A systematic review of the validity of non-invasive sleep-measuring devices in mid-to-late life adults: Future utility for Alzheimer's disease research.

Changes in sleep during mid-to-late life are associated with risk for Alzheimer's disease (AD). Mechanistic understanding of this association necessitates measurement tools able to quantify these sleep changes longitudinally and accurately. We conducted a systematic review with meta-analysis of validity studies of non-invasive sleep-measuring devices published since 2015 that record sleep metrics associated with AD in adults over 40 (mean 52.9, SD 6.1 years). We reviewed 52 studies, including 32 wearable and ten non-wearable single or multi-sensor devices validated against polysomnography (minimum one night). The apnoea hypopnoea index and oxygen desaturation index were accurately measured across devices. Total sleep time and sleep efficiency were significantly overestimated (p < 0.001) by mean 33.2 minutes and 7.6%, respectively. Slow wave sleep duration was inaccurately measured except by a headband device with electroencephalography. There was no significant difference in accuracy between participants with and without sleep disorders. Studies were undermined by high risk of bias from closed-access algorithms and classification thresholds, and incomplete reporting of accuracy data. Only one study investigated slow wave activity, and none investigated sleep spindles. Nonetheless, we have identified devices that could be used in future studies of sleep and AD risk and discuss some of the limitations of available research.

Retention of brivaracetam in adults with drug-resistant epilepsy at a single tertiary care center.

INTRODUCTION: Brivaracetam (BRV) is licensed as an adjunctive treatment for focal epilepsy. We describe our clinical experience with BRV at a large UK tertiary center. METHODS: Adults initiated on BRV between July 2015 and July 2020 were followed up until they discontinued BRV or September 2021. Data on epilepsy syndrome, duration, seizure types, concomitant and previous antiseizure medication (ASM) use, BRV dosing, efficacy, and side effects were recorded. Efficacy was categorized as temporary (minimum three months) or ongoing (at last follow-up) seizure freedom, ≥50% seizure reduction, or other benefits (e.g., no convulsions or daytime seizures). Brivaracetam retention was estimated using Kaplan-Meier survival analysis. RESULTS: Two-hundred people were treated with BRV, of whom 81% had focal epilepsy. The mean (interquartile range [IQR]) follow-up time was 707 (688) days, and the dose range was 50-600 mg daily. The mean (IQR) of the previous number of used ASMs was 6.9 (6.0), and concomitant use was 2.2 (1.0). One-hundred and eighty-eight people (94%) had previously discontinued levetiracetam (LEV), mainly due to side effects. 13/200 (6.5%) were seizure free for a minimum of six months during treatment, and 46/200 (23%) had a ≥50% reduction in seizure frequency for six months or more. Retention rates were 83% at six months, 71% at 12 months, and 57% at 36 months. Brivaracetam was mostly discontinued due to side effects (38/75, 51%) or lack of efficacy (28/75, 37%). Concomitant use of carbamazepine significantly increased the hazard ratio of discontinuing BRV due to side effects (p = 0.006). The most commonly reported side effects were low mood (20.5%), fatigue (18%) and aggressive behavior (8.5%). These side effects were less prevalent than when the same individuals took LEV (low mood, 59%; aggressive behavior, 43%). Intellectual disability was a risk factor for behavioral side effects (p = 0.004), and a pre-existing mood disorder significantly increased the likelihood of further episodes of low mood (p = 0.019). CONCLUSIONS: Brivaracetam was effective at a broad range of doses in managing drug-resistant epilepsy across various phenotypes, but less effective than LEV in those who switched due to poor tolerability on LEV. There were no new tolerability issues, but 77% of the individuals experiencing side effects on BRV also experienced similar side effects on LEV.

The past, present, and future of sleep measurement in mild cognitive impairment and early dementia-towards a core outcome set: a scoping review.

STUDY OBJECTIVES: Sleep abnormalities emerge early in dementia and may accelerate cognitive decline. Their accurate characterization may facilitate earlier clinical identification of dementia and allow for assessment of sleep intervention efficacy. This scoping review determines how sleep is currently measured and reported in Mild Cognitive Impairment (MCI) and early dementia, as a basis for future core outcome alignment. METHODS: This review follows the PRISMA Guidelines for Scoping Reviews. CINAHL, Embase, Medline, Psychinfo, and British Nursing Index databases were searched from inception-March 12, 2021. Included studies had participants diagnosed with MCI and early dementia and reported on sleep as a key objective/ outcome measure. RESULTS: Nineteen thousand five hundred and ninety-six titles were returned following duplicate removal with 188 studies [N] included in final analysis. Sleep data was reported on 17 139 unique, diagnostically diverse participants (n). "Unspecified MCI" was the most common diagnosis amongst patients with MCI (n = 5003, 60.6%). Despite technological advances, sleep was measured most commonly by validated questionnaires (n = 12 586, N = 131). Fewer participants underwent polysomnography (PSG) (n = 3492, N = 88) and actigraphy (n = 3359, N = 38) with little adoption of non-PSG electroencephalograms (EEG) (n = 74, N = 3). Sleep outcome parameters were reported heterogeneously. 62/165 (37.6%) were described only once in the literature (33/60 (60%) in interventional studies). There was underrepresentation of circadian (n = 725, N = 25) and micro-architectural (n = 360, N = 12) sleep parameters. CONCLUSIONS: Alongside under-researched areas, there is a need for more detailed diagnostic characterization. Due to outcome heterogeneity, we advocate for international consensus on core sleep outcome parameters to support causal inference and comparison of therapeutic sleep interventions.

New-onset seizures in older people: Clinical features, course and outcomes.

OBJECTIVE: The incidence of epilepsy increases with age. With current demographic trends, this presents a healthcare challenge. We investigated the clinical spectrum of first seizures, evaluated neuroimaging and EEG findings, and determined clinical outcomes, including anti-seizure medication (ASM) response in older people. In addition, we sought to understand the relative effects of age and frailty on ASM response. METHODS: A retrospective single centre cohort study of 207 cases ≥60 years' old, 113 of whom were eventually diagnosed with a first seizure in a specialist epilepsy clinic. RESULTS: 65/113 (57.5%) presented with either focal aware or focal impaired awareness seizures. Stroke was the most common aetiological association (31.9%, 36/113), and odds of seizure recurrence did not significantly differ between aetiologies. 55/86 (64.0%) who started an ASM had no seizure recurrence. 14/48 (29.2%) who underwent EEG had epileptiform abnormalities, however EEG result directly affected management in only 4/48 (8.3%). The most common MRI findings were small vessel disease (37/93, 39.8%), stroke (27/93, 29.0%) and global atrophy (14/93, 15.1%). Increasing age and frailty did not affect the odds of seizure recurrence or of experiencing ASM side effects. Severity of small vessel disease or atrophy did not affect odds of seizure recurrence. CONCLUSION: Our data inform the management of first seizures in older people and provisionally support the use of ASMs in patients with increasing age and frailty, despite concerns over polypharmacy and comorbidity. Our findings should be replicated in larger cohorts.

Study Protocol: The Heart and Brain Study.

BACKGROUND: It is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart-brain association remain unclear. Recent evidence suggests that impairments in vascular phenotypes and cerebrovascular reactivity (CVR) may play an important role in cognitive decline. The Heart and Brain Study combines state-of-the-art vascular ultrasound, cerebrovascular magnetic resonance imaging (MRI) and cognitive testing in participants of the long-running Whitehall II Imaging cohort to examine these processes together. This paper describes the study protocol, data pre-processing and overarching objectives. METHODS AND DESIGN: The 775 participants of the Whitehall II Imaging cohort, aged 65 years or older in 2019, have received clinical and vascular risk assessments at 5-year-intervals since 1985, as well as a 3T brain MRI scan and neuropsychological tests between 2012 and 2016 (Whitehall II Wave MRI-1). Approximately 25% of this cohort are selected for the Heart and Brain Study, which involves a single testing session at the University of Oxford (Wave MRI-2). Between 2019 and 2023, participants will undergo ultrasound scans of the ascending aorta and common carotid arteries, measures of central and peripheral blood pressure, and 3T MRI scans to measure CVR in response to 5% carbon dioxide in air, vessel-selective cerebral blood flow (CBF), and cerebrovascular lesions. The structural and diffusion MRI scans and neuropsychological battery conducted at Wave MRI-1 will also be repeated. Using this extensive life-course data, the Heart and Brain Study will examine how 30-year trajectories of vascular risk throughout midlife (40-70 years) affect vascular phenotypes, cerebrovascular health, longitudinal brain atrophy and cognitive decline at older ages. DISCUSSION: The study will generate one of the most comprehensive datasets to examine the longitudinal determinants of the heart-brain association. It will evaluate novel physiological processes in order to describe the optimal window for managing vascular risk in order to delay cognitive decline. Ultimately, the Heart and Brain Study will inform strategies to identify at-risk individuals for targeted interventions to prevent or delay dementia.

On the Use of Differential Scanning Calorimetry for Thermal Hazard Assessment of New Chemistry: Avoiding Explosive Mistakes.

Differential scanning calorimetry (DSC) is increasingly used as evidence to support a favourable safety profile of novel chemistry, or to highlight the need for caution. DSC enables preliminary assessment of the thermal hazards of a potentially energetic compound. However, unlike other standard characterisation methods, which have well defined formats for reporting data, the current reporting of DSC results for thermal hazard assessment has shown concerning trends. Around half of all results in 2019 did not include experimental details required to replicate the procedure. Furthermore, analysis for thermal hazard assessment is often only conducted in unsealed crucibles, which could lead to misleading results and dangerously incorrect conclusions. We highlight the specific issues with DSC analysis of hazardous compounds currently in the organic chemistry literature and provide simple "best practice" guidelines which will give chemists confidence in reported DSC results and the conclusions drawn from them.

The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers.

BACKGROUND: Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback. HYPOTHESES: We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback. METHODS: We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions. RESULTS: The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo. DISCUSSION: Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.

The effects of acute cannabidiol on cerebral blood flow and its relationship to memory: An arterial spin labelling magnetic resonance imaging study.

BACKGROUND: Cannabidiol (CBD) is being investigated as a potential treatment for several medical indications, many of which are characterised by altered memory processing. However, the mechanisms underlying these effects are unclear. AIMS: Our primary aim was to investigate how CBD influences cerebral blood flow (CBF) in regions involved in memory processing. Our secondary aim was to determine if the effects of CBD on CBF were associated with differences in working and episodic memory task performance. METHODS: We used a randomised, crossover, double-blind design in which 15 healthy participants were administered 600 mg oral CBD or placebo on separate days. We measured regional CBF at rest using arterial spin labelling 3 h after drug ingestion. We assessed working memory with the digit span (forward, backward) and n-back (0-back, 1-back, 2-back) tasks, and we used a prose recall task (immediate and delayed) to assess episodic memory. RESULTS: CBD increased CBF in the hippocampus (mean (95% confidence intervals) = 15.00 (5.78-24.21) mL/100 g/min, t14 = 3.489, Cohen's d = 0.75, p = 0.004). There were no differences in memory task performance, but there was a significant correlation whereby greater CBD-induced increases in orbitofrontal CBF were associated with reduced reaction time on the 2-back working memory task ( r= -0.73, p = 0.005). CONCLUSIONS: These findings suggest that CBD increases CBF to key regions involved in memory processing, particularly the hippocampus. These results identify potential mechanisms of CBD for a range of conditions associated with altered memory processing, including Alzheimer's disease, schizophrenia, post-traumatic stress disorder and cannabis-use disorders.

Thermal Stability and Explosive Hazard Assessment of Diazo Compounds and Diazo Transfer Reagents.

Despite their wide use in academia as metal-carbene precursors, diazo compounds are often avoided in industry owing to concerns over their instability, exothermic decomposition, and potential explosive behavior. The stability of sulfonyl azides and other diazo transfer reagents is relatively well understood, but there is little reliable data available for diazo compounds. This work first collates available sensitivity and thermal analysis data for diazo transfer reagents and diazo compounds to act as an accessible reference resource. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and accelerating rate calorimetry (ARC) data for the model donor/acceptor diazo compound ethyl (phenyl)diazoacetate are presented. We also present a rigorous DSC dataset with 43 other diazo compounds, enabling direct comparison to other energetic materials to provide a clear reference work to the academic and industrial chemistry communities. Interestingly, there is a wide range of onset temperatures (T onset) for this series of compounds, which varied between 75 and 160 °C. The thermal stability variation depends on the electronic effect of substituents and the amount of charge delocalization. A statistical model is demonstrated to predict the thermal stability of differently substituted phenyl diazoacetates. A maximum recommended process temperature (T D24) to avoid decomposition is estimated for selected diazo compounds. The average enthalpy of decomposition (ΔH D) for diazo compounds without other energetic functional groups is -102 kJ mol-1. Several diazo transfer reagents are analyzed using the same DSC protocol and found to have higher thermal stability, which is in general agreement with the reported values. For sulfonyl azide reagents, an average ΔH D of -201 kJ mol-1 is observed. High-quality thermal data from ARC experiments shows the initiation of decomposition for ethyl (phenyl)diazoacetate to be 60 °C, compared to that of 100 °C for the common diazo transfer reagent p-acetamidobenzenesulfonyl azide (p-ABSA). The Yoshida correlation is applied to DSC data for each diazo compound to provide an indication of both their impact sensitivity (IS) and explosivity. As a neat substance, none of the diazo compounds tested are predicted to be explosive, but many (particularly donor/acceptor diazo compounds) are predicted to be impact-sensitive. It is therefore recommended that manipulation, agitation, and other processing of neat diazo compounds are conducted with due care to avoid impacts, particularly in large quantities. The full dataset is presented to inform chemists of the nature and magnitude of hazards when using diazo compounds and diazo transfer reagents. Given the demonstrated potential for rapid heat generation and gas evolution, adequate temperature control and cautious addition of reagents that begin a reaction are strongly recommended when conducting reactions with diazo compounds.

Multicentre collaborative cohort study of the use of Kirschner wires for the management of supracondylar fractures in children.

PURPOSE: Supracondylar fractures of the humerus cause significant morbidity in children. Nerve damage and loss of fracture reduction are common recognised complications in patients with this injury. Uncertainty surrounds the optimal Kirschner wire configuration and diameter for closed reduction and pinning of these fractures. This study describes current practice and examined the association between wire configuration or diameter and outcomes (clinical and radiological) in the operative management of paediatric supracondylar fractures. METHODS: Children presenting with Gartland II or III supracondylar fractures at five hospitals in south-west England were eligible for inclusion. Collaborators scrutinised paper and electronic case notes. Outcome measures were maintenance of reduction and iatrogenic nerve injury. RESULTS: Altogether 209 patients were eligible for inclusion: 15.7% had a documented neurological deficit at presentation; 3.9% who were neurologically intact at presentation sustained a new deficit caused by treatment and 13.4% experienced a clinically significant loss of reduction following fixation. Maintenance of reduction was significantly better in patients treated specifically with crossed ×3 Kirschner wire configuration compared to all other configurations. The incidence of iatrogenic nerve injury was not significantly different between groups treated with different wire configurations. CONCLUSION: We present a large multicentre cohort study showing that crossed ×3 Kirschner wires are associated with better maintenance of reduction than crossed ×2 or lateral entry wires. Greater numbers would be required to properly investigate nerve injury relating to operative management of supracondylar fractures. We found significant variations in practice and compliance with the British Orthopaedic Association Standard for Trauma (BOAST) 11 guidelines.

Diazo-Transfer Reagent 2-Azido-4,6-dimethoxy-1,3,5-triazine Displays Highly Exothermic Decomposition Comparable to Tosyl Azide.

2-Azido-4,6-dimethoxy-1,3,5-triazine (ADT) was reported recently as a new "intrinsically safe" diazo-transfer reagent. This assessment was based on differential scanning calorimetry data indicating that ADT exhibits endothermic decomposition. We present DSC data on ADT that show exothermic decomposition with an initiation temperature ( Tinit) of 159 °C and an enthalpy of decomposition (Δ HD) of -1135 J g-1 (-207 kJ mol-1). We conclude that ADT is potentially explosive and must be treated with caution, being of comparable exothermic magnitude to tosyl azide (TsN3). A maximum recommended process temperature for ADT is 55 °C.

The neuropsychopharmacology of cannabis: A review of human imaging studies.

The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.