Effect of Smoking on Circulating Angiogenic Factors in High Risk Pregnancies

Objective: Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia. Study Design: We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0-22.6 weeks']). Smoking status was determined by self-report. Results: sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4-337.3] vs 95.9 [48.5-180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1-486.0] vs 152.2 [73.6-253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6-6.5] vs 6.8 [5.5-8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8-5.6] vs 5.3 [4.3-6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups. Conclusions: In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort

A pilot of the feasibility and usefulness of an aged obese model for use in stroke research

Background: Animal models of stroke have been criticised as having poor predictive validity, lacking risk factors prevalent in an aging population. This pilot study examined the development of comorbidities in a combined aged and high-fat diet model, and then examined the feasibility of modelling stroke in such rats. Methods: Twelve-month old male Wistar-Han rats (n=15) were fed a 60% fat diet for 8 months during which monthly serial blood samples were taken to assess the development of metabolic syndrome and pro-inflammatory markers. Following this, to pilot the suitability of these rats for undergoing surgical models of stroke, they underwent 30min of middle cerebral artery occlusion (MCAO) alongside younger controls fed a standard diet (n=10). Survival, weight and functional outcome were monitored, and blood vessels and tissues collected for analysis. Results: A high fat diet in aged rats led to substantial obesity. These rats did not develop type 2 diabetes or hypertension. There was thickening of the thoracic arterial wall and vacuole formation in the liver; but of the cytokines examined changes were not seen. MCAO surgery and behavioural assessment was possible in this model (with some caveats discussed in manuscript). Conclusions: This study shows MCAO is possible in aged, obese rats. However, this model is not ideal for recapitulating the complex comorbidities commonly seen in stroke patients

The Ups and Downs in Women's Employment: Shifting Composition or Behavior from 1970 to 2010?

This paper tracks factors contributing to the ups and downs in women’s employment from 1970 to 2010 using regression decompositions focusing on whether changes are due to shifts in the means (composition of women) or due to shifts in coefficients (inclinations of women to work for pay). Compositional shifts in education exerted a positive effect on women’s employment across all decades, while shifts in the composition of other family income, particularly at the highest deciles, depressed married women’s employment over the 1990s contributing to the slowdown in this decade. A positive coefficient effect of education was found in all decades, except the 1990s, when the effect was negative, depressing women’s employment. Further, positive coefficient results for other family income at the highest deciles bolstered married women’s employment over the 1990s. Models are run separately for married and single women demonstrating the varying results of other family income by marital status. This research was supported in part by an Upjohn Institute Early Career Research Award

Influence of family and friend smoking on intentions to smoke and smoking-related attitudes and refusal self-efficacy among 9-10 year old children from deprived neighbourhoods: a cross-sectional study.

BACKGROUND: Smoking often starts in early adolescence and addiction can occur rapidly. For effective smoking prevention there is a need to identify at risk groups of preadolescent children and whether gender-specific intervention components are necessary. This study aimed to examine associations between mother, father, sibling and friend smoking and cognitive vulnerability to smoking among preadolescent children living in deprived neighbourhoods. METHODS: Cross-sectional data was collected from 9-10 year old children (n =1143; 50.7% girls; 85.6% White British) from 43 primary schools in Merseyside, England. Children completed a questionnaire that assessed their smoking-related behaviour, intentions, attitudes, and refusal self-efficacy, as well as parent, sibling and friend smoking. Data for boys and girls were analysed separately using multilevel linear and logistic regression models, adjusting for individual cognitions and school and deprivation level. RESULTS: Compared to girls, boys had lower non-smoking intentions (P = 0.02), refusal self-efficacy (P = 0.04) and were less likely to agree that smoking is 'definitely' bad for health (P < 0.01). Friend smoking was negatively associated with non-smoking intentions in girls (P < 0.01) and boys (P < 0.01), and with refusal self-efficacy in girls (P < 0.01). Sibling smoking was negatively associated with non-smoking intentions in girls (P < 0.01) but a positive association was found in boys (P = 0.02). Boys who had a smoking friend were less likely to 'definitely' believe that the smoke from other people's cigarettes is harmful (OR 0.57, 95% CI: 0.35 to 0.91, P = 0.02). Further, boys with a smoking friend (OR 0.38, 95% CI: 0.21 to 0.69, P < 0.01) or a smoking sibling (OR 0.45, 95% CI: 0.21 to 0.98) were less likely to 'definitely' believe that smoking is bad for health. CONCLUSION: This study indicates that sibling and friend smoking may represent important influences on 9-10 year old children's cognitive vulnerability toward smoking. Whilst some differential findings by gender were observed, these may not be sufficient to warrant separate prevention interventions. However, further research is needed

A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage.

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. ΔMLH1, ΔMSH6, and ΔMSH2 signatures were similar to each other but distinct from ΔPMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies

A rapidly convecting lava lake at Masaya Volcano, Nicaragua

Lava lakes provide a rare opportunity to study conduit flow processes through direct observation of the exposed magma surface. The recent lava lake activity at Masaya volcano (Nicaragua), which commenced in 2015, displayed several unusual phenomena. We report on the dynamics of this rapidly convecting lake, which, to the best of our knowledge manifested the highest lava flow velocities ever reported for a lava lake: 13.7–16.4 m s−1, in addition to unusual fluid dynamic behavior involving alteration in surface flow direction. We studied this system with multiparametric and high time resolution remote sensing measurements, performed during June 2017, including ultraviolet camera observations of SO2 emission rates, near infrared thermal camera measurements and video analyses of the lake surface. Median SO2 emission rates of 3.1 (±0.8) and 3.7 (±0.9) kg s−1 were found, which are lower than previously published estimates, and could represent challenging remote sensing conditions or a waning in lava lake activity. Video analyses enabled characterization of frequent bursts of approximately hemispherical spherical-cap bubbles on the surface with diameters ranging 0.6–8.5 m (median of 2.6 m), and calculation of individual bubble masses, which contribute to active bubble bursting values estimated at 1.9 to 3.9 kg s−1. We show that only a small fraction, 7–17%, of total emission volumes are contributed by these bubbles, based on estimated emission rates of 22.5 and 26.9 kg s−1. Furthermore, periodicity analysis reveals regular 200–300 s oscillations in SO2 emissions. These are not shared by any of our other datasets and particularly during the contemporaenously acquried thermal data, hence, we tentatively assign an atmospheric causal generation mechanism, driven by atmospheric transport and turbulence phenomena, such as eddying. Overall, we highlight the uniquely high velocity and fluid dynamic behavior of Masaya lava lake

The patient reporting and action for a safe environment (PRASE) intervention: a feasibility study

Background: There is growing interest in the role of patients in improving patient safety. One such role is providing feedback on the safety of their care. Here we describe the development and feasibility testing of an intervention that collects patient feedback on patient safety, brings together staff to consider this feedback and to plan improvement strategies. We address two research questions: i) to explore the feasibility of the process of systematically collecting feedback from patients about the safety of care as part of the PRASE intervention; and, ii) to explore the feasibility and acceptability of the PRASE intervention for staff, and to understand more about how staff use the patient feedback for service improvement. Method: We conducted a feasibility study using a wait-list controlled design across six wards within an acute teaching hospital. Intervention wards were asked to participate in two cycles of the PRASE (Patient Reporting & Action for a Safe Environment) intervention across a six-month period. Participants were patients on participating wards. To explore the acceptability of the intervention for staff, observations of action planning meetings, interviews with a lead person for the intervention on each ward and recorded researcher reflections were analysed thematically and synthesised. Results: Recruitment of patients using computer tablets at their bedside was straightforward, with the majority of patients willing and able to provide feedback. Randomisation of the intervention was acceptable to staff, with no evidence of differential response rates between intervention and control groups. In general, ward staff were positive about the use of patient feedback for service improvement and were able to use the feedback as a basis for action planning, although engagement with the process was variable. Gathering a multidisciplinary team together for action planning was found to be challenging, and implementing action plans was sometimes hindered by the need to co-ordinate action across multiple services. Discussion: The PRASE intervention was found to be acceptable to staff and patients. However, before proceeding to a full cluster randomised controlled trial, the intervention requires adaptation to account for the difficulties in implementing action plans within three months, the need for a facilitator to support the action planning meetings, and the provision of training and senior management support for participating ward teams. Conclusions: The PRASE intervention represents a promising method for the systematic collection of patient feedback about the safety of hospital care