“Be beside me”: Exploring children and young people’s visions for belonging and citizenship

This paper reports on a study which focused on surveying children and young people (aged 4 to 17) regarding their experiences of childhood, schooling, family, and community. Participants focused on the importance of their connections to fellow children and young people, their families, and their educators. They identified ways for adults to care for them and to create connectedness and belonging whether at home or school. Participants also spoke to the value of their voices and views, and expressed a desire to be respected and recognised, whether on a personal level or with reference to broader systems such as government. Throughout the study, participants expressed appreciation regarding the opportunity to engage in research that explicitly focused on seeking and honouring their voices and views. For instance, one secondary-aged student stated, “Children can make a difference by sharing their perspective and expressing the way the world feels to them.” Recommendations are posed which have heightened relevance for educators, school leaders, and parents/carers. These relate to school culture, learning and teaching, caring for children, and relating to children

Letters To The Editor.

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Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

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Standard survey methods for estimating colony losses and explanatory risk factors in Apis mellifera

This chapter addresses survey methodology and questionnaire design for the collection of data pertaining to estimation of honey bee colony loss rates and identification of risk factors for colony loss. Sources of error in surveys are described. Advantages and disadvantages of different random and non-random sampling strategies and different modes of data collection are presented to enable the researcher to make an informed choice. We discuss survey and questionnaire methodology in some detail, for the purpose of raising awareness of issues to be considered during the survey design stage in order to minimise error and bias in the results. Aspects of survey design are illustrated using surveys in Scotland. Part of a standardized questionnaire is given as a further example, developed by the COLOSS working group for Monitoring and Diagnosis. Approaches to data analysis are described, focussing on estimation of loss rates. Dutch monitoring data from 2012 were used for an example of a statistical analysis with the public domain R software. We demonstrate the estimation of the overall proportion of losses and corresponding confidence interval using a quasi-binomial model to account for extra-binomial variation. We also illustrate generalized linear model fitting when incorporating a single risk factor, and derivation of relevant confidence intervals

The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends.

Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. Chaperones of the Hsp70 family can further disaggregate otherwise irreversible aggregate species such as α-synuclein fibrils, which accumulate in Parkinson's disease. However, the mechanisms and kinetics of this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical kinetics to study α-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse α-synuclein aggregation back to its soluble monomeric state. This reaction proceeds through first-order kinetics where monomer units are removed directly from the fibril ends with little contribution from intermediate fibril fragmentation steps. These findings extend our mechanistic understanding of the role of chaperones in the suppression of amyloid proliferation and in aggregate clearance, and inform on possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies

Early Menarche, Nulliparity, and the Risk for Premature and Early Natural Menopause

Study question: How the timing of menarche and parity link with premature and early natural 42 menopause? Summary answer: Early menarche (≤11 years) is a risk factor for both premature menopause (final 44 menstrual period, FMP <40 years) and early menopause (FMP 40-44 years), a risk that is amplified for nulliparous women. What is known already: Women with either premature or early menopause face increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, adjustment for confounding factors, and statistical power. Study design, size, duration: This pooled study comprises 51,450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia, and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Participants/materials, setting, methods: Age at menarche (categorised as ≤11, 12, 13, 14, and 15 56 or more years) and parity (categorised as no children, one child, and two or more children) were exposure of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorised as premature menopause (FMP before age 40), early menopause (FMP 40-44 years), 45-49 years, 50-51 years, 52-53 years, and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% confidence intervals (95%CI) for associations between menarche, parity and age at FMP adjusting for within-study correlation. Main results and the role of chance: The median age at FMP was 50 years (interquartile range 48 to 53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12-13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53 to 2.12) and early menopause (1.31, 1.19 to 1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84 to 2.77) and early menopause (1.32, 1.09 to 1.59). Women having early menarche and nulliparity were at over five folds increased risk of premature menopause (5.64, 4.04 to 7.87) and two folds increased risk of early menopause (2.16, 1.48 to 3.15) compared with women who had menarche at ≥12 years and two or more children. Limitations, reasons for caution: Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche which may have led to some degree of recall bias. Wider implications of the findings: Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause

Lessons from the COVID-19 pandemic to improve the health and social care and wellbeing of minoritised ethnic groups with chronic conditions or impairments: protocol for the mixed methods intersectional asset-based study CICADA

The pandemic has inequitably impacted the experiences of people living with ill health/impairments or from minoritised ethnic groups across all areas of life. Given possible parallels in inequities for disabled people and people from minoritised ethnic backgrounds, their existence before the pandemic and increase since, and the discriminations that each group faces, our interest is in understanding the interplay between being disabled AND being from a minoritised ethnic group. OBJECTIVE: The overarching aim of the CICADA project, building on this understanding, is to improve pandemic and longer-term support networks and access to and experiences of care, services and resources for these under-served groups, both during the pandemic and longer term, reducing inequities and enhancing social, health and wellbeing outcomes. METHODS: This mixed methods study involves three 'sweeps' of a new UK survey, secondary analyses of existing cohort and panel surveys, a rapid scoping review, a more granular review, and qualitative insights from over 200 semi-structured interviews including social network/map/photo elicitation methods, and two subsequent sets of remote participatory research workshops. Separate stakeholder co-creation meetings, running through the study, will develop analyses and outputs. Our longitudinal study design enables us to explore significant relationships between variables in the survey data we collect, and also changes in variables with time, including consideration of varying pandemic contexts. The qualitative data will provide more granular detail. We will take a strengths and assets-based approach, underpinned by the social model of disability and by intersectional considerations, to challenge discrimination. Our exploration of the social determinants of health and wellbeing is framed by the social ecological model. RESULTS: The CICADA project was funded by the Health and Social Care Delivery Research (HSDR) Programme of the National Institute for Health and Care Research (NIHR) in March 2021 and began in May 2021. Further work within the project (84 interviews) was commissioned in March 2022, focussing on mental health specifically in North-East England, Greater Manchester and the North-West Coast. Data collection began in August 2021, with the last participants due to be recruited in September 2022. As of January 2022, 5,792 survey respondents and 227 interviewees had provided data. From April 2022, the time of article submission, we will recruit participants for the sub-study and wave 2 of the surveys and qualitative work. We expect results to be published by winter 2022. CONCLUSIONS: In studying the experiences of disabled people with impairments and those living with chronic conditions who come from certain minoritised ethnic groups, we are aiming for transformative research to improve their health and wellbeing

Patterns of abundance across geographical ranges as a predictor for responses to climate change:Evidence from UK rocky shores

Aim: Understanding patterns in the abundance of species across thermal ranges can give useful insights into the potential impacts of climate change. The abundant-centre hypothesis suggests that species will reach peak abundance at the centre of their thermal range where conditions are optimal, but evidence in support of this hypothesis is mixed and limited in geographical and taxonomic scope. We tested the applicability of the abundant-centre hypothesis across a range of intertidal organisms using a large, citizen science-generated data set. Location: UK. Methods: Species' abundance records were matched with their location within their thermal range. Patterns in abundance distribution for individual species, and across aggregated species abundances, were analysed using Kruskal–Wallis tests and quantile general additive models. Results: Individually, invertebrate species showed increasing abundances in the cooler half of the thermal range and decreasing abundances in the warmer half of the thermal range. The overall shape for aggregated invertebrate species abundances reflected a broad peak, with a cool-skewed maximum abundance. Algal species showed little evidence for an abundant-centre distribution individually, but overall the aggregated species abundances suggested a hump-backed abundance distribution. Main Conclusions: Our study follows others in showing mixed support for the abundant-centre hypothesis at an individual species level, but demonstrates an increased predictability in species responses when an aggregated overall response is considered

CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study

Serological correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after vaccination ("vaccine breakthrough") have been described. However, T cell correlates of protection against breakthrough are incompletely defined, especially the specific contributions of CD4+ and CD8+ T cells. Here, 279 volunteers in the Protective Immunity from T Cells in Healthcare Workers (PITCH) UK cohort study were enrolled in a nested case-control study. Cases were those who tested SARS-CoV-2 PCR or lateral flow device (LFD) positive after two vaccine doses during the Delta-predominant era (n = 32), while controls were those who did not report a positive test or undergo anti-nucleocapsid immunoglobulin G (IgG) seroconversion during this period (n = 247). Previous SARS-CoV-2 infection prior to vaccination was associated with reduced odds of vaccine breakthrough. Using samples from 28 d after the second vaccine dose, before all breakthroughs occurred, we observed future cases had lower ancestral spike (S)- and receptor binding domain-specific IgG titers and S1- and S2-specific T cell interferon gamma (IFNγ) responses compared with controls, although these differences did not persist when individuals were stratified according to previous infection status before vaccination. In a subset of matched infection-naïve cases and controls, vaccine breakthrough cases had lower CD4+ and CD8+ IFNγ and tumor necrosis factor (TNF) responses to Delta S peptides compared with controls. For CD8+ responses, this difference appeared to be driven by reduced responses to Delta compared with ancestral peptides among cases; this reduced response to Delta peptides was not observed in controls. Our findings support a protective role for T cells against Delta breakthrough infection. IMPORTANCE Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough