Britain’s slow movement to a gender egalitarian equilibrium: parents and employment in the UK 2001–13

This article examines the working lives of British couple families across the first decade of the millennium using EU Labour Force Survey data (2001–13) taking a multiple equilibria approach. Some growth in dual full-time earners, increased working hours of mothers in part-time employment and a growing proportion of households with ‘non-standard’ working patterns are all identified, suggesting both a convergence and greater diversity in economic provisioning within parent couple households. Household employment patterns remain strongly associated with maternal education and family size but are becoming less sensitive to the age of the youngest child. The dual full-time earner model is growing in significance for British parents of young children but a new gender egalitarian equilibrium has not yet been reached

Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor

Purpose: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Methods: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. Results: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in Cmaxand AUC of panobinostat, respectively. No substantial change in Tmaxor half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Conclusions: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary

Attributable Outcomes of Endemic Clostridium difficile–associated Disease in Nonsurgical Patients

CDAD led to significantly worse outcomes in these patients

Ocean time series observations of changing marine ecosystems: An era of integration, synthesis, and societal applications

Sustained ocean time series are critical for characterizing marine ecosystem shifts in a time of accelerating, and at times unpredictable, changes. They represent the only means to distinguish between natural and anthropogenic forcings, and are the best tools to explore causal links and implications for human communities that depend on ocean resources. Since the inception of sustained ocean observations, ocean time series have withstood many challenges, most prominently availability of uninterrupted funding and retention of trained personnel. This OceanObs’19 review article provides an overarching vision for sustained ocean time series observations for the next decade, focusing on the growing challenges of maintaining sustained ocean time series, including ship-based and autonomous coastal and open-ocean platforms, as well as remote sensing. In addition to increased diversification of funding sources to include the private sector, NGOs, and other groups, more effective engagement of stakeholders and other end-users will be critical to ensure the sustainability of ocean time series programs. Building a cohesive international time series network will require dedicated capacity to coordinate across observing programs and leverage existing infrastructure and platforms of opportunity. This review article outlines near-term observing priorities and technology needs; explores potential mechanisms to broaden ocean time series data applications and end-user communities; and describes current tools and future requirements for managing increasingly complex multi-platform data streams and developing synthesis products that support science and society. The actionable recommendations outlined herein ultimately form the basis for a robust, sustainable, fit-for-purpose time series network that will foster a predictive understanding of changing ocean systems for the benefit of society

Current practice and surgical outcomes of neoadjuvant chemotherapy for early breast cancer : UK NeST study

Funding Information: This work was funded by a grant from the Association of Breast SurgeryPeer reviewedPublisher PD

Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk

Swift and XMM-Newton Observations of the Extraordinary GRB 060729: An afterglow with a more than 100 days X-ray light curve

We report the results of the Swift and XMM observations of the Swift-discovered long Gamma-Ray Burst GRB 060729 ($T_{90}$=115s). The afterglow of this burst was exceptionally bright in X-rays as well as at UV/Optical wavelengths showing an unusually long slow decay phase ($\alpha$=0.14\plm0.02) suggesting a larger energy injection phase at early times than in other bursts. The X-ray light curve displays a break at about 60 ks after the burst. The X-ray decay slope after the break is $\alpha$=1.29\plm0.03. Up to 125 days after the burst we do not detect a jet break, suggesting that the jet opening angle is larger than 28 degrees. In the first 2 minutes after the burst (rest frame) the X-ray spectrum of the burst changed dramatically from a hard X-ray spectrum to a very soft one. We find that the X-ray spectra at this early phase can all be fitted by an absorbed single power law model or alternatively by a blackbody plus power law model. The power law fits show that the X-ray spectrum becomes steeper while the absorption column density decreases. In Swift's UV/Optical telescope the afterglow was clearly detected up to 9 days after the burst in all 6 filters and even longer in some of the UV filters with the latest detection in the UVW1 31 days after the burst. A break at about 50 ks is clearly detected in all 6 UVOT filters from a shallow decay slope of about 0.3 and a steeper decay slope of 1.3. In addition to the \swift observations we also present and discuss the results from a 61 ks ToO observation by XMM. (Abriviated)Comment: Accepted to be published in the Astrophysical Journal, 28 pages, 10 figure

Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies

The Public Playground Paradox: "Child’s Joy" or Heterotopia of Fear?

Literature depicts children of the Global North withdrawing from public space to“acceptable islands”. Driven by fears both of and for children, the publicplayground – one such island – provides clear-cut distinctions between childhoodand adulthood. Extending this argument, this paper takes the original approach oftheoretically framing the playground as a heterotopia of deviance, examining –for the first time – three Greek public playground sites in relation to adjacentpublic space. Drawing on an ethnographic study in Athens, findings show fear tounderpin surveillance, control and playground boundary porosity. Normativeclassification as “children’s space” discourages adult engagement. However, in anovel and significant finding, a paradoxical phenomenon sees the playground’spresence simultaneously legitimizing playful behaviour in adjacent public spacefor children and adults. Extended playground play creates alternate orderings andnegotiates norms and hierarchies, suggesting significant wider potential toreconceptualise playground-urban design for an intergenerational public realm

Educational outreach in an integrated clinical management tool for nurse-led non-communicable chronic disease management in primary care in South Africa: pragmatic cluster randomised controlled trial

Background: In many low-income countries, care for patients with non-communicable diseases (NCDs) and mental health conditions is provided by nurses. The benefits of nurse substitution and supplementation in NCD care in high income settings are well recognised, but evidence from low- and middle-income countries is limited. Primary Care 101 (PC101) is a programme designed to support and expand nurses’ role in NCD care, comprising a clinical management tool with enhanced prescribing provisions for nurses, and educational outreach. We evaluated the effectiveness of the programme on primary care nurses’ capacity to manage NCDs (ISRCTN20283604). Methods and findings: In a cluster randomised controlled trial design, 38 public sector primary care clinics in the Western Cape province, South Africa, were randomised. Nurses in the intervention clinics were trained to use the PC101 management tool during educational outreach sessions delivered by health department trainers and authorised to prescribe an expanded range of drugs for several NCDs. Control clinics continued use of the Practical Approach to Lung Health and HIV /AIDS in South Africa (PALSA PLUS) management tool and usual training. Patients attending these clinics with one or more of hypertension (3227), diabetes (1842), chronic respiratory disease (1157) or screened positive for depression (2466), totalling 4393 patients, were enrolled between March 2011 and October 2011. Primary outcomes were treatment intensification for hypertension, diabetes, and chronic respiratory disease cohorts, defined as the proportion of patients in whom treatment was escalated during follow-up over 14 months, and case detection in the depression cohort. Primary outcome data were analysed for 2110 (97%) intervention and 2170 (97%) control group patients. Treatment intensification rates in intervention clinics were not superior to those in the control group clinics [hypertension: 44% in the intervention group versus 40% in the controls, risk ratio (RR) 1.08 (95% CI: 0.94 to 1.24; p=0.252); diabetes: 57% v 50%, RR 1.10 (0.97 to 1.24;p=0.126); chronic respiratory disease: 14% v 12%, RR 1.08 (0.75 to 1.55; p=0.674); and case detection of depression: 18% v 24%, RR 0.76 (0.53 to 1.10; p=0.142)]. No adverse effects of the nurses’ expanded scope of practice were observed. Limitations of the study include dependence on self-reported diagnoses for inclusion in the patient cohorts, limited data on uptake of PC101 by users, reliance on process outcomes, and insufficient resources to measure important health outcomes, such as HbA1c, at follow-up. Conclusions: Educational outreach to primary care nurses through use of a management tool involving an expanded role in managing NCDs, is feasible and safe but was not associated with treatment intensification or case detection for index diseases. This notwithstanding, the intervention, with adjustments to improve its effectiveness, has been adopted for implementation in primary care clinics throughout South Africa