The synthesis and potential applications of asymmetric silacycles

Although the use of silicon-based reagents has undergone rapid development during the last twenty years, the application of organosilicon chemistry to asymmetric synthesis has been somewhat slower to develop. The many problems associated with the use of 'Si-centred' chiral organosilicon compounds has led to the application of 'C-centred' chiral organosilicon compounds. This work has been aimed at the synthesis and application of cyclic silicon species. Routes towards the synthesis of medium-sized rings have been investigated as a potential application of enantiomerically pure silacycles. This work has led to the discovery of an unusual tandem cycloaddition-bond fragmentation reaction of 3-(dienylacyloxy)cycloalk-2- en-l-ones, which affords a-tetralone as the principal product. Most work has been directed at the synthesis of asymmetric silacycles. Two routes have been explored. Firstly, the double asymmetric hydrosilylation of dienes, catalysts based on many transition metals were used but little evidence of hydrosilylation was observed. The second route is that of the double asymmetric hydroboration of divinylsilanes. Asymmetric stoichiometric hydroboration led to products of moderate to high enantiomeric excess, whilst rhodium-catalysed hydroboration led to high yields of the achiral syn isomer. The diastereoselectivity has been found to vary according to the length of the tether between two phosphine ligands, with maximum diastereoselectivity being observed for butanodiphosphines. NMR studies have investigated the possibility that this is related to the stability of a divinylsilane-diphosphine rhodium complex. Finally, the formation of a variety of silacycles has been attempted. Boron- redistribution of the product of hydroboration with (-)-diisopinocampheylborane has been shown to occur with retention of stereochemistry and subsequent carbonylation led to the formation of asymmetric silacyclohexanones. Oxidation of the hydroboration product led to the formation of a silyldiol species. Reactions of this silyldiol have provided the basis for encouraging preliminary attempts at the formation of other heterosilacycles

Dyadic perspectives on loneliness and social isolation among people with dementia and spousal carers: findings from the IDEAL programme

YesThis study aims to investigate the impact of self and partner experiences of loneliness and social isolation on life satisfaction in people with dementia and their spousal carers. We used data from 1042 dementia caregiving dyads in the Improving the experience of Dementia and Enhancing Active Life (IDEAL) programme cohort. Loneliness was measured using the six-item De Jong Gierveld loneliness scale and social isolation using the six-item Lubben Social Network Scale. Data were analysed using the Actor-Partner Interdependence Model framework. Self-rated loneliness was associated with poorer life satisfaction for both people with dementia and carers. The initial partner effects observed between the loneliness of the carer and the life satisfaction of the person with dementia and between social isolation reported by the person with dementia and life satisfaction of the carer were reduced to nonsignificance once the quality of the relationship between them was considered. Experiencing greater loneliness and social isolation is linked with reduced life satisfaction for people with dementia and carers. However, having a positive view of the quality of the relationship between them reduced the impact of loneliness and social isolation on life satisfaction. Findings suggest the need to consider the experiences of both the person with dementia and the carer when investigating the impact of loneliness and social isolation. Individual interventions to mitigate loneliness or isolation may enhance life satisfaction for both partners and not simply the intervention recipient.‘Improving the experience of Dementia and Enhancing Active Life: living well with dementia. The IDEAL study’ was funded jointly by the Economic and Social Research Council (ESRC) and the National Institute for Health and Care Research (NIHR) through grant ES/L001853/2. ‘Improving the experience of Dementia and Enhancing Active Life: a longitudinal perspective on living well with dementia. The IDEAL-2 study’ is funded by Alzheimer’s Society, grant number 348, AS-PR2-16- 001

Comorbid health conditions and their impact on social isolation, loneliness, quality of life, and well-being in people with dementia: longitudinal findings from the IDEAL programme

BackgroundMost people with dementia have multiple health conditions. This study explores (1) number and type of health condition(s) in people with dementia overall and in relation to age, sex, dementia type, and cognition; (2) change in number of health conditions over two years; and (3) whether over time the number of health conditions at baseline is related to social isolation, loneliness, quality of life, and/or well-being.MethodsLongitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised people with dementia (n = 1490) living in the community (at baseline) in Great Britain. Health conditions using the Charlson Comorbidity Index, cognition, social isolation, loneliness, quality of life, and well-being were assessed over two years. Mixed effects modelling was used.ResultsOn average participants had 1.8 health conditions at baseline, excluding dementia; increasing to 2.5 conditions over two years. Those with vascular dementia or mixed (Alzheimer’s and vascular) dementia had more health conditions than those with Alzheimer’s disease. People aged ≥ 80 had more health conditions than those aged < 65 years. At baseline having more health conditions was associated with increased loneliness, poorer quality of life, and poorer well-being, but was either minimally or not associated with cognition, sex, and social isolation. Number of health conditions had either minimal or no influence on these variables over time.ConclusionsPeople with dementia in IDEAL generally had multiple health conditions and those with more health conditions were lonelier, had poorer quality of life, and poorer well-being

Health conditions in spousal caregivers of people with dementia and their relationships with stress, caregiving experiences, and social networks: longitudinal findings from the IDEAL programme

Objectives: Longitudinal evidence documenting health conditions in spousal caregivers of people with dementia and whether these influence caregivers’ outcomes is scarce. This study explores type and number of health conditions over two years in caregivers of people with dementia and subgroups based on age, sex, education, hours of care, informant-rated functional ability, neuropsychiatric symptoms, cognition of the person with dementia, and length of diagnosis in the person with dementia. It also explores whether over time the number of health conditions is associated with caregivers’ stress, positive experiences of caregiving, and social networks Methods: Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised spousal caregivers (n = 977) of people with dementia. Self-reported health conditions using the Charlson Comorbidity Index, stress, positive experiences of caregiving, and social network were assessed over two years. Mixed effect models were used Results: On average participants had 1.5 health conditions at baseline; increasing to 2.1 conditions over two years. More health conditions were reported by caregivers who were older, had no formal education, provided 10 + hours of care per day, and/or cared for a person with more neuropsychiatric symptoms at baseline. More baseline health conditions were associated with greater stress at baseline but not with stress over time

A Randomized Placebo-Controlled Trial of \u3cem\u3eN\u3c/em\u3e-Acetylcysteine for Cannabis Use Disorder in Adults

Background—Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults. Methods—In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18–50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200 mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants. Results—There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio = 1.00, 95% confidence interval 0.63 – 1.59; p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group. Conclusions—In contrast with prior findings in adolescents, there is no evidence that NAC 1200 mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors

A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2

Background: As vaccines against SARS-CoV-2 are now being rolled out, a better understanding of immunity to the virus, whether from infection, or passive or active immunisation, and the durability of this protection is required. This will benefit from the ability to measure antibody-based protection to SARS-CoV-2, ideally with rapid turnaround and without the need for laboratory-based testing. Methods: We have developed a lateral flow POC test that can measure levels of RBD-ACE2 neutralising antibody (NAb) from whole blood, with a result that can be determined by eye or quantitatively on a small instrument. We compared our lateral flow test with the gold-standard microneutralisation assay, using samples from convalescent and vaccinated donors, as well as immunised macaques. Findings: We show a high correlation between our lateral flow test with conventional neutralisation and that this test is applicable with animal samples. We also show that this assay is readily adaptable to test for protection to newly emerging SARS-CoV-2 variants, including the beta variant which revealed a marked reduction in NAb activity. Lastly, using a cohort of vaccinated humans, we demonstrate that our whole-blood test correlates closely with microneutralisation assay data (specificity 100% and sensitivity 96% at a microneutralisation cutoff of 1:40) and that fingerprick whole blood samples are sufficient for this test. Interpretation: Taken together, the COVID-19 NAb-testTM device described here provides a rapid readout of NAb based protection to SARS-CoV-2 at the point of care

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Developing Clinical and Research Priorities for Pain and Psychological Features in People With Patellofemoral Pain:An International Consensus Process With Health Care Professionals

OBJECTIVE: To decide clinical and research priorities on pain features and psychological factors in persons with patellofemoral pain. DESIGN: Consensus development process. METHODS: We undertook a 3-stage process consisting of (1) updating 2 systematic reviews on quantitative sensory testing of pain features and psychological factors in patellofemoral pain, (2) an online survey of health care professionals and persons with patellofemoral pain, and (3) a consensus meeting with expert health care professionals. Participants responded that they agreed, disagreed, or were unsure that a pain feature or psychological factor was important in clinical practice or as a research priority. Greater than 70% participant agreement was required for an item to be considered important in clinical practice or a research priority. RESULTS: Thirty-five health care professionals completed the survey, 20 of whom attended the consensus meeting. Thirty persons with patellofemoral pain also completed the survey. The review identified 5 pain features and 9 psychological factors—none reached 70% agreement in the patient survey, so all were considered at the meeting. Afte the meeting, pain catastrophizing, fear-avoidance beliefs, and pain self-efficacy were the only factors considered clinically important. All but the therma pain tests and 3 psychological factors were consid ered research priorities. CONCLUSION: Pain catastrophizing, pain self-efficacy, and fear-avoidance beliefs were factors considered important in treatment planning, clinical examination, and prognostication. Quantitative sensory tests for pain were not regarded as clinically important but were deemed to be research priorities, as were most psychological factors.</p

Implications of within-farm transmission for network dynamics:Consequences for the spread of avian influenza

AbstractThe importance of considering coupled interactions across multiple population scales has not previously been studied for highly pathogenic avian influenza (HPAI) in the British commercial poultry industry. By simulating the within-flock transmission of HPAI using a deterministic S-E-I-R model, and by incorporating an additional environmental class representing infectious faeces, we tracked the build-up of infectious faeces within a poultry house over time. A measure of the transmission risk (TR) was computed for each farm by linking the amount of infectious faeces present each day of an outbreak with data describing the daily on-farm visit schedules for a major British catching company. Larger flocks tended to have greater levels of these catching-team visits. However, where density-dependent contact was assumed, faster outbreak detection (according to an assumed mortality threshold) led to a decreased opportunity for catching-team visits to coincide with an outbreak. For this reason, maximum TR-levels were found for mid-range flock sizes (~25,000–35,000 birds). When assessing all factors simultaneously using multivariable linear regression on the simulated outputs, those related to the pattern of catching-team visits had the largest effect on TR, with the most important movement-related factor depending on the mode of transmission. Using social network analysis on a further database to inform a measure of between-farm connectivity, we identified a large fraction of farms (28%) that had both a high TR and a high potential impact at the between farm level. Our results have counter-intuitive implications for between-farm spread that could not be predicted based on flock size alone, and together with further knowledge of the relative importance of transmission risk and impact, could have implications for improved targeting of control measures