A REPORT BY THE ALL - PARTY PARLIAMENTARY GROUP ON A FIT AND HEALTHY CHILDHOOD THE IMPACT OF SOCIAL AND ECONOMIC INEQUALITIES ON CHILDREN’S HEALTH

A child born into circumstances of social and economic inequality in the 21st century United Kingdom will start life with one hand tied behind their back. Nowhere is the disparity of experience more marked than in that of health and this, in turn, impacts the entire life course. In the same way that priority is given to securing the national infrastructure, prioritising the health of children from all areas and in all circumstances from the outset would therefore seem to be prudent rather than profligate. Yet as this Report demonstrates,successive Governments have skimped rather thansaved; failedto build upon existing policy and played a costly policy game of ‘catching up later’ instead of deploying the early ntervention me asures that are cheaper andmore effective in the long term

Evaluating 'Prefer not to say' Around Sensitive Disclosures

As people's offline and online lives become increasingly entwined, the sensitivity of personal information disclosed online is increasing. Disclosures often occur through structured disclosure fields (e.g., drop-down lists). Prior research suggests these fields may limit privacy, with non-disclosing users being presumed to be hiding undesirable information. We investigated this around HIV status disclosure in online dating apps used by men who have sex with men. Our online study asked participants (N=183) to rate profiles where HIV status was either disclosed or undisclosed. We tested three designs for displaying undisclosed fields. Visibility of undisclosed fields had a significant effect on the way profiles were rated, and other profile information (e.g., ethnicity) could affect inferences that develop around undisclosed information. Our research highlights complexities around designing for non-disclosure and questions the voluntary nature of these fields. Further work is outlined to ensure disclosure control is appropriately implemented around online sensitive information disclosures

Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor

Glucocorticoid (GC) receptors (GRs) have profound anti-survival effects on human small cell lung cancer (SCLC). To explore the basis of these effects, protein partners for GRs were sought using a yeast two-hybrid screen. We discovered a novel gene, FAM33A, subsequently identified as a SKA1 partner and involved in mitosis, and so renamed Ska2. We produced an anti-peptide antibody that specifically recognized full-length human SKA2 to measure expression in human cell lines and tissues. There was a wide variation in expression across multiple cell lines, but none was detected in the liver cell line HepG2. A xenograft model of human SCLC had intense staining and archival tissue revealed SKA2 in several human lung and breast tumours. SKA2 was found in the cytoplasm, where it co-localized with GR, but nuclear expression of SKA2 was seen in breast tumours. SKA2 overexpression increased GC transactivation in HepG2 cells while SKA2 knockdown in A549 human lung epithelial cells decreased transactivation and prevented dexamethasone inhibition of proliferation. GC treatment decreased SKA2 protein levels in A549 cells, as did Staurosporine, phorbol ester and trichostatin A; all agents that inhibit cell proliferation. Overexpression of SKA2 potentiated the proliferative response to IGF-I exposure, and knockdown with shRNA caused cells to arrest in mitosis. SKA2 has recently been identified in HeLa S3 cells as part of a complex, which is critical for spindle checkpoint silencing and exit from mitosis. Our new data show involvement in cell proliferation and GC signalling, with implications for understanding how GCs impact on cell fate

Do acute elevations of serum creatinine in primary care engender an increased mortality risk?

Background: The significant impact Acute Kidney Injury (AKI) has on patient morbidity and mortality emphasizes the need for early recognition and effective treatment. AKI presenting to or occurring during hospitalisation has been widely studied but little is known about the incidence and outcomes of patients experiencing acute elevations in serum creatinine in the primary care setting where people are not subsequently admitted to hospital. The aim of this study was to define this incidence and explore its impact on mortality. Methods: The study cohort was identified by using hospital data bases over a six month period. Inclusion criteria: People with a serum creatinine request during the study period, 18 or over and not on renal replacement therapy. The patients were stratified by a rise in serum creatinine corresponding to the Acute Kidney Injury Network (AKIN) criteria for comparison purposes. Descriptive and survival data were then analysed. Ethical approval was granted from National Research Ethics Service (NRES) Committee South East Coast and from the National Information Governance Board. Results: The total study population was 61,432. 57,300 subjects with ‘no AKI’, mean age 64.The number (mean age) of acute serum creatinine rises overall were, ‘AKI 1’ 3,798 (72), ‘AKI 2’ 232 (73), and ‘AKI 3’ 102 (68) which equates to an overall incidence of 14,192 pmp/year (adult). Unadjusted 30 day survival was 99.9% in subjects with ‘no AKI’, compared to 98.6%, 90.1% and 82.3% in those with ‘AKI 1’, ‘AKI 2’ and ‘AKI 3’ respectively. After multivariable analysis adjusting for age, gender, baseline kidney function and co-morbidity the odds ratio of 30 day mortality was 5.3 (95% CI 3.6, 7.7), 36.8 (95% CI 21.6, 62.7) and 123 (95% CI 64.8, 235) respectively, compared to those without acute serum creatinine rises as defined. Conclusions: People who develop acute elevations of serum creatinine in primary care without being admitted to hospital have significantly worse outcomes than those with stable kidney function

Nearshore subtidal community response during and after sediment disturbance associated with dam removal

Dam removal is used increasingly to restore aquatic ecosystems and remove unnecessary or high-risk infrastructure. As the number of removals increases, there is a growing understanding about the hydrologic, geomorphic, and ecological responses to these removals. Most dam removal studies, however, focus on river and watershed responses to dam removal. The removal of two dams on the Elwha River provided a unique opportunity to characterize the response of nearshore (coastal) ecosystems. We conducted SCUBA surveys between 2011 and 2022 to quantify trajectories of change in a nearshore ecosystem during and after dam removal. We focused on the degree to which the abundances of kelp, benthic invertebrates, and fish changed in response to patterns of sediment fluxes during and after dam removal. Our findings point to two pathways of response depending on the disturbance mechanism and species type. Sites with persistent sediment deposition were characterized by wholesale community changes that did not recover to a before dam removal condition. Instead, the sites were colonized by new species that were largely absent prior to dam removal. Sites that experienced high turbidity but lacked persistent seafloor deposition were primarily characterized by a reduction in the abundance of kelp and other algae during dam removal and a rapid recovery after sediment flux to the nearshore declined. Dam removal influences on invertebrates and fish at these sites were more variable, benefiting some species and disadvantaging others. In addition to dam removal, sea star wasting syndrome and a marine heatwave exerted distinct controls on subtidal communities during the same period. The loss of the predatory sea star Pycnopodia helianthoides was associated with gains in some of its prey species, and kelp community changes reflected regional trends in ocean temperature and kelp abundance. The results presented here have important implications for understanding the response of marine ecosystems to future dam removals and similar sediment perturbation events

Observational study on variability between biobanks in the estimation of DNA concentration.

BACKGROUND: There is little confidence in the consistency of estimation of DNA concentrations when samples move between laboratories. Evidence on this consistency is largely anecdotal. Therefore there is a need first to measure this consistency among different laboratories and then identify and implement remedies. A pilot experiment to test logistics and provide initial data on consistency was therefore conceived. METHODS: DNA aliquots at nominal concentrations between 10 and 300 ng/mul were dispensed into the wells of 96-well plates by one participant - the coordinating centre. Participants estimated the concentration in each well and returned estimates to the coordinating centre. RESULTS: Considerable overall variability was observed among estimates. There were statistically significant differences between participants' measurements and between fluorescence emission and absorption spectroscopy. CONCLUSION: Anecdotal evidence of variability in DNA concentration estimation has been substantiated. Reduction in variability between participants will require the identification of major sources of variation, specification of effective remedies and their implementation

Approaches and challenges to the study of loess—Introduction to the LoessFest Special Issue

In September 2016, the annual meeting of the International Union for Quaternary Research's Loess and Pedostratigraphy Focus Group, traditionally referred to as a LoessFest, met in Eau Claire, Wisconsin, USA. The 2016 LoessFest focused on thin loess deposits and loess transportation surfaces. This LoessFest included 75 registered participants from 10 countries. Almost half of the participants were from outside the United States, and 18 of the participants were students. This review is the introduction to the special issue for Quaternary Research that originated from presentations and discussions at the 2016 LoessFest. This introduction highlights current understanding and ongoing work on loess in various regions of the world and provides brief summaries of some of the current approaches/strategies used to study loess deposits

Estimating the Impact of Plasma HIV-1 RNA Reductions on Heterosexual HIV-1 Transmission Risk

Background: The risk of sexual transmission of HIV-1 is strongly associated with the level of HIV-1 RNA in plasma making reduction in HIV-1 plasma levels an important target for HIV-1 prevention interventions. A quantitative understanding of the relationship of plasma HIV-1 RNA and HIV-1 transmission risk could help predict the impact of candidate HIV-1 prevention interventions that operate by reducing plasma HIV-1 levels, such as antiretroviral therapy (ART), therapeutic vaccines, and other non-ART interventions. Methodology/Principal Findings: We use prospective data collected from 2004 to 2008 in East and Southern African HIV-1 serodiscordant couples to model the relationship of plasma HIV-1 RNA levels and heterosexual transmission risk with confirmation of HIV-1 transmission events by HIV-1 sequencing. The model is based on follow-up of 3381 HIV-1 serodiscordant couples over 5017 person-years encompassing 108 genetically-linked HIV-1 transmission events. HIV-1 transmission risk was 2.27 per 100 person-years with a log-linear relationship to log10 plasma HIV-1 RNA. The model predicts that a decrease in average plasma HIV-1 RNA of 0.74 log10 copies/mL (95% CI 0.60 to 0.97) reduces heterosexual transmission risk by 50%, regardless of the average starting plasma HIV-1 level in the population and independent of other HIV-1-related population characteristics. In a simulated population with a similar plasma HIV-1 RNA distribution the model estimates that 90% of overall HIV-1 infections averted by a 0.74 copies/mL reduction in plasma HIV-1 RNA could be achieved by targeting this reduction to the 58% of the cohort with plasma HIV-1 levels ≥4 log10 copies/mL. Conclusions/Significance: This log-linear model of plasma HIV-1 levels and risk of sexual HIV-1 transmission may help estimate the impact on HIV-1 transmission and infections averted from candidate interventions that reduce plasma HIV-1 RNA levels

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome