Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia.

In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.

The Frequency and Content of Discussions About Alcohol Use in Primary Care and Application of the Chief Medical Officer's Low-Risk Drinking Guidelines: A Cross-Sectional Survey of General Practitioners and Practice Nurses in the UK.

AIMS: To examine how often general practitioners (GPs) and practice nurses (PNs) working in primary care discuss alcohol with patients, what factors prompt discussions, how they approach patient discussions and whether the Chief Medical Officers' (CMO) revised low-risk drinking guidelines are appropriately advised. METHODS: Cross-sectional survey with GPs and PNs working in primary care in the UK, conducted January-March 2017 (n = 2020). A vignette exercise examined what factors would prompt a discussion about alcohol, whether they would discuss before or after a patient reported exceeded the revised CMO guidelines (14 units per week) and whether the CMO drinking guidelines were appropriately advised. For all patients, participants were asked how often they discussed alcohol and how they approached the discussion (e.g. used screening tool). RESULTS: The most common prompts to discuss alcohol in the vignette exercise were physical cues (44.7% of participants) or alcohol-related symptoms (23.8%). Most practitioners (70.1%) said they would wait until a patient was exceeding CMO guidelines before instigating discussion. Two-fifths (38.1%) appropriately advised the CMO guidelines in the vignette exercise, with PNs less likely to do so than GPs (odds ratio [OR] = 0.77, P = 0.03). Less than half (44.7%) reportedly asked about alcohol always/often with all patients, with PNs more likely to ask always/often than GPs (OR = 2.22, P < 0.001). Almost three-quarters said they would enquire by asking about units (70.3%), compared to using screening tools. CONCLUSION: Further research is required to identify mechanisms to increase the frequency of discussions about alcohol and appropriate recommendation of the CMO drinking guidelines to patients.

Clustering of behavioural risk factors for health in UK adults in 2016: a cross-sectional survey.

BACKGROUND: Foods high in fat, sugar and salt (HFSS) are known to contribute to overweight and obesity. In addition to overweight and obesity, smoking, alcohol consumption and physical inactivity are known risk factors for non-communicable diseases, including several cancers and cardiovascular disease. METHODS: Secondary analysis of UK-representative cross-sectional survey data of 3293 adults aged 18+. Regression analyses were undertaken to understand the relationship between consumption of HFSS food and soft drinks, alcohol and tobacco and socio-demographics. Clustering analysis identified groupings of health risk factors. RESULTS: Males, those aged 18-24 and those from the more deprived groups consumed ready meals and fast food most frequently. Most of the sample (77.3%) engaged in at least one health risk behaviour. Six clusters were identified in the clustering analysis. Older (65+) female respondents were more likely to be inactive. Smokers exhibiting additional risk behaviours were more likely to be of working age from more deprived groups, and men over 65 were more likely to consume harmful levels of alcohol with additional risk factors. CONCLUSION: Policies and services in the UK tend to focus on changing behaviour to address individual risk factors. This study shows that policies and interventions need to address multiple risk factors.

Public awareness and healthcare professional advice for obesity as a risk factor for cancer in the UK: a cross-sectional survey.

Background: Overweight and obesity is the second biggest preventable cause of cancer after smoking, causing ~3.4 million deaths worldwide. This study provides current UK data on awareness of the link between obesity and cancer by socio-demographic factors, including BMI, and explores to what degree healthcare professionals provide weight management advice to patients. Methods: Cross-sectional survey of 3293 adults completed an online survey in February/March 2016, weighted to be representative of the UK population aged 18+. Results: Public awareness of the link between obesity and cancer is low (25.4% unprompted and 57.5% prompted). Higher levels of awareness existed for least deprived groups (P < 0.001), compared to more deprived groups. Most respondents had seen a healthcare practitioner in the past 12 months (91.6%) and 17.4% had received advice about their weight, although 48.4% of the sample were overweight/obese. Conclusion: Cancer is not at the forefront of people's minds when considering health conditions associated with overweight or obesity. Socio-economic disparities exist in health knowledge across the UK population, with adults from more affluent groups being most aware. Healthcare professionals are uniquely positioned to provide advice about weight, but opportunities for intervention are currently under-utilized in healthcare settings.