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ObjectivesWe aimed to determine age-specific rates of delirium and associated factors in acute medicine, and the impact of delirium on mortality and re-admission on long-term follow-up.DesignObservational study. Consecutive patients over two 8-week periods (2010, 2012) were screened for delirium on admission, using the confusion assessment method (CAM), and reviewed daily thereafter. Delirium diagnosis was made using the Diagnostic and Statistical Manual Fourth Edition (DSM IV) criteria. For patients aged ≥65 years, potentially important covariables identified in previous studies were collected with follow-up for death and re-admission until January 2014.Participants503 consecutive patients (age median=72, range 16–99 years, 236 (48%) male).SettingAcute general medicine.ResultsDelirium occurred in 101/503 (20%) (71 on admission, 30 during admission, 17 both), with risk increasing from 3% (6/195) at <65 years to 14% (10/74) for 65–74 years and 36% (85/234) at ≥75 years (p<0.0001). Among 308 patients aged >65 years, after adjustment for age, delirium was associated with previous falls (OR=2.47, 95% CI 1.45 to 4.22, p=0.001), prior dementia (2.08, 1.10 to 3.93, p=0.024), dependency (2.58, 1.48 to 4.48, p=0.001), low cognitive score (5.00, 2.50 to 9.99, p<0.0001), dehydration (3.53, 1.91 to 6.53, p<0.0001), severe illness (1.98, 1.17 to 3.38, p=0.011), pressure sore risk (5.56, 2.60 to 11.88, p<0.0001) and infection (4.88, 2.85 to 8.36, p<0.0001). Patients with delirium were more likely to fall (OR=4.55, 1.47 to 14.05, p=0.008), be incontinent of urine (3.76, 2.15 to 6.58, p<0.0001) or faeces (3.49, 1.81–6.73, p=0.0002) and be catheterised (5.08, 2.44 to 10.54, p<0.0001); and delirium was associated with stay >7 days (2.82, 1.68 to 4.75, p<0.0001), death (4.56, 1.71 to 12.17, p=0.003) and an increase in dependency among survivors (2.56, 1.37 to 4.76, p=0.003) with excess mortality still evident at 2-year follow-up. Patients with delirium had fewer re-admissions within 30-days (OR=0.32, 95% CI 0.09 to 1.1, p=0.07) and in total (median, IQR total re-admissions=0, 0–1 vs 1, 0–2, p=0.01).ConclusionsDelirium affected a fifth of acute medical admissions and a third of those aged ≥75 years, and was associated with increased mortality, institutionalisation and dependency, but not with increased risk of re-admission on follow-up.

Cranial cavity extraction is often the first step in quantitative neuroimaging analyses. However, few automated, validated extraction tools have been developed for non-contrast enhanced CT scans (NECT). The purpose of this study was to compare and contrast freely available tools in an unseen dataset of real-world clinical NECT head scans in order to assess the performance and generalisability of these tools. This study included data from a demographically representative sample of 428 patients who had completed NECT scans following hospitalisation for stroke. In a subset of the scans ( n  = 20), the intracranial spaces were segmented using automated tools and compared to the gold standard of manual delineation to calculate accuracy, precision, recall, and dice similarity coefficient (DSC) values. Further, three readers independently performed regional visual comparisons of the quality of the results in a larger dataset ( n  = 428). Three tools were found; one of these had unreliable performance so subsequent evaluation was discontinued. The remaining tools included one that was adapted from the FMRIB software library (fBET) and a convolutional neural network- based tool (rBET). Quantitative comparison showed comparable accuracy, precision, recall and DSC values (fBET: 0.984 ± 0.002; rBET: 0.984 ± 0.003; p  = 0.99) between the tools; however, intracranial volume was overestimated. Visual comparisons identified characteristic regional differences in the resulting cranial cavity segmentations. Overall fBET had highest visual quality ratings and was preferred by the readers in the majority of subject results (84%). However, both tools produced high quality extractions of the intracranial space and our findings should improve confidence in these automated CT tools. Pre- and post-processing techniques may further improve these results.

Background: The Montreal Cognitive Assessment (MoCA) appears more sensitive to mild cognitive impairment (MCI) than the Mini-Mental State Examination (MMSE): over 50% of TIA and stroke patients with an MMSE score of ≥27 (‘normal’ cognitive function) at ≥6 months after index event, score <26 on the MoCA, a cutoff which has good sensitivity and specificity for MCI in this population. We hypothesized that sensitivity of the MoCA to MCI might in part be due to detection of different patterns of cognitive domain impairment. We therefore compared performance on the MMSE and MoCA in subjects without major cognitive impairment (MMSE score of ≥24) with differing clinical characteristics: a TIA and stroke cohort in which frontal/executive deficits were expected to be prevalent and a memory research cohort. Methods: The MMSE and MoCA were done on consecutive patients with TIA or stroke in a population-based study (Oxford Vascular Study) 6 months or more after the index event and on consecutive subjects enrolled in a memory research cohort (the Oxford Project to Investigate Memory and Ageing). Patients with moderate-to-severe cognitive impairment (MMSE score of <24), dysphasia or inability to use the dominant arm were excluded. Results: Of 207 stroke patients (mean age ± SD: 72 ± 11.5 years, 54% male), 156 TIA patients (mean age 71 ± 12.1 years, 53% male) and 107 memory research subjects (mean age 76 ± 6.6 years, 46% male), stroke patients had the lowest mean ± SD cognitive scores (MMSE score of 27.7 ± 1.84 and MoCA score of 22.9 ± 3.6), whereas TIA (MMSE score of 28.4 ± 1.7 and MoCA score of 24.9 ± 3.3) and memory subject scores (MMSE score of 28.5 ± 1.7 and MoCA score of 25.5 ± 3.0) were more similar. Rates of MoCA score of <26 in subjects with normal MMSE ( ≥27) were lowest in memory subjects, intermediate in TIA and highest after stroke (34 vs. 48 vs. 67%, p < 0.001). The cerebrovascular patients scored lower than the memory subjects on all MoCA frontal/executive subtests with differences being most marked in visuoexecutive function, verbal fluency and sustained attention (all p < 0.0001) and in stroke versus TIA (after adjustment for age and education). Stroke patients performed worse than TIA patients only on MMSE orientation in contrast to 6/10 subtests of the MoCA. Results were similar after restricting analyses to those with an MMSE score of ≥27. Conclusions: The MoCA demonstrated more differences in cognitive profile between TIA, stroke and memory research subjects without major cognitive impairment than the MMSE. The MoCA showed between-group differences even in those with normal MMSE and would thus appear to be a useful brief tool to assess cognition in those with MCI, particularly where the ceiling effect of the MMSE is problematic.

BackgroundNecrotising otitis externa is a severe ear infection for which there are no established diagnostic or treatment guidelines.MethodThis study described clinical characteristics, management and outcomes for patients managed as necrotising otitis externa cases at a UK tertiary referral centre.ResultsA total of 58 (63 per cent) patients were classified as definite necrotising otitis externa cases, 31 (34 per cent) as probable cases and 3 (3 per cent) as possible cases. Median duration of intravenous and oral antimicrobial therapy was 6.0 weeks (0.49–44.9 weeks). Six per cent of patients relapsed a median of 16.4 weeks (interquartile range, 23–121) after stopping antimicrobials. Twenty-eight per cent of cases had complex disease. These patients were older (p = 0.042), had a longer duration of symptoms prior to imaging (p < 0.0001) and higher C-reactive protein at diagnosis (p = 0.005). Despite longer courses of intravenous antimicrobials (23 vs 14 days; p = 0.032), complex cases were more likely to relapse (p = 0.016).ConclusionA standardised case-definition of necrotising otitis externa is needed to optimise diagnosis, management and research.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with increased morbidity and mortality. It has remained unclear whether or not it is progressive. The evolution of OSA was examined in a retrospective case note study of 55 unselected patients of mean (SD) age 55.8 (10) years with mild to moderate disease untreated by interventional methods such as continuous positive airway pressure (CPAP) or surgery. Correlations between clinical and functional variables, upper airway anatomy, and change in disease severity were also investigated. METHODS: Patients underwent full polysomnography on two occasions (T0 and Tx) at a mean interval of 77 (50) weeks (range 17-229). In addition, upper airway imaging with computed tomographic scanning or cephalometry had been performed in 43 patients at T0. Morbidity before, during, and after the study period was assessed by questionnaire, as was smoking history and alcohol and sedative intake. RESULTS: The apnoea hypopnoea index (AHI) for the group as a whole increased from 21.8 (11.5) to 33.4 (21.3) (p = 0.0001). Using a 25% change in AHI to divide patients into worsened, stable, and improved groups showed that, although most of the patients deteriorated, 25 patients improved or remained stable. The change in AHI was not correlated with body mass index which remained stable at 29.7 (5.4) kg/m2 versus 29.7 (5.6) kg/m2. There was a trend for apnoea duration to increase. No patient reported increased alcohol consumption and only one patient reported increased use of sedatives between T0 and Tx. No correlation was found between change in AHI and age, time between recordings, anatomical measurements of the upper airway, respiratory function, oximetry, or arterial blood gas tensions. Total cardiovascular and cerebrovascular morbidity was high: hypertension (26 patients, 46%), cardiac arrhythmia (17 patients, 33%), angina (12 patients, 23%), myocardial infarction (10 patients, 19%), and stroke (10 patients, 19%). Twenty nine patients (52%) were prescribed CPAP after Tx, two of whom went on to have maxillofacial surgery. These 29 treated patients had significantly higher values of AHI at T0 and Tx and greater change in AHI than the untreated patients. CONCLUSIONS: This study shows that mild to moderate OSA has a tendency to worsen in the absence of significant weight gain and that upper airway anatomy and clinical variables do not appear to be useful in predicting progression. It follows that mild to moderate OSA justifies systematic follow up. Deterioration in AHI over a mean of 17 months led to interventional treatment in over 50% of patients in the study.

Risk of dementia after stroke is a major concern for patients and carers. Reliable data for risk of dementia, particularly after transient ischaemic attack or minor stroke, are scarce. We studied the risks of, and risk factors for, dementia before and after transient ischaemic attack and stroke. The Oxford Vascular Study is a prospective incidence study of all vascular events in a population of 92 728 people residing in Oxfordshire, UK. Patients with transient ischaemic attack or stroke occurring between April 1, 2002, and March 31, 2012, were ascertained with multiple methods, including assessment in a dedicated daily emergency clinic and daily review of all hospital admissions. Pre-event and post-event (incident) dementia were diagnosed at initial assessment and during 5-years' follow-up on the basis of cognitive testing supplemented by data obtained from hand searches of all hospital and primary care records. We assessed the association between post-event dementia and stroke severity (as measured with the US National Institutes of Health Stroke Scale [NIHSS] score), location (ie, dysphasia), previous events, markers of susceptibility or reserve (age, low education, pre-morbid dependency, leucoaraiosis), baseline cognition, and vascular risk factors with Cox regression models adjusted for age, sex, and education. We compared incidence and prevalence of dementia in our population with published UK population age-matched and sex-matched rates. Among 2305 patients (mean age 74·4 years [SD 13·0]), 688 (30%) had transient ischaemic attacks and 1617 (70%) had strokes. Pre-event dementia was diagnosed in 225 patients; prevalence was highest in severe stroke (ie, NIHSS >10) and lowest in transient ischaemic attack. Of 2080 patients without pre-event dementia, 1982 (95%) were followed up to the end of study or death. Post-event dementia occurred in 432 of 2080 patients during 5 years of follow-up. The incidence of post-event dementia at 1 year was 34·4% (95% CI 29·7–41·5) in patients with severe stroke (NIHSS score >10), 8·2% (6·2–10·2) in those with minor stroke (NIHSS score <3), and 5·2% (3·4–7·0) in those with transient ischaemic attack. Compared with the UK age-matched and sex-matched population, the 1-year standardised morbidity ratio for the incidence of dementia was 47·3 (95% CI 35·9–61·2), 5·8 (4·4–7·5), and 3·5 (2·5–4·8), respectively. Consequently, prevalence of dementia in 1-year survivors was brought forward by approximately 25 years in those who had severe strokes, 4 years in those who had minor strokes, and 2 years in those who had transient ischaemic attacks. 5-year risk of dementia was associated with age, event severity, previous stroke, dysphasia, baseline cognition, low education, pre-morbid dependency, leucoaraiosis, and diabetes (p<0·0001 for all comparisons, except for previous stroke [p=0·006]). The incidence of dementia in patients who have had a transient ischaemic attack or stroke varies substantially depending on clinical characteristics including lesion burden and susceptibility factors. Incidence of dementia is nearly 50 times higher in the year after a major stroke compared with that in the general population, but excess risk is substantially lower after transient ischaemic attack and minor stroke. Wellcome Trust, Wolfson Foundation, British Heart Foundation, National Institute for Health Research, and the National Institute for Health Research Oxford Biomedical Research Centre.

This article explores models of identity at the U.S. Air Force Academy. Drawing on qualitative data gathered through a number of focus groups with cadets, it finds that despite technological changes that have revolutionized the battle space and policy efforts to shift the cultural identity of the forces, ideal identities remain infused with concepts that value the classical model of the heroic masculine. It suggests that functionally, this highly prized “warrior” ethos is becoming less relevant but could have the effect of undermining efforts to “diversify” the Academy. In the absence of a fundamental reconsideration of what constitutes the “ideal” air force officer, efforts to alter the demography and exclusionary culture at the Academy will be stymied.

Reliable data on the prevalence and predictors of post-stroke dementia are needed to inform patients and carers, plan services and clinical trials, ascertain the overall burden of stroke, and understand its causes. However, published data on the prevalence and risk factors for pre-stroke and post-stroke dementia are conflicting. We undertook this systematic review to assess the heterogeneity in the reported rates and to identify risk factors for pre-stroke and post-stroke dementia. Studies published between 1950 and May 1, 2009, were identified from bibliographic databases, reference lists, and journal contents pages. Studies were included if they were on patients with symptomatic stroke, were published in English, reported on a series of consecutive eligible patients or volunteers in prospective cohort studies, included all stroke or all ischaemic stroke, measured dementia by standard criteria, and followed up patients for at least 3 months after stroke. Pooled rates of dementia were stratified by study setting, inclusion or exclusion of pre-stroke dementia, and by first, any, or recurrent stroke. Pooled odds ratios were calculated for factors associated with pre-stroke and post-stroke dementia. We identified 22 hospital-based and eight population-based eligible cohorts (7511 patients) described in 73 papers. The pooled prevalence of pre-stroke dementia was higher (14·4%, 95% CI 12·0–16·8) in hospital-based studies than in population-based studies (9·1%, 6·9–11·3). Although post-stroke (≤1 year) dementia rates were heterogeneous overall, 93% of the variance was explained by study methods and case mix; the rates ranged from 7·4% (4·8–10·0) in population-based studies of first-ever stroke in which pre-stroke dementia was excluded to 41·3% (29·6–53·1) in hospital-based studies of recurrent stroke in which pre-stroke dementia was included. The cumulative incidence of dementia after the first year was little greater (3·0%, 1·3–4·7) per year in hospital-based studies than expected on the basis of recurrent stroke alone. Medial temporal lobe atrophy, female sex, and a family history of dementia were strongly associated with pre-stroke dementia, whereas the characteristics and complications of the stroke and the presence of multiple lesions in time and place were more strongly associated with post-stroke dementia. After study methods and case mix are taken into account, reported estimates of the prevalence of dementia are consistent: 10% of patients had dementia before first stroke, 10% developed new dementia soon after first stroke, and more than a third had dementia after recurrent stroke. The strong association of post-stroke dementia with multiple strokes and the prognostic value of other stroke characteristics highlight the central causal role of stroke itself as opposed to the underlying vascular risk factors and, thus, the likely effect of optimum acute stroke care and secondary prevention in reducing the burden of dementia. None.

Telomeres are protein–DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein–DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein–protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein–protein interfaces within shelterin reveals a series of “domain–peptide” interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.

Web of Science (WoS) is the world’s oldest, most widely used and authoritative database of research publications and citations. Based on the Science Citation Index, founded by Eugene Garfield in 1964, it has expanded its selective, balanced, and complete coverage of the world’s leading research to cover around 34,000 journals today. A wide range of use cases are supported by WoS from daily search and discovery by researchers worldwide through to the supply of analytical data sets and the provision of specialized access to raw data for bibliometric partners. A long- and well-established network of such partners enables the Institute for Scientific Information (ISI) to continue to work closely with bibliometric groups around the world to the benefit of both the community and the services that the company provides to researchers and analysts.