Mitigating the impact of air pollution on dementia and brain health: Setting the policy agenda.

BACKGROUND: Emerging research suggests exposure to high levels of air pollution at critical points in the life-course is detrimental to brain health, including cognitive decline and dementia. Social determinants play a significant role, including socio-economic deprivation, environmental factors and heightened health and social inequalities. Policies have been proposed more generally, but their benefits for brain health have yet to be fully explored. OBJECTIVE AND METHODS: Over the course of two years, we worked as a consortium of 20+ academics in a participatory and consensus method to develop the first policy agenda for mitigating air pollution's impact on brain health and dementia, including an umbrella review and engaging 11 stakeholder organisations. RESULTS: We identified three policy domains and 14 priority areas. Research and Funding included: (1) embracing a complexities of place approach that (2) highlights vulnerable populations; (3) details the impact of ambient PM2.5 on brain health, including current and historical high-resolution exposure models; (4) emphasises the importance of indoor air pollution; (5) catalogues the multiple pathways to disease for brain health and dementia, including those most at risk; (6) embraces a life course perspective; and (7) radically rethinks funding. Education and Awareness included: (8) making this unrecognised public health issue known; (9) developing educational products; (10) attaching air pollution and brain health to existing strategies and campaigns; and (11) providing publicly available monitoring, assessment and screening tools. Policy Evaluation included: (12) conducting complex systems evaluation; (13) engaging in co-production; and (14) evaluating air quality policies for their brain health benefits. CONCLUSION: Given the pressing issues of brain health, dementia and air pollution, setting a policy agenda is crucial. Policy needs to be matched by scientific evidence and appropriate guidelines, including bespoke strategies to optimise impact and mitigate unintended consequences. The agenda provided here is the first step toward such a plan.

Reinforcing the supply chain of umifenovir and other antiviral drugs with retrosynthetic software.

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.

Healthy, happy places-a more integrated approach to creating health and well-being through the built environment?

INTRODUCTION: This paper explores how the built environment impacts upon health and well-being and suggests that there are opportunities for more integrated working between professionals and citizens to create healthier, happier places. SOURCES OF DATA: Policy and practice guidance is presented from the urban planning and design fields. Evidence and data are presented from a range of disciplines on housing, green infrastructure and mental well-being. AREAS OF AGREEMENT: There is an overwhelming agreement around the principles and rationale of incorporating health in planning and design processes. AREAS OF CONTROVERSY: These principles are not always implemented in practice. Challenges also exist around how different disciplines create and use evidence. GROWING POINTS: More innovative ways of working which incorporates health, public health, planners, designers and citizens, which responds to the needs of communities, should be tested. AREAS TIMELY FOR DEVELOPING RESEARCH: Health and public health professionals can contribute to the evidence base using objective measures to assess the impact of the built environment on mental health and well-being.

An expedient formal total synthesis of (-)-diazonamide A via a powerful, stereoselective O-aryl to C-aryl migration to form the C10 quaternary center.

During the course of studies on the synthesis of diazonamide A 1, an unusual O-aryl into C-aryl rearrangement was discovered that allows partial control of the absolute stereochemistry of the C-10 quaternary stereogenic center. Treatment of 30 with TBAF/THF gave the O-tyrosine ethers 31 and 32 (1:1), which on heating each separately in chloroform at reflux rearranged to 33 and 34 in ratios of 84:16 and 56:44, respectively. This corresponds to a 70% yield of the correct C-10 stereoisomer 33 and a 30% yield of the wrong C-10 stereoisomer 34. Attempts to convert 34 into 33 by ipso-protonation and equilibration were unsuccessful. Confirmation of the stereochemical outcome of the rearrangement was obtained by converting 33 into 37, an advanced intermediate in the first synthesis of diazonamide A by Nicolaou et al. It was also found that the success of the above rearrangement is sensitive to the protecting group on both the tryptophan nitrogen atom and the tyrosine nitrogen atom.

Thermal and acid-catalyzed Hofmann-Martius rearrangement of 3-N-aryl-2-oxindoles into 3-(arylamino)-2-oxindoles.

[reaction: see text] The Hofmann-Martius rearrangement of 3-N-aryl-2-oxindoles into 3-(arylamino)-2-oxindoles under thermal and acid-catalyzed conditions is described.

A mild thermal and acid-catalyzed rearrangement of O-aryl ethers into ortho-hydroxy arenes.

[reaction: see text] An unusual rearrangement of an O-aryl ether to an ortho-hydroxyaryl system was discovered during our studies on the synthesis of diazonamide A. We discuss the exploration of this rearrangement under mild thermal and both Brønsted and Lewis acid-catalyzed conditions.

Dearomatising rearrangements of lithiated thiophenecarboxamides.

Thiophene-3-carboxamides bearing allyl or benzyl substituents at nitrogen undergo dearomatising cyclisation on treatment with LDA. Rearrangements transform the dearomatised products into pyrrolinones, azepinones or partially saturated azepinothiophenes.

Nucleophilic addition to electron-rich heteroaromatics: dearomatizing anionic cyclizations of pyrrolecarboxamides.

[reaction: see text] Despite its electron-rich nature, a pyrrole ring is susceptible to intramolecular nucleophilic attack by organolithiums. The resulting dearomatizing anionic cyclization yields new 5- or 7-membered heterocyclic rings. Formation of a new 5-membered ring, by cyclization of an N-benzylpyrrolecarboxamide, is accompanied by ring opening of the original pyrrole to yield 3-aminovinylpyrrolinones. Formation of a new 7-membered ring, by cyclization of an N-allyl pyrrolecarboxamide, yields bicyclic pyrroloazepinones.