Placental Homing Peptide-microRNA Inhibitor Conjugates For Targeted Enhancement Of Intrinsic Placental Growth Signalling

Suboptimal placental growth and development are the underlying cause of many pregnancy complications. No treatments are available, primarily due to the risk of causing fetal teratogenicity. microRNAs (miRNAs) are short, non-coding RNA sequences that regulate multiple downstream genes; miR-145 and miR675 have previously been identified as negative regulators of placental growth. In this proof of principle study, we explored the feasibility of delivering miRNA inhibitors to the placentas of pregnant mice and developed novel placental homing peptide-microRNA inhibitor conjugates for targeted enhancement of intrinsic placental growth signalling. Scrambled-, miR-145- or miR-675 inhibitor sequences were synthesised from peptide nucleic acids and conjugated to the placental homing peptide CCGKRK. Intravenous administration of the miR-145- and miR-675 conjugates to pregnant C57BL/6J mice significantly increased fetal and placental weights compared to controls; the miR-675 conjugate significantly reduced placental miR-675 expression. When applied to human first trimester placental explants, the miR-145 conjugate significantly reduced placental miR-145 expression, and both conjugates induced significant enhancement of cytotrophoblast proliferation; no effect was observed in term placental explants. This study demonstrates that homing peptide-miRNA inhibitor conjugates can be exploited to promote placental growth; these novel therapeutics may represent an innovative strategy for targeted treatment of compromised placental development

Experience of, awareness of and help-seeking for potential cancer symptoms in smokers and non-smokers: A cross-sectional study

Background Presenting to primary care with potential cancer symptoms is contingent on one’s ability to recognize potentially serious symptoms. We investigated differences between smokers and non-smokers in symptoms experienced, awareness and consulting of potential respiratory, head and neck cancer symptoms. Methods Smokers and non-smokers aged over 50 from Yorkshire general practice lists were sent a postal questionnaire asking about symptoms, consulting and awareness of cancer symptoms. Data were analysed using STATA14. Results Response rate after one reminder was 30.5% (1205/3954). Smoking status was associated with experience of cough (p<0.001), breathlessness (p = 0.002) and tiredness (p = 0.004) with smokers (25.8% of population) more likely than never-smokers (53.6% of population) to experience all three symptoms (cough OR = 2.56;95%CI[1.75–3.75], breathlessness OR = 2.39;95%CI[1.43–4.00], tiredness OR = 1.57;95%CI[1.12–2.19]). Smoking status was associated with awareness of breathlessness as a potential cancer symptom (p = 0.035) and consulting for cough (p = 0.011) with smokers less likely to consult than never-smokers (OR = 0.37;95% CI[0.17–0.80]). Conclusion Our findings suggest that current smokers are more likely to experience cough, breathlessness and tiredness, but are less likely to consult for cough than never-smokers. To increase cancer awareness and promote consulting among smokers, innovative interventions improving symptom recognition and empowering smokers to seek help are required

Moving to capture children’s attention: developing a methodology for measuring visuomotor attention

Attention underpins many activities integral to a child’s development. However, methodological limitations currently make large-scale assessment of children’s attentional skill impractical, costly and lacking in ecological validity. Consequently we developed a measure of ‘Visual Motor Attention’ (VMA) - a construct defined as the ability to sustain and adapt visuomotor behaviour in response to task-relevant visual information. In a series of experiments, we evaluated the capability of our method to measure attentional processes and their contributions in guiding visuomotor behaviour. Experiment 1 established the method’s core features (ability to track stimuli moving on a tablet-computer screen with a hand-held stylus) and demonstrated its sensitivity to principled manipulations in adults’ attentional load. Experiment 2 standardised a format suitable for use with children and showed construct validity by capturing developmental changes in executive attention processes. Experiment 3 tested the hypothesis that children with and without coordination difficulties would show qualitatively different response patterns, finding an interaction between the cognitive and motor factors underpinning responses. Experiment 4 identified associations between VMA performance and existing standardised attention assessments and thereby confirmed convergent validity. These results establish a novel approach to measuring childhood attention that can produce meaningful functional assessments that capture how attention operates in an ecologically valid context (i.e. attention's specific contribution to visuomanual action)

Neighborhood deprivation and biomarkers of health in Britain: The mediating role of the physical environment

Background: Neighborhood deprivation has been consistently linked to poor individual health outcomes; however, studies exploring the mechanisms involved in this association are scarce. The objective of this study was to investigate whether objective measures of the physical environment mediate the association between neighborhood socioeconomic deprivation and biomarkers of health in Britain. Methods: We linked individual-level biomarker data from Understanding Society: The UK Household Longitudinal Survey (2010-2012) to neighborhood-level data from different governmental sources. Our outcome variables were forced expiratory volume in 1 s (FEV1%; n=16,347), systolic blood pressure (SBP; n=16,846), body mass index (BMI; n=19,417), and levels of C-reactive protein (CRP; n=11,825). Our measure of neighborhood socioeconomic deprivation was the Carstairs index, and the neighborhood-level mediators were levels of air pollutants (sulphur dioxide [SO2], particulate matter [PM10], nitrogen dioxide [NO2], and carbon monoxide [CO]), green space, and proximity to waste and industrial facilities. We fitted a multilevel mediation model following a multilevel structural equation framework in MPlus v7.4, adjusting for age, gender, and income. Results: Residents of poor neighborhoods and those exposed to higher pollution and less green space had worse health outcomes. However, only SO2exposure significantly and partially mediated the association between neighborhood socioeconomic deprivation and SBP, BMI, and CRP. Conclusion: Reducing air pollution exposure and increasing access to green space may improve population health but may not decrease health inequalities in Britain