cancers. Conclusion We observed a high tumor BRCA1/2 dysfunction rate in HGSC with a unique predominance of BRCA2 over BRCA1 mutations. While BRCA1/2 mutations conferred survival benefits in OC, no such association was observed with BRCA1 methylation

ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy

BACKGROUND: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. PRIMARY OBJECTIVE: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. STUDY HYPOTHESIS: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. TRIAL DESIGN: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). MAJOR INCLUSION CRITERIA: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. PRIMARY ENDPOINTS: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type. SAMPLE SIZE: 618 patients will be recruited. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03278717

Solvable three-state model of a driven double-well potential and coherent destruction of tunneling

A simple model for a particle in a double well is derived from discretizing its configuration space. The model contains as many free parameters as the original system and it respects all the existing symmetries. In the presence of an external periodic force both the continuous system and the discrete model are shown to possess a generalized time-reversal symmetry in addition to the known generalized parity. The impact of the driving force on the spectrum of the Floquet operator is studied. In particular, the occurrence of degenerate quasienergies causing coherent destruction of tunneling is discussed—to a large extent analytically—for arbitrary driving frequencies and barrier heights

The relation between media promotions and service volume for a statewide tobacco quitline and a web-based cessation program

<p>Abstract</p> <p>Background</p> <p>This observational study assessed the relation between mass media campaigns and service volume for a statewide tobacco cessation quitline and stand-alone web-based cessation program.</p> <p>Methods</p> <p>Multivariate regression analysis was used to identify how weekly calls to a cessation quitline and weekly registrations to a web-based cessation program are related to levels of broadcast media, media campaigns, and media types, controlling for the impact of external and earned media events.</p> <p>Results</p> <p>There was a positive relation between weekly broadcast targeted rating points and the number of weekly calls to a cessation quitline and the number of weekly registrations to a web-based cessation program. Additionally, print secondhand smoke ads and online cessation ads were positively related to weekly quitline calls. Television and radio cessation ads and radio smoke-free law ads were positively related to web program registration levels. There was a positive relation between the number of web registrations and the number of calls to the cessation quitline, with increases in registrations to the web in 1 week corresponding to increases in calls to the quitline in the subsequent week. Web program registration levels were more highly influenced by earned media and other external events than were quitline call volumes.</p> <p>Conclusion</p> <p>Overall, broadcast advertising had a greater impact on registrations for the web program than calls to the quitline. Furthermore, registrations for the web program influenced calls to the quitline. These two findings suggest the evolving roles of web-based cessation programs and Internet-use practices should be considered when creating cessation programs and media campaigns to promote them. Additionally, because different types of media and campaigns were positively associated with calls to the quitline and web registrations, developing mass media campaigns that offer a variety of messages and communicate through different types of media to motivate tobacco users to seek services appears important to reach tobacco users. Further research is needed to better understand the complexities and opportunities involved in simultaneous promotion of quitline and web-based cessation services.</p

Lifespan extension and the doctrine of double effect

Recent developments in biogerontology—the study of the biology of ageing—suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan—a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the ‘double effect argument’, has gone unnoticed. This article exposes and critically evaluates this ‘double effect argument’. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the ‘double effect argument’ is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning

Core-coupled states and split proton-neutron quasi-particle multiplets in 122-126Ag

Neutron-rich silver isotopes were populated in the fragmentation of a 136Xe beam and the relativistic fission of 238U. The fragments were mass analyzed with the GSI Fragment separator and subsequently implanted into a passive stopper. Isomeric transitions were detected by 105 HPGe detectors. Eight isomeric states were observed in 122-126Ag nuclei. The level schemes of 122,123,125Ag were revised and extended with isomeric transitions being observed for the first time. The excited states in the odd-mass silver isotopes are interpreted as core-coupled states. The isomeric states in the even-mass silver isotopes are discussed in the framework of the proton-neutron split multiplets. The results of shell-model calculations, performed for the most neutron-rich silver nuclei are compared to the experimental data

The association between workplace smoking bans and self-perceived, work-related stress among smoking workers

<p>Abstract</p> <p>Background</p> <p>There is substantial empirical evidence on the benefits of smoking bans; however, the unintended consequences of this anti-smoking measure have received little attention. This paper examines whether workplace smoking bans (WSB's) are associated with higher self-perceived, work-related stress among smoking workers.</p> <p>Methods</p> <p>A longitudinal representative sample of 3,237 individuals from the Canadian National Population Health Survey from 2000 to 2008 is used. Work-related stress is derived from a 12-item job questionnaire. Two categories of WSB's, full and partial, are included in the analysis, with no ban being the reference category. Analysis also controls for individual socio-demographic characteristics, health status, provincial and occupational fixed-effects. We use fixed-effects linear regression to control for individual time-invariant confounders, both measured and unmeasured, which can affect the relationship between WSB's and work-related stress. To examine the heterogeneous effects of WSB's, the analysis is stratified by gender and age. We check the robustness of our results by re-estimating the baseline specification with the addition of different control variables and a separate analysis for non-smokers.</p> <p>Results</p> <p>Multivariate analysis reveals a positive and statistically significant association between full <it>(β = 0.75, CI = 0.19-1.32) </it>or partial <it>(β = 0.69, CI = 0.12-1.26) </it>WSB's, and the level of self-perceived, work-related stress among smoking workers compared to those with no WSB. We also find that this association varies by gender and age. In particular, WSB's are significantly associated with higher work stress only for males and young adults (aged 18-40). No statistically significant association is found between WSB's and the level of self-perceived work-related stress among non-smoking workers.</p> <p>Conclusion</p> <p>The results of this study do not imply that WSB's are the main determinant of self-perceived, work-related stress among smokers but provides suggestive evidence that these may be positively related.</p

Anticipated and experienced discrimination amongst people with schizophrenia, bipolar disorder and major depressive disorder: a cross-sectional study.

BACKGROUND: The unfair treatment of individuals with severe mental illness has been linked to poorer physical and mental health outcomes. Additionally, anticipation of discrimination may lead some individuals to avoid participation in particular life areas, leading to greater isolation and social marginalisation. This study aimed to establish the levels and clinical and socio-demographic associations of anticipated and experienced discrimination amongst those diagnosed with a schizophrenia and comparator severe mental illnesses (bipolar and major depressive disorders). METHODS: This study was a cross-sectional analysis of anticipated and experienced discrimination from 202 individuals in South London (47% with schizophrenia, 32% with depression and 20% with bipolar disorder). RESULTS: 93% of the sample anticipated discrimination and 87% of participants had experienced discrimination in at least one area of life in the previous year. There was a significant association between the anticipation and the experience of discrimination. Higher levels of experienced discrimination were reported by those of a mixed ethnicity, and those with higher levels of education. Women anticipated more discrimination than men. Neither diagnosis nor levels of functioning were associated with the extent of discrimination. Clinical symptoms of anxiety, depression and suspiciousness were associated with more experienced and anticipated discrimination respectively. CONCLUSIONS: The unfair treatment of individuals with severe mental illnesses remains unacceptably common. Population level interventions are needed to reduce levels of discrimination and to safeguard individuals. Interventions are also required to assist those with severe mental illness to reduce internalised stigma and social avoidance

Impact of the Spanish Smoking Law on Exposure to Second-Hand Smoke and Respiratory Health in Hospitality Workers: A Cohort Study

A smoke-free law came into effect in Spain on 1st January 2006, affecting all enclosed workplaces except hospitality venues, whose proprietors can choose among totally a smoke-free policy, a partial restriction with designated smoking areas, or no restriction on smoking on the premises. We aimed to evaluate the impact of the law among hospitality workers by assessing second-hand smoke (SHS) exposure and the frequency of respiratory symptoms before and one year after the ban