Ensembles of endothelial and mural cells promote angiogenesis in prenatal human brain.

Interactions between angiogenesis and neurogenesis regulate embryonic brain development. However, a comprehensive understanding of the stages of vascular cell maturation is lacking, especially in the prenatal human brain. Using fluorescence-activated cell sorting, single-cell transcriptomics, and histological and ultrastructural analyses, we show that an ensemble of endothelial and mural cell subtypes tile the brain vasculature during the second trimester. These vascular cells follow distinct developmental trajectories and utilize diverse signaling mechanisms, including collagen, laminin, and midkine, to facilitate cell-cell communication and maturation. Interestingly, our results reveal that tip cells, a subtype of endothelial cells, are highly enriched near the ventricular zone, the site of active neurogenesis. Consistent with these observations, prenatal vascular cells transplanted into cortical organoids exhibit restricted lineage potential that favors tip cells, promotes neurogenesis, and reduces cellular stress. Together, our results uncover important mechanisms into vascular maturation during this critical period of human brain development.

The Importance of Timing.

Building a nervous system requires a precise sequence of genetic transitions, mediated in part by the temporal and spatial regulation of transcription factors. Quan et al. add to our understanding of this regulation by describing an evolutionarily conserved post-translational mechanism that rapidly extinguishes proneural protein activity in neural precursors.

What makes a multidisciplinary medication review and deprescribing intervention for older people work well in primary care? A realist review and synthesis.

BACKGROUND: A third of older people take five or more regular medications (polypharmacy). Conducting medication reviews in primary care is key to identify and reduce/ stop inappropriate medications (deprescribing). Recent recommendations for effective deprescribing include shared-decision making and a multidisciplinary approach. Our aim was to understand when, why, and how interventions for medication review and deprescribing in primary care involving multidisciplinary teams (MDTs) work (or do not work) for older people. METHODS: A realist synthesis following the Realist And Meta-narrative Evidence Syntheses: Evolving Standards guidelines was completed. A scoping literature review informed the generation of an initial programme theory. Systematic searches of different databases were conducted, and documents screened for eligibility, with data extracted based on a Context, Mechanisms, Outcome (CMO) configuration to develop further our programme theory. Documents were appraised based on assessments of relevance and rigour. A Stakeholder consultation with 26 primary care health care professionals (HCPs), 10 patients and three informal carers was conducted to test and refine the programme theory. Data synthesis was underpinned by Normalisation Process Theory to identify key mechanisms to enhance the implementation of MDT medication review and deprescribing in primary care. FINDINGS: A total of 2821 abstracts and 175 full-text documents were assessed for eligibility, with 28 included. Analysis of documents alongside stakeholder consultation outlined 33 CMO configurations categorised under four themes: 1) HCPs roles, responsibilities and relationships; 2) HCPs training and education; 3) the format and process of the medication review 4) involvement and education of patients and informal carers. A number of key mechanisms were identified including clearly defined roles and good communication between MDT members, integration of pharmacists in the team, simulation-based training or team building training, targeting high-risk patients, using deprescribing tools and drawing on expertise of other HCPs (e.g., nurses and frailty practitioners), involving patents and carers in the process, starting with 'quick wins', offering deprescribing as 'drug holidays', and ensuring appropriate and tailored follow-up plans that allow continuity of care and management. CONCLUSION: We identified key mechanisms that could inform the design of future interventions and services that successfully embed deprescribing in primary care.

Alkaline air: changing perspectives on nitrogen and air pollution in an ammonia-rich world.

Ammonia and ammonium have received less attention than other forms of air pollution, with limited progress in controlling emissions at UK, European and global scales. By contrast, these compounds have been of significant past interest to science and society, the recollection of which can inform future strategies. Sal ammoniac (nushadir, nao sha) is found to have been extremely valuable in long-distance trade (ca AD 600-1150) from Egypt and China, where 6-8 kg N could purchase a human life, while air pollution associated with nushadir collection was attributed to this nitrogen form. Ammonia was one of the keys to alchemy-seen as an early experimental mesocosm to understand the world-and later became of interest as 'alkaline air' within the eighteenth century development of pneumatic chemistry. The same economic, chemical and environmental properties are found to make ammonia and ammonium of huge relevance today. Successful control of acidifying SO2 and NOx emissions leaves atmospheric NH3 in excess in many areas, contributing to particulate matter (PM2.5) formation, while leading to a new significance of alkaline air, with adverse impacts on natural ecosystems. Investigations of epiphytic lichens and bog ecosystems show how the alkalinity effect of NH3 may explain its having three to five times the adverse effect of ammonium and nitrate, respectively. It is concluded that future air pollution policy should no longer neglect ammonia. Progress is likely to be mobilized by emphasizing the lost economic value of global N emissions ($200 billion yr-1), as part of developing the circular economy for sustainable nitrogen management. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Toward a Generic Analytical Framework for Sustainable Nitrogen Management: Application for China.

Managing reactive nitrogen (Nr) to achieve a sustainable balance between production of food, feed and fiber, and environmental protection is a grand challenge in the context of an increasingly affluent society. Here, we propose a novel framework for national nitrogen (N) assessments enabling a more consistent comparison of the uses, losses and impacts of Nr between countries, and improvement of Nr management for sustainable development at national and regional scales. This framework includes four key components: national scale N budgets, validation of N fluxes, cost-benefit analysis and Nr management strategies. We identify four critical factors for Nr management to achieve the sustainable development goals: N use efficiency (NUE), Nr recycling ratio (e.g., ratio of livestock excretion applied to cropland), human dietary patterns and food waste ratio. This framework was partly adopted from the European Nitrogen Assessment and now is successfully applied to China, where it contributed to trigger policy interventions toward improvements for future sustainable use of Nr. We demonstrate how other countries can also benefit from the application our framework, in order to include sustainable Nr management under future challenges of growing population, hence contributing to the achievement of some key sustainable development goals (SDGs).

Persistently normal blood tests in patients taking methotrexate for RA or azathioprine for IBD: a retrospective cohort study.

BACKGROUND: Disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate and azathioprine, are commonly used to treat rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Blood-test safety monitoring is mainly undertaken in primary care. Normal blood results are common. AIM: To determine the frequency and associations of persistently normal blood tests in patients with RA prescribed methotrexate, and patients with IBD prescribed azathioprine. DESIGN AND SETTING: Two-year retrospective study of a cohort taken from an electronic pseudonymised primary care/laboratory database covering >1.4 million patients across Hampshire, UK. METHOD: Patients with RA and IBD, and associated methotrexate and azathioprine prescriptions, respectively, were identified. Tests and test thresholds recommended by the National Institute for Health and Care Excellence were applied. Persistent normality was defined as no abnormalities of any tests nor alanine aminotransferase (ALT), white blood count (WBC), neutrophils, and estimated glomerular filtration rate (eGFR) individually. Logistic regression was used to identify associations with test normality. RESULTS: Of 702 265 adults, 7102 had RA and 8597 had IBD. In total, 3001 (42.3%) patients with RA were prescribed methotrexate and 1162 (13.5%) patients with IBD were prescribed azathioprine; persistently normal tests occurred in 1585 (52.8%) and 657 (56.5%) of the populations, respectively. In patients with RA on methotrexate, 585 (19.5%) had eGFR, 219 (7.3%) ALT, 217 (7.2%) WBC, and 202 (6.7%) neutrophil abnormalities. In patients with IBD on azathioprine, 138 (11.9%) had WBC, 88 (7.6%) eGFR, 72 (6.2%) ALT, and 65 (5.6%) neutrophil abnormalities. Those least likely to have persistent test normality were older and/or had comorbidities. CONCLUSION: Persistent test normality is common when monitoring these DMARDs, with few hepatic or haematological abnormalities. More stratified monitoring approaches should be explored.

Characterising risk of non-steroidal anti-inflammatory drug-related acute kidney injury: a retrospective cohort study.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for pain and inflammation. NSAID complications include acute kidney injury (AKI), causing burden to patients and health services through increased morbidity, mortality, and hospital admissions. AIM: To measure the extent of NSAID prescribing in an adult population, the degree to which patients with potential higher risk of AKI were exposed to NSAIDs, and to quantify their risk of AKI. DESIGN & SETTING: Retrospective 2-year closed-cohort study. METHOD: A retrospective cohort of adults was identified from a pseudonymised electronic primary care database in Hampshire, UK. The cohort had clinical information, prescribing data, and complete GP- and hospital-ordered biochemistry data. NSAID exposure (minimum one prescription in a 2-month period) was categorised as never, intermittent, and continuous, and first AKI using the national AKI e-alert algorithm. Descriptive statistics and logistic regression were used to explore NSAID prescribing patterns and AKI risk. RESULTS: The baseline population was 702 265. NSAID prescription fell from 19 364 (2.8%) to 16 251 (2.4%) over 2 years. NSAID prescribing was positively associated with older age, female sex, greater socioeconomic deprivation, and certain comorbidities (diabetes, hypertension, osteoarthritis, and rheumatoid arthritis) and negatively with cardiovascular disease (CVD) and heart failure. Among those prescribed NSAIDs, AKI was associated with older age, greater deprivation, chronic kidney disease (CKD), CVD, heart failure, diabetes, and hypertension. CONCLUSION: Despite generally good prescribing practice, NSAID prescribing was identified in some people at higher risk of AKI (for example, patients with CKD and older) for whom medication review and NSAID deprescribing should be considered.

A rapid review and narrative synthesis of hospital to community pharmacy transfer of care services in England.

OBJECTIVES: A new discharge medicines service in England has been proposed for rollout in July 2020. This study aims to appraise the evidence for hospital to community pharmacy referral services in England. A rapid review methodology was adopted, findings were synthesised and reported narratively. The PubMed search engine was used and specific pharmacy journals were searched in March 2020. Studies published since 2012, reporting on transfer of care (ToC) services provided from hospitals and community pharmacies in England were included. Study data analysed included clinical outcomes; findings relating to implementation, staff and patient perceptions and experiences. Studies were assessed for risk of bias using a critical appraisal checklist. KEY FINDINGS: Ten studies met the inclusion criteria. The ToC services varied in relation to patients targeted, mode of referral, and post-discharge service provided. There were some conservative observations that ToC services were associated with reduced hospital readmission rates, however other outcomes were less well substantiated. Pharmacy staff were generally supportive of these services for patient benefit, however, patient engagement and accessibility issues have been reported. SUMMARY: There is some emerging evidence that hospital to community pharmacy referral services are associated with reduced hospital readmission. Service delivery reported in these studies highlights barriers and facilitators to patient recruitment, engagement and follow-up and limitations on recording and measuring meaningful outcomes. Future work is recommended to take advantage of the implementation and delivery of the national service that includes the analysis of patient data at scale to substantiate evidence in this area.

Listening effort at signal-to-noise ratios that are typical of the school classroom.

OBJECTIVE: The aim of the study was to measure listening effort at typical classroom signal-to-noise ratios (SNRs). DESIGN: Listening effort was measured using a dual task paradigm. Participants repeated monosyllabic words presented in a background of children's chatter (primary task) at SNRs that are considered typical of the school classroom environment (quiet, +4, 0, -4 dB) while simultaneously rehearsing sets of five digits for recall (secondary task). High listening effort requires greater cognitive resources and is associated with reduced performance on the secondary task. STUDY SAMPLE: Thirty one normal-hearing children (9-12 years). RESULTS: Performance was generally maintained on the listening task when multitasking; however, performance decreased on the secondary recall task, especially at the more negative SNRs. CONCLUSIONS: This demonstrates that considerable listening effort is required when listening at SNRs that are typical of the school classroom.

Serotonergic Modulation of Walking in Drosophila.

To navigate complex environments, animals must generate highly robust, yet flexible, locomotor behaviors. For example, walking speed must be tailored to the needs of a particular environment. Not only must animals choose the correct speed and gait, they must also adapt to changing conditions and quickly respond to sudden and surprising new stimuli. Neuromodulators, particularly the small biogenic amine neurotransmitters, have the ability to rapidly alter the functional outputs of motor circuits. Here, we show that the serotonergic system in the vinegar fly, Drosophila melanogaster, can modulate walking speed in a variety of contexts and also change how flies respond to sudden changes in the environment. These multifaceted roles of serotonin in locomotion are differentially mediated by a family of serotonergic receptors with distinct activities and expression patterns.