Biology subjects

Davis, D.

Publications and source records attributed to Davis, D..

7 recordsLinked to original sources

bioRxiv2018

Key components of the delirium syndrome and mortality: greater impact of acute change and disorganised thinking in a prospective cohort study

BackgroundDelirium increases the risk of mortality during an acute hospital admission. Full syndromal delirium (FSD) is associated with greatest risk and subsyndromal delirium (SSD) is associated with intermediate risk, compared to patients with no delirium - suggesting a dose-response relationship. It is not clear how individual diagnostic symptoms of delirium influence the association with mortality. Our objectives were to measure the prevalence of FSD and SSD, and assess the effect that FSD, SSD and individual symptoms of delirium (from the Confusion Assessment Method-short version (s-CAM)) have on mortality rates.\n\nMethodsExploratory analysis of a prospective cohort (aged [≥] 70 years) with acute (unplanned) medical admission (4/6/2007-4/11/2007). The outcome was mortality (data censored 6/10/2011). The principal exposures were FSD and SSD compared to no delirium (as measured by the CAM), along with individual delirium symptoms on the CAM. Cox regression was used to estimate the impact FSD and SSD and individual CAM items had on mortality.\n\nResultsThe cohort (n=610) mean age was 83 (SD 7); 59% were female. On admission, 11% had FSD and 33% had SSD. Of the key diagnostic symptoms for delirium, 17% acute onset, 19% inattention, 17% disorganised thinking and 17% altered level of consciousness. Unadjusted analysis found FSD had an increased hazard ratio (HR) of 2.31 (95%CI 1.71, 3.12), for SSD the HR was 1.26 (1.00, 1.59). Adjusted analysis remained significant for FSD (1.55 95%CI 1.10, 2.18) but nonsignificant for SSD (HR=0.92 95% CI 0.70, 1.19). Two CAM items were significantly associated with mortality following adjustment: acute onset and disorganised thinking.\n\nConclusionWe observed a dose-response relationship between mortality and delirium, FSD had the greatest risk and SSD having intermediate risk. The CAM items \"acute onset\" and \"disorganised thinking\" drove the associations observed. Clinically, this highlights the necessity of identifying individual symptoms of delirium.

epidemiology↗

bioRxiv2018

The Delirium and Population Health Informatics Cohort study protocol: ascertaining the determinants and outcomes from delirium in a whole population.

BackgroundDelirium affects 25% of older inpatients and is associated with long-term cognitive impairment and future dementia. However, no population studies have systematically ascertained cognitive function before, cognitive deficits during, and cognitive impairment after delirium. Therefore, there is a need to address the following question: does delirium, and its features (including severity, duration, and presumed aetiologies), predict long-term cognitive impairment, independent of cognitive impairment at baseline?\n\nMethodsThe Delirium and Population Health Informatics Cohort (DELPHIC) study is an observational population-based cohort study based in the London Borough of Camden. It is recruiting 2000 individuals aged [≥]70 years and prospectively following them for two years, including daily ascertainment of all inpatient episodes for delirium. Daily inpatient assessments include the Memorial Delirium Assessment Scale, the Observational Scale for Level of Arousal, and the Hierarchical Assessment of Balance and Mobility. Data on delirium aetiology is also collected. The primary outcome is the change in the modified Telephone Interview for Cognitive Status at two years.\n\nDiscussionDELPHIC is the first population sample to assess older persons before, during and after hospitalisation. The cumulative incidence of delirium in the general population aged [≥]70 will be described. DELPHIC offers the opportunity to quantify the impact of delirium on cognitive and functional outcomes. Overall, DELPHIC will provide a real-time public health observatory whereby information from primary, secondary, intermediate and social care can be integrated to understand how acute illness is linked to health and social care outcomes.

epidemiology↗

bioRxiv2018

Vascular risk factors for male and female urgency urinary incontinence at age 68 from a British birth cohort study

ObjectiveTo investigate the prevalence of UUI at age 68 and the contribution of vascular risk factors to male and female UUI pathogenesis in addition to the associations with raised BMI\n\nSubjects and methods1762 participants were from the MRC National Survey for Health and Development (NSHD) birth cohort, who answered the International Consultation on Incontinence Questionnaire short form (ICIQ-SF) at age 68. Logistic regression was used to estimate associations between UUI and earlier life vascular risk factors including: lipid status, diabetes, hypertension, body mass index (BMI), previous stroke or transient ischaemic attack (TIA) diagnosis; adjusting for smoking status, physical activity, co-presentation of SUI symptoms, educational attainment and in women only, type of menopause, age at period cessation and use of hormone replacement therapy.\n\nResultsUUI was reported by 12% of men and 19% of women at 68. Female sex, previous stroke or TIA diagnosis, increased BMI and hypertension (in men only) at age 60-64 were independent risk factors for UUI. Female sex, increased BMI and a previous diagnosis of stroke/ TIA increased the relative risk of more severe UUI symptoms. Type and timing of menopause and HRT use did not alter the estimated associations between UUI and vascular risk factors in women.\n\nConclusionMultifactorial mechanisms lead to UUI and vascular risk factors may contribute to pathogenesis of bladder overactivity in addition to higher BMI. Severe UUI appears to be a distinct presentation with more specific contributory mechanisms than milder UUI.

epidemiology↗

bioRxiv2017

Delirium, frailty and mortality: interactions in a prospective study of hospitalized older people

BackgroundIt is unknown if the association between delirium and mortality is consistent for individuals across the whole range of health states. A bimodal relationship has been proposed, where delirium is particularly adverse for those with underlying frailty, but may have a smaller effect (perhaps even protective) if it is an early indicator of acute illness in fitter people. We investigated the impact of delirium on mortality in a cohort simultaneously evaluated for frailty.\n\nMethodsWe undertook an exploratory analysis of a cohort of consecutive acute medical admissions aged [≥]70. Delirium on admission was ascertained by psychiatrists. A Frailty Index (FI) was derived according to a standard approach. Deaths were notified from linked national mortality statistics. Cox regression was used to estimate associations between delirium, frailty and their interactions on mortality.\n\nResultsThe sample consisted of 710 individuals. Both delirium and frailty were independently associated with increased mortality rates (delirium: HR 2.4, 95%CI 1.8-3.3, p<0.01; frailty (per SD): HR 3.5, 95%CI 1.2-9.9, p=0.02). Estimating the effect of delirium in tertiles of FI, mortality was greatest in the lowest tertile: tertile 1 HR 3.4 (95%CI 2.1-5.6); tertile 2 HR 2.7 (95%CI 1.5-4.6); tertile 3 HR 1.9 (95% CI 1.2-3.0).\n\nConclusionWhile delirium and frailty contribute to mortality, the overall impact of delirium on admission appears to be greater at lower levels of frailty. In contrast to the hypothesis that there is a bimodal distribution for mortality, delirium appears to be particularly adverse when precipitated in fitter individuals.

epidemiology↗

bioRxiv2017

Delirium symptoms are associated with decline in cognitive function between ages 53 to 69: findings from a British birth cohort study.

INTRODUCTIONFew population studies have investigated whether longitudinal decline after delirium in mid-to-late life might affect specific cognitive domains.\n\nMETHODSParticipants from a birth cohort completing assessments of search speed, verbal memory and the Addenbrookes Cognitive Examination at age 69 were asked about delirium symptoms between ages 60-69. Linear regression models estimated associations between delirium symptoms and cognitive outcomes.\n\nRESULTSPeriod prevalence of delirium between 60 and 69 was 4% (95% CI 3.2%,4.9%). Self-reported symptoms of delirium over the seventh decade were associated with worse scores in the Addenbrookes Cognitive Examination (-1.7 points, 95% CI -3.2, -0.1, p=0.04). In association with delirium symptoms, verbal memory scores were initially lower, with subsequent decline in search speed by age 69. These effects were independent of other Alzheimers risk factors.\n\nDISCUSSIONDelirium symptoms may be common even at relatively younger ages, and their presence may herald cognitive decline, particularly in search speed, over this time period.

epidemiology↗

bioRxiv2017

Apolipoprotein-E (ApoE) ϵ4 and cognitive decline over the adult life course

We tested the association between APOE-{varepsilon}4 and processing speed and memory between ages 43 and 69 in a population-based birth cohort. Analyses of processing speed (using a timed letter search task) and episodic memory (a 15-item word learning test) were conducted at ages 43, 53, 60-64 and 69 years using linear and multivariable regression, adjusting for gender and childhood cognition. Linear mixed models, with random intercepts and slopes, were conducted to test the association between APOE and the rate of decline in these cognitive scores from age 43 to 69. Model fit was assessed with the Bayesian Information Criterion. A cross-sectional association between APOE-{varepsilon}4 and memory scores was detected at age 69 for both heterozygotes and homozygotes ({beta}=-0.68 & {beta}=-1.38 respectively, p=.03) with stronger associations in homozygotes; no associations were observed before this age. Homozygous carriers of APOE-{varepsilon}4 had a faster rate of decline in memory between ages 43 and 69, when compared to noncarriers, after adjusting for gender and childhood cognition ({beta}=-0.05, p=.04). There were no cross-sectional or longitudinal associations between APOE-{varepsilon}4 and processing speed. We conclude that APOE-{varepsilon}4 is associated with a subtly faster rate of memory decline from midlife to early old age; this may be due to effects of APOE-{varepsilon}4 becoming manifest around the latter stage of life. Continuing follow-up will determine what proportion of this increase will become clinically significant.

epidemiology↗

bioRxiv2017

Novel Compensatory Mechanisms Enable the Mutant KCNT1 Channels to Induce Seizures

Mutations in the sodium-activated potassium channel (KCNT1) gene are linked to epilepsy. Surprisingly, all KCNT1 mutations examined to date increase K+ current amplitude. These findings present a major neurophysiological paradox: how do gain-of-function KCNT1 mutations expected to silence neurons cause epilepsy? Here, we use Drosophila to show that expressing mutant KCNT1 in GABAergic neurons leads to seizures, consistent with the notion that silencing inhibitory neurons tips the balance towards hyperexcitation. Unexpectedly, mutant KCNT1 expressed in motoneurons also causes seizures. One striking observation is that mutant KCNT1 causes abnormally large and spontaneous EJPs (sEJPs). Our data suggest that these sEJPs result from local depolarization of synaptic terminals due to a reduction in Shaker channel levels and more active Na+ channels. Hence, we provide the first in vivo evidence that both disinhibition of inhibitory neurons and compensatory plasticity in motoneurons can account for the paradoxical effects of gain-of-function mutant KCNT1 in epilepsy.

neuroscience↗