One-pot near-ambient temperature syntheses of aryl(difluoroenol) derivatives from trifluoroethanol

Difluoroalkenylzinc reagents prepared from 1-(2’-methoxy-ethoxymethoxy)-2,2,2-trifluoroethane and 1-(N,N-diethylcarbamoyloxy)-2,2,2-trifluoroethane at ice bath temperatures, underwent Negishi coupling with a range of aryl halides in a convenient one pot procedure. While significant differences between the enol acetal and carbamate reagents were revealed, the Negishi protocol compared very favourably with alternative coupling procedures in terms of overall yields from trifluoroethanol

Drug Use in Street Sex worKers (DUSSK) study – results of a mixed methods feasibility study of a complex intervention to reduce illicit drug use in drug dependent female sex workers

OBJECTIVES: The majority of female street-based sex workers (SSWs) are dependent on illicit drugs and sell sex to fund their drug use. They typically face multiple traumatic experiences, starting at a young age, which continue through sex work involvement. Their trauma-related symptoms tend to increase when drug use is reduced, hindering sustained reduction. Providing specialist trauma care to address post-traumatic stress disorder (PTSD) alongside drug treatment may therefore improve treatment outcomes. Aims to (1) evaluate recruitment and retention of participants; (2) examine intervention experiences and acceptability; and (3) explore intervention costs using a mixed methods feasibility study. SETTING: Female SSW charity premises in a large UK inner city. PARTICIPANTS: Females aged 18 years or older, who have sold sex on the street and used heroin and/or crack cocaine at least once a week in the last calendar month. INTERVENTION: Female SSW-only drug treatment groups in a female SSW-only setting delivered by female staff. Targeted PTSD screening then treatment of positive diagnoses with eye movement desensitisation and reprocessing (EMDR) therapy by female staff from a specialist National Health Service trauma service. RESULTS: (1) Of 125 contacts, 11 met inclusion criteria and provided informed consent, 4 reached the intervention final stage, (2) service providers said working in collaboration with other services was valuable, the intervention was worthwhile and had a positive influence on participants. Participants viewed recruitment as acceptable and experienced the intervention positively. The unsettled nature of participant's lives was a key attendance barrier. (3) The total cost of the intervention was £11 710, with staff costs dominating. CONCLUSIONS: Recruitment and retention rates reflected study inclusion criteria targeting women with the most complex needs. Two participants received EMDR demonstrating that the three agencies working together was feasible. Staff heavy costs highlight the importance of supporting participant attendance to minimise per participant costs in a future trial

Protocol for a systematic review: Interventions for anxiety in school-aged children with autism spectrum disorder (ASD): a mixed methods systematic review

This review aims to synthesise evidence about interventions to reduce anxiety symptoms in school-aged children with autism spectrum disorder (ASD). While clinical studies will not be excluded per se, this review seeks to move beyond interventions that are relevant only for clinical practice and care in clinical settings and prioritise studies that draw out implications for school-aged children that will help their functioning in real-world settings such as school and the home. To achieve this aim, the review will employ a mixed-methods systematic review which can accommodate the anticipated diverse types of available studies. These studies are likely to use quantitative methods such as quasi-experimental, mixed-methods randomised control trial approaches as well as qualitative methods such as action-research and case-study designs. This publication outlines the methodology which will be used in the systematic review and covers the criteria for inclusion and exclusion of studies in the review, the search strategy to be used for identification of relevant studies, the bibliographic databases and other sources used for searching, the data collection process including the selection process and data synthesis and analysis, and the timeframe for this project

Speciation control during Suzuki-Miyaura cross-coupling of haloaryl and haloalkenyl MIDA boronic esters

Boronic acid solution speciation can be controlled during the Suzuki-Miyaura cross-coupling of haloaryl MIDA boronic esters to enable the formal homologation of boronic acid derivatives. The reaction is contingent upon control of the basic biphase and is thermodynamically driven: temperature control provides highly chemoselective access to either BMIDA adducts at room temperature or BPin products at elevated temperature. Control experiments and solubility analyses have provided some insight into the mechanistic operation of the formal homologation process

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate (1) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((R)-2-((S)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (23), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing

Cerebral Small Vessel Disease Burden and Longitudinal Cognitive Decline from age 73 to 82: the Lothian Birth Cohort 1936

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD’s association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised β: −0.201; 95% CI: [−0.36, −0.04]; pFDR = 0.022) and processing speed (−0.222; [−0.40, −0.04]; pFDR = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD’s association with greater decline in general cognitive ability remained significant, prior to FDR correction (−0.222; [−0.39, −0.06]; p = 0.008; pFDR = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline

Brain volumetric changes and cognitive ageing during the eighth decade of life

Later‐life changes in brain tissue volumes—decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)—are strong candidates to explain some of the variation in ageing‐related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow‐age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow‐up). We used latent variable modeling to extract error‐free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r‐values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning

We thank the participants of the three cohorts (UKB, Generation Scotland (STRADL) and LBC1936) for their participation and the research teams for their work in collecting, processing and giving access to these data for analysis. We are also thankful to the brain donors to the Allen Human Brain Atlas, BrainSpan Atlas and Human Brain Transcriptome Project, and to the people who collected and processed the data and made it openly available For the purpose of open access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewe

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|β| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning