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General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three subfamilies of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites. WebNetwork analysis to determine the maximally bridged ring (or rings) of molecules is used as part of a strategy for the syntheses of architecturally complex natural chemicals; this strategy is demonstrated via the synthesis of the diterpenoid alkaloids weisaconitine D and liljestrandinine. To complex molecules via network analysis Rich Sarpong and colleagues have developed a unified strategy for the synthesis of multiple members of the diterpenoid alkaloid family using a development of the 'network analysis' approach formalized by E. J. Corey in the 1970s. The authors used this framework to identify a versatile synthetic intermediate that facilitates syntheses of weisaconitine D and liljestrandinine, as well as the core of gomandonine. The web-based deterministic graphing program developed for this work has the potential to be more generally applicable to the analysis and synthesis of other architecturally challenging molecules.

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l-1) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

IntroductionBladder cancer (BC) is a common malignancy and one of the most expensive to manage. Radical cystectomy (RC) with pelvic lymphadenectomy is a gold standard treatment for high-risk BC. Reductions in morbidity and mortality from RC may be achieved through robot-assisted RC (RARC). Prospective comparisons between open RC (ORC) and RARC have been limited by sample size, use of extracorporeal reconstruction and use of outcomes important for ORC. Conversely, while RARC is gaining in popularity, there is little evidence to suggest it is superior to ORC. We are undertaking a prospective randomised controlled trial (RCT) to compare RARC with intracorporeal reconstruction (iRARC) and ORC using multimodal outcomes to explore qualitative and quantitative recovery after surgery.Methods and analysisiROC is a multicentre prospective RCT in English National Health Service (NHS) cancer centres. We will randomise 320 patients undergoing RC to either iRARC or ORC. Treatment allocation will occur after trial entry and consent. The primary outcome is days alive and out of hospital within the first 90 days from surgery. Secondary outcomes will measure functional recovery (activity trackers, chair-to-stand tests and health related quality of life (HRQOL) questionnaires), morbidity (complications and readmissions), cost-effectiveness (using EuroQol-5 Domain-5 levels (EQ-5D-5L) and unit costs) and surgeon fatigue. Patients will be analysed according to intention to treat. The primary outcome will be transformed and analysed using regression. All statistical assumptions will be investigated. Secondary outcomes will be analysed using appropriate regression methods. An internal feasibility study of the first 30 patients will evaluate recruitment rates, acceptance of randomised treatment choice, compliance outcome collection and to revise our sample size.Ethics and disseminationThe study has ethical approval (REC reference 16/NE/0418). Findings will be made available to patients, clinicians, funders and the NHS through peer-reviewed publications, social media and patient support groups.Trial registration numbersISRCTN13680280 and NCT03049410.

The ever-growing commercialization of poor-quality and substandard medicines, especially anti-infectives characterized by inadequate postmarket surveillance by stakeholders remains a major global health challenge, particularly in developing countries, where antibiotic drug resistance and its repercussions on human health remain dominant. This research sought to evaluate the pharmaceutical quality of six randomly selected brands of cefuroxime axetil tablets (250 mg) marketed in the Greater Accra region of Ghana. The selected brands were coded and subjected to both compendial and noncompendial tests. Statistical analysis and model-independent parameter (similarity factor, f2) were employed in analyzing the dissolution profiles of all the brands. All brands including the reference brand conformed to the pharmacopeial specifications for both compendial and noncompendial tests, indicating that they were of good quality. However, there were significant variations (p<0.05) in the disintegration time amongst the various brands. All the brands had ƒ2 values > 50 indicating similarity of their drug release profiles with the innovator. Hence, all the sampled cefuroxime axetil brands can be considered as pharmaceutical equivalents to the innovator drug. These brands can, therefore, be used as a substitute for the innovator drug by physicians to patients in cases of unaffordability or unavailability of the innovator brand.

IntroductionThe SUMMIT Study aims to assess the implementation of Low-Dose Computed Tomography (LDCT) for lung cancer screening in a high-risk population and to validate a multi-cancer early detection blood test. LDCT results are communicated to participants and their GPs by standardised letter. We aim to evaluate the turnaround time from the scan report to the subsequent management and communication of results via letter.MethodsResults are automatically sent to participants and GPs according to pre-defined management plans based on findings collected via proformatised radiology report. Possible outcomes from these reports are: urgent referrals for suspicious findings, nodule surveillance LDCT at 3 months, 12 month surveillance LDCT, or suitable for randomisation at Year 1 to annual or biennial LDCT (see figure 1). Participants with suspicious findings are reviewed by the study clinicians. Where appropriate an urgent referral to the participant’s local hospital is completed manually after discussion with the participant; the automated letters in these cases are delayed until contact is made with the participant and a clinical plan confirmed.ResultsWe report outcomes from the first 11,551 SUMMIT Study participants with completed baseline LDCT reports. We aim to action results within 5 days: 11,319 (98.0%) of all results letters were mailed to participants and 11,423 (98.9%) to their GPs within 5 days.645 (5.6%) participants required further review and consideration of an urgent referral. For these, 84.6% of results letters were mailed within 5 days, and 95.5% within 12 days. As expected, increased mailing times were observed in cases that were more complex, requiring liaison with an external clinical team or review of imaging at our internal weekly radiology meeting.Abstract P17 Figure 1DiscussionTimely reporting of results is crucial in establishing wider roll-out of lung cancer screening in the UK. The vast majority of results are automated and are reliably sent as programmed. A minority require further clinical input and image review, prior to completion of an onwards referral. We demonstrate a scalable and feasible approach to feeding back results following LDCT.

Introduction and ObjectivesThe SUMMIT Study aims to assess the implementation of low-dose Computed Tomography (LDCT) for lung cancer screening (LCS) in a high-risk population and to validate a multi-cancer early detection blood test. Invitees are identified via primary care records and invited to attend a Lung Health Check (LHC), where if eligible, LDCT is offered. Uptake of LCS has been low, whilst UK studies have demonstrated higher rates, these are still lower than other screening programmes. Research in other cancer screening settings suggests that re-invitation strategies improve uptake among non-responders, with recall routine practice in existing national screening programmes. We aim to quantify the uptake to re-invitation, something not previously tested in the LDCT screening context.MethodsRe-invitation and re-invitation reminder letters were sent to individuals who had not responded to the initial series of invitation letters (pre-invitation, invitation, reminder) within four months or longer. The content of the letters was designed using behavioural science evidence for strategies effective for non-responders in the colorectal cancer screening context, including the principles of scarcity, social norms for participation so far, personalisation to local London borough and GP endorsement. Responses from the first ten re-invited practices were analysed. Re-invitations were sent between 22nd January and 5th February 2020 and reminders between 5th and 19th February 2020. Data were analysed 21 days after the last reminder was sent.Results2,000 non-responders were sent re-invitation letters. 310 (15.5%) of those re-invited responded (range: 8.3%–21.2% per practice). The average response time was 19 days. Of those who responded, 186 (60.0%) were eligible for a LHC and 182 (97.8%) of those eligible booked a LHC appointment. Four people (2.2%), did not attend their booked appointment. Of those attending, 154 (86.5%) were eligible, of which 133 (86.4%) consented.ConclusionsThe re-invitation strategy impacted positively on screening uptake and participation by non-responders. These results may be an underrepresentation of the true effect, as invitees could contact the study team after the date of analysis. Work continues to assess the demographic and smoking-related characteristics of those who respond to re-invitation and how it interacts with the overall invitation strategy.

Quantum-information-inspired experiments in nuclear magnetic resonance spectroscopy may yield a pathway towards determining molecular structure and properties that are otherwise challenging to learn. We measure out-of-time-ordered correlators (OTOCs) [1-4] on two organic molecules suspended in a nematic liquid crystal, and investigate the utility of this data in performing structural learning tasks. We use OTOC measurements to augment molecular dynamics models, and to correct for known approximations in the underlying force fields. We demonstrate the utility of OTOCs in these models by estimating the mean ortho-meta H-H distance of toluene and the mean dihedral angle of 3',5'-dimethylbiphenyl, achieving similar accuracy and precision to independent spectroscopic measurements of both quantities. To ameliorate the apparent exponential classical cost of interpreting the above OTOC data, we simulate the molecular OTOCs on a Willow superconducting quantum processor, using AlphaEvolve-optimized [5] quantum circuits and arbitrary-angle fermionic simulation gates. We implement novel zero-noise extrapolation techniques based on the Pauli pathing model of operator dynamics [6], to repeat the learning experiments with root-mean-square error \\(0.05\\) over all circuits used. Our work highlights a computational protocol to interpret many-body echoes from nuclear magnetic systems using low resource quantum computation.

Striatal dopamine encodes reward, with recent work showing that dopamine release occurs in spatiotemporal waves. However, the mechanism of dopamine waves is unknown. Here we report that acetylcholine release in mouse striatum also exhibits wave activity, and that the spatial scale of striatal dopamine release is extended by nicotinic acetylcholine receptors. Based on these findings, and on our demonstration that single cholinergic interneurons can induce dopamine release, we hypothesized that the local reciprocal interaction between cholinergic interneurons and dopamine axons suffices to drive endogenous traveling waves. We show that the morphological and physiological properties of cholinergic interneuron – dopamine axon interactions can be modeled as a reaction-diffusion system that gives rise to traveling waves. Analytically-tractable versions of the model show that the structure and the nature of propagation of acetylcholine and dopamine traveling waves depend on their coupling, and that traveling waves can give rise to empirically observed correlations between these signals. Thus, our study provides evidence for striatal acetylcholine waves in vivo, and proposes a testable theoretical framework that predicts that the observed dopamine and acetylcholine waves are strongly coupled phenomena. Dopamine release occurs in spatiotemporal waves. Here the authors propose that dopamine waves arise locally in the striatum, and provide evidence for striatal acetylcholine waves.

Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10–29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, −0·5% (–5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1–2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Accurate assessment of cardiovascular disease (CVD) risk is crucial for effective prevention and resource allocation. However, few CVD risk estimation tools consider social determinants of health (SDoH), despite their known impact on CVD risk. We aimed to estimate 10-year CVD risk in the Eastern Caribbean Health Outcomes Research Network Cohort Study (ECS) across multiple risk estimation instruments and assess the association between SDoH and CVD risk. Five widely used CVD risk estimation tools (Framingham and WHO laboratory, both laboratory and non-laboratory-based, and ASCVD) were applied using data from ECS participants aged 40-74 without a history of CVD. SDoH variables included educational attainment, occupational status, household food security, and perceived social status. Multivariable logistic regression models were used to compare differences in the association between selected SDoH and high CVD risk according to the five instruments. Among 1,777 adult participants, estimated 10-year CVD risk varied substantially across tools. Framingham non-lab and ASCVD demonstrated strong agreement in categorizing participants as high risk. Framingham non-lab categorized the greatest percentage as high risk, followed by Framingham lab, ASCVD, WHO lab, and WHO non-lab. Fifteen times more people were classified as high risk by Framingham non-lab compared with WHO non-lab (31% vs 2%). Mean estimated 10-year risk in the sample was over 2.5 times higher using Framingham non-lab vs WHO non-lab (17.3% vs 6.6%). We found associations between food insecurity, those with the lowest level compared to the highest level of education, and non-professional occupation and increased estimated CVD risk. Our findings highlight significant discrepancies in CVD risk estimation across tools and underscore the potential impact of incorporating SDoH into risk assessment. Further research is needed to validate and refine existing risk tools, particularly in ethnically diverse populations and resource-constrained settings, and to develop race- and ethnicity-free risk estimation models that consider SDoH.