Reactive organoallyl species generated from aryl halides and allene: allylation of alpha,beta-unsaturated aldehydes and cyclic ketones employing Pd/In transmetallation processes

Allylation of α,β-unsaturated aldehydes and cyclic ketones promoted by Pd/In transmetallation processes has been studied. The unsaturated aldehydes underwent regioselective 1,2-addition to afford secondary homoally alcohols. The reactions have been performed using Pd(OAc)2/PPh3 as catalytic system and metallic indium affording the products in good yields. The same transformation with unsaturated ketones proved to be less efficient, while saturated cyclic ketones delivered generally excellent yields in the presence of CuI. In these latter processes the presence of a distal heteroatom influences the reaction rate

Piloting Eyes on the Baby: A Multiagency Training and Implementation Intervention Linking Sudden Unexpected Infant Death Prevention and Safeguarding

We describe the coproduction, pilot implementation, and user evaluation of an evidence-based training intervention addressing prevention of Sudden Unexpected Deaths in Infancy (SUDI) for the multiagency workforce supporting vulnerable families with babies in a northern English county. We aimed in this pilot study to improve knowledge, skills, and engagement of professionals and support staff providing services for vulnerable families with increased risk of SUDI. The training intervention was co-produced by the academic team and the project Steering Committee which comprised senior leaders from the local authority, health and care sectors, and third-sector organisations, and rolled out to multiagency teams between November 2022 and March 2023. Evaluation data were collected using a post-training questionnaire, followed up by the Normalisation Process Theory (NPT) NoMAD survey issued at two time-points post-training, and interviews with stakeholders. The evaluation, conducted from January to May 2023, aimed to assess how well the multiagency workforce accepted SUDI prevention as part of their remit and incorporated SUDI prevention activities into their everyday work. Most multiagency professionals and support staff were enthusiastic about the training and their role in SUDI prevention. Fewer health professionals completed the training than expected. Forty percent (397/993) of invited staff completed the training. Our results revealed initial lack of knowledge and confidence around SUDI prevention and targeted provision for vulnerable families which improved following the Eyes on the Baby training. The proportion of nonhealth professionals rating their knowledge of SUDI prevention as good or excellent increased significantly from 28% before training to 57% afterwards. Self-rated confidence in discussing SUDI prevention with families increased significantly from 71% to 97%. Health professionals’ ratings increased significantly for knowledge from 62% to 96%, and confidence from 85% to 100%. Use of NPT allowed us to identify that by the time of evaluation, the earliest adopters were cognitively involved with the programme and engaged in collective action, while later adopters had not yet reached this stage. We conclude that effective implementation of multiagency working for SUDI prevention can be accomplished by providing clear training and guidance for all staff who have regular or opportunistic contact with vulnerable families. Our next step is to evaluate the sustainability of MAW SUDI prevention over the medium to long term and assess the responses of recipient families to this approach

Multiagency approaches to preventing sudden unexpected death in infancy (SUDI): a review and analysis of UK policies

Background Recent reviews of sudden unexpected deaths in infancy (SUDI) in England recommend a multiagency working (MAW) approach to prevention but lack clear guidance around how this might be implemented.Aims In England, local authorities commission and oversee public health services. This review examines how local authority policies address implementation of MAW for SUDI prevention to understand local variations and identify strengths and weaknesses.Methods Using a comprehensive list of all metropolitan, county, unitary councils and London boroughs in England, we systematically searched local authority websites for relevant published documents and submitted freedom of information (FOI) requests where policies or guidance for SUDI prevention had not been sourced online. We extracted data from documents using a standardised form to summarise policy contents which were then collated, described and appraised.Findings We searched the websites of 152 council and London boroughs, identifying 36 relevant policies and guidelines for staff. We submitted 116 FOI requests which yielded 64 responses including six valid documents: 45% (52/116) of local authorities did not respond. Seventeen councils shared the same guidance under safeguarding partnerships; removal of duplicates resulted in 26 unique documents. Only 15% (4/26) of the documents included a detailed plan for how MAW approaches were to be implemented despite 73% (19/26) of the documents mentioning the importance of engaging the MAW in raising awareness of safe sleep for babies with vulnerable families. Five areas of variation were identified across policies: (1) scope, (2) responsibilities, (3) training, (4) implementation and (5) evaluation.Conclusions There are discrepancies between local authorities in England in whether and how MAW for SUDI prevention is carried out. Strengths and weaknesses of approaches are identified to inform future development of MAW for SUDI prevention

Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB

With the emergence of multidrug-resistant strains of <i>Mycobacterium tuberculosis</i> there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino–thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against <i>M. tuberculosis</i> strain H37Rv. The design, synthesis, and structure–activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome <i>c</i> oxidoreductase, part of the bc1-aa3-type cytochrome <i>c</i> oxidase complex that is responsible for driving oxygen-dependent respiration

A protocol for a pragmatic randomized controlled trial using the Health Teams Advancing Patient Experience: Strengthening Quality (Health TAPESTRY) platform approach to promote person-focused primary healthcare for older adults

Detailed description of the intervention [57, 84–89]. (DOC 63 kb

Development of a 2,4-diaminothiazole series for the treatment of human African trypanosomiasis highlights the importance of static-cidal screening of analogues

While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using phenotypic screening to guide structure-activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood-brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static-cidal screening of analogues

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL