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Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years 1 – 7 . However, the field has progressed greatly since the development of early programs such as LHASA 1 , 7 , for which reaction choices at each step were made by human operators. Multiple software platforms 6 , 8 – 14 are now capable of completely autonomous planning. But these programs ‘think’ only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary 15 , 16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program’s knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships 17 , 18 , allowing it to ‘strategize’ over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts.

Modern organic reaction discovery and development relies on the rapid assessment of large arrays of hypothesis-driven experiments. The time-intensive nature of reaction analysis presents the greatest practical barrier for the execution of this iterative process that underpins the development of new bioactive agents. Toward addressing this critical bottleneck, we report herein a high-throughput analysis (HTA) method of reaction mixtures by photocapture on a 384-spot diazirine-terminated self-assembled monolayer, and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) analysis. This analytical platform has been applied to the identification of a single-electron-promoted reductive coupling of acyl azolium species.

The aim of this study was to describe advertising expenditure for sugary drinks compared with alternative cold non‐alcoholic beverages (artificially sweetened beverages, plain water, plain milk) between 2016 and 2018 across Australian media channels. Monthly estimates of advertising expenditure for non‐alcoholic beverages were obtained from Nielsen Media and aggregated by product type and media. Total sugary drink advertising expenditure between 2016 and 2018 ($129.5M) significantly exceeded expenditure on artificially sweetened drinks ($23.26M), plain water ($14.27M), and plain milk ($31.30M). Television and out‐of‐home advertising accounted for the largest share of sugary drink advertising (45%, 35%). Expenditure on out‐of‐home advertising was more heavily dominated by sugary drinks (75%) than advertising in all media combined (65%). Sugary drink advertising peaked in warmer months and was lowest in August. Soft drinks (26%), flavoured milks (24%) and energy drinks (21%) accounted for the majority of sugary drink advertising. Cold non‐alcoholic beverage advertising in Australian media is dominated by the advertising of sugary drinks. Restricting unhealthy beverage advertising on television and out‐of‐home media may be most effective initially. However, comprehensive restrictions capturing a broader range of media and settings would be optimal to prevent displacement and limit advertising reach and exposure.

Mass media campaigns can change attitudes and behaviours to improve population health. However, a key challenge is achieving share of voice in a complex and cluttered media environment. The aim of this study was to compare advertising expenditure on public health campaigns for obesity prevention (and related healthy eating and physical activity campaigns) with competing commercial categories of (a) sugary drinks, (b) artificially sweetened drinks and (c) diet/weight loss products and programmes. These commercial products may either undermine or dilute public health messages by directly contributing to poor health or confusing the public about the best ways to sustain a healthy lifestyle. Monthly estimates of advertising expenditure in Australian media (television, outdoor, cinema, radio, newspapers, magazines and digital) were obtained from Nielsen Media for 2016–18. Eligible public health advertising expenditure for the entire period (total AUD $27M) was vastly outweighed by the commercial categories of sugary drinks (AUD$ 129M) and diet/weight loss products and services (AUD $122M). Artificially sweetened drinks accounted for an additional AUD$ 23M of expenditure. These results highlight the need to rebalance the ratio of advertising to support public health in Australia through increased funding for obesity prevention and related campaigns, and critically, through government regulation to limit competing commercial advertising.

Throughout a synthetic organic chemist’s career, reaction planning, execution, and analysis will be repeated countless times. The objective of my thesis research was to expedite this workflow to more efficiently access to novel, complex, and biologically useful molecules and synthetic methods. Since the mid 20th century there have been several significant advances that have fundamentally improved how organic chemists synthesize molecules and develop reactions. Among these developments are the institution of thorough mechanistic analysis, the introduction of structural and conformational analysis of molecules via spectroscopic methods, and the application of chromatographic methods to separate and analyze organic compounds. This thesis outlines our efforts to further accelerate synthetic organic advancement through the development and application of new synthetic planning and reaction screening technologies. The first chapter details our investigation and assessment of the retrosynthetic software, Chematica, a machine-learning program intended to accelerate synthetic planning. This chapter describes our attempts to synthesize three different targets, adhering to Chematica-generated routes. Such efforts allowed us to identify significant weaknesses present in the software, which, once corrected will likely improve the program. Supplementing the computer program’s route with necessary organic expertise, the first stereoselective syntheses of the natural product (–)-dauricine and its enantiomer (+)-dauricine were achieved. The second chapter focuses on our attempts to expedite reaction discovery and optimization. We introduce a novel high throughput photocapture platform that allows ~2,000 organic reactions to be screened in <2.5 hours, a substantial improvement from the 120+ hours that would be required using a conventional LC-MS method. This platform was applied to the discover a novel photoredox reaction transforming acyl azoliums to ketones via an intermolecular radical-radical coupling reaction. Finally, the third chapter briefly outlines our investigation into the compatibility between our diazirine photocapture platform and 110 different small organic molecules presenting common functional groups. This work outlines general guidelines that will guide future applications of this high-throughput platform in reaction discovery and optimization.

ObjectivesDomestic violence screening is advocated in some healthcare settings. Evidence that it increases referral to support agencies or improves health outcomes is limited. This study aimed to (1) investigate the proportion of hospital patients reporting domestic violence, (2) describe characteristics and previous hospital attendances of affected patients and (3) assess referrals to an in-house domestic violence advisor from Camden Safety Net.DesignA series of observational studies.SettingThree outpatient clinics at the Royal Free London NHS Foundation Trust.Participants10 158 patients screened for domestic violence in community gynaecology, genitourinary medicine (GUM) and HIV medicine clinics between 1 October 2013 and 30 June 2014. Also 2253 Camden Safety Net referrals over the same period.Main outcome measures(1) Percentage reporting domestic violence by age group gender, ethnicity and clinic. (2) Rates of hospital attendances in the past 3 years for those screening positive and negative. (3) Characteristics, uptake and risk assessment results for hospital in-house domestic violence referrals compared with Camden Safety Net referrals from other sources.ResultsOf the 10 158 patients screened, 57.4% were female with a median age of 30 years. Overall, 7.1% reported ever-experiencing domestic violence, ranging from 5.7% in GUM to 29.4% in HIV services. People screening positive for domestic violence had higher rates of previous emergency department attendances (rate ratio (RR) 1.63, 95% CI 1.09 to 2.48), emergency inpatient admissions (RR 2.27, 95% CI 1.37 to 3.84) and day-case admissions (RR 2.03, 95% CI 1.23 to 3.43) than those screening negative. The 77 hospital referrals to the hospital-based domestic violence advisor during the study period were more likely to be taken up and to be classified as high risk than referrals from elsewhere.ConclusionsSelective screening for domestic violence in high-risk hospital clinic populations has the potential to identify affected patients and promote good uptake of referrals for in-house domestic violence support.

Peroxisome proliferators are a diverse group of non-genotoxic rodent liver carcinogens that exert their effects without directly damaging or interacting with DNA. Non-genotoxic carcinogens cannot be identified on the basis of their structure or their effects on DNA. In order to assess the potential human hazard posed by these chemicals, the mechanism(s) responsible for their hepatocarcinogenicity must be established. A number of mechanisms have been proposed to explain the carcinogenicity of the peroxisome proliferators. One novel hypothesis is that peroxisome proliferators and other non-genotoxic carcinogens may both suppress the normal process of apoptosis in the liver and elevate mitosis, facilitating the survival and proliferation of damaged or potentially tumourigenic cells. In this thesis, the ability of peroxisome proliferators to suppress apoptosis has been examined in vitro using primary cultures of rat hepatocytes and the Reuber hepatoma cell line Fao. Following a systematic assessment of a range of hepatoma cell lines, Fao was validated as being a suitable model system for this purpose: Fao cells were found to be well differentiated, were easy to manipulate and responded to peroxisome proliferators. The peroxisome proliferators nafenopin and Wy-14,643 reversibly maintained the viability of primary cultures of rat hepatocytes which otherwise degenerated within 8 days of their establishment. Maintenance of hepatocyte viability was associated with a significant reduction in hepatocyte apoptosis. Apoptosis could be induced in primary hepatocyte and Fao cultures by treatment with the physiological negative growth regulator TGFβ1, which has been implicated in the control of hepatocyte apoptosis in vivo. Co-addition of nafenopin or Wy-14,643 reduced TGFβ1-induced hepatocyte and Fao apoptosis significantly. In contrast nafenopin had no effect on Fao apoptosis induced by the DNA damaging agents etoposide and hydroxyurea. Furthermore, nafenopin had no apparent effect on the level of expression of Bcl-2, a known suppressor of drug- induced apoptosis in a number of other cell systems. These results imply that peroxisome proliferators do not suppress apoptosis regardless of the death stimulus and that they may interfere specifically with the TGFβ1 signalling pathway. Maintenance of hepatocyte viability by nafenopin was not associated with a detectable change in the level of expression of TGFβ1 mRNA nor by a change in the mRNA for the mannose-6-phosphate receptor, which is believed to mediate the transport of TGFβ1 into hepatocytes from neighbouring cells. While these investigations into the molecular mechanism(s) by which peroxisome proliferators suppress apoptosis were not conclusive, the results presented in this thesis provide a solid foundation on which detailed mechanistic studies can be based in the future.