Factors affecting primary care practitioners' alcohol-related discussions with older adults: a qualitative study.

BACKGROUND: Risk of harm from drinking is heightened in later life, owing to age-related sensitivities to alcohol. Primary care services have a key role in supporting older people (aged ≥50 years) to make healthier decisions about alcohol. AIM: To examine primary care practitioners' perceptions of factors that promote and challenge their work to support older people in alcohol risk-reduction. DESIGN AND SETTING: Qualitative study consisting of semi-structured interviews and focus groups with primary care practitioners in Northern England. METHOD: Thirty-five practitioners (GPs, practice/district nurses, pharmacists, dentists, social care practitioners, and domiciliary carers) participated in eight interviews and five focus groups. Data were analysed thematically, applying principles of constant comparison. RESULTS: Practitioners highlighted particular sensitivities to discussing alcohol among older people, and reservations about older people's resistance to making changes in old age; given that drinking practices could be established, and promote socialisation and emotional wellbeing in later life. Age-related health issues increased older people's contact with practitioners, but management of older people's long-term conditions was prioritised over discussion of alcohol. Dedicated time to address alcohol in routine consultations with older people and training in alcohol intervention facilitated practitioners, particularly pharmacists and practice nurses. CONCLUSION: There are clear opportunities to support older people in primary care to make healthier decisions about alcohol. Dedicated time to address alcohol, training in identification of alcohol-related risks (particularly those associated with old age), and tailored interventions for older people, feasible to implement in practice settings, would help primary care practitioners to address older people's alcohol use.

Modeling human tumor-immune environments in vivo for the preclinical assessment of immunotherapies.

Despite the significant contributions of immunocompetent mouse models to the development and assessment of cancer immunotherapies, they inadequately represent the genetic and biological complexity of corresponding human cancers. Immunocompromised mice reconstituted with a human immune system (HIS) and engrafted with patient-derived tumor xenografts are a promising novel preclinical model for the study of human tumor-immune interactions. Whilst overcoming limitations of immunocompetent models, HIS-tumor models often rely on reconstitution with allogeneic immune cells, making it difficult to distinguish between anti-tumor and alloantigen responses. Models that comprise of autologous human tumor and human immune cells provide a platform that is more representative of the patient immune-tumor interaction. However, limited access to autologous tissues, short experimental windows, and poor retention of tumor microenvironment and tumor infiltrating lymphocyte components are major challenges affecting the establishment and application of autologous models. This review outlines existing preclinical murine models for the study of immuno-oncology, and highlights innovations that can be applied to improve the feasibility and efficacy of autologous models.

Use of human splenocytes in an innovative humanised mouse model for prediction of immunotherapy-induced cytokine release syndrome.

OBJECTIVES: Humanised mice have emerged as valuable models for pre-clinical testing of the safety and efficacy of immunotherapies. Given the variety of models available, selection of the most appropriate humanised mouse model is critical in study design. Here, we aimed to develop a model for predicting cytokine release syndrome (CRS) while minimising graft-versus-host disease (GvHD). METHODS: To overcome donor-induced variation, we directly compared the in vitro and in vivo immune phenotype of immunodeficient NSG mice reconstituted with human bone marrow (BM) CD34+ haematopoietic stem cells (HSCs), peripheral blood mononuclear cells (PBMCs) or spleen mononuclear cells (SPMCs) from the same human donors. SPMC engraftment in NSG-dKO mice, which lack MHC class I and II, was also evaluated as a strategy to limit GvHD. Another group of mice was engrafted with umbilical cord blood (UCB) CD34+ HSCs. Induction of CRS in vivo was investigated upon administration of the anti-CD3 monoclonal antibody OKT3. RESULTS: PBMC- and SPMC-reconstituted NSG mice showed short-term survival, with engrafted human T cells exhibiting mostly an effector memory phenotype. Survival in SPMC-reconstituted NSG-dKO mice was significantly longer. Conversely, both BM and UCB-HSC models showed longer survival, without demonstrable GvHD and a more naïve T-cell phenotype. PBMC- and SPMC-reconstituted mice, but not BM-HSC or UCB-HSC mice, experienced severe clinical signs of CRS upon administration of OKT3. CONCLUSION: PBMC- and SPMC-reconstituted NSG mice better predict OKT3-mediated CRS. The SPMC model allows generation of large experimental groups, and the use of NSG-dKO mice mitigates the limitation of early GvHD.

Extensive heterogeneity in somatic mutation and selection in the human bladder.

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.

Managing older people's perceptions of alcohol-related risk: a qualitative exploration in Northern English primary care.

BACKGROUND: Risk of harm from drinking increases with age as alcohol affects health conditions and medications that are common in later life. Different types of information and experiences affect older people's perceptions of alcohol's effects, which must be navigated when supporting healthier decisions on alcohol consumption. AIM: To explore how older people understand the effects of alcohol on their health; and how these perspectives are navigated in supportive discussions in primary care to promote healthier alcohol use. DESIGN AND SETTING: A qualitative study consisting of semi-structured interviews and focus groups with older, non-dependent drinkers and primary care practitioners in Northern England. METHOD: A total of 24 older adults aged ≥65 years and 35 primary care practitioners participated in interviews and focus groups. Data were analysed thematically, applying principles of constant comparison. RESULTS: Older adults were motivated to make changes to their alcohol use when they experienced symptoms, and if they felt that limiting consumption would enable them to maintain their quality of life. The results of alcohol-related screening were useful in providing insights into potential effects for individuals. Primary care practitioners motivated older people to make healthier decisions by highlighting individual risks of drinking, and potential gains of limiting intake. CONCLUSION: Later life is a time when older people may be open to making changes to their alcohol use, particularly when suggested by practitioners. Older people can struggle to recognise potential risks or perceive little gain in acting on perceived risks. Such perceptions may be challenging to navigate in supportive discussions.

Distinct microbial and immune niches of the human colon.

Gastrointestinal microbiota and immune cells interact closely and display regional specificity; however, little is known about how these communities differ with location. Here, we simultaneously assess microbiota and single immune cells across the healthy, adult human colon, with paired characterization of immune cells in the mesenteric lymph nodes, to delineate colonic immune niches at steady state. We describe distinct helper T cell activation and migration profiles along the colon and characterize the transcriptional adaptation trajectory of regulatory T cells between lymphoid tissue and colon. Finally, we show increasing B cell accumulation, clonal expansion and mutational frequency from the cecum to the sigmoid colon and link this to the increasing number of reactive bacterial species.

Health and social care providers' perspectives of older people's drinking: A systematic review and thematic synthesis of qualitative studies.

BACKGROUND: alcohol may increase risks to late-life health, due to its impact on conditions or medication. Older adults must weigh up the potential risks of drinking against perceived benefits associated with positive roles of alcohol in their social lives. Health and social care workers are in a key position to support older people's decisions about their alcohol use. OBJECTIVE: to systematically review and synthesise qualitative studies exploring health and social care providers' views and experiences of older people's drinking and its management in care services. METHOD: a pre-specified search strategy was applied to five electronic databases from inception to June 2018. Grey literature, relevant journals, references and citations of included articles were searched. Two independent reviewers sifted and quality-appraised articles. Included study findings were analysed through thematic synthesis. RESULTS: 18 unique studies were included. Four themes explained findings: uncertainty about drinking as a legitimate concern in care provision for older people; the impact of preconceptions on work with older adults; sensitivity surrounding alcohol use in later life; and negotiating responsibility for older adults' alcohol use. Discipline- and country-specific patterns are highlighted. CONCLUSIONS: reservations about addressing alcohol could mean that service providers do not intervene with older adults. Judgements of whether older care recipients' drinking warrants intervention are complex. Providers will need support and training to recognise and provide appropriate intervention for drinking amongst older care recipients.

Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology.

Significant advances in immunotherapies have resulted in the increasing need of predictive preclinical models to improve immunotherapeutic drug development, treatment combination, and to prevent or minimize toxicity in clinical trials. Immunodeficient mice reconstituted with human immune system (HIS), termed humanized mice or HIS mice, permit detailed analysis of human immune biology, development, and function. Although this model constitutes a great translational model, some aspects need to be improved as the incomplete engraftment of immune cells, graft versus host disease and the lack of human cytokines and growth factors. In this review, we discuss current HIS platforms, their pathology, and recent advances in their development to improve the quality of human immune cell reconstitution. We also highlight new technologies that can be used to better understand these models and how improved characterization is needed for their application in immuno-oncology safety, efficacy, and new modalities therapy development.

Drinking in later life: a systematic review and thematic synthesis of qualitative studies exploring older people's perceptions and experiences.

Background: alcohol presents risks to the health of older adults at levels that may have been 'safer' earlier in life. Moderate drinking is associated with some health benefits, and can play a positive role in older people's social lives. To support healthy ageing, we must understand older people's views with regards to their drinking. This study aims to synthesise qualitative evidence exploring the perceptions and experiences of alcohol use by adults aged 50 years and over. Methods: a pre-specified search strategy was applied to Medline, PsychINFO, Scopus, Applied Social Sciences Index and Abstracts and Cumulative Index to Nursing and Allied Health Literature databases from starting dates. Grey literature, relevant journals, references and citations of included articles were searched. Two independent reviewers sifted articles and assessed study quality. Principles of thematic analysis were applied to synthesise the findings from included studies. Results: of 2,056 unique articles identified, 25 articles met inclusion criteria. Four themes explained study findings: routines and rituals of older people's drinking; self-image as a responsible drinker; perceptions of alcohol and the ageing body; and older people's access to alcohol. Differences between gender, countries and social patterns are highlighted. Conclusions: older people perceive themselves as controlled and responsible drinkers. They may not recognise risks associated with alcohol, but appreciate its role in sustaining social and leisure activities important to health and well-being in later life. These are important considerations for intervention development. Drinking is routinised across the life course and may be difficult to change in retirement.