Explore the vast range of titles available.

The B-cell CLL/lymphoma 2 (BCL2) gene family encodes pro- and anti-apoptotic proteins that are critical regulators of programmed cell death. Higher levels of BCL2 expression in breast tumours have been shown to be an independent prognostic factor for improved survival from breast cancer. The promoter single nucleotide polymorphism (SNP) rs2279115 has been associated with both BCL2 expression and patient survival. The aim of this study was to attempt to replicate these observations in a cohort of 1015 UK women with breast cancer, and to compare genotype frequencies in cases and controls. In this study, 1015 breast cancer cases and 1034 control subjects were genotyped for the rs2279115 SNP by 5' nuclease PCR. Paraffin embedded tumour tissue for 342 case subjects was assembled into tissue microarrays, and the level of expression of BCL2 was established by immunohistochemistry. Kaplan Meier survival curves and Cox Proportional Hazards models were used to examine the effect of genotype on patient survival. The effect of SNP genotype on tumour BCL2 protein levels and breast cancer susceptibility was assessed by logistic regression. In this study higher BCL2 expression was significantly associated with improved survival from breast cancer (p=0.015), in keeping with previous reports. The SNP rs2279115 was not found to be associated with tumour expression of BCL2, (p=0.77), and neither was it associated with case/control status (p=0.25). There was no significant association between the SNP and overall survival (p=0.75). In conclusion, we found that higher tumour BCL2 expression is associated with improved survival from breast cancer, in keeping with previous studies. However, in contrast to a previous report, the promoter SNP rs2279115 was not associated with BCL2 expression or overall survival from breast cancer.

Childhood obesity levels continue to rise, with significant impact on individuals and the NHS. The ‘Complications of Excess Weight’ (CEW) clinics provide support to young people with complications of their weight. Our objective was to co-develop, with young people, a new intervention; AIM2Change, to enable young people to develop their intrinsic motivation to manage weight, using Acceptance and Commitment Therapy (ACT), with a person-centred approach. Young people from the Care of Childhood Obesity (CoCO) clinic in Bristol, UK, were recruited to co-develop this intervention. The study was registered on ISRCTN (ISRCTN16607863). The seven-session, ACT-based intervention was delivered one-to-one, securely online. Qualitative interviews were conducted after each intervention session was delivered. Qualitative data were coded and reviewed regularly to make iterative changes to individual sessions and the overall programme. Fourteen co-developers were recruited, of whom nine completed the co-development process (female = 4; median age (IQR)=15(1.5); 4 with a parent; Indices of Multiple Deprivation (IMD) median = 3.5, range = 1–10). Iterative changes made during co-development included introducing an earlier focus on eating behaviour and body image, with more practical activities to increase engagement. Thematic analysis of co-developer feedback identified four themes: theoretical understanding; delivery and receipt of therapy; view of strategies and engagement; real world benefits of co-development process. Framework analysis was conducted to map data pertaining to these themes into matrices according to each participant and session. Insights from the co-development process have shaped AIM2Change to optimise the intervention’s value, relevance and acceptability. Findings suggest that AIM2Change meets an unmet need in delivery of current childhood weight management services.

Purpose PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [ 11 C]PK-11195 limits accurate quantification. [ 18 F]GE-180, a novel TSPO ligand, displays superior binding to [ 11 C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [ 18 F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures. Methods Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [ 18 F]GE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution ( V T ) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region. Results The two-tissue compartment model was the best model. The average regional delivery rate constant ( K 1 ) was 0.01 mL cm −3  min −1 indicating low extraction across the blood–brain barrier (1 %). The estimated median V T across all ROIs was also low, ranging from 0.16 mL cm −3 in the striatum to 0.38 mL cm −3 in the thalamus. There were no significant differences in V T between HABs and MABs across all ROIs. Conclusion A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [ 18 F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1β in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1β involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1β as a pivotal catalyst for neuropathological processes in MPS IIIA. Synopsis A more severe neurocognitive decline is documented in Mucopolysaccharidosis type IIIA (MPS IIIA) patients who contract viral infections. To explore the link between inflammation and neurodegeneration, MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C) and the impact on brain pathology was assessed. Exacerbated Il-1β levels and caspase-1 activity were observed in the serum and brain of MPS IIIA mice challenged with a high acute poly(I:C) dose. MPS IIIA spatial memory deficit worsened in a dose-dependent manner following chronic administration of poly(I:C). Existing microgliosis and astrogliosis were exacerbated in the cortex and amygdala of MPS IIIA mice following chronic poly(I:C) administration. Neuronal and astrocytic cell damage was observed in the hippocampus of MPS IIIA mice following chronic poly(I:C) administration. Il-1β and the inflammasome remain central to neuropathological progression in MPS IIIA, as confirmed by our previous findings. A more severe neurocognitive decline is documented in Mucopolysaccharidosis type IIIA (MPS IIIA) patients who contract viral infections. To explore the link between inflammation and neurodegeneration, MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C) and the impact on brain pathology was assessed.

Background Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited. Methods We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status. Results No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p  = 0.003). Conclusion Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.

BackgroundNo validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres.MethodsWe evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information.ResultsThe full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell’s C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options.ConclusionBOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).

Childhood obesity levels continue to rise, with significant impact on individuals and the NHS. The 'Complications of Excess Weight' (CEW) clinics provide support to young people with complications of their weight. Our objective was to co-develop, with young people, a new intervention; AIM2Change, to enable young people to develop their intrinsic motivation to manage weight, using Acceptance and Commitment Therapy (ACT), with a person-centred approach. Young people from the Care of Childhood Obesity (CoCO) clinic in Bristol, UK, were recruited to co-develop this intervention. The study was registered on ISRCTN (ISRCTN16607863). The seven-session, ACT-based intervention was delivered one-to-one, securely online. Qualitative interviews were conducted after each intervention session was delivered. Qualitative data were coded and reviewed regularly to make iterative changes to individual sessions and the overall programme. Fourteen co-developers were recruited, of whom nine completed the co-development process (female = 4; median age (IQR)=15(1.5); 4 with a parent; Indices of Multiple Deprivation (IMD) median = 3.5, range = 1-10). Iterative changes made during co-development included introducing an earlier focus on eating behaviour and body image, with more practical activities to increase engagement. Thematic analysis of co-developer feedback identified four themes: theoretical understanding; delivery and receipt of therapy; view of strategies and engagement; real world benefits of co-development process. Framework analysis was conducted to map data pertaining to these themes into matrices according to each participant and session. Insights from the co-development process have shaped AIM2Change to optimise the intervention's value, relevance and acceptability. Findings suggest that AIM2Change meets an unmet need in delivery of current childhood weight management services.

Background A genetic neurodevelopmental disorder (GND) impacts all aspects of a child's and family's life. GNDs are rare; most have limited natural history data. We aimed to understand the impacts, obstacles, information barriers and coping strategies developed through parents' experience of receiving and living with a child's diagnosis. Design and Participants This analysis is part of the UK multicentre observational study of children with rare GNDs (GenROC). We conducted 17 semi‐structured online interviews with parents of children with GNDs (aged 0–15 years) from November 2023 to March 2024. Data were analysed following the principles of thematic analysis. Results We identified five themes. (1) Impact on the family around a genetic diagnosis: Distress begins well before a diagnosis is received; there is an impact upon the receipt itself and the ongoing impact on the family thereafter. (2) Impact of uncertainty, lack of data and ‘rareness’. The experience of parenting when so little is known about your child's condition. (3) Relationships with health professionals. Positive where parents are empowered and feel part of the team; negative where parents feel not heard/believed due to a professional lack of expertise/understanding. (4) Parent mental health: GNDs can be a significant burden to family life. The need to advocate for services has a negative impact. Feelings of isolation through rareness. (5) Coping strategies and factors that help: Support/Facebook groups are considered highly beneficial. Parents develop new positive identities, including that of advocate, professional and educator. Conclusions GNDs represent a major challenge for families, clinicians and service providers. Distressed parents are struggling to cope with challenges and suffer from poor mental health. Psychosocial support, better signposting and health professional education may help. Patient Contribution Patient Participant Involvement group (comprising five mothers and one father of children with varying GNDs, one young person with a GND, and one genetics family charity representative) contributed to topic guide development and methodology and provided feedback on results.

Introduced common mynas (Acridotheres tristis) can negatively impact native wildlife throughout the mynas’ non-indigenous range, and in Seychelles myna eradications have been attempted on some smaller islands to protect endemic and indigenous fauna. Initial attempts, relying on a quick knock-down of the population using toxicants, failed. Here we describe an eradication on North Island, Seychelles, that was accomplished by trapping, supported by shooting in the final stages. This eradication attempt was ultimately successful but took place in two stages spanning seven years and involved removing 1641 birds. During the second, successful, stage, morphometric data collected from caught mynas provided pointers to optimum times during the mynas’ annual cycle to target control activities. During both stages the trapping of non-target species interfered with the capture of mynas. The six main conclusions from this eradication are (i) eradication of mynas from small islands is feasible and achievable by trapping and shooting, without recourse to the use of toxicants; (ii) provision of adequate resources for the life of an eradication attempt, especially ensuring continuity of funding and staffing, is essential for the efficient removal of the whole population; (iii) knowledge of myna phenology can be used to target the optimal timing of an eradication attempt, (iv) post eradication, vigilance and capacity for immediate action must be maintained to remove any immigrant mynas, (v) further research on trap design is needed to minimise the capture of non-target species, and (vi) introduced endemic bird populations should be monitored to assess their responses to myna removal.