Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma (PRAD) and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Understanding paramedic work in general practice in the UK: a rapid realist synthesis.

BACKGROUND: General practice in the UK is under substantial pressure and practices are increasingly including paramedics as part of their workforce. Little is known about how different models of paramedic working may affect successful implementation of the role, as viewed from patient, clinician and system perspectives. This realist synthesis developed theories about 'models of paramedic working in general practice' in different UK contexts to understand their impact. METHODS: The rapid realist synthesis comprised data from: (1) empirical and grey literature searches; (2) semi-structured realist interviews with system leaders involved with the implementation of the role; and (3) a stakeholder event with healthcare professionals and the public, to develop initial programme theories that can be tested in future work. Sources were analysed using a realist approach that explored the data for novel or causal insights to generate initial programme theories. RESULTS: Empirical sources (n = 32), grey sources (n = 95), transcripts from system leader interviews (n = 7) and audio summaries from the stakeholder event (n = 22 participants) were synthesised into a single narrative document. The findings confirmed the presence of a wide variety of models of paramedic working in UK general practice. The perceived success of models was influenced by the extent to which the paramedic service was mature and embedded in practice, and according to four theory areas: (1) Primary care staff understanding and acceptance of the paramedic role; (2) Paramedic induction process, including access to training, supervision and development opportunities; (3) Patient understanding and acceptance of the role; (4) Variations in paramedic employment models. CONCLUSIONS: Variability in how the paramedic role is operating and embedding into general practice across the UK affects the success of the role. These findings provide a theoretical foundation for future research to investigate various 'models of paramedic working' in different contexts.

Parsing digital or analogue TCR performance through piconewton forces.

αß T-cell receptors (TCRs) recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP 366-374 /D b and PA 224-233 /D b , respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker upregulation in vitro . Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies. One Sentence Summary: Quality of ligand recognition in a T-cell repertoire is revealed through application of physical load on clonal T-cell receptor (TCR)-pMHC bonds.

KDM6A epigenetically regulates subtype plasticity in small cell lung cancer.

Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.

Prompt identification of struggling candidates in near peer-led basic life support training: piloting an online performance scoring system.

BACKGROUND: Bristol Medical School has adopted a near peer-led teaching approach to deliver Basic Life Support training to first year undergraduate medical students. Challenges arose when trying to identify early in the course which candidates were struggling with their learning, in sessions delivered to large cohorts. We developed and piloted a novel, online performance scoring system to better track and highlight candidate progress. METHODS: During this pilot, a 10-point scale was used to evaluate candidate performance at six time-points during their training. The scores were collated and entered on an anonymised secure spreadsheet, which was conditionally formatted to provide a visual representation of the score. A One-Way ANOVA was performed on the scores and trends analysed during each course to review candidate trajectory. Descriptive statistics were assessed. Values are presented as mean scores with standard deviation (x̄±SD). RESULTS: A significant linear trend was demonstrated (P < 0.001) for the progression of candidates over the course. The average session score increased from 4.61 ± 1.78 at the start to 7.92 ± 1.22 at the end of the final session. A threshold of less than 1SD below the mean was used to identify struggling candidates at any of the six given timepoints. This threshold enabled efficient highlighting of struggling candidates in real time. CONCLUSIONS: Although the system will be subject to further validation, our pilot has shown the use of a simple 10-point scoring system in combination with a visual representation of performance helps to identify struggling candidates earlier across large cohorts of students undertaking skills training such as Basic Life Support. This early identification enables effective and efficient remedial support.

Cross-cultural adaptation and its impact on research in emergency care.

The perspective of patients is increasingly recognised as important to care improvement and innovation. Patient questionnaires such as patient-reported outcome measures may often require cross-cultural adaptation (CCA) to gather their intended information most effectively when used in cultures and languages different to those in which they were developed. The use of CCA could be seen as a practical step in addressing the known problems of inclusion, diversity and access in medical research.An example of the recent adaptation of a patient-reported outcome measure for use with ED patients is used to explore some key features of CCA, introduce the importance of CCA to emergency care practitioners and highlight the limitations of CCA.

GP roles in emergency medical services: a systematic mapping review and narrative synthesis.

BACKGROUND: A significant proportion of emergency medical services (EMS) work is for problems that may be amenable to timely primary care management and could benefit from GP input. Utilising GPs in EMS may reduce avoidable emergency department (ED) conveyance, releasing emergency ambulances for higher-acuity care, and meeting patient needs earlier in the evolution of an emergency call. AIM: To collate and summarise evidence on how GPs are utilised in EMS. DESIGN & SETTING: Systematic mapping review and narrative synthesis. METHOD: A systematic literature search was conducted using search terms for general practice and emergency care. Primary research articles investigating the utilisation of GPs in non-critical EMS were included. An inductive framework was used to structure the results alongside a narrative synthesis. RESULTS: Twenty-one articles were included. GPs were embedded in EMS for urgent management of high-acuity patients or used as an intervention to avoid unnecessary ED conveyance in selected lower-acuity patients. The importance of interprofessional relationships and training for GPs involved in EMS was highlighted. No studies explored patient-reported outcomes. Outcomes measured were predominantly ED non-conveyance and admission avoidance, with GP services as an intervention reducing the likelihood of these outcomes. CONCLUSION: Embedding GPs in EMS might service different purposes depending on context. There is some evidence that GP EMS services may reduce the likelihood of ED conveyance and hospital admission in selected cases; it is unclear whether this is owing to case selection or GP involvement. Future research should incorporate patients' views and experiences.

ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma.

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.

Potential for Paramedic roles in Irish General Practice: A qualitative study of stakeholder's perspectives.

Background: Irish health policy emphasises the role of Primary Care and General Practice however, there is a growing shortage of General Practitioners (GPs) in Ireland. Paramedics have traditionally focused on emergency care in the community. More recently Paramedics have taken on roles in General Practice in international jurisdictions, but not yet in Ireland. This study aimed to explore key stakeholder perceptions of 'the potential for Paramedic roles in Irish General Practice'. Methods: We conducted an exploratory, qualitative stakeholder consultation study incorporating in-depth semi structured telephone interviews followed by thematic analysis. Interviews were conducted with a total of eighteen participants that included six senior Paramedics (Advanced Paramedics), seven General Practitioners (GPs), three Practice Nurses and two Practice Managers. Results: Participants in this study expressed polarised views on the potential for Paramedic roles in Irish General Practice. Paramedics were enthusiastic, highlighting opportunity for professional development and favourable working conditions. GPs, Practice Nurses and Managers were more circumspect and had concerns that Paramedic scope and skillset was not currently aligned to General Practice care. GPs, Practice Nurses and Managers emphasised a greater role for expanded General Practice Nursing. There were varied perceptions on what the potential role of a Paramedic in General Practice might entail, but consensus that Government support would be required to facilitate any potential developments. Conclusions: The findings of this research can inform future development of novel roles in Irish General Practice and suggests that there is appetite from within the Paramedic profession to pursue such roles. A pilot demonstration project, grounded in an action research framework could address data gaps and potential concerns. Any future developments should occur in tandem with and with due consideration for the expansion of General Practice Nursing in Ireland.

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

Mental health and help seeking among trauma-exposed emergency service staff: a qualitative evidence synthesis.

OBJECTIVES: To identify factors and contexts that may contribute to mental health and recovery from psychological difficulties for emergency service workers (ESWs) exposed to occupational trauma, and barriers and facilitators to help-seeking behaviour among trauma-exposed ESWs. BACKGROUND: ESWs are at greater risk of stressor-related psychopathology than the general population. Exposure to occupational stressors and trauma contribute to the observed rates of post-trauma psychopathology in this occupational group with implications for workforce sustainability. Types of organisational interventions offered to trauma-exposed ESWs are inconsistent across the UK, with uncertainty around how to engage staff. DESIGN: Four databases (OVID MEDLINE, EMBASE, PsycINFO and SCOPUS) were systematically searched from 1 January 1980 to March 2020, with citation tracking and reference chaining. A modified Critical Appraisal Skills Programme tool and quality appraisal prompts were used to identify fatally flawed studies. Qualitative studies of trauma-exposure in front-line ESWs were included, and data were extracted using a customised extraction table. Included studies were analysed using thematic synthesis. RESULTS: A qualitative evidence synthesis was conducted with 24 qualitative studies meeting inclusion criteria, as defined by the PerSPEcTiF framework. Fourteen descriptive themes emerged from this review, categorised into two overarching constructs: (1) factors contributing to mental health (such as the need for downtime, peer support and reassurance) and (2) factors influencing help-seeking behaviour (such as stigma, the content/form/mandatory nature of interventions, and mental health literacy issues including emotional awareness and education). CONCLUSION: ESWs reported disconnect between the organisations' cultural positioning on trauma-related mental health, the reality of undertaking the role and the perceived applicability and usefulness of trauma interventions. Following traumatic exposure, ESWs identify benefitting from recovery time and informal support from trusted colleagues. A culture which encourages help seeking and open dialogue around mental health may reduce stigma and improve recovery from mental ill health associated with trauma exposure.

Regression discontinuity analysis for pharmacovigilance: statin example reflected trial findings showing little evidence of harm.

OBJECTIVES: The study aims to explore the use of regression discontinuity analysis (RDA) to examine effects of prescription of statins on total cholesterol and adverse outcomes (type 2 diabetes, rhabdomyolysis and myopathy, myalgia and myositis, liver disease, CVD, and mortality). STUDY DESIGN AND SETTING: We conducted a prospective cohort study using the Clinical Practice Research Datalink including patients with QRISK scores of 10 to 30 in 2010 to 2013 who were last followed-up in October 2016. Comparing patients with QRISK≥20 and QRISK<20, we explored RDA assumptions, provided proof of concept analyses (total cholesterol as outcome), and investigated the effect of statins prescription on adverse outcomes. RESULT: RDA confirmed statin prescription reduced total cholesterol (Mean difference (MD) -1.33 mmol/L, 95%Confidence Interval (CI) -1.93 to -0.73). RDA provided little evidence for adverse effects on diabetes, myalgia and myositis, liver disease, CVD, or mortality. The RDA analysis findings are similar to RCT results. Findings from non-RDA analysis agree with published observational studies. CONCLUSION: RDA can be used with large routine clinical datasets to provide evidence on effects of medications which are prescribed according to a threshold. Testable RDA assumptions were satisfied, but confidence intervals were wide, partly due to the low compliance with the prescribing threshold.

Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

Factors affecting the documentation of spoken safety-netting advice in routine GP consultations: a cross-sectional study.

BACKGROUND: Previous studies have reported how often safety-netting is documented in medical records, but it is not known how this compares with what is verbalised and what factors might influence the consistency of documentation. AIM: To compare spoken and documented safety-netting advice and to explore factors associated with documentation. DESIGN AND SETTING: A cross-sectional study, using an existing GP consultations archive. METHOD: Observational coding involving classifying and quantifying medical record entries and comparison with spoken safety-netting advice in 295 video-/audio-recorded consultations. Associations were tested using logistic regression. RESULTS: Two-thirds of consultations (192/295) contained spoken safety-netting advice that applied to less than half of the problems assessed (242/516). Only one-third of consultations (94/295) had documented safety-netting advice, which covered 20.3% of problems (105/516). The practice of GPs varied widely, from those that did not document their safety-netting advice to those that nearly always did so (86.7%). GPs were more likely to document their safety-netting advice for new problems (P = 0.030), when only a single problem was discussed in a consultation (P = 0.040), and when they gave specific rather than generic safety-netting advice (P = 0.007). In consultations where multiple problems were assessed (n = 139), the frequency of spoken and documented safety-netting advice decreased the later a problem was assessed. CONCLUSION: GPs frequently do not document the safety-netting advice they have given to patients, which may have medicolegal implications in the event of an untoward incident. GPs should consider how safely they can assess and document more than one problem in a single consultation and this risk should be shared with patients to help manage expectations.

What factors are associated with ambulance use for non-emergency problems in children? A systematic mapping review and qualitative synthesis.

OBJECTIVE: To explore what factors are associated with ambulance use for non-emergency problems in children. METHODS: This study is a systematic mapping review and qualitative synthesis of published journal articles and grey literature. Searches were conducted on the following databases, for articles published between January 1980 and July 2020: MEDLINE, EMBASE, PsycINFO, CINAHL and AMED. A Google Scholar and a Web of Science search were undertaken to identify reports or proceedings not indexed in the above. Book chapters and theses were searched via the OpenSigle, EThOS and DART databases. A literature advisory group, including experts in the field, were contacted for relevant grey literature and unpublished reports. The inclusion criteria incorporated articles published in the English language reporting findings for the reasons behind why there are so many calls to the ambulance service for non-urgent problems in children. Data extraction was divided into two stages: extraction of data to generate a broad systematic literature 'map', and extraction of data from highly relevant papers using qualitative methods to undertake a focused qualitative synthesis. An initial table of themes associated with reasons for non-emergency calls to the ambulance for children formed the 'thematic map' element. The uniting feature running through all of the identified themes was the determination of 'inappropriateness' or 'appropriateness' of an ambulance call out, which was then adopted as the concept of focus for our qualitative synthesis. RESULTS: There were 27 articles used in the systematic mapping review and 17 in the qualitative synthesis stage of the review. Four themes were developed in the systematic mapping stage: socioeconomic status/geographical location, practical reasons, fear of consequences and parental education. Three analytical themes were developed in the qualitative synthesis stage including practicalities and logistics of obtaining care, arbitrary scoring system and retrospection. CONCLUSIONS: There is a lack of public and caregiver understanding about the use of ambulances for paediatrics. There are factors that appear specific to choosing ambulance care for children that are not so prominent in adults (fever, reassurance, fear of consequences). Future areas for attention to decrease ambulance activation for paediatric low-acuity reports were highlighted as: identifying strategies for helping caregivers to mitigate perceived risk, increasing availability of primary care, targeted education to particular geographical areas, education to first-time parents with infants and providing alternate means of transportation. PROSPERO REGISTRATION NUMBER: CRD42019160395.

Antibiotic prescribing in UK out-of-hours primary care services: a realist-informed scoping review of training and guidelines for healthcare professionals.

BACKGROUND: Antibiotic overuse has contributed to antimicrobial resistance, which is a global public health problem. In the UK, despite the fall in rates of antibiotic prescription since 2013, prescribing levels remain high in comparison with other European countries. Prescribing in out-of-hours (OOH) care provides unique challenges for prudent prescribing, for which professionals may not be prepared. AIM: To explore the guidance available to professionals on prescribing antibiotics for common infections in OOH primary care within the UK, with a focus on training resources, guidelines, and clinical recommendations. DESIGN & SETTING: A realist-informed scoping review of peer-reviewed articles and grey literature. METHOD: The review focused on antibiotic prescribing OOH (for example, clinical guidelines and training videos). General prescribing guidance was searched whenever OOH-focused resources were unavailable. Electronic databases and websites of national agencies and professional societies were searched following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Findings were organised according to realist review components, that is, mechanisms, contexts, and outcomes. RESULTS: In total, 46 clinical guidelines and eight training resources were identified. Clinical guidelines targeted adults and children, and included recommendations on prescription strategy, spectrum of the antibiotic prescribed, communication with patients, treatment duration, and decision-making processes. No clinical guidelines or training resources focusing specifically on OOH were found. CONCLUSION: The results highlight a lack of knowledge about whether existing resources address the challenges faced by OOH antibiotic prescribers. Further research is needed to explore the training needs of OOH health professionals, and whether further OOH-focused resources need to be developed given the rates of antibiotic prescribing in this setting.

CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor Cells and T Cells.

A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise antitumor immune function. We discovered that inhibition of CARM1, an epigenetic enzyme and cotranscriptional activator, elicited beneficial antitumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their antitumor function and preserved memory-like populations required for sustained antitumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells, and natural killer cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of CARM1 with a small molecule elicited potent antitumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this cotranscriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack. SIGNIFICANCE: Resistance to cancer immunotherapy remains a major challenge. Targeting of CARM1 enables immunotherapy of resistant tumors by enhancing T-cell functionality and preserving memory-like T-cell populations within tumors. CARM1 inhibition also sensitizes resistant tumor cells to immune attack by inducing a tumor cell-intrinsic type 1 interferon response.This article is highlighted in the In This Issue feature, p. 1861.

The diversity and function of sourdough starter microbiomes.

Humans have relied on sourdough starter microbial communities to make leavened bread for thousands of years, but only a small fraction of global sourdough biodiversity has been characterized. Working with a community-scientist network of bread bakers, we determined the microbial diversity of 500 sourdough starters from four continents. In sharp contrast with widespread assumptions, we found little evidence for biogeographic patterns in starter communities. Strong co-occurrence patterns observed in situ and recreated in vitro demonstrate that microbial interactions shape sourdough community structure. Variation in dough rise rates and aromas were largely explained by acetic acid bacteria, a mostly overlooked group of sourdough microbes. Our study reveals the extent of microbial diversity in an ancient fermented food across diverse cultural and geographic backgrounds.

Sourdough bread is an ancient fermented food that has sustained humans around the world for thousands of years. It is made from a sourdough 'starter culture' which is maintained, portioned, and shared among bread bakers around the world. The starter culture contains a community of microbes made up of yeasts and bacteria, which ferment the carbohydrates in flour and produce the carbon dioxide gas that makes the bread dough rise before baking. The different acids and enzymes produced by the microbial culture affect the bread's flavor, texture and shelf life. However, for such a dependable staple, sourdough bread cultures and the mixture of microbes they contain have scarcely been characterized. Previous studies have looked at the composition of starter cultures from regions within Europe. But there has never been a comprehensive study of how the microbial diversity of sourdough starters varies across and between continents. To investigate this, Landis, Oliverio et al. used genetic sequencing to characterize the microbial communities of sourdough starters from the homes of 500 bread bakers in North America, Europe and Australasia. Bread makers often think their bread's unique qualities are due to the local environment of where the sourdough starter was made. However, Landis, Oliverio et al. found that geographical location did not correlate with the diversity of the starter cultures studied. The data revealed that a group of microbes called acetic acid bacteria, which had been overlooked in past research, were relatively common in starter cultures. Moreover, starters with a greater abundance of this group of bacteria produced bread with a strong vinegar aroma and caused dough to rise at a slower rate. This research demonstrates which species of bacteria and yeast are most commonly found in sourdough starters, and suggests geographical location has little influence on the microbial diversity of these cultures. Instead, the diversity of microbes likely depends more on how the starter culture was made and how it is maintained over time.

Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production.

The mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from the dorsal telencephalon, whereas inhibitory interneurons are generated in its ventral portion. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear whether PRDM16 plays a similar role in neurogenesis in both dorsal and ventral progenitor lineages and, if so, whether it regulates common or unique networks of genes. Here, we show that Prdm16 expression in mouse medial ganglionic eminence (MGE) progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of forebrain GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. PRDM16 regulates convergent developmental gene expression programs in the cortex and MGE, which utilize both common and region-specific sets of genes to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

Urgent care for patients with dementia: a scoping review of associated factors and stakeholder experiences.

OBJECTIVES: People with dementia are more vulnerable to complications in urgent health situations due to older age, increased comorbidity, higher dependency on others and cognitive impairment. This review explored the factors associated with urgent care use in dementia and the experiences of people with dementia, informal carers and professionals. DESIGN: Scoping review. The search strategy and data synthesis were informed by people with dementia and carers. DATA SOURCES: Searches of CINAHL, Embase, Medline, PsycINFO, PubMed were conducted alongside handsearches of relevant journals and the grey literature through 15 January 2019. ELIGIBILITY CRITERIA: Empirical studies including all research designs, and other published literature exploring factors associated with urgent care use in prehospital and emergency room settings for people with dementia were included. Two authors independently screened studies for inclusion. DATA EXTRACTION AND SYNTHESIS: Data were extracted using charting techniques and findings were synthesised according to content and themes. RESULTS: Of 2967 records identified, 54 studies were included in the review. Specific factors that influenced use of urgent care included: (1) common age-related conditions occurring alongside dementia, (2) dementia as a diagnosis increasing or decreasing urgent care use, (3) informal and professional carers, (4) patient characteristics such as older age or behavioural symptoms and (5) the presence or absence of community support services. Included studies reported three crucial components of urgent care situations: (1) knowledge of the patient and dementia as a condition, (2) inadequate non-emergency health and social care support and (3) informal carer education and stress. CONCLUSIONS: The scoping review highlighted a wider variety of sometimes competing factors that were associated with urgent care situations. Improved and increased community support for non-urgent situations, such as integrated care, caregiver education and dementia specialists, will both mitigate avoidable urgent care use and improve the experience of those in crisis.